file unico viii - Società italiana di neurologia

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XLVII CONGRESSO SOCIETÀ ITALIANA DI
NEUROLOGIA
Venezia, 22-25 Ottobre 2016
Polo Congressuale – Lido di Venezia
Programma scientifico
22 OTTOBRE 2016
CORSI DI AGGIORNAMENTO A NUMERO CHIUSO 1 (RICHIESTO ACCREDITAMENTO A NUMERO CHIUSO)
ORE 11.00 – 17.00
Urgenze in neurologia
Moderatori: E.C. AGOSTONI (Milano), G. MICIELI (Pavia)
PRIMA PARTE
• Acuzie nei disturbi del movimento
A. BERARDELLI (Roma)
• Disturbi “funzionali” a esordio acuto
C. SERRATI (Genova)
Trattamento endovascolare: cambierà la gestione del paziente con ictus acuto?
• Le evidenze
D. TONI (Roma)
• L’organizzazione
E.C. AGOSTONI (Milano)
• Crisi epilettiche e stato di male in Pronto Soccorso
F. Minicucci (Milano)
• Disturbi parossistici notturni non epilettici
R. MANNI (Pavia)
SECONDA PARTE
Moderatori: G. TEDESCHI (Napoli), B. GIOMETTO (Padova)
• Rabdomiolisi e dolori muscolari acuti
A. TOSCANO (Messina)
• Crisi miasteniche
A. EVOLI (Roma)
pag. 1
• Neuropatie motorie acute
C. BRIANI (Padova)
• Patologie neurologiche acute: il setting neurologico è più vantaggioso?
G. MICIELI (Pavia)
TAVOLA ROTONDA
• Modelli organizzativi per la neurologia d’urgenza
Moderatore: F.A. DE FALCO (Napoli)
ORE 11.00 – 17.00
Ruolo della Risonanza Magnetica convenzionale e avanzata nella diagnosi e prognosi delle principali patologie neurologiche
Moderatori: M. FILIPPI (Milano), G. TEDESCHI (Napoli)
PRIMA PARTE
• Sclerosi Multipla
M. ROCCA (Milano)
• Malattie vascolari
A. BOZZAO (Roma)
• Tumori
A. FALINI (Milano)
• Vasculiti del sistema nervoso centrale
N. DE STEFANO (Siena)
SECONDA PARTE
Moderatori: N. DE STEFANO (Siena), M. ROCCA (Milano)
• Malattia di Alzheimer
A. PADOVANI (Brescia)
• Demenza fronto-temporale
F. AGOSTA (Milano)
• Sclerosi Laterale Amiotrofica
F. TROJISI (Napoli)
• Malattia di Parkinson
A. QUATTRONE (Catanzaro)
ORE 11.00 – 14.00
I criteri diagnostici per le demenze
Moderatori: D. GALIMBERTI (Milano), M. MUSICCO (Milano)
• I criteri del National Institute of Aging
A. CAGNIN (Padova)
• I criteri dell’International Working Group
D. PERANI (Milano)
• Discussione: convergenze e divergenze tra i due criteri
• Demenza con corpi di Lewy e Parkinson
L. BONANNI (Chieti)
pag. 2
• Demenze frontotemporali
D. GALIMBERTI (Milano)
ORE 11.00 – 14.00
Avanzamenti clinici e biomolecolari nella Doppler myocardial imaging
Moderatore: G. MEOLA (San Donato Milanese, MI)
• Abnormal splicing in myotonic dystrophy
D. FURLING (Paris, F)
• Fatica e disturbi del sonno
G. SICILIANO (Pisa)
• Imaging muscolare
M. GARIBALDI (Roma - Nice, F)
• Biomarkers in Doppler myocardial imaging
C. ANGELINI (Padova)
• Translational research in Doppler myocardial imaging: current approaches towards novel therapies
G. BASSEZ (Creteil, F)
ORE 11.00 – 14.00
Semeiotica dei disordini del movimento
Moderatori: G. ABBRUZZESE (Genova), P. CORTELLI (Bologna)
• Distonia
G. DE FAZIO (Bari)
• Tremore
• Disturbi funzionale del movimento
M. TINAZZI (Verona)
• Le ipocinesie
P. BARONE (Napoli)
ORE 11.00 – 14.00
Disordini di coscienza legati a gravi cerebrolesioni acquisite
Moderatori: P. BRAMANTI (Messina), P.M. ROSSINI (Roma)
• Neuroepidemiologia ed inquadramento diagnostico dei disordini di coscienza
P.M. ROSSINI (Roma)
• I percorsi
P. BRAMANTI (Messina)
• Trattamento riabilitativo
L. SALTUARI (Bolzano)
• Problematiche etiche e legislative
G.L. GIGLI (Roma)
pag. 3
ORE 11.00 – 14.00
La sindrome di Guillain Barrè Strohl 100 anni dopo: cosa c’è di nuovo?
Moderatori: G. CAVALETTI (Milano), A. SCHENONE (Genova)
• Inquadramento clinico terapeutico, fattori di rischio e misure di outcome
E. NOBILE ORAZIO (Milano)
• Le nodo-paranodopatie immunomediate
A. UNCINI (Chieti)
• La sindrome di Guillain Barrè cronica: una definizione errata o una realtà clinica da chiarire?
D. COCITO (Torino)
• Le plessopatie infiammatorie
C. BRIANI (Padova)
ORE 11.00 – 14.00
Nuove frontiere della stimolazione cerebrale non invasiva in neurologia
Moderatori: C. CALTAGIRONE (Roma), G. KOCH (Roma)
• Il contributo della coregistrazione TMS-EEG (Stimolazione Magnetica Transcranica-Elettroencefalogramma) nell’esplorazione del connettoma
corticale umano
C. MINIUSSI (Brescia)
• Integrazione globale della funzione cerebrale nei pazienti con disturbi dello stato di coscienza
M. MASSIMINI (Milano)
• La malattia di Alzheimer: un disturbo della plasticità corticale
G. KOCH (Roma)
• Stimolazione cerebrale non invasiva integrata con la robotica nella riabilitazione dell’ictus
V. Di Lazzaro (Roma)
ORE 11.00 – 14.00
Esame liquorale
Moderatori: D. FRANCIOTTA (Pavia), G.L. MANCARDI (Genova)
• Fisiopatologia e diagnostica neuro-immunologica generale
D. FRANCIOTTA (Pavia)
• Le malattie infettive
P. CINQUE (Milano)
• Le encefaliti immuno-mediate
B. GIOMETTO (Padova)
• Le malattie degenerative
L. PARNETTI (Perugia)
14.00-15.00 PAUSA PRANZO
pag. 4
SIMPOSIO
ORE 15.00 – 17.00
Riconoscere e gestire i problemi iatrogeni nell’anziano
in collaborazione con la Società Italiana di Neurogeriatria
Moderatori: C. CALTAGIRONE (Roma), E. COSTANZO (Catania)
• Concetti di neurofarmacologia clinica nell’anziano
S. CUZZOCREA (Messina)
• Disturbi del movimento indotti da farmaci
F.E. PONTIERI (Roma)
• Disturbi cognitivi indotti da farmaci
C. SERRATI (Genova)
• Disturbi dello stato di coscienza iatrogeni
G. BELELLI (Milano), M. MUSICCO (Milano)
• Sintesi generale e conclusioni
G. FABBRINI (Roma)
SIMPOSIO
ORE 15.00 – 17.00
Neurosonologia
in collaborazione con SINSEC- Società Italiana di NeuroSonologia Emodinamica Cerebrale
Moderatori: C. BARACCHINI (Padova), S. Ricci (Città di Castello – PG)
• Stenosi carotidea asintomatica: stima del rischio
C. FINOCCHI (Genova)
• Patologia ostruttiva del circolo posteriore: servono gli ultrasuoni?
C. BARACCHINI (Genova)
• TCD/TCCD: Revisione di accuratezza diagnostica
S.CENCIARELLI (Città di Castello – PG)
• Stroke mimics: soluzioni mediante ultrasuoni
G.GIUSSANI ( Lecco)
WORKSHOP 1
ORE 15.00 – 17.00
Le urgenze Neurologiche in gravidanza: organizzazione dei percorsi di cura
Moderatori: G. GIUSSANI (Milano), A. PROTTI (Milano)
• La gestione delle urgenze tra territorio e ospedale
R. ZANINI (Verona)
• Le emergenze neurochirurgiche e neurointerventistiche
M. PIANO (Milano)
• La cefalea acuta nella donna gravida
G. BONO (Pavia)
• Presentazione del volume: Neurological Emergency during Pregnancy
A. PROTTI (Milano)
WORKSHOP 2
ORE 15.00 – 17.00
pag. 5
Nuovi scenari nella stimolazione cerebrale profonda
Moderatori: L. LOPIANO (Torino), F. VALZANIA (Modena)
• Il Parkinson dopo la Deep Brain Stimulation: una nuova malattia?
F. CONTARINO (Leiden, D)
• Deep Brain Stimulation e urgenze
G. COSSU (Cagliari)
• Impatto nella pratica clinica delle recenti innovazioni
M.C. SENSI (Ferrara)
• Sostituzione del generatori d’impulsi: continuità terapeutica, durata e rimborsabilità
M.G. RIZZONE (Torino)
1
WORKSHOP 3
ORE 15.00 – 17.00
Ritmi circadiani e patologie neurologiche: insights fisiopatologici e implicazioni cliniche
Moderatori: R. FERRI (Troina - EN), F. PIZZA (Bologna)
• Ritmi circadiani e timing degli attacchi emicranici: implicazioni cliniche e fisiopatologiche
M. DE TOMMASO (Bari)
• I ritmi circadiani contano nell’epilessia? Occorrenza delle crisi e target terapeutici
R. MANNI (Pavia)
• Sonno, ritmi circadiani e patogenesi della malattia di Alzheimer
B. GUARNIERI (Città Sant’Angelo, PE)
• Sonno, stroke e modulazione circadiana della pressione arteriosa
C. LOMBARDI (Milano)
WORKSHOP 4
ORE 15.00 – 17.00
La neuropsicologia nella prassi della neurologia clinica
Moderatori: G. MICELI (Rovereto, TN), M.C. SILVERI (Roma), D. QUARANTA (Roma)
• La neuropsicologia a letto dell’ammalato
D. GROSSI (Napoli)
• La neuropsicologia in sala operatoria
C. PAPAGNO (Milano)
• La neuropsicologia in tribunale
A. STRACCIARI (Bologna)
• La neuropsicologia e le neuroimmagini
D. PERANI (Milano)
• La neuropsicologia in riabilitazione
A. MAZZUCCHI (Parma)
WORKSHOP 5
ORE 15.00 – 17.00
I luoghi assistenziali neurologici
Moderatori: V. NAPOLETANO (Bari), R. DI FEDE (Bari), M. NOTARIELLO (Foggia)
pag. 6
• Introduzione
G. TEDESCHI (Napoli)
• L’integrazione Ospedale Territorio nei cambiamenti dell’organizzazione dell’assistenza alle malattie del Sistema Nervoso
V. NAPOLETANO (Bari), L. PROVINCIALI (Ancona)
• UVM (Unità di Valutazione multidisciplinare)– PAI (Piano assistenziale individuale)– SMANDI ( Scuola valutazione multidimensionale
disabili)– ICF (Classificazione Internazionale del Funzionamento) e cure domiciliari quale alternativa a RSA(Residenze Sanitarie Assistenziali)
ed RSSA (Residenza Socio Sanitaria Assistenziale)– come fare un PAI (Piano assistenziale individuale)
A. RUSSELLO (Lecce)
• Il PTA ( Piano Terapeutico Aziendale) : quando le cure in Hospice, RSA (Residenze Sanitarie Assistenziali) ed RSA1 (Residenze Sanitarie
Assistenziali)
S. GEMMA (Foggia)
• Il modello HUB and Spoke, un servizio per la complessità organizzativa e assistenziale nelle macroaree regionali per le malattie
neurodegenerative
R. ELEOPRA (Mestre), R. QUATRALE (Udine)
• I luoghi fisici della Ricerca tra Presidio Ospedaliero e Presidio Territoriale di Assistenza
M.R. TOLA (Ferrara), E. MONTANARI (Fidenza)
10.30-ffff
WORKSHOP 6
ORE 15.00 – 17.00
Trattamenti in neuroncologia: casi clinico complessi
Moderatori: A. SILVANI (Milano), V. VILLANI (Roma)
• Gliomatosis cerebri o malattia demielinizzante
A. SALMAGGI (Lecco)
• Encefalite o neoplasia gliale?
E. MARCHIONI (Pavia)
• Disturbi neurologici in pazienti con tumore della mammella
R. RUDÀ (Torino)
• Lesione espansiva nel paziente anziano: glioblastoma o linfoma?
A. SILVANI (Milano)
17.00-17.30 PAUSA CAFFÈ
CERIMONIA DI INAUGURAZIONE
17.30 SALUTO DELLE AUTORITÀ
18.30 LETTURA MAGISTRALE
From Plague control in the republic of Venice to the new WHO (world health organitation) International health regulations
L. BERTINATO (Venezia)
23 OTTOBRE 2016
SESSIONE PLENARIA
ORE 8.30 – 10.30
Contributo dei neurologi italiani all’estero
Moderatori: C. FERRARESE (Milano), C. SERRATI (Genova), G. TEDESCHI (Napoli)
• Trauma cranico
R. SAVICA (Rochester, USA)
pag. 7
• Nuovi modelli assistenziali nel trattamento della fase avanzata della Malattia di Parkinson
A. FASANO (Toronto, CAN)
O. CICCARELLI (Londra, UK)
• Ictus ischemico ed emorragico sono malattie trattabili: la rivoluzione della neurochirurgia endovascolare
I. LINFANTE (Miami, USA)
11.00-13.00 SESSIONI DI COMUNICAZIONI ORALI SUI SEGUENTI ARGOMENTI
Casi clinici 1 ( vedi descrizione pagina 21), disordini del movimento 1 neuroimmunologia, cefalee 1, malattie cerebrovascolari 1, malattie del
motoneurone, malattie neuromuscolari,1 Sclerosi multipla 1, demenza 1
Saranno presentate 8 comunicazioni libere per ciascun argomento, che avranno come obiettivo l’aggiornamento sulle singole patologie
Elenco relatori a pag 21
13.30-14.30
CONFERENZE DIDATTICHE
ORE 13.00 – 14.30
Le mieliti
Progressi nel percorso dalla sindrome alla malattia
Moderatore: P. ANNUNZIATA (Siena)
• Le mieliti acute traverse: alla ricerca di nuovi marcatori di diagnosi e prognosi
P. ANNUNZIATA (Siena)
• Mieliti autoimmuni e post infettive
E. Marchioni (Pavia)
• Mieliti e malattie infiammatorie del connettivo
M. Zoccarato (Padova)
Patologie emergenti
Moderatore: B. GIOMETTO (Padova)
• Role of the WFN (World Federation of Neurology) toward world wide education to improve neurological care
W. GRISOLD (Vienna, A)
• Transient Neuro-Epidemiology in Africa: from infectious to vascular and degenerative factors
A. GALLO DIOPP (Dakar, SN)
• Encefalite erpetica ed Ac anti-NMDAR (The N-methyl-D-aspartate receptor): relazione tra infezione ed autoimmunità
B. GIOMETTO (Padova)
LETTURA
ORE 14:00 – 14:30
Disturbo del controllo degli impulsi e malattia di Parkinson
In collaborazione con UCB
Moderatori: P.Stanzione ( Roma )
Icarus: i risultati di uno studio osservazionale italiano
• A. ANTONINI (Milano)
pag. 8
SIMPOSIO
ORE 14.00-15.00
Rivaroxaban in Neurologia: evidenze ed esperienze
In collaborazione con Bayer
Moderatori: G. MICIELI (Pavia)
• Evidenze nel paziente impegnativo e conferme nella vita reale
M. DEL SETTE (Genova)
• Esperienza pratica clinica
M. PACIARONI (Perugia)
SIMPOSIO
ORE 14.00-15.00
Spasticità, plasticità e riabilitazione nella Sclerosi Multipla
In collaborazione con Almirall
Moderatori: G. COMI (Milano), P.BRAMANTI (Messina)
• Basi neurobiologiche degli interventi riabilitativi
D.CENTONZE (Roma)
• Terapia fisica e farmacologia nel management della spasticità in neuroriabilitazione
M. Rovaris (Milano)
• Discussione sui temi trattati nel simposio
SIMPOSIO
ORE 14.30-16.30
La medicina di genere e le malattie neurologiche e alle malattie neurologiche
Moderatori: C. PACI (San Benedetto del Tronto, AP), M.G. PISCAGLIA (Ravenna)
• Introduzione
L. PROVINCIALI (Ancona)
• Epidemiologia delle malattie neurologiche in relazione al sesso
E. BEGHI (Milano)
• Sclerosi Multipla e medicina di genere
C. TORTORELLA (Bari)
• Demenze e medicina di genere
P. MERLO (Bergamo)
• Medicina di genere e medicina di precisione
A. PROTTI (Milano)
• La normativa sulla medicina di genere
P. BOLDRINI (Roma)
• Discussione
(La discussione si baserà sugli argomenti tratti nel simposio)
SIMPOSIO
ORE 14.30-16.30
Demenze degenerative e vascolari: ha ancora un senso una distinzione netta?
Moderatori: C. CALTAGIRONE (Roma), M. SILVESTRINI (Ancona)
• Introduzione
pag. 9
C. CALTAGIRONE (Roma)
• Inquadramento nosografico e impatto epidemiologico delle forme miste
• Il contributo del neuroimaging alla diagnosi di deterioramento cognitivo vascolare
L. PANTONI (Firenze)
• I fattori di rischio comuni
M. SILVESTRINI (Ancona)
SIMPOSIO
ORE 15.00 -16.00
Nuovo approccio nel trattamento della depressione: “la multimodalità”
In collaborazione con Lundbeck
Moderatori:
L. PROVINCIALI
(Ancona)
• La multimodalità: nuovo approccio farmacologico per il trattamento della depressione maggiore
N.NICOLETTI (Roma)
• I sintomi cognitivi nel paziente depresso: impatto, diagnosi e cura
A.PADOVANI (Padova)
SIMPOSIO
ORE 15.00 -16.00
Teriflunomide: dagli studi registrativi, alle nuove evidenze, alla “real life”
Moderatori: M.G. MARROSU (Cagliari)
• Teriflunomide alla luce dell’evoluzione dei “treatment goals” in Sclerosi Multipla
D.CENTONZE (Roma)
• “Brain Atrophy” e progressione della disabilità
P. GALLO (Padova)
• La definizione del profilo scientifico di un farmaco: ruolo della “real life”
L. TROJANO (Bari)
SIMPOSIO
ORE 15.00-17.00
Nuove frontiere per l’ictus acuto tra innovazioni terapeutiche e vincoli organizzativi
in collaborazione con Italiana Stroke Organization - ISO
Moderatori: A. CAROLEI (L’Aquila)
• Registro SITS (Safe Implementation of Treatment in Stroke) e Registro endovascolare
D. TONI (Roma), S. MANGIAFICO (Firenze)
• Nuovi trial clinici: risultati, revisioni sistematiche e meta-analisi
I. LINFANTE (Miami, USA)
• Nuovi trial di confronto diretto
D. TONI (Roma)
• Documento di consenso
E.C. AGOSTONI (Milano)
pag. 10
SIMPOSIO
ORE 16.00 -17.00
Il futuro della Sclerosi Multipla:evidenze e prospettive
In collaborazione con Merck
Moderatori:
G. COMI
(Milano) - M. TROJANO (Bari)
• Immunità cellulare: nuovi target terapeutici
R. FURLAN (Milano)
• Efficacia delle nuove opzioni terapeutiche: Evidenze dagli studi clinici
G. COMI (Milano)
• Il profilo di sicurezza delle nuove opzioni terapeutiche
F. PATTI (Catania)
17.00-17.30 PRESENTAZIONE DEL VOLUME “CONDIVISIONE MULTIDISCIPLINARE DEL PERCORSO ASSISTENZIALE DELLA
SCLEROSI MULTIPLA”
A. FRANCIA (Roma)
WORKSHOP 7
ORE 17.30 – 19.30
Comorbilità nella Sclerosi Multipla
Moderatore: G.M. MARROSU (Cagliari)
• Nuovi criteri diagnostici di Risonanza Magnetica
M. FILIPPI (Milano)
• Rilevanza delle comorbilità nei trattamenti farmacologici
A. LUGARESI (Bologna)
• Impatto economico delle comorbilità
R. BERGAMASCHI (Pavia)
• Gestione delle comorbilità nel setting clinico
E. COCCO (Cagliari)
WORKSHOP 8
ORE 17.30 – 19.30
Cefalea cronica quotidiana
Moderatori: P. CORTELLI (Bologna), A. RUSSO (Napoli)
• Diagnosi e classificazione delle cefalee croniche primarie
M. RUSSO (Parma), P. TORELLI (Parma)
• Nuovi approcci diagnostici nelle cefalee croniche secondarie
M.R. MAZZA (Catanzaro), F. BONO (Catanzaro)
• Terapie farmacologiche e non delle cefalee croniche
G. COPPOLA (Roma), F. PIERELLI (Latina)
WORKSHOP 9
ORE 17.30 – 19.30
Terapia sintomatica nella grave disabilità neurologica
Moderatori: C.A. DEFANTI (Gazzaniga, BG), A. CONTE (Roma)
pag. 11
• “Sintomatico” o “palliativo”: due termini per la stessa cura o approcci diversi?
A. SOLARI (Milano)
• Dolore e spasticità nella Sclerosi Multipla
C. SOLARO (Genova)
• Dispnea e insufficienza respiratoria nella Sclerosi Laterale Amiotrofica
F.O. LOGULLO (Macerata)
• Gestione sintomatica del paziente con ictus nella STROKE UNIT
D. INZITARI (Firenze), V. CRESPI (Monza)
• Discussione
(Discussione sui temi trattati nella sessione)
WORKSHOP 10
ORE 17.30 – 19.30
Misurazione dell’atrofia in neurologia: stato dell’arte
Moderatori: G. ARABIA (Catanzaro), M.A. ROCCA (Milano)
• Misurazione dell’atrofia: aspetti tecnici e variabili fisiologiche
A. GIORGIO (Siena)
• Sclerosi multipla
A. GALLO (Napoli)
• Demenze
F. AGOSTA (Milano)
• Disturbi del movimento
G. ARABIA (Catanzaro)
WORKSHOP 11
ORE 17.30 – 19.30
Le demenze leucoencefalopatiche non vascolari
Moderatori: F. AGOSTA (Milano), M. MUSICCO (Milano)
• Introduzione
F. TAGLIAVINI (Milano)
• Meccanismi cellulari, metabolici e molecolari nelle leucodistrofie e leucopatie su base genetica
M. BUGIANI (Amsterdam, NL)
• Quadri di imaging delle leucodistrofie e leucopatie
VAN DER KNAPP (Amsterdam, NL)
• La leucoaraiosi è sempre di origine vascolare?
L. PANTONI (Firenze)
• Il caso del Cadasil
A. FEDERICO (Siena)
• Il caso dell’angiopatia amiloide cerebrale
F. PIAZZA (Milano)
• Profili neuropsicologi e clinici da danno della sostanza bianca nelle demenze
S. CAPPA (Pavia)
WORKSHOP 12
ORE 17.30 – 19.30
Paraparesi spastiche familiari: aggiornamenti sugli aspetti diagnostici e terapeutici
pag. 12
Moderatori: F. SANTORELLI (Pisa), A. TOSCANO (Messina)
• Clinica e diagnostica delle forme autosomico dominanti
G. DE MICHELE (Napoli)
• Clinica e diagnostica delle forme autosomico recessive
C. CASALI (Latina)
• Come procedere alla diagnosi genetica
M.T. BASSI (Bosisio Parini, MI)
• Terapia: presente e futuro
M.T. DOTTI (Siena)
10.30-ffff
WORKSHOP 13
ORE 17.30 – 19.30
Eredoatassie e dintorni. Dedicato alla memoria di Stefano Di Donato
Moderatori: D. DIODATO (Roma), M. ZEVIANI (Cambridge, UK)
• Stefano di Donato: neurologo, scienziato e maestro
A. FEDERICO (Siena)
• Eredoatassie: inquadramento clinico
A. FILLA (Napoli)
• Genetica molecolare e diagnostica avanzata delle eredoatassie
F. TARONI (Milano)
• Atassia di Friedreich: dai meccanismi molecolari alla terapia sperimentale
M. PANDOLFO (Bruxelles, B)
• La complessità genetica e patogenetica della malattia di Huntington
E. CATTANEO (Milano)
10.30-ff
WORKSHOP 14
ORE 17.30 – 19.30
Taupatie: disturbi della mente e del movimento
Moderatori: R. CERAVOLO (Pisa), F. MORGANTE (Messina)
• Aspetti clinici e classificazione
C. COLOSIMO (Roma, Terni)
• Aspetti clinici della FTD (Demenza Frontotemporale)
E. SCARPINI (Milano)
• Neuropatologia delle taupatie
P. PARCHI (Bologna)
• Neurofisiopatologia delle taupatie
M. BOLOGNA (Roma)
WORKSHOP 15
ORE 17.30 – 19.30
10.30-ffff
L’ictus, i nuovi movimenti, gli stakeholders ed il filo rosso delle evidenze scientifiche
Moderatori: V. PIRAS (Cagliari), S. RICCI (Città di Castello, PG)
• 118/PS
P. CANDELARESI (Milano)
pag. 13
• Neuroradiologo
E. CICERI (Verona)
• Giovane neurologo
V. OPPO (Milano)
• Neurologo
A. CICCONE (Mantova)
• Utente-Caregiver
A. MALAGUTTI (Mantova)
• Riabilitatore
M. TARICCO (Bologna)
• Il decisore
V. PANELLA (Roma)
WORKSHOP 16
ORE 17.30 – 19.30
Variabilità delle lesioni nelle malattie neurodegenerative: stadi di malattia o eterogeneità fenotipica?
Moderatori: M.B.A. MELONE (Napoli), E. PEGORARO (Padova)
• Malattia di Alzheimer e taupatie
G. GIACCONE (Milano)
• Parkinson e sinucleinopatie
S. FERRARI (Roma)
• Corea di Huntington
F.R. FUSCO (Roma)
• Sclerosi Laterale Amiotrofica e TDP43 (TAR DNA-binding protein)
M.T. GIORDANA (Torino)
24 OTTOBRE 2016
08.00-10.00 SESSIONE PLENARIA
Organizzazione dell’assistenza neurologica
Moderatori: E.C. AGOSTONI (Milano), L. LOPIANO (Torino), L. PROVINCIALI (Ancona)
• Nuovi orientamenti per fronteggiare la crisi sanitaria
F. SPANDONARO (Roma)
• Il ruolo delle Aziende di alta specialità nell’urgenza neurologica
A. ZOLI (Milano)
• Modelli di integrazione Ospedale-Territorio
M. FABI (Parma)
• Sostenibilità del sistema sanitario nazionale: un approccio value - based in neurologia
N. CARTABELLOTTA (Bologna)
10.00-11.00 ASSEMBLEA DEI SOCI SIN
pag. 14
- SOCIETA’ ITALIANA DI NEUROLOGIA
Casi Clinici 2 ( vedi descrizione pagina 21), Disordini del movimento 2, Neuropsicologia clinica, Cefalee 2, Malattie cerebrovascolari 2, malattie
degenerative, dolore, malattie neuromuscolari 2
Saranno presentate 8 comunicazioni libere per ciascun argomento, che avranno come obiettivo l’aggiornamento sulle singole patologie.
Lettura
ORE 12.30-13.30
Gestione del trattamento anticoagulante nei pazienti con fibrillazione atriale in ambito neurologico
In collaborazione con Pfizer & Bristol Myers Squibb
G. MICIELI (Pavia)
Simposio
ORE 12.30-13.30
Sclerosi Multipla oggi: una toria che sostiene il presente e guarda al futuro
In collaborazione con Teva
Moderatore: G. COMI (Milano)
• Copaxone, la storia continua
G. COMI (Milano)
• Dati real life: scelta dell’algoritmo terapeutico
M. TROJANO (Bari)
• Il carico gestionale nel trattamento della Sclerosi Multipla
L. PROVINCIALI (Ancona)
13.00-13.30 BREAKING NEWS
Risultati dalla Consensus Conference internazionale sulla Epilessia frontale notturna
P. TINUPER (Bologna)
Lettura
ORE 13.30 – 14.00
Malattia di Parkinson: identificare la fase avanzata e il corretto processo di referral
In collaborazione con Abbvie
Moderatore: L. LOPIANO (Torino)
Relatore: A. ANTONINI (Padova)
SIMPOSIO
ORE 13.30-15.30
Cambiare la storia di malattia del paziente SMRR (Sclerosi Multipla Remittente Recidivante): quale approccio?
In collaborazione con Biogen Italia
• Introduzione
P. GALLO (Padova)
Moderatori: M.P. AMATO (Firenze)
• Strategie di trattamento per il paziente mild-to-moderate: Peginterferone beta-1a e dimetilfumarato, approcci innovativi nella gestione del
paziente di I linea
P. PERINI (Padova)
pag. 15
Moderatori: P. GALLO (Padova)
• Strategie di trattamento per il paziente highly-active:
Natalizumab: “A decade of difference”
Daclizumab, un nuovo traguardo della ricerca scientifica
A.UCCELLI (Genova)
• Discussioni
• Conclusioni
M.P. AMATO (Firenze)
SIMPOSIO
ORE 13.45-15.30
La neuroinfiammazione nelle patologie neurologiche acute e croniche: nuove prospettive terapeutiche?
In collaborazione con Epitech group
Moderatori: C. Caltagirone (Roma), C Ferrarese (Milano), F. Orzi (Roma)
• Meccanismi di neuroinfiammazione
F. NICOLETTI (Roma)
• Il ruolo delle citochine
P.BOSSU’ (Roma)
• La neuroinfiammazione nell’ ictus ischemico
G.DE SIMONI (Milano)
• La neuroinfiammazione nelle malattie neurodegenerative
L.TREMOLIZZO (Milano)
• Nuove prospettive terapeutiche
S. CUZZOCREA (Messina)
SIMPOSIO
ORE 14.30-16.00
SYMPOSIUM OF THE ITALIAN NeuPSIG
Moderatore: G. CRUCCU (Roma)
• Chronic leg and back pain: the problems entailed by mixed pain
R. BARON (Kiel, D)
• The role of topical treatments: lidocaine versus capsaicin
S. TAMBURIN (Verona)
• Combination therapy: contrasting views
G. CRUCCU (Roma)
• New European guidelines on central stimulation therapy for chronic pain
A. TRUINI (Roma)
SIMPOSIO
ORE 14.30-16.00
Leber’s Hereditary Optic Neuropathy – Aspetti clinici, diagnostici e terapeutici
In collaborazione con Santhera
Moderatore: A. Toscano (Messina)
Co-Moderatore: P. Morandi Treu (Roma)
• Bisogni dei pazienti LHON (Leber’s Hereditary Optic Neuropathology ) e il valore dell’Associazione dei pazienti
pag. 16
P. MORANDI TREU (Roma)
• Neuropatia ottica ereditaria di Leber (LHON - Leber’s Hereditary Optic Neuropathology) : diagnostica differenziale, conferma genetica ed
inquadramento clinico terapeutico
V. CARELLI (Bologna)
• Impiego clinico di Raxone nell’ambito della LHON: i risultati della “Consensus on guidelines for idebenone
Administration in Leber’s hereditary optic neuropathy
C. LA MORGIA (Bologna)
• The clinical Development of Raxone for the LHON indication
G.METZ (Germania)
• Malattie Mitocondriali e Registri Nazionali e internazionali
P. SANTANTONIO (Roma)
SIMPOSIO
ORE 14.30-16.30
Network italiano per le forme autosomiche dominanti di malattia di Alzheimer e demenza frontotemporale
Moderatori: S. CAPPA (Milano),
• Introduzione
G. FRISONI (Milano)
• Procedure standardizzate per la valutazione delle forme genetiche di malattia di Alzheimer e demenza frontotemporale
M. PIEVANI (Brescia)
• Registro e biobanca per le forme genetiche di malattia di Alzheimer e demenza frontotemporale
F. TAGLIAVINI (Milano), D. GALIMBERTI (Milano)
• La consulenza genetica nelle forme familiari di malattia di Alzheimer e demenza frontotemporale
A.C. BRUNI (Lamezia Terme), S. SORBI (Firenze)
• Una rete sinergica per lo studio delle forme genetiche di malattia di Alzheimer e demenza frontotemporale
SIMPOSIO
ORE 14.30-16.30
Le tecniche neurofisiologiche nella prognosi delle patologie neurologiche
Moderatori: V. DI LAZZARO (Roma), L. LEOCANI (Milano)
• Stroke
V. DI LAZZARO (Roma)
• Malattie del motoneurone
A. QUARTARONE (Messina)
L. LEOCANI (Milano)
• Disturbi del Movimento
SIMPOSIO
ORE 15.30 -16.30
Genitorialità e Sclerosi Multipla
In collaborazione con Merck
Moderatori:
pag. 17
A. BERTOLOTTO (Orbassano
- TO) - G. TEDESCHI (Napoli)
• “Genitori si può, anche con la Sclerosi Multipla”
L. LAVORGNA (Napoli)
• Genitorialità e SM: le esigenze dei pazienti e il ruolo dell’associazione (AISM)
M. BATTAGLIA (Genova)
• Genitorialità e SM: le esigenze dei pazienti e il ruolo del clinico
M.G. MARROSU (Cagliari)
SIMPOSIO
ORE 16.30 - 17.30
La strategia di induzione: esperienze a confronto
Moderatori: G. COMI (Milano)
• Introduzione
G. COMI (Milano)
• Esperienze a confronto
L.MOIOLA (Milano), A.BERTOLOTTO (Torino), M.G. MARROSU (Cagliari)
• Discussione
WORKSHOPS 17
ORE 17.30-19.30
La terapia nella fase avanzata della malattia di Parkinson
Moderatori: A. ALBANESE (Milano), R. ELEOPRA (Udine)
• Quale terapia per quale paziente?
U. BONUCCELLI (Pisa)
• DBS (Deep Brain Stimulation): attualità e innovazioni future
M. ZIBETTI (Torino)
• Stimolazione Dopaminergica continua, con infusione intestinale
A. ANTONINI (Venezia)
WORKSHOPS 18
ORE 17.30-19.30
Malattie “semplici”, malattie “complesse” e target terapeutici comuni per il progresso della ricerca
Moderatori: L. OTTOBONI (Milano), M. SALVETTI (Roma)
• Malattie diverse, fisiopatologie condivise
M.G. MARROSU (Cagliari)
• Single gene mutations come modelli per autoimmunità multifattoriale
G. MATARESE (Napoli)
• Demielinizzazione centrale e periferica: target terapeutici condivisi?
C. TAVEGGIA (Milano)
• Terapie cellulari: sempre lo stesso grado di complessità?
L. OTTOBONI (Milano)
• Alterazioni sinaptiche immunomediate nella SM (Sclerosi Multipla) e in malattie orfane del SNC (Sistema Nervoso Centrale)
pag. 18
R. MANTEGAZZA (Milano)
• Verso un supporto “trasversale” alla ricerca clinica?
P. ZARATIN (Genova)
WORKSHOPS 19
ORE 17.30-19.30
10.30-ffff
Global Burden of Disease: un nuovo approccio alla definizione e allo studio delle malattie neurologiche nel mondo globale
Moderatori: E. BALDIN (Bologna), G. LOGROSCINO (Bari)
• Overview on Global Burden Diseases
L. MONASTA (Trieste)
• Epilessia in GBD (Global Burden Diseases)
E. BEGHI (Milano)
• Stroke in GBD (Global Burden Diseases)
S. RICCI (Città di Castello, PG)
• L’esperienza dei nefrologi nel GBD (Global Burden Diseases): cosa può insegnare ai neurologi?
G. Remuzzi (Milano)
• Demenza in GBD (Global Burden Diseases)
G. LOGROSCINO (Bari)
• Questions and answers
E. BALDIN (Bologna)
WORKSHOPS 20
ORE 17.30-19.30
10
Miopatie e malattie multisistemiche
Moderatori: G. SICILIANO (Pisa), L. VERCELLI (Torino)
• Il muscolo bersaglio del disturbo endocrino
C. RODOLICO (Messina)
• Miopatie infiammatorie e disordini reumatologici: quale sovrapposizione?
M. MIRABELLA (Roma)
• Critical illness e insufficienza multi organo
M. FILOSTO (Brescia)
• Ageing patologico e sarcopenia
G. SICILIANO (Pisa)
WORKSHOPS 21
ORE 17.30-19.30
La SLA (Sclerosi Laterale Amiotrofica): una malattia multisistemica
Moderatori: J. MANDRIOLI (Modena), N. TICOZZI (Milano)
• Eterogeneità genetica nella SLA (Sclerosi Laterale Amiotrofica)
F.L. CONFORTI (Cosenza)
• SLA (Sclerosi Laterale Amiotrofica) ed eterogeneità clinica: i sintomi non motori
A. CALVO (Torino)
• Approcci innovativi di imaging nelle malattie del motoneurone
F. AGOSTA (Milano)
• Dall’eterogeneità dei meccanismi patogenetici a nuovi target terapeutici
G. LAURIA (Milano)
pag. 19
WORKSHOPS 22
ORE 17.30-19.30
Difficoltà interpretative nella diagnosi strumentale
Moderatori: D. LIUZZI (Bari), R. PELLICCIARI (Bari)
• Certezze ed interpretazioni della neurografia
L. SANTORO (Napoli)
• L’EEG (Elettroencefalografia) nella diagnosi delle epilessie. Fatti, artefatti e misfatti
• Il neuroimaging nelle sindromi parkinsoniane: istruzioni per l’uso
R. CERAVOLO (Pisa)
• Il liquor cerebrospinale: dalla fisiopatologia della risposta immunitaria alla diagnostica in neuroimmonologia
C. AVOLIO (Foggia)
WORKSHOPS 23
ORE 17.30-19.30
Mancata diagnosi in epilessia
Moderatori: U. AGUGLIA (Catanzaro), A. COPPOLA (Napoli)
• Introduzione
S. STRIANO (Napoli)
• Epilessie generalizzate
A. GAMBARDELLA (Catanzaro)
• Epilessie parziali
• Casi clinici esemplificativi: sessione video
C. DI BONAVENTURA (Roma), E. FERLAZZO (Catanzaro)
(I video dei casi clinici tratteranno argomenti inerenti la diagnosi dell’epilsessia)
WORKSHOPS 24
ORE 17.30-19.30
Neurologia, arte e storia
Moderatori: G. ZANCHIN (Padova), F. PALADIN (Venezia)
• Le neuroscienze a Venezia
F. PALADIN (Venezia)
• Bisturi e pennelli: la pinacoteca di Antonio Scarpa (1752-1832)
G. ZANCHIN (Padova), F. MAGGIONI (Padova)
• Arte e melanconia: i miti, i simboli
D. CASSANO (Nocera Inferiore, SA)
• La neurologia e l’immagine in movimento: il ruolo del cinema
L. LORUSSO (Chiari, BS)
• L’attacco della valchiria: l’emicrania di Wagner
F. MAINARDI (Venezia), C. LISOTTO (San Vito al Tagliamento, PN), G. ZANCHIN (Padova)
WORKSHOPS 25
ORE 17.30-19.30
Le neuroscienze affettive in neurologia clinica
Moderatori: A. PADOVANI (Brescia), D. PERANI (Milano)
pag. 20
• Introduzione
C. CALTAGIRONE (Roma)
• Il ruolo del cervelletto nella regolazione delle emozioni
M. LEGGIO (Roma)
• I disturbi affettivi nella FTD (FrontoTemporale Disease) e nella AD (Alzheimer Disease)
S. CAPPA (Milano)
• I disturbi affettivi nell’epilessia temporale prima e dopo trattamento chirurgico
S. MELETTI (Modena)
• L’apatia nelle patologie neurodegenerative
D. GROSSI (Napoli)
25 OTTOBRE 2016
SESSIONE PLENARIA
ORE 9.00 – 11.00
Aggiornamenti nelle terapie
Moderatori: R. ELEOPRA (Udine), G.L. MANCARDI (Genova), A. QUATTRONE (Catanzaro)
• Malattie acute
D. TONI (Roma)
• Malattie croniche ed evolutive
U. BONUCCELLI (Pisa)
• Trattamento riabilitativo
G. ABBRUZZESE (Genova)
• Terapie palliative
G. MORETTO (Verona)
Epilessia, Sclerosi Multipla 2, Neuroimmagini, Neurofisiologia clinica, Neurogenetica, Demenze 2, Neurooncologia, riabilitazione neurologica
Saranno presentate 8 comunicazioni libere per ciascun argomento, che avranno come obiettivo l’aggiornamento sulle singole patologie
ORE 15.00 CHIUSURA DEI LAVORI CONGRESSUALI E
RAZIONALE
pag. 21
La Clinica Neurologica di Ancona e la comunità neurologica delle Marche si sentono particolarmente gratificate
dall’incarico di organizzare il XLVII Congresso della Società Italiana di Neurologia nell’anno 2016. La scelta di
realizzare l’evento a Venezia, testimonia la sinergia fra due sedi affacciate sul mare Adriatico, nelle quali è
particolarmente vivace la tradizione neurologica.
Venezia offre una testimonianza illustre e feconda della cura delle malattie e dell’assistenza rivolta alle persone
colpite da danni a carico del Sistema Nervoso, sia per gli aspetti della fase acuta che per gli impegni della postacuzie e della riabilitazione neurologica. Già in passato importanti eventi scientifici a valenza internazionale e
nazionale sono stati organizzati a Venezia da neurologi italiani e il fascino della sede può enfatizzare la visibilità
della comunità nazionale nelle sue espressioni scientifiche, assistenziali e didattiche.
A fronte di un crescente impegno nella ricerca neurologica, testimoniata da una posizione di rilievo nel ranking
internazionale, i neurologi italiani affrontano con crescente disagio le difficoltà correlate all’organizzazione
assistenziale. Dopo anni di costante riduzione delle risorse, realizzata in maniera talora indiscriminata, si è
chiamati a testimoniare l’impegno culturale e organizzativo teso a migliorare le condizioni della popolazione
affetta da compromissione del Sistema Nervoso. In molte Regioni Italiane si sono realizzati tentativi di
razionalizzazione dell’organizzazione assistenziale, ma la sproporzione fra domanda dell’utenza ed offerta
assistenziale specifica favorisce spesso risposte assistenziali non competenti, con conseguente danno ai
pazienti e spreco di risorse.
L’immagine rappresentata nell’annuncio potrebbe testimoniare il fervore dell’attività richiesta alla competenza
neurologica per le numerose malattie d’interesse. E’ chiaro che negli ultimi anni non è più giustificabile
l’atteggiamento di esaltazione del ruolo diagnostico isolato a fronte di una rassegnazione unita a “nichilismo
terapeutico”, che ha caratterizzato in passato la Neurologia Clinica, quando una diagnosi corretta
rappresentava l’obiettivo precipuo, e spesso finale, dell’impegno dei neurologi. Al giorno d’oggi l’assistenza si
estrinseca, anche e soprattutto, attraverso l’impiego di farmaci innovativi in grado di modificare il decorso delle
malattie, di trattamenti palliativi capaci di migliorare la qualità di vita in corso di malattia e di approcci
riabilitativi destinati ad ottimizzare le possibilità di recupero dell’autonomia nelle attività della vita quotidiana.
Alla luce di questi presupposti, le malattie neurologiche hanno perso le caratteristiche d’ineluttibilità legate alle
difficoltà diagnostiche e alle carenze assistenziali, dato che le competenze disponibili consentono possibilità
concrete di trattamento o di miglioramento della qualità di vita. Tali obiettivi richiedono una lucida
ridistribuzione delle risorse destinate alle strutture neurologiche degli ospedali e del territorio, al fine di
renderle adeguate all’attuale epidemiologia delle malattie del Sistema Nervoso e delle condizioni di disabilità
ad esse correlate.
Il XLVII Congresso della Società Italiana di Neurologia fornirà un palcoscenico ricco d’interesse e fascino ai
neurologi, alle associazioni e a tutti gli operatori sanitari coinvolti nell’assistenza alle persone colpite da
malattie acute e croniche del Sistema Nervoso. Tutte le condizioni d’interesse neurologico saranno trattate per
gli aspetti più innovativi e per le caratteristiche di impiego nella pratica clinica. Particolare risalto sarà dato alle
risorse terapeutiche recentemente disponibili e ai percorsi assistenziali codificati al fine di modificare
l’andamento delle molteplici malattie neurologiche.
pag. 22
Professioni alle quali si riferisce l'evento formativo:
pag. 23
pag. 24
COMUNICAZIONI ORALI DEI GIORNI 23 - 24 - 25 OTTOBRE 2016
23/10/2016
CASI CLINICI 1
A NOVEL MAPT DELETION AS CAUSE OF SPORADIC SPEECH APRAXIA EVOLVING TO
CORTICOBASAL SYNDROME
G. Mazzon, T. Cattaruzza, A. Menichelli, A. Fabretto, P. Manganotti
1
Neurological Clinic, Department of Medical, Surgical and Health Sciences, University of Trieste (Trieste);
Neuropsychology Unit, Department of Rehabilitation Medicine, University of Trieste (Trieste); 3Department of Advanced
Diagnostic and Clinical Trials- Medical Genetics, IRCCS Burlo Garofolo (Trieste)
2
Background: Speech apraxia is a disorder of speech motor planning/programming leading to slow rate, articulatory
distortion, distorted sound substitutions and syllables segmentation. It can be isolated or a component of a degenerative
syndrome such as Progressive Supranuclear Palsy or Corticobasal Syndrome. These diseases are often sporadic, but little is
known about their genetic basis.
Case Report: A 74-year-old right-handed man was referred to our Ambulatory Care for Memory Disorders with a 1-year
history of progressive isolated articulation impairment, without any other cognitive, motor or behavioural symptoms. His
family and past medical history were unremarkable except for depressive disorder. On first neurological evaluation, mild
dysphonia and articulatory apraxia with sound distortion and slow speech rate were found, confirmed as the prevailing
deficit on neuropsychological testing. Complete blood tests including thyroid hormones, vitamin B12 and folate were within
normal range. Brain Magnetic Resonance Imaging (MRI) showed mild cortical atrophy, particularly in bilateral (left greater
than right) temporopolar and parietal regions. During the following two years, speech disorder slightly worsened, while
mild segmental (not axial) bradykinesia, ideomotor apraxia and saccades fragmentation without vertical gaze impairment
appeared. Dysautonomic, behavioural or cognitive symptoms were denied. On neuropsychological follow-up, slow
progressing speech apraxia, lately associated with impairment on verbal/written production and visuospatial search speed
was found, with only subtle impairment of short-term memory and executive functions. Brain Single Photon Emission
Tomography (SPECT) with DaTSCAN revealed normal basal ganglia uptake; Brain Perfusion SPECT showed slight
asymmetric hypoperfusion in temporopolar and temporomesial regions. Cerebrospinal Fluid biomarkers (Aβ-42, Tau and PTau) analysis showed values within normal range. In the suspicion of FTD-spectrum syndrome, not fitting any clinical
diagnostic criteria, gene sequencing of MAPT, PGRN and C9ORF72 genes was performed, revealing a 5bp deletion (c.105119del,p.Gln35_Asp40delinsHis) in MAPT gene, not yet described in literature (HMGD professional®), and probably
disease causing in accordance with prediction softwares (Mutation Taster® and Polyphen® ). A final diagnosis of speech
apraxia leading to possible corticobasal syndrome was therefore made.
Conclusions: We describe the clinical profile evolution of a patient presenting with slowly progressive isolated speech
apraxia, supporting the idea that this rare speech disorder can be the first presentation of Corticobasal Syndrome. Moreover,
a novel probably disease-causing MAPT mutation never described before was found, underlying the importance of genetic
analysis – particularly in selected atypical cases - for in vivo understanding of possible pathophysiological disease process.
References:
− Rossi, G. & Tagliavini, F. Frontotemporal lobar degeneration: old knowledge and new insight into the pathogenetic
mechanisms of tau mutations. Front. Aging Neurosci. (2015);7:192
− Rossi, G. et al. The G389R mutation in the MAPT gene presenting as sporadic corticobasal syndrome. Mov.
Disord. Off. J. Mov. Disord. Soc. (2008);23:892–895
− Josephs, K. A. et al. The evolution of primary progressive apraxia of speech. Brain J. Neurol. 1(2014);37: 2783–
2795
GENETIC AND ENVIRONMENTAL FACTORS AFFECT BRAIN DIFFERENTLY IN DM1 MONOZYGOTIC
TWINS: THE EFFECT ON SOCIAL COGNITION AND DECISION-MAKING ABILITIES
L. Serra1, M. Bruschini1, A. Petrucci2, G. Meola3, M. Bozzali1
1
Neuroimaging Laboratory, Santa Lucia Foundation IRCCS (Roma); 2UOC Neurologia e Neurofisiopatologia, AO San
Camillo Forlanini (Roma); 3Department of Neurology, IRCCS Policlinico San Donato, University of Milan (Milano)
pag. 25
Aims: Myotonic dystrophy type-1 (DM1) is a genetic multisystem disorder (1) in which both social cognition deficits (2)
and brain abnormalities are currently recognised (3). Genetics and environmental factors modulate the brain development,
thus accounting for brain resilience. Here, investigated the heritability traits of DM1 brain features and corresponding
cognitive profiles.
Methods: Two monozygotic twins with a adult DM1 onset (LV and SV, 29 years old, Females, 11 years of education) were
investigated using an extensive assessment including social cognition (Theory of Mind, Emotional processing, Socialsituation test, moral-and-conventional knowledge), executive functions (Iowa-Gambling Task, Wisconsin-Card Sorting test,
Trial-Making Test, Tower of London, Raven’s Coloured Progressive Matrices, Cognitive Estimation Task), and Intelligent
quotient (IQ). Patients underwent 3T MRI including T1-weighetd volumes for voxel-based morphometry (VBM). Ten
gender-matched healthy subjects (HS) were used as controls for brain volumetric comparisons in either patient. Results:
Both patients reported a normal IQ. LV showed an extensive impairment of emotion processing underlying her social
cognition abilities, while SV showed a remarkable impairment in the cognitive aspects of social cognition. Both patients
revealed similar deficits in decision-making. VBM revealed similarities, but also differences in regional grey matter (GM)
atrophy distribution between LV and SV. In both cases GM atrophy was present in the posterior cingulate cortex (BA23/31)
and precuneus (BA7), and in the striatum. SV (but not LV) showed additional GM atrophy in her right dorsolateral
prefrontal cortex (BA46). With respect to white matter (WM), both patients revealed regional atrophy distributed to the
thalamus and the uncinate fasciculus.
Discussion: This study in monozygous DM1 twins indicates that emotional and cognitive components of social cognition
can be differently impaired across DM1 patients (2). These impairments are consistent with their different patterns of
regional brain atrophy. GM atrophy in most posterior brain areas (connected with the limbic system) accounts for the
emotional dysfunction observed in LV. GM atrophy in the dorsolateral prefrontal cortex accounts for the cognitive deficits
in social cognition observed in SV (2). The overlapping atrophy in the striatum (structure implicated in reward mechanisms)
might account for patients’ common deficits in decision-making. Overall, our DM1 twins showed differences in GM but not
in WM volumes. We speculate that WM might be more affected by genetics, while GM may be modulated by specific
environmental factors, such as education and social events experienced during lifetime (3). Interestingly these two
environmental factors seem to have impacted differently on individual patients’ dysfunctions.
References:
1. G. Meola, R. Cardani, “Myotonic dystrophies: An update on clinical aspects, genetic, pathology, and molecular
pathomechanisms”. Biochimca et Biophysica Acta (2015);1852:594-606
2. Serra L, Cercignani M, Bruschini M, Cipolotti L, Mancini M, Silvestri G, Petrucci A, Bucci E, Antonini G,
Licchelli L, Spanò B, Giacanelli M, Caltagirone C, Meola G, Bozzali M. "I Know that You Know that I Know":
Neural Substrates Associated with Social Cognition Deficits in DM1 Patients.” PLoS One (2016) Jun
3;11(6):e0156901
3. Serra L, Petrucci A, Spanò B, Torso M, Olivito G, Lispi L, Costanzi-Porrini S, Giulietti G, Koch G, Giacanelli M,
Caltagirone C, Cercignani M, Bozzali M. How genetics affects the brain to produce higher-level dysfunctions in
myotonic dystrophy type 1. Funct Neurol. (2015) Jan-Mar;30(1):21-31
NOVEL COMPOUND HETEROZYGOUS MUTATIONS IN THE CLN6 GENE ASSOCIATED WITH
AUTOSOMAL RECESSIVE KUFS DISEASE
G. Borzì1, L. Mumoli1, F. Abate1, S. Cavalli1, A. Labate1,2, A. Gambardella1,2
1
Institute of Neurology, Department of Medical and Surgical Sciences, University Magna Graecia (Catanzaro); 2Institute of
Molecular Bioimaging and Physiology, National Research Council (IBFM-CNR) (Catanzaro)
Purpose: Autosomal recessive Kufs disease (KD) type A is a rare form of neuronal-ceroid-lipofuscinosis presenting with
progressive myoclonus epilepsy that starts around the age of 30 years. The phenotype seems to be more heterogeneous than
previously assumed, so the diagnosis is markedly delayed or missed. Recessive mutations in CLN6 seem to be the major
cause of the disorder. Here, we report clinical and genetic findings in a KD family with two affected individuals.
Materials and methods: The two probands are a brother (40 y) and sister (42 y), with non-consanguineous parents. Since
their twenties, both of them experienced vibrating jerks of the mouth and upper limbs, induced by voluntary movements or
visual stimuli. In the following years, rare generalized tonic-clonic seizures also occurred. They were diagnosed juvenile
myoclonic epilepsy and received levetiracetam, which reduced myoclonus. In the following 5-10 years, myoclonus
progressively worsened, becoming a dominant symptom and causing severe motor impairment. They also experienced
progressive unsteadiness, difficulty in writing, speech and cognitive slowing. EEG/polygraphic recordings showed
pag. 26
generalized spike-waves and photo-paroxysmal response with a high sensitivity to low-frequency photic stimulation, with
1:1 spike to 1-Hz stimuli. Visual and auditory evoked potentials were normal, while somatosensory evoked potentials
revealed a large cortical potential, associate with C-reflex. In both patients, brain MRI showed cortical and subcortical
atrophy over both hemispheres with white matter abnormalities.
The two patients, their unaffected mother and brother underwent a genetic molecular study to search mutations of CLN6
(NM_017882.2).
Results: Gene sequencing of CLN6 identified both probands to be compound heterozygous for a c.721 A>G, P. M241V
mutation in exon 7; and c.814 C>G, P. L272V in exon 7. The healthy brother did not carry any mutation, the mother was a
carrier of the single c.721 A> G; P. M241V variant. These two variants are very rare and predicted to be damaging.
Conclusions: The results of this family further highlight the major role of the CLN6 gene for recessive KD type A. As its
diagnosis is challenging and is compounded by the relative rarity of the disorder, the CLN6 mutation screening should now
be considered as an initial diagnostic step in patients with adult-onset myoclonus, allowing early detection and avoiding
other costly and invasive investigations. In our family, early and very characteristic electro-clinical manifestations of KD
type A related to CLN6 mutations were massive and segmental myoclonus, as also low-frequency photo paroxysmal
response.
References:
− Arsov T, Smith KR, Damiano J, Franceschetti S, Canafoglia L, Bromhead CJ, Andermann E, Vears DF, Cossette
P, Rajagopalan S, McDougall A, Sofia V,Farrell M, Aguglia U, Zini A, Meletti S, Morbin M, Mullen S,
Andermann F, Mole SE, Bahlo M, Berkovic SF. Kufs disease, the major adult form of neuronal ceroid
lipofuscinosis, caused by mutations in CLN6. Am J Hum Genet. (2011) May 13;88(5):566-73
− Canafoglia L, Gilioli I, Invernizzi F, Sofia V, Fugnanesi V, Morbin M, Chiapparini L, Granata T, Binelli S, Scaioli
V, Garavaglia B, Nardocci N, Berkovic SF, Franceschetti S. Electroclinical spectrum of the neuronal ceroid
lipofuscinoses associated with CLN6 mutations. Neurology (2015) Jul 28;85(4):316-24
− Franceschetti S, Michelucci R, Canafoglia L, Striano P, Gambardella A, Magaudda A, Tinuper P, La Neve A,
Ferlazzo E, Gobbi G, Giallonardo AT, Capovilla G, Visani E, Panzica F, Avanzini G, Tassinari CA, Bianchi A,
Zara F; Collaborative LICE study group on PMEs. Progressive myoclonic epilepsies: definitive and still
undetermined causes. Neurology (2014) Feb 4;82(5):405-11
ACUTE HEMICHOREA AN UNUSUAL FIRST MULTIPLE SCLEROSIS PRESENTATION: TWO CASE
REPORTS
F. Cavallieri, G. Giovannini, E. Menozzi, S. Meletti, A. Chiari, J. Mandrioli, D. Ferraro, S. Contardi, P. Nichelli, F.
Valzania
Department of Neuroscience, S. Agostino-Estense Hospital and University of Modena and Reggio Emilia (Modena)
Introduction: Hyperkinetic movement disorders, in particular chorea, has been rarely reported in patients with Multiple
Sclerosis (MS) and almost never represent the first clinical manifestation. The few cases reported in the literature had basal
ganglia (mainly striatum) demyelinating plaques. We report two patients with acute hemichorea as the presenting symptoms
of
MS.
Case reports: Patient 1: A 39 year-old woman acutely developed subcontinuous, choreic movements in her right limbs
occasionally associated to ballistic movements and abnormal dystonic postures. Moreover continuous peribuccal and tongue
involuntary movements were noted. Brain MRI revealed a tumefactive, T2/FLAIR hyperintense, T1 hypointense contrastenhancing demyelinating lesion in the left cerebral peduncle, extending to the substantia nigra and subthalamic nucleus
(STN). Multiple others non-contrast-enhancing demyelinating lesions were also found. Isoelectric focusing (IEF) revealed
nine cerebrospinal fluid (CSF) oligoclonal bands (OB). A diagnosis of MS was made and the patient was treated with highdose methylprednisolone with improvement of symptoms. Patient 2: An 18 year-old man acutely developed intermittent
choreic and choreoathetoid movements associated with a dystonic posture of the left limbs, mostly involving the left hand,
dysarthric speech and mental slowing. Brain MRI revealed a right subthalamic T2/FLAIR hyperintense, contrast-enhancing
demyelinating lesion extending to the homolateral cerebral peduncle. Multiple non-contrast-enhancing demyelinating
lesions involved the left part of the pons-mesencephalic passage, the homolateral superior cerebellar peduncle, and the
corpus callosum. IEF revealed five CSF OB. A MS diagnosis was made and the patient was treated with high-dose
methylprednisolone with involuntary movements resolution in six days.
Discussion: Choreoathetosis, with different degrees of dystonia, represents the clinical manifestation of peak-dose
levodopa-induced dyskinesia in advanced Parkinson’s Disease (PD) that are possibly associated with STN hypoactivity, as
suggested by the occurrence of dyskinesias in MPTP monkeys and by the occurrence of hemichorea-hemiballism in around
pag. 27
15% of PD patients after subthalamotomy or during Deep Brain Stimulation (DBS). Historically, contralateral hemichorea
has been described in relation to subthalamic or thalamic lesions. In our case, the occurrence of demyelinating lesions in
basal ganglia could be explained by the presence of myelinated fibers within the subcortical grey nuclei. These
observations, the presence of contrast-enhancing STN lesions and the clinical improvement following steroid treatment,
suggest a direct relationship between the occurrence of the demyelinating lesions and the onset of the involuntary
movements. Aside from common cases induced by metabolic or vascular lesions, in young subjects this clinical picture
could suggest an unusual onset of a demyelinating disease.
References:
− Mehanna R, Jankovic J. Movement disorders in multiple sclerosis and other demyelinating diseases. J. Neurol Sci
(2013);328:1-8
− Lee MS, Marsden CD. Movement disorders following lesions of the thalamus or subthalamic region. Mov Disord.
(1994);9:493-507
− Guridi J, González-Redondo R, Obeso JA. Clinical features, pathophysiology, and treatment of levodopa-induced
dyskinesias in Parkinson’s disease. Parkinsons Dis. (2012);2012:943159
LIMB-SHAKING: AN EXCLUSIVE EPILEPTIC ORIGIN?
F. Notturno1, C. Tiseo1, D. Degan1, R. Ornello1, M. Lobene2, M. Pinelli3, A. Carolei1
1
Department of Neurology and Stroke Unit, Avezzano Hospital, University of L’Aquila (L’Aquila); 2Department of
Radiology, Avezzano Hospital, ASL1 AZ-SU-AQ (Avezzano, AQ); 3Department of Angiology, Avezzano Hospital, ASL1
AZ-SU-AQ (Avezzano, AQ)
Background: Limb-shaking syndrome is a rare presentation of internal carotid artery (ICA) occlusion. The syndrome is
characterized by brief and paroxysmal movements of the limbs, mainly observable with postural changes and is frequently
misdiagnosed as focal epileptic seizures. Methods: A 74-year old male patient complained of involuntary and intermittently
present left limbs movements, described as shaking and trembling, lasting from few seconds to three minutes.
Consciousness, speech, sensory and motor functions were normal, during and after the attacks. The episodes mainly
occurred after standing up from the supine position or during a prolonged laughter. Results: Arterial blood pressure was
110/70 mmHg in both supine and standing positions. A bruit over the right ICA was revealed. Doppler ultrasound
examination showed occlusion of the right ICA and near-occlusion of the right external carotid artery (ECA). Transtemporal window insonation of the right middle cerebral artery (MCA) showed a typical post-occlusive flow with reduction
of peak systolic and diastolic velocities. Breath-holding test documented an exhausted cerebrovascular reserve in the right
hemisphere. Brain magnetic resonance imaging, including diffusion weighted images, was normal. CT-angiography
confirmed the occlusion of the right ICA, a near-occlusion of the right ECA, and poor collateral circulation. CT-perfusion
showed an extensive perfusion deficit involving the whole right anterior circulation territory. The electroencephalogram did
not show any epileptic or focal slow waves activities. The patient was not eligible to revascularization procedure because of
the occlusion of the right ICA. In order to improve cerebral blood flow the ongoing antihypertensive treatment was stopped.
On day 2 limb-shaking movements resolved and the patient remained completely asymptomatic during the 6-month followup period.
Discussion: The patient was diagnosed as affected by limb-shaking syndrome. This is a rare form of hemodynamic transient
ischemic attack, determined by stenosis or occlusion of the ICA, causing a chronic cerebral hypoperfusion. Involuntary
limbs movements are the result of a focal critical reduction of cerebral blood flow occurring in the vascular watershed
territories of the anterior circulation. Because of the altered vasomotor reactivity, conditions that may further and transiently
compromise cerebral perfusion, such as rising, exercising, coughing, or laughing, favor the development of symptoms. The
absence of Jacksonian march, the spear of the face muscles, the absence of epileptiform activity are in favor of the vascular
origin of the symptoms. Early recognition of this syndrome is crucial for the timely improvement of cerebral perfusion by
carotid revascularization or blood pressure increase.
CEREBRAL SUPERFICIAL SIDEROSIS FOLLOWING CHRONIC INTRACRANIAL HYPOTENSION
E. Ferrante1, F. Rubino2, V. Prone1, A. Guccione1, A. Piperno3, S. Pelucchi3, E. Agostoni1
1
Neuroscience Department, Niguarda Cà Granda Hospital (Milano); 2Anaesthesiology Department, Niguarda Cà Granda
Hospital (Milano); 3Internal Medicine 2 Department, S. Gerardo Hospital Monza, Milano-Bicocca University (Milano)
pag. 28
Introduction: Superficial siderosis (SS) is a radiological and pathological condition in which hemosiderin is deposited in the
subpial layer of the central nervous system, which leads to slowly progressive neurological dysfunction. The distinct clinical
features are characterized by deafness, hyposmia, cerebellar ataxia, pyramidal signs, cognitive decline and bladder
disturbance.
Case Report: In February 2010 a 48 years old man presented a dislocation of the right shoulder while skiing. After 4 months
he presented hyposmia, bilater hearing loss and tinnitus, vertigo and nuchal stiffness without headache. After December
2011 the patient showed also imbalance. He was hospitalized in another neurological department and brain MRI showed a
diffuse cerebellar superficial siderosis with atrophy and without diffuse pachymeningeal enhancement (DPE). The CSF
exam and the spinal-MRI were normal. 4 years after the trauma a myelo-CT showed a C2-T11 anterior epidural CSF
collection without localization the real CSF leak site. In August 2015 the patient was admitted in our department. The
neurological examination showed anosmia, severe ipoacusia and mild imbalance at the tightrope walking test. Spinal myeloMRI showed anterior epidural CSF collection from C2 to T11 and brain MRI was unchanged. The lumber puncture showed
clear CSF with opening pressure of 5 cm H2O, protein 50 mg/dl, ferritine 71 ng/ml (n.v. 3.9-6.4) and some erythrocytes.
The intracranial hypotension (IH) was diagnosed and an epidural lumbar blood patch (EBP) was performed with imbalance
improvement and nuchal stiffness disappearance. In May 2016 a spinal myelo-MRI and CSF exam were unchanged.
Radionuclide cysternography at 4th hours showed a tracer increased uptake at anterior epidural cervical-thoracic junction
level, indicating the approximate CSF leak site and early tracer accumulation in the bladder, indirect sign of CSF leakage. A
thoracic targeted EBP at T3-T4 level was performed with recovered of the imbalance and improvement of the tinnitus.
Discussion: SS is a rare disease. The aetiology in about 50% of the cases is unknown. The principal cause might be the
chronic venous microbleeding. The microbleedings would caused by the breaking of the cerebellar bridge veins for the
brain sagging, the epidural and pial venous plexus engorgment that accompanies CSF hypotension, sclerosis of the epidural
venous plexus by choronic siderosis, leading to venous pial plexus hypertension with secondary prominent engorgement
with blood exudation.
Conclusion: In the cryptogenic cases of SS with an epidural fluid collection at spinal-MRI it might suspect IH also in
atypical cases without headache and DPE, treatable with EBP.
References:
− Cheng CY, Chen MH, Wang SJ, Lin KP A proposed mechanism of superficial siderosis supported by surgical and
neuroimaging findings. Med Hypotheses (2011) Jun;76(6):823-6
− Ferrante E, Arpino I, Citterio A, Wetzl R, Savino A. Epidural blood patch in Trendelenburg position pre-medicated
with acetazolamide to treat spontaneous intracrania lhypotension. European Journal of Neurology (2010);17:715–9
REVERSIBLE ATAXIA WITH CEREBELLUM HYPERINTENSITY DUE TO HYPOMAGNESEMIA AND
THIAMINE DEFICIENCY: A CASE REPORT
D. Baroncini1, P. Annovazzi1, S. Baldini1, G. Minonzio2, A. Ghezzi1, G. Comi3, M. Zaffaroni1
1
Multiple Sclerosis Study Center, ASST Valle Olona (Gallarate-VA); 2Neuroradiology Department, ASST Valle Olona
(Gallarate-VA); 3Department of Neurology and Institute of Experimental Neurology, University Vita-Salute San Raffaele
(Milano)
Objective: We present the case of a patient with a subacute reversible ataxia with evidence of cerebellar hyperintensity on
brain MRI.
Materials and Methods: Single patient case report.
Case Report: A 41 years-old man with an unremarkable family history presented to our hospital with a subacute onset of
slurred speech, oscillopsia, diffuse paresthesia and intermittent limb tremors. Past medical history included cigarettes
smoking, type II diabetes mellitus, arterial hypertension and a loss of 22 Kg in the past 3 months due to a low-calorie diet.
Ongoing medications were sitagliptin, metformin, bisoprolol, valsartan and omeprazole. In emergency care unit blood
exams showed severe sodium, potassium and magnesium depletion. Brain CT scan, EEG and EKG were normal.
Electrolytes supplementation led to full improvement of all symptoms except for dysarthria. Neurological consultation was
then requested: the clinical examination showed mild confusion, severe slurred speech, mild “no-no” head tremor, mild
dysdiadochokinesia, positive Romberg sign and difficulty in walking heel-to-toe. Brain MRI scans showed a T2 and DWI
hyperintensity in vermis and anterior cerebellar lobe. The patient was then admitted to our neurological department. General
blood exams, vitamin E and B12, celiac-related/classic onconeural/anti-GAD antibodies were normal. Folate levels were
low. Cerebral spinal fluid examination was unremarkable, with no oligoclonal bands. Extensive total body imaging (CT,
PET) and endoscopic exams were also negative. Intramuscular thiamine administration led to an initial partial recovery. We
pag. 29
repeat blood electrolytes finding again a severe magnesium deficiency. The combined parenteral supplementation of
thiamine and magnesium led finally to an almost complete recovery, with a full regression of the cerebellar hyperintensity
on
MRI.
Discussion: In the clinical picture of Wernicke encephalopathy cerebellar ataxia is often present, but only rarely cerebellar
alterations on brain MRI scans have been described (1). Furthermore, hypomagnesemia has been associated with a
reversible vermian cerebellar ataxia with nodulus involvement (2). Although we did not dose blood thiamine levels in the
acute phase, loss of weight due to diet restriction, exclusion of other causes and improvement after thiamine
supplementation support the diagnosis. Hypomagnesemia could have foster this atypical cerebellar presentation, as
magnesium is a crucial cofactor in thiamine metabolism and severe hypomagnesemia may lead to a refractory response to
thiamine until magnesium is given (3).
Conclusion: In the diagnostic work-up of patients with cerebellar ataxia hypomagnesemia and thiamine deficiency are
extremely important to unveil due to their potential correction.
References:
1. Jung Eun Kim, Tae Hyung Kim, In Kyu Yu, et al. Diffusion-Weighted MRI in Recurrent Wernicke’s
Encephalopathy: a Remarkable Cerebellar Lesion. J Clin Neurol (2006); 2(2):141-145
2. Santos AF, Sousa F, Rodrigues M, et al. Reversible cerebellar syndrome induced by hypomagnesemia. Neurology
and Clinical Neuroscience (2015);3:190–191
3. Sechi G., Serra A. Wernicke’s encephalopathy: new clinical settings and recent advances in diagnosis and
management. Lancet Neurol (2007);6:442–55
MIDBRAIN HEMIATROPHY IN A PATIENT WITH EARLY ONSET HEMIPARKINSONISM
A. Lupo1, G. Barbagallo1, G. Arabia1, L. Manfredini1, U. Sabatini2, A. Quattrone3
1
Institute of Neurology, University Magna Græcia (Catanzaro); 2Institute of Neuroradiology, University Magna Graecia
(Catanzaro); 3Institute of Neurology; Neuroimaging Research Unit, Institute of Molecular Bioimaging and Physiology,
University Magna Graecia; National Research Council (Catanzaro)
Introduction: A rare form of secondary parkinsonism has been recently reported as hemiparkinsonism-hemiatrophy
syndrome (HPHA). This condition is defined by the occurrence of a body hemiatrophy with features of an ipsilateral, early
onset, slowly progressive, levodopa-responsive hemiparkinsonism. The underlying pathogenesis is not well understood, but
perinatal cerebral insults seem to play a crucial role. Magnetic resonance imaging (MRI) may be normal or it can show a
controlateral brain asymmetry, ventricle asimmetry, hyperintense lesions in midbrain with or without nigral involvement
[1].
Case description: A 58-years-old man presented with a 12-year nonprogressive history of levodopa-responsive brachiocrural slowness and decrease in dexterity on the left side, with ipsilateral hand tremor. His past history was negative for
birth-related problems, even if since early childhood he had some clumsiness to the left upper and lower limbs and he was
aware of the asymmetry between the left and the right side. Neurological examination revealed slight brachio-crural atrophy
with mild rigidity and bradykinesia of his left side, rest and postural tremor in the ipsilateral hand. He did not show other
atypical hallmarks, such us autonomic disturbances, pyramidal signs and cognitive impairment. PINK1, Parkin, and DJ-1
mutations were negative. MRI 3T showed a right midbrain atrophy with the rarefaction of the substantia nigra, that was not
recognizable as the band of signal hypointensity on T2 sequence, laterally to the red nucleus. Dopamine transporter singlephoton emission computed tomography (DAT-SPECT) scan with 123I-ioflupane (FP-CIT) revealed a strictly unilateral
reduced striatal binding on the right side.
Discussion: Here we describe an early-onset, nonprogressive, levodopa-responsive hemiparkinsonism on the left side
associated with an ipsilateral body hemiatrophy. Furthermore, MRI showed an atrophy of the right midbrain combined with
an ipsilateral rarefaction of the substantia nigra. In according with these MRI findings, DAT-SPECT showed a significant
reduced uptake of FP-CIT only in the right striatum. In our patient, pure left hemiparkinsonism, ipsilateral brachio-crural
atrophy that was by himself recognized, and controlateral midbrain atrophy suggest a diagnosis of HPHA. The history of
cerebral injury occurring at birth or first few years of life is reported in nearly half of patients, although it has not been
documented in all cases of HPHA [2]. To our knowledge, this case represents the first description of a possible HPHA
associated to midbrain hemiatrophy and absence of the substanti nigra.
References:
1. Wijemanne S, Jankovic J. Hemiparkinsonism-hemiatrophy syndrome. Neurology (2007);69:1585-94
2. Giladi N, Burke RE, Kostic V, et al. Hemiparkinsonism-hemiatrophy syndrome: clinical and neuroradiologic
features. Neurology (1990);40:1731–1734
pag. 30
DISORDINI DEL MOVIMENTO 1
CLINICAL, NEUROPHYSIOLOGICAL AND IMAGING FEATURES OF ESSENTIAL TREMOR-PARKINSON
DISEASE (ET-PD) SYNDROME
G. Arabia1, A. Lupo1, L. Manfredini1, M. Caligiuri2, R. Nisticò2, G. Barbagallo1, I. Martino1, F. Novellino2, M. Salsone2, A.
Quattrone1
1
Institute of Neurology, University "Magna Graecia" (Catanzaro); 2Neuroimaging Research Unit, IBFM, National Research
Council (Catanzaro)
Objective: The relationship between essential tremor (ET) and Parkinson’s disease (PD) is strongly controversial. Some
authors have proposed a coincidental co-occurrence of ET and PD, whereas others suggested that ‘‘ET-PD’’ syndrome may
represent a distinct entity.1-3 The aim of the present study was to investigate the clinical, neurophysiological and imaging
features of patients with ET-PD in comparison with patients affected by ET, ET with resting tremor (r-ET) and tremordominant PD (t-PD).
Methods: A total of 122 patients referring to our Movement Disorders Center for tremor were included in this study.
Eighteen patients were affected by ET-PD, 40 patients with ET, 23 patients with r-ET, and 41 patients by t-PD. All patients
were classified according to the standardized clinical criteria. Clinical, neurophysiological, neuropsychological, and
imaging features of the included patients were analysed.
Results: No statistical differences were found in the comparisons among the study groups in terms of age, sex, family
history for tremor and/or PD, and cognitive status performances. Age at onset and disease duration of ET were similar in
ET, r-ET and ET-PD patients (p=0.56, Kruskal-Wallis test followed by pairwise Wilcoxon rank sum test and Bonferroni
correction). ET-PD and r-ET patients showed resting tremor with an EMG synchronous pattern, whereas the pattern was
alternating in t-PD patients. DAT-scan uptake was preserved in ET and r-ET patients (4.27 ± 0.59 and 4.46 ± 0.62,
respectively) and reduced in t-PD patients (2.12 ± 0.43). ET-PD patients showed moderately reduced uptake values (3.19 ±
1.02). MIBG scintigraphy uptake was abnormal in t-PD and preserved in ET and r-ET. In ET-PD patients, MIBG uptake
was only slightly reduced, suggesting a mild sympathetic cardiac denervation in these patients.
Conclusions. Our findings suggested that ET-PD might be considered a distinct clinical entity. Indeed, our study showed
that ET-PD patients, after a long history of ET, developed a parkinsonism with clinical, neurophysiological, and imaging
features differential from the classical PD.
References:
− Pahwa R, Koller WC. Is there a relationship between Parkinson’s disease and essential tremor? Clin
Neuropharmacol (1993);16:30-35
− LaRoia H, Louis ED. Association between essential tremor and other neurodegenerative diseases: what is the
epidemiological evidence. Neuorepidemiology (2011);37:1-10
− Fekete R, Jankovic J. Revisiting the relationship between essential tremor and Parkinson’s disease. Mov Disord
(2011);26:391-398
IMPAIRED HEART RATE VARIABILITY BY LONG TERM ECG RECORDING IN PARKINSON’S DISEASE:
A CASE-CONTROL STUDY
V. Arnao1, A. Cinturino1, G. Lanza1, G. Bellavia1, S. Mastrilli1, V. Perini1, S. Realmuto1, F. Valentino1, C. Buttà2, C.
Maida2, A. Tuttolomondo2, M. D'Amelio1
1
Department of Experimental Biomedicine and Clinical Neurosciences, University of Palermo (Palermo); 2Biomedical
Department
of
Internal
and
Specialistic
Medicine,
University
of
Palermo
(Palermo)
Introduction: Parkinson's disease (PD) is associated with autonomic dysfunction, controlled by circadian regulation.
Impaired cardiovascular autonomic regulation is an autonomic symptom of Parkinson’s disease (PD) and it may increase
long-term morbidity. Heart rate variability (HRV) decreases in PD and it can be considered a marker for cardiovascular
dysautonomia. 24-hour Holter recording could be a valid tool to characterizing cardiac autonomic state.
pag. 31
Objective: To evaluate the presence of autonomic symptoms in PD patients and to perform a time-domain assessment of
HRV by a long term 24-hour Holter recording.
Method: This is an observational, cross-sectional, comparative study. Patients with idiopathic PD and without comorbidity
impairing the HRV, and age-matched healthy persons were recruited at the Neurological Department starting from January
2013 to May 2015. Patient with suspected atypical or secondary parkinsonism were excluded. The levodopa Equivalent
Daily Dose (LED) has been calculated and medications have been recorded as Comorbidities have been recorded, using the
Cumulative Illness Rating Scale (CIRS). Each patient underwent an extensive evaluation including Hoehn & Yahr stage
(H&Y), Unified Parkinson’s Disease Rating Scale (UPDRS), and Scale for Outcomes in PD for autonomic symptoms
(SCOPA-AUT). A Time domain analysis of heart rate variability (HRV) using 24-hour ambulatory ECG was also
performed.
Results: A total of 18 patients with PD were identified (mean age was 55,6 ±8,8, disease duration: 5,01± 4,7); none of
patients and of the 18 age and sex matched controls was on anti-hypertensive, antiarrhythmic and mineral corticoid drugs.
Mean SCOPA-AUT scale score was 10,12 ± 7,34. PD patients were on HY stage 1-2 and mean LED was 311 ± 239,9. At
univariate analysis, compared to healthy controls, in 24-hour ambulatory ECG evaluation, SDNNindex (ISDNN) was
significantly lower (p 0,01) in PD patients. ISDNN significantly correlated with age (Rho -0.69, p B 0.02), LED (Rho -0.60,
p B 0.01), Levodopa dosage (Rho -0.57, p B 0.02) and SCOPA-AUT scale scores (Rho -0.47, p B 0.05). At multivariate
analysis (adjusted for age, LED and levodopa dosage and SCOPA-AUT score), older age (ORa 1.209, 1.18–1.493, p =
0.005), levodopa therapy (ORa 1.006, 1.003–1.014, p = 0.005) LED (ORa 1.09, 1.003–1.0155, p = 0.003) and SCOPAAUT scores (ORa 1.038, 1.002–1.299, p = 0.005) were independently associated with lower ISDNN value.
Conclusion: This study highlights the importance of autonomic dysfunction in PD. In our population characterized by mild
to moderate disease severity, most of patients had autonomic system involved and time-domain assessment of HRV could
be a potential tool to characterizing cardiovascular dysautonomia. Both cardiac sympathetic and parasympathetic
dysfunction are commonly reported in PD patients. Decrease of iSDNN in HRV may demonstrate overall sympathetic and
parasympathetic function in PD.
References:
− Verbaan D, Marinus J, Visser M, van Rooden SM, Stiggelbout AM, van Hilten JJ. Patient-reported autonomic
symptoms in Parkinson disease. Neurology (2007) Jul 24;69(4):333-41
− Visser M, Marinus J, Stiggelbout AM, Van Hilten JJ. Assessment of autonomic dysfunction in Parkinson's disease:
the SCOPA-AUT. Mov Disord. (2004) Nov;19(11):1306-12
− Brisinda D, Sorbo AR, Di Giacopo R, Venuti A, Bentivoglio AR, Fenici R. Cardiovascular autonomic nervous
system evaluation in Parkinson disease and multiple system atrophy. J Neurol Sci. (2014) Jan 15;336(1-2):197-202
DOPAMINE D2 RECEPTOR MEDIATED NEUROPROTECTION IN A LRRK2 GENETIC MODEL OF
PARKINSON DISEASE
A. Mancini1, A. Tozzi2, A. de Iure1, V. Durante1, M. Tantucci1, P. Mazzocchetti1, M. Di Filippo1, P. Calabresi1
1
Neurology Clinic, Department of Medicine, University of Perugia (Perugia); 2Section of Physiology and Biochemistry,
Department of Experimental Medicine, University of Perugia (Perugia)
Objectives: Parkinson Disease (PD) is a neurodegenerative disease in which genetic and environmental factors
synergistically lead to a loss of midbrain dopamine (DA) neurons. Mutations of Lrrk2 gene are responsible for the majority
of inherited cases of PD and can be also found in sporadic cases. The pathophysiological role of this kinase has yet to be
fully understood (1). Thus, we investigated possible alterations of striatal medium spiny neurons (MSNs) activity in a
genetic mouse model of PD carrying the G2019S knock-in (KI) mutation, which enhances Lrrk2 kinase activity (2,3). We
also evaluated in this model neuronal vulnerability to rotenone, a mitochondrial complex I inhibitor, known to be involved
in PD pathogenesis.
Materials and methods: Basal membrane properties and glutamatergic excitatory postsynaptic currents (EPSCs) were
recorded, by patch-clamp experiments, in MSNs from brain slices of mice carrying the Lrrk2 mutation observed in PD
patients (G2019S-KI) and control C57Bl/6 mice. Striatal DA release was measured by constant potential amperometry.
Neuronal vulnerability to rotenone was tested by measuring the progressive reduction of striatal field potential amplitude
(FPA).
Results: The amperometric analysis showed reduced striatal DA levels by 49% (p<.05) in KI mice. We found that the DAD2 receptor agonist quinpirole (10µM) markedly reduced spontaneous (31%,p<.05) and evoked EPSCs (38%,p<.05) in KI
and not in control mice, and that the application of a CB1-endocannabinoid receptor antagonist prevented this effect.
Interestingly, in mice lacking functional Lrrk2 (kinase-dead D1994S, Lrrk2 KO) quinpirole had no effects, suggesting the
pag. 32
need for Lrrk2 kinase activity in mediating the altered electrophysiological properties observed in KI mice. Moreover, the
rotenone-induced loss of the FPA was markedly enhanced in KI compared to control mice (24%,p<.05). This detrimental
effect could be reversed in KI mice, but not in controls, by the application of quinpirole, through the inhibition of the
cAMP/PKA intracellular pathway, since the blockage of PKA limited rotenone toxicity in KI mice by 35% (p<.05).
Discussion: We showed that the G2019S mutation is associated with an altered striatal DA and glutamate transmission. In
particular, we found a DA-D2R dependent reduction of striatal glutamate release through a CB1R-dependent mechanism.
Neurons from KI mice were found to be more vulnerable to mitochondrial dysfunction, and DA-D2R activation exerts a
neuro-protective role via the inhibition of cAMP/PKA intracellular pathway.
Conclusions: Neuroprotective pharmacological strategies targeting DA-D2R could be effective in counteracting the
synergistic effect of genetic and environmental predisposing factors in patients carrying the G2019S mutation.
References:
1. Cookson MR. The role of leucine-rich repeat kinase 2 (LRRK2) in Parkinson's disease. Nat Rev Neurosci. (2010)
Dec;11(12):791-7
2. Beccano-Kelly DA, Kuhlmann N, Tatarnikov I, Volta M, Munsie LN, Chou P, Cao LP, Han H, Tapia L, Farrer
MJ, Milnerwood AJ. Synaptic function is modulated by LRRK2 and glutamate release is increased in cortical
neurons of G2019S LRRK2 knock-in mice. Front Cell Neurosci. (2014) Sep 26;8:301
3. Yue M, Hinkle KM, Davies P, Trushina E, Fiesel FC, Christenson TA, Schroeder AS, Zhang L, Bowles E,
Behrouz B, Lincoln SJ, Beevers JE, Milnerwood AJ, Kurti A, McLean PJ, Fryer JD, Springer W, Dickson DW,
Farrer MJ, Melrose HL. Progressive dopaminergic alterations and mitochondrial abnormalities in LRRK2 G2019S
knock-in mice. Neurobiol Dis. (2015) Jun;78:172-95
TOPOGRAPHICAL DISTRIBUTION OF SKIN Α-SYNUCLEIN DEPOSITS IN IDIOPATHIC PARKINSON
DISEASE
V. Donadio1, A. Incensi1, G. Rizzo1, C. Scaglione2, S. Capellari1, E. Fileccia1, R. Liguori2
1
IRCCS Istituto Scienze Neurologiche (Bologna); 2IRCCS Istituto Scienze Neurologiche di Bologna and Department of
Biomedical and Neuromotor Science, University of Bologna (Bologna)
Objective: The variability of phosphorylated α-synuclein (p-syn) deposits in skin nerves represents an important obstacle for
the use of skin biopsy as diagnostic idiopathic Parkinson Disease (IPD) biomarker. Specific aims of this study in IPD were
to: 1) define the distribution of p-syn deposits along skin nerves in relationship to proximal and distal skin sites; 2) ascertain
possible difference of p-syn between left and right cervical sites in patients with asymmetric motor symptoms.
Methods: 24 patients fulfilling diagnostic criteria for IPD were studied including: 1) 12 patients with symmetric motor
symptoms and bilateral DatScan abnormalities; 2) 12 patients with motor asymmetry demonstrated by DatScan. Patients
underwent to skin biopsy searching for intraneural p-syn deposits: in symmetric patients skin samples were taken from
proximal (i.e. C7 and Th 12 paravertebral spine regions) and distal (i.e. thigh and leg) body sites whereas in asymmetric
patients from left and right C7 paravertebral skin sites.
Results: Symmetric patients showed p-syn positivity in 100% of cases in C7, 67% in Th12, 75% in the thigh and 57% in the
leg. In asymmetric cases 25% of patients displayed abnormal deposits only in the affected motor site, 50% in both sites
whereas 25% only in the non affected site.
Conclusions: 1) skin nerve p-syn deposits showed a centrifugal gradient with the cervical paravertebral site showing the
highest positivity; 2) cervical p-syn deposits did not follow motor side dysfunction in asymmetric patients who showed an
uniform distribution between right and left sides. These data may contribute to standardize the use of skin biopsy for the in
vivo IPD diagnosis.
SENSORY TRICK PHENOMENON IN CERVICAL DYSTONIA: A FUNCTIONAL MRI STUDY
E. Sarasso1, F. Agosta1, S. Amadio2, C. Butera2, F. Bianchi2, R. Guerriero2, A. Falini3, G. Comi2, U. Del Carro2, M.
Filippi1,2
1
Neuroimaging Research Unit, Department of Neurology, Institute of Experimental Neurology, San Raffaele Scientific
Institute - Vita-Salute San Raffaele University (Milano); 2Department of Neurology, San Raffaele Scientific Institute, VitaSalute San Raffaele University (Milano); 3Department of Neuroradiology, San Raffaele Scientific Institute, Vita-Salute San
Raffaele University (Milano)
pag. 33
Objective: Antagonistic gestures such as touching the face with fingertips (“sensory trick”) may relieve dystonic symptoms
in a percentage of patients with idiopathic cervical dystonia (DYT). The mechanism of the sensory trick action remains to
be fully understood. This study investigates the patterns of brain functional MRI (fMRI) activation during the imagination
of sensory tricks in patients with cervical DYT.
Materials and methods: We recruited 17 patients with cervical DYT treated with botulinum toxin. In 9 patients (DYT-trick),
sensory tricks almost reversed head rotation to primary position, while 8 patients (DYT-notrick) did not show any trick
effect. Both groups, immediately after the botulin injection, underwent a functional MRI task in which they were asked to
imagine an ipsilateral sensory trick (i.e., slight touch on the cheek). FMRI data were analyzed using the statistical
parametric mapping software. One-sample t tests assessed the average fMRI activity during task in each group. A secondlevel random effect analysis was performed to explore differences between groups.
Results: During the imagination of sensory tricks, both DYT groups showed a similar pattern of activation, including the
primary motor cortex, the cerebellum and the mirror neuron system (i.e., inferior frontal and superior parietal gyri).
Compared to DYT-notrick patients, DYT-trick cases showed an increased recruitment of the cerebellum bilaterally during
the task execution.
Discussion and conclusions: Both groups showed a common pattern of recruitment in sensorimotor areas and mirror neuron
system during the imagination of sensory tricks. The increased activation of the cerebellum in DYT-trick patients may
suggest a possible compensatory role of this area. Indeed, a few studies have shown that a direct stimulation of the
cerebellum and primary motor cortex is associated with a reduction of dystonia symptoms and to a better quality of life in
these patients.
RESTING-STATE FUNCTIONAL CONNECTIVITY PREDATES IMPULSE CONTROL DISORDERS IN
“DRUG-NAÏVE” PATIENTS WITH PD
A. Giordano1, R. De Micco1, L. Marcuccio1, M. De Stefano1, M. Siciliano1, F. Esposito2, A. Tessitore1, G. Tedeschi1
1
2
Department of Medical, Surgical, Neurological, Metabolic and Aging Sciences, Second University of Naples (Napoli);
Department of Medicine and Surgery, University of Salerno (Salerno)
Background: Impulse control disorders (ICDs) are common in Parkinson's disease (PD) generally thought to be related with
dopamine replacement therapy, demographic and other clinical risk factors (1). Previous studies have shown an impaired
corticostriatal and limbic regions connectivity in patients with ICD (2,3).
Objectives: Using resting-state (RS) functional MRI, we retrospectively investigated the functional correlates of ICD
symptoms, at baseline, in a cohort of “drug-naïve” patients with PD which successively developed ICD at follow up (ICD
+) compared with patients without ICD (ICD -).
Methods: Baseline 3Tesla MRI images of 20 “drug-naïve” PD patients, 10 ICD + and 10 ICD -, and 10 matched healthy
controls (HCs) were analyzed. The presence and the severity of ICDs at twelve months follow up was defined based on the
Questionnaire for Impulsive-Compulsive Disorders in Parkinson's Disease - Rating Scale. Single-subject and group-level
independent component analysis was used to investigate functional connectivity differences within the major resting state
networks between patients sub-groups and HCs. In addition, we used voxel-based morphometry to test whether betweengroup functional changes were related to structural differences.
Results: At baseline, a decreased connectivity within the default mode and the right fronto-parietal networks and an
increased connectivity within the salience network were detected when ICD + were compared with ICD - patients. Voxelbased morphometry analysis did not reveal any significant volume differences between all patients with PD and HCs and
between ICD + and ICD - groups. (p<0.05; FWE).
Discussion: Our findings demonstrated, for the first time, that an abnormal RS connectivity within default mode, frontoparietal and salience networks characterizes “drug naïve” patients who will eventually develop ICD while on dopaminergic
treatment
Conclusions: We hypothesize that these divergent cognitive and limbic networks connectivity changes at baseline could
represent an additional risk factor of incident ICDs in a sub group of “drug naïve” patients with PD.
References:
1. Weintraub D, David AS, Evans AH, Grant JE, Stacy M. Clinical spectrum of impulse control disorders in
Parkinson's disease. Mov Disord. (2015);30:121-127
2. Carriere N, Lopes R, Defebvre L, Delmaire C, Dujardin K. Impaired corticostriatal connectivity in impulse control
disorders in Parkinson disease. Neurology (2015);84:2116-2123
3. Cilia R, Cho SS, van Eimeren T, Marotta G, Siri C, Ko JH, Pellecchia G, Pezzoli G, Antonini A, Strafella AP.
Pathological gambling in patients with Parkinson's disease is associated with fronto-striatal disconnection: a path
modeling analysis. Mov Disord. (2011);26:225-233
pag. 34
SALIVARY TOTAL AND OLIGOMERIC ALPHA-SYNUCLEIN IN PARKINSON’S DISEASE
G. Vivacqua, A. Latorre, A. Suppa, G. Fabbrini, A. Berardelli
Department of Neurology and Psychiatry, Sapienza University of Rome (Roma)
Aims: Previous studies have detected total a-syn (a-syntotal) in saliva of PD patients, however, no studies have previously
examined salivary oligomeric a-syn (a-synolig) or a-synolig / a-syntotal ratio in saliva. The aim of this study is to evaluate
salivary concentration of total and oligomeric a-syn in the saliva of patients with PD and sex and age matched healthy
subjects.
Materials: We measured a-syntotal and a-synolig concentration in 60 PD patients and 40 age- and sex-comparable healthy
subjects, using ELISA analysis with two specific ELISA kits: SensoLyte 55550 for a-syntotal and MyBioSource
MBS043824
for
a-synolig.
Methods: PD was diagnosed following the United Kingdom Brain Bank Criteria. Samples of saliva were collected
following the protocol reported in previous studies by Devic et al. (2014). Clinical evaluation of each patient was performed
using MDS-Unified Parkinson's Disease Rating Scale, Beck Depression Inventory, Montreal Cognitive Assessment and
Frontal Assessment Battery. ELISA analysis was performed for each patient and healthy subject and a standard curve based
on the optical density was used to calculate the concentration of both a-syntotal and a-synolig. The ratio: a-synolig / asyntotal was calculated in each patient and healthy subject. Statistical significance was evaluated by Mann-Whitney U test.
Correlations were evaluated by Spearman's Rank Correlation Coefficient.
Results: Salivary a-syntotal was lower (z = -7.98; p<0.01), whereas a-synolig was higher (z = -7.82; p<0.01) in PD patients
than healthy subjects. The a-synolig/a-syntotal ratio was also higher in patients than in healthy subjects (z = -8.30; p<0.01).
Salivary a-syntotal concentration negatively correlated with that of a-synolig (r = -0.25; p=0.05), positively correlated with
MDS-UPDRS (r = 0.25; p=0.05) and negatively correlated with MoCA (r = -0.27; p=0.04) and FAB (r = -0.25; p=0.05).
Discussion: In PD, decreased salivary concentration of a-syntotal may reflect the reduction of a-syn monomers (a-synmon),
leading to the formation of insoluble intracellular inclusions and soluble oligomers. It is also supported by the negative
correlation detected between a-syntotal and a-synolig. Correlations between a-syntotal and the clinical features of PD
patients, indicates that salivary a-syn increases, as disease progresses, probably due to an increased synaptic degeneration.
Conclusions: Our study suggests that measurement of a-syn in saliva might be a useful method for help the diagnosis of PD
especially in the early stages of the disease.
Reference:
− Devic I, Hwang H, Edgar JS, Izutsu K, Presland R, Pan C, et al. Salivary a-synuclein and DJ-1: potential
biomarkers for Parkinson’s disease. Brain (2010);134:1-5
CAFFEINE CONSUMPTION AND THE 4-YEAR PROGRESSION OF DE NOVO PARKINSON’S DISEASE
M. Moccia1, R. Erro2, M. Picillo2, C. Vitale3, M. Amboni4, K. Longo4, E. Spina1, R. Allocca1, R. Palladino5, M. Pellecchia2,
P. Barone2
1
Department of Neurosciences, Federico II University (Napoli); 2Center for Neurodegenerative Diseases, University of
Salerno (Salerno); 3Department of Motor Sciences, Parthenope University (Napoli); 4Neurology Clinic, IDC Hermitage
Capodimonte (Napoli); 5Department of Primary Care and Public Helath, Imperial College (London-UK)
Objectives: The use of caffeine has been associated with a reduced risk of developing PD, and with more benign motor and
non-motor outcomes. However, previous studies reported variable findings possibly because of the heterogeneity of PD
populations and of the methods assessing caffeine consumption. In view of this, the current longitudinal study investigated
motor and non-motor correlates of caffeine use in a population of de novo PD patients during a 4-year observation period.
Methods: 79 newly diagnosed, drug-naïve PD subjects were evaluated at the time of PD diagnosis, and after 2 and 4 years.
The total caffeine consumption was calculated with the Caffeine Consumption Questionnaire at baseline and, then, was
confirmed at follow-up visits. Motor disability, motor complications and non-motor symptoms (NMS) were evaluated at
baseline and after 2 and 4 years with the UPDRS part III, UPDRS part IV and NMS Questionnaire (NMSQuest),
respectively. The time occurring from PD diagnosis to the need for L-dopa treatment was recorded.
pag. 35
Results: At Cox regression model, higher caffeine consumption was associated with a lower rate of starting L-Dopa
treatment (HR=0.689; 95%CI=0.474-0.994). At the mixed-effects linear regression models considering the whole study
period, each additional espresso cup (50 mg of caffeine) was more likely associated with 5-point lower UPDRS part III total
score (Coef=-0.01; 95%CI=-0.02--0.00; p=0.013), and with 5-point lower NMSQuest total score (Coef=-0.01; 95%CI=0.01--0.00; p=0.008), but not with UPDRS part IV total score (Coef=-0.00; 95%CI=-0.00-0.00; p=0.587).
Conclusions: Present results highlight the impact of different sources of caffeine on the burden of PD symptoms, and
strengthen the rationale for investigating adenosine A2A antagonists as an early adjunctive therapy for PD patients, in order
to prevent motor and non-motor disability accrual.
References:
− Postuma RB, Lang AE, Munhoz RP, Charland K, Pelletier A, Moscovich M, et al. Caffeine for treatment of
Parkinson disease: a randomized controlled trial. Neurology (2012);79:651–8
− Schwarzschild MA. Caffeine in Parkinson disease: Better for cruise control than snooze patrol? Neurology
(2012);79:616–618
− Wills A-MA, Eberly S, Tennis M, Lang AE, Messing S, Togasaki D, et al. Caffeine consumption and risk of
dyskinesia in CALM-PD. Mov Disord. (2013);28:380–3
NEUROIMMUNOLOGIA E NEUROINFETTIVOLOGIA
NMDAR ENCEPHALITIS FOLLOWING HERPES VIRUS ENCEPHALITIS
M. Zoccarato1, M. Gennuso2, S. Ottaviani3, F. Sanson4, S. Sartori5, I. Toldo5, L. Zuliani6, B. Giometto7
1
Neurology Unit, O.S.A. Padua (Padova); 2Neurology Unit, Maggiore Hospital (Crema); 3Department of Neuroscience,
Azienda Ospedaliera Universitaria Integrata di Verona (Verona); 4Neurology Service, Santorso Hospital, (Santorso, VI);
5
Pediatric Neurology Unit, Department of Woman and Child Health, University Hospital of Padua (Padova); 6Department
of Neurology, Ospedale Ca' Foncello (Treviso); 7Department of Neurology, Azienda ULSS 9 Treviso (Padova)
Objective: To report on 4 patients developing N-methyl-D-Aspartate receptor (NMDAR) encephalitis following herpes
simplex-1 encephalitis (HSE) and to review available data from the literature about this emerging form of post-infectious
disease.
Methods:
Retrospective
description
of
4
patients.
Review
of
the
literature.
Results: Four patients (3 males and 1 female; age range 7 – 27 years) diagnosed with Herpes Simplex-1 virus encephalitis
were treated with acyclovir and their initial symptoms improved. After a period ranging from 4 to 6 weeks from HSE onset
they developed relapsing neurological symptoms. In particular they all manifested confusion and psychiatric symptoms
(ranging from anxiety to delirium and hallucinations). The paediatric case, a 7-year-old girl, also developed movement
disorders and epileptic manifestations consisting of non-convulsive status epilepticus. Patients were studied by brain MRI
showing increased T2-hyperintense signal in the temporal regions in the adults and the evolution of temporal lobe
inflammation to atrophy in the child. Cerebrospinal fluid (CSF) showed markedly decreased cell count from the first lumbar
puncture (performed at the time of HSE onset) to the puncture performed after re-admission (from a mean of 302 to 18
leucocytes per cubic millimetre). At this time molecular tests for HSV-1 and other neurotropic viruses were negative
whereas the cell-based assay for NMDAR abs tested positive on serum and CSF. In 2 patients with available specimens,
retrospective testing of the CSF sampled at HSE onset was negative for NMDAR abs. Patients were treated with
corticosteroids, combined in 3 cases with plasma-exchange and all clearly improved after treatment.
Discussion and conclusion: Since 2012 a growing number of patients developing NMDAR encephalitis following HSE have
been reported in both adult and paediatric contexts. Our cases confirm data from the literature and highlight that after HSE,
in the presence of relapsing neurological symptoms (often psychiatric manifestations), a decrease in CSF cell count and a
negative molecular test for HSV, the search for anti-NMDAR must be performed to establish the autoimmune mechanism
behind the symptoms and promptly treat patients with immunotherapy.
RITUXIMAB AND MONTHLY IVIG IN A PATIENT WITH ANTI-NMDAR ENCEPHALITIS: ONE YEAR
FOLLOW-UP
M. Garnero1, D. Franciotta2, L. Strada3, G. Novi1, C. Lapucci1, M. Grandis1, E. Capello1, M. Canevari4, G. Mancardi1, L.
Benedetti1
1
Department of Neuroscience, Rehabilitation, Ophthalmology, Genetics, Maternal and Child Health, University of Genoa
pag. 36
and IRCCS AOU San Martino-IST (Genova); 2Laboratory of Neuroimmunology, C. Mondino National Neurological
Institute (Pavia); 3Department of Neurology, Galliera Hospital (Genova); 4Department of Neuroradiology, University of
Genoa and IRCCS AOU San Martino-IST (Genova)
Background: Anti N-methyl-D-aspartate receptor (NMDAR) encephalitis is an autoimmune disorder. The clinical
presentation included hallucinations, short term memory loss, impaired consciousness, seizures, behavioural change
(frequently agitation) and motor disturbance. The first-line treatment includes corticosteroids, intravenous immunoglobulins
(IVIg) or plasma exchange. Second-line immunosuppression may be necessary.
Case report: We report the case of a young woman, with a history of opiate abuse and epilepsy in childhood. She was
admitted to the psychiatric unit for psychomotor agitation and visual hallucinations in October 2014; a pregnancy was
demonstrated. The condition was interpreted as psychogenic and the pregnancy aborted. Subsequently alteration of
consciousness, seizures and orofacial dyskinesias appeared. The electroencephalogram recorded diffuse slow activity and
the cerebrospinal fluid (CSF) examination showed normal proteins, normal cell count, and oligoclonal IgG bands (OCBs)
that were equal in serum and CSF (mirror pattern). Brain magnetic resonance imaging (MRI) disclosed areas of
hyperintense signal in T2 and FLAIR sequences in both mesial temporal regions, with contrast enhancement on the left side
impressive for a limbic encephalitis. A body CT and positron emission tomography (PET) excluded a paraneoplastic
pathogenesis, serum antibodies anti-NMDAR were detected. Treatment with intravenous steroid and IVIg was performed
and, for a refractory epilepsy, antiepileptic drugs (AEDs) were started. Despite the therapy, one month after, she was
intubated and admitted to intensive care unit (ICU) for hemodynamic instability and status epilepticus. Percutaneous
tracheostomy and gastrostomy were performed. According to Dalmau et al (Lancet Neurology 2011) treatment with
Rituximab, at the dosage of 375 mg/m2 every week for a month, was administered and then monthly IVIg cycles were
performed. After resolving the status epilepticus and when the haemodynamic conditions became stable the patient was
transferred to rehabilitation center. At that time the patient presented a state of stupor, did not communicate, did not perform
simple orders and even less it was possible to administer neuropsychological tests. The condition was complicated by a
flaccid tetraparesis due to a critical illness polyneuropathy. After one year from the Rituximab administration and montly
IVIg beginning, the patient was alert, responded to simple questions and performed simple orders. The neurological
examination showed normal strenght in upper limbs and an improvement of paraparesis in lower limbs. Furthermore it was
possible to perform neuropsychological tests that recorded pathological results on memory and naming tasks.
Conclusion: The second-line immunotherapy with Rituximab followed by chronic administration of IVIg can be effective in
these patients.
AUTOIMMUNE LIMBIC ENCEPHALITIS (ALE) ASSOCIATED TO LEUCINE-RICH GLIOMA
INACTIVATED-1 (LGI-1) ANTIBODIES. REPORT OF TWO PATIENTS WITH PECULIAR FINDINGS
D. Zaino1, S. Bartalini1, C. Cioni1, S. Casali1, G. Vatti1, A. Cerase2, S. Sestini3, C. Manfredi1, P. Annunziata1, F. Giannini1
1
Department of Medicine, Surgery and Neurosciences, University of Siena (Siena); 2Neuroimaging and Neurointervention,
“Santa Maria alle Scotte” General Hospital of Siena (Siena); 3Nuclear Medicine Unit, Hospital of Prato (Prato)
Background: LGI-1, a neuronal surface antigen, is a subunit of voltage-gated potassium channel (VGKC) complex, dealing
with synaptic transmission(1). VGKC-complex antibodies (Ab) are involved in limbic encephalitis, acquired neuromyotonia
(Isaacs’syndrome) and Morvan’s syndrome. LGI-1 Ab-associated ALE is a rare and severe neurological disorder with
subacute memory impairment, multiform seizures, behavioral alterations and hypothalamic dysfunction. CASE 1: A 91year-old woman was referred to our department for sudden onset of stupor and brisk, brief and frequent (mean=1/minute)
randomly side-alternating involuntary movements, involving hemibody, as shown in the video. This clinical pattern, termed
facio-brachial dystonic seizures (FBDS)(2), has been reported as rare but specific sign of ALE. Furthermore the patient
developed hyponatremia and bowel paresis. LGI-1 Ab were identified by indirect immunofluorescence test in serum and
CSF. EEG showed marked slowing, pseudoperiodic diffuse sharp waves and no correlation with above described
paroxysms. MRI, including DWI and ADC map, showed normal findings. She was treated with AEDs, intravenous
immunoglobulin and corticosteroids(3). Two months later, marked reduction of FBDS have been observed and the
awareness completely recovered. CASE 2. A 55-year-old man, suffered from uncontrolled type 2 diabetes, presented a
subacute-onset of short-term memory loss, psychiatric and behavioral symptoms (hyperphagia) and generalized tonic-clonic
seizures. LGI-1 Ab were revealed in serum and CSF. Onconeural, anti-GAD, anti-NMDA and anti-CASPR2 Abs were
negative. EEG showed significant slow and disorganized rhythm pattern, without epileptic discharges. CT body didn’t show
any tumor. Brain MRI, performed at symptoms onset, showed increased signal of left mesial temporal lobe on T2
weighted/FLAIR images, without gadolinium enhancement. 18F-FDG-PET/CT showed right mesial temporal lobe
hypermetabolism. Five months later, he was admitted to our department. 18F-FDG-PET/CT follow up evidenced right
pag. 37
mesial temporal lobe hypometabolism and left insular hypermetabolism, whereas brain MRI was unmodified. PlasmaExchange was performed, followed by corticosteroid therapy(3).One-month follow up evidenced significant improvement
of behavioral disturbances and mild recovery of memory functions.
Discussion: Significant correlation between early diagnosis, treatment and outcome has been demonstrated(1,2). LGI-1 Ab
finding allowed diagnosis in two different clinical features of ALE. Considering that LGI-1 Abs seem not associated to
underlying cancer(1,2), we might conclude for idiopathic autoimmune pathogenesis which represents a diagnostic challenge
in extreme elderly, such our patient 1. PET follow up in ALE is rarely reported, although we suggest to be useful to monitor
the disease and therapeutic effects. In case 2, modifications of PET findings are likely caused by transient functional
compensation within the limbic network.
References:
1. Gao L. et al, Clinical characterization of autoimmune LGI1 antibody limbic encephalitis. Epilepsy &Behaviour
(2016);56:165-169
2. Irani S. et al, Faciobrachial dystonic seizures: the influence of immunotherapy on seizure control and prevention of
cognitive impairment in a broadening phenotype. Brain (2013);136:3151-3162
3. Lancaster E., The Diagnosis and Treatment of Autoimmune Encephalitis. J. Clin. Neurol (2016); 12(1):1-13
PREVALENCE OF ANTI-NEUROFASCIN-155 AND ANTI-CONTACTIN-1 ANTIBODIES IN CHRONIC
INFLAMMATORY
DEMYELINATING
POLYRADICULONEUROPATHY:
A
SEROLOGICAL
MULTICENTER STUDY IN ITALY
I. Callegari1, A. Cortese1, G. Lauria2, C. Briani3, M. Luigetti4, R. Fazio5, L. Benedetti6, G. Marfia7, M. Clerici8, M. Carpo9,
M. Corbo10, A. Mazzeo11, E. Nobile-Orazio12, C. Manso13, A. Berardinelli14, E. Zardini15, S. Romagnolo15, P. Dacci2, R.
Lombardi2, M. Campagnolo3, G. Bisogni4, F. Cerri5, C. De Michelis6, G. Mataluni16, G. Cafasso8, C. Stancanelli11, A.
Schenone6, E. Marchioni1, J. Devaux13, D. Franciotta1
1
Neuroscience Consortium, University of Pavia, Monza Policlinico and Pavia Mondino (Monza, Pavia); 2Department of
Clinical Neurosciences, IRCCS Foundation (Milano); 3Department of Neurosciences, University of Padova (Padova);
4
Department of Geriatrics, Neurosciences and Orthopedics, Institute of Neurology, Catholic University of Sacred Heart
(Roma); 5Department of Neurology, San Raffaele Scientific Institute (Milano); 6Department of Neuroscience,
Rehabilitation, Ophthalmology, Genetics, Maternal and Child Health (DiNOGMI), University of Genova and IRCCS AOU
San Martino-IST (Genova); 7Department of Neuroscience, Rehabilitation, Ophtalmology, Genetics and Maternal/Child
Sciences, University of Rome Tor Vergata (Roma); 8Department of Neurology and Stroke Unit, Ospedale di
Circolo/Fondazione Macchi (Varese); 9Neurology Unit, Ospedale Treviglio (Bergamo); 10Department of
Neurorehabilitation Sciences, Casa Cura Policlinico (CCP) (Milano); 11Department of Neurosciences, University of Messina
(Messina); 12Department of Medical Biotechnology and Translational Medicine (BIOMETRA), University of Milan, 2nd
Neurology, Humanitas Clinical and Research Center (Rozzano-MI); 13CNRS, Aix-Marseille Université (Marseille-F);
14
Unit of Child Neurology and Psychiatry, C. Mondino National Institute of Neurology Foundation, IRCCS (Pavia);
15
Laboratory of Neuroimmunology, C. Mondino National Institute of Neurology Foundation, IRCCS (Pavia); 16Department
of Neuroscience, University of Rome Tor Vergata (Roma)
Background and Objective: Antibodies to neurofascin-155 (NF155) and contactin-1 (CNTN1) have been identified in 3-7%
of Japanese or Caucasian patients with chronic inflammatory demyelinating polyradiculoneuropathy (CIDP). However,
their prevalence in Italian CIDP patients is unknown. Moreover, there is no consensus on the gold standard technique for
these antibodies testing, among ELISA, cell-based assay (CBA), and immunohistochemistry (IHC) on mouse/rat teased
fibers.
We aimed to assess: 1) anti-NF155 and anti-CNTN1 antibody prevalence, and the associated clinical features in a series of
160 patients with CIDP; 2) diagnostic accuracy of the currently available techniques for such autoantibody testing.
Methods: Serum samples from 160 patients fulfilling the ENFS/PNS criteria for definite CIDP were tested. Sera from
patients with GBS, multiple sclerosis (MS), other peripheral neuropathies, and sera from healthy subjects were used as
controls.
Results: By ELISA, serum antibodies to NF155 were found in 6 (3.7%), and to CNTN1 in 2 (1.2%) CIDP patients, but in no
disease or healthy control. Anti-NF155 and anti-CNTN1 antibody-positive cases were confirmed by the respective CBAs,
and showed paranodal staining by IHC on mouse teased nerve fibers. Anti-NF155 Abs were predominantly IgG4 in 3
patients, IgG3 in 1, IgG1 in 1 and not determinable in 1 case. Anti-CNTN1 were of IgG4 subtype in 1 case. Clinical features
of the patients with anti-NF155 IgG4 were consistent with those previously reported in 2 cases, as they presented
predominant distal weakness, sensory ataxia, tremor, and IVIg resistance, while the third patient had GBS-like onset of
pag. 38
aggressive CIDP. Contrarily, the NF155 patient with predominant IgG1-3 subclass had milder clinical phenotype and
responded to IVIg. Both anti-CNTN1-seropositive patients showed subacute onset of severe motor-sensory ataxic
neuropathy, with poor response to IVIg and steroids. One of them showed good and persistent recovery after
cyclophosphamide,
which
was
paralleled
by
disappearance
of
anti-CNTN1
Abs.
Discussion: In conclusion, we observed a low prevalence of anti-NF155 and anti-CNTN1 antibodies in Italian CIDP
patients. However, prevalence of these antibodies raises to ∼20% if only IVIg-resistant cases are considered. This
notwithstanding, the determination of these antibodies, followed by characterization of IgG subclass in positive cases,
entails clear clinical benefit, by guiding therapeutic choices, and cost-saving effects, by preventing ineffective prolonged
IVIg treatments. ELISA proved reproducible, showed high specificity, and could be used for the screening of anti-NF155
and anti-CNTN1 antibody in routine diagnostics. Nevertheless, confirmatory tests by CBA, and IgG subclass determination
in specialized laboratory seem to be mandatory.
References:
− Querol L. et al., Neurofascin IgG4 antibodies in CIDP associate with disabling tremor and poor response to IVIg,
Neurology (2014);82:879-886
− Ogata H. et al., Characterization of IgG4 anti-neurofascin 155 antibody- positive polyneuropathy, Annals of
Clinical and Translational Neurology (2015);2(10):960-971
− Devaux J. et al., Neurofascin-155 IgG4 in chronic inflammatory demyelinating polyneuropathy, Neurology
(2016);86:800-807
IMMUNE-MEDIATED EPILEPSY AND INTRAVENOUS IMMUNOGLOBULIN THERAPHY: A CLINICAL
EXPERIENCE
M. Petruzzo1, S. Pontecorvo1, M. Morreale1, S. Cianfanelli1, E. Quartuccio1, M. Iacobini2, A. Francia1
1
Department of Neurology and Psychiatry, Sapienza University (Roma); 2Department of Paediatrics, Sapienza University
(Roma)
Objectives: To assess efficacy of use of intravenous immunoglobulin (IvIg) for drug-resistant epilepsy in children.
Materials: We describe course of three young consecutive outpatients affected by drug-resistant likely immune-mediated
epilepsy (age between 9-14 years old) with suspected immune-mediated etiology Both pediatricians and us as neurologists
take care of theese patients at Policlinico Umberto I at Rome. Methods: Patients underwent blood assessment (routine
analysis, inflammation parameters, neurological assessment and electroencefalografy at baseline and after 6 months .We
treated patients with intravenous human normal immunoglobulins at dosage of 0,8gr/kg /monthly for a total of six cycles per
each. With the exception of the patient n°1, no anticonvulsant theraphy was associated with IvIg. Data collected included
patient demographics , seizure frequency and epilepsy sydrome type, presumed etiology for the seizures. Response to IvIg
was defined “positive” if either seizure freedom or >= 50% reduction of seizure was achieved.
Results: All seizures are focal and focal with secondary generalization. Prior to the initiation of treatment with IvIg, seizure
frequency was 100 monthly crisis in patient n°1, 90 monthly crisis in patient n°2 and 35 monthly crisis in patient n°3.
Previously, all patients had taken more than three antiepileptic drugs without any benefit. Following treatment with IvIg ,
the following outcomes were noted: patient n°1 had a 81 % reduction of monthly frequency of crisis , patient n°2 had 58 %
reduction, patient n°3 had a 85 % reduction. All three patients had a positive clinical response to treatment from baseline. In
addition a psychocognitive improvement has been also registered in school environment and in relationships with peers.
IvIgs were well tollerated by all children and a good safety profile was observed as reported in literature.
Discussions: We registered a global reduction of seizure frequency after six monthly cycles of IvIg as reported in literature,
without showing phisical or cognitive side effects (considering age of development of our patients). Intravenous
immunoglobulin are able to reduce multiple seizure types in a variety of epilepsy etiologies, including those of unknown
cause. A good profile of tolerability and safety was observed as reported in literature.
Conclusions: Human normal immunoglobulin can be considered as a valid and safe therapeutical alternative in selected
cases of drug-resistent epilepsy in pediatric population when politherapy failed, above all where antiepileptic drugs can
negatively influence cognitive development.
References:
− Kwan P, Schacter SC, Brodie MJ. Drug-resistant epilepsy. N.Engl. J. Med. (2011);365(10):919-926
− Walker L1, Pirmohamed M, Marson AG. Immunomodulatory interventions for focal epilepsy syndromes.Cochrane
Database Syst Rev. (2013) Jun 27;(6):CD009945.
− Mikati MA, Kurdi R, EL-Khoury Z, Rahi A, Raad W.Intravenous immunoglobulin therapy in intractable childhood
epilepsy: Open-label study and review of the literature. Epilepsy&Behavior (2010);1:90-94
pag. 39
A MULTICENTER STUDY ON THE DIAGNOSTIC SIGNIFICANCE OF A SINGLE CEREBROSPINAL FLUID
IGG BAND
D. Ferraro1, A. Simone1, E. Cocco2, M. Santangelo3, P. Immovilli4, M. Calabrese5, M. Di Filippo6, R. Orlandi1, R. Bedin1,
F. Vitetta1, A. Gallina6, C. Solaro7, C. Gasperini8, M. Rodegher9, P. Sola1
1
Department of Neurosciences, University of Modena and Reggio Emilia (Modena); 2Department of Public Health, Clinical
and Molecular Medicine, University of Cagliari (Cagliari); 3Neurology Unit, Ramazzini Hospital (Carpi-MO); 4Neurology
Unit, Department of Specialistic Medicine, G. da Saliceto Hospital (Piacenza); 5Department of Neurological and Movement
Sciences, University Hospital of Verona (Verona); 6Neurology Unit, Medicine Department, University of Perugia (Perugia);
7
Neurology Unit, PA Micone Hospital (Genova); 8Neurology Unit, San Camillo Forlanini Hospital (Roma); 9Neurology
Unit, IRCSS Policlinico San Donato (Milano)
Introduction: The finding of a single cerebrospinal fluid (CSF) Immunoglobulin G (IgG) band is rare and only few studies
have explored its frequency and diagnostic significance. Our aim was to establish 1) the diagnoses associated with the
finding of a single CSF IgG band, 2) the proportion of patients with a single IgG band who will be diagnosed with Multiple
Sclerosis (MS) within the following 2 years and 3) whether there are differences in the CSF characteristics of patients
subsequently diagnosed with MS compared to those with alternative diagnoses, in a multicenter study.
Methods: We collected clinical and CSF data of patients who showed a single CSF-restricted IgG band, with or without an
associated “mirror pattern”, at CSF isoelectric focusing (IEF) analysis, carried out for any reason, from 2005 onwards.
Results: Out of 8156 CSF IEF analyses, 113 showed a single CSF IgG band (1.4%). In another cohort of 500 CSF analyses
carried out for suspected MS, only 2 showed a single CSF IgG band (0.4%). A definite diagnosis was established in 98
patients. MS was diagnosed in 26 (27%) patients, other central nervous system (CNS) demyelinating diseases in 20 (20%),
CNS infections in 7 (7%), inflammatory peripheral nervous system (PNS) diseases in 6 (6%), CNS
autoimmune/paraneoplastic diseases in 5 (5%), cerebral tumours in 3 (3%), and other diagnoses in 31 (32%), including
CNS/PNS degenerative diseases (6%), spondylomyelopathy (3%), idiopathic intracranial hypertension (2%), headache
(2%), Tolosa-Hunt syndrome, reversible cerebral vasoconstriction syndrome, hereditary spastic paraparesis, DYT1-positive
dystonia and cerebral venous thrombosis. Patients who acquired a diagnosis of MS were significantly younger (38±13
versus 46±18 years; p=0.03) than those with other diagnoses. There were no differences in CSF data (cell number and type,
proteins, Link’s Index, CSF/serum albumin ratio, presence of additional “mirror pattern”) between the two groups.
Discussion and Conclusion: MS was the single most frequent diagnosis in patients with a single CSF IgG band.
Nevertheless, the majority of patients with a single CSF IgG band have neurological diseases other than MS or CNS
demyelinating diseases, the most frequent being CNS infections, inflammatory PNS diseases, CNS
autoimmune/paraneoplastic diseases and cerebral tumours. Patients with a subsequent diagnosis of MS are significantly
younger than those with other neurological diseases.
HUMAN HYPOCRETIN RECEPTOR 2 ANTIBODIES ARE RARELY FOUND IN IDIOPATHIC NARCOLEPSY
M. P. Giannoccaro1, P. Waters2, F. Pizza3, R. Liguori4, G. Plazzi4, A. Vincent2
1
Department of Biomedical and NeuroMotor Sciences (DiBiNeM), Alma Mater Studiorum, University of Bologna
(Bologna); 2Nuffield Department of Clinical Neurosciences, Oxford University (Oxford-UK); 3IRCCS Institute of
Neurological Sciences of Bologna, Bellaria Hospital (Bologna); 4IRCCS Institute of Neurological Sciences of Bologna,
University of Bologna (Bologna)
Objectives: Narcolepsy (NC) is caused by loss of hypothalamic hypocretin-secreting cells, and has been proposed to be
autoimmune, although no clear evidence of autoimunnity has been provided to date. Recently NC has been recognized more
commonly in children following H1N1 vaccination with Pandemrix. In 2015 Ahmed et al. [1] proposed a cross-reactivity
between H1N1 influenza virus and the hypocretin receptor 2 (HCRTR2), and identified HCRTR2 autoantibodies in 85% of
post-vaccination NC patients using a cell based ELISA (CBE). We established a cell-based assay (CBA) to test a group of
idiopathic NC patients for this antibody.
Methods: We studied 61 patients (41 adults, 20 children), including 50 narcolepsy type 1 (NT1, narcolepsy with cataplexy)
and 11 type 2 (NT2, without cataplexy), 22 patients with other sleep disorders and 11 healthy controls. Human embryonic
kidney cells were transiently transfected with a HCRTR2 construct. 36 hours post-transfection, live cells were incubated
with patients’ sera for 1 hour at 1:20 dilution, then fixed and incubated with secondary anti-human IgG (H + L chain or anti
Fc). For some sera, antibodies against the four IgG subclasses were used as secondary antibodies. A semi-quantitative
pag. 40
scoring system was used from 0 to 4 as in previous publications; samples scoring ≥ 1 were considered positive.
Results: Only 3/61 NC (5%) showed a score ≥ 1; anti-IgG Fc confirmed that the antibody was IgG. Anti-subclass identified
IgG3 in two patients and IgG1 and IgG2 in one. Sera from five additional narcolepsy patients and one patient with
idiopathic hypersomnia scored 0.5. Positive patients included one NT1 patient with associated psychotic features, one NT2
patient and a patient with cataplexy but normal Hcrt CSF levels.
Discussion: Compared with previous findings [1], there were only a few NC patients with HCRTR2 antibodies. The
difference may be related to the test used (CBE vs live CBA) or to the population included (post-vaccine vs idiopathic NC).
Interestingly, one patient presented a peculiar phenotype with cataplexy and normal levels of Hypocretin-1 in the CSF.
Conclusions: Antibodies against HCRTR2 are rare in patients with idiopathic narcolepsy, they have been detected in
patients with widely heterogeneous phenotypes and their significance is unclear.
Reference:
− Ahmed SS, Volkmuth W, Duca J, Corti L, Pallaoro M, Pezzicoli A, Karle A, Rigat F, Rappuoli R, Narasimhan V,
Julkunen I, Vuorela A, Vaarala O, Nohynek H, Pasini FL, Montomoli E, Trombetta C, Adams CM, Rothbard J,
Steinman L. Antibodies to influenza nucleoprotein cross-react with human hypocretin receptor 2. Sci Transl Med.
(2015);7(294):294ra105
SARCOIDOSIS OF THE SPINAL CORD: CLINICAL AND RADIOLOGICAL CHARACTERISTICS
G. Dalla Costa1, L. Sarro1, D. De Feo1, F. Sangalli1, B. Colombo1, L. Moiola1, N. Anzalone2, A. Falini2, G. Comi1, V.
Martinelli1
1
Department of Neurology, San Raffaele Hospital (Milano); 2Department of Neuroradiology, San Raffaele Hospital
(Milano)
Background Sarcoidosis of the spinal cord is a rare disease and its differential diagnosis is challeging as it often mimics
other inflammatory demyelinating syndromes both clinically and on neuroimaging results.
Methods: This is a case series on four patients presenting with a spinal cord syndrome ultimately confirmed as sarcoidosis at
histopathological examination. The aim of this study is to describe the typical features of spinal cord sarcoidosis.
Results: Four patients (mean age 50 years) have been followed-up over a median of 12 months after the onset of an isolated
myelitis. Two patients were females and two were males, and all of them had an unremarkable previous medical history. All
patients presented with sensory symptoms at the limbs, while two of them had motor deficit associated. Both the cervical
and dorsal tracts of the spinal cord were involved in three patients, while one patient presented with an extensive
involvement of the dorsal tract alone. The cerebrospinal fluid (CSF) showed elevated protein level (median 70 mg/dl) and
elevated white cell count (median 45/mm(3). Oligoclonal bands were present in two patients. Thoracic lymphnodes
enlargement, detected at CT and/or at PET examinations, not at clinical onset, but after repeated evaluations during the
follow up, eventually lead to the histopathologic confirmation of granuloma formations with lymphocytic infiltrates typical
of sarcoidosis in all cases. Of prominence, all patients presented with an initial linear leptomeningeal pattern of
enhancement and after each relapse of the disease progressive parenchymal involvement was observed. The patients
experienced clinical improvement with corticosteroids and/or immunosuppressive treatment.
Conclusions: Symptoms due to intramedullary cervical lesions can be the first manifestation of neurosarcoidosis. The
clinical course and neuroradiologic findings can mimic lynphoproliferative and demyelinating diseases. In neurosarcoisosis
the spread of the typical leptomeningeal inflammatory process to the Virchow-Robin spaces is believed to result in
parenchymal involvement, causing the centripetal involvement of the spinal cord at longitudinal assessments.
SCLEROSI MULTIPLA 1
BODY MASS INDEX AND SLOW TITRATION ARE PROTECTIVE FACTORS FOR DIMETHYL FUMARATE
GASTROINTESTINAL EVENTS IN A RELAPSING REMITTING MULTIPLE SCLEROSIS CLINICAL
SETTING
D. Paolicelli, A. Manni, A. Iaffaldano, V. Di Lecce, C. Tortorella, S. Zoccolella, M. Messina, P. Iaffaldano, R. Cortese, M.
Trojano
Department of Basic Medical Sciences, Neuroscience and Sense Organs, University of Bari Aldo Moro (Bari)
Background: The short-term safety profile for dimethyl fumarate (DMF) in the phase 3 trials was highly favorable and longpag. 41
term data from ENDORSE study confirmed a good benefit/risk ratio. However, the most frequent adverse events (AEs) in
patients receiving DMF include flushing, gastrointestinal (GI) events and a certain incidence of leukopenia and
lymphopenia.
Objective: We tried to correlate demographic and anthropometric measures to the most common safety and tolerability
issues in a cohort of 111 Relapsing Remitting Multiple Sclerosis (RRMS) patients treated with oral DMF 120 mg BID for 7
days (standard titration) or for 2-4 weeks (slower titration), and then increased to 240 mg BID.
Methods: At the time of DMF first prescription, anthropometric measures were performed. Lymphocyte and leukocyte
counts at baseline (T0) and after 3 (T3), 6 (T6) and 12 months (T12) of therapy were assessed by flow cytometry method.
Any AEs were reported immediately upon the occurrence or during the scheduled follow-up.
Results: The observation period was 10.3±5 months; 62% of subjects were female. The mean age at DMF beginning was
39.5 ± 11 years. The mean Body Mass Index (BMI) was 23.6±4.38. Seven patients interrupted the drug for AEs, one more
patient for lack of efficacy. Among our patients 45% experienced GI side effects and 68% flushing. The multivariate
analysis showed that a lower BMI (p<0.006) and a younger age at DMF (p=0.049) were related with a higher incidence of
GI events, especially nausea/vomiting. A slower titration did not influenced AEs, but among patients with standard titration,
a higher BMI was a protective factor for GI events (p= 0.003). In our setting 44% of patients experienced lymphopenia.
Compared with the T0 values, we observed a statistically significant reduction of 16% in total lymphocytes at T3
(1915±588 vs. 1656±960; p=0.009), and a further reduction was observed also from T3 to T6 (p=0.009), and remained
stable thereafter. T0 values of lymphocytes were related to the occurrence of lymphopenia (p=0.047).
Conclusion: Considering the safety profile of DMF, clinicians should evaluate demographic and anthropometric
characteristics of MS patients; furthermore, in patients with a lower BMI, a slower titration may be considered effective in
reducing GI symptoms. Further studies in larger cohorts will be necessary to confirm these findings.
References:
− Gold R, Kappos L, Arnold DL et al. Placebo-controlled phase 3 study of oral BG- 12 for relapsing multiple
sclerosis. N Engl J Med. (2012);367:1098–1107
− Pozzilli C, Philipps JT, Fox RJ et al. Long-term follow-up of the safety of delayed-release dimethyl fumarate in
RRMS: Interim results from the ENDORSE extension study. MSJ. (2014);20(S1):67–284
− Phillips JT, Erwin AA, Agrella S et al. Consensus Management of Gastrointestinal Events Associated with
Delayed-Release Dimethyl Fumarate: A Delphi Study. Neurol Ther. (2015);4:137–146
PRESENTATION OF THE ITALIAN NATALIZUMAB RELATED PML DATASET: DISEASE COURSE AND
OUTCOME OF 41 PATIENTS
N. De Rossi, C. Scarpazza, S. Rasia, C. Cordioli, R. Capra, N. on behalf of the Italian PML group
CSM Montichiari, Spedali Civili of Brescia (Brescia)
Aims: In order to analyze the Natalizumab-related Progressive Multifocal Leukoencephalopathy (PML) in Multiple
Sclerosis, a database collecting the clinical and radiological data of the Italian PML patients has been created.
Material: Up to April 2016, 44 PML Italian cases have been communicated to the pharmacovigilance of Biogen and 41
were shared in the Italian database. Clinical and neuroradiological data were collected by the site of Montichiari in
collaboration with 33 Italian sites.
Methods: Two neurologists and two neuroradiologists analyzed the data independently and the data were discussed in
parallel in eight meetings, with the aim to assess the detailed PML course in each patients, focusing on the clinical and MRI
findings. In the last two years, two national meetings have been organized in order to share the results of this collaborative
consortium.
Results: For all patients 71 clinical variables and a mean number of 5 MRI (221 in total) were collected; EDSS and
Karnofsky were available at PML onset and at 2 - 6 - 12 months of follow up. CSF JCv copies were detected at the first
spinal tap in 35 patients (5 pts were positive at a second tap and one patient was always negative). Thirty-four patients have
at least 1 year follow up; 3 and 4 patients have respectively 6 and 2 months of follow up. Twenty-nine patients developed
the immune reconstitution inflammatory syndrome (IRIS) at 83.3 days (mean) after NTZ withdrawal. Plasma exchange
(PLEX) do not have any impact on disability, but it anticipated IRIS (73.6±29.5 and 92.5±19.0 days from NTZ withdrawal
in PLEXyes and PLEXno respectively, p=0.04) and increased IRIS duration (110.7±73.0 and 59.5±33.2, p=0.04). Patients
were divided on the steroids use, administered independently (ExtSt) or during (DISt) the established IRIS. The EDSS
increases between PML onset and at the one year follow-up were respectively 1.3, and 0.2 in the ExtSt and DIst groups.
Discussion: The Italian dataset analysis confirm the negative prognostic value of the CSF JCv viral load. The absence of
viral copies does not exclude a clinical and radiological PML suspect and natalizumab must however be stopped. The
usefulness of PLEX is still not confirmed. Steroid therapy should be used only during established IRIS, preventing the
pag. 42
negative impact on the virus specific T cell response.
REAL-LIFE SAFETY, TOLERABILITY AND EFFICACY OF DIMETHYL FUMARATE: A MULTICENTRE
STUDY
G. Mallucci1, P. Annovazzi2, A. Favaretto3, V. Torri-Clerici4, M. Matta5, S. La Gioia6, V. D'Ambrosio1, M. Zaffaroni2, A.
Ghezzi2, P. Perini3, S. Rossi4, A. Bertolotto5, M. Rottoli6, M. Rovaris7, C. Montomoli8, R. Bergamaschi1
1
Inter-Department Multiple Sclerosis Research Centre, Neurological Institute IRCCS Mondino (Pavia); 2Multiple Sclerosis
Study Centre, ASST Valle Olona (Gallarate-VA); 3Department of Neurosciences, The Multiple Sclerosis Centre, University
Hospital of Padova –(Padova); 4Unit of Neuroimmunology, and Neuromuscular Diseases, Foundation IRCCS Neurological
Institute C. Besta (Milano); 5Regional Multiple Sclerosis Centre, San Luigi Gonzaga Hospital (Orbassano -TO);
6
Department of Neurology, Papa Giovanni XXIII Hospital (Bergamo); 7Multiple Sclerosis Center, Scientific Institute Santa
Maria Nascente, Don Carlo Gnocchi Foundation (Milano); 8Unit of Biostatistics and Clinical Epidemiology, Department of
Public Health, University of Pavia (Pavia)
Objectives: Aim of this study is to evaluate in a real world setting Dimethyl fumarate (DMF) safety, tolerability and
efficacy profile in multiple sclerosis (MS) treatment, and to identify predictors of DMF discontinuation.
Materials and methods: We enrolled all patients receiving DMF in seven northern Italy MS centres. Patients were
prospectively followed, collecting demographic and clinical data as well as laboratory assessment.
Results: We included 499 patients (66.7% F; mean age: 37.9+10.1 years; mean disease duration: 9.2+8.4years). Mean
annual relapse rate (ARR) in the two years before DMF was 0.72+0.8, median baseline EDSS was 1.5 (range 0-6.5) and
mean MSSS was 3.05+2.06. One hundred sixty five patients (33.1%) were treatment naïve or quitted disease modifying
drugs (DMDs) more than 12 months before DMF start. Two hundred and seventy-six (55.3%) switched to DMF from first
line DMDs (89.1% of whom from injectables and 10.1% from orals) due to loss of tolerability (55.4%) or inefficacy
(44.6%). Fifty-eight patients (11.6%) switched to DMF from second line DMDs due to safety reasons. The overall median
DMF treatment follow-up was 11 (1-26) months, 287 patients (57.5%) had at least 12 months of follow-up. Most frequent
adverse events (AEs) were flushing/pruritus (39.5%), gastrointestinal side effects (25.5%), and fatigue (1.8%). Four severe
AEs were reported (1 breast neoplasia, 2 lung neoplasia, and 1 uterine neoplasia). Most frequent laboratory testing
abnormality was lymphopenia (8.6%, none severe). Among patients completing one year of follow-up, 78.6% were relapse
free. Median time to first relapse was 109.5 days (range 6-623) and patients the first relapse occurred during the first
trimester in 27 (45%). The overall mean ARR significantly reduced compared to baseline (0.72+0.8 vs 0.21+0.5
p<0.0001);a lower baseline ARR was a predictor of relapse free status (HR 0.7; 95% CI: 0.6-0.9; p=0.006). Seventy-three
patients (14.6%) stopped DMF after a mean of 144+128 days; causes of stop were AEs (74.0%), disease activity (20.7%)
and pregnancy planning (5.1%). AEs were more frequent in patients that withdrew DMF treatment, compared to those
patients that continued it (OR 3.752, 95% CI 2.0-6.7, p<0.0001). In particular, gastrointestinal side effects were predictor of
DMF discontinuation (HR 0.4 95% CI: 0.3-0.7; p=0.03).
Discussion and conclusion: Despite the limitation of an open label study, our large observational data confirm the good
tolerability and safety of DMF. Moreover, a positive clinical effect (ARR decrease) was achieved, although in a short
treatment period.
ALEMTUZUMAB DURABLY SLOWS BRAIN VOLUME LOSS OVER 6 YEARS IN THE ABSENCE OF
CONTINUOUS TREATMENT IN PATIENTS WITH ACTIVE RRMS WHO WERE TREATMENT-NAIVE
(CARE-MS I) OR HAD AN INADEQUATE RESPONSE TO PRIOR THERAPY (CARE-MS II)
G. Comi1, A. Traboulsee2, M. Barnett3, C. LaGanke4, A. Rovira5, S. Schippling6, D. Margolin7, K. Thangavelu8, K.
Nakamura9, D. Arnold10
1
Department of Neurology, San Raffaele Scientific Institute, Vita-Salute San Raffaele University (Milano); 2Department of
Medicine, University of British Columbia (Vancouver-CDN); 3Brain and Mind Research Institute, University of Sydney
(Sydney-AUS); 4NA - North Central Neurology Associates (Cullman-USA); 5Department of Radiology, Vall d'Hebron
University Hospital (Barcelona-E); 6Neuroimmunology and Multiple Sclerosis Research, University Hospital Zurich and
University of Zurich (Zurich-CH); 7Medical Affairs, Sanofi Genzyme (Cambridge-USA); 8Biostatistics, Sanofi Genzyme
(Cambridge-USA); 9Department of Biomedical Engineering, Cleveland Clinic (Cleveland-USA); 10Department of
Neurology and Neurosurgery, Montreal Neurological Institute, McGill University (Montreal-CND)
pag. 43
Aims: Brain volume loss (BVL), a measure of brain atrophy, occurs early in the relapsing-remitting multiple sclerosis
(RRMS) disease course. Patients with active RRMS who were treatment-naive (CARE-MS I; NCT00530348) or had an
inadequate response (>/=1 relapse) to prior therapy at baseline (CARE-MS II; NCT00548405) demonstrated greater
improvements in relapse rate and various MRI outcomes with alemtuzumab versus subcutaneous interferon beta-1a (SC
IFNB-1a) over 2 years. In addition to the superior impact of alemtuzumab on reducing lesion activity vs SC IFNB-1a, MRI
efficacy outcomes also included significant slowing of BVL. An extension study (NCT00930553) showed durable efficacy
of alemtuzumab through 6 years in the absence of continuous treatment. Here we evaluate the effect of alemtuzumab on
BVL
over
6
years.
Materials: MRI scans were obtained at baseline and annually thereafter. BVL was derived by relative change in brain
parenchymal fraction.
Methods: In the CARE-MS studies, patients received 2 alemtuzumab 12 mg/day courses (5 consecutive days at baseline and
3 consecutive days 12 months later). Patients completing the studies could enter the extension, with as-needed alemtuzumab
for relapse or MRI activity. Alternate disease-modifying therapy (DMT) could be provided per investigator discretion.
Results: 349 (95%) CARE-MS I and 393 (93%) CARE-MS II alemtuzumab-treated patients entered the extension. Through
6 years, 325/349 (93%) CARE-MS I and 344/393 (88%) CARE-MS II patients remained on study. In CARE-MS I patients,
alemtuzumab slowed median yearly BVL over 2 years compared with SC IFNB-1a, and BVL remained low in Years 3-6
(Year 1: -0.59%, Year 2: -0.25%, Year 3: -0.19%, Year 4: -0.14%, Year 5: -0.20%, Year 6: -0.17%). In CARE-MS II
patients, median yearly BVL significantly decreased over 2 years compared with SC IFNB-1a, and remained low in Years
3-6 (Year 1: -0.48%, Year 2: -0.22%, Year 3: -0.10%, Year 4: -0.19%, Year 5: -0.07%, Year 6: -0.10%). These effects were
achieved with 63% (CARE-MS I) and 50% (CARE-MS II) of patients receiving no alemtuzumab retreatment after the
initial 2 alemtuzumab courses and no other DMT through Year 6.
Discussion: Slowing of BVL with alemtuzumab was maintained over 6 years. Median annual BVL was /=50% of patients
receiving
no
additional
treatment
since
the
initial
2
alemtuzumab
courses.
CONCLUSION: Based on these findings, alemtuzumab may provide uniquely durable efficacy in the absence of continuous
treatment for RRMS patients.
Study Support: Sanofi Genzyme and Bayer HealthCare Pharmaceuticals.
Aspects of the work described in this abstract were submitted at the 32nd Congress of the European Committee for
Treatment and Research in Multiple Sclerosis (ECTRIMS), September 14-17, 2016, London, United Kingdom. The authors
would like to acknowledge Dr Daniel Pelletier for his interpretation of the data and for his critical review of the abstract
content.
CEFALEE 1
FEATURES OF MIGRAINE WITH AURA IN PEDIATRIC AGE
M. Balestri1, D. Maiorani2, A. Capuano1, S. Tarantino1, R. Frusciante1, L. Papetti1, F. Vigevano1, M. Valeriani1
1
Headache Center, Neurology, Bambino Gesù Hospital (Roma);
2
Pediatric Unit, Hospital of Viterbo (Viterbo)
Objective: Though common in pediatric age, migraine with aura (MA) has been scarcely studied in children. Our aims were
to investigate: 1) the clinical characteristics of the aura in a cohort of MA children, and 2) the features of the headache
associated
with
the
aura.
Methods: The present study was based on data retrospectively collected from 164 MA children referred to our 3rd level
Headache Centre.
Results: In our patients, the visual symptoms were far more frequent (93%) than the somatosensory, motor, and speech
disturbances. The aura anticipated the headache onset in most cases (69.1%) and its duration ranged from 5 to 60 minutes.
When we divided our patients in 4 different age groups (less than 7 years, between 7 and 10 years, between 11 and 14 years,
more than 14 years), no difference in the aura characteristics was found between the groups. On the other hand, when the
headache type was classified according to the ICHD-IIIb criteria, migraine was diagnosed only in 40.2% of patients and the
diagnosis remained undetermined in 4.3% of MA children. However, if headache duration was not considered, the
migraineurs raised to 67% of patients and in no child the diagnosis was undetermined.
pag. 44
Discussion: Our pediatric population showed aura features that did not depend on the age and were similar to those of adult
patients. However, the headache could be difficult to be classified if headache duration was considered.
Conclusions: ICHD-IIIb criteria for aura are suitable also for children and adolescents.
FACTORS ASSOCIATED TO FREQUENT RELAPSE INTO MEDICATION OVERUSE IN CHRONIC
MIGRAINE PATIENTS: A 3-YEAR RETROSPECTIVE EVALUATION
L. Grazzi, A. Raggi
Neurology Public Health and Disability Unit, IRCCS Foundation Neurological Institute C. Besta (Milano)
Introduction: Chronic migraine (CM) is a negative evolution of migraine course characterized by headaches occurring 15 or
more days per month. It is often cause of medication overuse (MO). The treatment of CM with MO requires withdrawal of
overused drugs, prescription of individualized prophylaxis, and advice and education to prevent relapse into MO. A
subgroup of patients can be considered as “frequent relapsers” (FR), requiring two or more structured withdrawals over
three years. There are relatively few studies that specifically addressed the possible predictors of relapse.
Aim: To characterize FR patients in terms of disease features and associated psychosocial aspects.
Methods: A sample of 194 adult patients with CM-MO according to Silberstein’s criteria attending our Headache Center to
perform a withdrawal treatment were consecutively recruited between June 2011 and December 2012. They completed
standardized clinical interview which included previous withdrawal treatments, living situation, employment, as well as
questionnaires measuring disability (WHODAS 2.0), headaches frequency, depressive symptomatology (BDI-II). FR
patients were defined as those with at least one structured withdrawals in the three years before the current hospitalization.
Baseline differences between FR and non-FR were assessed using Chi-Squared and Student’s t-test.
Results: Complete information was available for 188 patients; 58 were considered as FR (30.8%). The mean number of
days with headache in 3 months was 63.9 in FR and 55.1 in non FR patients (P=.010); mean BDI-II score was 19.4 and 15.3
(P=.005); WHODAS 2.0 score was 34.8 and 29.1 (P=.005), respectively. Furthermore, 22% of FR and 10% of non-FR were
living alone (P=.023), and 48.3% of FR and 65.4% of non-FR had low education (P=.027). No differences were found for
gender, employment status, age, overuse of triptans vs. NSAIDS.
Discussion: In this retrospective study we found that several aspects related either to the clinical presentation of headache or
to psychosocial domains were significantly more common in those who undergo repeated withdrawal treatments, i.e. FR,
namely: higher frequency of headaches, living alone, having a lower education, higher disability scores, and higher
depression scores. Our data may contribute to the management of CM with MO and will be useful to guide future
prospective studies.
COGNITIVE DYSFUNCTIONS AND PSYCHOLOGICAL SYMPTOMS IN MIGRAINE WITHOUT AURA: A
CROSS-SECTIONAL STUDY
A. De Mase1, A. Russo2, G. Santangelo3, L. Trojano3, F. Falco3, L. Marcuccio2, M. Siciliano3, F. Conte2, F. Garramone3, A.
Tessitore2, G. Tedeschi2
1
Headache Center, Department of Medical, Surgical, Neurological, Metabolic and Aging Sciences, Second University of
Naples (Napoli); 3Department of Psychology, Second University of Naples (Caserta)
2
Objective: The aim of the study was to characterize the cognitive profile and psychological symptoms (i.e. depression,
anxiety and apathy) in drug-naïve migraine without aura (MwoA) patients.
Background: The occurrence of cognitive dysfunctions and psychological symptoms, as well as their mutual relationships,
in migraine patients are still debated.
Methods: Seventy-two consecutive MwoA patients, referred to the Italian University Headache Clinic and 72 healthy
subjects (HCs) were enrolled. Patients, during an attack-free period, and HCs completed Montreal Cognitive Assessment
(MoCA), Beck Depression Inventory-II (BDI-II), Selfversion of Apathy Evaluation Scale (AES-S) and State and Trait
Anxiety Inventory (STAI-Y-1 and 2). Clinical parameters of disease severity (i.e. disease duration, migraine attacks per
month, mean pain intensity during migraine attacks, migraine disability and impact on daily life) were recorded.
Results: Although performance of MwoA patients on MoCA was above Italian cut-off threshold (<15.5) suggesting
presence of cognitive impairment, MwoA patients achieved significantly lower scores than HCs on total MoCA scale (22.3
± 2.7 versus 25.4 ± 2.3) and on its attention (4.9 ± 1.1 versus 5.6 ± 0.7), memory (1.8 ± 1.4 versus 3.1 ± 1.3), visuospatial
pag. 45
(3.2 ± 0.9 versus 3.6 ± 0.6) and executive subscales (2.6 ± 1.1 versus 3.1 ± 0.8). In addition, we observed significant
correlations between MoCA executive domain subscore and the attack-related disability score (MIDAS). As for behavioral
profile, the percentage of depressive symptoms (4.2%), high state and trait anxiety (13.9% and 9.7%, respectively), and
apathy (11.1%) in MwoA patients were similar to that of HCs. No significant associations of behavioural symptoms with
cognitive performance and clinical parameters were found.
Conclusion: Drug-naïve MwoA patients are characterized by subtle cognitive dysfunctions and low percentage of
behavioural symptoms. The results support the importance of searching for subclinical cognitive disturbances in patients
with MwoA, who deserve to be followed-up to verify whether they develop clinically relevant disorders over time.
References:
− Lipton RB, Bigal ME. Migraine: epidemiology, impact, and risk factors for progression. Headache (2005); 45
(Suppl 1): S3-S13
− Burch RC, Loder S, Loder E, Smitherman TA. The prevalence and burden of migraine and severe headache in the
United States: updated statistics from government health surveillance studies. Headache (2015);55(1):21-34
− Rist PM, Kurth T. Migraine and cognitive decline: a topical review. Headache (2013); 53(4): 589-598
ANODAL TRANSCRANIAL DIRECT CURRENT STIMULATION (TDCS) OVER THE LEFT TEMPORAL
POLE RESTORES NORMAL VISUAL EVOKED POTENTIAL HABITUATION IN MIGRAINE BETWEEN
ATTACKS
F. Cortese1, I. Bove1, G. Coppola2, F. Pierelli1
1
Department of Medico-Surgical Sciences and Biotechnologies-ICOT, Sapienza University of Rome (Latina); 2Department
of Neurophysiology of Vision and Neurophthalmology, G. B. Bietti Foundation-IRCCS (Roma)
Objectives: In a resonace-based morphometry study in migraine patients, we have previously shown reduced grey matter
density of left temporal pole (TP) in between Attacks (Coppola et al, 2015). TP seems to be involved in integrative
multisensory processing. Whether dysfunction of this brain area may contribute to the interictal migraineur general
impairment in short and long term synaptic plasticity leading to deficient habituation to sensory stimuli is not known. Here,
we aim to verify whether a non-invasive increase of TP excitability by means of anodal transcranial direct current
stimulation (tDCS) may change the interictal abnormal multimodal sensory processing in migraine. Materials and Methods:
Twelve interictal migraineurs underwent visual (VEPs, 600 sweeps, 3.1Hz reversal rate, 15 min of arc check) and median
nerve somatosensory (SSEPs, 200 sweeps, 4.4Hz) evoked potentials before and immediately after 20-minute anodal tDCS
delivered over the left TP (2 mA, cathode placed on the right arm). We measured VEPs N1-P1 and SSEPs N20-P25
amplitudes respectively in 6 and in 2 sequential blocks of 100 sweeps as well as habituation as the slope of the linear
regression between block 1 to 6 for VEPs or between 1 to 2 for SSEPs.
Results: Before tDCS, migraine patients lacked habituation in response to both visual (+0.13) and somatosensory (+0.59)
repetitive stimulations. Anodal tDCS reverted to normal the interictally reduced VEPs habituation (-0.22, p=0.01), while left
lack of SSEP habituation unchanged (+0.17). Discussion: Our study shows for the first time that excitability enhancer
anodal tDCS over the TP could significantly normalize the interictal abnormal visual information processing in migraine,
and that this was not so for the somatosensory modality. This distinctive cortical finding in response to tDCS could be
related to the fact that the temporal pole belongs to the so-called ventral stream of the visual pathway.
Conclusions: It would be of particular interest to verify whether repeated daily sessions of tDCS over the TP could be used
as a prophylactic therapeutic intervention in migraine.
Reference:
− Coppola G, Di Renzo A, Tinelli E, Iacovelli E, Lepre C, Di Lorenzo C, Di Lorenzo G, Di Lenola D, Parisi V,
Serrao M, Pauri F, Fiermonte G, Bianco F, Pierelli F. Evidence for brain morphometric changes during the
migraine cycle: a magnetic resonance-based morphometry study. Cephalalgia (2015) Aug;35(9):783-91
SUBCLINICAL DYSFUNCTION OF THE VESTIBULAR SYSTEM IN MIGRAINE PATIENTS WITHOUT
HISTORY OF VERTIGO
L. Bernetti1, I. Corbelli1, C. Pellegrino2, A. Verzina1, P. Eusebi1, M. Faralli2, G. Ricci2, P. Sarchielli1, P. Calabresi1
1
Neurologic Clinic, Headache Centre, Department of Medicine, University of Perugia (Perugia); 2Otolaryngology and HeadNeck
Surgery
Clinic,
Department
of
Medicine,
University
of
Perugia
(Perugia)
pag. 46
Introduction and objectives: The association of migraine with vertigo and balance disorders is well recognized. Migraine is
more common in patients with vertigo than in those without and vertigo is more common in patients with migraine than in
those without [1].This suggests a central and peripheral shared origin of migraine and vertigo. The purpose of our study was
to investigate the presence of a potential subclinical dysfunction of the vestibular system in migraine patients without a
history of vertigo and dizziness compared with healthy control subjects.
Methods: According to ICHD-III beta criteria [2],episodic migraine with (MwA) and without aura patients (MwoA) were
enrolled in our Headache Center. Exclusion criteria were serious concomitant disease, symptomatic headaches, vestibular
and psychiatric diseases. Healthy control subjects (HC) were recruited from the healthy staff working at the hospital. All the
patients and the controls were subjected to a global vestibular examination with the following conventional tests: Sitting
Position, Pagnini –Mc Clure’s Test, Dix-Hallpike’s Test, Head Hanging test, Head Impulse Test, Subjective Visual Vertical,
Romberg Test, Fukuda Test and Caloric Vestibular Stimulation(CVS). The latter was performed by Fitzgerald-Hallpike’s
Test: each ear was irrigated into the external ear canal by hot water at 44°C for 45 seconds and there was a 5 minutes pause
between left and right ear. The induced nistagmus was analysed by video-nystagmography (VNG): the main parameter took
into consideration was the angular velocity of the slow phase during culmination phase (from 60s to 90s since the beginning
of the stimulation).
Results: A total of 33 migraine patients (76% female, 7 MwA e 26 MwoA) and 12 HC (33% female) were consecutively
enrolled. No statistically significant differences between patients and HC in demographical features. Each vestibular test
results were normal, except for CVS: right and left Angular Velocity (rAV, lAV) were highly correlated (r=0.88, p<0.001).
Right AV was higher in MwA (+13.7 95% CI = 5.2-22.1) and MwoA (+7.7 95% CI = 1.5-13.9) as compared to controls.
Left AV was higher in MwA (+12.0 95% CI = 4.6-19.5) and MwoA (+10.8 95% CI = 5.3-16.3) as compared to controls. No
significant differences were observed in terms of the differential of angular velocity between left and right side.
Discussion and Conclusions: Our findings show that even migraineurs who have never had vertigo, dizziness or imbalance
has a subclinical alteration of inner ear lateral canal function. This support the hypothesis that migraineurs has a vestibularcerebellar pathway dysfunction although not clinically evident.
References:
1. Neuhauser H, Leopold M, von Brevern M, Arnold G, Lempert T. The interrelations of migraine, vertigo and
migrainous vertigo. Neurology (2001); 56:436-441
2. Headache Classification Committee of the International Headache Society (IHS). The International Classification
of Headache Disorders, 3rd edition (beta version). Cephalalgia (2013) Jul;33(9):629-808
FUNCTIONAL CHANGES OF THE PAIN PROCESSING NETWORK AFTER EXTERNAL TRIGEMINAL
NEUROSTIMULATION IN MIGRAINE PATIENTS
A. Russo1, A. Tessitore1, F. Esposito2, F. Di Nardo1, L. Marcuccio1, F. Conte1, A. Giordano1, J. Schoenen3, G. Tedeschi1
1
Department of Medicine and Surgery, University of Salerno (Baronissi-SA); 3University Department of Neurology,
Citadelle Hospital (Liège, B)
2
Objective: To explore the functional reorganization of the pain processing network during trigeminal heat stimulation (THS)
after 60 days of external trigeminal neurostimulation (eTNS) in migraine without aura (MwoA) patients between attacks.
Methods: Using whole-brain BOLD-fMRI, functional response to THS at two different intensities
(41° and 51 °C) was investigated interictally in 16 adults MwoA patients before and after eTNS with the Cefaly® device.
We calculated the percentage of patients having at least a 50% reduction of monthly migraine attacks and migraine days
between baseline and the last month of eTNS. Secondary analyses evaluated associations between BOLD signal changes
and clinical features of migraine.
Results: Before eTNS treatment, there was no difference in BOLD-response between MwoA patients and HC during nopainful (41°C) THS, whereas the perigenual part of the right ACC revealed a greater BOLD-response in MwoA patients
when compared to HC painful (51°C). The same area demonstrated a significant reduced BOLD response induced by the
painful (51°C) THS in MwoA patients after eTNS (p=0.008). Correlation analyses showed only in the migraine group after
eTNS treatment, a significant negative correlation between both the perceived pain ratings during THS and pre-treatment
migraine attack frequency and ACC functional activity changes.
Conclusions: Our findings suggest that eTNS treatment with the Cefaly® device may induce a functional antinociceptive
pag. 47
modulation in the ACC that may be involved in the mechanisms underlying its preventive anti-migraine efficacy.
References:
− Schoenen J, Vandersmissen B, Jeangette S, Herroelen L, Vandenheede M, Gérard P, Magis D. Migraine
prevention with a supraorbital transcutaneous stimulator: a randomized controlled trial. Neurology (2013) Feb
19;80(8):697-704
− Russo A, Tessitore A, Esposito F, Marcuccio L, Giordano A, Conforti R, Truini A, Paccone A, d'Onofrio F,
Tedeschi G. Pain processing in patients with migraine: an event-related fMRI study during trigeminal nociceptive
stimulation. J Neurol. (2012) Sep;259(9):1903-12
− Russo A, Tessitore A, Conte F, Marcuccio L, Giordano A, Tedeschi G. Transcutaneous supraorbital
neurostimulation in "de novo" patients with migraine without aura: the first Italian experience. J Headache Pain
(2015);16:69
INDIRECT COSTS OF MIGRAINE IN EMERGENCY DEPARTMENT
A. Granato, J. Fantini, M. Ridolfi, P. Polverino, P. Manganotti
Department of Medical, Technological and Translational Sciences, Neurologic Clinic, Headache Centre, University of
Trieste (Trieste)
Background: Migraine is a frequent chief complaint in the Emergency Department (ED) accounting for 0.8-4.5% of all
admissions. It represents a major cause of lost work time and reduced work efficiency, with annual indirect costs around
five hundred euro per patient in general population in Western European Countries. No data on indirect costs of migraineurs
referring the ED are available.
Objective: To determine indirect costs in employees with migraine referring to ED.
Methods: A six-months prospective analysis of all consecutive patients referring to ED for headache and afterwards
evaluated in a dedicated Acute Headache Centre (AHC) of the University of Trieste was performed. Employees with an
AHC diagnosis of migraine (ICHD-3 beta criteria) were enrolled. Patients were properly treated in the AHC and were
followed-up in a three-month visit. Demographic and clinical characteristics, missed workdays [MW] and workdays with
reduction in work effectiveness [RWEW] over the preceding three months and in the 3-month follow-up period (MIDAS
scale), the daily costs of migraine-related MW and RWEW of each professional employee (quantified by mean daily wage,
National Statistical Institute wage data) were analysed with SPSS 21.0.
Results: We enrolled 63 patients (88.9% F, 11,1% M, mean age 39±10 years). Most frequent AHC diagnosis was migraine
without aura (35 patients, 55.6%). MW and RWEW in the preceding three months were 318 (median 5 days per person) and
987 (median 15 days per person) respectively, corresponding to € 45.591 total loss of wage cost. The indirect costs
estimated per year due to migraine-related absenteeism and pre-absenteeism were € 364.728 (€ 2.892 per patient). At threemonth follow-up visit, a significative reduction of 63.8% of MW (MW=115 [median 1 days per person]; p=0.001) and
47.5% of RPCW (RWEW=518 [median 8 days per person]; p=0.006) was found. The estimated annual wage costs saved
due to the proper AHC therapy was € 195.576.
Conclusions: Employees with migraine referring to ED have elevated wage losses due to absenteeism and preabsenteism.
Indirect costs in migraineurs in ED are about five-time higher than in migraineurs in general population. An Acute
Headache Centre dedicated to Emergency Department is effective in reducing more than half of indirect costs due to the
productivity loss caused by migraine.
TRANSIENT CORTICAL OEDEMA AND PERSISTENT NOMINUM APHASIA AFTER PROLONGED
ATTACK OF FAMILIAL HEMIPLEGIC MIGRAINE
A. Introna, M. Tappatà, I. Perrucci, T. Francavilla, M. Prudenzano, F. Dicuonzo, I. Simone, C. Tortorella
Department of Basic Medical Sciences, Neuroscience and Sense Organs, University of Bari "Aldo Moro" (Bari)
Introduction: Familial hemiplegic migraine (FHM) is a rare variant of migraine, associated with fully reversible motor
weakness and language, visual or sensory symptoms. Few reports have illustrated irreversible neurological deficits after
FHM prolonged attacks.
Case Report: A 36 years old, right-handed, caucasian woman was admitted to our neurological unit presenting right severe
hemiparesis, motor aphasia and right lateral hemianopsia, associated with severe left-sided headache and light increase of
temperature (37.8° C). Her husband reported she was going through a period of emotional stress. She became rapidly
pag. 48
stuporous and hemiplegic. She was born from a laborious delivery and needed for assistant teacher in school activities.
During her infancy she took valproate for recurrent convulsive febrile seizures, until remission at the age of seven. Many
relatives suffered of “hemiplegic attacks” during headache and febrile seizures. She experienced first hemiplegic migraine
at the age of 24. Attacks had a frequency of 1-2/year and neurological deficits were fully reversible within few hours
sleeping. She was under prophylactic treatment for migraine with low dose of amitriptyline, but her compliance to therapy
was poor. At admission the cerebrospinal fluid analysis was normal and bacteriological and virological screening was
negative, excluding encephalitis. CT and MRI scans were normal. One day after the onset of symptoms, a further MRI
showed cortical oedema in the left frontal-temporal-parietal area on DWI and FLAIR-weighted scans. Steroid therapy
(dexamethasone 16mg/die) was begun. The electroencephalogram showed diffuse slowing and low-voltage activity on the
left hemisphere. Clinical course was complicated by complex partial seizures so intravenous valproate was titolated up to
1400 mg/die. After twelve days she gradually recovered consciousness and motor deficit but nominum aphasia persisted.
When her vigilance improved, Acetazolamide 250 mg/die was administered. Topiramate 75 mg/die was started as
prophylactic drug. Brain MRI showed persistent cortical oedema up to three months. Genetic tests for CACNA1A, ATP1A2
and SCN1A are on going.
Conclusions: Cerebral oedema is found in many cases of migraine associated with alteration of consciousness. Even if
treatment of FHM is controversial, in our case cortical oedema justifies the use of steroids, which may also reduce pain and
probably mitigate cortical spreading depression. This case provides further evidence that FHM may be associated with
persistent neurological deficits in spite of the resolution of MRI abnormalities. Thus, a more aggressive use of prophylactic
medications in patients with ongoing attacks of FHM, regardless of attack frequency, may be recommended.
References:
− Jen JC. Familial Hemiplegic Migraine. 2001 Jul 17 [Updated 2015 May 14]. In: Pagon RA, Adam MP, Ardinger
HH, et al., editors. GeneReviews. Seattle (WA): University of Washington, Seattle; 1993-2016.
− Russell MB, Ducros A. Sporadic and familial hemiplegic migraine: pathophysiological mechanisms, clinical
characteristics, diagnosis, and management. Lancet Neurol. (2011) May;10(5):457-70
− Sánchez-Albisua et al Possible effect of corticoids on hemiplegic attacks in severe hemiplegic migraine. Pediatr
Neurol. (2013) Oct;49(4):286-8
MALATTIE CEREBROVASCOLARI 1
HIGH VALUES OF BASELINE AND 24-HOUR MEAN ARTERIAL PRESSURE ARE ASSOCIATED WITH
LOWER CHANCE OF EARLY NEUROLOGICAL IMPROVEMENT IN ACUTE STROKE PATIENTS
TREATED WITH THROMBOLYSIS
S. Lorenzano, D. Toni
Department of Neurology and Psychiatry, Treatment of Neurovascular Unit, Policlinico Umberto I Hospital, Sapienza
University of Rome (Roma)
Background and Objectives: The response to thrombolytic treatment in acute ischemic stroke (AIS) in the first hours can be
variable and patients may experience clinical improvement or clinical deterioration. Studies on the relation between blood
pressure (BP) and stroke outcome in the hyperacute phase of an ischemic stroke have shown contradictory results. The aim
of this study was to evaluate whether mean arterial pressure (MAP), as marker of brain perfusion, is associated with early
neurological improvement (ENI) in patients with AIS treated with IV thrombolysis.
Material and Methods: We analyzed data of AIS patients treated with IV rt-PA at the Unità di Trattamento Neurovascolare,
Sapienza University of Rome, with imaging data available, included in the SITS-ISTR (Safe Implementation of Treatment
in Stroke-International Stroke Thrombolysis Register) from January 2012 to December 2015. ENI was defined as a decrease
of >=4 points at 24-hr NIHSS from baseline or 24-hr NIHSS equals to 0 regardless the baseline NIHSS values.
Results: Overall, 440 patients were included, 183/423(43.3%) had ENI. Patients with ENI were more likely to have
cardioembolic stroke (p<0.001), lower SBP at baseline (p=0.005) and 24 hours (p<0.001), lower absolute values of MAP at
baseline (p=0.008) and 24 hours (p=0.005), a lower proportion of symptomatic intracerebral hemorrhage (SICH) per
NINDS definition. No associations was found between imaging findings, such as white matter hyperintensity, early
ischemic signs, and hyperdense MCA sign, and ENI. In the multivariate analysis model including the antihypertensive
treatment prior to the index stroke, MAP at baseline resulted as an independent predictor of ENI (OR 0.98, 95% CI 0.960.99; p=0.026). After including in the model antihypertensive treatment during the hospital stay, 24-hr MAP was selected as
independent predictor of ENI (OR 0.97, 95% CI 0.95-0.99; p=0.015). This indicates that the higher the absolute value of
MAP at baseline and 24 hours the lower the chance of achieving ENI is. Higher MAP values at baseline was also associated
pag. 49
with a poor outcome (mRS 3-6) at discharge (p=0.030). Furthermore, patients with SICH per ECASS definition were more
likely to have higher 24-hr MAP (p=0.024) and increase of MAP from baseline to 2 hours (p=0.011) and 7 days (p=0.003)
after thrombolysis.
Discussion: High baseline and 24-hr MAP values are associated with lower chance of achieving ENI after IV thrombolysis.
Further studies are needed to better understand whether acute BP dysregulation can influence different clinical courses in
the early phase of IV thrombolysis.
HEMODYNAMICS OF CEREBRAL CIRCULATION DURING THE VALSALVA MANEUVER AND PFO
ASSOCIATED ISCHEMIC STROKE SITE
M. Fischer , C. Sarti, Y. Failli, G. Pracucci, D. Inzitari
NEUROFARBA Department, Florence University (Firenze)
Background: Right-left shunt (RLS) through patent foramen ovale (PFO) represents a possible cause of stroke. Valsalva
maneuver (VM) causes or increases RLS. Some studies report a high frequency of posterior stroke in presence of PFO (1).
Preliminary data indicate that this may depend on a different hemodynamic response of the carotid and vertebrobasilar
system to VM with preservation of blood flow in the latter. Only one study, conducted with SPECT tecnique in 10 patients
with PFO, has shown higher blood flow in posterior compared to anterior circulation during VM (2).
Aim: The purpose of our study is to confirm literature preliminary data in a larger cohort of healthy young volunteers using
an ultrasonographic technique.
Methods: Evaluation of caliber and blood flow (ΦSp: Systolic Peak flow, ΦDp: Diastolic Peak, ΦM: Mean) of the internal
carotid (ICA) and vertebral artery (VA) at rest and during VM in 30 healthy young subjects (mean age 26,61 ± 3,71 years,
50% females) using ultrasonographic B-Mode and Color Doppler tecniques. All measurements were repeated 3 times for a
total of 6 values for both vessels and mean was calculated.
Results: Rest vs VM. ICA: 1- diameter: 0.436 vs 0.396 cm, absolute change (∆) 0,041 ± 0,025, 95% CI 0,032 – 0,050 (p
<0,001); 2- blood flow: ΦSp 83,947 vs 65,328 cm/s, ∆ 18,619 ± 12,27, 95% CI 14,035-23,201; ΦDp 34,310 vs 26,186 cm/s,
∆ 8,124 ± 4,518, 95% CI 6,473-9,811; ΦM 50,911 vs 39,217 cm/s, ∆ 11,694 ± 6,616, 95% CI 9,223-14,165 (p <0,001). VA:
1- diameter: 0,323 vs 0,355 cm, ∆ 0,032 ± 0,02, 95% CI -0,04 to -0,024, p <0,001; 2- blood flow: ΦSp 61,731 vs 61,433
cm/s, ∆ 0,298 ± 6,564, CI 95% -2,153 - 2,749, p=0,806; ΦDp 19,860 - 18,932, ∆ 0,928 ± 3,142, CI 95% -0,246 - 2,101,
p=0,117; ΦM 32,308 vs 31,125 cm/s, ∆ 1,183 ± 3,061, CI 95% 0,040 − 2,326, p 0,043
Conclusions: Our data show that compared to rest state, after VM, ICA diameter and blood flow decrease while VA
diameter increases and VA blood flow remains constant (ΦSp/ΦDp) or slightly decreases (ΦM), confirming a different
hemodynamic response of carotid and vertebrobasilar circulation to VM. This may explain the high prevalence of posterior
cerebral infarcts in patients with PFO through a mechanism of aspiration. If confirmed in larger study, site of lesions could
be included in an index to estimate the pathogenetic role of PFO in cryptogenic stroke.
References:
− Kim BJ, Kim NY, Kang DW; Provoked Right-to- Left Shunt in Patent Foramen Ovale Associates With Ischemic
Stroke in Posterior Circulation; Stroke (2014); 45(12): 3707- 3710
− Hayashida K, Fukuchi K, Inubushi M; Embolic Distribution Through Patent Foramen Ovale Demonstrated by
99mTc-MAA Brain SPECT After Valsalva Radionuclide Venography; J Nucl Med (2001); 42: 859 – 863
THE MONITORING OF BLOOD PRESSURE DURING THE ACUTE PHASE OF INTRACEREBRAL
HEMORRHAGE: PRELIMINARY RESULTS OF THE BP-MONICH STUDY
S. Vidale1, C. Pini2, S. Bellocchi3, E. Agostoni4, D. Pellegrino5, M. Arnaboldi1
1
Neurological Department, Sant'Anna Hospital (Como); 2Hypertension Centre, Sant'Anna Hospital (Como); 3Department of
Neurosurgery, Sant'Anna Hospital (Como); 4Neuroscience Department, Niguarda Ca' Granda Hospital (Milano);
5
Department
of
Internal
Medicine,
Sant'Anna
Hospital
(Como)
Background and purpose: Intracerebral hemorrhage has a higher mortality rate than ischemic stroke during the first month
after the acute event. Previous studies demonstrated the association between this negative outcome and some different
factors: clinical severity at admission, site and size of hemorrhagic lesion and rebleeding. The role of blood hypertension in
the acute phase of this condition is still debated and recent investigations had no conclusive findings concerning intensive
pag. 50
treatment. Aim of this study is the evaluation of the possible influence of blood pressure variability on clinical outcome in
hemorrhagic strokes.
Material and methods: All patients admitted to our Stroke Unit for spontaneuos intracerebral hemorrhage between January
2014 and January 2015 were enrolled. Demographic and clinical data, vascular risk factors and radiological findings were
registered for each patient. A standardized 24-hours blood pressure monitoring was performed whithin 48 hours from
symptom onset with a following registration after 5 days. Statistical analysis was performed using t-test and chi-square test.
Results: 49 patients were enrolled (median age: 72 years; male: 71%). The main vascular risk factor was blood hypertension
(64.3%). Antithrombotic or anticoagulant treatment was present in half of the patients. We observed a moderate clinical
severity at admission (median NIH: 10). 4 patients died during hospitalization. Median systolic and diastolic blood
pressures were 152 mmHg and 84 mmHg, respectively. Only 8 patients was dipper during the first blood pressure
monitoring. We observed a significant association between higher mean values of nocturnal blood pressure and clinical
severity at admission (p trend < 0.01) and a concomitant association between the non-dipper status and clinical outcome
(OR: 2.143; 95%CI: 1.438 – 2.733; p < 0.01).
Conclusion: Preliminary results of this study confirmed the influence of blood pressure trend on clinical severity at
admission and functional outcome. The importance of a blood pressure monitoring also in the acute phase of intracerebral
hemorrhage could be related to an attempt to restore a more physiological pressure trend by a prompt therapeutical
intervention.
ACUTE EXTRACRANIAL STENTING IS ASSOCIATED WITH FAVORABLE OUTCOME IN
ATHEROSCLEROTIC PATIENTS WITH TANDEM OCCLUSION OF ANTERIOR CIRCULATION TREATED
WITH MECHANICAL THROMBECTOMY
C. Motta1, S. Pizzuto1, R. Gandini2, P. Stanzione1, G. Koch1, F. Sallustio1
1
Stroke Unit, Department of Neuroscience, University of Rome Tor Vergata (Roma); 2Interventional Radiology and
Neuroradiology, Policlinic and University of Rome Tor Vergata, (Roma)
Objective: Acute tandem occlusion of the anterior circulation is associated with severe stroke symptoms, poor outcome and
a very limited response to systemic thrombolysis. Thrombectomy associated with stenting of the internal carotid artery
(CAS) has been suggested as an efficacious strategy for tandem occlusions. This approach is debated since the antiplatelet
therapy related to stenting is associated with higher risk of symptomatic intracranial hemorrhage (sICH). Because ischemic
stroke is etiologically heterogeneous (ie, atherosclerosis versus cardiac embolism), we hypothesized that different stroke
etiologies might respond differently to different kinds of treatment. The purpose of the present work is to investigate if
stenting of proximal occlusion is associated with favorable outcome depending on the stroke etiology in patients with
tandem occlusion of anterior circulation treated with mechanical thrombectomy.
Methods: Patients with acute ischemic stroke (AIS) due to intracranial occlusion of the middle cerebral artery (MCA) in
association with occlusion of the ipsilateral internal carotid artery (ICA) who underwent endovascular treatment in our
stroke center between 2012-2015 were retrospectively identified. Radiographic, clinical and demographic data were drawn
from imaging records and discharge reports. Modified Rankin Scale (mRS) after 3 months was adopted for outcome.
Endovascular treatment was associated to intravenous (i.v.) thrombolysis with tissue plasminogen activator (tPA), if there
were no contraindications, and CAS when necessary. TOAST classification was used to classify etiological diagnosis.
Thrombolysis in cerebral infarction (TICI) score described revascularization.
Results: Out of 60 patients 51.7% were atherothrombotic, 30% cardioembolic, 5% dissection and 13.3% of undetermined
origin. Thirty-two patients (53.3%) underwent CAS. Considering separately the cardioembolic and the atherothrombotic
group in a two-way ANOVA analysis, CAS was associated with a significant effect on clinical outcome only in the
atherosclerotic group (CAS, p=0.004; tPA, p=0.36; interaction, p=0.20). Conversely a significant effect of tPA was found
for the cardioembolic group (CAS, p=0.29; tPA, p=0.04; interaction, p= 0.71). Multivariate ordinal logistic regression in
order to evaluate the effect of tPA and CAS on mRS after 3 months showed that only for the atherosclerotic group CAS was
an independent variable associated with clinical outcome when adjusted for age, NIHSS at onset, time to recanalization,
TICI and sICH.
Conclusions: Stenting of extracranial ICA combined with mechanical thrombectomy can be an effective treatment for AIS
due to tandem occlusion of atherosclerotic origin. Cardioembolic tandem occlusion are besides susceptible of tPA treatment
in association with mechanical thrombectomy.
IMPACT OF ACUTE-PHASE COMPLICATIONS AND INTERVENTIONS ON 6-MONTH SURVIVAL AFTER
STROKE. A PROSPECTIVE OBSERVATIONAL STUDY IN FOUR ITALIAN REGIONS
pag. 51
A. Di Carlo1, M. Lamassa2, M. Franceschini3, L. Cecconi4, D. Inzitari2, A. Biggeri4, S. Ferro5
1
Istituto di Neuroscienze, Consiglio Nazionale delle Ricerche (Firenze); 2Department of NEUROFARBA, University of
Florence (Firenze); 3Department of Rehabilitation, San Raffaele University (Roma); 4DISIA Department, University of
Florence (Firenze); 5Department of Hospital Services, Emilia-Romagna Region Health Authority (Bologna)
Objective: To evaluate the impact of acute-phase variables on survival at 6 months from a first-ever stroke, taking into
account baseline conditions exerting a possible effect on the selected outcome. Methods: This survey is part of the National
Research Program: La Presa in Carico delle Persone con Ictus Cerebrale: Implementazione dei Percorsi di Cura Integrati e
degli Strumenti di Gestione, coordinated by the Emilia-Romagna Region, and supported by the Italian Ministry of Health.
The Program included a prospective observational study, which started in 2012, of acute stroke patients in four Regions:
Emilia-Romagna, Toscana, Umbria and Lazio. All consecutive patients admitted for a period of 3 months to the emergency
rooms of participating hospitals with a confirmed stroke were included. Exclusion criteria were age lower than 18 years, inhospital stroke, and death within 24 hours of admission. Data were collected by specially trained physicians.
Results: During the study, 1030 patients with first-ever stroke were enrolled (mean age 73.3±13.7 years, 52.1% males). At 6
months, 816 (79.2%) were alive, and 164 (15.9%) deceased. Information on survival status was missing for 50 (4.9%).
Clinical state in the acute-phase was significantly more severe in patients deceased at 6 months. They had more often a
diagnosis of intracerebral hemorrhage and of total anterior circulation infarct (TACI). Their NIHSS score was significantly
higher than in survivors, and they showed a higher frequency of acute-phase complications. Cox regression adjusted for
demographics, pre-stroke function, baseline diseases and risk factors, indicated that significant predictors of 6 months death
were altered consciousness (HR, 1.70; 95% CI, 1.14-2.53), TACI (HR, 2.13; 95% CI, 1.44-3.15), hyperthermia (HR, 1.70;
95% CI, 1.18-2.45), pneumonia (HR, 1.76; 95% CI, 1.18-2.61), heart failure (HR, 2.87; 95% CI, 1.34-6.13) and nasogastric
feeding (HR, 2.35; 95% CI, 1.53-3.60), while antiplatelet therapy (HR, 0.56; 95% CI, 0.39-0.79), and early mobilization
(HR, 0.55; 95% CI, 0.36-0.84) significantly increased the probability of 6-month survival.
Discussion and Conclusions: Studies on stroke outcome often evaluated the role of single acute-phase variables, while a
more global framework, also considering baseline determinants, is lacking. In a prospective survey of patients hospitalized
for first-ever stroke, controlling for baseline variables possibly influencing outcome, we found that stroke severity and
acute-phase complications significantly increased the risk of death at 6 months. Among acute-phase interventions, early
mobilization showed a positive effect on survival, adding information to the still limited evidence on the role of very early
rehabilitation after stroke.
RESULTS OF AN EDUCATIONAL CAMPAIGN ON STROKE AWARENESS IN NORD-WEST ITALY
C. Gandolfo1, F. Alberti2, M. Bandettini Di Poggio1, C. Bruno1, D. Curro'1, S. Del Medico3, M. Del Sette4, M. Garnero1, G.
Mancardi1, A. Mannironi5, D. Massucco1, N. Pizio6, N. Reale1, L. Ruiz7, D. Sassos1, S. Stara1, T. Tassinari8, E. Ursino7
1
(Genova); 2Department of Neurology, ASL1 Liguria (Sanremo); 3A.L.I.Ce. Alessandria ONLUS (Alessandria);
4
Department of Medicine and Neurological Unit, Galliera Hospital (Genova); 5Department of Neurology, ASL5 Liguria (La
Spezia); 6Department of Neurology, ASL4 Liguria (Lavagna-GE); 7Department of Neurology, Alessandria Hospital
(Alessandria); 8Department of Neurology, ASL2 Liguria (Pietra Ligure-SA)
Introduction: People often are not aware about onset symptoms of stroke, usefulness of primary prevention, efficacy of new
therapeutic strategies. In many cases, primary prevention is totally lacking, admission in hospital is too late for
thrombolysis, and patients are not referred to a stroke-unit. In order to enhance stroke awareness in Italian population, we
organized, in cooperation with Italian Society against Stroke (A.L.I.Ce.), and with a contribution of Rotarian District 2032
(Nord-West Italy), an educational campaign on stroke.
Method: The Project “Rotary against Stroke” is a 3 phases program: a) evaluation of stroke knowledge by a questionnaire,
followed by a lecture performed by expert neurologists (CG, MDS, EU); b) screening session for individual stroke risk
computation; c) analysis of stroke awareness improvement by a further evaluation of the same questionnaire of the first
phase. The project involved, until now, 22 Rotary Clubs in Liguria and South Piedmont, Italy.
Results: We involved in the project 550 subjects, male/female ratio: 2.6 (397/153), mean age±sd: 62.9±12.4 years. The
questionnaire contained simple questions with multiple choice answers on general knowledge of stroke, treatments of the
acute phase, stroke-units, risk factors, and early phase symptoms. In total, we analyzed 15,400 answers (first phase) in
comparison to 1,288 further answers (third phase). The proportion of erroneous answers changed from 23.7% at the first
phase to 15.3% at the third phase, with a statistical significant difference (χ2 = 46.5, p <.000001). In particular, the general
pag. 52
knowledge on stroke improved, as well as on the role of smoking, diabetes, and high cholesterol as risk factors. In the part
concerning onset symptoms, we observed a strong knowledge improvement on the role of visual disturbances, sudden
severe headache, and hemiparesis. Finally, in the part on therapy, we verified a significant knowledge improvement on
thrombolysis. On the contrary, we did not obtain knowledge improvement on the relevance of atrial fibrillation as risk
factor, and on the usefulness of admission in a stroke-unit.
Discussion and conclusion: In conclusion, we ascertained, in our population, a global high level of knowledge on stroke,
witch further significantly improved after the adhesion to the project including the attendance at an educational lecture on
stroke and at a clinical screening session. The future evolution of the program needs a particular attention in better
transmitting the important role of atrial fibrillation as risk factor as well as of the therapeutic importance of stroke-units.
DISTRIBUTION OF ISCHEMIC STROKE SUBTYPES: RESULTS FROM A POPULATION-BASED STUDY
AND OF A META-ANALYSIS FROM OTHER POPULATION BASED STUDIES
S. Sacco, C. Di Carmine, R. Ornello, L. Perciballi, D. Degan, C. Tiseo, F. Pistoia, A. Carolei
Dipartimento di Scienze Cliniche Applicata e Biotecnologie, Università degli Studi dell'Aquila (L'Aquila)
Background: Current evidence suggests that in recent years ischemic stroke (IS) incidence has decreased in Western
countries as a possible consequence of improved diagnosis and treatment of stroke risk factors; this may also have led to
changes in the distribution of ischemic stroke etiologies. We aimed to evaluate current distribution of IS subtypes in our
prospective population-based study and to perform a meta-analysis of available data regarding IS subtypes.
Methods: Cases of incident first-ever strokes were recorded over a two-year period (2011-2012) from multiple sources in
the district of L’Aquila, central Italy. Additionally, we performed a meta-analysis, according to the PRISMA guidelines, to
identify available studies reporting distribution of etiological subtypes of IS on consecutive cases of patients. Weighted
distributions were calculated and meta-regression technique applied to determine the temporal trend.
Results: Over the years 2011-2012, we included 858 patients (417 men; 48.6%) with a first-ever stroke; 634 patients
(73.9%) had an IS; 73 (11.5%) were due to large-artery atherosclerosis (LAA), 92 (14.5%) to small-artery occlusion (SAO),
220 (34.7%) to cardioembolism (CE), 29 (4.6%) to other determined etiologies, and 220 (34.7%) to undetermined cause.
We included in the meta-analysis 60 studies, out of 9,243 screened articles, collecting data from 1993 through 2013 in 28
countries. The final analysis included 107,859 incident ISs. Overall, 22% of ISs were caused by each LAA (95% CI 20-24),
CE (95% CI 20-24) and SAO (95% CI 21-24), whereas 27% of cases (95% CI, 25-29) were of undetermined origin and 3%
(95% CI 3-3) of other determined cause. Distribution of IS subtypes varied across ethnicity (P<0.05 for all subtypes). In
Whites the leading subtype was CE (28%, 95% CI 26-29) whereas in Asians it was LAA (32%, 95% CI 30-35). Trends over
time in the distribution of IS subtypes showed an increase in CE strokes (ρ= 0.029, P=0.004) in Whites from high-income
countries, a decrease in the proportion of SAO globally (rho=-0.039, P=0.001) that was mostly driven by Whites from highincome countries (rho=-0.051, P=0.001) and an increase over time in the proportion of LAA in Asians (rho=0.051,
P<0.001), again, from high-income countries (rho=0.049, P<0.001).
Discussion: Results of our population-based study and of a meta-analysis suggest that in Whites living in high-income
countries, CE is currently the leading cause of ischemic stroke as preventive strategies may have controlled the modifiable
risk factors causing LAA and SAO. In Asians, LAA is the leading IS subtype probably depending on genetics but also on
environmental factors. Implementation of future strategies to further reduce stroke burden should take into account those
unmet needs.
References:
− Adams HP, Bendixen BH, Kappelle LJ, Biller J, Love BB, Gordon DL, Marsh E. Classification of subtype of acute
ischemic stroke. Definitions for use in a multicenter clinical trial. TOAST. Trial of Org 10172 in Acute Stroke
Treatment. Stroke (1993);24:35-41
− Feigin VL, Forouzanfar MH, Krishnamurthi R, Mensah GA, Connor M, Bennett DA, O'Donnell M. Global and
regional burden of stroke during 1990-2010: findings from the Global Burden of Disease Study 2010. The Lancet
(2014);383:245-255
− Rothwell PM, Coull AJ, Giles MF, Howard SC, Silver LE, Bull LM, Farmer A. Change in stroke incidence,
mortality, case-fatality, severity, and risk factors in Oxfordshire, UK from 1981 to 2004 (Oxford Vascular Study).
The Lancet (2004);363:1925-1933
ALCOHOL INTAKE AND THE RISK OF INTRACEREBRAL HAEMORRHAGE. THE MULTICENTER
STUDY ON CEREBRAL HAEMORRHAGE IN ITALY (MUCH-ITALY).
pag. 53
P. Costa1, L. Iacoviello2, M. Zedde3, S. Marcheselli4, G. Silvestrelli5, M. L. DeLodovici6, M. Sessa7, A. Zini8, M. Paciaroni9,
C. Azzini10, M. Gamba11, M. Del Sette12, A. Toriello13, C. Gandolfo14, D. M. Bonifati15, R. Tassi16, A. Cavallini17, A.
Chiti18, R. S.Calabrò19, R. Musolino1, P. Bovi21, G. Tomelleri21, A. Di Castelnuovo2, L. Vandelli8, M. L.Dell’Acqua8, M.
Ritelli22, G. Agnelli9, A. De Vito10, N. Pugliese13, G. Martini16, A. Lanari5, A. Ciccone5, C. Lodigiani23, G. Malferrari3, D.
Strambo24, E. Del Zotto25, A. Morotti1, L. Poli1, V. De Giuli1, F. Caria1, M. Padroni1o, L. P. Cariddi6, E. Banfi23, P. La
Spina20, N. Marcello3, G. Micieli17, G. de Gaetano2, M. Colombi22, A. Padovani1, A. Pezzini1
1
Dipartimento di Scienze Cliniche e Sperimentali, Clinica Neurologica, Università degli Studi di Brescia (Brescia);
Laboratorio di Epidemiologia Molecolare e Nutrizionale, Dipartimento di Epidemiologia e Prevenzione, IRCCS Istituto
Neurologico Mediterraneo, NEUROMED (Pozzilli, IS);
3
S.C. Neurologia, IRCCS Arcispedale Santa Maria Nuova (Reggio Emilia);
4
Neurologia d’Urgenza and Stroke Unit, IRCCS Humanitas Research Hospital (Rozzano-MI);
5
Stroke Unit, Dipartimento di Neuroscienze, Ospedale Carlo Poma (Mantova);
6
U.O. Neurologia e Stroke, ASST-Sette Laghi , Università dell’Insubria (Varese);
7
UO Neurologia, Istituti Ospitalieri di Cremona (Cremona);
8
Stroke Unit, Clinica Neurologica, Nuovo Ospedale Civile “S. Agostino Estense” (Modena);
9
Stroke Unit and Divisione di Medicina Cardiovascolare, Università di Perugia (Perugia);
10
Stroke Unit, Divisione di Neurologia, Dipartimento di Neuroscienze e Riabilitazione, Azienda Ospedaliero-Universitaria
di Ferrara (Ferrara);
11
Stroke Unit, Neurologia Vascolare, ASST Spedali Civili di Brescia (Brescia);
12
Unità di Neurologia, E.O. Ospedali Galliera (Genova);
13
U.O.C. Neurologia, A.O Universitaria “San Giovanni di Dio e Ruggi d’Aragona” (Salerno);
14
Dipartimento di Neuroscienze, Riabilitazione, Oftalmologia, Genetica e Scienze Materno-Infantili, Università di Genova
(Genova);
15
Stroke Unit, U.O Neurologia, Ospedale “S. Chiara” (Trento);
16
Stroke Unit, AOU Senese (Siena);
17
U.C Malattie Cerebrovascolari e Stroke Unit and U.C Neurologia d’Urgenza, IRCCS Fondazione Istituto Neurologico
Nazionale "C. Mondino" (Pavia);
18
Neurologia, Azienda Ospedaliero Universitaria Pisana (Pisa);
19
Istituto di Ricovero e Cura a Carattere Scientifico, Centro Neurolesi Bonino-Pulejo (Messina);
20
Dipartimento di Neuroscienze, Scienze Psichiatriche e Anestesiologiche Clinica Neurologica, Università di Messina
(Messina);
21
USD Stroke Unit, DAI di Neuroscienze, Azienda Ospedaliera Universitaria Integrata Verona (Verona);
22
Divisione di Biologia e Genetica, Dipartimento di Medicina Molecolare e Traslazionale, Università degli Studi di Brescia
(Brescia)
23
Centro Trombosi, IRCCS Humanitas Research Hospital (Rozzano- MI);
24
Stroke Unit, U.O Neurologia, IRCCS Ospedale S. Raffaele (Milano);
25
U.O. di Recupero e Rieducazione Funzionale, IRCCS Fondazione Don Gnocchi (Rovato)
2
Background and objective: Although alcohol consumption has been related to intracerebral hemorrhage (ICH) in a number
previous studies, its role as susceptibility factor has not been firmly established. In particular, it is unclear whether its effects
on disease risk might depend on the pathogenic mechanisms leading to cerebral bleeding.
Methods: We performed a case-control analysis comparing a cohort of consecutive patients with ICH, aged ≥ 55 years,
prospectively enrolled between January 2002 and July 2014 as part of the Multicenter Study on Cerebral Haemorrhage in
Italy (MUCH-Italy) with a group of age and sex-matched stroke-free subjects from the population-based Moli-sani project.
Based on daily alcohol consumption, participants were dichotomized into excessive drinkers (>45 g of alcohol) and lightmoderate drinkers or non-drinkers. We constructed multivariable logistic regression models including demographics,
conventional vascular risk factors, and antithrombotic drugs as covariates. Based on the observation that hemorrhage
location (deep hemispheric versus lobar) is an important clue to etiology, analyses were performed separately for lobar and
deep ICH subjects versus control subjects.
Results: A total of 3,173 cases (mean age 75.79 ±9.65 years; males, 55.5%) and 3,155 controls (mean age 73.18 ±7.28
years; males, 55.4%) were enrolled. The prevalence of excessive alcohol consumers was similar between ICH cases and
controls (14.2%vs13.2 %, p=0.232), and alcohol intake was not associated with the overall risk of ICH after adjusting for
potential confounders (OR 1.09, 95% CI, 0.93–1.29; p=0.29). Conversely, excessive alcohol consumption was associated
with disease risk in the group of patients with deep ICH (OR 1.30, 95% CI, 1.05–1.6; p=0.01), as well as in that of people in
the fourth quartile of age (> 80 years; OR, 1.75; 95% CI, 1.14-2.69; p=0.01).The highest disease risk associated to excessive
alcohol intake was detected in patients aged over 80 years with deeply located hematomas (OR, 2.56; 95% CI, 1.38-4.75,
pag. 54
p=0.003), whereas no effect was found for lobar ICH. Within the group of patients at highest risk, untreated hypertension
was strongly associated to excessive alcohol consumption (OR, 5.01; 95% CI, 2.31-10.84; p≤0.001).
Conclusion: In people aged ≥ 55 years, excessive alcohol consumption increases the risk of deeply located ICH, especially
in older subjects with untreated hypertension. This suggests a prominent role for alcohol in the vascular pathologies
underlying deep ICH, but not in cerebral amyloid angiopathy causing bleeding in the lobar brain regions.
MALATTIE DEL MOTONEURONE
THE UTILITY OF MULTIMODAL IMAGING IN THE DIAGNOSIS OF ALS
F. Agosta1, P. Ferraro1, N. Riva2, M. Copetti3, Y. Falzone2, A. Chiò4, G. Sorarù5, A. Falini6, G. Comi2, M. Filippi1
1
Neuroimaging Research Unit, Division of Neuroscience, San Raffaele Scientific Institute, Vita-Salute San Raffaele
University (Milano); 2Department of Neurology, San Raffaele Scientific Institute, Vita-Salute San Raffaele
University (Milano); 3Biostatistics Unit, IRCCS-Ospedale Casa Sollievo della Sofferenza (San Giovanni Rotondo-FG);
4
ALS Center, “Rita Levi Montalcini”, Department of Neuroscience, University of Torino (Torino); 5Department of
Neurosciences, University of Padova (Padova); 6Department of Neuroradiology, San Raffaele Scientific Institute, VitaSalute San Raffaele University (Milano)
Objectives: To develop an automated method for identification of individual patients with amyotrophic lateral
sclerosis (ALS) using multimodal advanced structural Magnetic Resonance Imaging (MRI) data and to test the validity of
our approach in patients at onset with clinical syndromes suggestive of ALS, but not meeting criteria for ALS based on
revised El Escorial/Awaji criteria.
Materials and methods: 3D T1-weighted and diffusion tensor (DT) MRI were obtained from 113 sporadic (probable,
probable-laboratory supported, definite) ALS patients, 20 patients with ALS mimic disorders, and 40 healthy controls.
The diagnostic accuracy of precentral cortical thickness measures and DT MRI metrics of the corticospinal tract and motor
callosal fibers were assessed in a testing cohort and externally proved in a validation cohort using a random forest analysis.
Results: In the testing set (64 randomly selected sporadic ALS patients and healthy controls), precentral cortical thickness
showed 0.85 accuracy, 0.76 sensitivity, 1.00 specificity in differentiating ALS patients from healthy controls, while DT MRI
measures distinguished the two groups with 0.77 accuracy, 0.84 sensitivity, 0.65 specificity. In the same group, the
combination of cortical thickness and DT MRI metrics improved the classification pattern as follows: 0.87 accuracy,
0.88 sensitivity, 0.84 specificity. In the validation cohort (remaining 49 sporadic ALS vs mimic disorders), the best
diagnostic accuracy was reached by DT MRI (0.99 accuracy, 1.00 sensitivity, 0.94 specificity) while cortical thickness
measures provided the following discrimination values: 0.73 accuracy, 0.82 sensitivity, 0.56 specificity. The combined
approach distinguished ALS from mimic syndromes with 0.87 accuracy.
Discussion and Conclusions: A multimodal imaging approach that incorporates motor cortical and white matter alterations
yields statistically significant improvement in accuracy over using each modality separately in the individual ALS
patient classification. In order to distinguish ALS from mimic disorders, DT MRI represents the most powerful tool.
This study provides a roadmap for translation of MRI predictors of ALS into clinical daily practice.
Funded by: AriSLA (MacLearnALS Project).
DISEASE PROGRESSION IN SBMA: IS SERUM CREATININE A RELIABLE BIOMARKER?
G. Querin1, E. Da Re1, I. Martinelli1, L. Bello1, C. Bertolin1, D. Pareyson2, C. Mariotti2, E. Pegoraro1, G. Sorarù1
1
Department of Neurosciences, University of Padova (Padova); 2Clinic of Central and Peripheral Degenerative Neuropathies
Unit, Department of Clinical Neurosciences, IRCCS Foundation, C. Besta Neurological Institute (Milano)
Background: Spinal and bulbar muscular atrophy (SBMA) is an adult-onset, X-linked, lower motor neuron disease caused
by a CAG repeat expansion within the androgen receptor gene. No reliable index of disease progression has been
established so far and, nevertheless, there is a critical need for biomarkers discovery and validation in order to improve the
diagnostic process and organization of clinical trials (1).
Objective: We investigated if creatinine serum levels, a common used biomarker in neuromuscular diseases, could be a
pag. 55
reliable index of disease progression in SBMA.
Methods: We studied 65 SBMA patients. They underwent biochemical analysis including creatinine and CK serum levels
and completed a clinical protocol including 6 minute walk test (6MWT), functional scale (ALS-FRSr), ADL grade scale and
respiratory evaluation (fVC) at baseline and after 1 year. Spearman’s coefficient was used to assess correlations and a linear
regression was used to fit the obtained results. Student t test were used to compare means.
Results: A significant decrease of 6MWT values (p =0.003) and creatinine serum levels (p= 0.0031) was observed between
baseline and 12 months evaluation. Creatinine serum levels at baseline didn’t correlate with age of the patients, disease
duration and age of symptoms onset. They correlated with 6MWT (p=0.0006), total ALSFRS score (p< 0.001) and with
upper and lower limbs subscores at baseline (p< 0.001). A correlation was found also with the ADL grade (p<0.001) and
with the muscular force megascore for upper and lower limbs (p< 0.001).
Creatinine levels at baseline significantly correlated with ADL grade at 12 months (r= -0.54; p< 0.001), total ALSFRS score
at 12 months (r = 0.49; p=0.001), with his subscore for the lower limbs (r =0.58; p<0.001) and with muscle force for upper
and lower limbs (respectively r = 0.42 with p = 0.0006 and r = 0.57 with p> 0.0001). We fit a linear model to establish
which proportion of the variation in the 6MWT and in the ALSFRS-r subscore for lower limbs at the 12 months
examination was explicated by the creatinine serum levels at baseline. We found a R2 value respectively of 0.20 and of
0.34.
Conclusions: Our study evidences that serum creatinine could be a good predictor of disease progression in SBMA patients
and that it could be an early marker of clinical modifications over time. Our study could be a step forward filling the gap in
the research of reliable biomarkers for SBMA.
Reference:
1. Pennuto M, Greensmith L, Pradat PF et al. 210th ENMC International Workshop: Research and clinical
management of patients with spinal and bulbar muscular atrophy, 27-29 March, 2015, Naarden, The Netherlands.
Neuromuscul Disord. (2015);25:802-12
RESTING STATE FMRI SUBSTRATE OF AFFECTIVE THEORY OF
AMYOTROPHIC LATERAL SCLEROSIS
MIND IMPAIRMENT IN
F. Trojsi1, F. Di Nardo1, G. Santangelo2, M. Siciliano1, C. Passaniti2, C. Femiano1, G. Piccirillo1, M. Monsurrò1, F.
Esposito3, G. Tedeschi1
1
Department of Psychology, Second University of Naples (Caserta); 3Department of Medicine and Surgery, University of
Salerno (Baronissi, SA)
2
Background and Objectives: Amyotrophic lateral sclerosis (ALS) is frequently associated with cognitive and behavioural
disorders, including impairments of socio-emotional processing, considered as key features for the diagnosis of the
behavioral variant of frontotemporal dementia (bvFTD). Recent evidence displays some dysfunctions of Theory of Mind
(ToM), the ability to recognize thoughts (“cognitive” ToM) and emotions (“affective” ToM) of another, in both ALS and
bvFTD. However, the functional bases underlying deficits of both ToM subcomponents, still remain largely unexplored in
the ALS-FTD continuum. The present study was therefore designed to investigate whether ToM subcomponents deficits are
associated with ALS progression and to identify the dysfunctional brain resting state functional magnetic resonance imaging
(RS-fMRI) networks potentially related to ToM abnormalities.
Methods: We investigated functional connectivity of brain networks in a group of 21 patients with ALS (i.e., 9 with bulbar
onset or ALS-B and 12 with limb onset or ALS-L) in early stages of disease and 15 matched healthy controls. We also
explored neuropsychological performances, including cognitive and affective ToM and multi-domain cognitive functions, at
baseline and after one year from the first assessment.
Results: At baseline, no ToM or other cognitive performances deficits were reported in ALS patients compared to controls.
However, after one year, the ALS-B subset exhibited a significant impairment of the affective subcomponent of ToM. RSfMRI study showed a decreased connectivity within right and left frontoparietal, default mode and salience networks in the
ALS group. Moreover, within the default mode network (DMN), we also observed an increase of RS-fMRI signals in the
posterior cingulate cortex in the ALS group, with more enhanced functional connectivity in this area in patients with ALS-B
compared to those with ALS-L. Within the salience network, typically suppressed in bvFTD, we revealed a widespread
descrease of RS-fMRI signals in the left medium frontal gyrus in ALS-B patients compared to ALS-L ones.
Discussion and conclusions: Our findings showed that ALS and bvFTD broadly share common RS-fMRI connectivity
patterns, especially in case of ALS-B, providing clinical evidence for the presence of affective ToM deficit during the
disease course. In particular, our results confirm the hypothesis of a biologically more aggressive character of ALS-B,
pag. 56
suggesting that RS-fMRI abnormalities, involving extra-motor networks, may precede the clinical appearance of
neurobehavioural alterations.
DYSARTHRIA IN ALS: AN OBSERVATIONAL COHORT STUDY
A. Fasano1, C. Budriesi2, S. Casalino2, N. Fini2, F. Falzone2, J. Mandrioli2
1
2
Department of Biomedical, Metabolic, and Neural Science, University of Modena and Reggio Emilia (Modena);
Department of Neuroscience, St. Agostino-Estense Hospital (Modena)
Introduction: Dysarthria occurs in more than 80% of ALS patients and causes major disability, earlier in those with bulbar
onset who may become anarthric after a few months. There are few and small sample sized studies on dysarthria in ALS.
Our aim was to study clinical features of dysarthria in a cohort of patients with ALS followed at Modena ALS Centre.
Methods: Features of ALS patients’ verbal production were assessed evaluating articulation, voice, symptoms impacting on
the patient, strategy to overcome dysarthria, intellegibility, movements examination and various perceptive characteristics.
Results: We examined 84 well characterized patients(45M, 39F) who were followed up regularly in our Centre. Mean age at
onset was 61.48(±11.42) years and mean diagnostic delay was 12.83(±12.99) months. Phenotypes were as follows:
bulba(40.5%), classic(34.5%), flail arm and leg(14.6%), UMN-p(7%), respiratory(3.5%). Eight patents (9.5%) had
dementia. ALS was definite at diagnosis in 36 cases (42.9%), possible in 19 cases (22.6%). Mean BMI at diagnosis was
24.9 (±4.5), and mean FVC was 82.6% (±25.1). Mean time from disease onset to dysarthria onset was 11.5 (±17.7) months.
Mean time from onset to first speech examination was 20.3 (±18.5) months, shorter in bulbar cases. At first evaluation 36%
of patients showed difficulty with “R” letter and only 12% with other letters. The most common perceptive characteristics
were imprecise articulation (43%), weak voice (52%) and hoarse voice (43%). 30% of patients presented with
hypernasality. Mean maximal Phonatory-Duration-Rate was 10.3/sec. Fifty-one patients showed slow laborious speech
(61%) and 31 (36%) fatigability. The most common strategy to counteract dysarthria was repetition. 30% of patients
complained impact of dysarthria on mood and relationships, and 50% of patients said they were talking less than usual.
Mean self reported intelligibility in optimal condition was 77%, and mean reported intelligibility by the listener was 70%.
Fasciculations were the most common feature detected at examination;>50% of patients had tongue and palatal movements
preserved. At first speech evaluation dysarthria was globally considered mild in 52% of patients, moderate in 19.3%, severe
in 18% of patients. Time from disease onset to dysarthria onset was inversely correlated with survival (p<0.001).
Conclusions: Dysarthria in ALS should be assessed early and monitored regularly as it is correlated with survival.
Assessment methods should include qualitative and quantitative clinical scales of bulbar function and standardized
dysarthria scales. Further investigation, incorporating formal speech, swallow, and cognitive assessment should be
encouraged to better characterize dysarthria in ALS.
References:
− Mandrioli J, Biguzzi S, Guidi C, et al. Epidemiology of amyotrophic lateral sclerosis in Emilia Romagna Region
(Italy): A population based study. Amyotroph Lateral Scler Frontotemporal Degener. (2014) Jun; 15(3-4):262-8
− Tomik B1, Guiloff RJ. Dysarthria in amyotrophic lateral sclerosis: A review. Amyotroph Lateral Scler.
(2010);11(1-2):4-15
AMYOTROPHIC LATERAL SCLEROSIS: 20-YEAR OF GENDER EFFECT IN THE ACCESS TO
MECHANICAL VENTILATION
M. Gardinetti1, G. Morlini2, P. Arnone2, G. Marchesi3, F. Gambirasio1, M. Rottoli1, V. Bonito1
1
Neurology, ASST Papa Giovanni XXIII Hospital (Bergamo); 2Respiratory Medicine, ASST Papa Giovanni XXIII Hospital
(Bergamo); 3Intensive Care Unit, ASST Papa Giovanni XXIII Hospital (Bergamo)
Background and purpose: Respiratory failure is the main cause of mortality in patients with amyotrophic lateral sclerosis
(ALS). Non-invasive mechanical ventilation (NIV), mechanically cough assistance (MCA) and Tracheotomy (TMV) can
prolong survival. TMV may impose a major burden on patients and caregivers and influence the acceptance rate for this
therapeutic option. Beneficial effects on palliation of symptoms, improvement in quality of life and prolonged life have
been reported. We focused on the gender in the access to TMV and NIV of a cohort of ALS patients, followed in ALS
Clinical Center of Papa Giovanni XXIII Hospital in Bergamo (Italy).
Methods: Retrospective analyses from our ALS patients database, collected during 1995–2014; this period was divided into
four five-years period. We recorded demographic and clinical information for all patients and we evaluated gender effect on
pag. 57
disease progression through the revised ALS functional rating scale (ALSFRS-R), Muscle Research Coucil (MRC), arterial
blood gas (ABG) and spirometry.
Results: Between 1995 and 2014, we cared 520 ALS patients; about these 331 patients died, M/F 1,0; 88 (27%) were
submitted to TMV M/F 1.7. No significant difference in the age, Spinal/bulbar onset and ALSFRS-R between men and
women treated with TMV. During the 1st five-years period (1995-1999) 50 died, tracheotomy was carried out in 16 (32%)
patients M/F 1,3; on the 2nd five-years period (2000-2004) 76 died and 20 (26%) tracheostomised M/F 3.0; on the 3rd fiveyears period (2005-2009) 97 died and 28 (29%) tracheostomised M/F 1.8; in the last one (2010-2014) 87 died and 23 (27%)
tracheostomised M/F 1.2.
Discussion: Sociocultural variables influence the choice of tracheotomy; we are now evaluating if spreading of “advance
directives”, palliative care, home and retirement home caring can reduce the gender effect in TMV.
VOLTAGE-GATED POTASSIUM CHANNEL ANTIBODIES IN SLOW PROGRESSION MOTOR NEURON
DISEASE
M. Godani1, M. Zoccarato2, A. Beronio1, L. Zuliani3, L. Benedetti4, B. Giometto2, A. Mannironi1, M. Del Sette5, E. Raggio6,
R. Baldi6, A. Vincent7
1
Neurology Unit, Sant'Andrea Hospital (La Spezia); 2Neurology Unit, Sant'Antonio Hospital (Padova); 3Neurology Unit, Cà
Foncello Hospital (Treviso); 4Neurology Unit, San Martino Hospital (Genova); 5Neurology Unit, Galliera Hospital
(Genova); 6Epidemiology Unit, Sant'Andrea Hospital (La Spezia); 7Nuffield Department of Clinical Neurosciences, Oxford
University (Oxford-UK)
Background: The spectrum of autoimmune neurological diseases associated with voltage-gated potassium channel (VGKC)complex antibodies (Abs) ranges from peripheral nerve disorders to limbic encephalitis. Recently, low titers of VGKCcomplex Abs have been also reported in neurodegenerative disorders but their clinical relevance is unknown [1-2].
Objective: The aim of the study was to explore the prevalence of VGKC-complex Abs in slow progression motor neuron
disease (MND).
Methods: We compared eleven patients affected by slow progression MND with nine patients presenting typical progression
illness. Sera were tested for VGKC-complex Abs by radioimmunoassay. The distribution of VGKC-complex Abs was
analyzed with the Mann-Whitney U test.
Results: The statistical analysis showed a significant difference between the mean values in study and control group. A case
with long survival MND harboring VGKC-complex Abs and treated with intravenous immunoglobulins (IVIG) is
described.
Discussion: Recently it has been demonstrated that axonal degeneration rather than motor neuron loss is the cause of disease
acceleration in animal models and that the immune system made a major contribution to the variability of the disease
course. In particular the upregulation of immune molecoles such as complement and MHCI may be responsible of a more
efficient axonal preservation in the slowly progressing transgenic mice [3].
Conclusion: Although VGKC-complex Abs are not likely to be pathogenic these results could reflect the coexistence of an
immunological activation in patients with slow disease progression.
References:
− Fujita K, Yuasa T, Watanabe O, Takahashi Y, Hashiguchi S, Adachi K, et al. Voltage-gated potassium channel
complex antibodies in Creutzfeldt-Jakob disease. J Neurol. (2012) Oct;259(10):2249–50
− Nwosu VK, Royer JA, Stickler DE. Voltage gated potassium channel antibodies in amyotrophic lateral sclerosis.
Amyotroph Lateral Scler Off Publ World Fed Neurol Res Group Mot Neuron Dis. (2010) Aug;11(4):392–4
− Nardo G, Trolese MC, Tortarolo M, Vallarola A, Freschi M, Pasetto L et al. New insights on the mechanism of
disease course variability in ALS from mutant SOD1 mouse models. Brain Pathol. (2016);26:237-247
IS THERE A COHORT EFFECT IN ALS INCIDENCE? FINDING FROM AN ITALIAN POPULATION-BASED
REGISTER, 1995-2014
A. Chiò1, A. Calvo1, T. Bertuzzo1, S. Cammarosano1, A. Ilardi1, C. Moglia1, A. Canosa1, U. Manera1, P. Cugnasco1, L.
Solero1, F. Pisano2, R. Cantello3, E. Bersano3, G. Mora2, L. Mazzini3
1
Department of Neuroscience, University of Turin (Torino); 2Department of Neurological Rehabilitation, Salvatore Maugeri
Foundation IRCCS (Veruno-NO); 3Department of Neurology, University of Eastern Piedmont (Novara)
pag. 58
Background: Epidemiology of ALS has been widely studied in western countries, while fewer data are available for
developing areas. However, data on long term epidemiological trends of ALS are still quite scarse.
Aims: To evaluate the 20-years ALS epidemiological and demographic trends in the Piemonte and Valle d’Aosta Register
for
ALS
(PARALS),
a
prospective
ALS
epidemiological
register
in
Italy.
Methods: ALS cases meeting El Escorial diagnostic criteria were enrolled using multiple sources in the period 1995-2014 in
two Italian regions, Piemonte and Valle d’Aosta. Clinical and demographic data were collected, including survival.
Incidence rates were standardized to the 2001 Italian population. Confidence intervals were calculated using a Poisson
distribution.
Results: A total of 2699 patients were diagnosed in the period of the study, 1453 males and 1246 females (ratio 1.17:1). The
mean age at onset was 65.7 (SD 11.1) with a 1.2 years increase from the 1995-1999 (65.1, SD 11.1) to the 2005-2014 period
(66.3, SD 11.1) (p=0.002). This increase paralleled the increase of the median age of the Piemonte population in the same
period. The mean diagnostic delay decreased from 11.4 (SD 0.3) months to 10.9 (SD 0.3) months. The mean annual crude
incidence rate was 3.03/100,000 population (95% c.i., 2.85 to 3.22; males 3.37; females 2.71; male to female rate ratio
1:24:1). The crude incidence rate increased from 2.83 (2.66-3.01) (1995-1999) to 3.21 (3.02-3.42) (2005-2014) /100,000
population/year. However, when standardized to the 2001 Italian census, the incidence rate showed a minor increase, from
2.67 (2.51-2.84) (1995-2004) to 2.85 (2.68-3.03) (2005-2014)/100,000 population/year. The increasing trend of ALS
incidence was mostly due to the increase of the incidence rate in women (2.37 [2.17-2.58] vs 2.67 [2.48-2.88]) while the
incidence rate remained substantially steady among men (3.01 [2.79-3.31] vs. 3.06 [2.85-3.29]). Therefore, the male to
female adjusted rate ratio significantly decreased from 1.27:1 to 1.17:1 (p=0.01). The prevalence rate (December 31st,
2014)
was
10.6/100,000
population
(10.0-11.3).
Discussion: The epidemiology of ALS in the 20-year period of the study showed an increased mostly limited to women.
The increase of the crude incidence rate may be mostly ascribed to the increase of the median age of the population. This
findings points toward a strong genetic basis of ALS.
DTI CORRELATES OF DYSARTHRIC DEFICIT IN AMYOTROPHIC LATERAL SCLEROSIS
A. Merico1, M. De Marco2, A. Venneri1, F. Burgio1, G. Berta1, F. Meneghello1
1
San Camillo Hospital Foundation, IRCCS (Venezia Lido –VE); 2Department of Neuroscience, University of Sheffield,
(Sheffield – UK)
Objective: Dysarthria is a very common symptom in patients with Amyotrophic Lateral Sclerosis (ALS) which affects
communication effectiveness and quality of life. Dysarthria is the result of a dysfunctional interplay among breathing,
phonation, vocal resonance and articulation. It has been suggested that the integration of the various aspects that contribute
to speech execution is controlled by a complex cerebral network. Although most of the linguistic testing includes an
executive component, there is evidence that the linguistic alterations observed in ALS are, at least in part, independent of
executive dysfunction (Taylor et al., 2013).
Material and Method: In our previous study (De Marco et al., 2015), 23 ALS patients had a structural 3D MRI scan,
neuropsychological, linguistic and speech assessments. Twenty-three healthy adults of comparable age, education, whitematter hyperintensity load and intracranial volumes were also recruited. Between-group differences in grey matter and
white matter (WM) were examined to characterise ALS patients accurately. The association between residual speech and
volumetric maps was studied in these patients. Results demonstrated that ALS patients showed a pattern of WM reduction,
which was located in peri-cortical motor/premotor fibres bilaterally, and in a large volume extending from the
pons/midbrain to the cerebellum. A speech composite score was computed, and this was positively associated with
premotor/supplementary-motor WM bilaterally, and right cerebellar WM. Since premotor associations were found in
volumes where ALS patients showed WM reduction, this region is believed to be directly involved in speech execution in
this group. Since cerebellar associations were instead found in volumes free from shrinkage, this region is interpreted as
playing a modulatory role, compensating for the impact of ALS pathology. In this later study we carried out further analyses
on a larger sample of patients (34), to evaluate a possible association between residual pneumo-phono-articulatory abilities
and microstructural parameters of the white matter tracts (fractional anisotropy and mean diffusivity).
Results: The results showed negative correlations between pneumo-phono-articulatory abilities and mean diffusivity. All
significant results were found in the right hemisphere, in particular in the superior and inferior longitudinal fasciculi, in the
inferior fronto-occipital fasciculus and in the Inferior longitudinal fasciculus.
Discussion: These results seem to confirm a relationship between dysarthria and regions directly involved in speech
execution.
References:
pag. 59
−
−
Taylor LJ, Brown RG, Tsermentseli S, Al-Chalabi A, Shaw CE, Ellis CM, et al. Is language impairment more
common than executive dysfunction in amyotrophic lateral sclerosis? J Neurol Neurosurg Psychiatry
(2013);84:494–8
De Marco M, Merico A, et al. Morphometric correlates of dysarthric deficit in amyotrophic lateral sclerosis.
Amyotroph Lateral Scler Frontotemporal Degener. (2015) Jun 29:1-9
DEMENZA E INVECCHIAMENTO 1
MICROSTRUCTURAL DAMAGE OF THE WHITE MATTER IN THE FRONTAL ASLANT TRACT
ACCOUNT FOR VISUO-SPATIAL PERFORMANCES IN PATIENTS WITH ALZHEIMER’S DISEASE
L. Serra1, G. Bechi Gabrielli1, E. Tuzzi1, B. Spanò1, C. Marra2, C. Caltagirone3, M. Cercignani4, M. Bozzali1
1
Neuroimaging Laboratory, Santa Lucia Foundation IRCCS (Roma); 2Institute of Neurology, Catholic University (Roma);
Department of Clinical and Behavioural Neurology; Department of Neuroscience, Santa Lucia Foundation IRCCS;
University of Rome ‘Tor Vergata’ (Roma); 4Brighton & Sussex Medical School, Clinical Imaging Sciences Centre,
University
of
Sussex
(Brighton-UK)
3
Aim: Constructional praxis relies on a network consisting of inferior parietal and pre-motor regions, and it is thought to
require transformation of spatio-temporal representation (parietal regions) into movement sequences (pre-motor regions)
[1]. The Frontal Aslant Tract (FAT) has been recently described as a bundle connecting the Broca’s area to the
Supplementay Motor Area (SMA) and to the pre-SMA in both hemispheres [2; 3]. The functional properties of this
connection are currently unknown especially in dementia, such as Alzheimer’s disease (AD). We aimed to explore the
microstructural integrity of the FAT in patients with AD and its potential relationship with cognitive functioning.
Materials and Methods: 23 patients with AD, and 25 healthy subjects (HS) were enrolled All subjects underwent cognitive
evaluation and MRI examination at 3T. MRI including diffusion sequences used for probabilistic tractography analysis. We
reconstructed individual FAT bilaterally and assessed their microstructural integrity by both mean fractional anisotropy
(FA) value and by voxel-by-voxel analysis using SPM-8. Then, we used mean FA values for correlations with cognitive
measures.
Results: There were no differences in demographic variables between the two groups. Both analysis on mean FA and voxelwise analyses revealed that patients with AD showed decreased FA in the bilateral FAT respect to HS. In addition, we
showed in AD patients positive association between bilateral FAT and tests assessing constructional praxis and visuo-spatial
logical reasoning.
Discussion: The present results reveled a bilateral damage of FAT in patients with AD. Moreover, we found association
between damage to the FAT and constructive abilities, and it fits well with the knowledge of a functional involvement of
SMA and pre-SMA in the movement sequences required to successfully execute the constructive praxis task. We speculate
that praxis tasks can be mediated by integrity of the FAT in patients with AD.
Conclusions: The FAT is an associative bundle critically involved in the network sub serving the constructional praxis in
patients with AD.
References:
− Serra L, Fadda L, Perri R, Spanò B, Marra C, Castelli D, Torso M, Makovac E, Cercignani M, Caltagirone C,
Bozzali M. Constructional apraxia as a distinctive cognitive and structural brain feature of pre-senile Alzheimer's
disease. J Alzheimers Dis. (2014);38(2):391-402
− Catani M, Mesulam MM, Jakobsen E, Malik F, Martersteck A, Wieneke C, Thompson CK, Thiebaut de Schotten
M, Dell'Acqua F, Weintraub S, Rogalski E.A novel frontal pathway underlies verbal fluency in primary
progressive aphasia. Brain (2013) Aug;136(Pt 8):2619-28
− Martino J, De Lucas EM. Subcortical anatomy of the lateral association fascicles of the brain: A review. Clin Anat.
(2014) May;27(4):563-9
HOW NON-CONVERTER MCI PATIENTS COULD BE DISTINGUISHED FROM MCI DUE TO AD ALREADY
AT FIRST VISIT: A FDG-PET STUDY
A. Picco1, F. De Carli2, S. Morbelli3, M. Baucknhet3, D. Arnaldi1, N. Girtler1, A. Brugnolo1, A. Chincarini4, M. Pardini1, G.
Sambuceti3, M. Pagani5, F. Nobili1
pag. 60
1
Clinical Neurology, Dept. of Neuroscience (DINOGMI), University of Genova, IRCCS AOU San Martino-IST (Genova);
Institute of Bioimaging and Molecular Physiology, National Research Council (Genova); 3Nuclear Medicine Department of
Health Sciences (DISSAL), University of Genova, IRCCS AOU San Martino-IST (Genova); 4Section of Genova, I-16146, I
National Institute of Nuclear Physics (Genova); 5Institute of Cognitive Sciences and Technologies, National Research
Council (Roma)
2
Introduction: In the clinical practice, the challenge is not to distinguish normal subject from patients with overt Alzheimer’s
Disease (AD), but to discriminate Mild Cognitive Impairment (MCI) patients who will convert to dementia (MCI-AD) from
those who will not convert (ncMCI). FDG-PET is a widely used biomarker that could ideally work this out, but to date
analyses had a limited follow-up (FU) time. This might have hampered to focus on conversion-related regions because
ncMCI themselves can show hypometabolism in critical areas. In this study, we identify the baseline FDG-PET brain
regions discriminating MCI-AD from ncMCI with a minimum FU of 4 years.
Methods: We analyzed baseline FDG-PET of 95 consecutive MCI-AD (mean±SD= age:75.23±6.68; 30 males; MMSE
score:26.0±1.84; conversion time:3.82±1.76) and of 27 ncMCI (age:71.87±6.40; 16 males; MMSE score:26.85±1.41; FU
time:5.16±1.59). An in-house created Matlab-based script extracted uptake values from 45 Automated Anatomical
Labelling (AAL) Atlas volumes of interest (VOIs) in each hemisphere, then we merged regions with similar anatomofunctional characteristics into 12 meta-VOIs in each hemisphere. Global counts were normalized using mean cerebellar
counts. Analysis was performed by a non-linear classifier based on the Support Vector Machine (SVM) method with Radial
Basis Functions.
Results: SVM discriminates MCI-AD from ncMCI patients with more than 80% accuracy when using at least three metaVOI. Right putamen/pallidum/caudate (rPPC); left cingulate gyrus (lCC); right temporal pole (rTP) reached the highest
accuracy (82.8%, CI:76.1-89.5) with 80.0% sensitivity (CI:72.0-88.0) and 92.6% specificity (CI:82.7-100.0) after ‘leaveone-out’ cross-validation. Within this meta-VOI, mean FDG-PET uptake values were significantly lower in MCI-AD than
in ncMCI in lCC (mean±SE=1.054±0.01 vs 1.226±0.012; p<0.0001) and in rTP (0.987±0.008 vs 1.030±0.008; p=0.007).
Values relevant to rPPC were not significantly different between groups (1.065±0.007 vs 1.085±0.011) but this region
contributed to the discrimination acting as a reference: a larger difference between rPPC and the other two regions increased
conversion probability.
Discussion and conclusions: While amyloid biomarkers can detect AD pathology but no meaningful informations on
clinical stage and disease progression, FDG-PET can identify specific regions directly involved in progression to dementia,
which are spared in ncMCI patients. In this frame, specificity was even higher than sensitivity ensuring a good prognosis to
patients with preserved metabolic levels in lCC and rTP, but with similar metabolic levels in rPPC as MCI-AD, when seen
for the first time in a memory clinic. This could be pivotal even in the era of the new amyloid PET ligands.
References:
− Pagani et al. Volume of interest-based [18F]fluorodeoxyglucose PET discriminates MCI converting to Alzheimer's
disease from healthy controls. A European Alzheimer's Disease Consortium (EADC) study. Neuroimage Clin.
(2014) Nov 18;7:34-42
− Pagani et al. Metabolic spatial connectivity in amyotrophic lateral sclerosis as revealed by independent component
analysis. Hum Brain Mapp. (2016) Mar;37(3):942-53
− Arbizu J et al. Automated analysis of FDG PET as a tool for single-subject probabilistic prediction and detection of
Alzheimer’s disease dementia. Eur J Nucl Med Mol Imaging (2013);40:1394–1405
STRUCTURAL AND FUNCTIONAL BRAIN CONNECTOME ARCHITECTURE IN ALZHEIMER’S DISEASE
AND AMNESIC MILD COGNITIVE IMPAIRMENT PATIENTS
S. Basaia1, F. Agosta1, E. Canu1, S. Galantucci1, A. Meani1, F. Caso1, G. Magnani2, R. Santangelo2, M. Falautano2, A.
Falini3, G. Comi2, M. Filippi1,2
1
University (Milano); 2Department of Neurology, San Raffaele Scientific Institute, Vita-Salute San Raffaele University
(Milano); 3Department of Neuroradiology San Raffaele Scientific Institute, Vita-Salute San Raffaele University (Milano)
Objective: To investigate structural and functional brain network architecture, and their relationship, in Alzheimer’s disease
(AD) patients and in amnesic mild cognitive impairment converters to AD (c-aMCI) and noncoverters (nc-aMCI).
Materials:
The
study
involved
97
AD,
51
aMCI
(24
c-aMCI),
and
51
controls.
Methods: Subjects underwent 3D T1-weighted, Diffusion Tensor (DT) and resting-state functional MRI. Graph analysis and
connectomics were used to assess global topological network properties and structural and functional connectivity
pag. 61
differences among groups. All patients were clinically followed up for 2.5 years, and patients with aMCI were reclassified
into two groups (converters and nonconverters to AD).
Results: Compared with controls, AD and MCI patients showed altered global structural network measures (lower nodal
strength, clustering coefficient, and longer path length). Compared to other groups, AD showed also altered global
functional network properties (lower nodal strength and longer path length). At the regional network level, compared to
controls: AD and c-aMCI patients showed a widespread pattern of structural connectivity alterations; AD patients showed
decreased functional connectivity involving precuneus, inferior parietal nodes, hippocampi, middle occipital and superior
temporal nodes, bilaterally; c-aMCI patients showed decreased functional connectivity involving the anterior cingulate
cortex bilaterally, and the left precuneus and hippocampus; nc-aMCI showed only a few connections with altered structural
connectivity and no functional connectivity abnormalities. Compared to nc-aMCI cases, AD and c-aMCI patients showed
structural (but not functional) connectivity alterations involving hippocampi, parieto-occipital and middle fronto-temporal
nodes, with a greater extent in AD. In AD patients, the loss of structural connectivity correlated with the decreased
functional
connectivity
in
the
same
regions.
Discussion: Global graph properties of brain networks are severely altered in AD, and, structurally, also in the aMCI
groups. Regional analysis showed that structural network degeneration is widespread in both AD and c-aMCI, while
functional connectivity alterations are more focal affecting the limbic and parietotemporal pathways in both groups. In
keeping with the neuron-to-neuron propagation hypothesis, the larger pattern of brain network structural than functional
connectivity alterations in AD and c-aMCI patients suggests that a reduced structural integrity preceeds functional
connectivity changes. The more severe loss of structural connectivity in c-aMCI than nc-aMCI cases highlights the role of
DT
MRI
as
a
tool
to
predict
the
conversion
into
AD.
Conclusions: Graph analysis is a powerful approach to assess brain network degradation in AD and to identify predictors of
AD conversion in aMCI patients. Supported by: #GR-2010-2303035; ADDF #20131211.
BRAIN DIFFUSION-BASED HISTOGRAM ANALYSIS TO PREDICT CONVERSION FROM MCI TO AD
G. Giulietti1, M. Torso1, L. Serra1, B. Spanò1, C. Marra2, M. Cercignani3, M. Bozzali1
1
3
Neuroimaging Laboratory, IRCCS Santa Lucia Foundation (Roma); 2Institute of Neurology, Catholic University (Roma);
Clinical Imaging Sciences Centre, University of Sussex (Brighton-UK)
White matter involvement is known to occur early in Alzheimer’s disease (AD) and to actively contribute to disease
progression [1]. Aim of this study was to explore the added value of white matter histogram analysis applied to diffusion
tensor imaging (DTI) brain data in predicting the conversion from mild cognitive impairment (MCI) to AD. We investigated
57 patients with AD, 28 patients with amnestic MCI and 23 cognitively healthy subjects (HS). All participants received an
extensive neuropsychological examination and MRI scanning at 3.0T, including the acquisition of dual-echo turbo spinecho images, 3D-T1-weighted volumes, and DTI scans. MCI patients were clinically followed-up for 2 years. T1 images
were first segmented to obtain white matter (WM) masks. Then, lesions masks were drawn by using a semi-automated
contouring technique on hyperintensities in T2-weighted images; these masks were used for normal appearing white matter
(NAWM) mask definition. From DTI images, fractional anisotropy (FA), mean diffusivity (MD), axial diffusivity (AXD)
and radial diffusivity (RD) maps were computed. After image coregistration, NAWM histograms of all these DTI measures
were derived, and the following histogram quantities were estimated: peak height, peak location, mean value (MV), and
quartiles (C25, C50, C75) [2]. We run a between group comparison of all measures (p<0.05, Bonferroni corrected). Then,
receiver operating characteristic (ROC) and area under ROC curves (AUC) were estimated for each histogram-derived
measure surviving group comparisons. WM lesion volumes did not differ across groups, while FA and RD values within
lesions showed, respectively, lower and higher values in all patients (MCI and AD) compared to HS. NAWM histogram
analysis revealed significant differences between HS and patients in C25, C50 and MV of MD, AXD and RD. The AD
compared to the MCI group showed significantly higher values of C25AXD. ROC analysis revealed that this same
parameter has the best capability to discriminate between HS, MCI and AD patients, with the maximum value of AUC.
Finally, a C25AXD cut-off was identified to distinguish, at baseline, between MCI converters and non-converters over
clinical follow-up. This study confirms the WM involvement across AD evolution. This process mostly targets the NAWM,
but shows also a peculiar pattern of microscopic changes within patients’ WM lesions. C25AXD appears as the most
sensitive parameter with the ability to discriminate between MCI converters and non-converters in short time. We propose
C25AXD as a putative biomarker for future clinical trials.
References:
− Bozzali M, Serra L, Cercignani M. Quantitative MRI to understand Alzheimer's disease pathophysiology. Curr
Opin Neurol. (2016) May 25. [Epub ahead of print]
pag. 62
−
Tofts PS, Davies GR, Dehmeshki J. Histograms: Measuring Subtle Diffuse Disease. In: Quantitative MRI of the
brain: measuring changes caused by disease. P. Tofts (Ed). John Wiley & Sons, Ltd, Chichester, UK, (2003);581610
LONGITUDINAL CHANGES IN MOCA PERFORMANCES IN PATIENTS WITH MILD COGNITIVE
IMPAIRMENT AND SMALL VESSEL DISEASE. RESULTS FROM THE VMCI-TUSCANY STUDY
E. Salvadori1, A. Poggesi1, G. Pracucci1, A. Chiti2, L. Ciolli1, A. Del Bene1, I. Di Donato3, S. Marini1, S. Nannucci1, G.
Orlandi2, M. Pasi1, F. Pescini4, R. Valenti1, A. Federico3, M. Dotti3, U. Bonuccelli2, D. Inzitari1, L. Pantoni1
1
NEUROFARBA Department, Neuroscience Section, University of Florence (Firenze); 2Department of Neurosciences,
University of Pisa (Pisa); 3Department of Neurological and Behavioral Sciences, University of Siena (Siena); 4Stroke Unit,
Careggi University Hospital (Firenze)
Objectives: The Montreal Cognitive Assessment (MoCA) is a brief cognitive test originally designed to identify mild
cognitive impairment (MCI). MoCA includes cognitive domains typically affected in cerebral small vessel disease (SVD),
and has been proposed for the screening assessment of vascular cognitive impairment. Despite its popularity, there are no
data about longitudinal changes in MoCA performances in patients with SVD. We aimed to describe the changes in MoCA
performance in patients with MCI and SVD during 2-year follow-up.
Materials and Methods: The VMCI-Tuscany Study is a prospective, observational, multicenter study that enrolled patients
with MCI and evidence on MR of SVD (moderate-severe white matter hyperintensities). Patients underwent comprehensive
clinical, functional and neuropsychological assessments at baseline, and after 1-2 years. A MoCA score <5th centile of the
normal national population was classified as impaired. The primary outcome of the study was dementia diagnosed
according to DSM-V criteria.
Results: Among the 153 patients enrolled in the VMCI-Tuscany basal cohort, 138 (mean age 74.4±6.9 years; males: 57%)
had follow-up information sufficient to formulate dementia diagnosis, and 44 (32%) received a diagnosis of dementia. A
delta score (∆-MoCA), corresponding to the difference between basal MoCA score and MoCA score at dementia diagnosis,
was computed. MoCA performances changed from baseline to final evaluation as follows: percentages of patients with
impaired performance increased from 19% (basal) to 27% (1-year) and 31% (2-years), while percentages of patients with
normal performance decreased from 66%, to 58% and 56%, respectively. Comparing patients diagnosed as demented and
patients who remained stable, MoCA score at the basal evaluation resulted significantly different between groups (mean
MoCA score 18.1±4.8 and 20.7±4.9 respectively, p=.005), as well as ∆-MoCA (mean ∆-MoCA 2.6±4.3 and 1±3.2
respectively, p=.049). Multivariate logistic models using transition to dementia as a dependent variable, and basal MoCA
score or ∆-MoCA as predictors together with age, education, sex, hypertension, diabetes, and stroke, were applied. In both
models, only the basal MoCA score (OR=.886, 95%CI=.810-.970, p=.009) or the ∆-MoCA (OR=1.137, 95%CI=1.0141.276, p=.029) resulted significantly associated with the transition to dementia.
Discussion: In a sample of patients with MCI and SVD longitudinally evaluated for 2 years, MoCA scores resulted to be
sensitive to change over time, as a function of natural progression of the cerebrovascular disorder, independently of
demographic and vascular risk factors. MoCA was confirmed as a valid screening protocol with a good predictive power in
vascular cognitive impairment. (Study sponsored by Tuscany Region).
APOE POLYMORPHISM AND CORTICAL PLASTICITY ARE INDEPENDENTLY ASSOCIATED WITH
COGNITIVE DECLINE IN ALZHEIMER’S DISEASE
F. Di Lorenzo, C. Motta, V. Ponzo, S. Bonnì, C. Caltagirone, A. Martorana, G. Koch
Fondazione Santa Lucia, Tor Vergata University (Roma)
Objectives: APOE E4 allele associates not only with AD risk and a lower age onset, but also with faster cognitive decline
and greater cerebral atrophy, suggesting a key role of this polymorphism in modulating both disease risk and clinical
outcome. In this study we investigated the correlation between cognitive decline, motor cortical plasticity and cerebrospinal
fluid (CSF) biomarkers profile of AD patients divided by APOE polymorphism in E4 allele carriers (E4) and homozygous
E3 carriers.
Materials and Methods: A monophasic Magstim 200 device was used to deliver intermitted/continuous theta burst
stimulation (iTBS/cTBS) protocols. ELISA was used for determination of CSF biomarkers level. Forty-one AD patients
underwent lumbar puncture for CSF withdrawal, blood screening for APOE polymorphism, stimulation protocols applied
over the primary motor cortex and mini mental state examination (MMSE) at baseline and at 6-, 12- and 18-months.
pag. 63
Results: No difference was found in CSF biomarkers profile within the APOE variants group. I-TBS after-effects were
significantly reduced in E3 in comparison with E4 AD patients. Correlation analyses revealed that the individual amount of
iTBS induced plasticity correlated with delta-MMSE and total Tau showing that a less pronounced LTP-like plasticity and
higher total-Tau CSF levels were associated with a higher delta-MMSE. Only in apoE4 patients Tau pathology correlates
with cortical plasticity impairment and cognitive decline. A multivariate analysis showed that APOE polymorphism and
LTP-like plasticity, but not t-Tau levels, are independently able to predict delta-MMSE in AD patients.
Discussion: APOE variants show different level of cortical plasticity and are independently associated with clinical
progression in AD patients. APOE polymorphism and LTP-like plasticity impairment, but not CSF t-Tau levels, are
independently able to predict cognitive decline in AD patients.
Conclusions: Tau pathology is specific for ApoE4 group driving cortical plasticity impairment and cognitive decline.
ApoE4 patients represent a pure model of TAU-driven AD pathology. ApoE3 patients are characterized by different
mechanisms of cortical plasticity impairment and clinical symptoms. LTP impairment is a marker of pathophysiological
dysfunction in AD and, as such, it should be taken in account also for the adoption of new pharmacological strategies,
considering AD as a disorder of synaptic plasticity.
ASSOCIATION BETWEEN GAIT, COGNITION AND GREY MATTER VOLUMES IN MCI AND HEALTHY
CONTROLS
F. Meneghello1, E. Cosentino1, M. Mitolo1, C. Della Pieta’1, V. Iaia1, G. Levedianos1, A. Venneri2
1
Neurorehabilitation Department, IRCCS San Camillo Hospital Foundation (Venezia); 2Neurorehabilitation Department,
IRCCS San Camillo Hospital Foundation, University of Sheffield (Sheffield – UK)
Objective: Recent evidence shows that gait abnormalities, as well as cognitive decline, can be found early in the course of
Alzheimer’s disease (AD). However, only few studies have examined the differences in terms of cognitive abilities and
brain structures involved in gait control in AD. The goal of this study was to investigate differences in gait speed, cognition
and their association with grey matter volumes between healthy older people and patients with mild cognitive impairment
(MCI).
Materials: Thirty-four MCI patients and forty-two healthy controls were included in this study. All participants were
assessed with a neuropsychological testing and 3D structural MRI. The cognitive battery included 16 tests. T1-weighted
images were acquired. Quantitative gait measurements were collected from all participants walking a fixed distance (10 m)
along a delimited indoor walkway.
Methods: MRI signal was pre-processed and modelled with SPM 12. A standard VBM procedure was used to calculate
tissue-class volumetric maps. Total Intracranial Volume (TIV) was also extracted. Multiple-regression analyses were carried
out to identify brain regions in which grey-matter (GM) volume was significantly associated with average gait speed.
Additionally, age, education, MMSE and TIV were included in the models as nuisance regressors.
Results: A significant positive association between average gait speed and GM volumes was found in frontal areas and in
the cerebellum in the analysis which involved the overall sample including both MCI and healthy controls. A significant
association between average gait speed and GM volumes in the cerebellum was found when only data from the control
group were included in the analysis. Significant associations between average gait speed and GM volumes in a large
network of frontal and temporal areas and in the cerebellum were found when the data of only the MCI patients were
included in the analysis.
Discussion: Gait measurements are associated with cognitive performance in ageing. These appear to be linked to GM
volumetric decrements in regions which are affected by neurodegeneration due to AD early, as well as regions involved in
motor control and control of balance.
Conclusions: Measures of gait can be useful proxies of cognitive decline in healthy and abnormal ageing.
References:
− Bahureksa L., Najafi B., Saleh A., Sabbagh M., Coon D., Mohler M.J., Schwenk M. The Impact of Mild Cognitive
Impairment on gait and balance: A systematic review and meta-analysis of studies using instrumented assessment.
Gerontology (2016) [Epub ahead of print]
− Allali G, Annweiler C, Predovan D, Bherer L, Beauchet O. Brain volume changes in gait control in patients with
mild cognitive impairment compared to cognitively healthy individuals; GAIT study results. Exp Gerontol. (2016)
Apr;76:72-9
− Kikkert LH, Vuillerme N, van Campen JP, Hortobágyi T, Lamoth CJ. Walking ability to predict future cognitive
decline in old adults: A scoping review. Ageing Res Rev. (2016) May;27:1-14
pag. 64
NATURAL HISTORY OF MILD COGNITIVE IMPAIRMENT AND CEREBRAL SMALL VESSEL DISEASE:
LONGITUDINAL RESULTS FROM THE VMCI-TUSCANY STUDY
A. Poggesi1, E. Salvadori1, G. Pracucci1, A. Chiti2, L. Ciolli1, M. Cosottini2, N. De Stefano3, A. Del Bene1, I. Di Donato3, S.
Diciotti4, A. Ginestroni5, S. Marini1, S. Nannucci1, G. Orlandi2, M. Pasi1, F. Pescini6, R. Valenti1, M. Mascalchi7, A.
Federico3, M. Dotti3, U. Bonuccelli2, D. Inzitari1, L. Pantoni1
1
NEUROFARBA, Neuroscience Section, University of Florence (Firenze); 2Dept. Neuroscience, University of Pisa (Pisa);
Dept. of Neurological and Behavioral Sciences, University of Siena (Siena); 4Dept. Electrical, Electronic, and Information
Engineering 'Guglielmo Marconi', University of Bologna (Cesena); 5Neuroradiology Unit, Radiology Dept., Azienda
Ospedaliero-Universitaria Careggi (Firenze); 6Stroke Unit, Azienda Ospedaliero-Universitaria Careggi (Firenze);
7
Radiodiagnostic Section, Dept. Clinical Physiopathology, University of Florence (Firenze)
3
Objective: Mild cognitive impairment (MCI) is considered as a transitional state from normal cognition to dementia.
Although the concept of MCI derives from the field of Alzheimer’s disease, pre-dementia stages of vascular dementia also
exist. The impairment captured in MCI is not always progressive, with a proportion of cases reverting to normal or
remaining stable at follow-up. Our aim was to describe the natural history of MCI with cerebral small vessel disease during
a 2-year follow-up.
Methods: The Vascular MCI-Tuscany Study is a longitudinal, observational, Italian multicenter study that enrolled patients
with MCI, defined according to Winblad criteria, and evidence on MR of cerebral small vessel disease, defined as moderate
or severe white matter hyperintensities (WMH) according to a modified version of the Fazekas scale. On entry, patients
underwent comprehensive clinical, neuropsychological, and functional evaluation, that was repeated after 12 and 24
months. The primary outcome of the study was transition to dementia diagnosed according to DSM-V criteria.
Results: One-hundred-fifty-three patients (mean age 74.7+/-6.9; males: 55%) with MCI and moderate-severe WMH were
enrolled. After a median follow-up of 24 months (interquartile range 15-25 months), complete follow-up information,
sufficient to formulate dementia diagnosis, was available for 138 patients (mean age 74.4+/-6.9; males: 57%). Of these, 10
(7%) reverted to normal cognitive function, 84 (61%) remained MCI, and 44 (32%) received a diagnosis of dementia.
According to DSM-V criteria, 35 patients had mild dementia, 9 patients moderate dementia.
Conclusions: Data form the VMCI-Tuscany study showed that, after 2-year follow-up, at least one third of the study cohort
progressed to dementia, with few patients reverting to normal cognitive function. Future work will highlight which are the
major determinants, among clinical, neuroimaging and biological markers, of such transition.
The VMCI-Tuscany study is funded by Tuscany region (Programma per la Ricerca Regionale in Materia di Salute 2009).
MALATTIE NEUROMUSCOLARI 1
ATALUREN: AN OVERVIEW OF CLINICAL TRIAL RESULTS IN NONSENSE MUTATION DUCHENNE
MUSCULAR DYSTROPHY
G. P. Comi1, E. Bertini2, E. Mercuri3, S. Messina4, X. Luo5, G. Elfring5, H. Kroger5, P. Riebling5, T. Ong5, R. Spiegel5, S.
Peltz5, A. the Ataluren DMD Study Group6
1
Department of Pathophysiology and Transplantation (DEPT), University of Milan (Milano); 2Department of Neurosciences
Unit of Neuromuscolar and Neurodegenerative Disorders, Bambin Gesù Childrens’ Hospital (Roma); 3Department of
Paediatric Neurology, Catholic University (Roma); 4Department of and Experimental Medicine, University of Messina
(Messina); 5Clinical Development, PTC Therapeutics (South Plainfield-USA); 6Steering Committee, University Medical
Center Freiburg (Freiburg-D)
Objective: Provide an overview of ataluren clinical trial results in patients with nonsense mutation Duchenne muscular
dystrophy (nmDMD).
Background: Ataluren is the first drug to treat the underlying cause of nmDMD. It enables ribosomal readthrough of a
premature stop codon to produce full-length functional dystrophin, without affecting normal stop codons. Design/Methods:
Phase 2 and 3 clinical trials of ataluren in nmDMD were reviewed, with efficacy and safety/tolerability findings
summarized.
pag. 65
Results: Clinical trials of ataluren in nmDMD include: a Phase 2a proof-of-concept study (N=38) whose primary endpoint
was muscle dystrophin expression following 28 days of treatment; a Phase 2b randomized controlled trial (RCT) (N=174),
whose primary endpoint was change in six-minute walk distance (6MWD) over 48 weeks; an ongoing US-based open-label
extension study (N=108) evaluating long-term safety; an ongoing non-US-based open-label extension study (N=94)
evaluating long-term safety and efficacy; and a Phase 3 RCT, ACT DMD (N=228), whose primary endpoint was change in
6MWD over 48 weeks. The proof-of-concept study demonstrated increases in dystrophin production in post-treatment
muscle biopsies from ataluren-treated patients with nmDMD. The Phase 2b results demonstrated an ataluren treatment
effect in 6MWD, timed function tests, and other measures of physical functioning, with larger treatment effects observed in
patients at higher risk of ambulatory decline. This study was the basis for ataluren’s approval in the European Union. The
Phase 3 ACT DMD results demonstrated an ataluren treatment effect in patients with nmDMD in both primary and
secondary endpoints, particularly in those with a baseline 6MWD of 300−400m. Ataluren was consistently well-tolerated in
all three trials, as well as in the ongoing extension studies. Trial findings will be presented in detail.
Conclusions: The totality of the results demonstrates that ataluren enables nonsense mutation readthrough in the dystrophin
mRNA, producing functional dystrophin and slowing disease progression in patients with nmDMD. Study Supported By:
PTC Therapeutics Inc.
References:
− Bushby K, Finkel R, Wong B, Barohn R, Campbell C, Comi GP, Connolly AM, DayJW, Flanigan KM, Goemans
N, Jones KJ, Mercuri E, Quinlivan R, Renfroe JB, Russman B, Ryan MM, Tulinius M, Voit T, Moore SA, Lee
Sweeney H, Abresch RT, Coleman KL, Eagle M, Florence J, Gappmaier E, Glanzman AM, Henricson E, Barth J,
Elfring GL, Reha A, Spiegel RJ, O'donnell MW, Peltz SW, Mcdonald CM; PTC124-GD-007-DMD STUDY
GROUP. Ataluren treatment of patients with nonsense mutation dystrophinopathy. Muscle Nerve. (2014);
50(4):477-87
PATISIRAN, AN INVESTIGATIONAL RNAI THERAPEUTIC FOR THE TREATMENT OF HEREDITARY
ATTR AMYLOIDOSIS WITH POLYNEUROPATHY (HATTR-PN): BASELINE DEMOGRAPHICS FROM THE
PHASE 3 APOLLO STUDY
G. Vita1, D. Adams2, A. Gonzalez-Duar3, W. O'Riordan4, C. C. Yang5, T. Yamashita6, A. Kristen7, I. Tourney8, H.
Schmidt9, T. Coelho10, J. Berk11, K. P. Lin12, J. Chen13, J. Gollob13, O. B. Suhr14, on behalf of the APOLLO investigators
1
UOC di Neurologia, Dip. di Medicina Clinica e Sperimentale, Università di Messina (Messina); 2National Reference
Center for FAP (NNERF), APHP/ INSERM U 1195/ CHU Bicêtre, (Le Kremlin-Bicêtre, F); 3National Institute of Medical
Sciences and Nutrition, Salvador Zubiran (INCMNSZ) (Mexico City, Mexico); 4eStudy Site (La Mesa, USA); 5National
Taiwan University Hospital (Taipei, Taiwan); 6Kumamoto University, Kumamoto Hospital (Kumamoto, Japan);
7
Heidelberg University Hospital, (Heidelberg, D); 8University Multiprofile Hospital for Active Treatment (Sofia, Bulgaria);
9
Klinik Fur Transplantationsmedizin, University Hospital of Muenster (Muenster, D); 10Hospital de Santo António, Centro
Hospitalar do Porto (Porto, Portugal); 11Amyloid Treatment and Research Program, Boston University (Boston, USA);
12
Neurology Department, Taipei Veterans General Hospital (Taipei, Taiwan); 13Alnylam Pharmaceuticals (Cambridge,
USA); 14Department of Medicine, Umeå University (Umeå, Sweden)
Introduction: hATTR-PN, also known as familial amyloidotic polyneuropathy (FAP), is an inherited, progressive disease
leading to death within 5-15 years. It is due to a mutation in the transthyretin (TTR) gene, which causes misfolded TTR
proteins to accumulate as amyloid fibrils predominantly in peripheral nerves and other organs including the heart. It can
cause sensory, motor/autonomic dysfunction, resulting in significant disability and death. Use of patisiran, an
investigational RNA interference (RNAi) therapeutic targeting TTR, has been shown result in a >80% sustained mean
knockdown of serum TTR and was considered generally well tolerated in patients with hATTR-PN (1,2). Additionally, data
from the Phase 2 open-label extension study demonstrated evidence for potential disease stabilization at 18 months (2).
Materials and Methods: APOLLO is a Phase 3 international, randomized (2:1), double-blind study (NCT01960348)
evaluating the efficacy and safety of patisiran 0.3mg/kg IV or placebo once every 3 weeks in symptomatic patients hATTRPN (neurological impairment score [NIS] of 5-130). Select exclusion criteria included: prior liver transplantation, current
tetramer stabilizer use, PND score >3b, and NYHA class >2. The primary endpoint is change from baseline at 18 months in
pag. 66
the mNIS+7 composite neurologic impairment score; secondary endpoints include assessments of QOL and changes in
mBMI, motor/autonomic function.
Results: 225 patients with hATTR-PN were enrolled at 44 sites (19 countries) and representative of the global patient
population (EU: 51%; N. America: 21%; Asia Pacific: 20%; LatAm: 8%). Median age: 62 years (24-82); males: 74%;
Val30Met TTR mutation: 42%; non-V30M mutations: 58% (including 73 TTR genotypes); and previously TTR tetramer
stabilizer use: 53%. Measures of baseline disease severity showed - FAP Stage 1: 46%; FAP Stage 2: 53%; and mean
mBMI: 978.7 kg/cm2g/L (522-1530). Mean baseline NIS and mNIS+7 were 59.3 (6.0-141.6) and 78.8 (8.0-165.0),
respectively. NIS and mNIS+7 were highly correlated with FAP Stage and PND score. Echocardiographic evidence of
cardiac involvement noted in 54% of patients; with mean NT-proBNP and troponin levels of 1461 ng/L (40-7895) and 0.1
ng/mL
(0.1-1.0),
respectively.
Discussion and Conclusions: Baseline demographics demonstrate that the Phase 3 APOLLO study enrolled hATTR-PN
patients with a wide range of TTR genotypes and neuropathy severity, including >50% with cardiac involvement. This is
the largest, controlled study of patients with hATTR-PN to date and is representative of the global patient population.
References:
1. Suhr OB, Coelho T, Buades J, et al. Efficacy and safety of patisiran for FAP: a phase II multi-dose study. Orphanet
J Rare Dis. (2015);10:109
2. Adams D, Suhr OB, Conceicao I, et al. Phase 2 OLE study of patisiran, an RNAi Therapeutic for FAP. Neurology
(2016); 86(16):S38.003
RETREATMENT WITH RITUXIMAB IN ANTI-MAG POLYNEUROPATHY: IS THE B-CELL-ACTIVATING
FACTOR (BAFF) A NEGATIVE PROGNOSTIC FACTOR?
M. Garnero1, D. Franciotta2, C. Briani3, M. Campagnolo3, M. Grandis1, S. Fabbri1, A. Beronio4, G. Mancardi1, A.
Schenone1, L. Benedetti1
1
(Genova); 2Laboratory of Neuroimmunology, C. Mondino National Neurological Institute, University of Pavia (Pavia);
3
Department of Neurosciences, University of Padua (Padova); 4Department of Neurology, S. Andrea Hospital (La Spezia)
Introduction: The B-cell depleting anti-CD20 monoclonal antibody Rituximab is the main therapeutic choice for antimyelin-associated glycoprotein (MAG) polyneuropathy. B-cell-activating factor (BAFF) is a key costimulatory molecule
for B-cell survival, proliferation and immunoglobulin production. BAFF induced furthermore modifications on B-cell
homeostatic regulation, in particular the increase of the numbers of long lived plasmacells, Ig- producing, compared to the
short lived plasmacells. As previously reported, serum BAFF values > 1665 pg/ml can predict the lack of response or the
precocity of relapse in Rituximab-treated patients with anti-MAG polyneuropathy. Analogously, higher serum BAFF levels
were associated with resistance to Rituximab in patient with lymphoma or Sjogren syndrome.
Patients and Methods: Nineteen patients with anti-MAG polyneuropathy responding to rituximab, 375 mg/sq for four
consecutive weekly infusions, were prospectively studied for 6-13 years (average 9 years). Clinical deterioration was
defined as worsening by one point in at least two scales including MRC sumscore, INCAT Disability Scale and INCAT
sensory sumscore and required additional Rituximab cycles. BAFF concentrations were measured in serum samples before
and after the first and subsequent admistrations of Rituximab by a commercial ELISA. The kit employed a monoclonal
antibody specific for BAFF, and a peroxide-linked anti-BAFF polyclonal antibody.
Results: Four patients maintained the improvement through the last follow-up. Among the fifteen patients deteriorating a
total of thirteen patients received multiple courses of Rituximab. Retreatment cycles were generally administered in an
interval time never less than 2 years. Nine of thirteen patients receiving multiple courses of Rituximab improved their
clinical status again while in three the results were less satisfactory than those following the first treatment. Drug resistance
was recorded in one patient after the fourth cycle. In these last four patients we recorded that the values of BAFF increased
progressively after each cycle of Rituximab.
Conclusion: We observed that serum BAFF concentration progressive increase after repeated cycles of Rituximab and this
correlates with a reduced clinical benefit as if it develops a resistance to the retreatment. These findings confirm what has
already been observed by Dalakas et al. (Neurology 2008) that Rituximab may be associated with anti-BAFF agents in order
to prevent the development of resistance to the treatment. Targeting BAFF could be beneficial, given the consequent
reduction in the survival of BAFF-dependent, rituximab-insensitive long-lived plasma cells.
pag. 67
DEFLAZACORT TREATMENT AND SPP1 RS8357094 GENOTYPE IMPACT OPN PROTEIN LEVEL IN
PRIMARY MUSCLE CELLS OF DUCHENNE MUSCULAR DYSTROPHY PATIENTS
L. Bello1, S. Vianello1, B. Pantic1, E. Galletta1, D. Borgia1, B. Gavassini1, G. Soraru'1, L. Vitiello2, E. Pegoraro1
1
Department of Neurosciences, University of Padua (Padova); 2Department of Biology, University of Padua (Padova)
Aims: Osteopontin (OPN), the protein product of the SPP1 gene, plays a role in Duchenne muscular dystrophy (DMD)
pathophysiology as a modulator of muscle inflammation and regeneration. A polymorphism in the SPP1 promoter
(rs28357094) has been recognized as a genetic modifier of disease severity, and possibly of response to glucocorticoid (GC)
treatment, with a dominant effect. We aimed to study SPP1 mRNA and OPN protein expression in primary human
myoblasts and myotube cultures, both normal and dystrophin-deficient, in basal conditions and in response to GCs.
Materials and Methods: DMD proliferating primary myoblasts and differentiated myotubes, derived from muscle biopsies
of 12 DMD patients and 9 controls with defined rs28357094 genotypes (TT versus TG), were treated for 72h with the GC
drug deflazacort (DFZ). SPP1 mRNA was quantified by rtPCR, and OPN protein was quantified by Western Blot. OPN
protein was detected as two 55/50 kDa bands (confirmed by siRNA gene silencing).
Results: There was a trend towards higher SPP1 mRNA expression with the TT genotype. No significant difference in OPN
mRNA or protein was detected in DFZ-treated DMD myoblasts or myotubes compared to control cells. However, when
DMD cells were stratified according to rs28357094 genotype, DFZ treatment resulted in a significant increase in OPN
protein in both myoblasts and myotubes carrying the TG genotype, with a significant interaction term between treatment
and genotype. We did not observe a strong linear correlation between mRNA expression and protein levels. Both healthy
and DMD myoblasts and myotubes expressed high levels of OPN protein. A shift towards the 50 kDa protein band was
observed in the transition from myoblast to myotube and to mature muscle. Increase in OPN protein was observed in DMD
myotubes carrying TG genotype at rs28357094.
Discussion: Expression data confirmed that the T allele at rs28357094 renders the SPP1 promoter more active in basal
conditions. Conversely, the G allele seems to enhance gene expression when GCs are administered. There is a complex
regulation of OPN protein expression, which involves post-transcriptional mechanisms as well as post-translational
modifications, ultimately leading to greater OPN abundance in DMD myotubes carrying the rs28357094 TG genotype.
Conclusions: These findings are in concordance with clinical studies showing a stunted long-term effect of GC treatment in
carriers of the G allele at 28357094, suggesting that this SNP is a pharmacogenetic predictor of poorer GC response, rather
than a modifier of disease progression per se.
CLENBUTEROL AMELIORATES THE PHENOTYPE OF SPINAL AND BULBAR MUSCULAR ATROPHY
MICE AND PATIENT-DERIVED MYOTUBES
G. Soraru1, C. Milioto2, A. Malena1, M. Polanco2, D. Borgia1, E. Pegoraro1, E. Maino2, M. Pennuto2
1
Department of Neurosciences, University of Padua (Padova); 2Dulbecco Telethon Institute, Centre for Integrative Biology,
University of Trento (Trento)
Objectives: Spinal and bulbar muscular atrophy (SBMA) is a neuromuscular disease characterized by the loss of lower
motor neurons. SBMA is caused by the expansion of a polyglutamine tract in the gene coding for androgen receptor (AR).
Expression of polyglutamine-expanded AR causes damage not only to motor neurons, but also to skeletal muscle cells. Here
we investigated the effect of beta-agonist stimulation in SBMA muscle cells and knock-in mice.
Materials and Methods: We treated C2C12 myotubes expressing polyglutamine-expanded AR, knock-in SBMA mice, and
SBMA
patient-derived
myotubes
with
the
beta-agonist
clenbuterol.
Results: We showed that treatment of C2C12 myotubes expressing polyglutamine-expanded AR with the beta-agonist
clenbuterol increases myotube width. This effect was associated with activation of the phosphatidylinositol-3-kinase
(PI3K)/Akt and adenylyl cyclase (AC)/protein kinase A (PKA) pathways, suggesting that clenbuterol induces SBMA
myotube hypertrophy through activation of these pathways. Notably, clenbuterol treatment decreased the accumulation of
polyglutamine-expanded AR. Treatment of SBMA mice with clenbuterol started at disease onset ameliorated motor
function, extended survival, and improved muscle pathology. Clenbuterol reduced the glycolytic-to-oxidative fiber-type
switch occurring in SBMA glycolytic muscles and induced hypertrophy of both glycolytic and oxidative fibers. Importantly,
clenbuterol induced hypertrophy of primary myotubes derived from SBMA patients.
Discussion and Conclusion: These results indicate that beta-agonist stimulation with clenbuterol is a novel therapeutic
strategy for SBMA.
pag. 68
AN ITALIAN MULTICENTER DATABASE FOR THE DIAGNOSIS AND THERAPY OF CHRONIC
INFLAMMATORY DEMYELINATING POLYRADICULONEUROPATHY (CIDP) AND ITS VARIANTS
G. Liberatore1, D. Cocito2, M. Filosto3, S. Jann4, M. Clerici5, A. Cortese6, G. Lauria7, G. Cavaletti8, M. Carpo9, R. Fazio10,
G. Antonini11, M. Luigetti12, M. Ruiz13, E. Peci2, A. Todeschini3, E. Verrengia4, L. Piccolo6, E. Beghi14, E. Nobile Orazio1
1
IRCCS Humanitas Clinical and Research Center, Milan University (Milano); 2Department of Neuroscience, Città della
Salute e della Scienza Hospital (Torino); 3Neurology Clinic, Spedali Civili Hospital (Brescia); 4Department of
Neuroscience, Niguarda Cà Granda Hospital (Milano); 5Department of Neuroscience, Fondazione Macchi Hospital
(Varese); 6Mondino National Neurological Institute, IRCCS Fondazione Mondino (Pavia); 73rd Neurology Unit, IRCCS
Carlo Besta Neurological Institute (Milano); 8Department of Neurology, Milano Bicocca University, S. Gerardo Hospital
(Monza); 9Neurology Unit, Treviglio Hospital (Treviglio-BG); 10Neurological Institute, IRCCS San Raffaele Hospital
(Milano); 11Department of Neuroscience, S. Andrea Hospital, Univesity of Rome (Roma); 12Institute of Neurology,
Policlinico Universitario Agostimo Gemelli, UCSC (Roma); 13Institute of Neurology, University of Padua (Padova);
14
Department of Neuroscience, IRCCS Mario Negri Institute (Milano)
Background: Chronic inflammatory demyelinating polyradiculoneuropathy (CIDP) is a chronic and disabling disease that
often improves with immune therapy. Several variants of CIDP have been reported including purely motor, sensory, distal,
asymmetric or focal forms. The relation of these variants to CIDP remains unclear also considering that some of them may
have a different response to therapy. The lack of clear diagnostic criteria for these variants may also explain the different
proportion and response to therapies among different series of patients.
Methods: We implemented a web-based database to collect the data from large series of patients with CIDP followed by
Italian Centers with expertise on CIDP in order to determine the frequency and characteristic of these variants, the
diagnostic criteria used for the diagnosis, the possible evolution into typical CIDP, the association with specific anti-nerve
antibodies, and their response to therapy. The association of CIDP and variants with antecedent events, life and dietary
habits and concomitant diseases will be also examined. All the patients will be evaluated at the time of inclusion and tested
for the presence of different anti-nerve antibodies. Patients will be followed for two years to monitor their outcome and
response to therapy.
Results: The study started on October 2015 and by May 31, 2016 we included 160 patients with CIDP and variants (95 men,
65 women), aged 18-86 years (median 62). Almost half of the patient had a purely motor (19%) or sensory (28%)
presentation but, at the time of inclusion after a mean disease duration of 7.9 years (range 0.5-38 years), 87% had a
sensorimotor impairment while only few remained with purely sensory (6%) or motor (7%) symptoms. A consistent
proportion of patients developed fatigue (71%) and pain (38%). The diagnosis of CIDP was confirmed by the EFNS/PNS
criteria in 84% of patients. CIDP was typical in 90% and atypical in 10%. CSF studies were diagnostic in 80% of the
patients while nerve biopsy or imaging (US or NMR) in 62% and 60%. Improvement after one or more therapies was
reported by 87% of the patients with a positive response to IVIg (85%), steroids (47%), plasma exchange (71%) and
immunosuppressant (33%). Conclusions: These preliminary data confirm that studies with multicenter database can be very
useful in providing information on the natural history, course, diagnosis and response to therapy in patients with CIDP and
variants.
LIPOMATOSIS INCIDENCE AND CHARACTERISTICS IN AN ITALIAN COHORT OF MITOCHONDRIAL
PATIENTS
E. Barca1, O. Musumeci1, C. Lamperti2, G. Comi3, M. Moggio4, T. Mongini5, G. Siciliano6, M. Filosto7, E. Pegoraro8, S.
Servidei9, D. Ronchi3, L. Vercelli5, D. Orsucci6, L. Bello8, G. Primiano9, M. Zeviani10, M. Mancuso6, A. Toscano1
1
Department of Clinical and Experimental Medicine, Neurology and Neuromuscolar Disease Unit, Messina University
(Messina); 2Unit of Molecular Neurogenetics, The Foundation "Carlo Besta" Institute of Neurology (Milano); 3Dino Ferrari
Centre, Neuroscience Section, Department of Pathophysiology and Transplantation (DEPT), University of Milan (Milano);
4
Neuromuscular Unit, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, and Dino Ferrari Centre, University
of Milan (Milano); 5Department of Neuroscience, University of Turin (Torino); 6Neurological Clinic, University of Pisa
(Pisa); 7Neurological Clinic, University Hospital Spedali Civili, University of Brescia (Brescia); 8Neurological Clinic,
University of Padova (Padova); 9Institute of Neurology, Catholic University of the Sacred Heart (Roma); 10Mitochondrial
Biology Unit, Medical Research Council (Cambridge-UK)
Introduction: Lipomas have often been associated with mtDNA mutations and were mainly observed in patients with
mutation in mitochondrial tRNA lysine which is also the most frequent mutation associated with MERRF. Up to date, no
pag. 69
systematic studies have been developed in order to assess the incidence of lipomas in large cohorts of mitochondrial
patients. The aim of this study is to analyze the incidence and characteristics of lipomas among an Italian cohort of patients
with mitochondrial diseases.
Methods: Retrospective, database-based study (Nation-wide Italian Collaborative Network of Mitochondrial Diseases) of
patients with lipomas.
Results: A total of 17 patients with lipomas have been identified among the 1086mitochondrial patients,enrolled in the
Italian database. About 20% showed a classical MERRF syndrome whereas the others disclosed myopathy (40%), one
CPEO and other two only an isolated lipomatosis. Lactate was elevated in almost all the examined patients. Muscle biopsy
was available in 10/17 patients: in all of them mitochondrial abnormalities were present. 90% had mutations in mtDNA
coding for tRNA lysine. Interestingly,two patients had multiple mitochondrial DNA deletions in muscle. Lipomas were
multiple in 11 out of 17 patients and in about 50% were symmetric. In all patients, lipomas were localized along the
cervical-cranial-thoracic region.
Conclusion: Our data confirm the strong association between multiple lipomas and lysine tRNA mutations, although the
presence of two patients with muscle mtDNA multiple deletions confirm that mutation in other genes may lead to a similar
phenotype.
References:
− Altmann J, et al. Expanded phenotypic spectrum of the m.8344A>G "MERRF" mutation: data from the German
mitoNET registry. J Neurol. (2016); 263(5):961-72
− Sawyer SL, et al. Homozygous mutations in MFN2 cause multiple symmetric lipomatosis associated with
neuropathy. Hum Mol Genet. (2015); 24(18):5109-14
− Mancuso M, et al. Phenotypic heterogeneity of the 8344A>G mtDNA "MERRF" mutation. Neurology (2013);
80(22):2049-54
DISEASE PROGRESSION AND CLINICAL HISTORY IN 246 PATIENTS FROM THE FSHD ITALIAN
REGISTRY
L. Vercelli1, G. Ricci2, M. Cao3, E. Rolle1, V. Ponzalino1, L. Ruggiero4, F. Mele5, M. Govi5, A. Nikolic5, L. Villa6, E.
Bucci7, R. Di Giacomo8, M. Scarlato9, B. Pasanisi10, G. Tomelleri11, M. Filosto12, L. Maggi10, S. Previtali9, C. Rodolico13,
A. Di Muzio8, G. Antonini7, M. Moggio6, L. Santoro4, C. Angelini14, E. Pegoraro3, R. Tupler5, T. Mongini1
1
Department of Neurosciences, Center for Neuromuscular Diseases, University of Turin (Torino); 2Department of Clinical
and Experimental Medicine, Neurological Clinic, University of Pisa (Pisa), 3Department of Neurosciences, University of
Padua (Padova); 4Department of Neurosciences, Reproductive and Odontostomatological Sciences, University Federico II
of Naples (Napoli); 5Department of Life Sciences, University of Modena and Reggio Emilia (Modena); 6Neuromuscular
Unit, Fondazione IRCCS Ca’ Granda Ospedale Maggiore Policlinico, Dino Ferrari Center (Milano); 7Department of
Neuroscience, Mental Health and Sensory Organs, S. Andrea Hospital, University of Rome "Sapienza" (Roma); 8Center for
Neuromuscular Disease, CeSI, University "G. D'Annunzio" (Chieti); 9Neuromuscular Repair Unit, INSPE and Division of
Neuroscience, IRCSS San Raffaele Scientific Institute (Milano); 10IRCCS Foundation C. Besta Neurological Institute
(Milano); 11Department of Neurological, Neuropsychological, Morphological and Movement Sciences, University of
Verona (Verona); 12Neurology Clinic, ‘‘Spedali Civili’’ Hospital (Brescia); 13Department of Neurosciences, Policlinico "G.
Martino", University of Messina (Messina); 14IRCCS San Camillo (Venezia)
Objective: Facio-Scapulo-Humeral muscular dystrophy (FSHD) is a rare genetic disorder, with a distinctive and peculiar
phenotype: a progressive asymmetric facial, shoulder girdle and pectoral muscle weakness and atrophy, with a descending
progression to involve the distal lower extremity muscles before affecting the hip girdle muscles. The Italian Network for
FSHD designed a longitudinal study to assess disease progression on a long-term period because FSHD is known having a
slowly disease deterioration but literature is poor about long follow up in these pathology or study have few cases.
Materials and Methods: The study was performed by collecting data from the Italian FSHD Registry, based on a nationwide
collaboration. We have selected the patients, genetically confirmed, with a follow up at least 5-years long (first evaluation
2007-2011; second one 2013-2016). We have used MRC scale, FSHD clinical score in both examinations and the new
concept of Comprehensive Clinical Evaluation Form (CCEF)*, a tool which defines various clinical categories by the
combination of different features, typical or atypical for FSHD.
Results: The patients were 246 (110 females, 136 males, aged 12-84 years, with a D4Z4 allele ≤41kb). We have observed a
limited decline in FSHD disease: the mean deterioration was 1 point to FSHD clinical score but index cases have worsened
more than relatives while incomplete phenotypes (B categories) or carriers with a FSHD score equal to 0 (C categories) did
pag. 70
not progress in 5-years. 4% subjects have lost ambulation and 3% became NIMV-dependent cases. Patients with an
intermediate FSHD score worsened more than the other groups.
Discussion: FSHD is one of the most common muscular dystrophies but despite a great number of clinical studies, little is
known about the real progression over the years and about the natural history of the disease. Our Italian study is the first
longitudinal study with a large cohort of patients We need FSHD patients with complete phenotype (A categories) and
index cases for design a potential therapeutic future study because in these categories we observe the greatest decline than
the other groups.
Conclusions: Our data stress the importance to rely on more sensitive outcome measures, specifically designed to monitor
disease
progression
in
view
of
future
clinical
trials.
Reference:
− G Ricci, L Ruggieri, L Vercelli et al. A novel clinical tool to classify facioscapulohumeral muscular dystrophy
phenotypes. J Neurol (2016);263:1204–1214
24/10/2016
CASI CLINICI 2
CEREBRAL AMYLOID ANGIOPATHY-RELATED INFLAMMATION WITH PSEUDOTUMORAL
PRESENTATION: CLINICORADIOLOGICAL FEATURES AND COURSE IN A PATIENT
C. Piantadosi, M. Bassetti, A. Casini, A. Cobianchi, A. Salerno, L. Bove
Neurology Unit, San Giovanni-Addolorata Hospital (Roma)
Background: Cerebral Amyloid Angiopathy-related inflammation (CAA-ri) is a less frequent manifestation of Cerebral
Amyloid Angiopathy (CAA) and results from an inflammatory response to β-amyloid protein in the blood vessel walls [1].
Objectives: To describe the clinicoradiological features and to point out the course in a patient with CAA-ri.
Case report: A 74-year-old woman, after the death of the husband, began to have memory impairment and agitation, treated
with neuroleptics at medium-high dosage. A cerebral CT scan showed minor abnormalities. About five months later, slowly
progressive right hemiparesis presented; a generalized seizure also occurred and the patient was promptly transported to our
hospital. At admission brain CT scan revealed diffuse left hemispheric edema. The neurological examination detected a
confused and disorientated patient and right hemiparesis. An EEG recorded abundant delta waves and epileptiform
abnormalities, bilaterally located but prevailing on left side. A cerebral neoplastic disorder was suspected and intravenous
dexamethasone (8 mg/day for 40 kg body-weight) and levetiracetam were soon started. Routine blood tests (including ESR
) were all normal as well as the tumor markers and tests for anti-phospholipid and anti-thyroid antibodies, systemic lupus
erythematosus and other connective tissue diseases. Brain MRI (performed under sedation) showed: diffuse left hemispheric
hyperintesity on FLAIR sequences (consistent with vasogenic edema); no enhancement on postcontrast T1-weighted
images; microbleeds on gradient echo sequences (T2*-GRE). The microbleeds were distributed in cerebral lobes and were
very numerous with a starry-sky appearance. The diagnosis of probable CAA-ri was made according to the recently
published criteria [2]. Dexamethasone was switched to oral prednisone (50 mg/day for a month and tapered within three
months), levetiracetam was continued. Control MRI showed marked reduction of edema. The right hemiparesis regressed,
walking became stable, no more seizures happened but memory loss did not improve with persistent disorientation and need
of supervision.
Discussion: CAA-ri can mimic a brain tumor for clinical and radiological aspects [3]. Cerebro-meningeal biopsy can be
dangerous to elderly patients and not informative. It has become crucial for the diagnosis of CAA-ri to perform brain MRI
with also T2*-GRE or susceptibility-weighted imaging (SWI) as reported in recently validated criteria [2]. Nonetheless, it is
advisable to carry out further studies which should better clarify treatment, course and prognosis of CAA-ri.
Conclusions: Cerebro-meningeal biopsy is no longer required for diagnosis of CAA-ri. Dissolving inflammatory edema, the
corticosteroid treatment can improve different symptoms of CAA-ri but the prognosis remains that of underlying CAA.
References:
1. Charidimou A, Gang Q, Werring DJ. Sporadic cerebral amyloid angiopathy revisited: recent insights into
pathophysiology and clinical spectrum. J Neurol Neurosurg Psychiatry (2012);83(2):124-37
2. Auriel E, Charidimou A, Gurol ME, Ni J, Van Etten ES, Martinez-Ramirez S, Boulouis G, Piazza F, DiFrancesco
JC, Frosch MP, Pontes-Neto OV, Shoamanesh A, Reijmer Y, Vashkevich A, Ayres AM, Schwab KM,
Viswanathan A, Greenberg SM. Validation of Clinicoradiological Criteria for the Diagnosis of Cerebral Amyloid
pag. 71
3.
Angiopathy-Related Inflammation. JAMA Neurol (2016);73(2):197-202
Ronsin S, Deiana G, Geraldo AF, Durand-Dubief F, Thomas-Maisonneuve L, Formaglio M, Desestret V,
Meyronet D, Nighoghossian N, Berthezène Y, Honnorat J, Ducray F. Pseudotumoral presentation of cerebral
amyloid angiopathy-related inflammation. Neurology (2016);86(10):912-9
THE TRICKY DIAGNOSIS OF ADULT-ONSET ALEXANDER DISEASE
L. Marcuccio1, A. Tessitore1, A. Giordano1, M. Cirillo2, G. Tedeschi1
1
Department of Medical, Surgical Neurological, Metabolic and Aging Sciences, Second University of Naples (Napoli);
Neuroradiology Unit, Department of Clinical and Experimental Medicine and Surgery, Second University of Naples
(Napoli)
2
Case: We report a 60-year-old woman referred to our hospital for a progressive 7 years history of speech and swallow
disturbances, walking difficulties, imbalance and episodic falls. Family and personal clinical histories were unremarkable.
Phenomenology: Neurological examination revealed broad-based and shuffling gait with freezing (in starting and in
turning), gaze evoked nystagmus, hypermetric saccades without slowing of vertical saccades, dysarthria, dysphagia and
dysphonia, bradykinesia (right >left) and axial rigidity, bilateral hyperactive deep tendon reflexes. The patient needs aid for
walking or for daily life activities.
Investigations: General blood examinations, thyroid, vit B12 and folic acid, VDRL/TPHA were unremarkable.
Cerebrospinal fluid (CSF) analysis was negative. Electrophysiological evaluation (EMG and MEP) was normal.
Neuropsychological evaluation showed no cognitive impairment. Brain and spinal MRI showed marked atrophy from the
medulla oblongata to the cervical spinal cord, involving midbrain tegmentum and sparing the pontine base (“tadpole sign”),
mild cerebellar atrophy with enlargement of the fourth ventricle and symmetrical striatal lesions.
Discussion and results: Several differential diagnosis were considered (multiple sclerosis, motor neuron disease, MSA, SCA
and cervical myelopathy); moreover Alexander disease was suspected. Genetic testing revealed one heterozygous mutation
on exon 1 of the GFAP (glial fibrillary acidic protein) gene (c.221T>C, p.Met74Thr), mutation associated to the adult forms
of Alexander disease.
Conclusion: Although very rare, adult onset of Alexander disease should be considered (and genetic testing performed) in
the differential diagnosis of parkinsonism plus syndrome when typical MRI findings were observed even in absence of a
positive familiar history.
References:
− Pareyson D, Fancellu R, Mariotti C, Romano S, Salmaggi A, Carella F, Girotti F, Gattellaro G, Carriero MR,
Farina L, Ceccherini I, Savoiardo M. Adult-onset Alexander disease: a series of eleven unrelated cases with review
of the literature. Brain (2008) Sep;131(Pt 9):2321-31
− Namekawa M, Takiyama Y, Honda J, Shimazaki H, Sakoe K, Nakano I. Adult-onset Alexander disease with
typical "tadpole" brainstem atrophy and unusual bilateral basal ganglia involvement: a case report and review of
the literature. BMC Neurol. (2010) Apr 1;10:21
− Farina L, Pareyson D, Minati L, Ceccherini I, Chiapparini L, Romano S, Gambaro P, Fancellu R, Savoiardo M.
Can MR imaging diagnose adult-onset Alexander disease? AJNR Am J Neuroradiol. (2008) Jun;29(6):1190-6
ACTION AND STIMULUS-INDUCED FOCAL MYOCLONUS ASSOCIATED WITH BREAST CANCER: A
CASE REPORT OF AN ATYPICAL PARANEOPLASTIC SYNDROME
D. Baroncini1, S. Baldini1, P. Annovazzi1, G. Minonzio2, A. Ghezzi1, G. Comi3, M. Zaffaroni1
1
Multiple Sclerosis Study Center, ASST Valle Olona (Gallarate-VA); 2Department of Neuroradiology, ASST Valle Olona
(Gallarate-VA); 3Department of Neurology and Institute of Experimental Neurology, University Vita-Salute San Raffaele
(Milano)
Objective: To present the case of an action/stimulus-induced focal myoclonus in a woman with breast cancer.
Materials and Methods: Single patient case report.
Case Report: A 50 years-old woman presented to our attention with a 2 months history of involuntary movement in the left
foot, worsened by movement and walking, and improved by rest. She also complained brief episodes of general stiffness
pag. 72
and trismus, without loss of consciousness. Past medical history included bilateral cheratoconus and arterial hypertension.
She was previously investigated in another Hospital (EMG-ENG, routine blood exams, chest radiograph, EEG, brain and
spinal cord MRI) with no definite diagnosis. She received clonazepam and oral prednisone, with minimum benefits, and
also neuroleptics in the suspect of a psychogenic movement disorder. After few weeks she complained also a mild dysartria
and right hand movement clumsiness. She was then admitted to our department. Neurological examination showed an
action and stimulus-induced (tactile plantar stimulation) myoclonus of the left foot with a mild diffusion on the leg, slight
dysarthria, prevalence of DTRs on lower left limb and an incorrect left cutaneous plantar response. Walking worsened the
myoclonus. Brain/thoracic spinal cord MRI, evoked potential and video-EEG were unremarkable. Autoantibodies (ANA,
ANCA, antiphospholipid, anti-GAD, celiac disease-related) were negative. CSF examination (including oligoclonal bands)
resulted normal. Suspecting a paraneoplastic syndrome we requested a total body CT scan that revealed a left breast cancer,
with linfonodal metastasis. Classic and non-classic (anti-AMPA, anti-GABA, anti-LG1, anti-CASPR2, anti-VGKC)
onconeural antibodies were negative. After surgical removal of breast tumor the myoclonus was reduced, but after few
weeks it worsen again. We then treated the patient with high dose intravenous steroid, with a substantial improvement. At
now the patient is still on neurological and oncological follow-up and she is receiving oral steroid therapy.
Discussion: Isolated myoclonus has been rarely described in the spectrum of paraneoplastic syndrome [1]. In this case, the
episodes of diffuse stiffness and the mild dysarthria were the clues that lead us to think about a paraneoplastic/autoimmune
disorder. Although classic and non-classic onconeural antibodies were negative, the presence of breast cancer, the initial
improvement after its surgical removal and the rapid response to intravenous steroid therapy support the diagnosis of a
paraneoplastic syndrome (“possible” according to Graus criteria) [2].
Conclusion: Diagnosis of paraneoplastic disorders need a higher level of suspicion, especially if the presentation eludes
from the so-called classic syndromes.
References:
1. Salsano E, Ciano C, Romano S et al. Propriospinal myoclonus with life threatening tonic spasms as paraneoplastic
presentation of breast cancer. J Neurol Neurosurg Psychiatry (2006) Mar;77(3):422-4
2. F Graus, J Y Delattre, J C Antoine et al. Recommended diagnostic criteria for paraneoplastic neurological
syndromes. J Neurol Neurosurg Psychiatry (2004);75:1135–1140
RUBRAL OR PSYCHOGENIC TREMOR?
T. Bocci1, D. Barloscio1, A. De Rosa1, L. Parenti1, A. Priori2, F. Sartucci1
1
2
Department of Clinical and Experimental Medicine, Cisanello Neurology Unit, Pisa University Medical School (Pisa);
Department of Neurological Sciences, Fondazione IRCCS Ospedale Maggiore Policlinico, University of Milan (Milano)
Objectives: Rubral tremor is a rare kind of hyperkinetic movement disorder, clinically characterized by irregular,
monolateral, high-amplitude jerks, sharing a quite similar frequency with those observed in Parkinson’s disease. It may be
caused by mesencephalic lesions, ranging from midbrain infarctions to traumatic injury and neoplasias; it has been also
reported after thalamic stroke, likely emerging from lesions upstream of the rubral and nigral outflow system. Lesions of the
superior cerebellar peduncle, midbrain tegmentum or posterior part of the thalamus may cause this peculiar tremor;
probably, lesions of the red nucleus itself are not sufficient for its production. We report the case of a man referred to our
attention because of an atypical ipsilateral hand tremor.
Materials and Methods: A video report was made. Patient presented a combined resting-postural-kinetic tremor. We
bilaterally performed a surface polymyography from the extensor digitorum communis (EDC) and flexor carpi radialis
(FCR) muscles. Brainstem reflexes were also assessed; in particular, we evaluated the habituation phenomenon of the blink
reflex (BR). Motor Evoked Potentials (MEPs) were recorded from the abductor digiti minimi (ADM) of the right hand.
Results: At the first clinical evaluation, tremor showed the classical features of a rubral tremor. Neuroimaging revealed an
intracranial dermoid cyst at the right pontocerebellar angle with brainstem dislocation. However, both the spontaneous
variability of tremor frequency and frequency entrainment induced by contralateral rhythmic tasks do not suggest an organic
aetiology. Polymyography revealed: 1) a paradoxical increase of tremor amplitude with mass loading; 2) jerks’
synchronization between antagonistic muscles during voluntary contralateral motor performances; 3) tremor inhibition
while asking the patient to make a ballistic movement. The BR habituation was preserved. During motor imagery, MEPs
were paradoxically smaller than at rest, as extensively reported in psychogenic movement disorders.
Discussion: To our knowledge, intracranial dermoid cyst was never reported elsewhere as a potential cause of rubral tremor.
More important, however, jerks were very atypical in our patient. In particular, basing both on clinical and
pag. 73
neurophysiological findings, we may suggest a complete psychogenic genesis or, at least in part, a possible co-existence of a
rubral tremor with psychogenic traits.
Conclusions: Tremor diagnosis should be based on a careful clinical, neurophysiological and radiological assessment. Our
case strengthen the importance of surface electromyography in tremors; at the same time, our results prompt further studies
to re-define electrodiagnostic criteria in hyperkinetic movement disorders, possibly updating the floating border between
organic and psychogenic disease.
A CASE OF RAPIDLY PROGRESSIVE DEMENTIA: WHIPPLE DISEASE OF CNS
M. E. Pessa1, A. Baldi2, S. D'Anna2
1
Clinic of Neurology and Neurorehabilitation, University of Udine (Udine); 2Neurology, San Tommaso dei Battuti Hospital
(Portogruaro, VE)
A 72-year old woman came to our attention for worsening within few weeks of confusion, aphasia, ataxia and urinary
incontinence. She had suffered for 4-5 months of mild cognitive impairment with short-time memory loss, disorientation
and mood depression. Her medical history was remarkable for hypertension, diabetes mellitus II and Whipple Disease,
diagnosed in 1985 and treated from the last relapse (2011) with trimethoprim–sulfamethoxazole (160+800mg/day). During
hospitalization she became drowsy and aphasic,she developed partial status epilepticus and oculomasticatory myorhythmia
(a characteristical sign of WD of CNS). MRI signs were nonspecific with severe cortical atrophy and expansion of
subarachnoid spaces and ventricular cavities, but CSF analysis revealed 34 cells/mm (70% lymphocytes) with PCR positive
for Tropheryma Whippelii (TW). Antimicrobial treatment was started with ceftriaxone, doxycycline, hydroxycholoroquine
and trimethoprim–sulfamethoxazole i.v, with mild gradual improvement in the level of consciousness (she began to answer
simple questions and to interact with those around her). We reported a case of Whipple Disease with CNS involvement after
about 30 years from diagnosis. This eventuality is not frequent, but really also not so rare, especially after so many years of
illness (10). Whipple’s disease (WD) is a multi-systemic chronic relapsing infection due to Tropheryma Whippelii, a grampositive bacterium ubiquitously present in the environment. It is a very rare disease (approximate annual incidence
1/1.000.000) that characteristically affects middle-aged Caucasian subjects (1).The infection occurs through human to
human transmission and is often asymptomatic or results in self-limiting gastroenteritis,but in predisposed individuals
probably an immune deficiency allows the survival of TW that, over the course of many years, spreads systemically (3).
CNS involvement is observed in 20% to 40% of cases. Our patient presented a frequent clinical picture of WD of CNS with
rapidly progressive dementia associated with oculomasticatory myorhythmia (that is a characteristic sign of WD) (10). We
would emphasize the importance of considering also WD in cases of rapidly progressive cognitive impairment (especially
with medical history of recurrent arthralgias, diarrhea, weight loss) because it is a potentially treatable cause of dementia
and is probably underestimated due to its difficult diagnosis.
References:
1. Gerard A, Sarrot-Reynauld F, Liozon E, et al. Neurologic presentation of Whipple disease: report of 12 cases and
review of the literature. Medicine (Baltimore) (2002);81:443-457
2. Schneider T, Moos V, Loddenkemper C et al. Whipple’s disease: new aspects of pathogenesis and treatment.
Lancet Infect Dis (2008) 8:179–190
3. Moos V, Kunkel D, Marth T et al. Reduced peripheral and mucosal Tropheryma whipplei-specific Th1 response in
patients with Whipple’s disease. J Immunol (2006)177:2015–2022
EXPANDING CLINICAL PHENOTYPES OF FRAGILE X-ASSOCIATED TREMOR/ATAXIA
L. I. Manfredini1, G. Arabia1, A. Lupo1, G. Mastroianni1, M. Mancini1, G. Barbagallo1, M. Morelli1, M. Salsone2, A.
Quattrone2
1
2
Institute of Neurology, Department of Medical and Surgical Sciences, University of Magna Graecia (Catanzaro);
Neuroimaging Research Unit, Institute of Molecular Bioimaging and Physiology, National Research Council (Catanzaro)
Background: The fragile X-associated tremor/ataxia syndrome (FXTAS) is a neurodegenerative disorder consisting of
progressive intention tremor and cerebellar ataxia recently described in men with the premutation (55 to 200 CGG repeats)
in the promoter region of the fragile X mental retardation 1 (FMR1) gene and with grandchildren with fragile X syndrome
(FXS). The most frequent magnetic resonance imaging (MRI) features are cerebral, cerebellar atrophy and periventricular
white matter iperintensities. During the last decade, additional clinical features have been described, such as orthostatic,
pag. 74
post-prandial hypotension and peripheral neuropathy. We present here a patient carrying an FMR1 premutation allele,
without a family history for FXS, whom clinical features expand the FXTAS phenotype.
Clinical case: A 49 years-old man referred to our clinic with a 6-years history of tremor of the limbs and gait ataxia,
associated with occasional syncopal episodes, occurring after meals and prolonged standing position. Neurological
examination showed rest, postural and intention tremor of the upper and lower estremities and ataxic gait. Mild bradykinesia
and rigidity of the limbs were also present. Autonomic tests showed an orthostatic and post-prandrial hypotension. In
standing position, a marked decrease of systolic blood pressure (SBP) of 34 mmHg (normal values up to 20 mmHg)
occured. After a standardized meal, the diastolic blood pressure (DBP) had a decrease of 14 mmHg (normal values up to 10
mmHg). The patient also performed a 24-hour non invasive ambulatory recording of blood pressure. The patient’s blood
pressure profile showed a circadian rhythm with marked decrease of pressure values during the night (SBP, minimum value:
80 mmHG; DBP, minimum value: 45 mmHg). This pattern characterized by a reduction over 20 % of the night average
systolic pressure compared to the average daytime pressure is defined as “extreme dipper”. Brain MRI demonstrated a
marked cerebellar and cerebral atrophy. Genetic analysis revealed FMRI premutation with 57 CGG expansions.
Discussion: Our case report expanded the clinical spectrum of FXTAS, presenting a new sign of nocturnal dysautonomia. In
patients with FXTAS, autonomic dysfunction has been reported mainly in terms of impotence, hypertension, bladder
dysfunction and orthostatic hypotension. Here, we reported for the first time a marked nocturnal hypotension, defined
“extreme dipper” in a patient with FXTAS. Circadian dysautonomia may be underdiagnosed. Our case suggested that the
noctural non-invasive ambulatory recording of blood pressure may be a useful testing to accurately investigate the
autonomic disfunction of patients with FXTAS.
References:
− P. Pugliese, G. Annesi, N. Cutuli, G. Arabia, G. Nicoletti, F. Annesi, P. Tarantino, A. Gambardella, P. Valentino,
M. Zappia, A. Quattrone, MD. The fragile X premutation presenting as postprandial hypotension. Neurology
(2004); 63 (11): 2188-2189
− Deborah A Hall, Rachael C Birch, Mathieu Anheim, Aia E Jønch, Elizabeth Pintado, Joanne O’Keefe, Julian N
Trollor, Glenn T Stebbins, Randi J Hagerman, Stanley Fahn, Elizabeth Berry-Kravis and Maureen A Leehey.
Journal of Neurodevelopmental Disorders (2014);6:31
ACUTE CONFUSIONAL MIGRAINE (ACM) IN CADASIL: ROLE OF ELECTROENCEPHALOGRAM (EEG)
E. P. Verrengia, E. Ferrante, S. Jann, S. Meregalli, E. Agostoni
Niguarda Hospital, Bicocca University (Milano)
Purpose: ACM (Acute Confusional Migraine) can represent a clinical manifestation of CADASIL (Cerebral Autosomal
Dominant Arteriopathy with Subcortical Infarcts and Leukoencephalopathy). EEG (electroencephalogram) can represent a
useful tool to evaluate this condition.
Material and methods: We report two stereotypic confusional events in migraine in the same CADASIL patient. Results: A
54-year-old woman with diagnosis of Cerebral Autosomal Dominant Arteriopathy with Subcortical Infarcts and
Leukoencephalopathy (CADASIL) was admitted to our Hospital in February 2016. Patient history includes recurrent stroke,
chronic headache since childhood classified as migraine with visual aura, typical neuroimaging findings. She has no family
history of stroke and dementia. The assumption of no cognitive decline was based on her ability to perform business
activity. The diagnosis was confirmed by mutation in Notch3 gene in 2006. In December 2015 she was hospitalized in
London with a severe headache associated with visual impairment (migraine with aura), agitation and speech disturbance.
Patient confusion lasted four days. Brain computed tomography (TC) in acute phase was negative and EEG, performed five
days after the clinical event, was normal. In absence of new ischemic lesions on DWI-MRI (Diffusion Weighted ImagingMagnetic Resonance), she was treated with Levetiracetam 500 mg twice a day. In February 2016 she was evaluated in our
Emergency Department with a similar episode compared to the one of London 2015. The patient presented a prolonged
duration visual aura migraine since early morning. During this episode, she presented agitation associated with an inability
to communicate and to comprehend spoken words. Agitation was treated with benzodiazepines with a resolution in 24 hrs,
but she presented an alteration of cognitive/behavioral status for seven days. In acute phase, in absence of new lesions on
TC scan, an EEG revealed a disorganized track with slow bilateral activity, non-reactivity to algic stimuli, no epileptiform
figures. Her brain DWI-MRI revealed pre-existing infarcts, leukoencephalopathy, hemosiderin foci, but no recent ischemic
lesions. Based on basal features and subsequent improvement of EEG, we decided to discontinue antiepileptic therapy. In
June 2016 the patient was able to perform her work activities in absence of ACM events.
Discussion and conclusions: We describe two episodes of ACM in the same CADASIL patient, lasted four and seven days
respectively. EEG shows a typical pattern in acute phase ACM and excludes seizure related to pre-existing cerebral infarcts.
Further data are required to support the role of EEG to qualify this phenomenon.
pag. 75
References:
− Swati Sathe, Edgar DePeralta, Gregory Pastores, Edwin H. Kolodny. Acute Confusional Migraine May Be a
Presenting Feature of CADASIL. Headache (2009);49:590-596
− Cheng-Tsung Hsiao, Yun-Chung Chen, Yo-Tsen Liu, Bing-Wen Soong, Yi-Chung Lee. Acute simultaneous
multiple lacunar infarcts as the initial presentation of cerebral autosomal dominant arteriopathy with subcortical
infarcts and leukoencephalopathy. Journal of the Chinese Medical Association (2015);78:424-426
− Liem MK, Oberstein SA, van der Grond J, Ferrari MD, Haan J. CADASIL and migraine: A narrative review.
Cephalalgia (2010) Nov;30(11):1284-9
A CASE-REPORT OF MIGRAINE “SINE HEADACHE”
A. Taga, M. Russo, A. Genovese, M. Trapasso, G. Manzoni, P. Torelli
Department of Clinical and Experimental Medicine, University of Parma (Parma)
Background and objectives: We describe a case of a female patient whose typical migraine attacks transformed into
migraine
attacks
with
a
full
spectre
of
associated
symptoms
but
without
headache.
Case report: A 53-year old woman was evaluated in May 2016, complaining of a long history of migraine without aura
(MO), with onset at 16 years old, characterized by unilateral, pulsating, severe headache attacks, associated with
photophobia, phonophobia, osmophobia, nausea and inconstantly vomiting. She used successfully triptans (sumatriptan or
rizatriptan) as abortive therapy. The patient recognized some migraine triggers, including weekend and the menstrual
window; the mean attacks frequency was two or three per month. Her past medical history was unremarkable and didn’t
include the so-called “childhood periodic syndromes” [1]; she had a family history of MO (mother and a sister). Since
November 2015, in concomitance with premenopausal menstrual dysregulation, the patient reported the occurence of
episodes of nausea and vomiting, associated with photophobia, phonophobia, osmophobia but without headache. Similarly
to her “typical” migraine attacks, these episodes lasted one to three days when untreated; they responded well to the triptans,
but not to the common antiemetics (metoclopramide and domperidone); the reported triggers and the frequency were the
same of the previous migraine attacks. The patient reported also some residual but infrequent migraine attacks with
headache. Alternative diagnoses were excluded through extensive laboratory tests (including endocrine, metabolic and
infective screening), gastrointestinal examinations (including gastroscopy, colonoscopy and abdominal US) and urologic
evaluations; a brain MRI scan excluded CNS abnormalities.
Discussion and conclusions: To date, there aren’t literature data on otherwise typical migraine attacks without headache. A
similar eventuality has been described only for cluster headache [2]. On the other hand, the current IHS classification [1]
recognizes some syndromes historically noted to occur in childhood (previously kown as "childhood periodic syndromes"),
but which occur in adults, too, and which include among the others: recurrent gastrointestinal disturbance and cyclic
vomiting syndrome. However, our case is not comparable to these entities for the absence of the abdominal pain and for the
unpredictable temporal pattern of nausea and vomiting episodes. We hypothesize that a functional dysregulation of the
hypothalamo-brainstem connectivity [3] (which is a supposed to be a generator of migrainous pain and associated
symptoms) may generate migraine attacks with a full spectre of associated symptoms, but without headache.
References:
1. Headache Classification Committee of the International Headache Society (IHS). The International Classification
of Headache Disorders, 3rd edition (beta version). Cephalalgia (2013);33:629–808
2. Dilli E, Dodick DW. Extracephalic cluster (cluster sine headache). Neurology (2008);70(16):1362-3
3. Schulte LH, May A. The migraine generator revisited: continuous scanning of the migraine cycle over 30 days and
three spontaneous attacks. Brain (2016) (published ahed of print, doi: http://dx.doi.org/10.1093/brain/aww097)
DISORDINI DEL MOVIMENTO 2
CLINICAL, ELECTROPHYSIOLOGICAL AND MRI FINDINGS IN ESSENTIAL TREMOR WITH AND
WITHOUT RESTING TREMOR
R. Nisticò1, M. Caligiuri1, G. Arabia2, F. Novellino1, M. Salsone1, M. Morelli2, G. Barbagallo2, A. Lupo2, A. Cherubini1, A.
Quattrone2
1
Institute of Molecular Imaging and Physiology (IBFM-CNR), National Research Council (Catanzaro); 2Institute of
Neurology, University Magna Graecia (Catanzaro)
pag. 76
Background: The etiopathogenesis of essential tremor (ET) is still debated, since the predominant role of circuit dysfunction
or brain degenerative changes has not been clearly established. The relationship with Parkinson's Disease (PD) is also
controversial and resting tremor occurs in up to 20 % of rET.(1) The aim of this study was to evaluate brainstem
interneuronal excitability by blink reflex recovery cycle (BRrc ) (2) in patients with rET compared with patients with ET. In
addition we used probabilistic tractography and network analysis to investigate the structural integrity of the motor circuit in
classical ET, rET and healthy controls (HC).
Methods: We investigated 25 patients with ET (14 female, mean age 65.1 ± 10.4), 22 patients with rET (10 female, mean
age 64.9 ± 13.4) and 25 age and sex matched HC. All patients underwent to BRrc, and MRI protocol incuding whole-brain
3D T1-weighted and diffusion-weighted MRI. The following regions, known to be part of the motor circuit, were
automatically identified on T1 images: putamen, caudate nucleus, globus pallidus, thalamus, cerebellum, precentral cortex
and supplementary motor area (SMA). Probabilistic tractography between these nodes was performed on diffusion data in
network-mode, in order to reconstruct connections in the motor circuit and to obtain connectivity matrices necessary for
computing connectomics measures.
Results: All patients with rET had an increased R2-BRrc while all patients with ET had a normal BRrc comparable to that
of control subjects. Network analysis revealed increased nodal efficiency of the cerebellum in ET and in rET compared to
HC. Patients with rET showed increased nodal efficiencies in bilateral globus pallidus, left precentral cortex and left caudate
compared to both ET and HC. Thalamic nodal efficiency was increased in rET compared to HC.
Discussion: Our results help clarify both electrophysiological and structural differences of two different phenotypes of ET.
Patients with rET had an increased R2 recovery component of BRrc whereas patients with ET had a normal BRrc
comparable to that of control subjects. The pallidal dysfunction, mainly related to its connection to the thalamus, was
identified as a possible neuroimaging correlate of resting tremor in ET.
Conclusions: Our findings indicate the possible clinical usefulness of BRrcc for differentiating rET from ET. In ET and
rET, dysfunction of both the globus pallidus and the thalamus may play an important role in explaining different clinical
presentations of the disease.
References:
1. Nicoletti V, Cecchi P, Frosini D et al. Morphometric and functional MRI changes in essential tremor with and
without resting tremor. J Neurol. (2015) Mar;262(3):719-28. doi: 10.1007/s00415-014-7626-y. Epub 2015 Jan 9
2. Nisticò R, Pirritano D, Novellino F et al. Blink reflex recovery cycle in patients with essential tremor associated
with resting tremor. Neurology (2012) Oct 2;79(14):1490-5. doi: 10.1212/WNL.0b013e31826d5f83. Epub 2012
Sep 19
THALAMIC PROTON MAGNETIC RESONANCE SPECTROSCOPY CAN DISTINGUISH ESSENTIAL
TREMOR WITH RESTING TREMOR FROM TREMOR-DOMINANT PARKINSON'S DISEASE: A PILOT
STUDY
G. Barbagallo1, A. Cherubini2, G. Arabia1, F. Novellino2, M. Salsone2, R. Nisticò2, M. Caracciolo2, F. Rocca2, I. Martino1,2,
C. Chiriaco2, A. Quattrone1,2
1
Institute of Neurology, University Magna Graecia (Catanzaro); 2Neuroimaging Research Unit, Institute of Molecular
Bioimaging and Physiology, National Research Council (Catanzaro)
Background: Several pathological, surgical, electrophysiological, and imaging studies have shown that the thalamus plays
an important role in tremor generation [1]. Distinguishing Essential Tremor with resting tremor (rET) from tremor-dominant
PD (tPD) may be challenging especially in the first stages of the diseases, in the absence of DAT-SPECT investigation.
Aims: The aims of the study were (1) to investigate the presence of metabolic alterations in the thalamus of patients with
rET and tPD using proton magnetic resonance spectroscopy (1H-MRS), and (2) to evaluate the possible usefulness of the
1H-MRS for differentiating subjects with tPD from those with rET.
Materials and Methods: Thirteen patients with tPD, 10 with rET and 10 healthy controls participated in this study. After
conventional MR imaging, single-voxel 1H-MRS (TR=2000 ms; TE=28 ms) was performed by using a PROBE-SV system
implemented on a 3 tesla scanner (GE, General Electric Medical Systems, Milwaukee, WI). A voxel of 10 × 10 × 15 mm
was acquired in each thalamus of all subjects. Peak areas of N-acetyl-aspartate with N-acetyl-aspartyl-glutamate (NAA),
creatine with phosphocreatine (Cr), and glycerophosphocholine with phosphocholine (Cho), were calculated using a version
6.3-1K of the fitting program LCModel for each voxel [2]. Comparative and discriminant analyses were performed on the
mean values of the bilateral NAA/Cr, a neural density marker, and Cho/Cr, a membrane marker.
pag. 77
Results: Patients with tPD showed a significant reduction of NAA/Cr and Cho/Cr ratios, compared to rET and healthy
controls. Remarkably, logistic regression and receiver operating characteristic (ROC) curves showed that the combination
of both spectroscopic markers (i.e. NAA/Cr and Cho/Cr) was able to obtain a 100% accuracy in distinguishing patients with
tPD
from
those
with
rET.
Discussion and Conclusions: Our study demonstrates that thalamic 1H-MRS may help to distinguish tPD from rET,
showing its potential usefulness for differentiating these diseases characterized by the presence of resting tremor.
References:
1. Helmich RC, Hallett M, Deuschl G, Toni I, Bloem BR. Cerebral causes and consequences of parkinsonian resting
tremor: a tale of two circuits? Brain (2012);135:3206-26
2. Provencher SW. Automatic quantitation of localized in vivo 1H spectra with LC Model. NMR in biomedicine
(2001);14(4):260-264
PREDICTION OF COGNITIVE WORSENING IN DE NOVO PARKINSON DISEASE: USE OF BIOMARKERS
IN CLINICAL SETTING
D. Arnaldi1, F. De Carli2, A. Brugnolo1, N. Girtler1, A. Picco1, M. Ferrara1, L. Proietti1, M. Bauckneht3, S. Morbelli3, F.
Nobili1
1
DINOGMI, IRCCS San Martino IST, University of Genoa (Genova); 2Institute of Bioimaging and Molecular Physiology,
National Research Council (Genova); 3DISSAL, IRCCS-San Martino IST, University of Genoa (Genova)
Objective: To define the best predictors of future cognitive worsening among clinical and neuropsychological features,
resting EEG and dopamine transporter (DAT) imaging in a group of patients with newly diagnosed Parkinson disease (PD).
Methods: Fifty-four de novo, drug naïve PD patients were prospectively evaluated by clinical and neuropsychological
assessment, resting EEG and 123I-FP-CIT-SPECT. The patients were classified into mainly motor, diffuse/malignant and
intermediate PD subtypes according to Fereshtehnejad et al [1]. Follow-up cognitive outcome was defined by identifying
cognitively stable or worsened patients after an average time of five years (4.8±2.2). The best predictors of cognitive
outcome were evaluated by logistic regression on baseline clinical, neuropsychological, demographic, quantitative EEG
(qEEG) and 123I-FP-CIT-SPECT data. Cross-validated, receiver operator characteristic (ROC) analysis was used to
measure the accuracy of the baseline predictors of cognitive outcome. qEEG and 123I-FP-CIT-SPECT cut-point values to
be
used
in
single
subject
were
also
computed.
Results: The best predictors of future cognitive worsening were the posterior mean qEEG frequency (82% accuracy; cutpoint 8.3 Hz) and the 123I-FP-CIT-SPECT specific to non-displaceable binding ratio (SBR) at caudate level (80% accuracy;
cut-point 2.3) (p<0.0001 for both measures). The prediction accuracy was meaningfully lower for age (68%), phonological
verbal fluency (65%), Trailmaking test A (63%) and B (72%) scores. Baseline PD subtypes characterization was moderately
related to the cognitive outcome (p=0.024).
Conclusions: Both resting EEG and DAT imaging are good predictors of future cognitive worsening at an average time of
five years, in de novo, drug naïve PD patients, better than age, neuropsychological tests and clinical subtype. Cut-point
values for qEEG and 123I-FP-CIT-SPECT SBR to be used in single subject are proposed. Our findings highlight the
importance of the biomarker approach to PD since baseline evaluation. In particular, qEEG is a widely available and lowcost methodology and could be applied for prognostic purpose and for monitoring cognitive evolution in PD patients.
Reference:
− Fereshtehnejad SM, Romenets SR, Anang JB, Latreille V, Gagnon JF, Postuma RB. New Clinical Subtypes of
Parkinson Disease and Their Longitudinal Progression: A Prospective Cohort Comparison With Other Phenotypes.
JAMA neurology (2015);72:863-873
LONGITUDINAL CLINICAL AND MRI BRAIN CHANGES IN MULTIPLE SYSTEM ATROPHY
F. Caso1, F. Agosta1, I. Nikolic2, M. Lukić3, I. Petrović3, I. Stanković3, P. Valsasina1, V. Kostic3, M. Filippi1
1
Neuroimaging Research Unit, Institute of Experimental Neurology, Division of Neuroscience, San Raffaele Scientific
Institute, Vita-Salute San Raffaele University (Milano); 2Center for Radiology and MRI, University of Belgrade (BelgradeSRB); 3Clinic of Neurology, Faculty of Medicine, University of Belgrade (Belgrade-SRB)
pag. 78
Objective: To study longitudinally clinical, cognitive, and neuroimaging brain changes in patients with multiple system
atrophy-parkinsonian type (MSA-p) (1, 2).
Materials: We enrolled 25 MSA-p patients and 21 healthy controls.
Methods: MSA-p patients underwent a clinical/neuropsychological evaluation and MRI scan at baseline and after a mean
follow-up (FU) of 1.1 years. Baseline MRI was obtained from controls. Baseline and longitudinal cortical and white matter
(WM) changes in MSA-p patients were assessed using cortical thickness and diffusion tensor (DT) MRI analysis,
respectively.
Results: During follow up, MSA-p patients showed a worsening of motor impairment, cognitive deficits and behavioural
changes. At baseline, MRI study did not detect significant cortical and WM abnormalities in MSA-p patients compared with
controls. After 1.1 years, MSA-p patients showed only a subtle, focal thinning of the frontotemporal cortices. Conversely,
they showed significant, severe WM changes involving the corpus callosum, and frontotemporal and frontoparietal
connections bilaterally (anterior>posterior). No longitudinal changes were observed in the infratentorial regions. In MSA-p,
the progressive involvement of corpus callosum, external capsule, and long-range associative WM pathways was associated
with the worsening of cognitive deficits and behavioral changes.
Discussion: In MSA-p patients, the progression of WM microstructural damage is prominent compared to cortical damage
and
it
is
related
to
the
worsening
of
cognitive
and
behavioural
symptoms.
Conclusions: This is the first longitudinal, multimodal MRI study of MSA-p patients. In MSA-p patients, WM changes
were detected mainly in supratentorial regions and showed a significant impact on MSA-p clinical features. Conversely,
cortical damage was only modest. DT MRI has the potential to offer promising biomarkers for monitoring MSA-p and
predicting the clinical evolution.
References:
− Gilman S, Wenning GK, Low PA et al. Second consensus statement on the diagnosis of multiple system atrophy.
Neurology (2008);71: 670–6
− Stefanova N, Bücke P, Duerr S, Wenning GK. Multiple system atrophy: an update. Lancet Neurol. (2009)
Dec;8(12):1172-8
PROGNOSTIC INDICATORS OF SURVIVAL IN 136 MULTIPLE SYSTEM ATROPHY PATIENTS
G. Giannini1, G. Calandra-Buonaura1, M. Bacchi-Reggiani2, F. Provini1, P. Cortelli1
1
IRCCS Institute of Neurological Sciences of Bologna, Department of Biomedical and NeuroMotor Sciences (DiBiNeM),
Alma Mater Studiorum, University of Bologna (Bologna); 2Department of Experimental, Diagnostic and Specialty
Medicine (DIMES), Alma Mater Studiorum, University of Bologna (Bologna)
Objective: To determine the predictive value of different clinical factors on shortened survival in a cohort of multiple
system atrophy (MSA) patients referred to a tertiary centre.
Materials and Method: We retrospectively identified all patients with a final clinical diagnosis of MSA referred to our
Department between 1991 and 2014 and evaluated at least once a year during the disease course. Diagnosis of MSA was
independently confirmed by three neurologists expert in movement disorders from data available at the last follow-up
evaluation according to international criteria. Clinical data were collected from medical records and updated at every
follow-up visit. Survival data were defined based on time to death from the disease onset and calculated using Kaplan-Meier
curves. To identify variables associated with survival in MSA, univariate and multivariable Cox regression analyses were
performed. The following variables were studied: age at disease onset, sex, predominant clinical phenotype (parkinsonian
vs. cerebellar), presence of stridor, type of disease onset (cerebellar, parkinsonian or autonomic) and mode of autonomic
onset (orthostatic hypotension vs. urinary dysfunction). Statistical analyses were performed using the statistical software
STATA®, version 14.0. A p-value less than 0.05 (2-sided) was considered significant.
Results: A total of 136 MSA patients were included (88 males; 68 MSA with predominant Parkinsonism), 113 were
deceased at the time of the study. The mean ± standard deviation age at disease onset was 57.26 ± 8.70 years and the median
(interquartile range) of disease duration was 7 years (5-9). On Kaplan-Meier curve the median duration of illness was 7.84
years. The univariate Cox regression analyses of the influence of clinical factors on survival showed that neither MSA
subtype, sex, age at disease onset nor presence of stridor were significantly associated with survival. The autonomic disease
onset and the mode of autonomic onset (orthostatic hypotension) were associated with shortened survival in a univariate
analysis and remained independent predictors of mortality in the multivariable model (HR= 1.70, CI 95%= 1.12-2.58, p=
0.013 and HR= 1.74, CI 95%= 1.09-2.76, p= 0.019 respectively).
pag. 79
Conclusions: The study showed that autonomic disease onset and, in particular, the onset with orthostatic hypotension
predicted unfavourable survival in patients with MSA. These results could be useful in optimizing therapy and clinical
management.
THE EFFECT OF L-DOPA/CARBIDOPA INTESTINAL GEL IN PARKINSON'S DISEASE ASSESSED USING
NEUROPHYSIOLOGICAL TECHNIQUES
D. Belvisi1, M. Bologna1, A. Latorre2, F. Di Biasio1, A. Conte1,2, N. Modugno1,2, A. Berardelli1,2, G. Fabbrini1,2
1
IRCCS Neuromed Institute, Sapienza, Università di Roma (Pozzilli-IS); 2Department of Neurology and Psychiatry,
Sapienza University of Rome (Roma)
Introduction: Continuous dopaminergic stimulation is a therapeutic option in the advanced stages of Parkinson’s disease
(PD). L-Dopa/Carbidopa intestinal gel (LCIG) delivered to the proximal jejunum allows a stable and smooth plasmatic
concentration of L-Dopa. Despite the evidence of the efficacy of LCIG on motor and non-motor symptoms in PD, no
studies have objectively investigated the effects of LGIG on motor and non-motor abnormalities by using
neurophysiological techniques.
Methods: We studied 11 with advanced PD patients in therapy with LCIG and 11 age-matched healthy subjects. Motor
impairment was measured by kinematic recording of repetitive finger movements (finger tapping), recorded using a 3D
optoelectronic system (SMART). Patients were instructed to tap the index finger against the thumb repeatedly as rapidly
and with as large amplitude as possible for 15 seconds. Movement amplitude, velocity and rhythm were measured. Sensory
abnormalities were evaluated using the somatosensory tactile discrimination threshold (STDT). STDT was tested by
delivering paired stimuli starting with an interstimulus interval of 0 ms (simultaneous pair), and progressively increasing
interstimulus intervals in 10 ms steps. STDT was evaluated in two different body regions bilaterally: the index finger
(‘hand’) and the periorbital region (‘eye’). All patients were studied in OFF and ON phase.
Results: The kinematic analysis of finger tapping showed that PD patients in the OFF medication condition had a markedly
lower amplitude and velocity and impaired rhythm than HS and no progressive reduction in both movement kinematics
during finger tapping. Similar results were obtained when comparing PD patients ON medication and HS thus indicating
that LCIG did not normalize the kinematic variables analyzed. However, movement amplitude and velocity were improved
upon LCIG infusion as showed by the significant difference of the kinematic variables between the OFF and ON condition.
STDT values were significantly higher PD patients OFF and ON medication in comparison to HS independently from the
medication status, the body side and region tested. In PD patients STDT values tested in ON medication condition
improved, but did not normalize, in comparison to those obtained in OFF medication condition.
Conclusions: Continuous dopaminergic stimulation improves but does not normalize motor and sensory abnormalities in
advanced PD. LCIG is able to reverse, at least in part, functional abnormalities causing motor and sensory deficit, but is not
able to compensate alternative mechanisms, possibly including anatomical abnormalities of basal ganglia nuclei and cortical
areas resulting in bradykinesia and sensory deficits in advanced PD.
PAIN THRESHOLD AND PAIN TOLERANCE IN FUNCTIONAL AND IDIOPATHIC DYSTONIA
A. Matinella1, F. Morgante2, E. Andrenelli3, C. Allegra2, C. Terranova2, P. Girlanda2, M. Tinazzi1
1
Department of Neurological and Movement Sciences, Neurology Unit, University of Verona (Verona); 2Department of
Clinical and Experimental Medicine, University of Messina (Messina); 3Department of Experimental and Clinical Medicine,
Neurorehabilitation Clinic, "Politecnica delle Marche" University (Ancona)
Objectives: Pain is often experiences by patients affected by functional dystonia, sometimes at a degree which is
disproportionate to the extent of motor symptoms and occur in body segments not affected by involuntary movements.
Painful sensations are also experienced by patients with idiopathic cervical dystonia in the affected body part. Aim of the
present study was to assess pain threshold and pain tolerance in patients with functional and idiopathic dystonia.
Methods: We enrolled 10 patients with idiopathic cervical dystonia, 10 patients with functional dystonia and 14 age- and
gender matched healthy controls. Pain threshold and pain tolerance were assessed giving square wave electrical pulses of
increasing intensity delivered to the index finger of each hand through skin ring electrodes. The lowest intensity of stimulus
(0.5 mA) was increased by 0.5 mA steps until the subjects perceived the electrical stimulus (tactile threshold). Then, the
intensity of electrical stimulus was increased by 0.5 mA steps until the subjects reported a change in sensation from
unpainful to ‘‘faintly painful’’ (pain threshold, P-Th). Finally, the intensity was increased by 1 mA steps until the subjects
pag. 80
reported an ‘‘intolerable’’ painful sensation (pain tolerance, P-Tol).
Results: In functional dystonia patients we recorded a significant increase of P-Th (p < 0.01) and P-Tol (p< 0.0001)
compared to idiopathic cervical dystonia and control healthy subjects. The increase of P-Th and P-Tol did not correlate with
disease duration.
Discussion: We demonstrate that patients with functional dystonia a marked increase of pain threshold and pain tolerance
compare to patients with idiopathic dystonia and healthy control subjects. We might hypothesize that the abnormal
connectivity between the motor and the limbic system which characterized functional dystonia might account for increased
pain perception. That is, increased pain thresholds might be linked to an alteration of the emotional aspect of pain
processing in functional dystonia.
Conclusion: Pain processing is different in patients with functional and idiopathic dystonia, with significant increase of pain
thresholds in functional dystonia.
ORTHOSTATIC HYPOTENSION INCREASES THE RISK OF FALLS IN IDIOPATHIC PARKINSON'S
DISEASE PATIENTS
M. Sarchioto1, M. Zibetti1, S. Maule2, V. Milazzo2, E. Montanaro1, A. Romagnolo1, A. Merola1, L. Lopiano1
1
Dipartimento di Neuroscienze, Università di Torino (Torino); 2Dipartimento di Scienze Mediche, Università di Torino
(Torino)
Objective: Orthostatic hypotension (OH) is believed to contribute to cause falls in Parkinson's disease (PD) patients, but few
studies have assessed it directly. In this work we evaluated the correlation between falls and OH in patients with PD.
Materials: Thirty six consecutive patients diagnosed with idiopathic PD were recruited. Patients who presented atypical
parkinsonian features, older than 80 years or having positive history for diabetes mellitus, chronic renal failure, atrial
fibrillation or other arrhythmias were excluded.
Methods: Motor features were scored using Unified Parkinson’s Disease Rating Scale part III (UPDRS III) and Hoen and
Yahr’s (H&Y) staging. Patient’s global postural assessment was evaluated using a 4-item axial motor subscore, calculated
using the sum of MDS-UPDRS motor examination items from 3.27 to 3.30 and three more tests: Time Up and Go (TUG),
Push and Release (P&R) and Freezing of Gate Questionnaire (FOG). A brief cognitive screening was performed using
Montreal Cognitive Assessment (MoCa). Patient’s autonomic functions were studied using postural blood pressure test for
orthostatic hypotension (OH). Anamnestic data for falls were collected by asking patients for any falls occurred in the
previous 12 months. They were also followed up for falls in the next 6 months.
Results: The mean age was 63.7 (SD 9.6) years and the mean disease duration was 6.5 (SD 3.5) years. A statistically
significant association was found between falls and OH (p=0.04). Falls also inversely correlated with the value of systolic
blood pressure reduction measured at the 1st and 3rd minute during tilt test (p=0.01 for both conditions) and directly
correlate with the systolic blood pressure reduction between supine and 1st minute orthostatic measurement (∆p) (p=0.02).
A multiple regression model taking into account possible confounding variables of axial symptoms and cognitive status
(MoCA) showed that ∆p remained a significant predictor of falls (t = 2.6, p=0.01).
Discussion: Our data demonstrate a role of OH as a risk factor for falls in patients with idiopathic PD. Data suggest that
there is a strict correlation between sistolic blood pressure values and falls, infact the lower is the value of it the greater is
the probability of falls for patients. Data also demonstrate that higher is the gap between sistolic and diastolic blood pressure
values, the higher is the chance of falls.
Conclusions: Careful monitoring of supine and orthostatic blood pressure may be useful for detecting individuals with PD at
risk of falls and may be a significant modifiable factor for falls prevention.
References:
− Kerr GK, Worringham CJ, Cole MH, Lacherez PF, Wood JM, Silburn PA. Predictors of future falls in Parkinson
disease. Neurology (2010) Jul 13;75(2):116-24
− Vikas Kotagal, Roger L. Albin, Martijn L.T.M. Müller, Robert A. Koeppe, Kirk A. Frey, Nicolaas I. Bohnen.
Modifiable cardiovascular risk factors and axial motor impairments in Parkinson disease. Neurology
(2014);82:1514–1520
− Palma JA, Gomez-Esteban JC, Norcliffe-Kaufmann L, Martinez J, Tijero B, Berganzo K, Kaufmann H. Orthostatic
hypotension in Parkinson disease: how much you fall or how low you go? Movement Disorders (2015) Apr
15;30(5):639-45
NEUROPSICOLOGIA CLINICA
pag. 81
ITEM CONSISTENCY IN RETRIEVING PERSON-SPECIFIC SEMANTIC INFORMATION FROM FACES
AND VOICES: AN EXPLORATORY STUDY IN HEALTHY SUBJECTS
C. Piccininni1, G. Gainotti1, L. Trojano2, S. Luzzi3, C. Papagno2, G. Carlesimo4, C. Marra1, D. Quaranta1
1
Research Center for Neuropsychology, Institute of Neurology, Catholic University (Roma); 2Department of Psychology,
Second University of Naples (Caserta); 3Department of Clinical and Experimental Medicine, Polytechnic University of
Marche (Ancona); 4Laboratory of Clinical and Behavioural Neurology, IRCCS Santa Lucia Foundation (Roma)
Objectives: Faces and voices are the most important stimuli for the recognition of familiar people, but their efficacy is not
symmetrical. Previous evidence has shown an advantage of face over voice in semantic information retrieval. These
findings are at variance with models assuming that semantic information is stored in an unitary fashion. As proposed by
previous authors [1], a further clarification of this issue could come from the assessment of consistency across modalities
(face and voice) for individual test items. In fact, an unitary amodal person-specific semantic system would correspond to a
high level of consistency across modalities, whereas low levels of consistency would favour the hypothesis of a multi-modal
system. The aim of the present study was to evaluate item consistency across modalities in healthy subjects who underwent
the Famous People Recognition Battery (FPRB), a standardized test [2] devised to assess familiarity and semantic
information retrieval from face and voice.
Materials: We enrolled 155 healthy subjects who underwent the FPRB. The FPRB consists of two subtests in which subjects
are requested to recognize the same 40 famous persons through their faces and voices, distinguishing them from 20
unknown people, and assessing identification of persons recognized as familiar. Identification is estimated with a semantic
score ranging 0-3.
Methods: Consistency between scores obtained in the face and voice modalities was assessed by the intraclass correlation
coefficient (ICC) between the semantic score obtained for voices and faces. Only scores obtained by subjects who
experienced a familiarity feeling for both modalities were taken into account.
Results: For most of the stimuli (26/40, 65%) the familiarity feeling was more easily evoked from faces. The total semantic
scores from voices and faces were significantly different (69.81±24.326 vs 101.06±15.288; p<0.001). In most cases (22/40,
55%) the semantic score for each item was higher when information was retrieved from faces. The ICC varied markedly
across the stimuli (range: -0,001 - 0,623), being generally quite low (median=0.208).
Discussion: Our data confirm the advantage of faces over voices in retrieval of person-specific semantic information even
when only subjects who retrieved familiarity feelings in both modalities were taken into account. The rather low and
variable level of consistency is at variance with models assuming an amodal person-specific semantic system.
Conclusion: The low level of consistency across modalities in retrieving semantic information from voices and faces
support the hypothesis that information about person is stored in a multimodal fashion.
References:
1. Barton JJ, Corrow SL. Recognizing and identifying people: A neuropsychological review. Cortex. (2016)
Feb;75:132-50
2. Quaranta D, Piccininni C, Carlesimo GA, Luzzi S, Marra C, Papagno C, Trojano L, Gainotti G. Recognition
disorders for famous faces and voices: a review of the literature and normative data of a new test battery. Neurol
Sci. (2016) Mar;37(3):345-52
MENTAL SIMULATION OF WHOLE-BODY MOVEMENTS IN PATIENTS WITH ISOLATED CERVICAL
DYSTONIA
F. Falco1, R. Allocca1, M. Esposito1, C. Vitale2, S. Peluso1, G. Santangelo3, M. Consono3
1
Department of Neuroscience, Reproductive Sciences and Dentistry, Federico II (Napoli); 2Department of Motor Science
and Welness, Parthenope (Napoli) 3Department of Psychology, Second University (Napoli)
Objective: To explore mental transformation of whole-body images in patients with isolated cervical dystonia (CD).
Background: Mental transformation of bodies or of body-part images is performed by simulating one's own actual
movements, and is likely to rely upon brain systems involved in motor planning and execution. Patients with CD have
various clinical presentations with different degrees of postural abnormality consistent with severity of dystonia. Previous
evidence showed that CD patients were slower and less accurate than healthy controls in mentally rotating both affected
(neck) and unaffected (hands and feet) body parts, but they also showed a non-significant decrement in their ability to
mentally transform non-corporeal objects (Fiorio et al. 2007). Thus, it cannot be established whether CD patients are unable
to simulate one's own body movements (embodied simulation) or have a more general deficit in mental rotation. Here, we
pag. 82
tested embodied simulation processes in CD patients by a whole-body transformation task.
Methods: Eighteen patients with isolated CD under treatment with botulinum toxin and no general cognitive disorders, as
assessed by formal neuropsychological examination, and 18 healthy controls, matched for age and education, underwent the
whole-body transformation task. Participants had to perform left-right judgments on a schematic figure representing a frontfacing or a back-facing human body in different spatial orientations (Conson et al. 2014). Both Reaction Times (RTs) and
error rates were recorded.
Results: A four-way mixed-design ANOVA was performed on correct RTs, with stimulus posture (front-facing and backfacing) and stimulus orientation (0°, 90°, 180° and 270°) as within-subject factors, and with group (CD patients and
controls) as a between-subject factor. The main result was a significant interaction among the three factor, F(3,102)=3,350,
p= .047, partial h2 = .107, demonstrating that CD patients were slower than controls when judging back-facing, but not
front-facing bodies, in specific spatial orientations.
Conclusions: These findings showing that CD patients were specifically impaired in mentally transforming back-facing
body images suggest that simulation of whole-body movements is impaired in this clinical population when embodied
simulation processes come into play.
References:
− Albanese A., Bhatia K., Bressman S. B., DeLong M. R., Fahn S., Fung V. S., Lang A. E. Phenomenology and
classification of dystonia: a consensus update. Movement Disorders (2013); 28(7):863-873
− Albright A. L., Barry M. J., Shafron D. H., Ferson S. S. Intrathecal baclofen for generalized dystonia.
Developmental Medicine & Child Neurology, (2001);43(10), 652-657
− Conson M., Pistoia F., Sarà M., Grossi D., Trojano, L. Recognition and mental manipulation of body parts
dissociate in locked-in syndrome. Brain and Cognition (2010);73(3):189-193
GRAY AND WHITE MATTER DAMAGE DIFFERENTLY CORRELATED WITH COGNITION IN ADULT
MULTIPLE SCLEROSIS PATIENTS WITH DIFFERENT AGE OF DISEASE ONSET
M. A. Rocca1, L. Vacchi1, B. Colombo2, M. Rodegher2, L. Moiola2, A. Ghezzi3, G. Comi2, A. Falini4, M. Filippi1
1
Neuroimaging Research Unit, Institute of Experimental Neurology, Division of Neuroscience, San Raffaele Scientific
Institute and Vita-Salute San Raffaele University (Milano); 2Department of Neurology, San Raffaele Scientific Institute and
Vita-Salute San Raffaele University (Milano); 3Multiple Sclerosis Center, Gallarate Hospital (Gallarate, VA); 4Department
of Neuroradiology, San Raffaele Scientific Institute and Vita-Salute San Raffaele University (Milano)
Background: Age of MS onset may influence clinical status during adulthood.
Aims: To explore the relationship between the patterns of brain gray matter (GM) atrophy and white matter (WM)
microstructural abnormalities and cognitive performances in adult MS patients according to their age of disease onset.
Methods: 3D T1-weighted and diffusion tensor (DT) MRI scans were acquired from 41 pediatric-onset (PO), 42 agematched (AOA) and 35 disease duration-matched (AODD) adult-onset MS patients. Fifty-eight healthy controls were also
studied. Whole-brain voxel-wise methods were used to define the regional distribution of damage in the brain GM and WM,
using tract-based spatial statistics (TBSS) and voxel based morphometry (VBM). Between-group comparisons were
adjusted for age or disease duration, as appropriate. Correlations with cognitive performances were estimated (age-adjusted
analyses).
Results: Comparable cognitive performances were observed in POMS versus AOA or AODD patients. In POMS patients,
atrophy of frontal and subcortical areas correlated with poor memory performance. Moreover, decreased FA in the main
WM tracts and increased MD in the main supra-tentorial tracts correlated with deficits at the main cognitive domains. In
AOA-MS and AODD-MS patients, decreased FA and an increased MD in the corpus callosum, cingulum, corona radiata,
internal and external capsule, superior longitudinal fasciculus and posterior thalamic radiation correlated poor performance
at the attentive domain only.
Conclusions: Although POMS had similar cognitive performance, the relationship between cognitive abnormalities and
brain structural damage was more distributed than in patients with similar age and disease duration. This suggests the role of
structural maturational aspects in the proper development of cognitive skills and the possible presence of different MS
pathogenic mechanisms during childhood that may alter brain structural development, in particular WM connections.
Partially supported by a grant from Italian Ministry of Health (GR-2009-1529671).
MENTAL IMAGERY OF POSITIVE LIFE EXPERIENCES: THE NEURAL BASES OF EUDAIMONIC AND
HEDONIC HAPPINESS
pag. 83
G. Testa1, M. Rusconi1, T. Costa2, A. Suardi1, F. Cauda2, M. Diano2, S. Duca3, I. Sotgiu1
1
Department of Human and Social Sciences, University of Bergamo (Bergamo); 2Department of Psychology, University of
Turin (Torino); 3GCS-fMRI, Department of Neuroradiology, Koelliker Hospital (Torino)
Aims: In recent years, neuroimaging studies using mood induction procedures (MIP) have been conducted to investigate the
neural correlates of happiness. However, a well-defined neural network for happiness has not been determined yet, mainly
because of methodological and theoretical limitations (Suardi et al., 2016). Indeed, researchers using MIP asked participants
to imagine or recall happy events during brain scanning. However, they did not guide participants in generating their mental
imageries or recollections, thus increasing the activation of interindividually and intraindividually variable neural networks.
A second limitation concerns the absolute lack of neuroimaging studies taking into account the theoretical distinction,
proposed in the field of Positive Psychology, between eudaimonic happiness (i.e., the positive psychological condition
derived from the development of one's best potentials) and hedonic happiness (i.e., the experience of pleasure and positive
affect). In the present functional magnetic resonance imaging (fMRI) study, a novel mental imagery task allowed us to
investigate the neural correlates of both eudaimonic and hedonic happiness.
Materials: During fMRI scanning, participants were cued with written sentences describing three different classes of events:
Hedonic (HE), eudaimonic (EE), and neutral events. (NE). In order to enhance vividness during the imagery task, each
event description included four features: Sensory details, emotional feelings, interoceptive activations, and movements.
Method: Seventeen students (7 males, 10 females; mean age = 25.06, SD= 5.05) underwent fMRI while cued with written
sentences. Participants were asked to image themselves into the described event. A block-design experimental protocol
randomly alternating the three different events categories (HE, EE, NE) was used. RESULTS: Compared to NE, HE and EE
events activated a network of frontal, temporal and parietal regions, as well as subcortical structures. In the direct HE/EE
comparison, HE events showed enhanced activity in medial/middle frontal regions and anterior cingulate cortex, whereas
EE showed increased activity in the right precentral gyrus. Discussion: Mental imagery of hedonic events was related to
increased activity in regions which are typically implicated in reward representation and self-referential processing
(Kringelbach, 2005). By contrast, mental imagery of eudaimonic events showed higher activation in the right precentral
gyrus, which has been linked to goal-directed actions and cognitive reappraisal (Seo et al., 2014). Conclusions: Results
suggest that imagining hedonic and eudaimonic happy life experiences is associated with relatively differentiated brain
circuits, underlying distinct functions.
References:
− Kringelbach, M. L., The human orbitofrontal cortex: Linking reward to hedonic experience. Nature Reviews
Neuroscience (2005);6(9):691-702
− Seo, D., Olman, C.A., Haut, K.M., Sinha, R., MacDonald,Angus W., & Patrick, C.J., Neural correlates of
preparatory and regulatory control over positive and negative emotion. Social Cognitive and Affective
Neuroscience (2014);9(4):494-504
− Suardi, A., Sotgiu, I., Costa, T., Cauda, F., & Rusconi, M., The neural correlates of happiness: A review of PET
and fMRI studies using autobiographical recall methods. Cognitive, Affective & Behavioral Neuroscience
(2016);16(3):383-392
MULTIFOCAL COGNITIVE DYSFUNCTION
EXPLORATORY CROSS-SECTIONAL STUDY
IN
HIGH-DOSE
BENZODIAZEPINE
USERS.
AN
A. Federico1, S. Tamburin1, A. Maier1, M. Faccini2, R. Casari2, F. Lugoboni2
1
Department of Neuroscience, Biomedicine and Movement Sciences, University of Verona (Verona); 2Department of
Internal Medicine, Addiction Unit, University Hospital of Verona (Verona)
Objective: Benzodiazepine (BZD) is the most widely prescribed drug class in developed countries. High-dose BZD abuse
represents an emerging phenomenon. Cognitive deficits in long-term BZD users have long been known, but previous results
might have been biased by patients’ old age and coexisting neurological psychiatric and/or neurological conditions.
Aims: The study was aimed to explore the neuropsychological effect of high-dose BDZ dependence.
Materials and Methods: We recruited a group of middle-aged high-dose BZD users with no neurological or psychiatric
comorbidity, except anxiety or depression. They underwent a battery of cognitive tests to explore verbal, visuospatial
memory, working memory, attention, and executive functions.
Results: All the neuropsychological measures were significantly worse in patients than controls. Coexisting alcohol
dependence and the severity of depression did not influence cognitive tests.
pag. 84
Discussion: Patients with high-dose BZD intake show profound changes in cognitive function.
Conclusions: The impact of cognition should be considered in this population of patients, who may be involved in risky
activities or have high work responsibilities.
THALAMIC LESIONS AFFECT THE SOMATIC MARKER: A DISCONNECTION HYPOTHESIS
L. Serra1, M. Bruschini1, C. Ottaviani1, S. Fagioli1, L. Fadda2, C. Caltagirone2, G. Carlesimo2, M. Bozzali1
1
Neuroimaging Laboratory, Santa Lucia Foundation IRCCS (Roma); 2Department of Clinical and Behavioural Neurology;
Department of Neuroscience, Santa Lucia Foundation IRCCS; University of Rome ‘Tor Vergata’ (Roma)
Aim: To use an approach based on diffusion tractography to characterise the cortico-thalamic connectivity in a patient
presenting with bilateral infarct of the thalami (1), but no evidence of cognitive deficits in everyday life, with the only
exception of increased emotionality, anxiety and an episode of disinhibition. Methods: Patient L.C. suffered from a bilateral
damage of the anterior region of the thalamus. He underwent an extensive neuropsychological assessment including the
IOWA gambling task (IGT), with and without heart rate variability (HRV) assessment. Patient underwent also an MRI scan
at 3T, including a T1-weighted volume. Patient’s lesions were manually segmented. T1-volume was normalised to standard
space, and the same transformations was applied to the lesion masks. Finally ten healthy controls (HC) underwent a
diffusion tensor imaging (DTI) scan. DTI data from HC were normalised to standard space and averaged. An atlas of
Brodmann areas (BA) was used to parcellate the prefrontal cortex. Probabilistic tractography (2) was used to assess the
probability of connection between each voxel of the thalamus and each frontal BA. The resulting map of corticothalamic
connections was superimposed onto the patient’ lesion masks.
Results: L.C. reported significant IGT deficits in association with impairments in the somatic marker response indexed by
HRV. The MRI exam documented an asymmetrical bilateral damage of the centromedian parafascicular complex,
considerably larger on the right side. Patient’s lesions fell within areas of the thalamus connected with the anterior cingulate
cortex (BA 32) and with the dorsolateral prefrontal cortex (BA9). Discussion: Patient’s thalamic lesions produced
disconnection with brain areas involved with both decision making abilities and autonomic regulation (3).
Conclusions: We speculate that thalamic lesions affect the somatic marker as a consequence of disconnection mechanism.
References:
− Serra L, Cercignani M, Carlesimo GA, Fadda L, Tini N, Giulietti G, Caltagirone C, Bozzali M. Connectivity-based
parcellation of the thalamus explains specific cognitive and behavioural symptoms in patients with bilateral
thalamic infarct. PLoS One (2013) Jun 3;8(6):e64578
− Parker GJ, Haroon HA, Wheeler-Kingshott CA. A framework for a streamline-based probabilistic index of
connectivity (PICo) using a structural interpretation of MRI diffusion measurements. J Magn Reson Imaging
(2003); 18: 242-54
− Vogt BA. Submodalities of emotion in the context of cingulate subregions. Cortex (2014) Oct;59:197-202
LONGITUDINAL CHANGES IN NEUROPSYCHOLOGICAL CHARACTERISTICS OF ADOLESCENTS WITH
SPECIFIC LEARNING DISABILITIES
F. Mattioli1, C. Stampatori1, F. Bellomi1, V. Trebeschi2, E. Zanetti2, F. Gitti2, E. Fazzi2
1
Neuropsychology Unit, Spedali Civili (Brescia); 2Childhood Neuropsychiatry, Spedali Civili (Brescia)
Objective: Though Specific Learning Disabilities (SLD) are considered, as genetically determined, to be stable over the
lifespan, some changes in clinical manifestation of Dyslexia, Dyscalculia, Dysortography and Dysgraphia have been
described and their evolution over time needs to be further investigated. The aim of this study is to describe in a group of
italian subjects with SLD, the longitudinal change in their neuropsychological evaluation up to secondary school.
Materials and Methods: We studied 35 subjects (26 males and 9 females) diagnosed to have a SLD when they attended the
elementary school (mean age 9.72) after a mean 7 years follow up (mean age 16). Their neurological examination was
normal as well as the IQ (Total 102.48± 9.42; Verbal IQ 99.37±10.11 and Performance IQ 105.75±11.87). DDE2 (Sartori et
al., 2007) for testing reading and writing and AC-MT (Cornoldi et al., Erickson 2003) or BDE (Biancardi, 2004) or MT
Avanzate (Cornoldi, OS, 2010) for calculation were used and the diagnosis made according to the recommended guidelines
(Italian Consensus Conference, 2010). Raw scores were compared within group between the baseline and the follow up
(Wilcoxon test).
Results: Consistently diagnosed dyslexic at both examinations were 60%, dysortographics were 31.4% and Dyscalculics
17.1%. In only 8.33% Dyslexia was not confirmed at follow up, Dysortography in 40% of cases. Dyscalculia in 14.4%. A
pag. 85
statistically significant reduction from baseline to follow up in errors during word reading (6.77 vs. 5.41; p=.02), in word
reading time (154.89” vs. 97.07”; p=.00) and non word reading time (113.97 vs. 71.84; p.00) was found as well as a
significant reduction in errors during writing to dictation of words (4 vs. 1.39; p=.027), non words (4.1 vs. 2.21, p=.017) and
phrases (7.2 vs. 2.8; p=.004). On the contrary errors in non word reading resulted unchanged at follow up (11.3 vs. 6.44;
p=ns).
Discussion: In our group of Italian SLD subjects we were not able to confirm consistency of diagnosis over time. Dyslexia
showed the greater consistency, whereas Dysortography tended to disappear in 40% of cases. The test resulting to be
consistently impaired over time was non word errors.
Conclusions: Clinical manifestations of SLD may change over time, with the greater consistency observed in Dyslexia,
compared to Dysortography and Dyscalculia. Measuring non word errors in adolescents with suspected Dyslexia appears to
be possibly sufficient to confirm the diagnosis
References:
− Sartori G et al. Batteria per la valutazione della dislessia e disortografia evolutiva DDE2, Giunti OS (2007)
− Cornoldi C et al. MT avanzate, Giunti OS, 2010; Cornoldi C and Cazzola C. ACMT Test di valutazione delle
abilità di calcolo e problem solving da 11 a 14 anni, Erickson 2003
− Biancardi A and Nicoletti C. Batteria per la Discalculia Evolutiva (BDE) Omega Edizioni (2004)
EFFECTS OF A VIRTUAL REALITY-BASED TRAINING WITH BST-NIRVANA ON COGNITIVE
RECOVERY IN STROKE PATIENTS: PRELIMINARY DATA
R. De Luca1, R. Calabrò1, S. Leonardi1, B. Aragona1, F. Santamaria1, D. Latella1, P. Tomasello1, F. Sciarrone1, M. Maggio1,
M. Russo1, P. Bramanti2
1
Behavioral and Robotic Rehabilitation Laboratory, IRCCS Neurolesi Center (Messina); 2Scientific Director IRCCS
Neurolesi Center (Messina)
Objective: This study aimed to determine the effects of a virtual reality (VR) training with Bts Nirvana, using the
Interactive-Semi-Immersive Program (I-SIP), on the recovery of cognitive functions in stroke patients.
Material: We enrolled 12 patients (6 experimental group - EG; and 6 control group - CG) affected by stroke (in post acute
phase, i.e. 3-6 months after the vascular event), who received cognitive therapy at the Laboratory of the Behavioral and
Cognitive Rehabilitation in Neurolesi Center in Messina, between July and August 2015.
Methods: EG underwent a virtual cognitive rehabilitation training with Bst Nirvana in addition to standard treatment and
CG was submitted to conventional neurorehabilitation. All the patients were evaluated by a specific psychometric battery, at
the beginning (T0 -Time or baseline) and at the end of the each training (T1-follow-up). EG took part in the VR exercise
program for 45 minutes each day, three times per week, for 8 weeks.
Results: In the EG, there were significant differences in the Montreal Cognitive Assessment (MOCA) (p= 0,02): in selective
attention assessment scores (p=0,01), in verbal memory (p=0,03) and visuo-spatial and constructive abilities (p= 0,01),
between the baseline and endpoint. Discussion. Post-stroke cognitive impairment occurs frequently in patients with stroke.
Cognition, particularly attention and visuo-spatial ability, is strongly associated with quality of life after stroke. New
interactive technologies help therapists in neurorehabilitation in order to increase neurological patients' autonomy and
quality of life. VR and interactive video gaming have emerged as recent treatment approaches in stroke rehabilitation. VR
can be used as an enhancement to conventional therapy for patients with conditions ranging from musculoskeletal problems,
to stroke-induced paralysis, to cognitive deficits.
Conclusion: According to these preliminary data, the VR with I-SIP can be a useful complementary treatment to stimulate
global cognitive recovery, and can be considered an additional treatment for attention, memory and visuo-spatial
dysfunctions. Further studies should develop systematic protocols for cognitive rehabilitation training employing VR.
References:
− Sun JH, Tan L, Yu JT. Post-stroke cognitive impairment: epidemiology,mechanisms and management. Ann Transl
Med. (2014) Aug;2(8):80
− Laver KE, George S, Thomas S, Deutsch JE, Crotty M. Virtual reality for stroke rehabilitation. Cochrane Database
Syst Rev. (2015) Feb 12;2:CD008349
− Gamito P, Oliveira J, Coelho C, Morais D, Lopes P, Pacheco J, Brito R, Soares F, Santos N, Barata AF. Cognitive
training on stroke patients via virtual reality-based serious games. Disabil Rehabil. (2015) Mar 5:1-4
pag. 86
CEFALEE 2
LONG-TERM EXPERIENCE OF ONABOTULINUMTOXINA IN A LARGE SERIES OF CHRONIC MIGRAINE
PATIENTS
M. Trimboli, A. P. Andreou, M. Murphy, A. Al-Kaisy, G. Lambru
The Headache Centre, Guy's and St. Thomas' NHS Foundation Trust (London, UK)
Aims: We described the long-term outcome of a large series of chronic migraine (CM) patients treated with
OnabotulinumtoxinA (BoNT-A) in a real-life setting. Additionally, we assessed whether the follow-the-pain strategy
improves clinical outcomes compared to the fixed-site, fixed-dose PREEMPT paradigm (155 U).
Methods: We evaluated the effectiveness of BoNT-A in our CM patients treated between 2012 and 2016, following the
NICE criteria. Patients received BoNT-A between 155U-185U according to the PREEMPT paradigm. Several outcome
measures were collected and analysed including changes from baseline in headache days and migraine-related disability,
measured using headache diaries and the Headache Impact Test (HIT-6) respectively. Patients with medication overuse
(MO) that did not respond to withdrawal strategies were included. Patients were also divided in those treated with an
average number of BoNT-A units between 155-164 and those treated with 165-185 units.
Results: Out of 200 treated patients, 145 (133 women, 12 men) received at least two BoNT-A cycles. Of these 37/145
patients received at least five cycles, 45/145 patients received at least nine cycles and 11/145 patients at least 13 cycles.
After the second treatment a total of 97/145 (67%) reported at least 30% reduction in headache days from baseline: in
particular, 25/145(17%) patients reported 30-49% reduction, 40/145(28%) patients reported 50-74%, and 32/145(22%)
patients reported ≥75%. The proportion of patients with MO at baseline (46%) was reduced to 15% after two treatments. At
least 30% reduction in headache days was achieved by 72 of the 93 (77%) patients that continued the treatment after one
year, by 38/45 (84%) patients after two years and by 8/11 (73%) patients after three years. The average HIT-6 score was
reduced from 69 at baseline to 62.8 at last visit. Sixteen percent of patients scored ≤55 on HIT-6 at their most recent visit. In
both groups BoNT-A therapy significantly reduced the number of headache days compared to baseline (P ≤0.026). The
group of patients that received >165 U did not show a significant reduction in headache days compared the group who
received 155 U (P ≥0.306).
Conclusions: Our preliminary findings show sustained benefit of BoNT-A in the majority of CM patients with and without
MO. The follow-the-pain strategy may not offer additional benefits compared to the standard paradigm. A comparison
between larger series of patients treated with 155U vs patients treated with 185U may be required before implementing our
findings in clinical practice.
RESTING STATE CONNECTIVITY BETWEEN DEFAULT MODE NETWORK AND INSULA ENCODES PAIN
INTENSITY DURING SPONTANEOUS MIGRAINE ATTACKS
G. Coppola1, A. Di Renzo1, E. Tinelli2, C. Di Lorenzo3, V. Parisi1, F. Pierelli4
1
Department of Neurophysiology of Vision and Neurophthalmology, G.B. Bietti Foundation-IRCCS (Roma); 2Department
of Neurology and Psychiatry, Neuroradiology Section, Sapienza University of Rome (Roma); 3Neurology Section, Don
Carlo Gnocchi Onlus Foundation (Milano); 4Department of Medico-Surgical Sciences and Biotechnologies, Sapienza
University of Rome Polo Pontino (Latina)
Background: Previous functional magnetic resonance imaging (MRI) studies have revealed that greater ongoing clinical
pain in different chronic pain populations, such as fibromyalgia and chronic low-back pain, is associated with proportional
greater resting default mode network (DMN) connectivity to insula. Here, we investigated seed-based resting state DMNinsula connectivity during the acute head pain that characterizes spontaneous recurrent migraine attacks.
Method: Thirteen patients with untreated migraine without aura (MI) underwent 3T MRI scans during the initial 6 hours of
a spontaneous full-blown migraine attack and were compared to a group of 19 healthy volunteers (HV). We collected seedbased resting state data in the four core regions consistently identified in the DMN: medial prefrontal cortex (MPFC),
pag. 87
posterior cingulate cortex (PCC), and left and right inferior parietal lobules (IPLs). Moreover, we collected seed-based
resting state data from the insula bilaterally.
Results: Compared to HV, MI patients showed stronger bilateral insula connectivity to the medial prefrontal cortex (MPFC)
region of interest. In MI, the strength of insula-MPFC connectivity, as measured by calculating the Spearman's rank
correlation coefficient, was negatively correlated with pain intensity (visual analogue scale) during migraine (r= -0.566, p=
0.05).
Conclusion: To sum up, we documented for the first time that greater subjective intensity of pain during migraine is
associated with proportional weaker DMN-insula connectivity. Notably, this finding seems to be specific to acute migraine
head pain since it was dissimilar to that reported in previous studies investigating the association between chronic extracephalic painful conditions and DMN-insula connectivity.
MODIFICATIONS OF GRAY MATTER VOLUME IN MIGRAINE PATIENTS OVER FOUR YEARS: A
TENSOR-BASED MORPHOMETRY STUDY
R. Messina1, B. Colombo1, E. Pagani2, A. Falini3, G. Comi1, M. Filippi2, M. Rocca2
1
Department of Neurology, San Raffaele Scientific Institute, Vita-Salute San Raffaele University (Milano); 2Neuroimaging
Research Unit, INSPE, Division of Neuroscience, San Raffaele Scientific Institute, Vita-Salute San Raffaele University
(Milano); 3Department of Neuroradiology, San Raffaele Scientific Institute, Vita-Salute San Raffaele University (Milano)
Background: Previous studies have shown diffuse gray matter (GM) abnormalities in regions involved in pain and visual
processing in migraine patients. A longitudinal study found GM atrophy of sensory-discriminative brain regions in these
patients after one year.
Objectives: To explore longitudinal GM changes over a four-year follow up in migraine patients and their association with
patients’ clinical characteristics and disease activity.
Methods: Using a 3.0 Tesla scanner, brain dual-echo and 3D T1-weighted scans were acquired from 25 patients with
migraine and 25 healthy controls at baseline and after 4 years (range of follow-up years: controls 1.7-6.6, patients: 2.9-5.6).
Tensor-Based Morphometry and SPM12 were used to assess longitudinal changes of GM volumes in migraine patients after
4 years and according to the disease duration and attack frequency and their changes.
Results: Eight patients (32%) reported an increased number of migraine attacks at follow up. At baseline, compared to
controls, migraine patients showed cerebellar GM atrophy and higher volume of regions of the right fronto-temporo-parietal
lobes. At follow up, compared to controls, migraine patients had an increased volume of fronto-parietal regions, which was
related to a higher number of migraine attacks at baseline (r=0.58, p<0.001) and was more prominent in those patients with
increasing number of attacks during the study. At follow up, compared to controls, migraine patients developed GM atrophy
of the right thalamus and occipital areas. Thalamic atrophy was more pronounced in patients with a longer disease duration.
Conclusions: The migraine brain changes dynamically over time. Various pathophysiological mechanism might affect
different brain regions in migraineurs after 4 years. GM volume increase of fronto-parietal areas involved in nociception
might represent a compensatory response to high migraine attack frequency. GM atrophy of the thalamus, which plays a
fundamental role in migraine pathophysiology, might be influenced by disease progression.
DOES MIGRAINE FOLLOW BENIGN PAROXYSMAL TORTICOLLIS AND CYCLICAL VOMITING?
M. Valeriani, M. Bernucci, R. Frusciante, S. Tarantino, L. Papetti, A. Capuano, F. Vigevano
Headache Center, Neurology, Ospedale Bambino Gesù (Roma)
Objective: Migraine equivalents are clinical conditions often involving children who do not suffer from headache. The
relationship between migraine equivalents and subsequent headache has been rarely demonstrated in the same sample of
children. The aim of our study is to investigate whether children referred for cyclical vomiting (CV) or benign paroxysmal
torticollis (BPT) developed migraine at distance from the first observation.
Methods: The study is based on an online survey addressed to 30 families with children affected by CV and 34 families with
children affected by BPT, between January 2000 and December 2013.
Results: Migraine was diagnosed in 61% and 41% of the children previously affected by CV and BPT, respectively.
Headache appeared at the age of 7 years in 35% and 14% of children with previous diagnosis of CV and BPT, respectively.
As for CV children, 48.5% complained abdominal migraine, 42% limb pain, 32% motion sickness, 12% paroxysmal
vertigo, 9.7% BPT. As for BPT children, 73% had abdominal migraine, 55% paroxysmal vertigo, 45% limb pain, 27%
motion sickness, 27% CV. No further migraine equivalent was referred by 6% and 45% of the patients with CV and BPT,
pag. 88
respectively.
Discussion: Our data suggest that CV and BPT can be considered as symptoms of the migraine disease, which can precede
the appearance of the headache.
Conclusions: CV and BPT should be considered as manifestations of the migrainous disease, especially in pediatric age.
CIRCADIAN RHYTHM AND ATTACKS FREQUENCY IN MIGRAINE WITHOUT AURA PATIENTS
G. Viticchi1, L. Falsetti2, M. Bartolini1, L. Buratti1, S. Salvemini1, L. Provinciali1, M. Silvestrini1
1
Neurological Clinic, Clinical and Experimental Medicine Department, Marche Polytechnic University (Ancona); 2Internal
and
Subintensive
Medicine,
Ospedali
Riuniti
(Ancona)
Background: Existing evidences suggest a link between sleep characteristics and migraine but the circadian rhythm in
migraine patients has not been exhaustively investigated. The Morningness-Eveningness Questionnaire (MEQ-SA) is a
validated, simple and self-administrating test able to identify different typology of human circadian rhythms. Aim of this
study was to investigate the circadian rhythm in migraine patients in the attempt to evaluate the possible links with headache
characteristics.
Methods: During a six-month period, all the patients admitted to our Headache center with a new diagnosis of Migraine
without Aura (MWoA) were enrolled. All of them were submitted to MEQ-SA and to collection of data about their
headache (frequency, age of onset, years of pathology and severity of symptoms). We classified patients as early-rising,
intermediate-rising and late-rising according to MEQ-SA results. The number of monthly attacks was also coded as an
ordinal variable, subdividing the sample in subjects with less than 5 attacks, 6-10 attacks, 11-15 attacks and more than 15
attacks per months. The relationship between MEQ-SA score and number of monthly attacks and between MEQ-SA score
and years from disease onset were explored with multiple regressions, choosing the best-fitting trendline. Lastly, we
evaluated the probability of number of monthly attacks according to sleep type by an ordinal regression model.
Results: 52 subjects were finally enrolled. We observed a logarithmic relationship between the number of monthly attacks
and MEQ-SA score (r2=0,805; p<0,0001) and, similarly, a logarithmic relationship between the years from MWoA onset
and MEQ-SA score (r2=0,719; p<0,0001). In the ordinal regression model, the cumulative probability of monthly attack per
category was significantly different, according to sleep type: early-rising subjects had a higher probability of <5
attacks/month (70,9%) if compared to intermediate-rising (63,4%) or late-rising (55%) subjects (p<0,0001).
Discussion: Determination of circadian rhythm is a relevant element in sleep disorders management, but it is not usually
evaluated in migraine patients. Migraine is a multifactorial disease and sleep quality seems to have a significant influence in
patients’quality of life. A routine evaluation of sleep characteristics and circadian rhythm may add some relevant
information that could be helpful for a better management of migraine.
Reference:
− Horne J, Östberg O. A self-assessment questionnaire to determine morningness eveningness in human circadian
rhythms. Int J Chronobiol (1976);4:97–110
ONABOTULINUMTOXINA FOR CHRONIC MIGRAINE: AN ITALIAN REAL LIFE MULTICENTER
EXPERIENCE
F. Vernieri1, M. Paolucci1, G. Viticchi2, C. Altamura1, R. Altavilla1, M. Bartolini2, D. D'Amico3, G. Gambale1, M.
Silvestrini2, L. Grazzi3
1
Neurology Unit, Campus Bio-Medico University of Rome (Roma); 2Neurological Clinic, Politechnic University of Marche
3
(Ancona);
Istituto
Neurologico
Carlo
Besta
(Milano)
Background: OnabotulinumtoxinA is a preventive treatment option for chronic migraine (CM) [1]; its cranio-cervical
injections, following PREEMPT protocol, decrease not only headache frequency [2], but also perceived pain intensity,
increasing CM patients’ quality of life [3]. In Italy, OnabotulinumtoxinA was approved for the treatment of CM in 2013.
Aim of this study is to analyze and compare the experience with this treatment in various Italian centers, with particular
attention to patients’ quality of life and pain perception.
Materials and Methods: We retrospectively reviewed and compared the case histories of 97 patients enrolled at three Italian
headache centers: Università Campus Bio-Medico Roma, Istituto Neurologico Besta Milano, Clinica Neurologica
Università di Ancona. We compared headache frequency, drug assumption, pain intensity through 11 point Box Scale (BS11) and Present Pain Intensity (PPI), changes in functioning through 6-point Behavioral Rating Scale (BRS-6), quality of
pag. 89
pain through Short-form McGill Pain Assessment Questionnaire (SF-MPQ) and disability through Migraine Disability
Assessment (MIDAS) and Headache Impact Test (HIT-6) questionnaires at the beginning of the treatment (1st injection,
T0), at 6 months (3rd injection, T2) and after 12 months (5th injection, T4).
Results: We found no difference in mean age (50y, p=,143), sex distribution (female: 81,4%, p=,859), baseline headache
frequency (median 18 days/month, p=,581) and drug assumption (median 15 drug/month, p=,311) across centers. We found
a global significant reduction in median headache frequency and drug assumption at T2 (22%, p=,000 and 20%, p=,003
respectively) and T4 (33%, p=,000 and 20%, p=,003 respectively), without significant difference between centers (Roma,
Milano). At T2, we demonstrated a global significant reduction in BS-11, PPI, BRS-6 and SF-MPQ point and, at T4, in BS11 and SF-MPQ; there was no significant differences between centers (Roma, Ancona), except for BRS-6 at T2 (p=,035).
We found no difference at any time among centers for MIDAS score (Roma, Milano) and HIT-6 score (Roma, Ancona).
MIDAS score was significantly reduced at T2 (49%, p=,012) and T4 (70%, p=,002). HIT-6 showed a non-significant
reduction, but at T4 we found that the 31% of patients had a score ≤60 and a reduction from T0 of ≥5 points.
Conclusions: The population selected for the treatment was homogeneous at the three centers. The results were very
consistent across centers, also compared to the literature data, confirming the validity of onabotulinumtoxinA not only in the
reduction of headache frequency, but also in reducing the impact of headaches on daily life.
References:
1. Aurora SK, Dodick DW, Turkel CC, DeGryse RE, Silberstein SD, Lipton RB, Diener H-C, Brin MF, PREEMPT 1
Chronic Migraine Study Group. OnabotulinumtoxinA for treatment of chronic migraine: results from the doubleblind, randomized, placebo-controlled phase of the PREEMPT 1 trial. Cephalalgia (2010);30:793–803
2. Diener H-C, Dodick DW, Aurora SK, Turkel CC, DeGryse RE, Lipton RB, Silberstein SD, Brin MF, PREEMPT 2
Chronic Migraine Study Group. OnabotulinumtoxinA for treatment of chronic migraine: results from the doubleblind, randomized, placebo-controlled phase of the PREEMPT 2 trial. Cephalalgia (2010);30:804–814
3. Lipton RB, Varon SF, Grosberg B, McAllister PJ, Freitag F, Aurora SK, Dodick DW, Silberstein SD, Diener H-C,
DeGryse RE, et al. OnabotulinumtoxinA improves quality of life and reduces impact of chronic migraine.
Neurology (2011),77:1465–1472
CLUSTER HEADACHE COMORBIDITY WITH OTHER PRIMARY HEADACHES: A CROSS-SECTIONAL
STUDY ON A CASE SERIES OF 817 CLUSTER HEADACHE PATIENTS
A. Taga, M. Russo, A. Genovese, G. Manzoni, P. Torelli
Department of Clinical and Experimental Medicine, University of Parma (Parma)
Background and objectives: There are only few literature data on the co-occurrence of cluster headache (CH) and other
primary headaches [1, 2], concerning mainly with migraine. The aim of the present study is to investigate the occurrence of
primary headaches in a series of CH patients and to determine whether this coexistence influences the clinical phenotype of
CH.
Materials and methods: A cross-sectional study was performed in all consecutive patients referred to the Parma Headache
Centre between 1975 and 2015 affected by CH; these cases were subsequently reviewed applying the ICHD3-beta criteria
of
the
International
Headache
Society
[3].
Results: The overall sample comprised 817 CH patients (594 men, 223 women, male-to-female ratio 2.7); 137 CH patients
reported at least another comorbid primary headache, with a higher proportion of women (62 men, 75 women, male-tofemale ratio 0.8). When considering each diagnosis individually, we identified 81 migraines (63 without and 18 with aura),
74 tension type headaches (TTH), five other primary headaches (group 4 of ICHD3-beta), and a case of paroxysmal
hemicrania. We compared CH patients with exclusively comorbid migraine (21 men, 39 women) to CH patients without
comorbid migraine (570 men, 170 women). A higher proportion of women was found in the first group; smoking habits and
alcohol intake were significantly (p<0.05) less frequent while coffee intake was significantly higher among patients with
comorbid migraine. We found statistically significant differences in the time course of CH cases with comorbid migraine:
cluster duration (44.2 ±34.4 vs 67.2±64.3 days) and frequency (0.9± 0.7 vs 1.3 ± 1.1) were lower, while attack duration was
longer (122.4±52.8 minutes vs 78.9±55.5 minutes). Other features of CH attacks (i.e. intensity, pain side, cranial autonomic
symptoms and restlessness) were similar in the two groups, except for the presence of osmophobia which was more
common in men with comorbid migraine (2/21 vs 12/570). A similar analysis was performed in CH cases with exclusively
comorbid TTH (32 men, 22 women) but it didn’t show any significant difference in CH phenotype.
Discussion and conclusions: The prevalence of primary headaches among CH sufferers is not different from what expected
according to their prevalence in the general population [2]. When focusing on migraine solely, its occurrence in our study is
pag. 90
within the wide range (i.e. 1% to 65%) reported in literature [1, 2]. The coexistence of migraine but not of TTH seems to
influence some peculiar demographic and clinical features of CH sufferers.
References:
1. Bahra A, May A, Goadsby PJ. Cluster Headache: a prospective clinical study with diagnostic implications.
Neurology (2002);58:354-361
2. D’Amico D, Centonze V, Grazzi L, Leone M, Ricchetti G, Bussone G. Coexistence of migraine and cluster
headache: report of 10 cases and possible pathogenetic implications. Headache (1997);37:21-25
3. Headache Classification Subcommittee of the International Headache Society. The International Classification of
Headache Disorders, 3rd edition (beta version). Cephalalgia (2013);33:629-808
NEUROLOGICAL SOFT SIGNS ARE INCREASED IN PRIMARY HEADACHE PATIENTS: IMPLICATIONS
FOR CLINICAL PRACTICE?
L. Tremolizzo1, S. Ferrario2, D. Selvatico2, L. Fumagalli3, C. Ferrarese1, I. Appollonio1
1
School of Medicine and NeuroMI, UNIMIB (Monza); 2School of Medicine, UNIMIB (Monza); 3Neurology, San Gerardo
Hospital (Monza)
Introduction: Neurological soft signs (NSS) are semeiological features primarily developed in psychiatric settings and
usually not assessed during the standard neurological examination. However, they have been recently proposed as potential
markers for minor brain circuit alterations, especially the cerebellar-thalamic-prefrontal network. Primary headache patients
present with normal neurological examination and frequent psychiatric comorbidity. Aim of this work consisted in the
exploratory assessment of NSS in primary headache (PH) outpatients.
Patients and Methods: 30 consecutive PH patients (20 migraine [MH] and 10 tension-type headache [TTH]) were recruited
together with 30 matched healthy controls (CTRL). NSS were quantified with the Heidelberg scale; clinical characteristics
and brain MRI were additionally obtained in all patients, besides anxiety (STAI-Y), depression (HAM-D) and quality of life
(SF-36) scores.
Results: Compared to controls, NSS were increased by 70 and 90% in TTH and MH, respectively (p<0.001, after
controlling for age and education). Headache type and characteristics did not influence NSS presentation. PH patients with
white matter hyper-intensities (WMH) at brain MRI had significantly higher NSS scores compared to both normal controls
and PH patients without WMH. Furthermore, NSS in PH patients significantly correlated with both HAM-D (r=0.53,
p<0.003) and STAI-Y scores (state r=0.41, p<0.03), whereas no correlation was present with SF-36 scores.
Discussion: The presence of NSS identifies a subset of primary headache patients sharing the same comorbidities and/or
minimal brain anomalies, suggesting that tailored prophylactic options might apply to them.
References:
− Schroder J, Niethammer R, Geider FJ, Reitz C, Binkert M, Jauss M, Sauer H. Neurological soft signs in
schizophrenia. Schizophr. Res. (1991);6:25-30
− Tremolizzo L, Ferrario S, Pellegrini A, Fumagalli L, Ferrarese C, Appollonio I. Neurological soft signs in primary
headache patients. Neurosci Lett. (2015);595:41-4
MALATTIE CEREBROVASCOLARI 2
MORTALITY AND HOSPITAL READMISSIONS WITHIN THE FIRST YEAR AFTER STROKE: RESULTS
FROM A PROSPECTIVE POPULATION-BASED REGISTRY
D. Degan, C. Tiseo, R. Ornello, F. Pistoia, A. Carolei, S. Sacco
Department of Neurology and Stroke Unit, Avezzano Hospital, University of L’Aquila (L'Aquila)
Background: We aimed to assess the predictors of mortality and of hospital readmission during the first year after the index
stroke in a population-based setting.
Methods: Prospective, population-based registry, including all patients residing in the L’Aquila district with a first-ever
stroke in 2011-2012. All patients were followed-up to one year and mortality data were recorded together with information
on hospital readmissions for any cause after discharge. Logistic regression and Cox analysis were performed to assess
predictors of mortality and hospital readmission in models including sex, age, stroke subtype (ischemic vs hemorrhagic),
arterial hypertension, diabetes mellitus, hypercholesterolemia, coronary heart disease, peripheral artery disease and the
National Institutes of Health Stroke Scale (NIHSS) score of the index stroke as covariates.
pag. 91
Results: Eight hundred and fifty-eight patients were included. One hundred and fifty-two (17.7%) patients were excluded
from the final analyses because they died during hospitalization for the index stroke. At the one year follow up, 245 patients
(132 men, 53.9%; mean age±SD:73.6±13.3 years), were readmitted to hospital, 141 (57.5%) once and 104 (42.5%) twice or
more; 289 (71.5%) patients had died (125 men, 43.2%; mean age±SD:80.0±10.6 years). Globally, 424 hospital readmissions
were registered (209 in men and 214 in women). The most frequent reasons for rehospitalization were stroke recurrences
and transient ischemic attacks (50 cases, 11.8%), respiratory diseases (44, 10.4%), cardiac failure (42, 9.9%), infections (39,
9.2%), cancer and its complications (38, 8.9%), and acute coronary syndromes (9, 2.1%). Predictors of hospital readmission
were hemorrhagic stroke (Odds Ratio [OR] =1.54; 95% Confidence Interval [CI] =1.02-2.34; p=0.03) and NIHSS score on
admission for the index stroke (OR=1.02; 95% CI 1.00-1.05; p=0.01). Thirty-four (8.0%) rehospitalized patients died. The
Cox analysis showed that age was a predictor of mortality (Hazard Ratio [HR] = 1.06; 95% CI=1.02-1.11; p=0.03) and that
NIHSS score on admission for the index stroke was an independent predictor of mortality (HR=1.14; 95% CI=1.08-1.19;
p<0.001), while hospital readmission was not an independent predictor of mortality (HR=1.18; 95% CI=0.55-2.53;
p=0.664).
Conclusions: Our data highlight the importance of the early management of acute stroke and suggest that, among patients
with a first-ever stroke, mostly if hemorrhagic, the post-stroke care needs to be further improved, in order to reduce
mortality and prevent rehospitalization.
EFFICIENCY OF HUB-AND-SPOKE SYSTEM FOR ACUTE STROKE TREATMENT IN A MACRO-AREA OF
LOMBARDY
E. Zago1, S. Vidale2, M. Longoni1, C. Motto1, V. Oppo1, L. Valvassori3, M. Piano3, P. Gambaro4, P. Perrone5, C. Tadeo6, M.
Riggio7, M. Riva8, C. Spreafico9, D. Zarcone10, M. Migliori11, E. Agostoni1
1
Neuroscience Department, Niguarda Hospital, University of Milan (Milano); 2Neurological Department, S. Anna Hospital
(Como); 3Neuroradiology Service, Niguarda Hospital (Milano); 4Neurological Department, Sacco Hospital (Milano);
5
Neurological Department, Civil Hospital (Legnano, MI); 6Neurological Department, Clinical Institute Città Studi (Milano);
7
Neurological Department, Salvini Hospital (Garbagnate Milanese, MI); 8Neurological Department, Lodi Hospital (Lodi);
9
Neurological Department, Desio Hospital (Desio, MB); 10Neurological Department, Sant'Antonio Abate Hospital
(Gallarate, VA); 11AREU Lombardy - Emergency-Urgency Regional Agency (Milano)
Objectives: Endovascular thrombectomy added to intravenous alteplase more than doubles the odds of a favourable
modified Rankin Scale (mRS) score compared with best medical therapy alone in patients with acute ischemic stroke due to
anterior circulation large vessels occlusion [1]. Whether is better to centralize emergency medical transport to endovascular
capable centers (Hub) or to establish a transport network between primary facilities where intravenous alteplase is given
(Spoke) and Hub-centers is still matter of debate [2]. Aim of the study was to analyse the efficiency of a Hub-and-Spoke
system
for
acute
ischemic
stroke
treatment
in
a
large
area
of
Lombardy.
Materials and Methods: We retrospectively reviewed data of patients who performed endovascular thrombectomy for an
acute ischemic stroke at Milan Niguarda hospital (Hub center) between January 2014 and April 2016. We compared
treatment delay and clinical outcome between those patients who were first transported to the Hub-center and those who
first arrived to a Spoke-center, where (if no contraindications existed) they received intravenous alteplase, and then were
transferred to the Hub-center. Involved spoke centers were Hospitals of Legnano, Lodi, Garbagnate, Gallarate, Desio and
Milan
Clinical
Institute
Città
Studi
and
Sacco
Hospitals.
Results: Of 103 total patients who performed mechanical thrombectomy in the selected period 46 were first hospitalized at
Hub-Center and 57 came from Spoke-centers. Initial median NIHSS score did not differ between the two groups (17 ± 6 for
Hub-center patients, 16 ± 6 for Spoke-centers patients), a significant delay was observed in symptom onset-groin puncture
time for Spoke-centers patients with respect to Hub-center patients (241 ± 74 min vs 202 ± 105 min, p=0.03). The two
groups did not differ in term of proportion of patients independent (with a mRS 0-2) at discharge from hospital (35% of
Hub-center patients and 33% of Spoke-centers patients) and in term of proportion of patients that achieved a significant
clinical improvement of 4 NIHSS score points or more at discharge (65% in both groups).
Discussion and conclusions: Despite treatment delay for patients who first arrived to Spoke-centers and then performed
thrombectomy at Hub-center, the proportion of patients with a favourable clinical outcome at discharge did not differ
between the two groups. Our data supports Hub-and-Spoke network as a functional system to manage acute ischemic stroke
treatment in a large geographical area, ensuring similar rates of good clinical outcome for all treated patients, independently
of first arrival center.
References:
1. Goyal M, Menon BK, van Zham WH et al. Endovascular thrombectomy after large-vessel ischaemic stroke: a
meta-analysis of individual patient data from five randomized trials. Lancet (2016) Apr 23; 387(10029): 1723-31
pag. 92
2.
Goyal M, Jadhav AP, Bonafe A et al. Analysis of workflow and time to treatment and the effects on outcome in
endovascular treatment of acute ischemic stroke: results from the SWIFT-PRIME randomized control trial.
Radiology (2016) Jun; 279(3): 888-97
FUNCTIONAL OUTCOME IN POST-STROKE: CIRCADIAN VARIABILITY AND CARDIAC AUTONOMIC
DYSFUNCTION AT ADMISSION NEUROMOTOR REHABILITATION PROGRAM
A. Bassi1, M. Iosa1, F. Colivicchi2, C. Caltagirone3, M. Bozzali4
1
NeuroRehabilitation, IRCCS Santa Lucia Foundation Rome (Roma); 2Cardiovascular Department, San Filippo Neri
Hospital (Roma); 3Department of Neurology, University of Rome ‘Tor Vergata’ (Roma); 4Neuroimaging Laboratory,
IRCCS Santa Lucia Foundation (Roma)
Aim: Acute phase of ischemic stroke may produce various cardiac changes (echocardiographic, electrocardiographic,
enzymatic) as well as autonomic dysregulation characterized by a predominance of sympathetic activity. Heart rate
variability (HRV), an accepted method to quantify autonomic cardiac modulation, is known to undergo a circadian
dependent regulation (1). Nevertheless, the circadian effect on HRV is still an area of research which has been poorly
explored. On the other hand, cardiac autonomic dysregulation in post acute stroke patients rehabilitation programs is linked
to unfavourable functional outcome (2). Aim of this study was therefore to evaluate the circadian impact of cardioautonomic unbalance on post-stroke patients rehabilitation outcome.
Methods: Twenty-two consecutive patients (M/F=10/12; mean [SD] age = 64.5 [8.2] years) in a sub-acute stage (within 30
days from the index event) after their first-ever acute stroke were recruited for the present study. The presence of major
concurrent medical conditions potentially interfering with HRV were carefully excluded in all patients. Neuroimaging scans
were used to assess patients’ anatomical distribution of brain lesions. 24-hours holter monitoring was used to characterize
HRV characteristics (SDNN; rMSSD; LF/HF). The final outcome of a 60 days rehabilitation program was evaluated by
Barthel Index (BI) score. Effectiveness of functional outcome was computed as the difference between the BI-score at
discharge and at admission, divided by the maximum achievable improvement (100 – admission score) multiplied by 100.
We computed the Pearson’s correlation coefficient between the analyses parameters. The alpha level was set at 0.05.
Results: Significant correlations were found between patients’ positive outcome after rehabilitation and their SDNN/rMSSD
at baseline (R=0.598, p=0.019). When we separately analysed the SDNN/rMSSD measured over three different timewindows (i.e., morning; afternoon; night, 3), we found the highest correlations with clinical recovery in the morning
(R=0.654, p=0.008) and afternoon (R=0.584, p=0.022), but not in the night (R=0.491, p=0.063). Additionally, the ratio
between morning and night of SDNN/rMSSD was found only moderately associated with patients’ rehabilitation outcome
(R=0.380, p=0.162).
Discussion: This study suggests the importance of defining the presence or absence of HRV alterations and their circadian
rhythms in stroke patients who are candidates for neuro-rehabilitation. Indeed, HRV measures allow to obtain some relevant
information on the potential rehabilitation outcome of post-strok patients, with relevant implications for their clinical
management.
References:
− Kawamura H, Ozawa Y, Izumi Yet al. Non-dipping blood pressure variations in adult Kazakhs are derived from
decreased daytime physical activity and increased nighttime sympathetic activity. Clin Exp Hypertens (2016);
38(2):194-202
− Bassi A, Colivicchi F, Santini Met al. Gender-Specific Predictors of Functional Outcome after Stroke
Rehabilitation:Potential Role of the Autonomic Nervous System. Eur Neurol (2010);63:279–284
− R. Balocchi, F. Cantini, M. Varanini et al. Revisiting the potential of time-domain indexes in short-term HRV
analysis. Biomedizinische Technik (2006);51(4):190–193
THE FLORENCE STROKE NETWORK: IMPROVEMENT IN ACUTE ISCHEMIC STROKE CARE
M. Baldereschi1, F. Bellomo2, P. D’Onofrio3, P. Francesconi4, V. Di Fabrizio4, S. Gaggelli4, L. De Vito5, M. Pratesi6, D.
Balzi7, M. Mechi2, D. Inzitari8
1
Institute of Neuroscience, Italian National Research Council (Firenze); 2Clinical Networks Management, Tuscany Health
System (Firenze); 3Dept. of Geriatrics, Azienda Ospedaliero Universitaria Careggi (Firenze); 4Dept. Epidemiology, Health
pag. 93
Regional Agency (Firenze); 5CO 118, SIS 118 (Firenze); 6EMS, USL Toscana Centro (Firenze); 7Epidemiology Unit, USL
Toscana Centro (Firenze); 8Dept. NEUROFARBA, Azienda Ospeedaliero Universitaria Careggi (Firenze)
Aims: An organized, evidence-based approach to managing stroke can reduce mortality and morbidity and improve
functional outcome for stroke patients. Variations in stroke care have been highlighted in Tuscany, with many patients not
receiving evidence-based care. To address these concerns, a strategic planning process has been launched by the Tuscany
Health System in early 2015 to develop and implement a new governance for the regional stroke network . The network was
piloted throughout the Florence area: Florence Stroke Network (FSN).
Materials and Methods: A coordinated system of care where Emergency Medical Services and hospitals function as a
unified whole across Florence area was set up in 2015 to improve acute stroke care. The FSN relies on the development and
implementation of standardized protocols related to each step of the acute stroke care: prehospital stroke code activation, inhospital acute stroke coordinated procedures, inclusion and exclusion criteria for t-PA and thrombectomy treatments,
transfer and drip&ship procedures. We included all patients with acute ischemic stroke consecutively admitted to each FSN
hospitals from January 1, 2014 to December 31, 2015, using hospital discharge diagnoses (SDO). The 434.*1 and 433*1
ICD9 codes were aggregated to determine a primary diagnosis of ischemic stroke; procedure code 99.10 identified t-PA
treatments, code 39.74 thrombectomy. We measured short-term FSN efficacy by estimating and comparing numbers and
rates of acute ischemic stroke treatments before (2014) and after (2015) FSN implementation.
Results: The network spans across 3500 Km2 and 1million inhabitans, with 1 hospital with no stroke services, 3 urban
spoke hospitals, 1 suburban spoke hospital, and 1hub hospital. Through 2014, 956 patients with acute ischemic stroke were
admitted and 57 (6%) were treated with t-PA. Number and proportions of t-PA treatments increased up to 88 and 9.2%
(p=.008) in 2015. Number of treatments significantly increased in every spoke hospital as well in the hub hospital. A total of
16 Drip&ship tranfers were activated with 4 thrombectomies performed eventually by the hub hospital in 2015, compared to
none in 2014.
Conclusions and Implications: The logistic interventions provided by the FSN proved associated with a significant increase
in acute ischemic stroke treatments. More stroke patients have received the benefits of t-PA and thrombectomy. This study
could evaluate only short-term hospital-based care, information on longer-term outcomes are being collected. Next steps
include the geographical expanding of the stroke network to the whole Tuscany region.
References:
− Fargen KM, Jauch E, Khatri P, Baxter B, Schirmer CM, Turk AS, Mocco J. Needed dialog: regionalization of
stroke systems of care along the trauma model. Stroke (2015) Jun;46(6):1719-26
−
Spolaore P, Brocco S, Fedeli U, Visentin C, Schievano E, Avossa F, Milan G, Toso V, Vanuzzo D, Pilotto L,
Pessina AC, Bonita R. Measuring accuracy of discharge diagnoses for a region-wide surveillance of hospitalized
strokes. Stroke (2005) May;36(5):1031-4
−
Alonso de Leciñana M, Fuentes B, Ximénez-Carrillo Á, Vivancos J, Masjuan J, Gil-Nuñez A, Martínez-Sánchez
P, Zapata-Wainberg G, Cruz-Culebras A, García-Pastor A, Díaz-Otero F, Fandiño E, Frutos R, Caniego JL,
Méndez JC, Fernández-Prieto A, Bárcena-Ruiz E, Díez-Tejedor E; Madrid Stroke Network. A collaborative system
for endovascular treatment of acute ischaemic stroke: the Madrid Stroke Network experience. Eur J Neurol. (2016)
Feb;23(2):297-303
MIGRAINE AND ISCHEMIC STROKE CAUSED BY CERVICAL ARTERY DISSECTION. THE ITALIAN
PROJECT ON STROKE IN YOUNG ADULTS (IPSYS)
V. De Giuli1, C. Lodigiani2, R. Patella3, M. L. Zedde4, C. Gandolfo5, A. Zini6, M. L. DeLodovici7, M. Paciaroni8, C.
Azzini9, M. Del Sette10, A. Toriello11, R. Musolino12, R. S. Calabrò13, P. Bovi14, A. Adami15, A. Giossi16, G. Silvestrelli17,
M. Sessa16, A. Cavallini18, S. Marcheselli19, D. M. Bonifati20, N. Checcarelli21, L. Tancredi22, A. De Vito9, A. Chiti23, E. Del
Zotto24, G. Tomelleri14, A. Spalloni3, E. Giorli25, P. Costa1, L. Poli1, A. Morotti1, F. Caria1, V. Piras26, C. Gentile27, G.
Giacalone28, E. Banfi2, L. Vandelli6, G. Volpe11, N. Pugliese11, M. Rasura3, A. M. Simone6, E. M. Lotti29, M. Gamba30, P.
Cerrato31, L. Cucurachi32, G. Micieli19, M. Melis26, D. Massucco5, S. Bonaiti1, C. D'Amore8, G. Malferrari4, I. Casetta9, P.
Bramanti13, C. Stilo12, L. Iacoviello34, A. Padovani1, A. Pezzini1
1
Neurology Unit, Department of Clinical and Experimental Sciences, University of Brescia, (Brescia); 2Thrombosis Center,
IRCCS Istituto Clinico Humanitas (Milano); 3Stroke Unit, “Azienda Ospedaliera Sant’Andrea”, La Sapienza University
(Roma); 4Neurology Unit, IRCCS Arcispedale “Santa Maria Nuova” (Reggio Emilia); 5Department of Neurosciences,
Rehabilitation, Ophthalmology, Genetics and Mother-Child Sciences, University of Genova (Genova); 6Stroke Unit,
Neurology Unit, “Nuovo Ospedale Civile S. Agostino Estense” (Modena); 7Stroke Unit, Neurology Unit, “ASST - Sette
Laghi”, University of Insubria (Varese); 8Stroke Unit and Division of Cardiovascular Medicine, University of Perugia
pag. 94
(Perugia); 9Stroke Unit, Neurology Unit, Department of Neurosciences and Rehabilitation, A.O. and University of Ferrara
(Ferrara); 10Neurology Unit, Galliera Hospital (Genova); 11Neurology Unit, “San Giovanni di Dio e Ruggi d’Aragona”,
University of Salerno (Salerno); 12Department of Neuroscience, Neurological Clinic, University of Messina (Messina);
13
IRCCS, “Centro Neurolesi Bonino-Pulejo” (Messina); 14Neurology Unit, Borgo Trento Hospital, University of Verona
(Verona); 15 Stroke Centre, Sacro Cuore Hospital (Verona); 16Neurology Unit, “Istituti Ospitalieri di Cremona” (Cremona);
17
Department of Neurosciences, Carlo Poma Hospital (Mantova); 18Stroke Unit, IRCCS “C. Mondino” (Pavia); 19Stroke
Unit, Neurology Unit, “IRCCS Humanitas Research Hospital”, (Rozzano-MI); 20Neurology Unit, Treviso Hospital
(Treviso); 21Neurology Unit, Valduce Hospital, (Como); 22Neurology Unit, Sant’Anna Hospital (Como); 23Neurology Unit,
A.O. and University of Pisa (Pisa); 24Rehabilitation Unit, “IRCCS Fondazione Don Gnocchi” (Rovato-BS); 25Neurology
Unit, S. Andrea Hospital (La Spezia); 26Stroke Unit, “G. Brotzu” Hospital (Cagliari); 27Neurology Unit, “Santa Maria della
Misericordia” Hospital, University of Udine (Udine); 28Neurology Unit, “San Raffaele” (Milano); 29Neurology Unit,
Ravenna Hospital (Ravenna); 30 Stroke Unit, Spedali Civili Hospital (Brescia); 31Department of Neurosciences, Stroke Unit,
University of Torino (Torino); 32Stroke Unit, Neurology Unit, “S. Chiara” Hospital (Trento); 34Laboratory of Molecular and
Nutritional Epidemiology, Department of Epidemiology and Prevention, “IRCCS Istituto Neurologico Mediterraneo”,
NEUROMED (Pozzili-IS)
Objective: Sparse reports suggest a link between migraine and cervical artery dissection (CeAD), but the results on migraine
aura status (migraine with aura [MA] or migraine without aura [MO]) and CeAD have been controversial. This might have
implication in understanding the complex relation between migraine and ischemic stroke (IS).
Methods: Using a case-control design, we 1) assessed whether the frequency of migraine and its subtypes (presence or
absence of an aura) differs between CeAD patients with IS and non-CeAD IS patients, and 2) compared CeAD patients with
and without migraine in terms of putative risk factors, in a large cohort of patients with first-ever IS who were 18 to 45
years of age, as part of the multicenter Italian Project on Stroke in Young Adults (IPSYS).
Results: A total of 2,485 patients (mean age, 36.8 ± 7.1 years; women, 46.8%) were included in the IPSYS registry between
January 2000 through June 2015. The cause of IS was spontaneous CeAD (sCeAD) in 334 (13.4%), while 2,151 (86.6%)
patients had an IS due to a cause other than CeAD (non-CeAD IS). Migraine was more common among CeAD patients
compared to non-CeAD patients (30.8 vs 24.4%, p = 0.012), and the difference was mainly due to migraine without aura
(MO, 24.0 vs 15.6%, p<0.001). As opposed to migraine with aura (MA), MO was independently associated to CeAD (OR,
1.74; 95% CI, 1.30 – 2.33) in multivariable regression analysis adjusted for demographics and putative risk factors. This
association was independent of sex, though its strength was higher in men (OR, 2.11; 95% CI: 1.38 – 3.24) than in women
(OR, 1.50; 95% CI: 1.01 – 2.23), and was more prominent in the lowest age tertile (OR, 1.89; 95% CI, 1.02 – 3.49). The
vascular risk factor profile was similar in migrainous and non-migrainous CeAD patients, but a more frequent involvement
of the carotid arteries was observed in the former group.
Conclusion: in IS patients aged 18 to 45 years, MO is more common among those with CeAD than among those with nonCeAD. The mechanisms and possible causative link remain to be proved.
References:
− T.M. Metso, T. Tatlisumak, S. Debette, J. Dallongeville et al. Migraine in cervical artery dissection and ischemic
stroke patients. Neurology (2012);78:1221–1228
− Rist PM, Diener HC, Kurth T, Schurks M. Migraine, migraine aura, and cervical artery dissection: a systematic
review and meta-analysis. Cephalalgia (2011);31:886–896
− Tzourio C, Benslamia L, Guillon B, et al. Migraine and the risk of cervical artery dissection: A case-control study.
Neurology (2002);59:435– 437
STROKE ETIOLOGIC SUBTYPE MAY INFLUENCE THE RATE OF HYPERDENSE MIDDLE CEREBRAL
ARTERY SIGN DISAPPEARANCE AFTER INTRAVENOUS THROMBOLYSIS
S. Forlivesi, P. Bovi, G. Tomelleri, N. Micheletti, M. Carletti, G. Moretto, M. Cappellari
Stroke Unit, AOUI Verona (Verona)
Objectives: Disappearance of hyperdense middle cerebral artery sign (HMCAS) on non-contrast brain computed
tomography (CT) scan is a reliable sign of arterial recanalization after intravenous (IV) thrombolysis for acute ischemic
stroke. This study aims to assess whether stroke etiologic subtype may influence the rate of HMCAS disappearance and the
clinical outcome after IV thrombolysis.
Materials and Methods: We conducted a retrospective analysis of data prospectively collected from 1031 consecutive stroke
patients treated with IV thrombolysis. Outcome measures were HMCAS disappearance on follow-up CT scan performed
pag. 95
within 22-36 hours of IV thrombolysis, neurologic improvement (NIH Stroke Scale [NIHSS] ≤4 points from baseline or
NIHSS score of 0) at 7 days, and excellent functional outcome (modified Rankin Scale [mRS] score ≤1) at 3 months.
Results: Of 256 patients with HMCAS on admission CT scan, 125 (48.8%) had a cardioembolic stroke, 67 (26.2%) an
atherosclerotic stroke, 58 (22.7%) a stroke of undetermined etiology, and 6 (2.3%) a stroke secondary to carotid artery
dissection. HMCAS disappearance occurred in 145 (56.6%) patients, neurologic improvement at 7 days in 122 (55.0%)
patients, and mRS score ≤1 at 3 months in 64 (32.8%) patients. Compared with cardioembolic stroke patients, patients with
atherosclerotic stroke had lower rates of HMCAS disappearance (OR 0.29, 95% CI 0.15-0.58; p<0.001), neurologic
improvement (OR 0.42, 95% CI 0.22-0.82; p=0.011), and mRS score ≤1 (OR 0.18, 95% CI 0.06-0.52; p=0.002). No
significant differences in outcome measures were found between cardioembolic strokes and strokes of undetermined
etiology.
Discussion: The present study shows that in patients with acute ischemic stroke and HMCAS on admission CT scan,
atherosclerotic stroke is associated with a lower rate of HMCAS disappearance and a worse clinical outcome after IV
thrombolysis, compared with cardioembolic stroke. Differences between cardioembolic and atherosclerotic stroke in
HMCAS disappearance after IV thrombolysis may be explained by structural differences of clots among stroke subtypes. In
contrast with well-organized and platelet-rich atherosclerotic clots (white thrombi), cardioembolic clots (red thrombi) allow
rt-PA to penetrate and distribute homogeneously, resulting in better thrombus dissolution and arterial recanalization. The
identification of unfavorable predictors of HMCAS disappearance after IV rt-PA, such as large-artery atherosclerosis, could
guide the rapid selection of candidates for endovascular treatment.
Conclusions: This study suggests that in patients with acute ischemic stroke and HMCAS on admission CT scan,
atherosclerotic stroke is associated with lower rates of HMCAS disappearance, neurologic improvement, and excellent
functional outcome after IV thrombolysis, compared with cardioembolic stroke.
References:
− Mair G, von Kummer R, Morris Z et al. Effect of alteplase on CT hyperdense artery sign and outcome after
ischemic stroke. Neurology (2016);86:118-125
− Molina CA, Montaner J, Arenillas JF, Ribo M, Rubiera M, Alvarez-Sabín J. Differential pattern of tissue
plasminogen activator-induced proximal middle cerebral artery recanalization among stroke subtypes. Stroke
(2004);35:486-490
− Puig J, Pedraza S, Demchuk A et al. Quantification of thrombus Hounsfield units on noncontrast CT predicts
stroke subtype and early recanalization after intravenous recombinant tissue plasminogen activator. AJNR
(2012);33:90-96
COMPARISON OF DIFFERENT TOOLS IN THE EVALUATION OF PATENT FORAMEN OVALE AND
POSSIBLE LIMITATIONS UNRELATED TO THE DIFFERENT PROCEDURES
S. Ricci, A. Lupato, M. Turazzini, R. Del Colle, V. Annese, T. Tiziana, A. Polo
Department of Neurology, Mater Salutis Hospital (Legnago, VR)
Background: There are several comparative study of accuracy between contrast transcranial Doppler (c-TCD), transthoracic
echocardiography (c-TTE) and transesophageal echocardiography (c-TEE) in the detection of patent foramen ovale (PFO),
with often conflicting results. Currently c-TEE is the reference technique to assess the size and anatomy of PFO and to
determine the origin of right-to-left shunt (RLS), but it’s semi-invasive and Valsalva maneuver (VM) often is not adequate
performed because of intubation and sedation. The aim of this study was to compare the accuracy of c-TCD, c-TTE and cTEE in diagnosis and quantification of PFO minimizing the variability by the simultaneous execution of techniques and to
establish if patients characteristics may affect the accuracy.
Methods: We prospectively evaluated 172 patients with high clinical suspected PFO. Simultaneous TCD/TTE and
TCD/TEE were performed using agitated saline solution to detect RLS at baseline and after VM . The severity of the RLS
was quantified as mild, moderate or severe according to the number of microbubbles detected. Patients characteristics
included age, gender and body mass index (BMI).
Results: In total, 96 (56%) of 172 evaluated patients were diagnosed with PFO. The RLS was visualized at baseline by TCD
in 96 patients (55.8%), by TTE in 79 (45.9%) and by TEE in 95 (55.2%). The concordance at baseline was excellent
between TCD/TTE and between TCD/TEE (k=0.81;P<0.0001 and k=0.98;P>0.0001 respectively) and good between
TTE/TEE (K=0.78;P<0.0001). VM produced an improvement in the RLS of 20% with all techniques but was ineffective in
25 patients (26%) during TEE. About the quantification of RLS, the concordance between TCD/TTE was good
(k=0.79;P<0.0001) at baseline and discrete (k=0.57;P<0.0001) during VM. BMI was higher (29.6±4.7) in patients with
positive DTC and negative TTE (OR=1.21, 95%CI:1.07-1.38; P=0.003) compared to patients with PFO at DTC (23.6±3.9)
pag. 96
and PFO at TTE (24.7±4.7). No differences were found referring to age and gender.
Discussion and Conclusion: In the present study the simultaneous execution of c-DTC, c-TTE and c-TEE confirmed that
MV is a limitation for c-TEE in quantifying the RLS. Unexpectedly, the patients characteristics influenced only c-TTE;
besides, a high BMI lead to c-TTE diagnostic failure. The c-DTC allows a wider detection of PFO with better quantification
of shunt severity during VM and in our opinion, it should be preferred in the patients with high BMI.
References:
− Di Tullio M, Sacco RL, Venketasubramanian N, Sherman D, Mohr JP, Homma S. Comparison of diagnostic
techniques for the detection of a patent foramen ovale in stroke patients. Stroke (1993);24:1020–4
− Caputi L, Carriero MR, Falcone C, et al. Transcranial Doppler and transesophageal echocardiography: comparison
of both techniques and prospective clinical relevance of transcranial Doppler in patent foramen ovale detection. J
Stroke Cerebrovasc Dis. (2009);18:343–348
− Komar M, Olszowska M, Przewlocki T, et al. Transcranial Doppler ultrasonography should it be the first choice
for persistent foramen ovale screening? Cardiovas Ultrasound. (2014);12:16
INTRACRANIAL ARTERIAL DOLICHOECTASIA: POSSIBLE ASSOCIATION WITH CEREBRAL SMALL
VESSEL DISEASE AND SYSTEMIC ARTERIOPATHY
F. Fierini1, A. Poggesi1, M. Acquafresca2, E. Fainardi3, M. Moretti3, S. Nannucci1, R. Valenti1, F. Pescini4, E. Salvadori1, G.
Chiti1, I. Donnini1, S. Marini1, M. Pasi1, V. Rinnoci1, D. Inzitari1, L. Pantoni1
1
NEUROFARBA Department, Neuroscience Section, University of Florence (Firenze); 2Radiology Unit 4, Department of
Diagnostic Imaging, Careggi Hospital (Firenze); 3Neuroradiology Unit, Department of Diagnostic Imaging, Careggi
Hospital (Firenze); 4Stroke Unit, Cardiovascular Department, Careggi Hospital (Firenze)
Objectives: To identify patients with dolicho-arteries and intracranial arterial dolichoectasia (IADE) and describe the
possible coexistence of cerebral small vessel disease (SVD) and systemic arteriopathy. Materials and methods: Patients with
dolicho-arteries and IADE were identified among those attending the Florence VAS-COG Clinic and Stroke Unit of our
hospital. Medical records from the period 2005-2014 were retrospectively revised to assess demographic and clinicoradiological characteristics. Starting from December 2014, prospectively identified IADE patients underwent a predefined
protocol including: clinical history assessment; brain MRI, with visual rating of SVD features, including white matter
hyperintensities (WMH), lacunes, perivascular spaces, microbleeds, and brain atrophy; neck, thoraco-abdominal aorta, and
lower limbs CT angiography.
Results: Thirty patients with dolicho-arteries and 29 patients with IADE have been retrospectively identified (45/59 males,
mean age 72.3±10.5 years). The basilar artery was involved in 95% of cases. Among the 44/59 (74.6%) who had a personal
history of stroke, 37/44 (84.1%) had had an ischemic stroke and 7/44 (15.9%) a hemorrhagic stroke. Among patients with a
history of ischemic stroke, 12/37 (32.4%) had had a lacunar stroke and 25/37 (67.6%) a non-lacunar stroke. The presence of
leukoaraiosis on basal neuroimaging (CT or MRI) was detected in 48/59 (81.4%) patients. In the prospective case series,
IADE was detected in 7 patients (6 males, mean age 68.8±7.2 years); 6/7 had hypertension, 1/7 had diabetes, 3/7 had
hypercholesterolemia, none were current smokers, and 2/7 had a history of myocardial infarction. All patients had
dolichoectasia of the basilar artery, 1 also with carotid siphons ectasia, and 1 with carotid siphons and middle cerebral
arteries ectasia. On brain MRI, all patients had WMH (mild in 1, moderate in 3, severe in 3 patients), 5/7 had at least one
lacunar infarct, and all had dilated perivascular spaces. At least one microbleed was detected in 6/7 patients. A certain
degree of global cortical atrophy was present in 6/7 patients. Based on extracranial CT angiography, 6/7 patients had
ectasias on at least one extracranial artery (n=5 abdominal aorta ectasia, n=3 thoracic aorta ectasia, n=3 iliac artery ectasia,
n=1 superficial femoral artery ectasia), while 1/7 did not have any other enlargement.
Discussion and conclusions: Our data seem to corroborate the current hypothesis of an association between IADE and
cerebral SVD [1]. In IADE patients the involvement of the brain-supplying arteries is probably part of a systemic
arteriopathy [2], thus suggesting the usefulness of the whole arterial tree assessment in clinical practice.
References:
− Pico F, Labreuche J, Cohen A, Touboul PJ, Amarenco P; GENIC investigators. Intracranial arterial dolichoectasia
is associated with enlarged descending thoracic aorta. Neurology (2004);63:2016-2021
− Pico F, Labreuche J, Touboul PJ, Leys D, Amarenco P; GENIC investigators. Intracranial arterial dolichoectasia
and small-vessel disease in stroke patients. Ann Neurol (2005);57:472-479
MALATTIE DEGENERATIVE
pag. 97
CSF LYSOSOMAL ENZYMES ACTIVITY AND GBA1 GENOTYPING IN THE BIOFIND PD COHORT
S. Paciotti1, P. Eusebi2, S. Zampieri3, A. Dardis3, D. Chiasserini2, A. Tasegian1, T. Beccari1, N. Tambasco2, P. Calabresi2, L.
Parnetti2
1
Department of Pharmaceutical Sciences, University of Perugia (Perugia); 2Department of Medicine, University of Perugia
(Perugia); 3Regional Coordinating Centre for Rare Diseases, University Hospital "Santa Maria della Misericordia" (Udine)
Objectives: Lysosomal dysfunction plays a central role in Parkinson’s disease (PD). Several reports have shown that
mutations in the GBA1 gene, encoding the lysosomal hydrolase β-glucocerebrosidase (GCase) represent the most common
genetic risk factor for PD (1). However, GCase activity is reduced in brain and in CSF (2,3) of PD patients with and without
GBA1 mutations, and alterations in the activity of other lysosomal enzymes have also been observed in PD patients. We
sought to confirm the role of the lysosomal enzymes GCase, β-hexosaminidase and Cathepsin D as biomarkers of PD and to
assess the relationship between GBA1 mutations and GCase activity in CSF of a well-characterized PD cohort.
Materials: We measured CSF lysosomal enzyme activities and analyzed the whole GBA1 sequence in 79 PD and 61
controls from the BioFIND (Fox Investigation for New Discovery of Biomarkers in Parkinson’s Disease) cohort. BioFIND
is a cross-sectional, multi-center biomarker study that established a repository of clinical information and biospecimen
samples from 118 moderate to advanced PD and 88 healthy controls.
Methods: Lysosomal enzyme specific activities were measured in CSF using specific assays. GBA1 gene was analyzed by
massive parallel pair end sequencing. The exonic variants were confirmed by Sanger sequencing. Univariate and
multivariate statistics were used to investigate the diagnostic performance of the enzyme activities and the relationship
between GCase activity and GBA1 mutations.
Results: ROC analysis showed that both GCase (AUC=0.72, 95% CI=0.63-0.80) and Cathepsin D (AUC=0.68, 95%
CI=0.59-0.77) performed well in discriminating PD from controls. The diagnostic accuracy significantly improved by
combining GCase, Cathepsin D and β-hexosaminidase (AUC=0.77, 95% CI=0.69-0.85). GCase activity was significantly
associated with MoCA scores (r=0.22, p=0.048). Moreover the levels of GCase and Cathepsin D were reduced in advanced
PD (H&Y≥2, -22%, p=0.003 and -15%, p=0.015). Three controls and 10 patients presented GBA1 mutations and showed
significantly lower GCase activity compared with non-carriers (-27%, p=0.042). However, a significant reduction of GCase
in PD patients was found even after exclusion of GBA1 mutation carriers (-25%, p<0.001).
Discussion: Our data confirm the potential diagnostic role of GCase in PD, also suggesting the added value of combined
measurement of GCase, Cathepsin D and β-hexosaminidase. Furthermore, our results indicate that multiple molecular
mechanisms, besides GBA1 mutations, might contribute to the reduction of GCase activity in PD patients.
Conclusions: We confirm the utility of GCase, Cathepsin D and β-hexosaminidase specific activities as part of a biomarker
panel to aid in PD diagnosis.
References:
1. Schapira AH, Chiasserini D, Beccari T, Parnetti L. Glucocerebrosidase in Parkinson's disease: Insights into
pathogenesis and prospects for treatment. Mov Disord. (2016) doi: 10.1002/mds.26616.
2. Chiasserini D, Paciotti S, Eusebi P, Persichetti E, Tasegian A, Kurzawa-Akanbi M, Chinnery PF, Morris CM,
Calabresi P, Parnetti L, Beccari T. Selective loss of glucocerebrosidase activity in sporadic Parkinson’s disease and
dementia with Lewy bodies. Mol Neurodegener. (2015);10:15
3. Parnetti L, Chiasserini D, Persichetti E, Eusebi P, Varghese S, Qureshi MM, Dardis A, Deganuto M, De Carlo C,
Castrioto A, Balducci C, Paciotti S, Tambasco N, Bembi B, Bonanni L, Onofrj M, Rossi A, Beccari T, El-Agnaf O,
Calabresi P. Cerebrospinal fluid lysosomal enzymes and alpha-synuclein in Parkinson's disease. Mov Disord.
(2014); 29(8):1019-27
HYPO-METABOLISM IN CORTICOBASAL
PATHOLOGY: A BRAIN FGD-PET STUDY
SYNDROME
ACCORDING
TO
THE
UNDERLYING
M. Pardini1, F. Nobili1, B. Ghetti2, S. Spina2, S. Morbelli3, E. Wassermann4, E. Huey5, J. Grafman6
1
DiNOGMI, University of Genoa, and IRCCS AOU San Martino-IST (Genova); 2Department of Pathology and Laboratory
Medicine, Indiana University School of Medicine (Indianapolis, USA); 3DISSAL, University of Genoa, and IRCCS AOU
San Martino-IST (Genova); 4NINDS, NIH (Bethesda, USA); 5Department of Neurology, Columbia University Medical
Center (New York, USA); 6Department of Physical Medicine and Rehabilitation, Northwestern University Feinberg School
of Medicine (Chicago, USA)
pag. 98
Objectives: Corticobasal Syndrome (CBS) has been associated with different neuropathologies mainly including
Corticobasal Degeneration (CBD), Alzheimer’s Disease (AD) and Progressive Supranuclear Palsy (PSP). To date the FDGPET patterns of hypo-metabolism due to each of these conditions in CBS remain poorly understood (1). In this study we
decided to evaluate the potential of brain FDG-PET to shed light on topographic differences in brain metabolism among
subjects with a clinical diagnosis of CBS and with different underling pathologies evaluated with post-mortem
neuropathological examination.
Methods: 36 subjects with a diagnosis of CBS were recruited. All subjects were diagnosed with CBS based on the
consensus between two independent neurologists, according to current criteria, and underwent a brain FDG-PET scan after
the diagnosis. Based on the post-mortem pathological diagnoses subjects were divided into the following groups: CBS-CBD
(13 subjects), CBS-AD (10 subjects), CBS-PSP (5 subjects) and CBS-other (8 subjects). Fifteen age-matched healthy
subjects undergoing FDG-PET were the control group (HC). Scans were flipped as needed to have the most affected
hemisphere displayed on the right side of the image. Using the SPM12 pipeline, a whole brain voxel-wise analysis was
performed to compare the whole of CBS patients and each CBS subgroup with controls A threshold of p<0.05 FWEcorrected for multiple comparisons and a minimum cluster size of 100 was applied to all analyses unless noted otherwise
(age as a nuisance variable).
Results: Compared to HC, CBS subjects presented a significant reduced metabolism in peri-rolandic regions of the most
affected hemisphere, as well as in the ipsilateral basal ganglia. Taking into account only subjects with CBS-CBD, a similar
pattern was observed, however with a more marked, bilateral involvement of the basal ganglia. Compared to HC, CBS-AD
subjects presented with a posterior, asymmetric, bilateral pattern of hypo-metabolism, including the lateral parietal and
temporal lobes and the posterior cingulate. Lastly, subjects with CBS- PSP presented with a more frontal pattern of hypometabolism, with significant clusters including the anterior cingulate and the primary motor cortex (p<0.00001 uncorrected,
k=100). A conjunction analysis revealed that the primary motor cortex was the only area with significant hypo-metabolism
in all CBS groups.
Discussion and conclusions: In subjects with CBS the different underling pathologies are associated with different patterns
of hypo-metabolism as assessed by the FDG-PET in vivo. Lastly our data suggest that FDG-PET scans could help in the
etiological diagnosis of subjects with CBS in vivo.
Reference:
− Boeve BF. The multiple phenotypes of corticobasal syndrome and corticobasal degeneration: implications for
further study. J Mol Neurosci. (2011) Nov;45(3):350-3
IMPAIRED LTP-LIKE CORTICAL
PRESYMPTOMATIC GENETIC FTD
PLASTICITY
AND
INTRACORTICAL
FACILITATION
IN
A. Benussi1, M. Cosseddu1, I. Filareto1, V. Dell'Era1, S. Archetti2, M. Cotelli3, A. Micheli4, A. Padovani1, B. Borroni1
1
Centre for Ageing Brain and Neurodegenerative Disorders, Department of Clinical and Experimental Sciences, Neurology
Unit, University of Brescia (Brescia); 2III Laboratory of Analysis, Spedali Civili Hospital (Brescia); 3Neurology Unit, Valle
Camonica Hospital (Brescia); 4Neurology Unit, Casa di Cura San Francesco (Bergamo)
Objectives: Transcranial magnetic stimulation (TMS) has become a safe and non-invasive tool to assess specific cortical
circuits in the central nervous system. The aim of this work was to evaluate specific neurophysiological parameters in
presymptomatic and symptomatic patients bearing a pathogenic mutation for Frontotemporal Dementia (FTD).
Materials and Methods: Multiple neurophysiological biomarkers were assessed using a TMS multi-paradigm approach in
thirteen presymptomatic (n=13 GRN) and fourteen symptomatic (n=11 GRN, n=3 C9orf72) patients with a pathogenic
mutation for FTD, and nineteen healthy controls (HC). We assessed short-interval intracortical inhibition (SICI), intracortical facilitation (ICF), long-interval intracortical inhibition (LICI), short-latency afferent inhibition (SAI) and long term
potentiation (LTP)-like cortical plasticity.
Results: ICF was reduced in presymptomatic carriers (expected symptoms’ onset 16.8±8.3 years) compared to HC
(p<0.001), as well as LTP-like plasticity (p<0.001). SICI, LICI and SAI did not differ significantly between groups. In
symptomatic carriers, we observed a decrease in SICI compared to presymptomatic carriers (p<0.001), while ICF, LICI,
SAI and LTP-like plasticity did not differ between groups (p=0.981, p=0.141, p=0.443, p=0.853 respectively).
Discussion: In the present work, we observed a significant impairment in ICF and LTP-like cortical plasticity in
asymptomatic subjects bearing a pathogenic GRN mutation for FTD, at more than 15 years before expected symptom onset.
SICI, as well as ICF, resulted impaired to a greater extent in symptomatic carriers. SICI is considered to reflect short-lasting
postsynaptic inhibition mediated through the GABAA receptor at the level of local interneurons, while ICF is thought to
represent a net facilitation most likely mediated by glutamatergic NMDA receptors. The impairment of SICI in FTD could
be supported by the evidence of the toxic effects of mutant tau (P301L) on GABAergic interneurons, which leads to a loss
pag. 99
of GABAergic function. The impairment in LTP-like plasticity is supported by the notion that TDP-43 and mutant tau
aggregates impair spinogenesis, synapse assembly and synaptic plasticity, processes which result impaired also in GRN
knockout mice, even before the onset of neuropathological abnormalities.
Conclusions: In conclusion, these biomarkers could support the diagnosis of autosomal dominant FTD, and be used as a
screening tool to predict mutation status in at-risk subjects, possibly providing the footprints of specific physiopathological
processes in the development of this disease.
References:
− Burrell JR, Kiernan MC, Vucic S, Hodges JR. Motor Neuron dysfunction in frontotemporal dementia. Brain
(2011);134(9):2582-2594
− Rossini PM, Burke D, Chen R, et al. Non-invasive electrical and magnetic stimulation of the brain, spinal cord,
roots and peripheral nerves: Basic principles and procedures for routine clinical and research application. An
updated report from an I.F.C.N. Committee. Clin Neurophysiol. (2015);126(6):1071-1107
− Benussi A, Padovani A, Borroni B. Transcranial Magnetic Stimulation in Alzheimer’s Disease and Cortical
Dementias. J Alzheimers Dis Parkinsonism ( 2015);5(3):1-7
FRDA EPIDEMIOLOGY IN LAZIO REGION ITALY
C. Casali1, G. GRASP Group2
1
Department SBMC, Sapienza University (Roma); 2GRASP (Roma)
Objectives: Friedreich's ataxia (FA) is the most common form of autosomal recessive ataxia in Caucasians and possibly
worldwide with a prevalence of ~2/100,000. However few studies have addressed its prevalence in population-based
systematic surveys. We decided to gather information about its prevalence in the Lazio Region in 2015 (total population
5.892.425).
Materials and methods: An ad hoc study group (named GRASP, Gruppo Romano Atassie e paraparesi SPastiche) was
convened including all major neurological centers in Lazio. Neuropediatricians, cardiologists and orthopedics were also
asked to share relevant information so that the actual epidemiologic coverage has been assumed to be essentially complete.
Patient information has been revised and possible overlapping through different centers has been ruled out. All patients
were residents in Lazio at 30/11/2015, independently of their provenance from different areas of the country or ethnic
background. All had received a genetically confirmed diagnosis of FRDA.
Results: 64 patients have been identified (24 males and 40 females, aged 10-76 years). Total prevalence was 1,09 x 105 (M
0.84, F 1.31). As expected the prevalence according to age was highest in the second (1.50), third (1.45) and fourth (2.05)
decades of life. Genetically 61 patients carried GAA expansions in both X25/FXN alleles. Three patients (4.68%) carried a
point mutation on one allele and a GAA expansion on the other. Clinically 56 (87.5%) patients were diagnosed as typical
juvenile-onset FRDA (onset <25 years of age), 3 LOFA (late-onset FA, onset >25 years of age), and 5 VLOFA (very late
onset FA, onset >40 years).
Conclusions: We believe such systematic assessment of rare diseases prevalence is needed to develop speciphic plans of
public health intervention. Furthermore cooperation of different clinical centers should be encouraged to gather uniform
information and relevant series for planning clinical intervention.
References:
− Pandolfo M. Friedreich ataxia: the clinical picture. J Neurol (2009);256(Suppl.1):3–8
− Wedding IM, Kroken M, Henriksen SP, Selmer KK, Fiskerstrand T, Knappskog PM, Berge T, Tallaksen CM.
Friedreich ataxia in Norway - an epidemiological, molecular and clinical study. Orphanet J Rare Dis. (2015) Sep
4;10:108
− Hamza W, Ali Pacha L, Hamadouche T, Muller J, Drouot N, Ferrat F, Makri S, Chaouch M, Tazir M, Koenig M,
Benhassine T. Molecular and clinical study of a cohort of 110 Algerian patients with autosomal recessive ataxia.
BMC Med Genet. (2015) Jun 12;16:36
LTP-LIKE CORTICAL PLASTICITY IS
INDEPENDENTLY FROM AGE OF ONSET
DISRUPTED
IN
ALZHEIMER’S
F. Di Lorenzo, V. Ponzo, S. Bonnì, C. Motta, M. Bozzali, C. Caltagirone, A. Martorana, G. Koch
Fondazione Santa Lucia, Tor Vergata University (Roma)
pag. 100
DISEASE
PATIENTS
Objective: Early Onset Alzheimer Disease (EOAD) shares the same pathological features of Late Onset Alzheimer disease
(LOAD). However it is unknown if AD pathology induces in EOAD similar modification in synaptic functions as those
described in LOAD. We used transcranial magnetic stimulation tools to investigate the mechanisms of cortical plasticity and
sensory-motor integration in AD patients with a wide range of disease onset.
Materials and Methods: We evaluated newly diagnosed sporadic AD (n=54) in comparison with healthy age-matched
controls (HS n=24). Cortical plasticity mechanisms of long-term potentiation (LTP) or of long-term depression (LTD) were
assessed using respectively intermittent (iTBS) or continuous theta burst stimulation (cTBS) protocols. Sensory-motor
integration was evaluated by means of short afferent inhibition (SAI) protocol.
Results: AD showed an impairment of LTP-like cortical plasticity that was reversed to a paradoxical LTD after iTBS in
comparison to HS. LTD-like cortical plasticity was similar across groups. LTP-like cortical plasticity did not correlate with
age. AD patients presenting with more altered LTP-like cortical plasticity had more severe cognitive decline at 18 months.
SAI was impaired in AD and showed a strong correlation with the individual age of subjects rather than with disease age of
onset.
Discussion: Cortical LTP disruption is a central mechanism of AD that is independent from age of onset. AD can be
described primarily as a disorder of LTP-like cortical plasticity not influenced by physiological ageing and associated with a
more severe cognitive decline.
Conclusions: LTP impairment is AD-dependent, and could be considered as a neurophysiological marker of disease, while
the SAI dysfunction is age-dependent thus representing more likely a marker of the interaction between physiological and
pathological ageing.
RIGHT SEMANTIC DEMENTIA IN RIGHT-HANDEDNESS: A CASE REPORT
A. Dell'Edera, F. Caso, R. Cardamone, R. Santangelo, G. Cecchetti, S. Mazzeo, M. Falautano, V. Martinelli, G. Comi, G.
Magnani
Department of Neurology, Institute of Experimental Neurology, San Raffaele Scientific Institute, Vita-Salute San Raffaele
University (Milano)
Objective: To describe clinical, genetic and neuroanatomical features of a patient with the right temporal lobe variant
(RTLV) of the semantic variant of primary progressive aphasia (svPPA). SvPPA has been classically associated with left
anterior temporal damage. Nevertheless, almost 25% of svPPA patients show prominent right-sided damage and behavioral
disturbances, (mainly in emotional processing), in addition to language deficits. Thus, the differential diagnosis between this
syndrome and the behavioral variant of frontotemporal dementia (bvFTD) is usually challenging. Currently, no consensus
criteria exist for the RTLV of svPPA [1].
Materials: A 60-years-old right-handed woman was admitted to our Hospital in 2016. The husband reported in the last year
difficulties in the comprehension of low-frequency words, reduction of empathy, rigid and obsessive behavior. Recently,
she had working troubles due to her difficulties in social interaction with colleagues. Her father was affected by
unclassifiable dementia.
Methods: The patient underwent neurological and neuropsychological examination, Edinburgh handedness questionnaire
(EHQ), blood and cerebrospinal fluid (CSF) screening, electroencephalogram, brain MRI and 18FDG-PET. A genetic
analysis for the main genes associated with FTLD was performed.
Results: EHQ scores indicated strong right-handedness. General neurological exam was normal except for the presence of
glabellar and snout reflexes. Neuropsychological evaluation revealed deficits with abstract reasoning, especially in
emotional relevant setting. Regards to language, word-finding and naming deficits, and mildly impaired single words
comprehension were detected. Her CSF profile was congruent with non-AD pathology. EEG was unremarkable. MRI
revealed severe atrophy in right temporal regions mildly extended to dorsolateral prefrontal cortex (DLPFC). Consistently,
18FDG-PET showed severe hypomethabolism in right temporal pole and milder involvement also of left temporal pole,
right DLPFC, right orbital cortex and bilateral medial frontal gyrus.
Discussion: We described a rare case of RTLV of svPPA, characterized by affected emotion processing, including abnormal
social cognition and aspect of theory of mind [2], language dysfunction, and severe right temporal damage. This picture is
different from the bvFTD cases that usually present with prominent frontal damage, deficits in working memory, executive
function and increased apathy [1]. The different presentation is more evident at disease onset than after the spread of the
underlying pathological process.
Conclusions: Distinguishing the RTLV of svPPA from bvFTD is critical, given the likely different underlying
neuropathology involving syndrome-specific networks and the potential patients’ enrollment in protein-specific treatments
as they become available.
References:
pag. 101
−
−
González-Caballero, Abellán-Miralles, Sáenz-Sanjuan, Right temporal lobe variant of frontotemporal dementia.
Journal of Clinical Neuroscience (2015);22:1139–1143
Irish, Hodge, Piguet, Right anterior temporal lobe dysfunction underlies theory of mind impairments in semantic
dementia. Brain (2014);137:1241–1253
DOPAMINE IMBALANCE IN HUNTINGTON'S DISEASE: WHEN THE INHIBITION OF AUTOPHAGY CAN
LEAD TO CELL CATASTROPHE
M. A. Melone1, C. Vidoni2, A. Castiglioni2, C. Seca2, C. Isidoro2
1
Dipartimento Medico-Chirurgico di Internistica Clinica e Sperimentale & Centro Interuniversitario di Ricerca in
Neuroscienze (CIRN), Seconda Università di Napoli (Napoli); 2Department of Health Sciences, Laboratory of Molecular
Pathology and Nanobioimaging, Università del Piemonte Orientale “A. Avogadro” (Novara)
Background: Huntington Disease (HD) is a neurodegenerative condition caused by abnormal expansions (>37) of a
polyglutamine (PolyQ) tract in the huntingtin protein (Htt). Dopamine (DA) induces oxidative stress and causes toxicity in
neurons. DA may exacerbate neuronal loss in the striatum. Autophagy is a lysosomal degradation pathway known to clear
protein aggregates. We hypothesized that DA could induce toxicity in Htt-expressing dopaminergic neurons by inhibiting
the clearing activity of the autophagy system.
Materials and Methods: Normal and mutant Htt were ectopically expressed in dopaminergic human neuroblastoma SHSY5Y cells. The autophagic activity and Htt expression were studied by Western blotting and immunofluorescence.
Apoptosis was assessed by FACS analysis, Propidium Iodide (PI) staining and Western blotting.
Results: Hyper-expression of mutant Htt “per se” reduced cell proliferation and induced cell death. These effects were
associated with impairment of the autophagy pathway. DA caused apoptotic and necrotic cell death in SH-SY5Y cells
expressing the mutant Htt. In the latter cells, DA further reduced the formation of autophagosome, thus preventing the
degradation of Htt aggregates. DA induced oxidative stress at mitochondrial level with generation of anion superoxide ROS.
Conclusions: DA causes the death of neurons expressing the mutant Htt through the inhibition of the autophagy degradation
pathway. We suggest that DA-induced mitochondrial oxidative stress promotes the generation of ROS that inhibit ATG4,
the enzyme needed for the LC3 I to LC3 II conversion. Our data help explain why alterations in DA function conjugate to
the inhibition of autophagy system may play a significant role in the motor and cognitive symptoms of HD.
Acknowledgements MIUR (PRIN contract #20109MXHMR_004, to MABM)
ABRUPT WITHDRAWAL OF IMMUNOSUPPRESSIVE DRUGS: A POTENTIAL TRIGGER FOR CAA-RI
I. Colombo1, G. Calabrese1, B. Bordo1, L. Chiapparini2, S. Auricchio3, F. Piazza4, M. Longoni4, I. Santilli1
1
Neurology Unit, Hospital of Desio, ASST Monza (Desio-MB); 2Neuroradiology Unit, Fondazione C. Besta (Milano);
3Nephrology Unit, Hospital of Desio, ASST Monza (Desio-MB) 4School of Medicine and Surgery, Milan Center for
Neuroscience (NeuroMi), University of Milano-Bicocca (Monza)
Objectives: Cerebral amyloid angiopathy-related inflammation (CAA-ri) is a rare but potentially treatable cause of
dementia, secondary to an inflammatory response to beta-amyloid (Ab) in cerebral vessels. Acute-onset cognitive
behavioral abnormalities, focal deficits, seizures, or headache are the most common presentations. MRI tipically shows
asymmetric T2 or FLAIR hyperintensities, minimal gadolinium enhancement, and microbleeds at cortico-subcortical
junction. During the acute phase, anti-Ab autoantibodies are increased (1). CAA-ri usually responds to steroids. According
to the proposed diagnostic criteria (2), it may be possible to diagnose patients based on clinical and MRI findings alone,
obviating the need for brain biopsy. We report the first case of CAA-ri occurring after immunosuppressive
withdrawal. Materials and methods: A 53-year-old man, affected with polycistic disease and late-stage uremia, underwent
kidney allotransplantation. Eleven years later light cell cancer was detected on the transplanted kidney, which was excised.
Immunosuppressive drugs, including cyclosporine and mycophenolate, were abruptly withdrawn and hemodialysis started.
After one month drowsiness and apathy were observed and interpreted as reactive depression. Three months later he was
admitted in our department due to right hemianopsia and aphasia. Complex partial seizures occurred and were treated with
antiepileptic drugs. EEG showed diffuse delta activity. A brain MRI demonstrated FLAIR hyperintensities in left
parasagittal parieto-temporal and temporo-occipital regions, suggesting brain edema, together with minute hemosiderin
depositions at Gradient- sequences. No contrast enhancement was observed. CAA-ri was suspected. At cerebrospinal fluid
examination proteins were 162 mg/dl and anti-Abeta autoantibodies resulted positive. The patient was treated with 1 mg/kg
pag. 102
prednisone with progressive resolution of symptoms within four weeks. Five months later disappearance of edema was the
main feature at MRI. Six months after steroids start, tapering is still ongoing, remaining the patient
asymptomatic. Discussion and conclusions: It is likely that in our patient mood changes were the first presentation of CAAri and no MRI was performed at that time. It is remarkable that neurological and psychiatric onset occurred just one month
after immunosuppressive withdrawal. We argue that this abrupt change in the modulation of immune system was the trigger
for CAA-ri. Thus, in CAA-ri patients both cerebral amyloid angiopathy and inflammation of blood vessels coexist. Our case
report reinforces the idea that autoimmunity plays a role in the causation of this vasculitis.
References:
1. Greenberg SM, Savoiardo M, et al. Anti-amyloid β autoantibodies in cerebral amyloid angiopathy-related
inflammation: implications for amyloid-modifying therapies. Ann Neurol. (2013) Apr;73(4):449-58
2. Auriel E, Charidimou A, Gurol ME, et al. Validation of Clinicoradiological Criteria for the Diagnosis of Cerebral
Amyloid Angiopathy-Related Inflammation. JAMA Neurol. (2016) Feb 1;73(2):197-202
DOLORE
EXPECTATION TO FEEL MORE PAIN DISRUPTS LASER-PAIN AND LASER EVOKED POTENTIAL
AMPLITUDES HABITUATION
C. Pazzaglia1, E. Testani2, R. Giordano2, L. Padua1,2, M. Valeriani3
1
Department of Neurology, Don Carlo Gnocchi Onlus Foundation (Milano); 2Department of Neuroscience, Catholic
University of Sacred Heart (Roma); 3Neurology Unit, Ospedale Pediatrico Bambino Gesù, IRCCS, Center for SensoryMotor Interaction, Aalborg University (Roma, Aalborg, DK)
Objective: Increased pain perception due to the expectation to feel more pain is called nocebo effect. The present study
aimed at investigating whether: 1) the mere expectation to feel more pain after the administration of an inert drug may affect
the laser-pain rating and the laser evoked potential (LEP) amplitude, and 2) the learning potentiates the nocebo effect.
Materials: Eighteen healthy volunteers were told that an inert cream, applied on the right hand, would increase the laserpain and LEP amplitude to right hand stimulation.
Methods: Subjects were randomly assigned to either “verbal session” or “conditioning session”. In the “verbal session”,
LEPs to both right and left hand stimulation were recorded at the same intensity before (baseline) and after cream
application. In the “conditioning session”, after an initial cream application the laser stimulus intensity was increased
surreptitiously to make the subjects believe that the treatment really increased pain sensation. Then, the cream was reapplied
and LEPs were recorded at the same stimulus intensity as at the baseline.
Results: It was found that the verbal suggestion to feel more pain disrupted the physiological habituation of the laser-pain
rating and LEP amplitude to treated (right) hand stimulation. Discussion: Unlike it was previously demonstrated for the
placebo effect, the learning did not potentiate the nocebo effect.
Conclusions: That the mere expectation to feel more pain has evident consequences on both psychophysical and
neurophysiological level can be relevant from a clinical point of view.
THE DIAGNOSTIC ACCURACY OF LASER EVOKED POTENTIALS IN DIABETIC SMALL FIBRE
NEUROPATHY
E. Galosi, S. La Cesa, G. Di Stefano, C. Leone, A. Fasolino, A. Pepe, A. Di Lionardo, S. Piroso, A. Truini, G. Cruccu
Department of Neurology and Psychiatry, University La Sapienza (Roma)
Although laser evoked potential (LEP) recording is the most widely agreed neurophysiological tool for investigating
nociceptive pathway in patients with neuropathic pain, the diagnostic accuracy of this technique has not yet been
documented. In this clinical and neurophysiological study we aimed at assessing sensitivity and specificity of LEPs in a
representative neuropathic pain condition, i.e. diabetic small fibre neuropathy. We have carried out 288 LEP recordings
from face, hand and foot in 73 healthy subjects to collect age-corrected normative ranges for face, hand and foot. After
having screened 172 patients with diabetic neuropathy, we have selected 23 patients with possible pure small fibre
neuropathy. In these patients, using the skin biopsy as a gold standard we have calculated sensitivity and specificity of
LEPs. In healthy participants LEP amplitude decreased from face to foot. While age strongly influenced normative ranges
pag. 103
for all LEP variables, gender did not affect LEP amplitude. By applying age-corrected normative ranges for LEPs, we found
that LEPs have a sensitivity and specificity of 76% and 80%. Our clinical and neurophysiological study providing agecorrected normative ranges for the main LEP data and their diagnostic accuracy, helps to improve the clinical reliability of
LEPs as a diagnostic tool, and indicates that this technique might be an alternative diagnostic tool to the skin biopsy for a
definite diagnosis of diabetic small fibre neuropathy.
References:
− Valeriani M, Pazzaglia C, Cruccu G, Truini A. Clinical usefulness of laser evoked potentials. Neurophysiol Clin.
(2012) Oct;42(5):345-53
− Truini A, Galeotti F, Romaniello A, Virtuoso M, Iannetti GD, Cruccu G. Laser-evoked potentials: normative
values. Clin Neurophysiol. (2005) Apr;116(4):821-6
− Truini A, Biasiotta A, La Cesa S, Di Stefano G, Galeotti F, Petrucci MT, Inghilleri M, Cartoni C, Pergolini M,
Cruccu G. Mechanisms of pain in distal symmetric polyneuropathy: a combined clinical and neurophysiological
study. Pain (2010) Sep;150(3):516-21
PERIPHERAL NERVE STIMULATION OF THE UPPER LIMB FOR NEUROPATHIC PAIN AFTER NERVE
INJURIES: A LONG-LASTING EFFICACY IN PAIN RELIEF
G. Devigili1, C. Lettieri1, S. Rinaldo1, G. Stevanato2, R. Eleopra1
1
Department of Neurology, Santa Maria della Misericordia University Hospital (Udine); 2Neurosurgery Unit, Dell'Angelo
Hospital (Mestre-VE)
Introduction: The peripheral nerve stimulation showed good efficacy in treatment of peripheral neuropathic pain (NP) after
nerve injuries. However, the evidences of the long-term efficacy and safety are still lacking. The aim of study was to
evaluate the long-term outcome in patients after PNS implants. Therefore we designed an OFF-ON stimulation paradigm in
order to evaluate the timing of effects on pain relief and changing in sensory profiles.
Methods: We prospectically evaluate 12 patients with severe intractable pain after nerve of upper limb or brachial plexus
injuries. All underwent surgical implant a quadripolar electrode lead for PNS placed on the sensory nerve fibers of the nerve
mainly involved in pain symptoms. All patients underwent the neuroalgological evaluation and quantitative sensory testing
and pain questionnaries at baseline and at follow-up evaluation (after 1, 6, 12 months and every year after implant). In all
the parameters of stimulation were placed with a subliminal sensation not perceived. During the follow-up the patients
performed a blinded switch OFF of stimulation and neuroalgological evaluation and QST was performed. Then the
stimulator was switch ON and a second neuroalgological and QST evaluation was performed.
Results: All the patients experienced pain relief after implant (mean of 76.2% improvement NRS) and positive phenomena
like allodynia were almost disappeared. All the patients showed a persistent pain relief during the follow-up period range
from 1.4 months to 9 years. During the blinded OFF stimulation in all the pain reappeared with the same quality of pain
present at the onset, regardless of the duration of PNS. The reappearance of pain in all was less then the minute (mean of 38
seconds). After 1 hour also the autonomic symptoms (skin flushing and swelling) occurred. The patients experience pain
relief after around one minute to the turning ON the stimulation. No significant adverse events occurred. The warm and cold
thresholds were reduced only in patients with peripheral nerve lesion, distally to the brachial plexus.
Conclusion: The results support the long lasting efficacy in pain relief of PNS for peripheral neuropathic pain supported by
the blinded paradigm of evaluation. The surgical technique is safety with poor risk of lead dislocation.
MOTOR CORTEX TRNS AMELIORATES PAIN, ANXIETY, DEPRESSION AND COGNITIVE IMPAIRMENT
IN PATIENTS WITH FIBROMYALGIA: PRELIMINARY RESULTS OF A RANDOMIZED SHAMCONTROLLED TRIAL
G. La Bianca1, M. Curatolo2, M. Romano2, M. Sorce2, B. Fierro1, F. Brighina1
1
2
Department of Experimental Biomedicine and Clinical Neuroscience (BIONEC), University of Palermo (Palermo);
Neurology Unit, Hospitals Villa Sofia-Cervello (Palermo)
Objective: Fibromyalgia (FMS) is a complex clinical syndrome characterized by widespread muscoloskeletal pain, chronic
fatigue, cognitive deficit, sleep and mood disorders. Most pharmacological therapies based on antidepressants, painkillers
pag. 104
and muscle relaxants showed limited effectiveness in this disease. For this reason, it’s very important to search and improve
new therapeutic means can act directly on the neural circuits responsible for the processing of pain and involved in the
typical cognitive impairment, called ‘fibrofog’ (1). Many studies have shown motor cortex transcranial direct-current
stimulation (tDCS) and motor cortex repetitive transcranial magnetic stimulation (rTMS) are able to reduce perceived pain
levels and number of tender points. Instead, stimulation of dorsolateral prefrontal cortex (DLPFC) was correlated to
reduction of anxiety and depression (2) and cognitive improvement (3). Recently a new transcranial electrical stimulation
approach, random noise stimulation (tRNS), based on fastly and random frequency changing alternating current, likely
acting through stochastic resonance activation mechanisms, was found effective in ameliorate working memory and pain in
limited series (3). Here we aimed to explore clinical and neuropsychological effects of primary motor cortex (M1) tRNS in
FMS patients.
Materials and methods: Twenty female patients with FMS between the ages of 26 and 67 were randomized into two
treatment groups undergoing daily stimulation sessions for two weeks (weekend free): one received active, real tRNS and
the other one sham, placebo tRNS. Each patient was evaluated, before and after treatment, through Visual Analogue Scale
(VAS), Fibromyalgia Impact Questionnaire (FIQ), Mini-Mental State Examination (MMSE), Hospital Anxiety and
Depression Scale (HANDS) and other specific neurophychological tests, such as Trail Making Test (TMT), Rey Auditory
Verbal Learning Test (AVLT), Forward and Backward Digit Span.
Results: M1 active tRNS, compared to sham, induced a general improvement of FMS clinical picture: pain, depression and
anxiety scores showed significant and relevant reduction (about 40%) and consistent improvement was also reported in
working memory and QoL scores.
Discussion and conclusions: These findings suggest M1 tRNS can be very effective in relieving symptoms of fibromyalgia.
Differently from motor cortex tDCS, tRNS seems able to counteract not only pain but also cognitive disturbance in these
patients. This could follow to the invoked mechanism of stochastic resonance that would bring to a synchronization of
neural firing so inducing more spreading and lasting effects.
References:
1. Howard M. Kravitz, Robert S. Katz Fibrofog and fibromyalgia: a narrative review and implications for clinical
practice, Rheumatology Int (2015);35:1115-1125
2. Hou WH, Wang TY, Kang JH. The effects of add-on non-invasive brain stimulation in fibromyalgia: a metaanalysis and meta-regression of randomized controlled trials. Rheumatology (Oxford) (2016) May 5
3. Mulquiney PG, Hoy KE, Daskalakis ZJ, Fitzgerald PB. Improving working memory: exploring the effect of
transcranial random noise stimulation and transcranial direct current stimulation on the dorsolateral prefrontal
cortex. Clin Neurophysiol. (2011) Dec;122(12):2384-9
DIAGNOSING AND ASSESSING PAIN IN NEUROREHABILITATION: FROM TRANSLATIONAL
RESEARCH TO THE CLINICAL SETTING. RESULTS AND RECOMMENDATIONS OF THE ITALIAN
CONSENSUS CONFERENCE ON PAIN IN NEUROREHABILITATION (ICCPN)
S. Tamburin1, C. Porro2, A. Truini3, V. Tugnoli4, E. Alfonsi5, L. Berliocchi6, C. Cacciatori1, M. Lacerenza7, F. Magrinelli1,
P. Marchettini8, P. Sacerdote9, M. Valeriani10, G. Sandrini5
1
Department of Neurosciences, Biomedicine and Movement Sciences, University of Verona (Verona); 2Department of
Biomedical, Metabolic and Neural Sciences, University of Modena and Reggio Emilia (Modena); 3Department of
Neurology and Psychiatry, University Sapienza (Roma); 4Neurology Unit, University Hospital of Ferrara (Ferrara);
5
Department of Brain and Behavioral Sciences, University of Pavia (Pavia); 6Department of Health Sciences, University
Magna Graecia of Catanzaro (Catanzaro); 7Pain Medicine Center, Casa di Cura San Pio X, Opera San Camillo Foundation
(Milano); 8Pain Medicine Center, Hospital San Raffaele (Milano); 9Department of Pharmacological and Biomolecular
Sciences, University of Milan (Milano); 10Division of Neurology, Ospedale Pediatrico Bambino Gesù, IRCCS (Roma)
Background and aims: Pain is very common in neurorehabilitation, where it may either be a target for treatment or have a
negative effect on rehabilitation procedures and outcomes. Guidelines or consensus on diagnosis and assessment of pain,
and translational evidence from animal models are largely lacking in this setting.
Methods: The Italian Consensus Conference on Pain in Neurorehabilitation (ICCPN) collected evidence on animal models
for the treatment of pain, potential predictive biomarkers for response to treatment in preclinical models, the definition and
diagnostic criteria for nociceptive and neuropathic pain (NP), screening tools and questionnaires, and diagnostic clinical and
instrumental techniques for separating nociceptive from NP and for the assessment of pain in the field of
neurorehabilitation.
Results: Promising preliminary preclinical data support some therapeutic approaches to pain, but there is a strong need of
pag. 105
adequate preclinical models, experimental settings, outcome measures, and biomarkers that could be more relevant for pain
in neurorehabilitation field. Data on diagnosis and assessment of nociceptive and NP are very scanty in neurorehabilitation,
but those from other contexts can be adapted and translated in this specific setting.
Discussion and Conclusions: The present ICCPN recommendations may give information on the relevance of current
preclinical models, and be helpful for ameliorating pain diagnosis and assessment, which are prerequisites for better
application and tailoring of current pharmacological and non-pharmacological treatments for pain in neurorehabilitation.
They may also be useful for future studies aimed to fill the knowledge gaps on these topics.
CEREBELLAR DIRECT CURRENT STIMULATION MODULATES PAIN PERCEPTION AND ITS CORTICAL
CORRELATES IN HUMANS
T. Bocci1, D. Barloscio1, L. Parenti1, M. Bartolotta1, A. De Rosa1, R. Ferrucci2, A. Priori2, M. Valeriani3, F. Sartucci1
1
Department of Clinical and Experimental Medicine, Cisanello Neurology Unit, Pisa University Medical School (Pisa);
Department of Neurological Sciences, Fondazione IRCCS Ospedale Maggiore Policlinico, University of Milan (Milano);
3
Division of Neurology, Ospedale Bambino Gesù, IRCCS (Roma)
2
Introduction: The cerebellum is involved in a wide number of integrative functions, ranging from working memory and
associative learning to motor control, but its role in pain perception and nociceptive processing is poorly understood. We
evaluated the effects of transcranial cerebellar direct current stimulation (tcDCS) by studying the changes in perceptive
threshold (PT), pain intensity (VAS) and laser evoked potentials (LEPs) variables (amplitude and latency of both N1 and
N2/P2 responses).
Materials and Methods: Fifteen subjects were studied before and after anodal, cathodal and sham tcDCS. LEPs were
obtained using a Nd:YAP laser (wavelength 1.04 µm, pulse 164 duration 2–20 ms, maximum energy 7 J). The laser beam
was transmitted from the generator to the stimulating probe via a 10m length optical fibre; signals were then amplified, band
pass filtered (0.1–200 Hz, time analysis 1000 ms). The dorsum of the left hand was stimulated by laser pulses (individual
variability: 3.89–15.75 J/cm2) with short duration (5 ms) and small diameter spots (5 mm). VAS was evaluated by
delivering laser pulses at two different intensities, respectively two and three times the PT.
Results: Cathodal polarization dampened the PT and increased the VAS score, while the anodal one had opposite effects
(p<0.001). Cathodal tcDCS increased significantly LEPs amplitudes and decreased their latencies, whereas anodal tcDCS
elicited opposite effects (p<0.0005).
Discussion: tcDCS modulates pain perception and its cortical correlates. As it is effective on N1 and N2/P2 components and
these responses are generated by parallel and partially segregated spinal pathways reaching different cortical targets, we
speculate that the cerebellum modulates the activity of both somatosensory and cingulate cortices, thus interfering with the
sensory-discriminative as well as emotional dimensions of pain.
Conclusions: Present findings prompt investigation of the tsDCS as a novel, safe therapeutic tool in chronic pain patients.
References:
− Bocci T, Santarcangelo EL, Vannini B, Torzini A, Carli G, Ferrucci R, Priori A, Valeriani M, Sartucci F Cerebellar
direct current stimulation modulates pain perception in humans. Restor Neurol Neurosci. (2015);33(5):597-609
− Bocci T, Barloscio D, Parenti L, Sartucci F, Carli G, Santarcangelo EL. High hypnotizability impairs the cerebellar
control of pain. Cerebellum (2016). in press
WHOLE EXOME SEQUENCING APPROACH FOR THE IDENTIFICATION OF PAIN-RELATED
MUTATIONS IN AN ITALIAN COHORT OF FAMILIAL AND EARLY-ONSET PATIENTS AFFECTED BY
IDIOPATHIC PERIPHERAL NEUROPATHY
M. Marchi1, S. Santoro2, M. Sorosina2, A. Zauli2, L. Grevendonk2, D. Cazzato1, R. Lombardi1, C. Faber3, M. Gerrits4, R.
Almomani4, J. Hoeijmakers3, I. Merkies3, H. Fadavi5, R. Malik5, D. Ziegler6, G. Boenhof6, I. Lopez7, G. Comi8, S. DibHajj9, S. Waxman9, A. Quattrini10, F. Martinelli Boneschi2, G. Lauria1
1
Neuroalgology Unit and Skin Biopsy, Peripheral Neuropathy and Neuropathic Pain Center, IRCCS Foundation Carlo Besta
Neurological Institute (Milano); 2Laboratory of Human Genetics of Neurological Disorders, INSPE, San Raffaele Scientific
Institute (Milano); 3Dept. of Neurology, Maastricht University Medical Center (Maastricht-NL); 4Clinical Genetics,
Maastricht University Medical Center (Maastricht-NL); 5Centre for Endocrinology and Diabetes, University of Manchester
and Central Manchester NHS Foundation Trust (Manchester-UK); 6German Diabetes Center, Medical Faculty Heinrich
pag. 106
Heine University (Düsseldorf-D); 7Laboratory of Neuropathology, INSPE, San Raffaele Scientific Institute (Milano); 8Dept.
of Neurology, San Raffaele Scientific Institute (Milano); 9Dept. of Neurology, Yale University School of Medicine (New
Haven-USA); 10Laboratory of Neuropathology, INSPE, San Raffaele Scientific Institute (Milano)
Introduction: Neuropathic pain is a frequent feature of peripheral neuropathy causing a significant impact on patients’
quality of life and health care costs. The Consortium of 9 partners from 6 countries coordinated by IRCCS Neurological
Institute Besta is engaged in the project for Probing the Role of Sodium Channels in Painful Neuropathies (the PROPANE
STUDY).
Aim: We propose to use a whole exome sequencing approach in a cohort of familial and early-onset painful neuropathic
patients to identify rare variants causative of the disease, to achieve a stratification of patients at high-risk for neuropathic
pain and to enhance our understanding of underlying mechanisms.
Material and Methods: Inclusion criteria were (i) families with ≥2 affected members or (ii) patients with an early-onset of
disease (<40 years). Ten Italian families with a total of 29 patients and 11 healthy controls, as well as 36 early-onset Italian
patients were recruited. DNA extracted from peripheral blood were enriched using the Agilent SureSelect Human All Exon
QXT V5. Paired-end sequencing (2x101bp) was performed on Illumina Hiseq2500 platform. Reads were trimmed and
aligned with BWA using hg19 as reference genome. Variants were identified using GATK pipeline and annotated using
SnpEff suite. We focused on variants according to their depth (<6), evolutionary conservation (GERP++RS>0), mutation
frequency (<0.01 for MODERATE and <0.05 for HIGH impact variants), in silico predicted effect (Polyphen2 >0.15, SIFT
<0.05, and MetaSVM >0) and segregating under a transmission model according to the pedigree in familial cases or shared
among patients in the early-onset sporadic cohort.
Results: Until now we sequenced 23 subjects belonging to 8 families reaching a mean coverage of 90X and 36 early-onset
patients. In the first two families, characterized by an autosomal dominant transmission, a mean of 17.000 variants of HIGH
and MODERATE impact were identified. Following a dominant transmission model, a total of 49 and 40 rare/novel variants
with a putative functional role were identified respectively in the first and second family. Analyses on additional families
and early-onset cases are ongoing at present time.
Discussion and conclusions: The application of exome-sequencing in familial or atypical cases of painful neuropathy is
effective in identifying causative genes, and can help to better understand the pathophysiology of the disease.
VENLAFAXINE AND OXYCODONE HAVE DIFFERENT EFFECTS ON SPINAL AND SUPRA- SPINAL
ACTIVITY IN MAN
M. Valeriani1, D. Lelic2, I. Fisher2, A. Dahan3, A. Drewes1
1
Neurologia, Ospedale Bambino Gesù (Roma); 2Department of Gastroenterology and Hepatology, Aalborg University
Hospital (Aalborg, DK); 3Department of Anesthesiology, Leiden University Medical Center (Leiden, NL)
Objective: This study aimed to explore how oxycodone (opioid) and venlafaxine (SNRI) modulate the non-nociceptive
somatosensory processing. This could give us important information about the analgesic mechanisms of action of both
drugs.
Methods: Twenty volunteers were included in this randomized, cross-over, double blinded experimental study comparing
treatment with venlafaxine and oxycodone to placebo. Spinal and full scalp cortical somatosensory evoked potentials
(SEPs) to median nerve stimulation were recorded before and after five days of treatment.
Results: In the venlafaxine arm, the P11 and N60-80 latencies were reduced (P<0.01), whereas the P25 amplitude was
decreased (P=0.01). Oxycodone increased the P14 (P=0.03) and N30 (P=0.04) amplitudes and the N60-80 latency (P<0.05).
The brainstem and primary somatosensory cortex source strengths were increased in oxycodone arm, whereas the primary
somatosensory cortex strength was decreased in venlafaxine arm (P<0.05).
Discussion: While venlafaxine determines changes in the non-nociceptive somatosensory pathway at both spinal and
cortical
level,
oxycodone
acts
at
brainstem
and
cortical
level.
Conclusions: Opioids and SNRIs exert different central effects.
MALATTIE NEUROMUSCOLARI 2
EPSTEIN-BARR VIRUS DETECTION IN THYMOMA ASSOCIATED WITH MYASTHENIA GRAVIS:
POSSIBLE IMPLICATIONS FOR AUTOIMMUNITY
pag. 107
P. Cavalcante1, S. Franzi1, B. Galbardi1, C. Barzago1, L. Maggi1, S. Bonanno1, G. Camera1, A. Biasiucci2, T. Motta2, C.
Giardina2, C. Antozzi1, F. Baggi1, T. De Pas3, M. Barberis4, P. Bernasconi1, R. Mantegazza1
1
Neurology IV, Neurological Institute ‘Carlo Besta’ (Milano); 2Pathological Anatomy, Azienda Ospedaliera Bolognini
(Seriate – BG); 3Unit of Sarcomas and Thymomas, European Institute of Oncology (Milano); 4Histopathology and
Molecular Diagnostics Unit, European Institute of Oncology (Milano)
Objective: The thymus plays a major role in the etiology of myasthenia gravis (MG), a B-cell mediated autoimmune
disorder affecting the neuromuscular junction. Thymic abnormalities are present in most MG patients, including hyperplasia
and thymoma, an epithelial tumor of the thymus. Recently, we provided evidence of Epstein-Barr virus (EBV) persistence
and reactivation in B cells and plasma cells of MG hyperplastic thymuses, suggesting that EBV might contribute to intrathymic B-cell dysregulation and autoimmunity in MG patients. Here, we sought evidence of EBV presence in MG
thymomas, to investigate whether EBV may be involved in thymoma-associated MG.
Materials and methods: Twenty-six thymomas from MG patients, fourteen thymomas from patients without MG and six
normal thymuses from healthy subjects were analysed using qPCR for EBV DNA and EBV-encoded small RNA 1
(EBER1), nested PCR for the lytic transcript BZLF1, in situ hybridization for EBERs, and immunohistochemistry for EBV
latency proteins (EBNA1, LMP1, and LMP2A).
Results: EBV DNA was detected in 14/26 (53.8%) MG thymomas and only in 3/14 (21.4%) non-MG thymomas, with viral
load values being up to 986 in MG and up to 352 EBV genome copies per 10^6 tissue cells in non-MG samples. Most MG
thymomas (85%), and only the three EBV DNA-positive non-MG thymomas, were positive for the EBER1 transcript.
BZLF1 mRNA was undetectable in both MG and non-MG tumors. Variable numbers of cells expressing EBERs were
detected in MG thymomas (56%), whose non-tumoral adjacent thymic tissues were EBER-negative, whereas non-MG
thymomas were all negative for EBERs, in both tumoral and non-tumoral thymic tissue. Cells positive for EBNA1 and
LMP1 were frequently identified in MG thymomas, but only rarely they were detected in the non-MG tumors. In MG
thymomas, EBV-positive cells were mainly of B-cell phenotype; indeed, the MG neoplastic tissues were characterized by
an increased number of tumor-infiltrating B cells, variable proportions of which expressed LMP1 and LMP2A proteins.
Discussion: EBV was detected at higher frequency in MG than non-MG thymomas. The expression pattern of EBV markers
suggests latent EBV infection, but not viral reactivation, in MG thymomas. In these tumors EBV-infected cells were mainly
B-cells, and only rarely thymic epithelial cells, suggesting an association between EBV and MG, rather than between EBV
and thymoma. Conclusions: EBV-infected B cells are commonly present in thymoma of myasthenic patients, suggesting a
contribution of EBV infection to B-cell dysfunction and B-cell-mediated autoimmunity in MG associated with thymoma.
PERIPHERAL DYSREGULATED MOLECULES ASSOCIATED WITH MYASTHENIA GRAVIS: POSSIBLE
ROLE OF NOVEL PLAYERS IN DISEASE PATHOGENESIS?
C. Barzago1, J. Lum2, P. Cavalcante1, R. Calogero3, P. Bernasconi1, R. Mantegazza1, F. Zolezzi2, L. Mori2
1
3
Neurology IV, Neurological Institute Carlo Besta (Milano); 2Singapore Immunology Network, A*STAR (Singapore-SGP);
Department of Molecular Biotechnology and Health Sciences, University of Turin (Torino)
Objective: Myasthenia gravis (MG), a B-cell mediated autoimmune disease that affects the neuromuscular junction, is
believe to initiate in the thymus that is considered a key site of autoimmunity onset in acetylcholine receptor-positive MG
patients (AChR-MG). However, the precise mechanisms involved in the perpetuation of the autoimmune processes in the
peripheral vascular system are poorly studied. Here, we analyse the transcriptome in peripheral blood cells of AChR-MG
patients compared to age- and gender-matched healthy controls, to discover possible molecules that may be associated with
AChR-MG pathogenesis.
Material and methods: We applied the RNA-sequencing technique on a 'discovery' cohort composed by 11 AChR-MG
patients and 6 healthy controls. Results were then selected by Ingenuity Pathway Analysis (IPA) software and subsequently
analysed by NanoString technology and qPCR in a 'validation' cohort composed by the discovery cohort plus 6 AChR-MG
patients and 6 healthy controls.
Results: Transcriptome data indicated that 128 genes and 9 microRNA (miRNA) precursors were differentially expressed
between patients and controls. IPA also showed that the dysregulated transcripts were highly associated with ‘infection-’
and ‘inflammatory-related’ categories. These results were confirmed in the validation cohort by NanoString technology
applied on some selected ‘infection’ and ‘inflammatory-associated’ transcripts. Moreover, transcriptome data were also
analysed based on IPA prediction of mRNA-miRNA interactions; some dysregulated miRNAs and their putative transcripts
pag. 108
were selected and validated. We observed that miR-612, pre-miR-3651, miR-3651, and miR-3654 were upregulated; on the
contrary, two miR-612- and one miR-3651-putative target transcripts were significantly downregulated in AChR-MG
patients compared to healthy controls.
Discussion: Our data suggest that the peripheral transcriptome in AChR-MG patients is perturbed and it is associated with
dysregulated molecules related to ‘infection’ and ‘inflammation’. Thus, the putative role of differentially expressed
molecules associated with ‘infection’ and ‘inflammatory’ pathways in AChR-MG patients may represent possible
mechanisms responsible for the perpetuation of the immunological dysfunctions in the peripheral vascular system.
Conclusions: Our study may contribute to gain knowledge on the molecular mechanisms associated with AChR-MG
pathogenesis in periphery, towards the future development of new therapeutic strategies.
GUILLAIN-BARRE’ SYNDROME ONE HUNDRED YEARS AFTER THE ORIGINAL DESCRIPTION: A
THIRTEEN-YEARS RETROSPECTIVE STUDY IN PROVINCE OF LA SPEZIA
L. Benedetti1, A. Beronio2, E. Giorli2, S. Parodi2, C. Sani3, A. Derchi3, C. Amodeo3, P. Delia4, F. Rollandi4, F. Massa1, G.
Mancardi1, A. Mannironi2
1
Department of Neuroscience, Rehabilitation, Ophthalmology, Genetics, Maternal and Child Health, University of Genova
and IRCCS AOU San Martino-IST (Genova); 2Department of Neurology, Sant’Andrea Hospital (La Spezia); 3U.O Intensive
Care Unit, Sant’Andrea Hospital (La Spezia); 4Transfusion Center, Sant’Andrea Hospital (La Spezia)
Introduction: Guillain-Barrè syndrome (GBS) is a peripheral neuropathy characterized by acute onset and rapidly
developing motor weakness. In Europe the annual incidence rate is between 0.84 and 1.91/100000. In Europe and North
America only 5% of patients with GBS corresponds to axonal subtypes, which in Central and South America, Japan and
China account for 30-47% of cases. Objective: To assess the annual incidence and clinical features of typical GBS and its
main variants in province of La Spezia.
Materials and methods: A retrospective analysis was carried out on patients resident in province of La Spezia and admitted
to Sant’Andrea Hospital from 1 January 2003 to 31 December 2015. Results: A total of 86 patients (males 58; females 28)
aged 21-90 years (mean 62,07) fulfilled the diagnostic criteria for GBS. The mean annual incidence was 3/100000 (range:
minimal 0.9/100000 in 2005 and maximal 5.37/100000 in 2011) significantly higher than the European incidence, p<0.001.
A significant tendency for clustering in the spring months was noted (42%) (p=0.0029). Forty-one cases (47%) were
classificated as AIDP, 30 (35%) as AMAN/AMSAN, 11 cases (13%) as variant forms, and 4 (5%) as not classificable.
AIDP predominates in “Golfo dei Poeti” (50%) and “Val di Magra” (63.2%), whereas AMAN/AMSAN in “Val di Vara “
(63.6%) and “Riviera Spezzina” (62.5%). P=0.024.
Conclusions: In La Spezia province GBS incidence especially of its AMAN subtype, outweighs that usually reported in
Europe. AIDP predominates in the east of the province whereas AMAN/AMSAN in the west (p=0.003). Prospective studies
to determine possible relationships between GBS incidence and exposure to environmental factors are warranted.
TTR-FAP ITALIAN REGISTRY: A COLLABORATIVE NETWORK FOR DEFINITION OF NATURAL
HISTORY, PSYCHOSOCIAL BURDEN, STANDARDS OF CARE AND CLINICAL TRIALS
G. Vita1, G. Merlini2, C. Rapezzi3, L. Magliano4, M. Sabatelli5, M. Grandis6, G. Fabrizi7, D. Pareyson8, L. Santoro9, A.
Mauro10, L. Gentile1, C. Stancanelli11, M. Russo12, A. Mazzeo1; for the Italian TTR-FAP Network
1
Dept. of Clinical and Experimental Medicine, University of Messina (Messina); 2Biotechnology Research Labs, IRCCSFondazione Policlinico S. Matteo (Pavia); 3Dept. of Specialistic, Diagnostic and Experimental Medicine, University of
Bologna (Bologna); 4Dept. of Psycology, Second University of Naples (Napoli); 5Dept. of Geriatrics, Neurosciences and
Orthopedics, Catholic University of the Sacred Heart (Roma); 6DINOGMI, University of Genoa (Genova); 7Dept. of
Neurological and Movement Sciences, University of Verona (Verona); 8Dept. of Clinical Neurosciences, IRCSS-Carlo
Besta Foundation (Milano); 9Dept. of Neurosciences and Reproduction and Odontostomatological Sciences, Federico II
University of Naples (Napoli); 10Istituto Auxologico Italiano, University of Turin (Torino); 11Biomedical Dept. of Internal
and Specialistic Medicine, University of Palermo (Palermo); 12NEMO SUD Clinical Centre, AOU Policlinico (Messina)
Preliminary results indicate that Italy has a peculiar geographical distribution of transthyretin-related familial amyloid
polyneuropathy (TTR-FAP) with less than one-fourth of the patients carrying the common Met30 mutation and endemic
foci of other mutations especially in Southern Italy. Moreover, there is conflicting evidence from the literature about interpag. 109
and intramutation variability, and very few data on longitudinal changes and psychosocial burden. The objective of this
multicenter study is to create a web-based TTR-FAP National Registry with collection of clinical information and
assessment of clinical scales. Moreover, it will provide answers to important issues including epidemiology, disease course,
longitudinal changes in motor outcome measures (OM), genotype-phenotype correlations, psychosocial burden, and
professional support. Furthermore, the study is also aiming to validate the 6-minute walk test (6MWT) to be used as a novel
OM in TTR-FAP, and to facilitate feasibility and planning of future clinical trials. Patients are enrolled to the Registry and
the following data are recorded at baseline and after 6 and 12 months: FAP stage, CADT (Compound Autonomic
Dysfunction Test), Kumamoto scale, Postural Hypotension Test, NIS (Neuropathy Impairment Score) and its subscale NISLL (NIS-Lower Limbs), CMTNS and CMTES (CMT Neuropathy Score and CMT Examination Score), 6MWT (6-minute
walk test), modified Body Mass Index, Rasch-built Overall Disability Scale, Norfolk Quality of Life-Diabetic Neuropathy.
Heart examination is performed at baseline and after 12 months by assessment of blood NT-proBNP (N-terminal prohormone brain natriuretic peptide) and troponins, ECG, echocardiography, cardiac MR and Technetium-99 mdiphosphonate scintigraphy. Finally, FPQ (Family Problems Questionnaire), FPQ-P (FPQ-Patient version) and SNQ (Social
Network Questionnaire) are administered to assess psychosocial burden and professional support. We have tested 20
patients according to different disease stage with 6MWT. Validity and reliability have been analysed by comparison with
CADT, Kumamoto scale, NIS-LL and CMTES. According to the patients population followed by different centers,we aim
at enrolling to the Registry almost 300 patients and approximately 100 asymptomatic TTR gene mutation carriers. A call
will be diffused to all Italian neurologists, through the Italian Society of Neurology: i) asking to send genetically diagnosed
patients to the nearest centre belonging to the Network; ii) to highlight the neurologists about red flags, so that they can
refer suspected patients for diagnosis. Funded by a Telethon-UILDM grant (GUP15010).
CHARCOT-MARIE-TOOTH TYPE 2 AND DISTAL HEREDITARY MOTOR NEUROPATHY: CLINICAL,
NEUROPHYSIOLOGICAL AND GENETIC FINDINGS FROM A SINGLE-CENTRE EXPERIENCE
A. Romano1, G. Bisogni1, G. Fabrizi2, F. Taioli2, M. Ferrarini2, D. Bernardo1, P. Rossini1, M. Sabatelli1, M. Luigetti1
1
Neurology, Catholic University of the Sacred Heart (Roma); 2Neurology, University of Verona (Verona)
Introduction: Charcot-Marie-Tooth (CMT) disease is a group of clinically and genetically heterogeneous motor and sensory
neuropathies classically divided into demyelinating (CMT1) and axonal forms (CMT2). Distal hereditary motor neuropathy
(dHMN) is a motor neuronopathy which resembles CMT, but lacks a significant clinical or neurophysiologic sensory
involvement. Final genetic diagnosis is poor in CMT2 and in dHMN when compared with CMT1.
Patients and Methods: We report clinical, neurophysiological and genetic findings from 45 patients with CMT2 or dHMN
observed over a 20-year period.
Results: Patients were divided into three phenotypes based on clinical and neurophysiological examination: CMT2 patients
showed progressive distal muscular atrophy and weakness associated with distal sensory loss; dHMN patients presented
progressive distal muscular atrophy and weakness lacking significant clinical or neurophysiologic sensory involvement;
CMT2/dHMN patients showed a predominantly motor impairment with slight neurophysiological sensory involvement.
Twenty-seven patients were apparently sporadic cases, while eighteen patients had a family history. Neurological
examination revealed absent ankle reflexes in 36 patients, normal in 3 and brisk in 6. Knee tendon reflexes were absent in
28 patients, normal in 5 and brisk in 12. In upper limbs, reflexes were absent in 28 patients, normal in 5 and brisk in 12.
Babinski sign was detectable in 7 patients. All patients exhibited tibio-peroneal muscular weakness and atrophy. In upper
limbs, distal weakness and wasting were observed in 21 patients; in 3 patients upper limbs weakness and atrophy were
confined to thenar muscles. Final diagnosis was achieved in 16 index patients with a success rate (41%) comparable to
previous reports: 6 mutations in MFN2, 4 mutations in HSPB1, 2 mutations in BSCL2, 3 mutations in GJB1, 1 mutation in
MPZ. Four mutations were novel, while the others have been already described. Our results confirm the high frequency of
MFN2 mutation in CMT2. 3 out of 4 patients harboring HSPB1 mutations had a CMT2/dHMN phenotype, confirming that
dHMN and CMT2 phenotypes may overlap, while the remaining patient exhibited a classic dHMN. All patients harboring
BSCL2 mutations disclosed pyramidal signs, and 3 out of 4 classically showed thenar muscles atrophy. We rarely detected
mutations in GJB1 and MPZ and failed to find GDAP1 mutations, that have been frequently associated with CMT2 in
Southern Italy population.
Conclusions: Since next-generation sequencing won't be easy to access, epidemiological data and clinical “phenotyping”
remain the best strategy for clinicians to reach a correct genetic diagnosis in CMT2 and dHMN patients.
References:
− Luigetti M, Fabrizi GM, Bisogni G, Romano A, Taioli F, Sabatelli M et al. Charcot-Marie-Tooth type 2 and distal
hereditary motor neuropathy: Clinical, neurophysiological and genetic findings from a single-centre experience.
pag. 110
−
−
Clin Neurol Neurosurg. (2016);144:67–71
Capponi S, Geroldi A, Fossa P, Grandis M, Ciotti P, Gulli R, Schenone A, Mandich P, Bellone E. HSPB1 and
HSPB8 in inherited neuropathies: study of an Italian cohort of dHMN and CMT2 patients. J. Peripher. Nerv. Syst.
(2011);16:287–294
Manganelli F, Tozza S, Pisciotta C, Bellone E, Iodice R, Nolano M, Geroldi A, Capponi S, Mandich P, Santoro L.
Charcot-Marie-Tooth disease: frequency of genetic subtypes in a Southern Italy population. J. Peripher. Nerv. Syst.
(2014);19:292–298
MUSCLE MRI IN BECKER MUSCULAR DYSTROPHY AND CORRELATION WITH DMD MUTATIONS AND
OUTCOME MEASURES
A. Barp1, L. Bello1, P. Campadello1, C. Semplicini1, G. Soraru'1, L. Caumo1, R. Zanato2, P. Ortolan2, R. Stramare2, E.
Pegoraro1
1
Department of Neuroscience DNS, University of Padua (Padova); 2Department of Medicine DIMED, University of Padua
(Padova)
Objective: To find a specific pattern of muscular involvement (fatty replacement and edematous involvement) on muscle
Magnetic Resonance (MRI), in patients with Becker Muscular Dystrophy (BMD), and to evaluate any correlations of
muscle MRI imaging with DMD mutations and the main outcome measures, North Star Ambulatory Assessment (NSAA)
and
6
minute
walk
test
(6MWT);
Materials and Methods: 55 molecularly confirmed BMD patients (aged 7-69 yrs) were evaluated at baseline with MRI to
ascertain the degree of fat infiltration at the lower limbs (T1W sequences) according to the Mercuri scale, and edema score
(STIR sequence); all patients were evaluated with functional scales (NSAA and 6MWT) at baseline (T0), and subsequently
after one year (T1).
Results: Fat infiltration and edema mainly affect specific muscle groups, in particular gluteus maximus (32/55), vastus
lateralis (36/55), biceps femoris (39/54) and gastrocnemius medialis (39/55). Severity of muscle involvement was
significantly correlated with DMD mutation: patients with single deletion of exon 48 or with deletions including exon 51
showed a milder muscular involvement at MRI when compared with other deletions or mutation classes. NSAA and 6MWT
are strongly correlates with MRI muscular involvement at baseline (p<0.001). Vastus lateralis fat infiltration scores
correlate significantly at baseline with 6MWT (rho = -0.61, p<0.001) and NSAA (rho = -0.91, p<0.001) and predict
functional changes after 1 year (6MWT rho = -0.42, p = 0.004, NSAA rho = -0.67, p<0.001). These findings were
confirmed also in biceps femoris and gastrocnemius medialis.
Discussion: muscle MRI in patients with Becker Muscular Dystrophy has a distinct pattern of involvement, in particular
quadriceps, gluteus maximus, biceps femoris and gastrocnemius appeared mainly affected. The severity of involvement is
milder in BMD patients with single deletion of exon 48 or with deletions bordering the exon 51. BMD patients with a
severe muscular involvement on muscle MRI at baseline seem to have a more rapid progression of the disease, evaluated
with NSAA and 6MWT.
Conclusions: Severity of muscular involvement at muscle MRI is strongly correlated to specific DMD mutations and with
clinically meaningful outcome measures. Muscle MRI seems also predictive of disease progression.
References:
− Monforte M, Mercuri E, Laschena F, Ricci E, Tasca G. Calf muscle involvement in Becker muscular dystrophy:
when size does not matter. J Neurol Sci. (2014) Dec 15;347(1-2):301-4
− Tasca G, Iannaccone E, Monforte M, Masciullo M, Bianco F, Laschena F, Ottaviani P, Pelliccioni M, Pane M,
Mercuri E, Ricci E. Muscle MRI in Becker muscular dystrophy. Neuromuscul Disord. (2012) Oct 1;22 Suppl
2:S100-6
VOXEL-WISE ANALYSES REVEALED WHITE MATTER MICROSTRUCTURAL DAMAGE IN PATIENTS
WITH DM1: A TRACTOGRAPHY STUDY
L. Serra1, G. Bechi Gabrielli1, E. Carapelle2, A. Petrucci3, G. Silvestri4, B. Spanò1, G. Meola5, M. Cercignani6, M. Bozzali1
1
Neuroimaging Laboratory, Santa Lucia Foundation IRCCS (Roma); 2Clinic of Nervous System Diseases, University of
Foggia (Foggia); 3UOC Neurologia e Neurofisiopatologia, AO San Camillo Forlanini (Roma); 4Institute of Neurology,
Catholic University of Sacred Heart (Roma); 5Department of Neurology, IRCCS Policlinico San Donato, University of
Milan (Milano) 6Clinical Imaging Sciences Centre, University of Sussex (Brighton, UK)
pag. 111
Aims: Myotonic dystrophy type-1 is the most common muscular dystrophy in the adulthood [1], grey and white matter
damages have been shown [2-3]. A only one previous study showed microstructural changes in the corpus callosum in DM1
patients [2]. Aim of the present study is to investigate microstructural damage in a large number of the white matter tracts
and their association with clinical and cognitive patients’ characteristics.
Method: 29 DM1 patients and 30 healthy subjects (HS) were recruited. All participants underwent an extensive
neuropsychological assessment and 3T MRI acquisition protocol including diffusion sequences used for probabilistic
tractography analysis. We reconstructed individually several tracts: CorticoSpinal tracts (CST), Frontal Aslant Tract (FAT),
Inferior Frontoccipital Facsiculus (IFOF), Inferior Longitudinal Fasciculus (ILF), Superior Longitudinal Fasciculus (SLF),
inferior and superior Cingulum (iCi and sCi), bilaterally and corpus callosum (CC). We assessed their microstructural
integrity by both mean fractional anisotropy (FA) value and by voxel-by-voxel analysis using SPM-8. Then, we used mean
FA values for correlations with genetic, clinical and cognitive measures in patients only.
Results: There were no differences in demographic variables between the two groups. Both analysis on mean FA and voxelwise analyses revealed that patients with DM1 showed significantly decreased FA in all white matter tracts respect to HS.
Moreover, in DM1 patients we found significant correlations between voxel by voxel FA of several tracts and genetics,
clinical and cognitive characteristics.
Conclusions: This study showed that microstructural damage involves all major tracts in DM1 brains and that these
abnormalities were directly linked with patients’ genetic load. Moreover tracts’ damage may contribute to the cognitive
disabilities observed in patients with DM1.
References:
1. G. Meola, R. Cardani, “Myotonic dystrophies: An update on clinical aspects, genetic, pathology, and molecular
pathomechanisms”. Biochimca et Biophysica Acta (2015);1852:594-606
2. Serra L, Petrucci A, Spanò B, Torso M, Olivito G, Lispi L, Costanzi-Porrini S, Giulietti G, Koch G, Giacanelli M,
Caltagirone C, Cercignani M, Bozzali M. How genetics affects the brain to produce higher-level dysfunctions in
myotonic dystrophy type 1. Funct Neurol. (2015) Jan-Mar;30(1):21-31
3. Ota M, Sato N, Ohya Y, Aoki Y, Mizukami K, Mori T, Asada T. Relationship between diffusion tensor imaging
and brain morphology in patients with myotonic dystrophy. Neurosci Lett. (2006) Oct 30;407(3):234-9
LONG-TERM FOLLOW-UP AND IgG ANTI rh-GAA ASSESSMENT IN LATE-ONSET POMPE DISEASE
A. Todeschini, I. Volonghi, S. Rota, A. Galvagni, S. Damioli, A. Padovani, M. Filosto
Clinical Neurology, Section for Neuromuscular Diseases and Neuropathies, University Hospital “Spedali Civili” (Brescia)
Objectives: Late-onset Pompe disease (LOPD) is an autosomal recessive metabolic disorder due to deficiency of the
lysosomal acid alpha-glucosidase enzyme. On 2006 the US Food and Drug Administration approved alglucosidase alfa
(rhGAA; biologically active recombinant human alglucosidase alfa produced in Chinese Hamster Ovary cells) as an enzyme
replacement therapy for Pompe Disease. Long-term efficacy of enzyme replacement therapy (ERT) in LOPD has been
evaluated only in a limited number of patients and the role of IgG anti rh-GAA antibodies in modulating efficacy of
treatment is still unknown. The aims of this retrospective cohort study are to investigate: 1) the long term effects of ERT in
a cohort of LOPD patients; 2) the role of anti rh-GAA antibodies on clinical outcomes and response to ERT.
Materials and Methods: We report clinical and functional findings from 9 LOPD patients treated with ERT for a time
ranging between 3 and 9.5 years. Serial measurements of IgG anti rh-GAA antibodies were performed in 7 of them.
Results: At the end of observation, respiratory function tests improved or were stable in 66% of cases; the walked distance
at 6MWT improved in 88% of the patients up to 24 months, while in the subsequent follow-up (up to 108 months), 63% of
them slowly reduced the walked meters. Overall, in 71% of the patients (5/7) we observed a correlation between antibody
titer (AT) and clinical conditions. Particularly, in 42% of the patients (3/7), worsening of clinical conditions correlated with
increase in AT over time. In 15% of them (1/7), stability of clinical conditions was associated with stable AT and in another
15% (1/7) a reduction in AT was associated with clinical improvement. Only in 28% of the cases (2/7), clinical conditions
remain stable despite the increase of AT over time.
Discussion: Our results confirm ERT long-term effectiveness, though it appears to be reduced over time compared to the
first two years of therapy. A correlation between functional deterioration and production of anti rh-GAA antibodies seems
to be present in most patients but these findings need to be confirmed in multiple patient cohorts.
pag. 112
25/10/2016
EPILESSIA
ANALYSIS OF FACIAL ASYMMETRY AND DYSMORPHISM IN EPILEPSY
S. Balestrini1, K. Chinthapalli1, M. Suttie2, P. Hammond2, S. Sisodiya1
1
Institute of Neurology, University College of London (London-UK); 2Nuffield Department of Obstetrics & Gynaecology,
University of Oxford (Oxford-UK)
Objectives: There is variable clinical expressivity in each specific form of epilepsy and this represents a major issue in
epilepsy classification and clinical management. Genotype–phenotype correlations are very helpful to understand the origin
and the mechanisms underlying the spectrum of clinical variability in epilepsy. In the current study, we use novel
phenotyping, 3D stereophotogrammetry and dense surface models, to evaluate facial asymmetry and dysmorphism in
people with focal epilepsies aiming to generate new tools to explore genetic contribution to these epilepsies.
Material and methods: We consecutively recruited 859 people with epilepsy attending the epilepsy clinic at the National
Hospital for Neurology and Neurosurgery, London (UK). We classified the epilepsy diagnosis, according to the ILAE
Classification of Epilepsies and Epileptic Syndromes. We built dense surface models (DSMs) for the full face and face
patches including both original faces and mirrored forms. The size of the vector raw difference between DSM
representations of original and mirrored image was used as an estimate of raw facial asymmetry. We also interpreted each
raw difference as a surface in its own right and normalised its mesh point displacements from corresponding points on the
mean surface differences of age-sex matched individuals from 205 healthy controls to produce an asymmetry signature. The
size of the signature vector was computed as an estimate of normalised facial asymmetry.
Results: Cases with focal cryptogenic and idiopathic generalised epilepsy showed more raw asymmetry compared to
controls (p=0.018 and p=0.014, two-sample t-test, respectively). There was no significant difference between focal
symptomatic cases and controls. The opposite pattern was observed when considering the normalised asymmetry measure:
no difference emerged when comparing focal cryptogenic or idiopathic generalised epilepsy cases with controls, whilst
cases with focal symptomatic epilepsy associated with unilateral lesions showed higher normalised asymmetry than controls
(p<0.001, two-sample t-test).
Discussion: Facial structure development is driven by complex molecular interactions between surface ectoderm and
underlying forebrain and neural crest cells. The increased level of raw facial asymmetry in cases with focal cryptogenic and
idiopathic generalised epilepsy might be explained by a potential genetic cause, with underlying common genetic pathways
between
face
and
brain
development.
Conclusions: 3D stereophotogrammetry and dense surface models could represent a powerful novel phenotyping process
that will permit greater understanding of genetic data, improved discrimination between pathogenic and non-pathogenic
variation, and further insight on genetics of facial and neural development.
THE PATHOGENIC ROLE OF OCCULT ENCEPHALO-MENINGOCELE IN TEMPORAL LOBE EPILEPSY
SUPPORTED BY THE FIRST CASE-CONTROL STUDY
M. Ascoli1, G. Pustorino2, E. Ferlazzo2, S. Calabrò2, S. Gasparini2, C. Sueri3, V. Cianci3, E. Africa4, P. Versace4, A.
Gangemi4, A. Porcelli4, M. Campello5, L. Arcudi6, U. Aguglia2
1
CRE, Magna Graecia University (Catanzaro); 2Department of Medical and Surgical Sciences, Magna Græcia University
(Catanzaro); 3Regional Epilepsy Centre, Azienda Bianchi-Melacrino-Morelli Hospital (Reggio Calabria); 4Neuroradiology
Unit, Azienda Bianchi-Melacrino-Morelli Hospital (Reggio Calabria); 5Neurosurgery Unit, Azienda Bianchi-MelacrinoMorelli Hospital (Reggio Calabria); 6Stroke Unit, Azienda Bianchi-Melacrino-Morelli Hospital (Reggio Calabria)
Introduction: Bone defects of the skull base in middle cranial fossa may lead to temporal encephalo-meningocele (1). The
prevalence of this condition in general population and in patients with temporal lobe epilepsy (TLE) is unknown, while its
role in the pathogenesis of TLE is still debated (1-3). The aim of this case-control study is to evaluate the pathogenic role of
occult encephalo-meningocele in cryptogenic TLE.
Materials and method: We included 96 patients with TLE (44 males, mean age 49.5 + 17 years) and 96 controls (43 males,
mean age 57.8 + 21.28 years: 45 with stroke, 40 with headache, 11 with multiple sclerosis). A 1.5T brain MRI targeted to
highlight herniation of cerebral parenchyma and dura mater through the bony skull defect was performed in all subjects.
pag. 113
Patients with encephalo-meningocele at MRI underwent a thin layer (0.6 mm thickness) spiral CT of the skull to detect bone
cranial defects in middle cranial fossa. In order to evaluate differences between groups, Chi-squared test was performed.
Results: Bone defects of the skull base were significantly more frequent (p=0.014) in TLE patients (7/96) rather than
controls (0/96). Seven of TLE patients had skull bone defects (4 had encephalo-meningocele, 3 meningocele only). Two out
of four patients with encephalo-meningocele were drug-resistant and became seizure-free after lesionectomy (follow-up 3090 months).
Conclusions and discussion: Data suggests a significant association between bone defects of the skull base in middle cranial
fossa and TLE. Patients with drug-resistant TLE are seizure-free after simple lesionectomy.
References:
− Saavalainen T, et al. Temporal anteroinferiorencephalocele Neurology (2015);85:1467-1474
− Gasparini S, et al. Refractory epilepsy and encephalocele: lesionectomy or tailored surgery? Seizure
(2014);23:583-4
− Giulioni M, et al. Tailored surgery for drug-resistant epilepsy due to temporal pole encephalocele
andmicrodysgenesis. Seizure (2014); 23:164-6
PRE-SEIZURE ARCHITECTURE OF THE LOCAL CONNECTIONS OF THE EPILEPTIC FOCUS EXAMINED
VIA GRAPH-THEORY
F. Vecchio1, F. Miraglia1, C. Vollono2, F. Fuggetta3, P. Baramanti4, B. Cioni5, P. Rossini2
1
Brain Connectivity Laboratory, IRCCS San Raffaele Pisana (Roma); 2Institute of Neurology, Dept. Geriatrics,
Neuroscience & Orthopedics, Catholic University, Policlinic A. Gemelli (Roma); 3Institute of Neurosurgery, Dept Surgery
of Head and Neck, Catholic University, Policlinic A. Gemelli (Roma); 4Neurology, IRCCS Centro Neurolesi Bonino-Pulejo
(Messina); 5Institute of Neurosurgery, Dept Surgery of Head and Neck, Catholic University, Policlinic A. Gemelli (Roma)
Objective: Epilepsy is a neurological disorder characterized by sudden and unpredictable occurrence of paroxysmal
neuronal firing and sometimes evolving in clinically evident seizure. To predict seizure event, small-world characteristic in
nine minutes before seizure, divided in three 3-minutes periods (T0, T1, T2) were investigated.
Materials and Method: Intracerebral recordings were obtained from 10 patients with drug resistant focal epilepsy examined
by means of stereotactically implanted electrodes; analysis was focused in a period of low spiking (Baseline) and during
two seizures for each subject. Weighted and undirected networks were built. Network vertices are electrodes’ contacts close
to epileptic focus, edges are weighted by mscohere (=magnitude squared coherence).
Results: Differences were observed between Baseline and T1 and between Baseline and T2 in Theta band; and between
Baseline and T1, Baseline and T2, and near-significant difference between T0 and T2 in Alpha 2 band. Moreover, an intraband index was computed for small worldness as difference between Theta and Alpha 2. It was found a growing index trend
from
Baseline
to
T2.
Discussion: Cortical network features a specific pre-seizure architecture which could predict the incoming epileptic seizure.
Conclusions: This study opens interesting avenues for future researches investigating brain connectivity modifications
approximating a clinical seizure also in order to address a preventive therapy.
BRAIN TUMOR LOCATION INFLUENCES THE ONSET OF ACUTE PSYCHIATRIC ADVERSE EVENTS OF
LEVETIRACETAM THERAPY. AN OBSERVATIONAL STUDY
L. R. Pisani1, V. Belcastro2, S. Bellocchi3, P. Casiraghi3, G. Gorgone4, S. Marino5, P. Bramanti6, M. Mula7, F. Pisani8
1
IRCCS Centro Neurolesi "Bonino Pulejo " (Messina); 2Neurology Unit, Department of Neurosciences, S. Anna Hospital
(Como); 3Neurosurgery Unit ASST Lariana Sant'Anna Hospital of Como (Como); 4Neurology Unit, S. Giovanni di Dio
Hospital (Crotone); 5Department of Biomedical Sciences and Morphological and Functional Imaging, Univarsità degli studi
di Messina (Messina); 6Scientific Direction, IRCCS Centro Neurolesi Bonino Pulejo (Messina); 7Atkinson Morley Regional
Neuroscience, Centre St George’s Institute of Medical and Biomedical Sciences, Centre St George’s University Hospitals,
NHS Foundation Trust and St George’s University of London (London, UK); 8Dpt of Experimental and Clinical Medicine,
University of Messina (Messina)
Aim: The present retrospective study has explored possible correlations among brain lesion location, onset of psychiatric
disorders and the use of antiepileptic drug (AEDs) in a population of patients with brain tumor and epilepsy.
Materials: This study examined clinical, radiological, pathological, and follow-up data of pts who underwent surgical
pag. 114
evaluation of a brain tumor at the Department of Neurosciences of S. Anna Hospital, Como, between January 2008 and
December 2015.The medical records of 283 patients with various types of brain tumor (127M/158F, mean age +- SD:
61,4+14.4 years) were analysed. Patients with grade III and IV of glioma , previous history of psychiatric disorders and of
epileptic seizures were excluded. For this study we evaluated only patients with "low grade" brain tumors and solid intraaxial tumors without inflitration of brain parenchyma , scheduled for surgery or already operated and/or treated with
radiotherapy and/or chemotherapy.
Methods: Psychiatric manifestations were classified according to the Diagnostic and Statistical Manual of Mental Disorders
(DSM-IV). Psychiatric manifestations occurring after initiation of AED therapy were considered as AED-related-psychiatric
adverse events (PAE) in these conditions: i) onset within 4 weeks after the beginning of AED therapy; ii) disappearance on
drug discontinuation; iii) absence of any other identified possible concurrent cause. The possible influence of the following
variables were taken into consideration: a) location of EEG epileptic abnormalities, b) location and neuroradiologic features
of the tumor, d) family history of psychiatric disorders, e) AED drug dose and regimen; f) tumor excision already or not yet
performed.
Results: Unvariate analysis shows a significant association of PAE occurance with location of the tumor in the frontal lobe
and treatment with levetiracetam. It can be hypothesized that LEV interfere with specific frontal circuits, possibly already
damaged by the tumor, contributing to reduce further the activity of frontal lobe and to trigger acute PAE. PAE rapidly
disappeared after LEV discontinuation. Discussion: The main finding of this study is that only patients on LEV therapy with
a frontal location of a brain tumor are at risk to develop PAE, suggesting that other features, apart from a given specific
profile of patient, may be relevant in the development of treatment-emergent PAE (1-3).
Conclusions: The results of the present study suggest that an AED alternative to levetiracetam should be chosen to treat
epileptic seizures in patients with a brain tumor located in the frontal lobe to minimize the possible onset of PAE.
References:
1. Mula M, Trimble MR, Yuen A, Liu RS, Sander JW. Psychiatric adverse events during levetiracetam therapy.
Neurology (2003);61(5):704-6
2. Mula M, Agrawal N, Mustafa Z, Mohanalingham K, Cock HR, Lozsadi DA, von Oertzen TJ. Self-reported
aggressiveness during treatment with levetiracetam correlates with depression. Epilepsy Behav. (2015);45:64-7
3. Van Breemen MS, \Wilms EB, Vecht CJ. Epilepsy in patients with brain tumours: epidemiology, mechanisms, and
management. Lancet Neurol. (2007);6(5):421-30
CLINICAL SEMIOLOGY AND SEIZURE SPREAD PATTERNS OF BASAL-FRONTAL SEIZURES
C. Luisi1, L. Minotti2, P. Kahane2
1
Neurology Clinic, University of Bari (Bari); 2Neurology Department, Albert Michallon University Hospital (Grenoble- F)
Purpose: Well documented cases of orbitofrontal (OF) seizures are rare. In the 24 cases reported in literature, the main
clinical signs included loss of consciousness, autonomic changes and motor manifestations (versive, automotor, hypermotor
and secondary tonic-clonic generalization) (1-3). Here we report six additional cases, in whom seizure semiology was
studied according to SEEG spread patterns.
Method: Among the patients suffering from drug-resistant focal epilepsy operated from 2004 to 2015 in our center, six (6
M) showed an ictal onset zone localized in orbitofrontal cortex (OFC). General characteristics: age at surgery 31.5 years
(13-57); duration of epilepsy 11 years (4-20); MRI: positive in 4 cases (all OF), negative in 2. Interictal and ictal scalp EEG
abnormalities involved the fronto-central (n=1), the fronto-temporal (n=4), or the temporal regions (n=1). SEEG were
unilateral in all but 1 case, centered over the fronto-insulo-temporal regions. Resection was restricted to OFC in 4 cases, and
included the anterior insula (AI) in 2. All patients were seizure-free post-operatively with a follow-up of 3.9 years (0.5-12).
Results: Four main patterns were identified: (1) localized OFC discharges, that were clinically silent; (2) OFC onset
spreading to motor cortex, which consisted in cephalic sensation followed by unresponsiveness, gestural automatisms, head
version and STCG; (3) OFC onset spreading to fronto-mesial cortex, characterized by epigastric or dream sensation,
hypermotor behaviour, grasping, pouting and urination; (4) OFC onset spreading to temporal lobe (4a: mesial; 4b:
neocortical), characterized either by an epigastric/thoracic oppression and breathlesness (4a), or laughing behaviour,
oroalimentary automatisms, and dystonic posturing without aura (4b). Seizure duration was 10-20” in pattern 1-3 and longer
in the others. Discharges were initially clinically silent from 4” to 28”, and heart rate changes were detected in all cases.
Early involvement of AI and anterior cingulate gyrus (ACG), and spread to temporal neocortex and pole were observed in
patterns 2-3-4.
Conclusion: OFC is a polymodal multiconnected region, as suggested by studies of connectivity in animals and humans (1).
Four spread patterns were identified, related to different clinical manifestations. Seizure semiology can be clinically silent if
pag. 115
the discharge is confined to OFC. Early involvement of AI and ACG suggests their key role in the anatomo-functional
network connecting OFC to fronto-temporal structures.
References:
1. AV Alexopoulos and N Tandon, Basal frontal lobe epilepsy, Texbook of Epilepsy Surgery (2008); 37:287-313
2. M. F. Kriegel, D. W. Roberts and B. C. Jobst, Orbitofrontal and Insular Epilepsy, Journal of Clinical
Neurophysiology (2012);29(5):385-391
3. C. Munari and J. Bancaud, Electroclinical Symptomatology of Partial Seizures of Orbital Frontal Origin, Advances
in Neurology (1992);57:257-265
“WHEN SEIZURES LEAVE YOU SPEECHLESS”: PROPOSAL FOR A PROTOCOL FOR ICTAL LANGUAGE
EVALUATION
L. Ferri1, F. Bisulli2, L. Alvisi2, M. Fabbri3, S. Boscarato3, V. Menghi1, B. Mostacci2, L. Licchetta2, C. Stipa1, L. di Vito1, C.
Leta1, P. Tinuper2
1
Department of Biomedical and NeuroMotor Sciences, University of Bologna (Bologna); 2Department of Biomedical and
NeuroMotor Sciences; IRCCS Istituto delle Scienze Neurologiche Bologna, University of Bologna (Bologna); 3Alma Mater
Studiorum, University of Bologna (Bologna)
Objective: The language evaluation during an epileptic seizure is crucial to determine if a patient is a good candidate for
epilepsy surgery. To date, no validated protocols exist in the literature, but only anecdotic case reports with a precise
syndromic characterization of language deficit and poor description of examination methods. Moreover, language
assessment during seizures changes depending on the centre, on the examiner and her/his specific training. In this light, we
decided to develop a standardized protocol for the evaluation of language deficit during epileptic seizures.
Materials: A neurophysiology technician reviewed all video-EEG recordings from 1987 to 2015 and selected those in which
an apparent language impairment was present.
Methods: A multidisciplinary team (neurologists, speech therapists, neurophysiology technicians) reviewed the ictal
semiology of selected video-EEG recordings and excluded those in which consciousness was compromised, that were not
tested or had poor audio/video quality. If a patient had more than one seizure, we picked up the most informative one.
Subsequently, the speech therapists tried to characterize the language deficit, following the Boston classification system,
and to underline the critical issue in the ictal language evaluation.
Results: From the original pool of 276 seizures, we selected 20 seizures for 20 patients (12 F, mean age 37.7, 18 righthanded). In 8/20 patients the ictal examination was adequate to characterize the language deficit, in 4 patients it was
possible to draw only partial conclusions, while in the remaining patients the amount of information was not sufficient to
characterize the deficit. The speech analysis revealed critical points related to the nature of the seizure and to the methods of
examination. Following these critical issues, we created a standardized protocol for the evaluation of language deficit during
epileptic seizures, consisting in language testing in hierarchical sequence.
Discussion: The presence of ictal aphasia at onset could be a major criterion of exclusion from the surgical approach, it is
therefore imperative to correctly classify language deficits. The shortness and paroxysmal nature of seizure, the need to test
multiple skills and the lack of education in language deficit could limit the evaluation of language. We believe that a
standardized protocol could be a useful tool to characterize the language impairment.
Conclusion: To our knowledge, this is the first study to propose a standardized protocol for the evaluation of ictal language.
It is currently underway a validation study to figure out the usefulness of the protocol.
References:
− Benatar M. Ictal aphasia Epilepsy & Behavior (2002);3(5):413-9
− Gallo M.A. Logopedia dell'afasia (2012) ed. Cleup, Padova
− Commissione LICE per la Chirurgia dell'Epilessia Percorsi diagnostico terapeutici in chirurgia dell'epilessia (2009)
EPILEPSY IN HEMIPLEGIC
IMPLICATIONS
MIGRAINE:
NEW
GENETIC
FINDINGS
AND
THEIR
CLINICAL
C. Costa1, P. Prontera2, P. Sarchielli1, S. Caproni1, C. Bedetti1, M. Romoli1, L. Cupini3, P. Calabresi1
1
Department of Medicine, Section of Neurology, S. Maria della Misericordia Hospital, University of Perugia (Perugia);
Medical Genetics Unit, Department of Surgical and Biomedical Sciences, University of Perugia, Hospital "S. M. della
Misericordia" Perugia); 3Headache and Cerebrovascular Diseases Center, Ospedale S. Eugenio (Roma)
2
pag. 116
Objective: We performed a systematic review on the comorbidities of familial and sporadic hemiplegic migraine (F/SHM),
as well as seizure/epilepsy in patients with CACNA1A, ATP1A2 or SCN1A mutations. Our aim was to identify the
genotypes associated with seizure/epilepsy and to establish the presence of mutational hot spots, in order to predict their
clinical effects. This information could reduce the existing gap of knowledge regarding the genetic background linking
migraine and epilepsy.
Materials and Methods: We followed PRISMA 2009 guidelines for systematic review. A search in MEDLINE from
September 1993 to January 2015, was performed covering the time from the identification of the first HM gene. We also
searched in both the Human Gene Mutation and Leiden Open Variation Databases for mutations in the CACNA1A,
ATP1A2 and SCN1A genes and their related phenotypes. After having examined the clinical characteristics of the patients,
we selected those having seizures, febrile seizures or epilepsy. For each gene, we determined both the frequency and the
positions at protein levels of these mutations, as well as the penetrance of epilepsy within families.
Results: From this review, we were able to establish that in HM, the relative number of mutations associated with
seizure/epilepsy was elevated not only for SCN1A (60%) and ATP1A2 genes (40,9%), but also for the CACNA1A gene
(35%), where the penetrance of epilepsy for the latter had the highest value (61%). Concerning F/SHM-Epilepsy1
(F/SHME1) and F/SHME2 endophenotypes, we observed a prevalent involvement of the trans-membrane domains, and a
strong genotype-phenotype correlation in F/SHME1 when the positively charged aminaocids were involved. F/SHME1
included mainly sporadic cases (80%), compared to F/SHME2 (64%) which had many familial cases. Whereas the few
SCN1A mutations associated with HM and epilepsy (FHME3) all belonged to familial cases. In fact, these genotypephenotype correlations seem to depend on the functional effects of the mutations rather than their positions in the canal
proteins.
Discussion and Conclusions: Among the HM cases with seizure/epilepsy, we observed mutational hot spots in the
transmembrane domains of CACNA1A and ATP1A2 proteins. These findings could lead to a better understanding of the
pathological mechanisms underlying migraine and epilepsy, and therein guaranteeing the most appropriate therapeutic
approach.
TOWARDS NEW STANDARDS FOR INTERICTAL MEG SOURCE IMAGING: COMPARISON BETWEEN
DIPOLE FITTING (ECD) AND DISTRIBUTED SOURCE IMAGING USING COHERENT MAXIMUM
ENTROPY ON THE MEAN (CMEM)
G. Pellegrino1, T. Hedrich2, J. Hall3, F. Dubeau4, E. Kobayashi4, C. Grova2
1
Montreal Neurological Institute, McGill University (Montreal-CDN); 2Biomedical Eng. Department, McGill University
(Montreal-CDN); 3Neurosurgery, Montreal Neurological Institute (Montreal-CDN); 4Epilepsy, Montreal Neurological
Institute (Montreal-CDN)
Objective: MEG source imaging of interictal spikes is clinically useful in the presurgical workup of epilepsy patients, as it
can improve the positioning of invasive EEG electrodes or even guide resection. Current clinical guidelines recommend the
technique of the Equivalent Current Dipole (ECD) as inverse solution and highlight that other methods are not widely
accepted for clinical purposes (Bagic, 2011). Nonetheless, distributed source imaging has gained popularity in the last
twenty years, because it overcomes some of the limitations of ECD and provides maps of activations. In this study we
sought to qualitatively and quantitatively compare ECD vs cMEM (coherent Maximum Entropy on the Mean), a distributed
source imaging approach specifically developed to recover the spatial extent of the generators of interictal discharges along
the cortical surface (Grova, 2016; Pellegrino, 2016).
Materials & Methods: 340 MEG source localizations from 49 refractory focal patients with a well-defined epileptic focus
(invasive EEG/MRI lesion/ Surgery) were included. For temporal lobe epilepsy, the focus was usually involving both
mesial and neocortical temporal regions. A qualitative comparison based on the evaluation of sublobar concordance with the
epileptic focus was complemented by a quantitative assessment of: a) actual distance in millimetres between the source and
the epileptic focus; b) intra-subject reproducibility. Multiple head models, all built from individual MRI, were evaluated.
Results: cMEM outperformed or showed a similar performance to ECD for all the investigated measures. cMEM sublobar
concordance was higher than ECD (277/340 vs 235/340, Chi-Square =13.9453, p<0.001), especially in neocortical epilepsy
(neocortical: cMEM 174/206 (84%); ECD 137/206 (67%), Chi-Square 17.96, p<0.001). The actual distance from the focus
was very good for both methods (median<5mm). However it was significantly lower for cMEM than ECD (median of the
difference: 1.31mm, z=4.827, p<0.001), especially for neocortical generators (Neocortical: z=-4.250, p<0.001; Temporal:
z=-2.332, p=0.020). The generators localized by ECD were significantly deeper than cMEM z=2.850, p=0.004). The
intrasubject reproducibility did not differ between the two methods (p>0.100). We also evaluated that the choice of the head
model had no significant impact on the median distance from the focus.
pag. 117
Discussion and conclusion: Compared to standard ECD, distributed source imaging (cMEM) has similar or better accuracy
and the important advantage of producing more realistic maps of the generator and of its cortical extent. Therefore, this
approach should be preferred to ECD and routinely applied in the clinical practice.
Funding: GP is funded by Richard and Edith Strauss Canada Foundation. Study supported by CIHR (MOP-93614), NSERC,
FRQS, CECR.
References:
− Bagic AI, Knowlton RC, Rose DF, Ebersole JS; ACMEGS Clinical Practice Guideline (CPG) Committee.
American Clinical Magnetoencephalography Society Clinical Practice Guideline 1: recording and analysis of
spontaneous cerebral activity. J Clin Neurophysiol. (2011) Aug;28(4):348-54
− Pellegrino G, Hedrich T, Chowdhury R, Hall JA, Lina JM, Dubeau F, Kobayashi E, Grova C. Source localization
of the seizure onset zone from ictal EEG/MEG data. Hum Brain Mapp. (2016) Apr 5. doi: 10.1002/hbm.23191.
− Grova C, Aiguabella M, Zelmann R, Lina JM, Hall JA, Kobayashi E. Intracranial EEG potentials estimated from
MEG sources: A new approach to correlate MEG and iEEG data in epilepsy. Hum Brain Mapp. (2016)
May;37(5):1661-83. doi: 10.1002/hbm.23127.
SCLEROSI MULTIPLA 2
CORTICAL LESION LOAD CORRELATES WITH PERIVENTRICULAR NAWM DAMAGE SEVERITY IN
PPMS
M. Pardini1, L. Fleysher2, C. Farrell3, M. Fabian3, A. Miller3, D. Chard4, F. Lublin3, M. Inglese5
1
DiNOGMI, University of Genoa (Genova); 2Department of Radiology, Icahn School of Medicine at Mount Sinai (New
York, USA); 3Department of Neurology, Icahn School of Medicine at Mount Sinai (New York, USA); 4Department of
Neuroinflammation, UCL Institute of Neurology (London, UK); 5Department of Neurology, Radiology and Neuroscience,
Icahn School of Medicine at Mount Sinai (New York, USA)
Background and Objectives: In subjects with relapse-onset MS it has been recently shown that a more severe periventricular
white matter lesion burden is associated with a more marked thinning of the cortical ribbon, possibly pointing to a common
pathogenetic mechanism between these two facets of MS pathology (1). Starting from this observation, we decided to
explore if in subjects with primary progressive multiple sclerosis (PPMS) cortical lesion load is associated with the severity
of periventricular normal appearing white matter (NAWM) damage, as assessed with diffusion weighted imaging (DWI).
Methods: Twenty-three subjects with PPMS and nineteen healthy controls were included in the study. T1 volumetric,
PD/T2, phase-sensitive inversion recovery (PSIR) and DWI images were acquired at 3T for all subjects. WM lesions were
identified on PD/T2 sequences and were then co-registered to diffusion data. Mean diffusivity (MD) NAWM maps were
created excluding WM lesions and a 2 mm-thick peri-lesional rim. Skeletonized NAWM MD maps were then computed
using the TBSS pipeline. In each skeletonized NAWM MD map those supra-tentorial voxels with a distance from the lateral
ventricles between 2 and 6 mm were included in the periventricular NAWM mask while those voxels of skeletonized WM
with a distance from the lateral ventricles higher than 6 mm were included in the deep NAWM mask. Mean MD values
were computed separately for these two masks for each subject. Lastly, cortical lesions volumes were assessed on PSIR
images.
Results: As expected skeletonized NAWM was abnormal in PPMS compared to HC. In the PPMS group, a significant
correlation was observed between skeletonized periventricular NAWM MD values and cortical lesion load with a greater
cortical lesion burden being associated with more abnormal periventricular NAWM MD. Conversely, there was no
correlation between cortical lesion load and deep NAWM MD values.
Discussion: Our data suggest that a common factor play a role in the development of both cortical lesion and periventricular
NAWM damage in subjects with PPMS. The proximity of cerebrospinal fluid (CSF) to both the cerebral cortex and
periventricular NAWM and the role played by CSF in cortical lesion formation seem to imply that CSF-mediated soluble
are also involved in modulating NAWM damage in PPMS.
Reference:
1. Jehna M, Pirpamer L, Khalil M, Fuchs S, Ropele S, Langkammer C, Pichler A, Stulnig F, Deutschmann H,
Fazekas F, Enzinger C. Periventricular lesions correlate with cortical thinning in multiple sclerosis. Ann Neurol.
(2015) Oct;78(4):530-9
pag. 118
THALAMUS AND CAUDATE DAMAGE AS A MARKER OF NEURODEGENERATION PROGRESSION AND
CLINICAL DISEASE SEVERITY IN PATIENTS WITH MULTIPLE SCLEROSIS
B. Spano'1, G. Giulietti1, M. Cercignani1,2, V. Pisani3, M. Morreale4, U. Nocentini5, A. Francia6, C. Caltagirone7, M.
Bozzali1
1
Neuroimaging Laboratory, IRCSS Santa Lucia Foundation (Roma); 2CISC, Brighton & Sussex Medical School (Brighton,
UK); 3Neurology and Neurorehabilitation Unit, Santa Lucia Foundation IRCCS (Roma); 4Neurovascular Diagnosis Unit,
Department of Medical and Surgical Sciences and Biotechnology, Section of Neurology, Multiple Sclerosis Center,
Department of Neurology and Psychiatry, Sapienza, University of Rome (Roma); 5Neurology and Neurorehabilitation Unit,
Santa Lucia Foundation, IRCCS, Department of Neuroscience, University of Rome "Tor Vergata" (Roma); 6Multiple
Sclerosis Center, Department of Neurology and Psychiatry, Sapienza University of Rome (Roma); 7Department of
Neuroscience, University of Rome "Tor Vergata", Department of Clinical and Behavioural Neurology, Santa Lucia
Foundation, IRCCS (Roma)
Aims: One of the hypotheses put forward to explain the changing course of MS from relapsing-remittingMS to secondaryprogressiveMS, postulates that grey matter pathology(neuronal,axonal-degeneration), is subclinical in the early relapsingremittingMS, but dominates the clinical picture of the secondary-progressiveMS by causing irreversible and progressive
disability. We used NODDI[1] to investigate neurite changes in normal-appearing white(NAWM) and grey(NAGM) matter
of patients with relapsing-remittingMS and secondary-progressiveMS, and whether these changes are correlated with
clinical disease severity scores.In order to discriminate whether NODDIfindings reflect axons and/or neuropil modifications
we combined NODDI with ACM[2], able to map axon's connectivity within the parenchymal brain.
Materials-Methods: 20relapsing-remittingMS and 15secondary-progressiveMS patients and 20age- sex-matched healthycontrols had a3T-MRI, including dual-echo, FLAIR, volumetric, diffusion MRI (dMRI[1]) scans. For patients a total T2lesion mask was created and used to confine the statistical analysis to the parenchyma excluding the lesions. dMRI data
were processed according to the NODDI[1,3] and the ACM[2] protocols to obtain NODDI and ACM maps, respectively.
For both NODDI and ACM separate voxel-wise-analyses were used to assess between-group differences and the
relationship between EDSS and MSFC outcomes and MRImetrics. All statistical analyses were carried out in
SPM8.Statistical threshold was set to p-FWE-cluster-level-corrected<0.05.
Results-Discussions: Compared with HC, secondary-progressiveMS showed widespread loss of neurite integrity (decrease
of density) along with a loss of fibre coherences (increase of dispersion) in both NAWM and NAGM (cortical, subcortical),
while neurite/fibre abnormalities in relapsing-remittingMS were more limited and mainly located within the NAWM.
Similar changes as a those observed compared with healthy-controls were found in secondary-progressiveMS when
compared with relapsing-remittingMS. Those areas also showed significant correlations with clinical scales. Interestingly,
we also found that the orientation-dispersion in the caudate nuclei and thalami was significantly lower in secondaryprogressiveMS than healthy-controls. In the same areas, in patients, orientation-dispersion changes were inversely and
directly correlate with EDSS and MSFC scores, respectively. This result can be due to selective degeneration of a single
axon population, which impacts estimation of dispersion. Supporting this view, a direct comparison between secondaryprogressiveMS and HC returned a pattern of ACM reduction involving thalami and caudate nuclei. Post-Hoc-ThalamusParcellation: In each subject, probabilistictractography was performed to parcellate the thalamus into regions structurally
connected to different cortical areas. Between-group comparisons showed interesting correspondence with NODDI and
ACM results.
Conclusions: Our results confirm the presence of widespread NAGM abnormalities in MS, which are more severe in
secondary-progressiveMS than relapsing-remittingMS, and correlate with clinical disability. The changes occurring in the
caudate and the thalamus may result from selective degeneration of a single axonal population and reflect progressive
GMdegeneration in patients with relapsing-remittingMS and secondary-progressiveMS.
References:
− Zhang H1, Schneider T, Wheeler-Kingshott CA, Alexander DC. NODDI: practical in vivo neurite orientation
dispersion and density imaging of the human brain. Neuroimage (2012);61:1000-1016
− Bozzali M, Spanò B, Parker GJ, Giulietti G, Castelli M, Basile B, Rossi S, Serra L, Magnani G, Nocentini U,
Caltagirone C, Centonze D, Cercignani M. Anatomical brain connectivity can assess cognitive dysfunction in
multiple sclerosis. Mult Scler. (2013);19:1161-8
pag. 119
−
Daducci A, Canales-Rodríguez EJ, Zhang H3, Dyrby TB, Alexander DC3, Thiran JP. Accelerated Microstructure
Imaging via Convex Optimization (AMICO) from diffusion MRI data. Neuroimage (2015);105:32-44
NEUROPSYCHOLOGICAL FEATURES CAN HELP IN PREDICTING DISEASE EVOLUTION IN BENIGN
MULTIPLE SCLEROSIS PATIENTS: A 12- YEAR STUDY
L. Razzolini1, M. L Stromillo2, E. Portaccio1, B. Goretti1, C. Niccolai1, M. Giannini1, L. Pastò1, I. Righini1, B. Hakiki1, M.
Battaglini2, A. Giorgio2, M. L Bartolozzi3, L. Guidi3, N. De Stefano2, M. P Amato1
1
Department NEUROFARBA, Section of Neurosciences, University of Florence (Firenze); 2Department of Neurological
and Behavioral Sciences, University of Siena (Siena); 3Neurology Unit, Hospital of Empoli (Empoli)
Background: In a previous 5-year follow-up study on benign multiple sclerosis (BMS), we found that presence of cognitive
impairment (CI) and higher cortical and subcortical magnetic resonance (MR) brain damage was related to higher risk of
shifting to a no longer benign (NLB) course. Objectives: To assess longer-term role of neuropsychological and MR
parameters in predicting disease evolution in BMS patients.
Methods: At baseline, 46 BMS patients (Expanded Disability Status Scale (EDSS) score<3.0 and disease duration>15
years) underwent neuropsychological assessment through the Rao’s Brief Repeatable Battery and brain MRI quantitative
measurement of T2 and T1 lesion volumes (T2LV and T1LV), total and regional brain volumes and magnetization transfer
ratio (MTr). After a mean follow-up of 12.5+0.4 years, patients still having an EDSS score<3.5 were classified as “still
benign” (SB), whereas patients having an EDSS score>4.0 and/or shifting to a secondary progressive (SP) course were
defined as NLB. Possible prognostic predictors were assessed through a multivariate Cox survival analysis.
Results: At baseline, severe cognitive impairment (CI, failure of > 3 tests) was detected in 13 (28.3%) patients. By the end
of the 12-year follow-up period, 13 patients (28.3%) were classified as NBL. Among these, 7 (15.2%) shifted to an SP
course. Baseline predictors of NLB disease course after 12 years were CI (53.8% vs 15.2% patients, p=0.007), higher T1LV
(10.0+6.3vs 5.7+5.6 cm3, p=0.045) and, marginally, male sex (53.8% vs 24.2% patients, p=0.054). In the multivariate
analysis, CI was the only significant predictor of NLB status (HR=5.2;95%CI 1.7-15.5;p=0.003). Moreover, predictors of
SP status were higher age at baseline (HR=1.2;95%CI 1.1-1.3;p=0.003) and, marginally, T1LV (HR=1.1;95%CI 1.01.3;p=0.075).
Conclusions: These findings highlight the need to include cognitive preservation in the definition of BMS and provide
further long-term evidence for the prognostic role of CI in BMS patients.
ATTENTION AND PROCESSING SPEED PERFORMANCE IN MULTIPLE SCLEROSIS IS MOSTLY
RELATED TO CEREBELLAR AND THALAMIC VOLUME
R. Docimo1, A. Bisecco1, S. Stamenova1, G. Caiazzo2, A. d'Ambrosio1, R. Sacco1, S. Esposito1, M. Cirillo3, F. Esposito4, S.
Bonavita1, G. Tedeschi1, A. Gallo1
1
I Division of Neurology, Department of Medical, Surgical, Neurological, Metabolic and Aging Sciences, Second
University of Naples (Napoli); 2MRI Center “SUN-FISM”, Second University of Naples and Institute of Diagnosis and Care
“Hermitage-Capodimonte” (Napoli); 3Neuroradiology Service, Department of Radiology, Second University of Naples
(Napoli); 4Department of Medicine and Surgery, University of Salerno (Baronissi -SA)
Objective: Cognitive impairment (CI), mainly involving attention and processing speed (A-PS) is a common and disabling
symptom in MS. Among others, Symbol Digit Modalities Test (SDMT) is one of the more sensitive and reliable test to
assess A-PS deficits in MS. Structural MRI correlates of A-PS in MS still need to be clarified. The objective of this study is
to investigate, in a large group of MS patients, by means of Voxel-Based-Morphometry analysis, the relationship between
regional gray matter (GM) atrophy and A-PS.
Methods: 141 MS patients and 67 HC underwent a 3T-MRI protocol including high-resolution 3D-T1 imaging. All subjects
underwent a neurological evaluation and SDMT. VBM analysis was performed to assess: 1) correlations between regional
GM volume and SDMT performance in MS patients; 2) presence of GM atrophy (MS vs HC) in regions showing
correlations. Results are reported at p < 0.01, corrected for multiple comparisons.
Results: A significant negative correlation was found between regional GM volume and SDMT score at the level of the
thalamus, cerebellum, left putamen, and occipital cortex in MS patients. Thalamus and cerebellum also showed significant
GM atrophy in MS patients, compared to HC.
Conclusions: Our study supports the role of thalamus and cerebellum atrophy as the most relevant structural substrates of APS deficits in MS.
pag. 120
TIME MATTERS IN MULTIPLE SCLEROSIS: INTERNATIONAL CONSENSUS RECOMMENDATIONS ON
DIAGNOSIS, MANAGEMENT AND TREATMENT ACCESS
G. Comi, G. Giovannoni, H. Butzkueven, S. Dhib-Jalbut, J. Hobart, G. Kobelt, G. Pepper, M. Sormani, C. Thalheim, A.
Traboulsee, T. Vollmer
1
Department of Neurology, San Raffaele Scientific Institute, Vita-Salute San Raffaele University (Milano); 2Blizard
Institute, Barts and the London School of Medicine and Dentistry, Queen Mary University London (London-UK);
3
Melbourne Brain Centre, Royal Melbourne Hospital, University of Melbourne (Parkville- AUS); 4Department of
Neurology, RUTGERS-Robert Wood Johnson Medical School (New Brunswick-USA); 5Plymouth University Peninsula
Schools of Medicine and Dentistry, Plymouth University (Plymouth-UK); 6President European Health Economics
(Mulhouse-F); 7Co-founder - Shift.ms (Leeds-UK); 8Biostatistics Unit, University of Genoa (Genova); 9Patient advocate
Multiple sclerosis (Brussels-B); 10Department of Medicine, University of British Columbia (Vancouver-CDN);
11
Department of Neurology, University of Colorado Denver (Aurora-USA)
Aims: Disease understanding, diagnostic criteria, treatment options and monitoring procedures in multiple sclerosis (MS)
are rapidly evolving. Here we present international consensus recommendations for improving diagnosis, management and
treatment
access
in
MS.
Materials and methods: Structured discussions and literature searches conducted in 2015 examined the personal and
economic impact of MS, current practice in diagnosis, treatment and management, definitions of disease activity and
barriers
to
accessing
disease-modifying
therapies
(DMTs).
Results and discussion: Delays often occur before a person with symptoms suggestive of MS sees a neurologist. Campaigns
to raise awareness of MS are needed, as are initiatives to improve access to MS healthcare professionals and services. We
recommend a clear treatment goal: to maximize neurological reserve, cognitive function and physical function by reducing
disease activity. Treatment should start early, with DMT and lifestyle measures. All parameters that predict relapses and
disability progression should be included in the definition of disease activity and monitored regularly when practical. On
suboptimal control of disease activity, switching to a DMT with a different mechanism of action should be considered. A
shared decision-making process that embodies dialog and considers all appropriate DMTs should be implemented.
Monitoring data should be recorded formally in registries to generate real-world evidence. In many jurisdictions, access to
DMTs is limited. In the 14 countries examined, the proportion of people with MS receiving a DMT in 2013 was in the range
of 13-69%. To improve treatment access the relevant bodies should consider all costs to all parties when conducting
economic evaluations and encourage the continuing investigation, development and use of cost-effective therapeutic
strategies and alternative financing models.
Conclusions: The consensus findings of an international author group recommend a therapeutic strategy based on proactive
monitoring and shared decision-making in MS. Early diagnosis and improved treatment access are also key components.
INCIDENCE, SEVERITY, DURATION, AND TREATMENT OF CUTANEOUS ADVERSE EVENTS IN THE
DECIDE STUDY OF DACLIZUMAB HYP VERSUS INTRAMUSCULAR INTERFERON BETA-1A IN
PATIENTS WITH RELAPSING-REMITTING MULTIPLE SCLEROSIS
F. Patti1, E. D'Amico1, L. Kircik2, K. Krueger3, F. Hougeir4, A. Friedman5, N. Lucas6, J. Elkin6, P. McCrosker6
1
MS center, Policlinico Gaspare Rodolico, University of Catania (Catania); 2Mount Sinai Hospital (New York – USA); 3The
Rockefeller University (New York- USA); 4Douglas Dermatology and Skin Cancer Specialists (Douglasville - USA);
5
Albert Einstein College of Medicine (New York, - USA); 6Biogen (Cambridge – USA)
Objective: An increased risk of cutaneous adverse events (AEs) was observed in the previous placebo-controlled SELECT
study of daclizumab high-yield process (DAC HYP) in patients with relapsing-remitting multiple sclerosis (RRMS). Our
aim is to describe the incidence, severity, duration, and steroid treatment of cutaneous AEs reported in the DECIDE study
versus intramuscular (IM) interferon (IFN) beta-1a.
Materials and Methods: DECIDE was a randomised, double-blind, active-controlled study of DAC HYP 150mg
subcutaneous every 4 weeks vs IFN beta-1a 30mcgIM once weekly in RRMS patients for up to 144 weeks. AE severity was
based on investigator assessment and serious AEs on standard criteria. Duration of cutaneous AEs and steroid use were
evaluated post hoc and categorised by worst cutaneous AE reported in the order of serious, severe, moderate, and mild.
Results: 1841 patients (DAC HYP n=919; IFN beta-1a n=922) were enrolled in DECIDE. Over 144 weeks,344 (37%) DAC
pag. 121
HYP patients and 176 (19%) IFN beta-1a patients reported a cutaneous AE. Overall, 191 (21%) vs 122 (13%) patients
experienced mild, 132 (14%) vs 51 (6%) moderate, and 21 (2%) vs 3 (<1%) severe cutaneous AEs in the DAC HYP vs IFN
beta-1a groups. Serious cutaneous AEs were reported in 14 (2%) DAC HYP patients and 1 (<1%) IFN beta-1a patient.
Among patients with a cutaneous AE categorised by worst cutaneous AE reported, 190 (55%) vs 122 (69%) had mild, 129
(38%) vs 50 (28%) had moderate, 11 (3%) vs 3 (2%) had severe, and 14 (4%) vs 1 (<1%) had serious cutaneous AEs for
DAC HYP vs IFN beta-1a. The median (mean) duration in days for a cutaneous AE was as follows: mild 22.0 (58.8) vs 19.5
(62.1), moderate 40.5 (72.9) vs 21.5 (52.1), severe 70.5 (127.5) vs 12.0 (12.0), serious 54.0 (111.1) vs 6.0 (6.0) for DAC
HYP vs IFN beta-1a. Most patients with mild (154/190 [81%] DAC HYP vs 106/122 [87%] IFN beta-1a) or moderate
(94/129 [73%] vs 36/50 [72%]) cutaneous AEs received topical steroids or were not treated with steroids,whereas treatment
with systemic corticosteroids was more common in patients with severe (8/11 [73%] DAC HYP vs 1/3 [33%]IFN beta-1a)
or serious (10/14 [71%] vs 0/1) cutaneous AEs.
Discussion and Conclusions: Cutaneous AEs were more common with DAC HYP than IFN beta-1a. Most patients with
mild or moderate events were treated or not with topical corticosteroids. Severe or serious event rates were low and these
events were generally managed with systemic corticosteroids.
PROGNOSTIC ROLE OF CEREBROSPINAL FLUID NEUROFILAMENT, CHITINASE-3-LIKE AND TAU
LEVELS IN PATIENTS WITH CLINICALLY ISOLATED SYNDROME
D. Ferraro, A. Simone, R. Bedin, F. Vitetta, A. Canovi, P. Nichelli, P. Sola
Department of Neurosciences, University of Modena and Reggio Emilia (Modena)
Introduction: In Multiple Sclerosis (MS), numerous findings suggest that axonal loss is ultimately responsible for the
development of irreversible neurological deficits, which is likely to emerge as a consequence of nerve injury starting in
early phases of the disease.
Objective: The aim of our study was to investigate the prognostic role of cerebrospinal fluid (CSF) biomarkers related to
axonal damage and glial activation such as neurofilaments (NFL), total-tau and chitinase-3-like 1 (CHI3L1) in patients with
Clinically Isolated Syndrome (CIS).
Methods and Materials: CSF of patients with CIS was examined for the presence of NFL, total-tau and CHI3L1. The
median biomarker level was used as a cut-off to define high or low levels. Outcomes for logistic regression and survival
analysis were: diagnosis of Clinically Definite MS (CDMS), defined by a clinical relapse, and disability milestones defined
as an EDSS of 3, 4 and 6. Correlations between biomarkers and clinical, MRI and CSF parameters, including IgMOB, were
analyzed using Spearman’s rank test (with Bonferroni correction).
Results: We included 101 patients in the study (64F, mean age: 35±10 years). Mean follow-up duration was 72 months (24109). A relapse occurred in 52% of patients. Median CSF amounts of NFL, CHI3L1 and tau were: 995ng/ml, 118ng/ml and
156pg/ml, respectively. NFL levels correlated with number of baseline brain and spinal cord MRI lesions, with the number
of brain gadolinium-enhancing lesion and with EDSS at two years and at final follow-up. CHI3L1 correlated with age at
onset, IgG Index and with EDSS at two years. Tau correlated with number of baseline brain gadolinium-enhancing MRI
lesions, with CSF/serum albumin and with EDSS at final follow-up. Only high NFL values were associated with an
increased risk of a relapse (OR: 3.9 CI95: 1.7-8.9; p=0.001) and with a shorter time to a relapse during follow-up (Log-rank
test: p=0.002) or to an EDSS of 3 or 4 (Log-rank test: p=0.004 and: p=0.01, respectively).
Discussion and Conclusion: In patients with CIS, high CSF NFL levels, but not high CHI3L1 or tau levels, were shown to
increase the risk of a CDMS diagnosis and were associated with a shorter time to a CDMS diagnosis and to disability
milestones during follow-up.
EPSTEIN BARR VIRUS GENOME VARIABILITY IN MULTIPLE SCLEROSIS
R. Mechelli1, C. Manzari2, M. Chiara3, E. Picari2, E. Anastasiadou4, R. Bigi5, C. Buscarinu1, A. D'Erchia2, P. Trivedi5, D.
Horner3, G. Pesole2, G. Ristori1, M. Salvetti1
1
Centre for Experimental Neurological Therapies (CENTERS), Department of Neurosciences, Mental Health and Sensory
2
Organs (NESMOS), Sapienza University of Rome (Roma);
Department of Bioscience, Biotechnology and
Biopharmaceutics, University of Bari 'Aldo Moro' (Bari); 3Department of Biosciences, University of Milan (Milano);
4
Department of Pathology, Beth Israel Deaconess Medical Center, Harvard Medical School (Boston-USA); 5Department of
Experimental Medicine, Sapienza University (Roma)
Background: Our recent study showed a possible association between Epstein-Barr virus (EBV) genomic variants and
pag. 122
multiple sclerosis (MS), reinforcing the idea that EBV might contribute to disease development (Mechelli et al. Neurology,
2015). We analysed a region of the viral DNA coding for Epstein-Barr nuclear antigen 2 (EBNA2) protein in peripheral
blood of persons with relapsing-remitting MS and healthy donors (HD), showing that MS risk significantly correlated with
an excess of 1.2 allele and under-representation of 1.3B allele.
Objective: We cannot exclude that allele frequencies at additional loci of the complex EBV genome may also correlate with
MS. To explore this issue we generated near complete genome sequences for 27 selected viral genomes.
Methods: We established spontaneous outgrowth lymphoblastoid cell lines carrying an endogenous EBV strain (spLCL) as
unlimited source of viral DNA. We used Sure Select capture system to obtain an enrichment of viral DNA (Agilent
Technologies) that was subjected to a paired-end 2x121 bp sequencing on the Illumina MiSeq platform. We sequenced EBV
genomes obtained from 18 MS-derived and 9 from HD-derived spLCLs. During the enrollment of the patients we
considered only subjects free from therapy for a long time or who were treatment naïve.
Results: All genomes were assembled into large contiguous DNA sequences (contigs) and compared with the B95-8
reference genome (NC_007605). Overall 3478 SNPs were identified and among these about 400 are completely new. The
average number of SNPs is nearly the same in MS and controls. Specific regions of the viral episome show higher level of
variability both in patients and in controls (Figure). Particular substitutions or substitution patterns are more frequent in viral
isolates from MS patients than from controls.
Conclusions: Our results showed that other regions besides EBNA2 coding sequence may be characterized by sequence
variations associated with MS that deserve to be further explored. We demonstrate the appropriateness of deep-sequencing
platforms and spLCL to highlight genetic variations in a virus that latently infects peripheral blood cells at a very low
frequency.
Reference:
− Mechelli R, Manzari C, Policano C, et al. EpsteinBarr virus genetic variants associated with multiple sclerosis.
Neurology (2015);84(13):1362-8
NEUROIMMAGINI
STRUCTURAL CONNECTIVITY ABNORMALITIES UNDERLYING
PEDIATRIC MULTIPLE SCLEROSIS
COGNITIVE IMPAIRMENT IN
E. De Meo1, M. Rocca2, E. Pagani2, L. Moiola1, A. Ghezzi3, P. Veggiotti4, R. Capra5, M. Amato6, L. Vacchi2, A. Fiorino1, L.
Pippolo3, M. Pera4, G. Comi1, A. Falini7, M. Filippi2
1
Department of Neurology, San Raffaele Scientific Institute, Vita-Salute San Raffaele University (Milano); 2Neuroimaging
Research Unit, INSPE, Division of Neuroscience, San Raffaele Scientific Institute, Vita-Salute San Raffaele University
(Milano); 3Multiple Sclerosis Center, Gallarate Hospital (Gallarate-VA); 4Department of Child Neurology and Psychiatry,
C. Mondino National Neurological Institute (Pavia); 5Multiple Sclerosis Center, Spedali Civili of Brescia (Brescia);
6
Department of Neurology, University of Florence (Firenze); 7Department of Neuroradiology, San Raffaele Scientific
Institute, Vita-Salute San Raffaele University (Milano)
Background: A large proportion of pediatric MS patients experiences cognitive deficits, with a prominent involvement of
linguistic abilities in addition to memory, attention, and executive functions.
Aims: By applying diffusion tensor (DT) MRI, we aim at describing brain structural network architecture in pediatric MS
patients and to detect structural connectivity abnormalities underlying cognitive dysfunction across the different cognitive
domains.
Methods: DT and dual-echo MRI scans were obtained using a 3.0 T scanner from 53 pediatric MS patients and 26 age- and
sex-matched healthy controls (HC). Whole-brain networks were constructed using graph theory. Between-group differences
of global and local network connectivity metrics were investigated. Partial correlations between network metrics and Zscores for each of cognitive domain and a global Z-score of cognitive function controlling for age and sex were performed.
Results: All global network metrics showed significant differences between pediatric MS patients and HC. Compared to
HC, pediatric MS patients lost hubs in the right superior frontal gyrus (SFG), middle occipital gyrus, caudate nucleus and
cerebellum crus II and in the left precentral gyrus, temporal pole, thalamus and cerebellum crus I. Global cognitive
functioning showed significant positive correlation with the strength of connections of hubs located in the right superior
parietal lobe and the precuneus bilaterally. Impairment in language functions, as well as verbal memory impairment were
significantly related to reduced strength of the hubs located in frontal and temporal, while visual-spatial memory, attention
and information processing speed impairment appeared were associated to a reduced strength in several hubs located in
pag. 123
frontal, parietal and occipital lobes.
Conclusions: This study showed abnormalities in global network metrics in pediatric MS patients with limited differences in
hubs distribution, indicating a partial preservation of brain network architecture. Our findings suggest that cognitive
impairment is mainly associated to a globally reduced strength of connections of the nodes identified as hubs, likely due to
diffuse normal appearing white matter damage, more than to a local damage, resulting in alteration and loss of efficiency in
information transmission.
Partially supported by grants from Italian Ministry of Health (GR-2009-1529671) and Fondazione Italiana Sclerosi Multipla
(FISM2011/R/19 & FISM 2012/R/8).
A COMPREHENSIVE ASSESSMENT OF CERVICAL CORD LESIONS IN PATIENTS WITH MULTIPLE
SCLEROSIS ON T1-MPRAGE AT 3T: RELATIONSHIP WITH CORD ATROPHY AND DISABILITY
M. A. Rocca1, P. Valsasina1, P. Preziosa1, M. Aboulwafa1, M. Horsfield2, G. Comi3, A. Falini4, M. Filippi1
1
Neuroimaging Research Unit, INSPE, Division of Neuroscience, San Raffaele Scientific Institute, Vita-Salute San Raffaele
University (Milano); 2Xinapse Systems Ltd (Colchester, Essex, UK); 3Department of Neurology, San Raffaele Scientific
Institute, Vita-Salute San Raffaele University (Milano); 4Department of Neuroradiology, San Raffaele Scientific Institute,
Vita-Salute San Raffaele University (Milano)
Aims: We characterized the spatial distribution of cervical cord T1 lesions in a large cohort of multiple sclerosis (MS)
patients; assessed the influence of cord T1 lesions on atrophy quantification and analyzed their association with disability.
Methods: 3Tesla cervical cord sagittal 3D T1-weighted scans were acquired from 63 relapsing remitting (RR), 30 secondary
progressive (SP), 20 primary progressive (PP), 20 benign (B) MS and 47 healthy controls. Cord T1-hypointense lesions
were identified and binary lesion masks were produced. The active surface (AS) method was applied to calculate crosssectional area (CSA). Between-group comparisons of T1 lesions and cord atrophy were performed with ANOVA models
(age-adjusted).
Results: T1 hypointense lesions were detected in 114 MS patients, with a higher frequency in SPMS vs RRMS, and PPMS
vs RRMS and SPMS patients. Cord atrophy was found in MS patients vs controls, and in RRMS and PPMS vs controls,
RRMS vs BMS and SPMS vs RRMS patients. Whole-cord CSA was not correlated with cord T1 lesion number. The
regional distribution of cord atrophy was modestly correlated with T1 lesion number. There was a strong correlation
between cord atrophy and T1 lesions and disability, both at a global and regional analysis.
Conclusions: T1 hypointense cervical cord lesions were detected in a large proportion (85%) of MS patients. T1 lesions did
not influence cord area estimates produced by the AS method. The association between cord T1 lesions and cord atrophy
was modest. However, both cord T1 lesions and atrophy contributed, independently, to patient physical disability.
This study has been partially supported by a grant from Fondazione Italiana Sclerosi multipla (FISM 2014/PMS/6).
NO DIFFERENCES IN SPINAL CORD WHITE AND GREY MATTER DTI CHANGES BETWEEN
NEUROMYELITIS OPTICA SPECTRUM DISORDER AND MULTIPLE SCLEROSIS
R. Cortese1, L. Magnollay2, F. De Angelis2, F. Prados2, F. Grussu2, C. Tur2, M. Yiannakas2, D. R Altmann2, D. Miller2, S.
Ourselin3, C. AM Gandini Wheeler-Kingshott2, I. L Simone4, F. Barkhof2, O. Ciccarelli2
1
Department of Basic Medical Sciences, Neurosciences and Sense Organs, University of Bari (Bitonto-BA); 2Queen Square
MS Centre, NMR Research Unit, Department of Neuroinflammation, UCL Institute of Neurology (London-UK);
3
Translational Imaging Group, Centre for Medical Image Computing - UCL (London-UK); 4Department of Basic Medical
Sciences, Neurosciences and Sense Organs, University of Bari (Bari)
Background: It has been suggested that neuromyelitis optica spectrum disorders (NMOSD) shows more spinal cord (SC)
atrophy than brain atrophy, while multiple sclerosis (MS) shows more brain atrophy. Diffusion tensor imaging (DTI) has
demonstrated the pathological involvement of the white matter (WM) and grey matter (GM) of the SC in MS.
Objectives: (i) To calculate DTI measures in the GM and WM of SC, and brain and SC atrophy in patients with NMOSD;
(ii) to compare them to
MS;
(iii) to explore their relationship
with clinical
disability.
Methods: 18 NMOSD (16 with LETM involving the cervical cord, 14F, mean age 52yrs[SD11]), 19 relapsing-remitting MS
patients (5 with cervical cord lesions, 15F, mean age 42yrs[SD10]) and 25 HC (18F, mean age 37yrs[SD13]) were scanned
at 3T. Brain parenchymal fraction (BPF), grey matter fraction (GMF), white matter fraction, cord cross-sectional area
(CSA) and SC DTI metrics (fractional anisotropy, mean diffusivity, radial diffusivity, axial diffusivity) in the GM and WM
columns were measured and compared among groups. Physical disability was assessed using the expanded disability status
pag. 124
scale (EDSS), 9 hole peg test and timed 25 foot walk test (TWT). We used multiple regressions to compare imaging
measures between groups and Spearman-correlation to explore the relationship between MRI parameters and clinical
measures.
Results: There were no differences in SC DTI metrics in the GM and WM between NMOSD and HC, MS and HC, and
patient groups. NMOSD patients showed a borderline significant smaller CSA than HC (mean[SD] 77.65 mm²[2.40] vs
83.74 mm²[1.98]; p:0.069); MS patients had a smaller CSA (mean 76.24 mm²[2.16]) than HC (p:0.013), with no difference
between patient groups. MS patients had lower BPF than NMOSD (mean[SD] 0.75[0.003] vs 0.76[0.003]; p:0.04) and HC
(mean 0.75[0.003] vs 0.76[0.003]; p<0.01) and lower GMF than HC (mean 0.44[0.002] vs 0.45[0.002]; p:0.03). In
NMOSD,
CSA
correlated
with
EDSS
[rs:-0.46,
p:0.05],
and
TWT
[rs:-0.5,
p:0.039).
Conclusion: Pathological involvement of SC, as reflected by DTI, does not differ between NMOSD and MS, despite a
different pattern and extent of SC lesions between the two diseases. However the sample size was small. Our study confirms
that brain atrophy is greater in MS than NMOSD and that in NMOSD, CSA is the best correlates of clinical disability.
References:
− Liu Y, Wang J, Daams M, Weiler F, Hahn HK, Duan Y, Huang J, Ren Z, Ye J, Dong H, Vrenken H, Wattjes MP,
Shi FD, Li K, Barkhof F. Differential patterns of spinal cord and brain atrophy in NMO and MS. Neurology (2015)
Apr 7;84(14):1465-72
− H Kearney, T Schneider, M C Yiannakas, D R Altmann, A M Wheeler-Kingshott, O Ciccarelli, D H Miller. Spinal
cord grey matter abnormalities are associated with secondary progression and physical disability in multiple
sclerosis. J Neurol Neurosurg Psychiatry (2015) Jun;86(6):608-14
− Benedetti B, Valsasina P, Judica E, Martinelli V, Ghezzi A, Capra R, Bergamaschi R, Comi G, Filippi M. Grading
cervical cord damage in neuromyelitis optica and MS by diffusion tensor MRI. Neurology (2006) Jul
11;67(1):161-3
FATIGUE IN MULTIPLE SCLEROSIS: THE CONTRIBUTION OF RESTING-STATE FUNCTIONAL
CONNECTIVITY REORGANIZATION
A. Bisecco1, F. Di Nardo2, R. Docimo1, G. Caiazzo2, A. d'Ambrosio1, R. Sacco1, S. Bonavita1, M. Cirillo3, F. Esposito4, G.
Tedeschi1, A. Gallo1
1
Division of Neurology, Department of Medical, Surgical, Neurological, Metabolic and Aging Sciences, Second University
of Naples (Napoli); 2MRI Research Center SUN-FISM, Second University of Naples, (Napoli); 3Neuroradiology Service,
Department of Radiology, Second University of Naples (Napoli); 4Department of Medicine and Surgery, University of
Salerno (Baronissi-SA)
Objectives: To investigate resting-state functional connectivity (RS-FC) of the default mode network (DMN) and of
sensorimotor network (SMN) in multiple sclerosis (MS) patients with (F) and without (NF) fatigue.
Background: Fatigue affects a large proportion of patients with MS. Despite its relevance and frequency in MS, the
pathophysiology of MS-related fatigue is still poorly understood and controversial.
Materials and Methods: Sixty not-depressed relapsing remitting (RR) MS patients and 30 sex, age and education-matched
healthy controls (HC) underwent a 3T magnetic resonance imaging (MRI) protocol including structural and resting-state
fMRI (RS-fMRI) sequences. MS patients were evaluated by a neurological examination and the Fatigue Severity Scale
(FSS). Functional connectivity of the DMN and SMN was evaluated by independent component analysis (ICA). Regional
gray matter atrophy was assessed by voxel-based morphometry (VBM).
Results: Thirty RRMS patients were fatigued (F-MS). Compared to HC: 1) NF-MS patients showed a stronger RS-FC in the
posterior cingulate cortex (PCC) of the DMN and a reduced RS-FC in the pre-central gyrus of the SMN; 2) F-MS patients
showed a stronger RS-FC in the PCC and a reduced RS-FC in the ACC of the DMN. F-MS patients, compared to NF-MS
patients, revealed: 1) an increased RS-FC in the PCC and a reduced RS-FC in the ACC of the DMN and 2) an increased RSFC in the precentral gyrus and in the supplementary motor area of the SMN. All detected RS-FC changes did not co-localize
with regional gray matter atrophy.
Discussion: Fatigue in RRMS is associated to relevant RS-FC changes, including an antero-posterior reorganization of the
DMN and a strengthening of the SMN.
Conclusions: These results further supports the hypothesis that fatigue in MS is mostly subtended by a functional
rearrangement of frontal networks.
AGING DOES NOT INDUCE CAUDATE NUCLEI AND THALAMI HYPOINTENSITIES IN HEALTHY
SUBJECTS: A 3.0 TESLA MR IMAGING STUDY
pag. 125
M. Morelli1, F. Bono1, B. Vescio2, G. Nicoletti2, M. Salsone2, F. Novellino2, G. Arabia1, M. Mancini1, G. Mastroianni1, M.
Mazza1, G. Ferrigno1, C. Chiriaco1, V. Vaiti2, F. Rocca2, A. Quattrone1
1
Institute of Neurology, Magna Graecia University (Catanzaro); 2Neuroimaging Research Unit, National Research Council
(Catanzaro)
Introduction: Several neuropathological evidences have shown that mineral accumulates in the brain deep gray nuclei
occurs both in aging and in several neurodegenerative diseases. (1,2) Cerebral mineral deposition produces a marked
shortening of the transverse relaxation time which causes hypointensity in T2*-weighted gradient echo (GE) MR images.
However, the diagnostic value of the hypointensities of deep gray nuclei on brain MRI is scarce, because it is not possibile
to differentiate hypointensities of healthy subjects from those of patients with neurodegenerative diseases. (3)
Objective: To identify the pattern of the deep gray nuclei hypointensities in normal subjects and to assess the relationship
between aging and frequencies of loss of signal in the deep gray matter structures, we performed a brain MRI in large
sample of healthy subjects on 3.0 Tesla MR unit.
Methods: We enrolled 217 healthy subjects with age range from 20 to 79 years (mean age ± SD, 50.4 ± 17.1 years; 104 men
and 113 women) and all participants underwent 3.0 Tesla MRI examination. Signal intensity of globus pallidus, putamen,
caudate, thalamus and dentate nuclei was visually assessed on axial T2*-weighted GE scans. Hypointensities of globus
pallidus, putamen, caudate and thalamus were considered as lower signal intensity areas in these structures compared to the
signal intensity of the centrum semiovale, a brain region that is expected to show no low signal intensity at any time.
Hypointensities of dentate nuclei were considered as lower signal intensity areas in these structures compared to the signal
intensity of the surrounding cerebellar white matter.
Results: On T2*-weighted GE imaging, hypointensities were detected more frequently in globus pallidus (35.4%; 77 of
217) that than in dentate (32.7%; 71 of 217) or putamen (7.8%; 17 of 217). A consistent effect of aging on the hypointensity
frequencies was evident in globus pallidus (P < 0.001), putamen (P < 0.001) and dentate nuclei (P < 0.001). None of the
study participants showed variations of MR signal intensity in the caudate or thalamic nuclei.
Conclusions: our data demonstrate that healthy subjects have hypointensities in globus pallidus, putamen and dentate nuclei,
and that there is not relationship between aging and hypointensities of caudate nuclei and thalamus. These findings suggest
that detection of caudate or thalamic hypointensities on brain MRI should prompt the clinician to consider the possibility of
a neurodegenerative disease.
References:
1. Hallgren B, Sourander P. The effect of age on the non-haemin iron in the human brain. J Neurochem (1958);3:4151
2. Haacke EM, Cheng NY, House MJ, Liu Q, Neelavalli J, Ogg RJ, Khan A, Ayaz M, Kirsch W, Obenaus A.
Imaging iron stores in the brain using magnetic resonance imaging. Magn Reson Imaging (2005);23:1-25
3. Arabia G, Morelli M, Paglionico S, Novellino F, Salsone M, Giofrè L, Torchia G, Nicoletti G, Messina D, Condino
F, Lanza P, Gallo O, Quattrone A. An magnetic resonance imaging T2*-weighted sequence at short echo time to
detect putaminal hypointensity in Parkinsonisms. Mov Disord (2010);25: 2728-34
MAGNETIC RESONANCE IMAGING IN CEREBROTENDINOUS XANTHOMATOSIS: A SINGLE-CENTRE
EXPERIENCE
A. Mignarri1, L. Monti2, I. Grazzini2, P. Galluzzi2, N. De Stefano1, A. Federico1, M. Dotti1
1
Unit of Neurology and Neurometabolic Disorders, Department of Medicine, Surgery and Neurosciences, University of
Siena (Siena); 2Unit of Diagnostic and Therapeutic Neuroradiology, Azienda Ospedaliera Siena (Siena)
Background: Cerebrotendinous xanthomatosis (CTX) is a rare autosomal recessive disease due to mutations in CYP27A1
causing deposition of toxic bile acids intermediates. CTX phenotype includes systemic signs and neurological impairment,
which is strongly invalidating if treatment with chenodeoxycholic acid (CDCA) is not started early. Brain magnetic
resonance imaging (MRI) represents an essential diagnostic tool, showing dentate nuclei signal alterations as the most
important hallmark. However, the spectrum of MRI findings is worth to be reappraised, also in the light of phenotype and
disability. Moreover, clinical and neuroimaging follow up data are needed. Methods: We performed clinical evaluation and
brain MRI in 38 CTX patients consecutively admitted to our centre. Also, 16 subjects who were untreated underwent
clinical and MRI follow up after a period of 2-4 years. Brain CT, and spinal MRI were also performed in selected cases.
Results: The main brain MRI abnormalities were cortical (68% of patients) and cerebellar (71%) atrophy, T2/FLAIR
hyperintensity of subcortical (58%), periventricular (89%), and cerebellar (55%) white matter, brainstem T2/FLAIR
pag. 126
hyperintense lesions (50%), and dentate nuclei signal alteration. Regarding the dentate nuclei, T2/FLAIR hyperintense
lesions were present in 84% of patients, while the remaining 16% did not show any alteration. In addition to the “classical”
T2/FLAIR hyperintensity of the dentate nuclei, we observed T1/FLAIR hypointensity consistent with vacuolation (26% of
patients) which often extended to the cerebellar white matter, and T1/FLAIR/SW hypointense alterations which where
hyperdense at CT compatibly with calcification (21%). Interestingly, in all patients with spared dentate nuclei we found
periventricular white matter signal alteration. Long-term follow-up showed that clinical and neuroradiological stability or
worsening were almost invariably associated. In patients with cerebellar vacuolation, disability and MRI worsened over
time. On the other hand, subjects without cerebellar vacuolation or lacking dentate lesions were clinically and
neuroradiologically stable at follow up.
Discussion: Our study adds important information on the diagnostic and prognostic role of MRI in CTX. The brains of CTX
patients very often show both supratentorial and infratentorial abnormalities including atrophy and white matter lesions, and
present a spectrum of dentate nuclei alterations which may represent different stages of the disease but can also be observed
independently. In particular, the presence or the development of cerebellar vacuolation due to neuroaxonal loss appears to
be the most important neuroradiological marker of disease progression and poor response to therapy, while the absence of
dentate nuclei signal alteration is an indicator of good prognosis.
RS-FMRI CORRELATES OF CENTRAL SENSITIZATION IN MIGRAINE PATIENTS
D. Mattavelli1, G. Preziosa1, F. Mele1, L. Giani1, V. Leta1, M. Ferrari1, C. Mariotti d'Alessandro1, F. Baglio2, C. Lovati1, C.
Mariani1
1
Neurology Department, “ASST Fatebenefratelli Sacco”, University of Milan (Milano); 2MR Research Laboratory, IRCCS
Don Gnocchi Foundation ONLUS (Milano)
Objectives: To assess the presence of resting-state functional MRI correlates of frequency of attacks, disease duration,
osmophobia and allodynia in migraineurs compared to healthy controls. Materials and Methods: Following ICHD-III
criteria, twenty-nine chronic (chMP, n=14) or episodic (epMP, n=15) migraine patients [MP, n=29; mean age: 39.1 ± 12.9
years (range 22-62); mean monthly frequency of attacks 13.2 ± 8.9 (4-30); mean disease duration: 23.9 ± 13.2 years (4-43)]
were screened at baseline for disease duration, number of monthly migraine attacks and associated symptoms. Moreover,
MP were tested for the presence of osmophobia and rated for level of allodynia using the Allodynia Symptom Checklist
(ASC) scale. Fifteen age- and sex-matched healthy controls (HC) were recruited. The entire population underwent a brain
resting-state functional MRI (rs-fMRI) using a 1.5T magnet. Then, after main resting-state brain networks (RSN)
visualization via an independent component analysis (ICA), functional connectivity (FC) was quantified using dualregression (FWE <0.05). Finally, correlations analyses between clinical variables (ASC score, frequency of monthly
migraine attacks and disease duration) and MRI data were performed.
Results: Among MP, allodynia was present in 14/29 (48.28%). Allodynia was more represented in chMP than in epMP
(8/14 and 6/15, respectively). Osmophobia was registered in 15/29 (51.72%) of MP, equally distributed between chMP and
epMP (7/14 vs 8/15, respectively). Between the 14 RSN components emerged from ICA analysis of rs-fMRI data, we found
a significant FC reduction in MP vs. HC in default mode network (DMN), sensory-motor network (SMN), salience, frontal,
fronto-parietal and visual networks. Negative correlations were found between frequency of monthly migraine attacks and
FC between DMN and visual network in the allodynic subsample. Positive correlations were found between: a) frequency
of monthly migraine attacks and FC between frontal network and SMN in both allodynic and osmophobic subsamples and
FC between visual and fronto-parietal network in the osmophobic subsample; b) disease duration and FC between DMN
and fronto-parietal network in the osmophobic subsample.
Discussion and Conclusion: Considering the results of this study and the current scientific literature, it is possible to
speculate that migraine could be associated with functional reorganization of cerebral areas involved in pain modulation
proportionally to frequency of attacks and presence of symptoms of transformation like allodynia and osmophobia. Clinical
transformation seems consequently to be the expression of the functional changes of the neuronal connectivity.
References:
− Schwedt TJ, Chong CD. Functional imaging and migraine: new connections? Curr Opin Neurol. (2015)
Jun;28(3):265-70
− Tessitore A, Russo A, Giordano A, Conte F, Corbo D, De Stefano M, Cirillo S, Cirillo M, Esposito F, Tedeschi G.
Disrupted default mode network connectivity in migraine without aura. J Headache Pain. (2013) Nov 8;14:89
− Colombo B, Rocca MA, Messina R, Guerrieri S, Filippi M. Resting-state fMRI functional connectivity: a new
perspective to evaluate pain modulation in migraine? Neurol Sci. (2015) May;36 Suppl 1:41-5
DISTINCT PATTERNS OF BRAIN ATROPHY IN GENETIC FRONTOTEMPORAL DEMENTIA: VISUAL
pag. 127
RATING SCALES IN THE GENFI COHORT
G. Fumagalli1, P. Basilico1, S. Harding2, A. Arighi1, M. Bocchetta2, M. Mercurio1, K. Dick2, J. van Swieten3, B. Borroni4,
C. Graff5, M. Masellis6, F. Tagliavini7, J. Rowe8, R. Laforce9, E. Finger10, G. Frisoni11, A. Mendoca12, S. Sorbi13, E.
Scarpini1, J. Rohrer2, D. Galimberti1
1
IRCCS Policlinico Hospital of Milan, University of Milan (Milano); 2Dementia Research Centre, University college
London (London-UK); 3Department of Neurology, Erasmus Medical Centre (Rotterdam-NL); 4Department of Neurology,
University of Brescia (Brescia); 5Department of Neurology, Karolinska Institutet (Stockholm-S); 6Department of
Neurology, University of Toronto (Toronto-CDN); 7Department of Neurology, Besta Hospital (Milano); 8Department of
Neurology, University of Cambridge (Cambridge-UK); 9Department of Neurology, Université Laval (Quebec-USA);
10
Department of Neurology, University of Western Ontario (London Ontario….); 11Department of Neurology, IRCCS
Fatebenefratelli Brescia (Brescia); 12Department of Neurology, Universidade de Lisboa (Lisbona-E); 13Department of
Neurology, University of Florence (Firenze)
Frontotemporal dementia (FTD) is a clinically, radiologically and genetically heterogeneous disorder. Mutations in the three
main genes (MAPT, GRN, C9orf72 expansion) can have different profiles of brain atrophy. The objectives of our study
were to compare the pattern of atrophy of symptomatic subjects among different genetic groups and to look for presymptomatic signs of atrophy in at-risk subjects. We used six visual rating scales of brain atrophy: orbito-frontal (OF),
anterior cingulate (AC), fronto-insula (FI), anterior temporal (AT), medial temporal (MT) and posterior (PA). Two raters,
blind for clinical and genetic data, reviewed 343 scans from the GENFI cohort that consisted of 150 controls, 130
presymptomatic (64 GRN, 24 MAPT, 42 C9orf72) and 63 symptomatic (17 GRN, 15 MAPT, 31 C9orf72). Inter rater
reliability of scan assessment was good with intraclass correlation coefficients (ICC) ranging from 0.73 of PA to 0.88 of
MT. MAPT mutation carriers compared with GRN were more atrophic in the AT (Mann Whitney U test 0.002) and MT
(0.005) but less in OF (0.016), AC (0.004), FI (0.014) and PA (<0.001). C9orf72 patients compared to GRN show less OF
atrophy (0.043) while compared to MAPT had greater PA (< 0.001) but less AT (0.001). Comparing presymptomatic to
controls only the MAPT mutation carrier group showed a significant difference in the scores of MT atrophy (0.037). The
identification of typical pattern of atrophy at the MRI (more frontal and parietal in GRN, more anterior and medial temporal
in MAPT, widespread in C9orf72) can help in directing genetic analysis in symptomatic patients. Signs of atrophy can be
identified in presymptomatic subjects even by using visual rating scales.
NEUROFISIOLOGIA CLINICA
NAVIGATED TRANSCRANIAL MAGNETIC STIMULATION (NTMS) FOR PREOPERATIVE MAPPING IN
MOTOR AREAS TUMOR SURGERY: COMPARISON WITH FUNCTIONAL MAGNETIC RESONANCE
IMAGING (FMRI) AND INTRAOPERATIVE DIRECT CORTICAL STIMULATION
C. Lettieri1, R. Budai1, T. Ius2, S. Rinaldo1, G. Devigili1, F. Muggiolu2, M. Skrap2, R. Eleopra1
1
Neurology Unit, University Hospital (Udine); 2Neurosurgery Unit, University Hospital (Udine)
Background and Objective: Navigated transcranial magnetic stimulation (nTMS) is a novel technology in the field of
neurosurgery for noninvasive delineation of cortical functional topography. Recent studies show that it can detect eloquent
cortical areas directly, comparable to intraoperative direct cortical stimulation (DCS). The aim of this study was to evaluate
the nTMS in comparison with functional magnetic resonance imaging (fMRI) in the setting of brain tumors involving motor
areas.
Materials and Methods: Eighteen consecutive patients affected by frontal lobe brain tumors were enrolled in the study. All
patients received an fMRI and nTMS examination preoperatively. Consistency of preoperative mapping with intraoperative
DCS was assessed off-line by means of the neuronavigation system.
Results: nTMS produced statistically significant higher accuracy scores of the motor area localization than fMRI.
Conclusions: nTMS represents an useful and reliable technique during preoperative planning for surgical decision making in
the clinical setting.
References:
pag. 128
−
−
−
Krieg SM, Shiban E, Buchmann N, Gempt J, Foerschler A, Meyer B, et al. Utility of presurgical navigated
transcranial magnetic brain stimulation for the resection of tumors in eloquent motor areas. J Neurosurg
(2012);116: 994-1001. Epub 2012 Feb 3
Takahashi S, Vajkoczy P, Picht T. Navigated transcranial magnetic stimulation for mapping the motor cortex in
patients with rolandic brain tumors. Neurosurg Focus (2013);34(4):E3. doi: 10.3171/2013.1.FOCUS133
Coburger J, Musahl C, Henkes H, Horvath-Rizea D, Bittl M, Weissbach C, et al. Comparison of navigated
transcranial magnetic stimulation and functional magnetic resonance imaging for preoperative mapping in rolandic
tumor surgery. Neurosurg Rev. (2013);36(1): 65-75; discussion 75-6. doi: 10.1007/s10143-012-0413-2. Epub 2012
Aug 11
PRESYNAPTIC AND POSTSYNAPTIC INHIBITION IN THE HUMAN DORSAL COLUMN NUCLEI
M. Valeriani1, P. Mazzone2, A. Insola3
1
Department of Neurology, Pediatric Hospital Bambino Gesù (Roma); 2Operative Unit for Stereotactic and Functional
Neurosurgery, Regional Center for Functional Neurosurgery and DBS, CTO Hospital (Roma); 3Operative Unit for
Neurophysiopathology, CTO Hospital (Roma)
Objectives: The study aimed to investigate the site of the movement related inhibition of the human dorsal column nuclei.
Methods: Median nerve somatosensory evoked potentials (SEPs) were recorded from 18 patients suffering from Parkinson’s
disease, who underwent electrode implantation in the pedunculopontine (PPTg) nucleus for deep brain stimulation. SEPs
were recorded from the PPTg electrode contacts at rest and during either active or passive movement of the thumb of the
stimulated wrist.
Results: The PPTg electrode recorded a triphasic potential generated in the cuneate nucleus. The PPTg potential was
subtended by 2 high frequency oscillation (HFO) components: 1) an earlier one with 1000 Hz frequency, and 2) a later one
with 1700 Hz frequency. Both HFO components were reduced by movement.
Discussion: We suggest that the 1000 Hz and 1700 Hz HFO bursts are generated at pre- and post-synaptical level,
respectively.
Conclusions: Movement exerts both pre- and post-synaptic inhibition on dorsal column nuclei.
EMG WITH LONG EXERCISE TEST IN MCARDLE DISEASE
C. Semplicini1, M. Arzel-Hezode2, T. Stojkovic3, A. Behin3, B. Eymard3, P. Laforet3, E. Fournier2
1
Department of Neuroscience, University of Padua (Padova); 2Department of Neurophysiology, Hopital Pitie-Salpetriere
3
(Paris-F);
Paris-Est
Neuromuscular
Center,
Hopital
Pitie-Salpetriere
(Paris-F)
Background: Standard electromyography (EMG) is routinely performed during the diagnostic process of myopathies, but its
role is limited in metabolic myopathies with exercise intolerance, such as McArdle disease (glycogenosis type V, GSDV).
Aim: To evaluate a provocative test (the Long Exercise Test, LET) in the EMG diagnosis of GSDV.
Methods: Twenty-five patients (17 males, 41±17 years) with confirmed diagnosis of GSDV underwent an EMG study
(including nerve conduction studies, repetitive nerve stimulation, needle EMG) completed with LET. Briefly, the compound
muscle action potential (CMAP) responses were recorded from right abductor digiti minimi (ADM) muscle before and after
5 min of maximal ADM isometric contraction, with the same protocol proposed for muscle channelopathies.
Results: Needle EMG showed myopathic pattern only in 5/25 patients. LET disclosed a significant post-exercise decrease in
CMAP amplitude in 23/25 patients (92%). The decrement appeared immediately after exercise (average -20%) and reached
its maximum (-30%) at 30 min, after a transient plateau phase (lasting 5 to 15 min). This pattern was not observed in
controls: healthy subjects, patients referring for rhabdomyolysis (exluding GSDV), muscle channelopaties. Interestingly,
GSDV patients with normal LET (n=2) presented milder symptoms or minimal myophosphorylase activity on muscle
biopsy.
Discussion and Conclusion: EMG combined with LET detects a peculiar pattern in McArdle disease. This test is sensitive
and specific (>90%), safe and non-invasive. It may orient molecular analysis toward myophophorylase gene in patients
referred for exercise intolerance with hyperCKemia at rest. The abnormalities observed on LET in GSDV explore and
further confirm and the complex biochemical mechanisms determined by the absence of myophosphorylase activity, beyond
the simple glycolytic blockage, such as the reduction of ATP levels and the consequent membrane pumps disfunction. LET
could neurophysiologically demonstrate the post-exercise sarcolemmal inexcitability that is one of the causes of symptoms
occurring after (and not during) efforts in McArdle patients, such as long-lasting myalgias and exhaustion, persistant muscle
pag. 129
contractures, etc. The possibility to evaluate and quantify these post-effort symptoms, and the correlation between the mild
clinical features and the residual biochemical defect in the two patients presenting normal LET, suggest that LET con be
used as outcome measure for potential treatments in GSDV. The LET is an important in vivo study of muscle functioning
not only in primary muscle channelopathies but also in metabolic myopathies that secondarily affect ionic pumps.
References:
− Fournier E et al. Electromyography guides toward subgroups of mutations in muscle channelopathies. Ann Neurol.
(2004);56:650-6
− Vissing J, Haller RG. Mechanisms of exertional fatigue in muscle glycogenoses. Neuromuscul Disord. (2012);22
3:S168-71
− Santalla A et al. McArdle disease: a unique study model in sports medicine. Sports Med. (2014);44:1531-4
EVALUATION OF NEOSTIGMINE RESPONSIVENESS WITH CONCENTRIC-NEEDLE SINGLE FIBER
ELECTROMYOGRAPHY IN MYASTHENIA GRAVIS: A COMPARATIVE STUDY
G. Sciacca, E. Reggio, A. Nicoletti, M. Zappia
Department GF Ingrassia, Section of Neurosciences, University of Catania (Catania)
Introduction: Neostigmine test consists of administration of an intramuscular dose of neostigmine 0.5 mg to demonstrate an
improvement of clinical deficits in patients with Myasthenia Gravis (MG) lasting 2-4 hours. MG-Composite (MGC) scale
measures and weights functional domains affected in the disease (1). The aim of this study is to introduce a new method to
confirm MG diagnosis. We compared Concentric-Needle Single Fiber Electromyography (CN-SFEMG) and MGC score in
ocular and generalized MG patients before and after neostigmine test to prove a neurophysiological melioration in response
to acetylcholinesterase-inhibitors.
Materials and Methods: 27 subjects, whose 10 with ocular MG and 17 with generalized MG, underwent MGC scale and
CN-SFEMG before and after 90 minutes from neostigmine 0.5 mg administration intramuscularly. MGC score and mean
consecutive difference (MCD), potentials pairs having block and single pair jitter were compared before and after
neostigmine test.
Results: Decrement of MGC score after neostigmine administration was not statistically significant (p=0.19) in ocular MG
patients, whereas MGC score significantly improved in generalized group (p=0.04). MCD and percentage of potential pairs
with increased jitter significantly improved after neostigmine administration in all ocular MG patients, (p=0.013 and
p=0.001). MCD, percentage of potential pairs with increased jitter and percentage of potential pairs with blocking in
extensor digitorum communis of 13 generalized MG patients after neostigmine test significantly improved with a p-value of
0.003, 0.001 and 0.026, respectively. MCD of orbicularis oculi in 4 generalized MG patients after neostigmine
administration significantly improved (p=0.024).
Discussion: Two reports previously described the comparison of jitter before and after administration of cholinesteraseinhibitors, evaluating the sensitivity of frontalis stimulated-SFEMG after prostigmine administration (2) and comparing
repetitive-nerve-stimulation of MuSK-Ab-positive and negative patients before and after neostigmine test (3). In our study
we observed a significant improvement of MCD in all patients, both ocular MG and generalized one, regardless of muscle
examined, after neostigmine test. Therefore, MCD may be considered the most reliable parameter of CN-SFEMG to
examine pharmacological response to acetylcholinesterase-inhibitors in both ocular and generalized form.
Conclusion: MCD is a reliable index of subclinical response to acetylcholinesterase-inhibitors in both forms of MG. Clinical
response to neostigmine test has been demonstrated by decrease of MGC score in generalized MG patients, but not in ocular
form. The evaluation of MCD before and after neostigmine test in all MG suspicious patients, especially in seronegative
ocular form, could be an useful and objective instrument for MG diagnosis.
References:
1) Burns TM, Conaway M, Sanders DB; on behalf of the MG-QOL15 study group. The MG Composite. A valid and
reliable outcome measure for myasthenia gravis. Neurology (2010);74: 1434-1440
2) Valls-Canals J, Montero J, Pradas J. Stimulated single fiber EMG of the frontalis muscle in the diagnosis of ocular
myasthenia. Muscle Nerve (2000);23(5):779-783
3) Shin HY, Park HJ, Lee HE, Choi YC, Kim SM. Clinical and Electrophysiologic Responses to Acetylcholinesterase
Inhibitors in MuSK-Antibody-Positive Myasthenia Gravis: Evidence for Cholinergic Neuromuscular
Hyperactivity. J Clin Neurol 2014; 10(2): 119-124. doi: 10.3988/jcn.2014.10.2.119.
CEREBELLAR THETA BURST STIMULATION MODULATES
INTERCONNECTED PARIETAL AND MOTOR AREAS
pag. 130
THE
NEURAL
ACTIVITY
OF
E. Casula1, M. Pellicciari1, V. Ponzo1, M. Stampanoni Bassi1, D. Veniero1, C. Caltagirone2, G. Koch1
1
Non-invasive Brain Stimulation Unit, Santa Lucia Foundation IRCCS (Roma); 2Clinical and Behavioural Neurology
Laboratory, Santa Lucia Foundation IRCCS (Roma)
Voluntary movement control and execution are regulated by the influence of the cerebellar output over different
interconnected cortical areas, through dentato-thalamo connections. However, little is known about the mechanisms through
which the cerebellum exerts its control over the cortex, especially in non-motor areas. In the present study we combined
transcranial magnetic stimulation (TMS) and electroencephalography (EEG) to directly assess the effects of cerebellar
theta-burst stimulation (TBS) over the controlateral primary motor cortex (M1) and posterior parietal cortex (PPC) in a
group of healthy volunteers. 20 healthy volunteers were randomly assigned to a real TBS group receiving continuous
(cTBS) and intermittent (iTBS) in two different sessions; or to a sham TBS group. 80 TMS single-pulses were applied over
M1 and PPC before and after cerebellar TBS, during EEG recordings. We found a TBS-dependent bidirectional modulation
over TMS-evoked activity; specifically, cTBS increased whereas iTBS decreased activity between 100 and 200 ms after
TMS, in a similar manner over both M1 and PPC areas. On the oscillatory domain, TBS induced specific changes over M1
natural frequencies of oscillation: TMS-evoked alpha activity was decreased by cTBS whereas beta activity was enhanced
by iTBS. No effects were observed after sham stimulation. Our data provide novel evidence showing that the cerebellum
exerts its control on the cortex likely by impinging on specific set of interneurons dependent on GABA-ergic activity. We
show that cerebellar TBS modulates cortical excitability of distant interconnected cortical areas by acting through common
temporal, spatial and frequency domains. The current study provides novel physiological knowledge supporting the notion
that by non-invasively stimulating the cerebellum it is possible to bi-directionally modulate specific cortical circuits that
receive input from the lateral cerebellum. Hence, cerebellar TBS makes possible to change at the same time and in the same
direction the activity of different cortical areas forming part of the parieto-frontal network.
CORTICAL EFFECTS OF DERMAL PROPRIOCEPTIVE STIMULATION THROUGH WHOLE-BODY
VIBRATION: A TMS AND QEEG STUDY
M. Fichera , E. Houdayer, A. Maffei, G. Comi, L. Leocani
IRCCS Ospedale San Raffaele - Vita-Salute San Raffaele - Milano
San Raffaele Scientific Institute - Vita-Salute San Raffaele University - Milan
/-/-/
Objective: In the last few years multifocal vibration (MFV) has been reported to modify posture and speed recovery after
physical exercise. The aim of this study is to assess whether MFV, delivered via KEOPE-GPR (global proprioceptive
resonance) system, developed for stimulating Meissner and Pacini corpuscles in the skin without significant stimulation of
deeper structures, can modify resting state EEG and motor cortex excitability as evaluated by transcranial magnetic
stimulation (TMS).
Methods: Eleven healthy subjects were included in this study. All subjects underwent a resting state EEG recording of six
minutes (three with eyes closed and three minutes with eyes open) for evaluation of resting cortical rhythms, before and
after one 12-minutes session of MFV with KEOPE-GPR. Subjects were resting on a platform delivering vibratory stimuli
on ten points located bilaterally under their hands, back, gluteal region, popliteal fossa, heels, at 40-80 Hz. Data obtained
were collapsed in four region of interest (ROIs): frontal, central, temporal and occipital. Frequency bands of interest were δ
(0.5-3.5 Hz), θ (4-7.5 Hz), α1(8-10.5 Hz), α2 (11-12.5 Hz), β1 (13-19.5 Hz), and β2 (20-30 Hz). The ratio between slow
(delta+theta) and faster (alpha1+alpha2) rhythms was evaluated using paired t-test. Subsequent statistical analysis was
carried on using repeated measures ANOVA (RM-ANOVA) using time (2-levels), side (2-levels) and rhythm (6-levels) as
within-subjects factors for each ROI. Motor cortex excitability was assessed on the right first dorsal interossesus-FDI
muscle testing resting motor threshold-RMT, cortical silent period-CSP, short intracortical inhibition-SICI and facilitationICF, motor evoked potential at maximum stimulator output-MEPmax. Statistics were performed with paired t for RMT,
CSP and MEPmax and RM-ANOVA for SICI and ICF, with interstimulus interval-ISI (4-levels) and time (2-levels).
Results: No significant changes were observed on eyes-closed qEEG. With eyes-open, the MFV was associated with
reduced slow/fast frequency ratio (p<.001 for all regions), with significant effect of rhythm and time*rhythm interaction in
frontal (p.046), central (p.003) and temporal (p.004) regions. Post-hoc analysis showed alpha1 and decrease in delta band
relative power in frontal, central and temporal regions. No significant changes were found on cortical excitability measures.
Discussion: MFV can modulate oscillatory activity as observed by qEEG. The increase in alpha band observed in central
pag. 131
regions could be related to an enhancement in mu rhythm.
LASER-EVOKED POTENTIALS AND SKIN BIOPSY TO EVALUATE SMALL FIBER NEUROPATHY IN
FEMALE PATIENTS WITH FABRY DISEASE
R. Infante1, V. Donadio2, E. Pagliarani2, A. Incensi2, V. Di Stasi2, R. Liguori1
1
IRCCS Institute of Neurological Sciences, AUSL of Bologna, Department of Biomedical and NeuroMotor Sciences
(DiBiNeM), University of Bologna (Bologna); 2IRCCS Institute of Neurological Sciences, AUSL of Bologna (Bologna)
Introduction: Fabry Disease is a rare, X-linked, lysosomal storage disease caused by mutations in the gene encoding the acid
hydrolase enzyme alpha-galactosidase. Deficiency in this enzyme causes intracellular accumulation of Gb3 and related
glycosphingolipids in a wide range of cell types throughout the body [1]. The major clinical manifestations include pain in
the hands and feet (acroparesthesia), angiokeratoma, as well as renal, cardiac and cerebrovascular disease. Thus far, many
studies have documented a small fiber loss in distal leg segments of these patients but a direct correlation between laserevoked potentials (LEPs) and skin biopsy is lacking.
Objective and methods: Eight consecutive female patients (age 49.3 ± 16.9) with genetic diagnosis of Fabry Disease were
recruited in order to verify a possible correlation between laser-evoked potentials (LEPs) and skin biopsy (from thigh and
lower leg, by using a 3 mm punch) [2]. LEPs were carried out using an Nd-YAP laser (1340 nm) by stimulating hand, foot
and face skin surface to evaluate potentials from A∆ and C fibers. [3] Skin biopsy and LEP data in patients were compared
to a subset of normative values. Patients underwent motor and sensory conduction velocities from bilateral Tibial and Sural
nerves.
Results: LEPs and skin biopsy mainly showed abnormalities in the distal site whereas motor and sensory conduction
velocities were normal. These data suggested a selective length-dependent small fiber neuropathy in patients with Fabry
disease. Five patients showed abnormal LEPs (63%) and seven patients presented abnormal skin biopsy (88%). Considering
the 5 patients with abnormal LEP 4 of them displayed abnormal skin biopsy (80%).
Conclusions: We found a good concordance between laser-evoked potentials and skin biopsy in evaluating small nerve fiber
neuropathy in patients with Fabry disease. Furthermore skin biopsy seems to present a higher sensitivity in disclosing the
small fiber damage in Fabry disease although a larger number of patients is needed before drawing any definite conclusion.
References:
1. Desnick RJ, Ioannou YA, Eng CM: α-Galactosidase A deficiency: Fabry disease In The metabolic and molecular
bases of inherited disease. 8th edition. Edited by Scriver CR, Beaudet AL, Sly WS, Valle D. New York, USA:
McGraw Hill; (2001):3733–3774.
2. Donadio V, Incensi A, Giannoccaro MP, Cortelli P, Di Stasi V, Pizza F, Jaber MA, Baruzzi A, Liguori R.
Peripheral autonomic neuropathy: diagnostic contribution of skin biopsy. J Neuropathol Exp Neurol. (2012)
Nov;71(11):1000-8
3. Cruccu G1, Aminoff MJ, Curio G, Guerit JM, Kakigi R, Mauguiere F, Rossini PM, Treede RD, Garcia-Larrea L.
Recommendations for the clinical use of somatosensory-evoked potentials. Clin Neurophysiol. (2008)
Aug;119(8):1705-19
MODULATION OF POSTERIOR PARIETAL CORTEX BY NON INVASIVE BRAIN STIMULATION:
EFFECTS ON MEMORY PROCESSES IN HEALTHY VOLUNTEERS
F. Giacalone1, V. Chiarelli1, A. Costumati1, F. Aleo2, G. Giglia1, T. Piccoli1
1
Department of Experimental Biomedicine and Clinical Neurosciences, University of Palermo (Palermo); 2Department of
Neurosciences and Imaging, University of Chieti (Chieti)
Objective: Posterior parietal cortex (PPC) is part of the default mode network (DMN), a set of connected brain regions
known to be anti-correlated to task-related networks. Dysfunction of the DMN regions have been reported in Alzheimer's
disease and in its early stage Mild Cognitive Impairment (MCI), both characterized by memory deficits. Our study aimed to
evaluate how performance in a verbal memory task changes in response to transcranial direct current stimulation (tDCS)
applied over the left PPC of healthy people.
Materials and Methods: Fifteen right-handed healthy volunteers (mean age 25, range 22-30, 67% Female) underwent three
different experimental sessions with anodal, cathodal and sham stimulation respectively, over the left PPC (2mA, for 20')
pag. 132
every seven days. Left PPC was identified by the P3 location of the EEG 10/20 system. Reference electrode was placed
over contralateral frontal region. Each stimulation was followed by a verbal memory task. Reaction times (RTs) and
accuracy were recorded as behavioral output.
Results and Discussion: Repeated measures ANOVA revealed a significant reduction of accuracy on a memory task after
anodal stimulation over PPC compared to sham (p=0,004). We found no difference in accuracy after cathodal stimulation
neither in RTs in any condition. PPC is considered part of the DMN. Normally, activation of a cognitive task-related
network is accompanied by the deactivation of the DMN. Here we showed that excitatory stimulation of PPC is able to
interfere with memory performances, thus supporting the hypotheses of a competitive role of DMN towards the majority of
task-related networks. The finding of no effect on memory processes after inhibitory modulation is consistent with the
reported complex effects of cathodal tDCS on behavioral measures. Previous studies showed that tDCS improves cognitive
performance when stimulation and task were performed simultaneously, whereas task execution after tDCS stimulation was
not significantly improved. We speculate that inhibitory modulation on DMN during a cognitive test execution might leads
to a facilitation on the task-related activity and better cognitive performance. Whether cathodal stimulation induces changes
in memory function remain to be further elucidated. Conclusion: Our study provides interesting evidences of the
interference with memory tasks that we can operate with tDCS. These results invite to further examine the effects of restingstate network inhibition during a memory task. Moreover, this protocol allows for assessment of future trial on patients with
memory decline, such as in MCI patients.
References:
− Buckner RL, Andrew-Hanna JR, Schacter DL The brain’s default network: anatomy, function, and relevance to
disease, Annals of the New York Academy of Sciences (2008);1124:1-38
− Teo F, Hoy KE, Daskalakis ZJ, Fitzgerald PB Investigating the role of current strength in tDCS modulation of
working memory performance in healthy controls. Front. Psychiatry (2011); 2-45
− Nozari N, Woodard K, Thompson-Schill SL Consequences of Cathodal Stimulation for Behavior: When Does It
Help and When Does It Hurt Performance? PLoS ONE (2014);9(1):e84338. doi: 10.1371/journal.pone.0084338
NEUROGENETICA CLINICA
DNAJC13 EXON 24 MUTATION SCREENING IN FAMILIAL PARKINSON'S DISEASE FROM SOUTH ITALY
M. Gagliardi1, G. Iannello1, A. Donato1, G. Annesi1, A. Quattrone2
1
2
Institute of Molecular Bioimaging and Physiology, National Research Council, Section of Germaneto (Catanzaro);
Institute of Neurology, Department of Medical and Surgical Sciences, University Magna Graecia (Catanzaro)
Introduction: Parkinson's disease (PD) is the second most common neurodegenerative disorder, and the most common
neurodegenerative form of parkinsonism. Approximately 14% of patients report a positive family history of PD, and firstdegree relatives are estimated to have a two fold to sevenfold increased risk of disease. A pathogenic mutation (p.N855S) in
DNAJC13 (DnaJ [Hsp40] Homolog, Subfamily C, Member 13) was linked to autosomal dominant Lewy body PD in a
Dutch-German-Russian Mennonite multi-incident kindred, and was found in four additional patients. DNAJC13 (RME-8) is
a DnaJ-domain-containing protein that regulates endosomal trafficking and protein recycling. The p.N855S mutation causes
an accumulation of receptors in endosomal compartments. In this study, we performed a comprehensive screening of
DNAJC13 in familial parkinsonism to assess the frequency of known and novel rare nonsynonymous mutations.
Patients and Methods: All patients were examined and observed longitudinally by movement disorder neurologists and
diagnosed with PD according to published criteria. All participants gave informed consent, and the study has been approved
by local ethics boards. To estimate the frequency of the Asn855Ser (in familial PD), we screened this variant in a southern
Italy PD cohort and control subjects. Our population included 165 patients with familial PD, having at least 1 relative
among their first degree, second degree, in third degree family members with a formal diagnosis of PD, major PD genes had
been analyzed and they were excluded. Genomic DNA was extracted from peripheral blood by standard method. The
purified polymerase chain reaction products were sequenced on an ABI 3500 Genetic Analyzed.
Results and Conclusion: The recent nomination of DNAJC13 p.Asn855Ser as a cause of autosomal dominant PD adds to the
list of candidate genes for this complex neurodegenerative disorder. Our sequencing analysis of 165 patients with PD
identified one carrier of p.Arg903Lys novel mutation in exon 24 of the DNAJC13 gene, highlighting the conserved nature
of this region of the gene/protein. The p.N855S mutation was not identified in our patients. The carrier of p.Arg903Lys has
late-onset PD (AAO 65), and his mother have parkinsonism.
Reference:
− Vilarino-Guell C, Rajput A, Milnerwood AJ, et al. DNAJC13 mutations in Parkinson disease. Hum Mol Genet.
pag. 133
(2014) Apr 1;23(7):1794-801
GAIT PATTERNS IN PATIENTS WITH HEREDITARY SPASTIC PARAPARESIS
C. Casali1, L. Leonardi2, C. Marcotulli2, A. Longobardi2, M. Rinaldi3, A. Ranavolo4, G. Martino5, C. Conte6, T. Varrecchia3,
F. Draicchio4, F. Lacquaniti7, F. Pierelli8, M. Serrao2
1
Department SBMC, Sapienza University (Roma); 2SBMC Department, Sapienza University (Latina); 3Department of
Engineering, Roma TRE University (Roma); 4Department of Occupational and Environmental Medicine, Epidemiology and
Hygiene, INAIL (Roma); 5Centre of Space Bio-Medicine, University of Rome Tor Vergata (Roma); 6Fondazione Don
Gnocchi (Milano); 7Department of Systems Medicine, University of Rome Tor Vergata (Roma); 8IRCCS Neuromed
(Pozzilli-IS)
Objectives: Herein we describe the gait patterns in Hereditary Spastic Paraparesis (HSP) in terms of time-distance,
kinematic, kinetic and electromyographic characteristics, and to identify subgroups of patients according to specific
kinematic features of walking.
Materials and methods: 50 patients with HSP were evaluated by means of computerized gait analysis and compared to a
group of 50 matched healthy participants. We computed time-distance parameters of walking, and the range of angular
motion (RoM) at hip, knee, and ankle joints, and at the trunk and pelvis. Lower limb joint moments and muscle coactivation values were also evaluated.
Results: Three distinct subgroups of HSP patients were identified based on the RoM values. Subgroup 1 was characterized
by reduced hip, knee and ankle joint RoMs. Patients of this subgroup were the most severely affected from a clinical
standpoint, had the most marked spasticity, and walked at the slowest speed. Subgroup 3 was characterized by an increased
hip joint RoM, but knee and ankle joint RoM values were close to control values. These patients were the least affected, and
showed the highest walking speed. Finally, subgroup 2 showed reduced knee and ankle joint RoMs, and hip RoM values
close to control values. Disease severity and gait speed in subgroup 2 were intermediate between those of subgroups 1 and
3.
Conclusions: We identified three distinctive gait patterns in patients with HSP that correlated robustly with clinical data.
The ability to distinguish specific features in gait patterns of patients with HSP may help tailoring pharmacological and
rehabilitative treatments to individual needs, and may be used in evaluating possible future treatments.
SEVERE METHYLENETETRAHYDROFOLATE REDUCTASE (MTHFR) DEFICIENCY: A RARE,
POTENTIALLY TREATABLE CAUSE OF JUVENILE-ONSET HEREDITARY COMPLICATED
HEREDITARY SPASTIC PARAPLEGIA
A. Perna, G. Silvestri
Department of Geriatrics, Orthopaedic and Neuroscience, Institute of Neurology, Catholic University of Sacred Heart
(Roma)
Objectives: To describe two siblings affected by severe MTHFR deficiency manifesting adult-onset progressive spastic
ataxia, responsive to betaine treatment.
Materials: two 27 and 23 year-old siblings, with history of delayed language development and mild mental retardation
developed progressive walking difficulties during their twenties. Family history was negative for neurological diseases.
Methods: diagnostic assessment included: brain and spinal cord MRI, neuropsychological, neurophysiological, ORL and
ophthalmological evaluations, routine blood tests, VLCFA, B12 and folate serum determination, lysosomal enzyme
activities on leukocytes, serum and urine organic acids and aminoacid determination. Molecular screening included analysis
of common AD-SCA, FRDA and FMR-1 loci, SPG7 and SACS. Sequencing of MTHFR coding regions and flanking
sequences in genomic DNA were performed.
Results: Both patients showed spastic ataxia, dysarthria, brisk O.T reflexes and bilateral Babinski. Evoked potentials central
responses were delayed. EEG showed diffuse slowing. Nerve studies documented a sensory-motor polyneuropathy. Brain
MRI showed simmetric T2- weighted and FLAIR hyperintensities in the periventricular white matter. MRI-angiography
was normal. Lysosomal enzymes and VLCFA were normal. Molecular screening for neurodegenerative SCA was negative.
Severe homocisteinemia ( values > 150 micromol/l) associated with homocystinuria and hypomethioninemia, suggestive of
severe MTHFR deficiency, was documented in both patients. Molecular analysis of MTHFR documented in both siblings a
compound heterozigosity for a c237-2G>A intronic substitution and a c1320G>A, both of which would affect mRNA
pag. 134
splicing. Both parents were heterozigous for only one of the two mutations. The common heterozigous c 665C>T was also
detected in both siblings and their father. High doses of betaine, folinic acid, vitamin B12 and B6 and profilactic ASA 100
mg/die were started. Serial clinico-diagnostic re-evaluations showed an improvement of their clinical and diagnostic
findings.
Discussion: Severe MTHFR deficiency is a rare , treatable inherited metabolic condition, with onset usually in infancy or
early childhood. A marked hyperhomocisteinemia associated with hypomethioninemia is the biochemical hallmark of this
condition. Late- onset MTHFR deficiency manifesting with psychiatric and/or neurological symptoms, as those displayed
by our patients, has been rarely described. Also in our patients treatment with betaine, folinic acid, vitamin B12 and B6
produced a clear benefit on clinical, biochemical neurophysiological and brain MRI features.
Conclusion: Severe MTHFR deficiency can be a rare cause of autosomal recessive spastic ataxia in adults, and therefore
should be considered in its differential diagnosis. Its screening is easy, based on homocysteine serum determination, and its
treatment improves neurological symptoms and may prevent further progression.
References:
− Lossos A, Teltsh O, Milman T, Meiner V, Rozen R, Leclerc D, Schwahn BC, Karp N, Rosenblatt DS, Watkins D,
Shaag A, Korman SH, Heyman SN, Gal A, Newman JP, Steiner-Birmanns B, Abramsky O, Kohn Y. Severe
methylenetetrahydrofolate reductase deficiency: clinical clues to a potentially treatable cause of adult-onset
hereditary spastic paraplegia. JAMA Neurol. (2014) Jul 1;71(7):901-4
− Diekman EF, de Koning TJ, Verhoeven-Duif NM, Rovers MM, van Hasselt PM. Survival and psychomotor
development with early betaine treatment in patients with severe methylenetetrahydrofolate reductase deficiency.
JAMA Neurol. (2014) Feb;71(2):188-94
IDENTIFICATION OF MUTATIONS IN PATIENTS FROM SOUTHERN ITALY WITH AMYOTROPHIC
LATERAL SCLEROSIS USING MULTIGENE PANEL TESTING
G. Annesi1, P. Valentino2, M. Gagliardi1, G. Iannello1, E. Filippelli2, A. Granata2, A. Donato1, D. Malanga3, G.
Viglietto3, A. Quattrone2
1
Institute of Molecular Bioimaging and Physiology, Section of Germaneto, National Research Council (Germaneto-CZ);
Institute of Neurology, Department of Medical and Surgical Sciences, University Magna Graecia (Germaneto-CZ);
3
Department of Experimental and Clinical Medicine, University Magna Graecia (Germaneto-CZ)
2
Introduction: Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease that primarily affects motor neurons,
resulting in progressive paralysis and death .About 2 in 100,000 people per year are diagnosed with ALS and the disease is
often ruthlessly progressive. The majority of ALS cases are sporadic, meaning that they occur with no family history of the
disease (sALS). The remaining 5-10% of cases are familial (fALS), where the disease is inherited in a Mendelian, generally
dominant, fashion within a family. While sALS has a complex etiology, with both environmental and genetic factors thought
to play a role, in recent years several genes have been linked to both fALS and sALS. In part due to the accessibility of next
generation sequencing techniques In this study, we performed multigene panel testing to identify mutations in ALS-related
genes.
Patients and Methods: We rolled 25 consecutive patients with sporadic ALS; All participants gave written informed consent,
which was approved by the ethical committee of the University "Magna Graecia" of Catanzaro, Italy. Exome sequencing
was performed using the Ion AmpliSeq Exome kit on Ion Torrent Proton Sequencer. In total, 21 genes were ultimately
selected for the targeted sequencing panel. Several bioinformatics analyses were performed to identify the
functional and structural significance of missense mutations or splice-site variants observed in patients.
Results and Discussion: Based on a comparison with the dbSNP and HGMD databases, we identified known and
unknown pathogenic variants of the 19 ALS-related genes in 25 ALS patients. None of the patients in our cohort harbored
the hexanucleotide repeat expansion of C9orf72. We searched dbSNP and HGMD to identify known pathogenic
variants that had been previously reported to cause ALS. We also identified novel nonsynonymous variants that were
classified as "Probably Damaging" by Poly- Phen2 and Mutation Taster which yielded a list of novel potentially pathogenic
variants. All variants screened were validated by Sanger sequencing Among the potentially pathogenic variants, we
focused on nonsynonymous variants that did not appear in genome databases and were predicted to be pathogenic by an in
silico analysis. Thus, we may have overlooked insertions or deletions that might play a role in the onset of ALS, which
represents a limitation of this study. In conclusion, we have performed the first comprehensive genetic screening of ALSrelated genes with NGS in a small ALS cohort from Calabria.
Reference:
− Renton AE, Chiò A, Traynor BJ. State of play in amyotrophic lateral sclerosis genetics. Nat Neurosci.
(2014) Jan;17(1):17-23
pag. 135
THE NEUROBIOLOGICAL BASES OF COGNITIVE DISORDERS
SYNDROME/EHLERS-DANLOS SYNDROME, HYPERMOBILITY TYPE
IN
JOINT
HYPERMOBILITY
M. Bruschini1, L. Serra1, B. Spanò1, G. Giulietti1, M. Castori2, S. Morlino2, C. Blundo3, P. Grammatico2, M. Colombi4, C.
Caltagirone5, M. Bozzali1
1
Neuroimaging Laboratory, Santa Lucia Foundation IRCCS (Roma); 2Department of Molecular Medicine, University of
Rome 'La Sapienza', San Camillo-Forlanini Hospital (Roma); 3Division of Neurology and Neurophysiopatology, San
Camillo-Forlanini Hospital (Roma); 4Department of Molecular and Translational Medicine, University of Brescia (Brescia);
5
Department of Neuroscience; Department of Clinical and Behavioural Neurology, Santa Lucia Foundation IRCCS,
University of Rome 'Tor Vergata' (Roma)
Objectives: Joint Hypermobility Syndrome/Ehlers-Danlos Syndrome, Hypermobility type [JHS/EDS-HT] is a
heterogeneous connective tissue disorder. Currently, JHS/EDS-HT is considered an autosomal dominant trait whit nearly
complete, age dependent penetrance, and variable expressivity, mainly characterized by generalized joint hypermobility,
complications of joint instability, minor skin changes, and musculoskeletal pain [1]. The JHS/EDS-HT clinical spectrum is
wide, and includes neurological, neuropsychiatric, and neuropsychological symptoms. We studied the neurocognitive
profile of patients whit JHS/EDS-HT to identify specific patterns of cognitive deficits and their neurobiological basis.
Materials and Methods: We recruited a cohort of 35 patients with clinical diagnosis of JHS/EDS-HT [2]. A group of 25
healthy controls (HC) matched for age, gender, and education level with our patients, were also enrolled. To investigate the
different cognitive domains, all participants (HC and JHS/EDS-HT patients) underwent an extensive neuropsychological
battery, including the following tests: verbal episodic long-term memory: 15-Word List; visuo-spatial episodic long-term
memory: Complex Rey’s Figure; short-term memory: Digit span Forward and Backward, and the Corsi Block Tapping task;
reasoning: Raven’s Coloured Progressive Matrices; constructional praxis: Copy of Complex Rey’s Figure; executive
functions: Phonological Word Fluency, and Trial Making Test (Part TMT-A and part TMT-B). One way ANOVA was
performed to compare patients with JHS/EDS-HT and HC, in the neuropsychological measures. All participants underwent
3T MRI for voxel-based morphometry (VBM). Cross-sectional analysis and correlations between grey matter (GM)
volumes and neuropsychological tests were performed.
Results: The neuropsychological assessment revealed some abnormalities in patients’ cognitive profiles. Indeed, JHS/EDSHT patients showed significantly lower scores than controls at tests exploring visuo-spatial short-term memory, complex
constructional praxis, and logical-deductive reasoning. Moreover, JHS/EDS-HT patients performed significantly worse than
HC at Trial Making Test. VBM revealed a significant increase of GM volumes in JHS/EDS-HT patients compared to HC,
involving anterior and posterior cingulate bilaterally. Moreover we found significant positive correlations between GM
volumes and TMT-A scores in the anterior cingulum bilaterally, and between GM volumes and TMT-B scores and right
cerebellum.
Discussion and conclusions: This study showed, for the first time, that Ehlers-Danlos Syndrome, hypermobility type,
associates with specific cognitive profile, characterized by a selective impairment of visuo-spatial and visuo-constructive
skills. Moreover, the cognitive deficits have been found associated with an abnormal increase of the grey matter volumes.
References:
− Castori M., Colombi M. Generalized joint hypermobility, joint hypermobility syndrome and Ehlers-Danlos
syndrome, hypermobility type. Am J Med Genet C Semin Med Genet. (2015);169C:1-5
− Beighton P., et al. “Ehlers-Danlos Syndrome: revised nosology, Villefranche, 1997”. Ehlers-Danlos Foundation
(USA) and Ehlers-Danlos Support Group (UK). Am J Med. Genet. (1998);77:31-37
− Barletta-Rodolfi et al. Kit del Neuropsicologo italiano. Dynamicon Edizioni, (2011) M
CADASIL DUE TO TRUNCATING NOTCH3 GENE MUTATION: THE FIRST BIOPSY-PROVEN CASE
L. G. Pradotto1, M. Mencarelli2, M. Giordana3, S. Gallone4, G. Gentile4, D. Lauro5, A. Milesi1, A. Di Blasio2, A. Mauro3
1
Division of Neurology and Neurorehabilitation, IRCCS Istituto Auxologico Italiano (Piancavallo, VB); 2Laboratory of
Molecular Biology, IRCCS Istituto Auxologico Italiano (Milano); 3Department of Neuroscience, University of Turin
pag. 136
(Torino); 4Department of Neuroscience and Mental Health, Città della Salute e della Scienza (Torino); 5Surgical
Dermatology, Città della Salute e della Scienza (Torino)
Introduction: Cerebral Autosomal Dominant Arteriopathy with Subcortical Infarcts and Leukoencephalopathy (CADASIL)
is systemic small vessel disease in which early onset ischemic strokes and vascular dementia are the main clinical features.
Degeneration of vascular smooth muscle cells (VSMCs) and extracellular accumulation of granular osmiophilic materials
(GOMs) are its pathological hallmarks. CADASIL is due to stereotyped NOTCH3 gene mutations which alter the even
number of cysteines in one of 34 EGF-like repeats of the extracellular Notch3 domain (N3ECD). NOTCH3 gene truncating
mutations were reported in CADASIL-like phenotype and their pathogenic role is still under discussion, as biopsy
confirmation is still lacking. We report a biopsy proven CADASIL patient carrying a new truncating NOTCH3 gene
mutation.
Case Report: A 60-year-old man underwent our observation for migraine with aura, cerebrovascular ischemic events and
typical leukoencephalopathy. The NOTCH3 gene analysis identified the new heterozygous c2727_2728insG insertion
mutation. This frameshift mutation was never reported previously and leaded to a complex alteration of Notch3
(pCys884Trpfs*7), causing the substitution of the cysteine 884 with a tryptophan, the insertion of six new amino acids,
including a new cysteine, and finally the truncation of the protein. The new pCys884Trpfs*7 mutation affected the EGF-like
repeat 22 without altering the odd number of cysteines in this repeat but changing the sixth cysteine position. Skin biopsy
study identified GOMs, VSMC degeneration, and abundant cellular debris.
Discussion: This is the first report of a truncating mutation of Notch3 causing CADASIL. Very few NOTCH3 gene
mutations leading to a premature termination of the protein product were reported. The p.Arg103X Notch3 mutation was
associated with CADASIL-like phenotype, but without GOM identification. The p.Cys67ProfsX34 Notch3 mutation was
identified in a CADASIL patient, but it did not co-segregate with the disease. The homozygous NOTCH3 gene c.C2898A
null mutation was associated with childhood-onset cavitating leukoencephalopathy, VSMC degeneration, but GOMs were
not identified. Comparing to these truncating mutations, our pCys884Trpfs*7 mutation is quite different, as it generated a
long fragment of containing 22 EGF-like repeats and caused a shift of the sixth cysteine position within EGF-like repeat 22,
interfering with disulfide bridge formation. The disruption of a normal disulfide bridge is hypothesized causing the
misfolding of the affected EGF-like repeat, leading to the multimerization of mutated N3ECD and, finally, to VSMC
degeneration. In conclusion, our report expanded the spectrum of Notch3 gene mutation causing CADASIL and gave new
insights in the pathogenic mechanism by which NOTCH3 gene mutations cause CADASIL.
NEUROPHTHALMOLOGICAL AND CLINICAL FINDINGS IN WOLFRAM SYNDROME: INDICATIONS OF
MITOCHONDRIAL DYSFUNCTION
C. La Morgia1, M. Carbonelli2, L. Caporali1, F. Sadun3, C. Tonon4, R. Lodi4, M. Valentino1, P. Barboni2, R. Liguori1, V.
Carelli1
1
IRCCS ISNB, UOC Neurology Clinic, Bellaria Hospital, University of Bologna (Bologna); 2IRCCS ISNB, UOC
Neurology Clinic, Bellaria Hospital (Bologna); 3Ophthalmology Unit, S. Giovanni Evangelista Hospital (Tivoli);
4
Functional MR Unit, S. Orsola-Malpighi Hospital, University of Bologna (Bologna)
Objectives: Wolfram type 1 (WFS1) recessive mutations are associated with Wolfram syndrome (WS), defined by earlyonset diabetes mellitus and optic atrophy (1). A longstanding debate concerned the possible mitochondrial dysfunction in
WS, apparently resolved by the identification the WFS1, a protein mostly localized on the endoplasmic reticulum. We here
explore the possible occurrence of mitochondrial dysfunction in a case-series of WS patients and report clinical,
neuroradiological and ophthalmological findings.
Materials and Methods: We investigated a cohort of 11 WFS1 adult cases (34.3 ± 13.4 years). Neurophthalmological
examination included visual acuity, color vision, pupil, visual field, optical coherence tomography, and fundus picture. In a
subgroup of patients we also evaluated lactic acid after standardized exercise, brain-MRI and spectroscopy.
Results: Age at onset of visual loss was 10.1 ± 4.1 years. All but one had diabetes mellitus and 7/9 had abnormal lactic acid
after exercise. Brain MRI variably demonstrated cortical, brainstem and cerebellar atrophy and white matter changes. Brain
H1-MRS showed lactic acid traces in 1/3. Visual acuity was 0.19 ± 0.18 with impaired color vision in all cases, and
abnormal pupillary response in 7/11. Fundus oculi demonstrated diffuse pallor in 8/11 (more temporal in 3/8) and temporal
pallor in 3/11. Visual fields demonstrated generalized defect in 9/11 and central scotoma in 2/11. OCT demonstrated diffuse
and severe retinal nerve fiber thinning in all cases (p<0.001).
Conclusions: Neurophthalmological phenotype has been purely investigated in WFS1 (2). Severe optic atrophy, more
evident in the temporal sector concordant with a postmortem study showing a mitochondrial pattern of axonal loss (3), and
abnormal lactic acid after exercise, both possibly support a mitochondrial dysfunction in WFS1.
pag. 137
References:
1. Rigoli L, Di Bella C. Wolfram syndrome 1 and Wolfram syndrome 2. Curr Opin Pediatr. (2012) Aug;24(4):512-7
2. Hoekel J, Chisholm SA, Al-Lozi A, Hershey T, Tychsen L; Washington University Wolfram Study Group.
Ophthalmologic correlates of disease severity in children and adolescents with Wolfram syndrome. J AAPOS.
(2014) Oct;18(5):461-465.e1.
3. Ross-Cisneros FN, Pan BX, Silva RA, Miller NR, Albini TA, Tranebjaerg L, Rendtorff ND, Lodahl M, MoraesFilho MN, Moraes MN, Salomao SR, Berezovsky A, Belfort R Jr, Carelli V, Sadun AA. Optic nerve
histopathology in a case of Wolfram Syndrome: a mitochondrial pattern of axonal loss. Mitochondrion. (2013)
Nov;13(6):841-5
A TARGETED-RESEQUENCING PANEL FOR THE ANALYSIS OF 24 GENES ALTERED IN LEBER
CONGENITAL AMAUROSIS
C. Cereda1, A. Asaro1, S. Zucca1, G. Grieco1, M. Valente1, M. Plumari1, S. Signorini2
1
Center of Genomics and post-Genomics, C. Mondino National Neurological Institute (Pavia); 2Child Neurology and
Psychiatry Unit, C. Mondino National Neurological Institute (Pavia)
Objectives: Leber congenital amaurosis (LCA) is a group of early-onset childhood retinal dystrophies characterized by
vision loss, nystagmus and severe retinal dysfunction. Currently, mutations in over 20 genes have been reported to cause
LCA, mostly with an autosomal recessive pattern of inheritance, although genetic heterogeneity hinders the achievement of
a molecular diagnosis. The aim of this study was to obtain a fast and accurate strategy for genetic diagnosis of LCA, to
expand the spectrum of the pathogenic variants and to clarify the patterns of inheritance for not sufficiently characterized
LCA forms.
Materials and Methods: Twenty-seven index patients, referred with diagnosis of LCA were selected for the analysis of 24
genes known be alterated in this disease. Neurophthalmological symptoms typical of LCA were generally observed in all
subjects: congenital blindness or severe visual impairment, severely reduced or absent electroretinogram, nystagmus,
oculodigital sign and variable fundus aspect. Molecular analysis was performed in coding regions by a TruSeq Custom
Amplicon (Illumina) assay for targeted-resequencing.
Results: Two and one mutations were detected in 16 and 6 patients, respectively. Sanger sequencing of uncovered regions
identified further mutations in 4 patients. The segregation analysis was performed on the available parents. Twenty cases
were fully diagnosed: 7 homozygotes and 12 compound heterozygotes (recessive genes), and one heterozygous subject, the
latter one with a pathogenic variant in dominant CRX gene, not present in the parents and likewise reported in literature as
de novo mutation in an unrelated family. Interestingly, this patient displayed light gazing, myopia, astigmatism, mild
craniofacial dysmorphism and mild cognitive impairment. Overall, 32 different pathogenetic variants were identified, some
of which were new mutations. Discussion: Most pathogenic variants were truncating mutations, stop-gains or frameshift
indels, although missense and splicing mutations were also identified. Despite the small number of analyzed patients, the
highest frequency of mutations was found in 6 major recessive genes (GUCY2D, AIPL1, CEP290, SPATA7, NMNAT1,
RPGRIP1) in agreement with data from previous studies.
Conclusions: In a high percentage of confidently diagnosed LCA patients, mutations may be found in known recessive
genes. Our targeted-resequencing gene panel allows to detect a high number of described and new mutations, turning out to
be a method valid for the genetic diagnosis of LCA and useful for the genotype-phenotype correlation in this disease.
DEMENZA E INVECCHIAMENTO 2
ALTERED EXPRESSION OF NON-CODING RNAS IN NEURAL-DERIVED SERUM EXOSOMES IN
PATIENTS WITH FRONTOTEMPORAL DEMENTIA
D. Galimberti1, C. Fenoglio1, M. Serpente1, S. Cioffi1, M. Arcaro1, E. Oldoni1, G. Fumagalli1, A. Arighi1, P. Basilico1, A.
Cattaneo2, L. Porretti2, E. Scarpini1
1
Dept. of Pathophysiology and Transplantation, University of Milan, Fondazione Ca’ Granda, IRCCS Ospedale Maggiore
Policlinico (Milano); 2Clinical Chemistry and Microbiology Laboratory, Flow Cytometry and Experimental Hepatology
Service, Fondazione Ca’ Granda, IRCCS Ospedale Maggiore Policlinico (Milano)
pag. 138
Background: Blood contains exosomes released by various cell types, which may serve as potential biomarkers for
diagnostic and prognostic use. Exosomes are a class of endosome-derived membrane vesicles shed by neural cells, which
contain proteins and other constituents of their cellular origin. Exosomes are a naturally enriched source of non coding
(nc)RNAs such as micro(mi)RNA and long non coding (lnc)RNA; therefore their identification at serum level in neural
derived exosomes would provide new insights for the identification of reliable peripheral biomarkers in FTD. The aim of
our study was to detect a specific neuronal signature of ncRNAs at serum level that could be considered as biomarker of
pathology.
Aims and Methods: We set up methods for total ncRNA extraction from neural derived exosomes. Serum from 5 FTD, 5
healthy controls was incubated with ExoQuick exosome precipitation solution (SBI). Subsequently, exosomes were
enriched for neural sources by anti-human L1CAM antibody immunolabel and analyzed by flow cytometry (FACS Aria,
BD). The total exosome RNA and Protein isolation kit (Thermo Fisher) was used to isolate ncRNAs from neural derived
exosomes. ncRNA profiling was performed by testing the expression of 84 miRNAs (miFinder array, Qiagen) and the
expression of 160 lncRNAs (lncRNA Finder and Inflammatory response and Autoimmunity lncRNA arrays, Qiagen).
Results: A robust dysregulation in several ncRNAs levels in patients compared with controls was observed. In particular, 7
miRNAs were downregulated and 5 out of 84 showed upregulated expression levels. Conversely, 58 lncRNAs were found
to be downregulated whereas 25 out of 160 were found to be upregulated. Among these, TUG-1 levels, a lncRNA expressed
in brain and found to be involved in neurodegeneration, was found to be significantly increased in patients compared with
controls (2.5 fold change, P<0.05).
Discussion: These preliminary results showed a different signature between FTD patients versus controls. The investigation
for the first time of a specific signature constructed by ncRNAs from neural derived serum exosomes could have a great
potential in the field of clinical biomarkers discovery for FTD, and could also contribute to clarify the molecular
mechanisms underneath FTD pathology.
ATXN2 POLYQ INTERMEDIATE REPEATS
FRONTOTEMPORAL LOBAR DEGENERATION
INFLUENCE
THE
CLINICAL
PHENOTYPE
IN
E. Rubino1, C. Mancini2, P. Ferrero3, M. Ferrone4, S. Bianca1, A. Vacca1, S. Boschi1, M. Zucca1, L. Orsi3, S. Gentile3, L.
Pinessi1, A. Brusco2, I. Rainero1
1
Department of Neuroscience "Rita Levi Montalcini", University of Turin (Torino); 2Department of Medical Sciences,
University of Turin (Torino); 3Neurology I, AOU Città della Salute e della Scienza di Torino (Torino); 4Medical Genetics
Unit, AOU Città della Salute e della Scienza di Torino (Torino)
Objectives: Several studies showed that frontotemporal lobar degeneration (FTLD) and amyotrophic lateral sclerosis (ALS)
share a significant genetic background. Genes linked to both diseases may converge into common pathogenic pathways,
explaining the overlap of clinical symptoms. The ataxin-2 (ATXN2) gene is located on 12q24.12 and encodes ataxin, a
multifunctional protein implicated in several cellular activities like mRNA processing, and endocytosis. Intermediate repeat
expansions (27-33 CAG repeats, polyQ) of the Ataxin2 (ATXN2) gene are risk factor for ALS and influence ALS
phenotype, whereas expansions ≥34 repeats cause spinocerebellar ataxia type 2. At present, the role of ATXN2 in FTLD has
been scarcely investigated. The aim of this study was to investigate whether ATXN2 is a risk factor for frontotemporal lobar
degeneration or influence the clinical presentation.
Material and Methods: Two hundred and forty three unrelated patients with FTLD and 176 controls were involved in the
study. The ATXN2 CAG repeat in exon 1 (NM_002973.3) was amplified in cases and controls. We also evaluated whether
the expansions in ATXN2 associated with FTLD were pure or interrupted CAG repeats.
Results: No difference in the frequency of intermediate CAG repeats in ATXN2 gene was found between FTLD patients
and controls (p=0.234). Neither patients nor controls showed a fully expanded ATXN2 allele. CAG repeats were not
interrupted in FTLD patients with 30 and 32 repeats. Patients with an increased number of CAG repeats had an earlier onset
of the disease than those without intermediate expansions (p= 0.037). Patients with intermediate repeat expansions
presented more frequently with parkinsonism (p=0.006, odds ratio 4.2, 95% CI 1.4–12.6). In addition, executive dysfunction
correlates with intermediate length expansions (Pearson's correlation, p=0.038).
Discussion and conclusions: Our study confirmed that intermediate CAG expansion of the ATXN2 gene is not a genetic
risk factor for FTLD. However, intermediate CAG repeat expansions influence the clinical phenotype also in patients with
FTLD, being associated to a significantly earlier onset of the disease and parkinsonian features.
DIFFERENT HIPPOCAMPAL SUBFIELDS INVOLVEMENT IN AD AND PDD: A MULTIMODAL 3T MRI
STUDY
pag. 139
F. Novellino1, R. Vasta1, A. Sarica1, C. Chiriaco1, M. Vaccaro2, M. Morelli2, M. Salsone1, G. Arabia2, F. Rocca1, G.
Nicoletti1, A. Quattrone1,2
1
Institute of Bioimaging and Molecular Physiology, National Research Council (Catanzaro); 2Institute of Neurology,
University “Magna Graecia” (Catanzaro)
Objective: We performed a multimodal hippocampal MRI study in a sample of patients with Alzheimer’s Disease (AD) and
Parkinson’s Disease with Dementia (PDD) to investigate how changes in whole hippocampus and his subfields relate to
memory recall and recognition in different forms of dementia. For this purpose, we correlated hippocampal MRI findings
with mnesic assessment trough the Free and Cued Selective Reminding Test (FCSRT), a hippocampal-targeted
neuropsychological paradigm.
Methods: The study sample included 22 AD, 18 PDD, and 21 PD patients, and 17 healthy controls. A careful
neuropsychological assessment (including FCSRT) and a 3-T MRI protocol (including whole-brain T1-weighted and
Diffusion Tensor Imaging [DTI]) were performed. Volume, mean diffusivity (MD) and fractional anisotropy (FA) of
automatically segmented hippocampus (whole and subfields) were extracted, as well as a shape analysis of hippocampus.
Correlations between MRI-derived parameters and clinical and neuropsychological evaluations were also performed.
Results: ANOVA showed a strong overall difference among the groups in the entire hippocampus in volume (left and right:
p<0.0001) and MD values (left and right: p< 0.0001), with a grading in the increase of both these measures according to the
order AD, PDD, PD and controls. FA values also showed significant differences among groups (left: p<0.001; right:
p=0.002). In the subfields analyses, the comparison between AD and PDD groups revealed a significant volume reduction
in the right subiculum (p=0.02), an increased MD in the bilateral CA1 (right p=0.004; left p=0.016) and hippocampal fissure
(right p=0.007; left p=0.006), in the left presubiculum (p=0.015), and in the right CA4-DG (p=0.018) and subiculum
(p=0.013). A significant correlation between FCRST scores and hippocampal subfields measurement was found in AD
group. Shape-analysis also corroborated these results showing a significant correlation in AD group between CA1 and
subiculum in the right hippocampus.
Discussion and conclusion: The combination of an in vivo analysis of hippocampal subfields with the FCSRT paradigm
provided important insights into whether memory processing is associated with the function of specific hippocampal
subfields and improved knowledge of anatomo-clinical correlates of cognitive impairment across different diseases. These
results show that hippocampal subregions have different vulnerability to AD-linked damage. Subiculum, CA4DG and
presubiculum were the regions more strictly involved in AD and related to cued recall. The assessment of regional
hippocampal changes may improve the knowledge of specific AD-related mnesic profile, and provide more refined
recognition of AD patients
References:
− Dubois B., Feldman H.H., Jacova C. et al. Research criteria for the diagnosis of Alzheimer’s disease: revising the
NINCDS–ADRDA criteria. Lancet Neurol. (2007):6;734–746
− Sarazin M, Chauviré V, Gerardin E, et al. The amnestic syndrome of hippocampal type in Alzheimer's disease: an
MRI study. J Alzheimers Dis. (2010);22:285-94
A QUALITATIVE MRI-DWI SCORE PROVIDES USEFUL INSIGHT INTO CLINICAL PHENOTYPE,
MOLECULAR SUBTYPE AND SURVIVAL IN CREUTZFELDT-JAKOB DISEASE
F. Fragiacomo1, G. Gazzola1, S. Viccinanza2, G. Zanusso3, B. Giometto4, R. Manara2, A. Cagnin1
1
Department of Neurosciences, University of Padua (Padova); 2Department of Medicine and Surgery, University of Salerno
(Salerno); 3Department of Neurological and Movement Sciences, University of Verona (Verona); 4Neurology Clinic,
Sant'Antonio Hospital (Padova)
Objectives: Neuroradiological criteria for diagnosis of sporadic Creutzfeldt-Jakob disease (sCJD) include hyperintensity on
DWI or FLAIR sequences in at least two cortical regions (parietal, temporal or occipital), or in the caudate nucleus and
putamen. However, there are only few studies exploring which MRI sequences and brain regions are more informative to
support CJD diagnosis. Aim of this study was to validate a new qualitative MRI score in CJD diagnosis and to study the
relationship between MRI lesion patterns and clinical features.
Materials and methods: 32 patients with diagnosis of definite or probable CJD (either by autopsy or with RT-Quick-CSF
technique) and 16 healthy subjects were included. All participants had a MRI study with both DWI and FLAIR sequences.
Clinical features and PRNP gene polymorphism were also recorded. MRI images were evaluated with a semi-quantitative
score, which separately considered the extent and degree t of MRI signal intensity in 22 brain regions, both in DWI and
FLAIR.
pag. 140
Results: In CJD patients the semi-quantitative score showed a better definition of MRI lesions (extent and hyperintensiy) in
DWI compared to FLAIR for cortical regions (p <0.01). Insula and cerebellum were the only regions that did not
differentiate CJD patients from controls, neither in intensity nor in extent of MRI signal. Among CJD patients the VV
subgroup had the lowest scores in the cortical regions while the MM subgroup showed lower scores in the thalamus.
Involvement of pulvinar and hockey stick sign were prevalent in MV2 subgroup. The cognitive-behavioral clinical
phenotype was associated with a greater extent (p=0,01) and hyperintensity (p<0,01) of cortical lesions in respect to the
ataxic phenotype, in which the subcortical lesion load was prominent. A positive correlation between the cortical lesion load
and disease duration (signal intensity: r=0,60; p<0,01; lesion extent: r=0,47; p=0,02) and an inverse correlation between the
extent of cortical (p=0,04) and subcortical (p=0,05) lesions and survival were found.
Discussion and conclusions: Our results suggest that MRI analysis for suspected CJD should analyzed DWI-based images,
observing all cortical regions including frontal lobes and excluding insula and cerebellum. Moreover, analysis of extension
and degree of signal alterations in DWI provides information on the likely molecular subtype and also have prognostic
value for survival.
HOW CHRONIC OBSTRUCTIVE PULMONARY DISEASE MAY COMPLICATE ALZHEIMER’S DISEASE: A
COMORBIDITY PROBLEM
G. Tondo, E. Terazzi, P. Prandi, F. De Marchi, M. Sacchetti, R. Cantello
Department of Translational Medicine, Section of Neurology, University of Eastern Piedmont (Novara)
Aims: Chronic obstructive pulmonary disease (COPD) is a common lung illness that entails a clear deterioration in the
quality of life; furthermore it may be associated with worsening of cognitive performance. By means of a retrospective
study on patients with Alzheimer's Disease (AD) with and without COPD, we analyzed clinical and neuropsychological
variables to verify if COPD plays a pejorative role on cognitive or functional autonomy in patients with dementia.
Materials: We enrolled 17 adult patients (AD-COPD) with probable AD (according to NINCDS-ADRDA criteria) and
COPD (diagnosed according to Global Initiative for COPD guidelines) and 17 with AD only (AD); they were matched for
sex, age, educational level and Mini Mental State Examination (MMSE) at the disease onset.
Method: We analyzed cognitive and behavioral aspects. Global cognitive status was estimated using MMSE at the first
assessment and after 24 months. Memory, executive functions, praxia and language were the cognitive functions analyzed.
The two groups were also compared for the presence of anxiety, depression or delirium.
Results: AD-COPD had worse performances in executive functions tests than AD; no significant differences were found
comparing other cognitive domains; no significant difference there was between the two groups considering the decrease in
MMSE score. Regarding behavioral aspects, the most remarkable result was a higher incidence of delirium in AD-COPD
than in AD (53% vs 12%), with a statistical significance (p 0.025); moreover AD-COPD also showed an higher presence of
depression (35% vs 18%).
Discussion: COPD is known to be associated with the development of cognitive deficits. Executive functions and attention,
memory and logical reasoning are the cognitive domains usually most affected. In this context, MMSE has a low diagnostic
accuracy to underline effective cognitive impairment in AD-COPD. It’s also clearly documented an association between
COPD and behavioral disorders, such as depression, anxiety and delirium.
Conclusions: Our study shows a higher frequency of frontal deficits and behavioral disturbances in patients with AD and
COPD in comparison with patients with AD only. In particular, we found a greater incidence of delirium, just in the early
stages of the disease. Comorbidity with COPD could make more complex the management of AD patients, that could
benefit from a closer and multidisciplinary monitoring.
References:
− Schou L, Østergaard B, Rasmussen LS, Rydahl-Hansen S, Phanareth K. Cognitive dysfunction in patients with
chronic obstructive pulmonary disease e A systematic review, Respiratory Medicine, (2012);106:1071-1081
− De Carolis A, Giubilei F, Caselli G, Casolla B, Cavallari M, Vanacore N, Leonori R, Scrocchia I, Fersini A,
Quercia A, Orzi F. Chronic Obstructive Pulmonary Disease Is Associated with Altered Neuropsychological
Performance in Young Adults, Dement Geriatr Cogn Disord Extra, (2011);1:402–408
− Wilson I. Depression in the patient with COPD, International Journal of COPD (2006):1(1);61–64
SKIN NERVE α-SYNUCLEIN DEPOSITS AS POSSIBLE NEW BIOMARKER FOR DEMENTIA WITH LEWY
BODIES
V. Donadio1, A. Incensi1, S. Capellari1, G. Rizzo2, R. Pantieri1, M. Stanzani Maserati1, G. Devigili3, R. Eleopra3, F.
Montini1, A. Baruzzi1, R. Liguori2
pag. 141
1
IRCCS Istituto Scienze Neurologiche (Bologna); 2IRCCS Istituto Scienze Neurologiche di Bologna and Department of
Biomedical and Neuromotor Science, University of Bologna (Bologna); 3Neurological Unit, Dept of Neuroscience,
University Hospital of Udine (Udine)
Objective: To investigate whether: 1) phosphorylated α-synuclein (p-syn) deposits in peripheral nerves might represent a
useful biomarker in dementia Lewy Body (DLB) helping to differentiate DLB from other forms of dementia; 2) small fiber
neuropathy (SFN) may be part of DLB pathological picture contributing to autonomic dysfunctions.
Methods: 21 well-characterized DLB patients (12 of them complaining autonomic symptoms particularly orthostatic
hypotension) were studied together with 23 patients with dementia of different pathogenesis (Dementia without synucleinDWS) including 13 patients fulfilling diagnostic criteria for Alzheimer’s disease, 6 with Frontotemporal Dementia and 4
with vascular dementia. Twenty-five age-matched healthy subjects served as controls. Subjects underwent: nerve
conduction velocities from the leg to evaluate large nerve fibers; skin biopsy from proximal (i.e. cervical) and distal (i.e.
thigh and distal leg) sites to study small nerve fibers and deposits of phosphorylated α-synuclein, considered the
pathological form of α-synuclein.
Results: P-syn was not found in any skin sample in DWS patients and controls but it was found in all DLB patients with a
proximal-distal gradient with all patients positive in the cervical site. Patients complaining of autonomic symptoms showed
higher widespread positivity of analyzed skin samples than patients without autonomic symptoms. Furthermore DLB
patients showed a length-dependent SFN particularly important in patients complaining autonomic symptoms.
Conclusions: 1) p-syn in peripheral nerves is a sensitive biomarker for DLB diagnosis helping to differentiate DLB from
other forms of dementia; 2) SFN was part of DLB pathological picture contributing to induce autonomic symptoms.
GENDER DIFFERENCES IN DELIRIUM VULNERABILITY IN ACUTE NEUROLOGICAL INPATIENTS
L. Rozzini, A. Ceraso, A. Padovani
1
Department of Clinical and Experimental Sciences, University of Brescia (Brescia); 2Department of Medical and Surgical
Specialties, Radiological Sciences and Public Health, University of Brescia (Brescia)
Objective: Delirium is a common syndrome among elderly patients. It is considered as an independent risk factor for
undiagnosed and subsequent impairment, regarding both cognitive and functional domains. Male sex is seemingly
predisposing to delirium occurrence; gender differences in risk factors for greater delirium severity have been analysed
within literature, suggesting that women with higher frailty and co-morbidity at baseline experience more serious delirium,
while, for men, severity steps up in those with less education. It is not clear whether gender plays a significant role in
determining delirium recovery trajectories and associated short-term outcomes. Our aim was to investigate this matter in an
acute neurological setting.
Materials: 83 consecutive neurological inpatients (males=42, females=41) developing prevalent or incident delirium.
Subjects who developed delirium due to abstinence from alcohol weren’t included.
Methods: Patients were studied for age, education, premorbid dementia, MMSE, APACHE, CIRS, Rankin, Tinetti, albumin
level, politheraphy, Barthel Index (at admission and discharge), delirium motor subtype, delirium presumable cause, length
of hospitalisation, and allocation. Influence of gender on each recorded parameter was investigated.
Results: Mean age and education level were similar between genders, as were mean MMSE scores and length of hospital
stay; infective conditions (especially urinary tract and lung infections) were the most recurring cause (34,1% in females and
35,7% in males respectively). Women more often presented hypoactive delirium (females: 26,8% vs males: 16,7%); while
men developed hyperactive or mixed form (females: 73,2% vs males: 83,3%). Females appeared to have greater comorbility and higher motor impairment at baseline than males (at admission: Barthel Index 55,3±28,3 vs 60,9±38,7, p>0.05;
Tinetti 17,5±9,9 vs 20,3±6,9, p >0,05; Rankin 3,1±1,4 vs 2,4±1,6; p<0,05), suggesting that males may actually have higher
vulnerability to delirium. Mean Barthel Index reduction rate at discharge was lower in females in comparison with males (9,0 ± 23,9 vs -19,8 ± 25,9, p=0,05), implying that men were likely to suffer higher functional deterioration immediately
after delirium.
Discussion: Our data fortify previous literature’s hypothesis concerning higher susceptibility to delirium in males, from both
development and recovery course point of view: further research is vital to confirm this finding and to investigate its
potential long-term prognostic implications. We are currently exploring (with 6-months follow-up evaluation) the potential
higher long-term functional impairment in males.
Conclusions: Demonstration of contrasting health consequences of delirium in men and women may be critical for
developing individualised interventions for prevention, treatment and monitoring of this condition.
References:
pag. 142
−
−
−
Inouye S.K., Westendorp R.G.J. et al., Delirium in elderly people, Lancet (2014);383:911-922
Kolanowski A.M., Hill N.L.; Kurum E., Fick D.M. et al., Gender differences in factors associated with delirium
severity in older adults with dementia, Arch. Psych. Nurs. (2014);28:187-192
Jackson T.A. et al., Predicting outcome in older hospital patients with delirium: a systematic literature review. Int
Geriatr Psych (2016) Apr;31(4):392-9
IN VIVO CORRELATES OF PATHOLOGICAL DIAGNOSIS IN CLINICAL VARIANTS OF PRIMARY
PROGRESSIVE APHASIA
E. G. Spinelli1, M. Mandelli2, M. Santos2, S. Wilson2, F. Agosta1, J. Trojanowski3, E. Huang2, L. Grinberg2, B. Miller2, W.
Seeley2, G. Comi4, M. Filippi1, M. Gorno-Tempini2
1
University (Milano); 2Memory and Aging Center, University of California (San Francisco, USA); 3Department of Pathology
and Laboratory Medicine, University of Pennsylvania (Philadelphia, USA); 4Department of Neurology, San Raffaele
Scientific Institute, Vita-Salute San Raffaele University (Milano)
Objectives: Clinical and neuroanatomical heterogeneity within clinical variants of primary progressive aphasia (PPA) is
thought to derive from specific pathologic correlates. Large clinicopathological series of prospectively evaluated PPA
patients are still lacking. This study aims to investigate the relationship between in vivo clinical, cognitive and MRI features
and neuropathological findings in a large cohort of PPA patients defined by current diagnostic criteria.
Materials: Data were collected from 70 patients with sporadic PPA, divided into 29 semantic (svPPA), 26 nonfluent/agrammatic
(nfvPPA),
11
logopenic
(lvPPA)
and
4
mixed
PPA.
Methods: Neuropathological diagnoses were established following standard protocols. Patterns of grey matter (GM) and
white matter (WM) atrophy at presentation were assessed and tested as predictors of pathological diagnosis using support
vector
machine
(SVM)
algorithms.
Results: A clinical diagnosis of PPA was associated with frontotemporal lobar degeneration (FTLD) with TDP inclusions in
41%, FTLD-tau in 40%, and Alzheimer’s disease (AD) pathology in 19% of cases. Each variant was associated with one
typical pathology: 25/29 (86%) svPPA showed FTLD-TDP, 22/26 (85%) nfvPPA showed FTLD-tau, and all 11 lvPPA had
AD. Within FTLD-tau, Pick’s disease (PiD) was observed across all variants except for lvPPA. Within FTLD-tau, Pick’s
disease (PiD) was observed across all clinical variants but lvPPA. Compared with pathologically typical svPPA-TDP,
svPPA-tau showed significant extrapyramidal signs, greater behavioral and executive impairment, and severe striatal,
medial temporal and orbitofrontal GM and WM atrophy. Compared with nfvPPA-tau, nfvPPA-TDP patients showed
absence of behavioral symptoms and selective GM atrophy. PiD was associated with early neuropsychiatric symptoms and
extensive frontotemporal atrophy. Combining GM and WM volumes, SVM analysis showed the highest accuracy (92.9%)
to
distinguish
FTLD-tau
and
FTLD-TDP
pathologies
across
variants.
Discussion and conclusion: The application of current diagnostic criteria allowed for strong clinicopathological
relationships within PPA variants, although specific clinical and early anatomical features may suggest atypical pathological
diagnosis within each variant in vivo. Particularly, the differential involvement of WM shown by neuroimaging may
constitute a key biomarker to discriminate FTLD pathological subtypes.
NEUROONCOLOGIA
THE UTILITY OF MOLECULAR PCR ASSAYS TO DETECT CLONAL REARRANGEMENT IN
IMMUNOGLOBULIN AND T-CELL RECEPTOR VDJ-REGION GENES IN CSF SAMPLES OF SUSPECTED
LYMPHOPROLIFERATIVE DISEASES
F. Massa1, C. Lapucci1, E. Giorli2, M. Godani2, S. Zupo3, G. Cerruti3, D. Siccardi4, S. Boni5, C. Serrati6, G. Mancardi1, L.
Benedetti1
1
Department of Neuroscience, Rehabilitation, Ophthalmology, Genetics, Maternal and Child Health (DINOGMI),
University of Genova, IRCCS AOU San Martino-IST (Genova); 2Department of Neurology, S. Andrea Hospital (La
Spezia); 3Molecular Diagnostic Unit, IRCCS AOU San Martino-Institute of National Cancer Research (Genova);
4
Department of Neurosurgery, IRCCS AOU San Martino-IST (Genova); 5U.O Infectious Diseases and Hepatology Unit, S.
Andrea Hospital (La Spezia); 6Department of Neurology, IRCCS AOU San Martino-IST (Genova)
pag. 143
Objectives: CNS lymphoproliferative diseases are rare malignant tumors occurring with or without systemic involvement.
Histopathological approach is considered the diagnostic gold standard, but its risks and technical pitfalls limit routinary and
widespread use. According to literature a combined approach comprehensive of clinical, radiological, serum and
cerebrospinal fluid (CSF) studies represents a useful presurgical evaluation. CSF citology can identify atypical lymphoid
cells with high specificity but low sensibility. Clonal rearrangement in immunoglobulin and T-cell receptor genes is
reported to have a sensitivity of 58% and a specificity of 85% in detection of monoclonal cells production, giving indirect
sign of lymphoproliferative neoplasms. Aim of our study is to analyse retrospectively the clinical significance of clonal
rearrangement detection through molecular PCR assays in CSF samples of patients with suspicious lymphoproliferative
diseases.
Materials and Methods: We retrospectively analysed 42 patients which performed molecular CSF analysis to investigate
clinically or radiologically suspicious lymphoproliferative diseases. We collected standardized PCR assays able to detect
clonal rearrangement in immunoglobulin and T-cell receptor VDJ-region genes in CSF samples, of whom DNA was
extracted. PCR-amplified gene segments were distinguished, according to their length, by capillary electrophoresis in
monoclonal, oligoclonal, or policlonal VDJ-region gene rearrangement pattern. These data were matched to available
histological reports from brain biopsy or to clinically or radiologically-driven diagnoses when brain biopsy was not
obtainable.
Results: According to clonal rearrangement in immunoglobulin heavy chain VDJ-region genes in CSF samples, 10 of 42
patterns were policlonal (23,80%), 18 oligoclonal (42,85%), 3 monoclononal (7,14%), while in the remaining 11 patients
(26,19%) one single clonal peak was detected in a background of oligoclonal pattern. Lymphoproliferative disease was
assessed in 1/10 of B policlonal patterns, in 4/18 (22,22%) of oligoclonal patterns, in 2/3 (66,66 %) of monoclonal patterns
and in 9/11 (81,81%) of patients with one single peak in oligoclonal patterns.
Discussion: This is the first study to evaluate the clinical significance of PCR-assayed clonal rearrangement in B- or T-cells
in CSF. Our results show that the majority of patients in which a single clonal peak in immunoglobulin heavy chain VDJregion genes was detected, both isolated or in a oligoclonal background, actually have an history of systemic or primary
CNS lymphoproliferative disease.
Conclusions: PCR assessment can be a useful tool to detect clonal population in CSF of suspicious lymphoproliferative
disease, enforcing indication to invasive bioptic procedures and allowing a specific therapeutic approach. Further studies are
warranted.
References:
− Scott BJ, Douglas VC,Tihan T, Rubenstein JL, Josephson SA. A Systematic Approach to the Diagnosis of
Suspected Central Nervous System Lymphoma. JAMA Neurol. (2013) March 1; 70(3): 311–319
− Weller M, Stevens A, Sommer N, Schabet M, Wiethölter H. Humoral CSF parameters in the differential diagnosis
of hematologic CNS neoplasia. Acta Neurol Scand. (1992); 86(2):129–133
− Baehring JM, Hochberg FH, Betensky RA, Longtine J, Sklar J. Immunoglobulin gene rearrangement analysis in
cerebrospinal fluid of patients with lymphoproliferative processes. J Neurol Sci. (2006); 247(2):208–216
RELAPSING - BUT NOT COMPLETELY REMITTING - STROKE-LIKE MIGRAINE ATTACKS AFTER
RADIATION THERAPY (SMART) SYNDROME: A CASE REPORT
G. Perini1, L. Diamanti1, P. Bini2, L. Farina2, E. Rognone2, S. Bastianello1, A. Costa1, M. Ceroni1, E. Marchioni2
1
C. Mondino Neurological National Institute IRCCS, C. Mondino Neurological National Institute IRCCS/University of
Pavia (Pavia); 2C. Mondino Neurological National Institute IRCCS, C. Mondino Neurological National Institute IRCCS
(Pavia)
Background: Stroke-Like Migraine Attacks after Radiation Therapy (SMART) is a late-delayed radiation-induced
complication, characterized by transient, and possibly recurrent, neurological symptoms and/or signs, due to unilateral
cortical impairment (1). The recovery, which ranges from hours to weeks, can be partial or complete (2). The most typical
brain MRI findings are reversible unilateral gyriform enhancement on T1-images, abnormal T2/FLAIR signal with mild
mass effect, and sequelae, such as cortical laminar necrosis.
Case Report: We present the case of 41-year-old man, that underwent whole-brain radiation therapy in 1988 for cerebellar
medulloblastoma. After decades, he presented recurrent and prolonged episodes of unilateral cortical dysfunction,
predominantly in the posterior areas of the brain, not always with complete recovery. In 2006 and 2010 he presented with
left and right homonymous hemianopia respectively, with MRI evidences of cortical gadolinium enhancement and
correlative abnormal T2 and FLAIR signal. EEG showed correspondent lobe seizures. He manifested also frequent migraine
attacks, with or without aura. During the last episode in April 2016, the neurological examination revealed left
pag. 144
homonymous hemianopia, right homonymous quadrantanopia and mild left hemiparesis. Brain MRI evidenced T2/FLAIR
hyperintensity in the right temporo-parieto-occipital hemisphere, with moderate mass effect, and T1 gyral enhancement in
the same areas. Gliotic/malacic sequelae was present in the left occipital lobe. CSF analysis showed increased protein levels
(albumin, 45 mg/dl) without significant pleocytosis (8 lymphocytes/mm3). EEG showed focal slow abnormalities,
corresponding to the lesion. The patient received intravenous steroids, and subsequently oral tapering. The follow up is still
ongoing, but the visual deficit is improving. A brain MRI in June 2016 confirms radiological improvement as well.
Discussion and Conclusion: SMART should always be considered in presence of focal neurological symptoms and/or signs,
and positive history of whole-brain radiation therapy (3). Brain MRI can confirm the diagnosis, because the radiological
abnormalities are typical. Our case report demonstrates that SMART syndrome can be recurrent, even though not always
reversible. The pathogenesis is still unknown, but it is postulated a postirradiation inflammatory endothelial damage which
may lower the threshold required to develop episodic CNS hyperexcitability. Prompt diagnosis is desirable, because of the
apparent steroid responsiveness.
References:
1. Black DF, Bartleson JD, Bell ML, et al. SMART: stroke-like migraine attacks after radiation therapy. Cephalalgia
(2006) Sep;26(9):1137-42
2. Black DF, Morris JM, Lindell EP, et al. Stroke-like migraine attacks after radiation therapy (SMART) syndrome is
not always completely reversible: a case series. AJNR Am J Neuroradiol. (2013) Dec;34(12):2298-303
3. Di Stefano AL, Berzero G, Vitali P, et al. Acute late-onset encephalopathy after radiotherapy: an unusual lifethreatening complication. Neurology (2013) Sep10;81(11):1014-7
EFFICACY AND TOLERABILITY OF LACOSAMIDE IN PATIENTS WITH GLIOMA: FINAL RESULTS OF A
PROSPECTIVE STUDY
A. Pellerino, M. Magistrello, F. Franchino, E. Nicolotto, R. Soffietti, R. Rudà
Dept. Neuro-Oncology, City of Health and Science Hospital (Torino)
Background: Lacosamide (LCM) has been suggested in some retrospective studies to improve seizure control as an add-on
treatment in brain tumor patients. We present the final results of a prospective study on a cohort of low grade and high grade
gliomas and active epilepsy who received LCM.
Methods: Eligibility criteria were as follows: 1) age > 18 years; 2) biopsy-proven grade II or III or IV gliomas according to
WHO 2007; 3) persisting seizures (seizure frequency > 1 per month) despite a treatment with 1 or more antiepileptic drugs
(AEDs) for at least 3 months and adequate serum concentration; 4) stable steroid dose 5) available information on tumor
response on MRI according to RANO criteria following chemotherapy or radiotherapy. LCM was given to a target dose of
200-400 mg/day. The endpoints were seizure freedom and > 50% decrease of seizure frequency at 3-9 months.
Results: Since January 2012, 71 patients were enrolled. There were 26 grade II gliomas, 20 grade III and 25 glioblastomas.
Sixty-eight patients (96%) had partial seizures and 3 patients (4%) had generalized seizures. Forty-six patients (64.79%)
were on AED monotherapy while 25 (35.21%) on polytherapy. Reasons for introduction of LCM were lack of efficacy of
previous AEDs with either PD in 33 (46.48%) or without PD in 38 (53.52%). Median duration of follow up was 9 months
(range 3-18 months). Among low grade gliomas after 3 months of LCM 20/26 patients (76.9%) had a reduction of >50% of
seizure frequency while seizure freedom was obtained in 9 (34.6%); at 9 months we observe a reduction > 50% of seizure
frequency in 22/24 patients (91.7%) and a seizure freedom in 11 (42.3%). As for high grade gliomas after 3 months 33/45
patients (73.3%) had a reduction of >50% of seizure frequency while seizure freedom was obtained in 21 (46.6%); at 9
months we observe a reduction > 50% of seizure frequency in 28 patients (82.3%) and a seizure freedom in 18 (52.9%). A
resolution of an epileptic status was obtained in 6 patients of whom one receiving LCM alone. In 4 responding patients we
reduce the doses of concomitant AEDs. Most patients (87.3%) did not report toxicities: in 5 cases LCM was withdrawn due
to side effects or inefficacy.
Conclusion: LCM has showed significant activity as add-on therapy in both LGG and HGG gliomas regardless of tumor
response to antineoplastic treatment and with a good tolerability profile.
THIRD LINE CHEMOTHERAPY IN GLIOBLASTOMA PATIENTS
V. Villani1, A. Fabi2, S. Telera3, I. Terrenato4, L. Maruccci5, M. Carosi6, C. Carapella3, A. Vidiri7, A. Pace1
1
3
Neuro-Oncology Unit, Regina Elena Cancer Institute (Roma); 2Oncology, National Cancer Insitute Regina Elena (Roma);
Neurosurgery, National Cancer Insitute Regina Elena (Roma); 4Biostatistic, National Cancer Insitute Regina Elena (Roma);
pag. 145
5
Radiotherapy, National Cancer Insitute Regina Elena (Roma); 6Pathology Unit, National Cancer Insitute Regina Elena
(Roma); 7Radiology, National Cancer Insitute Regina Elena (Roma)
Objective: Today is not clear the exact management of recurrent or resistant disease. Advances in surgical approaches,
radiotherapy, and chemotherapy are contributing to incremental improvements in survival of the patients with glioblastoma
(GBM). Long survivors are often treated with more lines of chemotherapy (CT) but no data are available about the real
impact of third line of CT. The aim of the study was evaluate the benefit in term of time to progression free survival (PFS)
and overall survival (OS) of receive 3 or more lines of CT.
Methods: We retrospectively analyzed the clinical characteristics of GBM patients treated with ≥ lines CT at the Regina
Elena Cancer Institute.
Results: 264 GBM were included in this analysis. Mean age was 60 (26-87) years; 166 male and 98 female; 210 patients
received at least 3 line of CT and 54 patients received more of 3 lines of CT. Median PFS was 3 months. MGMT
methilation status was obtained not significantly correlated to PFS or OS. OS from diagnosis is 19 months and significantly
difference we observed in patients methilated (27 months (20.6-33.4) vs 18 months (15.1-20.9) p=0.001), with more line of
therapies 16 months (14.2-17.8) vs 28 months (21.1-34.9) p<0.0001 and the 23 months (20.2-25.8) vs 18 months (15.920.1) p=0.011.
Conclusion: The role of third line chemotherapy in GBM progressing after second line treatment failure requires to be better
defined in order to avoid futile treatment in HGG patients with short life expectancy.
NEUROPSYCHIATRIC ADVERSE EVENTS OF ANTIEPILEPTIC DRUGS IN PATIENTS WITH BRAIN
TUMOUR RELATED EPILEPSY
M. Romoli1, C. Bedetti1, S. Dispenza2, C. Di Bonaventura3, E. Nardi Cesarini1, P. Eusebi4, M. Maschio2, C. Costa1, P.
Calabresi1
1
Neurology Clinic, University Hospital of Perugia (Perugia); 2Center for Tumour-Related Epilepsy, La Sapienza University,
Policlinico Umberto I (Roma); 3Epilepsy Unit, La Sapienza University, Policlinico Umberto I (Roma); 4Health Planning
Service, Regional Health Autority of Umbria (Perugia)
Background: In patients with brain tumour related epilepsy (BTRE), seizure control is paramount. Tolerability and
pharmacokinetic interactions should determine the choice of antiepileptic drugs (AED), leading clinicians to prefer new
AEDs (1,2). This study assessed the rates of neuropsychiatric adverse events (NPAEs) associated with AEDs in patients
with BTRE.
Methods: This observational, prospective, multicentre study enrolled 259 patients with BTRE after neurosurgery. All
patients received AED monotherapy: efficacy was assessed through clinical diaries, while NPAEs were collected using the
NPI-12 questionnaire.
Results: Patients with frontal lobe tumour had a 3.21 relative risk (RR) increase of NPAEs (p<.01). Among them, patients
receiving levetiracetam (LVT) had higher prevalence of NPAEs compared to every other AED. Moreover, independently
from cancer localisation, treatment with LVT was associated with higher frequencies and magnitudes of NPAEs (RR 3.60,
p<.01) compared to other AEDs. Evaluating non-neurobehavioral adverse events (AEs) of AEDs, no significant differences
in prevalence were detected according to tumour site, cancer type or AED therapy.
Discussion: The results of this study revealed differences in NPAEs among patients with BTRE, according to both AED and
cancer site. In particular, LVT had worse neuropsychiatric tolerability profile than other AEDs, especially in patients with
frontal lobe tumours. Since NPAEs lead to poor compliance and a high dropout rate, clinicians need to carefully consider all
options when prescribing an AED for BTRE, especially in patients with frontal lobe tumours.
References:
1. Maschio M. Brain Tumor-Related Epilepsy. Curr Neuropharmacol (2012);10:124-133
2. Perucca E. Optimizing antiepileptic drug treatment in tumoral epilepsy. Epilepsia (2013);54 (Suppl.9): 97-104
QUALITY OF LIFE (QOL) AND NEURO-COGNITIVE EVALUATION (NC) IN PATIENTS TREATED WITH
RADIATION THERAPY FOR BRAIN METASTASIS: AN OBSERVATIONAL PROSPECTIVE CLINICAL
TRIAL – AIRO-SNC GROUP
S. Caratozzolo1, I. Milanesi2, M. Buglione3, S. Gipponi4, M. Cerniauskaite5, S. Pedretti3, F. Berrini5, F. Foscarini3, P.
Ghirardelli3, S. Pandini3, L. Fariselli2, S. M Magrini3, A. Padovani1
pag. 146
1
Department of Clinical and Experimental Science, University of Brescia (Brescia); 2Radiotherapy, Istituto Neurologico
Besta (Milano); 3Radiation Oncology Unit, University and Spedali civili (Brescia); 4Neurology Department, Spedali Civili
(Brescia); 5Neuropsychology, Istituto Neurologico Besta (Milano)
Aims: The possible neurocognitive (NC) effect of radiation therapy (RT)has become one of the main issues when choosing
treatment for patients (pts)with brain metastases. Aim of this study (supported by the AIRO-SNC group) is therefore to
evaluate neuro-cognitive and QoL outcome in pts treated with RT for brain metastases.
Methods: Pts had a NC evaluation and QoL testing before treatment, during RT and during follow up (mini mental status
examination - MMSE, trail making test - TMT A and B, clock drawing test - CDT; EORTC QoLC30 and BN20).
Differences in basal points were analyzed with ANOVA test. Results: In the last two years, 77 patients were enrolled
(M/F=31/46). Median age was 58 (range 28-77); 63% and 37% of the pts were in RPA class 1 and 2, respectively; 33% had
GPA score between 1.5-2, and 53% between 2.5-3. The primary tumor was lung in 43%, breast in 30% and melanoma in
12%. 51% of the pts had no neurological symptoms at diagnosis; 16% of the symptomatic patients had headache. 55% of
the pts had only one lesion, 13% and 16% respectively 2 and 3 lesions. 61% of the pts had cortical and 38% subcortical
localizations. At presentation, a surgical approach was chosen in 40% of cases. Forty-eight patients (62%) received whole
brain irradiation(WB); 9 of them were also submitted to simultaneous integrated boost(SIB) and 2 had stereotactic RT(SRS)
after WB; 29 pts had SRS (38%) without WB; 19% of pts received also concomitant chemotherapy. Fifty-three pts (69%)
were receiving steroids before RT. Basal MMSE was between 24-30 (no neurological alteration) in 94% of the pts, 4% had
a score of 20-23 (suspected neurological alteration); none showed a score under 21. Basal MMSE and CDT mean points did
not differ in patients treated with WB vs SRS. Mean TMT A, B, A+B were 65, 158, 92 and 44, 91, 46 respectively in WB
and SRS group. Twenty patients(26%) had anti-epileptic drugs before RT. During treatment, 12% and 15% of the pts
reported respectively G1 and G2 headache; G1 and G2 fatigue was recorded respectively in 27% and 15% of the evaluable
pts. The use of steroid increased during RT in 15 pts(20%).
Conclusions: NC and QoL testing has been time consuming but feasible. Almost all the patients (94%) had no
neurocognitive disturbance at diagnosis. The mature data of the study and the NC scoring evolution after RT will be
presented.
References:
− Hardesty DA, Nakaji P. The Current and Future Treatment of Brain Metastases. Front Surg. (2016) May 25;3:30
− Habets EJ, Dirven L, Wiggenraad RG, Verbeek-de Kanter A, Lycklama À Nijeholt GJ, Zwinkels H, Klein M,
Taphoorn MJ. Neurocognitive functioning and health-related quality of life in patients treated with stereotactic
radiotherapy for brain metastases: a prospective study. Neuro Oncol. (2016) Mar;18(3):435-44
− Peters S, Bexelius C, Munk V, Leighl N. impact of brain metastasis on quality of life, resource utilization and
survival in patients with non-small-cell lung cancer. Cancer Treat Rev. (2016) Apr;45:139-62
LGI1: EXPRESSION IN TUMOR TISSUE AND DETECTION OF AUTOANTIBODIES IN PATIENTS WITH
GLIOBLASTOMA
E. Pasini1, R. Michelucci1, E. Dazzo2, D. De Biase3, S. Furlan2, C. Nobile2
1
Unit of Neurology, IRCCS Institute of Neurological Sciences of Bologna (Bologna); 2Neuroscience Institute of Padua,
CNR (Padova); 3Unit of Anatomic Pathology, Bellaria Hospital, University of Bologna (Bologna)
Objectives: The LGI1 gene has been linked to malignant progression of glioma tumors, and a role for this gene in the
development of glioma-related epilepsy has been hypothesized. To investigate the possible involvement of LGI1 in
glioblastoma-associated epilepsy, we analyzed the expression of the Lgi1 protein in tumor tissue and searched for Lgi1
autoantibodies in patients with and without epilepsy.
Materials and Methods: Twenty-four patients affected with glioblastoma (11 with and 13 without epilepsy) were recruited
for study. Tumor tissue samples were obtained following surgery and Lgi1 protein levels were analyzed by immunoblot.
Detection of serum autoantibodies against Lgi1 was performed by a cell-based assay in 5 patients.
Results: We detected variable amounts of Lgi1 protein in the tumor tissues from 9/24 (37%) patients. Lgi1 was detected in
6/11 (54%) patients with epilepsy, and in 3/13 (23%) patients without epilepsy (p-value non significant). In addition, we
tested the sera of 5 patients for Lgi1 autoantibodies and found these autoantibodies in 2 patients, both suffering from
epilepsy and expressing Lgi1 in tumor tissue.
Discussion and Conclusions: Our data suggest that 1) about 1/3 of glioblastoma tumors express the Lgi1 protein; 2)
expression of Lgi1 may be considerably more frequent in tumors of patients with epilepsy than in those of patients without
epilepsy; 3) occurrence of Lgi1 autoantibodies may characterize a proportion of patients with glioblastoma. Future studies
on a larger patient cohort are needed to determine the relationship between tumor Lgi1 expression, Lgi1 autoantibodies and
pag. 147
epilepsy in glioblastoma patients.
Reference:
− Kunapuli P, Chitta KS, Cowell JK Suppression of the cell proliferation and invasion 9 phenotypes in glioma cells
by the LGI1 gene. Oncogene (2003);22:3985–3991
NEUROLOGICAL MANIFESTATIONS IN BREAST CANCER CHEMOTHERAPY: A NEW POSSIBLE
ASSOCIATION WITH B12 DEFICIENCY?
M. Ciocca1, A. Bramati2, A. Moretti2, M. Pirovano1, V. Fetoni1, P. Marino1, G. Farina2
1
2
Emergency Department, Neurology Service, Fatebenefratelli Hospital, ASST Fatebenefratelli Sacco, Milan, Italy
Oncology Department, Fatebenefratelli Hospital, ASST Fatebenefratelli Sacco, Milan, Italy
Objectives: Early diagnosis and multimodal treatment have improved breast cancer (BC) survival rates, but quality of life
may still be decreased by treatment side effects. The most frequent neurological manifestation is chemotherapy-induced
peripheral neuropathy (CIPN). In particular, taxanes are the most frequently used drugs for BC and the main cause for
CIPN. Vitamin B12 (B12) deficiency causes a wide range of neurological manifestations: the most common is sub-acute
combined degeneration (SCD), sometimes associated with polyneuropathy. B12 deficiency has never been described as a
complication in BC chemotherapy.
Methods: We describe 2 patients, affected by BC treated with a combination of Transtuzumab, Pertuzumab and Docetaxel,
developing unexpected neurological symptoms. Blood test and neurological examination before the first chemotherapy
administration
were
unremarkable
in
both
cases.
Results and discussion: The first case is a 71 year-old woman presenting with a 10-day history of non-painful paraesthesia
and unsteady gait. On examination she had ataxic gait, loss of vibration and joint position sense, positive Romberg sign,
absent tendon reflexes and bilateral extensor plantar responses. She had a 10 years history of insulin dependent diabetes.
Routine blood test, cerebrospinal fluid analysis, brain and spinal cord imaging were unremarkable. Chemotherapy with
Docetaxel was discontinued, suspecting a CIPN. Because neurological symptoms didn’t improve one month after
discontinuation, other laboratory tests were performed, revealing B12 deficiency. A SCD associated with CIPN was
suspected and she was treated with intramuscular B12 injections for one week and then with daily oral B12. Three months
later, paraesthesia disappeared and her walking and balance were normal. A nerve conduction studies was performed,
showing only a mild sensory axonal polyneuropathy. The second case is a 79 year-old woman presenting with a two months
history of painful paraesthesia in upper and lower limbs. In addition, she had loss of vibration and joint position sense,
absent tendon reflexes and ataxic gate. She was diagnosed with a CIPN due to Docetaxel and the drug was discontinued.
After two months, she was admitted in hospital because sensory loss progressed (“coasting”-like effect). Blood tests
revealed B12 deficiency and she was treated with daily oral B12 supplementation. One month later, sensory symptoms were
mildly improved.
Conclusion: We described two new cases of treatment related neurological manifestations, both due to B12 deficiency: a
SCD associated with a mild CIPN and a CIPN with a coasting-like effect. We suggest to assess B12 levels in patients
treated with Transtuzumab, Pertuzumab and Docetaxel for BC.
References:
− Pereira S, Fontes F, Sonin T, Dias T, Fragoso M, Castro-Lopes J, Lunet N. Neurological complications of breast
cancer: study protocol of a prospective cohort study. BMJ Open. (2014) Oct 28; 4 (10)
− Kumar N. Neurologic aspects of cobalamin (B12) deficiency. Handb Clin Neurol. (2014);120:915-26.
RIABILITAZIONE NEUROLOGICA E NEUROTRAUMATOLOGIA
A WEARABLE PROPRIOCEPTIVE STABILIZER (EQUISTASI) FOR REHABILITATION OF LIMB AND
GAIT ATAXIA IN HEREDITARY CEREBELLAR ATAXIAS: A PILOT OPEN-LABELED STUDY
L. Leonardi1, C. Marcotulli1, G. Arcuria1, M. Serrao1, F. Pierelli2, A. Filla3, F. Saccà3, G. Aceto3, C. Casali1
1
Department of Medical-Surgical Sciences and Biotechnologies, Sapienza University of Rome (Latina); 2IRCCS Neuromed
(Pozzilli-IS); 3Department of Neurosciences, Odontostomatological and Reproductive Sciences, University Federico II
pag. 148
(Napoli)
Background: Muscle spindles endings are extremely sensitive to externally applied vibrations, and under such
circumstances they convey proprioceptive inflows to the central nervous system that modulate the spinal reflexes
excitability or the muscle responses elicited by postural perturbations. The aim of this pilot study is to test the feasibility and
effectiveness of a wearable proprioceptive stabilizer (Equistasi) that emits focal mechanical vibrations in patients affected
by hereditary cerebellar ataxias.
Methods: Twelve adult patients (3 females and 8 males; 2 with SCA3, 3 with SCA2, 1 with SCA1, 6 with FRDA) wore an
active device for 3 weeks. All the patients were able to walk alone or with minimal assistance and continued their program
of physical training during the whole study duration. There were no statistically significant differences in term of disease
duration, SARA score, BMI, weight and height between SCAs and FRDA groups. Assessments were performed at baseline,
after the device use (T1), and three weeks after (T2). SARA, 9-HPT, PATA, 6MWT, spatio-temporal gait parameters
measured with BTS-G-Walk inertial sensor, were used as study endpoints.
Results: Three patients with FRDA were lost from follow up because of lack of compliance in device use. Nine patients (6
SCAa and 4 FRDA) were evaluated at T1. Improvement in SARA (from 10,7 to 9,5, P 0,027), 9-HPT dominant hand (from
37,5 sec to 33,3 sec, P 0,008), 9-HPT non dominant hand (from 37,5 sec to 33,3 sec, P 0,038), PATA test (from 18,4 to
21,5, P 0,011), 6MWT (from 322,1 mt to 380,1 mt, P 0,036), cadence (from 96,8 steps/min to 105,9 steps min, P 0,021),
length of cycle (from 1,17 mt to 1,22 mt, P 0,017), support right/cycle (from 69,4% to 65,3%, P 0,011), support left/cycle
(from 67,9% to 62,7%, P 0,038), flight right/cycle (from 30,5% to 34,6%, P 0,011), flight left/cycle (from 17% to 13,8%, P
0,038). No statistically significant differences in terms of speed, length of step right/cycle, length of step left/cycle were
detected. No significant outcome differences were disclosed between SCAs group and FRDA group. T2 data are still not
available. All patients tolerated the device well, without reported adverse effects.
Conclusions: This small open-labeled study represent a first preliminary evidence that focal mechanical vibration exerted by
a wearable proprioceptive stabilizer might improve limb and gait ataxia in patient with hereditary cerebellar ataxias. This is
an ongoing study and T2 data are still not available. Therefore, we still have no information about the persistence of clinical
scale and gait modifications after the device discontinuation. Further wider randomized-controlled studies are necessary to
establish the effectiveness of this non-pharmacological rehabilitative therapeutic approach to limb and gait ataxia in
hereditary cerebellar ataxias.
References:
− Alfonsi E, Paone P, Tassorelli C, et al. Acute effects of high-frequency microfocal vibratory stimulation on the H
reflex of the soleus muscle. A double-blind study in healthy subjects. Functional Neurology (2015);30(4):269-274.
doi:10.11138/FNeur/2015.30.4.269.
− Volpe D, Giantin MG, Fasano A. A Wearable Proprioceptive Stabilizer (Equistasi®) for Rehabilitation of Postural
Instability in Parkinson’s Disease: A Phase II Randomized Double-Blind, Double-Dummy, Controlled Study.
Quinn TJ, ed. PLoS ONE. (2014);9(11):e112065. doi:10.1371/journal.pone.0112065.
− Schwesig R., Leuchte S., Fischer D., Ullmann R., Kluttig A. Inertial sensor based reference gait data for healthy
subjects. Gait and Posture (2011); 33(4):673-8
LACK OF IMPROVEMENT IN QUANTITATIVE GAIT ANALYSIS AFTER BOTULINUM TOXIN INJECTION
IN PATIENTS WITH MULTIPLE SCLEROSIS
G. Coghe1, M. Pau2, F. Corona2, S. Caggiari2, J. Frau1, C. Inglese3, L. Lorefice1, G. Fenu1, M. Marrosu4, E. Cocco1
1
Department of Public Health, Clinical and Molecular Medicine, University of Cagliari (Cagliari); 2Department of
Mechanical, Chemical and Materials Engineering, University of Cagliari (Cagliari); 3Multiple Sclerosis Center, ASL8
(Cagliari); 4Department of Medical Science, University of Cagliari (Cagliari)
Background: There are limited evidences regarding the impact of BT therapy for spasticity on active function in patients
with MS. The effects of BT therapy on gait and walking performance have been studied in stroke patients. However, since
MS has a peculiar spasticity pattern, the stroke studies cannot be extrapolated to the MS.
Objective: To quantitatively assess the functional modifications in gait induced by BT in MS.
Methods: A group of patients were enrolled. Inclusion criteria were a diagnosis of MS according to the 2010 McDonald
criteria, being able to walk for at least 10m regardless of the use of aids. Moreover all participants were valid candidates to
TB with the following pattern of infiltration: tibial posterior, soleus, gastrocnemius lateralis and medialis according to
medical judgment. For each patient was evaluated, NRS, three-dimensional gait analysis (spatial–temporal and kinematic) at
baseline and one month after the TB injection. For statistical analysis only the parameters of the treated leg were considered.
pag. 149
Kinematic data were expressed by means of Gait Profile Score (GPS). Variation of each parameter was evaluated by means
of
two-way
repeated
measures
ANOVA.
Results: Fourteen patients were enrolled (10 female and 4 male); Mean age was 50.4 (SD ±12.3) mean EDSS was 4.9 (SD
±1.3). The statistical analysis was carried out on 16 treated legs. Mean reduction of NRS after TB injection was 1.14 (SD
±1.16) (not statistically significant). Out of 14 patients 8 referred an improvement. None of the gait spatial–temporal
parameters revealed an improvement after treatment. In particular speed (p=0.367) and stride length (p=0.671). Regarding
the kinematics data nor the GPS (p=0.676) neither the GVS of targeted joints (knee flex ext p=0.606 and ankle plantardorsal-flexion
p=
0.973)
reduced
after
treatment.
Conclusion: To our knowledge this is one of the first studies specifically targeting objective gait data on MS after treatment
with BT injection. Despite the subjective improvement reported and the reduction of muscle tone, it remains impossible to
demonstrate a quantifiable gain of function on gait patterns either in spatial temporal data and kinematics.
DEVELOPMENT AND VALIDATION OF THE COMORBIDITIES COMA SCALE (COCOS) IN PATIENTS
WITH VEGETATIVE STATE AND MINIMALLY CONSCIOUS STATE
F. Pistoia1, A. Carolei1, S. Sacco1, Y. Guller2, A. De Tanti31, A. Casalena4, C. Pistarini5, B. Cazzulani5, G. Bellaviti5, J.
Giacino2
1
Neurological Institute, Department of Biotechnological and Applied Clinical Sciences, University of L'Aquila (L'Aquila);
Department of Physical Medicine and Rehabilitation, Spaulding Rehabilitation Hospital and Harvard Medical School
(Boston); 3Post-Acute Care and Rehabilitation Unit, Cardinal Ferrari Rehabilitation Centre (Fontanellato, PR); 4Post-Acute
Care and Rehabilitation Unit, Sant'Agnese Rehabilitation Centre (Pineto, TE); 5Post-Acute Care and Rehabilitation Unit,
Maugeri Foundation (Pavia)
2
Objectives: To develop and validate a new scale for the assessment of comorbidities in severely brain-injured patients with
Vegetative State (VS) and Minimally Conscious State (MCS).
Materials and Methods: 54 severely brain-injured patients, who were consecutively admitted to the acute inpatient brain
injury rehabilitation units of the Maugeri Foundation (Pavia) and the Santa Agnese Rehabilitation Center (Teramo) with a
diagnosis of VS or MCS, were investigated through the Comorbidities Coma Scale (CoCoS). Data were obtained
prospectively in 25 patients and drawn retrospectively from preexisting medical records in 29 patients. Interrater and testretest reliability of the CoCoS were assessed by the weighted Cohen’s kappa (Kw). Concurrent validity of the CoCoS, as
compared to the Greenfield Scale for comorbidities, was evaluated by ρ Spearman’s correlation coefficient.
Results: Interrater [Kw 0.95 (95% CI 0.92.-0.98)] and test-retest reliability [Kw 0.98 (95% CI 0.95.-1.00) - 0.99 (0.98-1.00)
] were excellent for the CoCoS total scores. Interater and test-retest reliability were excellent for subanalyses of data
prospectively and retrospectively collected as for each of the items of the scale. CoCoS total scores correlated significantly
with total scores of the Greenfield Scale for comorbidities (ρ=0.938, 95% CI 0.895-0.964; P<0.0001) indicating concurrent
validity.
Discussion: Previous findings showed that medical comorbidities are very common in patients with disorders of
consciousness and that survival and consciousness recovery are strongly influenced by their cumulative number and
severity. However, a specific tool for the assessment of comorbidities in these patients was lacking. Our findings show that
the CoCoS is able to provide reliable findings about the presence of comorbidities in patients with consciousness
impairment as a result of a severe brain injury. Reliable findings can be obtained whether the scale is administered
prospectively or retrospectively, showing that data on comorbidities may be collected either through the direct clinical
assessment of patients or through the evaluation of medical records.
Conclusions: The present scale may represent a valuable tool for daily clinical practice and prognosis cohort studies.
References:
− Sarà M, Pistoia F. Bedside detection of awareness in the vegetative state. Lancet (2012);379:1702-3
− Pistoia F, Sacco S, Franceschini M, Sarà M, Pistarini C, Cazzulani B, Simonelli I, Pasqualetti P, Carolei A.
Comorbidities: a key issue in patients with disorders of consciousness. J Neurotrauma (2015);32:682-8
− Whyte J, Nordenbo AM, Kalmar K, Merges B, Bagiella E, Chang H, Yablon S, Cho S, Hammond F, Khademi A,
Giacino J. Medical complications during inpatient rehabilitation among patients with traumatic disorders of
consciousness. Arch Phys Med Rehabil (2013);94:1877-83
INFLUENCE OF COMORBIDITIES ON OUTCOMES OF PATIENTS IN VEGETATIVE STATE AND
MINIMALLY CONSCIOUS STATE: A PILOT STUDY
pag. 150
A. Casalena1, F. Pistoia2, A. De Tanti1, S. Sacco2, A. Carolei2
1
Cardinal Ferrari Centre, Santo Stefano Rehabilitation Institute (Parma); 2Department of Biotechnological and Applied
Clinical Sciences, Neurological Institute, University of L'Aquila (L'Aquila)
Objective: Patients with Vegetative State (VS) and Minimally Conscious State (MCS) are managed within Post-Acute Care
(PAC) units where further medical stabilization and rehabilitation are provided. Previous studies suggest that these patients
suffer from multiple comorbidities, which strongly influence the chances of recovery. The aim of this study was to identify
the impact of comorbidities on outcomes.
Materials and methods: All patients consecutively admitted to the PAC unit of the Centro Cardinal Ferrari, Fontanellato,
Parma, Italy, from May 1, 2014 to April 30, 2015, were investigated. All patients were assessed for possible inclusion in the
study within 1 week from admission. Inclusion criteria were a diagnosis of VS or MCS following stroke, traumatic brain
injury (TBI), post-anoxic encephalopathy (PAE) and other acute diseases. The initial diagnosis was made through repeated
observations along a 1-week period according to clinical criteria and by the use of the Coma Recovery Scale–Revised
(CRS-R), Italian version. Included patients were assessed along a 6-month follow-up period through the CRS-R and the
Comorbidities Coma Scale (CoCoS) in order to identify clinical transitions along the spectrum of recovery of consciousness
and the burden of comorbidities on outcomes. Six-month outcomes included death and full recovery of consciousness.
Results: Out of 112 patients who were admitted within the study period, 79 patients (mean age±SD 56.1±17.1 years) were
included in the study. Stroke was the most frequent disease (42%) followed by TBI (38%), PAE (15%), and tumors (5%).
Most of the patients were admitted to the PAC unit between 15 and 60 days from the acute injury (73%). On admission, the
most frequent diagnosis was VS (n=41; 52%), followed by MCS (n=38; 48%). During the follow-up period, the most
frequently encountered comorbidities were anemia (n=71; 90%), urinary tract infections (n=66; 83%), and upper respiratory
tract infections (n=59; 75%). The presence of respiratory infections was the strongest predictor of death (HR 6.9; 95% CI,
2.22-21.8; p=0.001) while the occurrence of autonomic dysfunction (OR 0.6; 95% CI, 0.41-0.92; p=0.019), arrhythmias
without organic heart diseases (OR 0.3; 95% CI, 0.20-0.65; p=0.001), and hydrocephalus (OR 0.4; 95% CI, 0.29-0.73;
p=0.001) were negative predictors of full recovery of consciousness.
Discussion: When establishing a prognosis in patients with disorders of consciousness, we should take into account not only
the primitive disease, but also the burden of comorbidities, which, either independently or in combination, increase the risk
of death or interfere with consciousness recovery.
References:
− Sacco S, Altobelli E, Pistarini C, Cerone D, Cazzulani B, Carolei A. Validation of the Italian version of the
ComaRecovery Scale-Revised (CRS-R). Brain Inj (2011);25:488–495
− Pistoia F, Sacco S, Franceschini M, Sarà M, Pistarini C, Cazzulani B, Simonelli I, Pasqualetti P, and Carolei A.
Comorbidities: A Key Issue in Patients with Disorders of Consciousness. Journal of Neurotrauma (2015);32:682–
688
− Pistoia F, Sacco S, Stewart JE, Carolei A. Postanoxic vegetative state: avoiding the self-fulfilling prophecy.
Neurohospitalist (2015);5(1):7
TRANSCRANICAL DIRECT CURRENT STIMULATION IN POST-STROKE APHASIA REHABILITATION:
BILATERAL VS UNILATERAL ONLINE STIMULATION
A. Torrente1, G. Giglia1, M. Gangitano1, T. Piccoli1, F. Brighina1, B. Fierro1, V. Di Stefano2
1
2
Department of Experimental Biomedicine and Clinical Neuroscience (BioNeC), University of Palermo (Palermo);
Department of Neuroscience, Imaging and Clinical Sciences, University G. d'Annunzio of Chieti-Pescara (Chieti)
Objective: Aphasia is the most common post-stroke cognitive disorder and it severely impacts activities of daily living
(ADL) and social interactions. Speech and language rehabilitative treatments are able to promote recovery and recently
interesting results have been obtained by application of non invasive brain stimulation techniques like transcranical Direct
Current Stimulation (tDCS) and Transcranical Magnetic Stimulation (TMS). TMS and tDCS can improve post-stroke
aphasia, even if no agreement at now exists about the stimulation parameters to employ to achieve optimal rehabilitative
outcome1. Here we aim to evaluate the efficacy of repeated sessions of tDCS as additional treatment to standard
behavioural rehabilitation in stroke patients affected by aphasia comparing bilateral-tDCS with unilateral leftsided-tDCS
and sham-tDCS.
Materials and Methods: We enrolled at now twenty-two post-stroke aphasia patients with single left-brain lesion at CT or
MRI scan. The language disorder was investigated through selected subitems of Aachener Aphasie Test(AAT) administered
before and after the treatment. Patients were randomly assigned to 3 treatments types: 1. behavioural rehabilitation +
pag. 151
bilateral tDCS(7); 2. behavioural rehabilitation + unilateral tDCS(8); 3. behavioural rehabilitation + sham tDCS(7). As
concerns tDCS montage, anode was always placed on the left inferior frontal gyrus (IFG), while cathodal electrode was
positioned on contralateral supraorbital area for unilateral-tDCS and on the right side homologue of IFG area for bilateral
tDCS. tDCS (1,5 mA intensity for 20 min) was delivered online during a picture naming task in daily session for two
consecutive weeks (week-end free) for a total of 10 stimulation sessions.
Results: Preliminary data show that both dual and single-tDCS lead to significant improvements in outcome measures (AAT
scores, in particular for denomination subitems) as compared to baseline evaluation and sham-tDCS.
Discussion: tDCS represents a useful tool for aphasia rehabilitation, both in single and dual-mode. It is well tolerated and
IFG stimulation (left anodal-tDCS or both left-anodal and right-cathodal) lead patients to naming and general speech
improvements. Further studies on dual-tDCS are required for a standardized clinical application.
Conclusions: Both single and dual-online-tDCS lead to significant improvements compared to sham. If right hemisphere
plays an inhibiting role on the left one, we should expect a more relevant positive effect of dual-tDCS than single one.
Anyway, there are several variables to consider, such as time distance from stroke and rehabilitation and size of the lesion.
Reference:
− de Aguiar V, Paolazzi CL, Miceli G. tDCS in post-stroke aphasia: the role of stimulation parameters, behavioral
treatment and patient characteristics. Cortex (2015);63:296-316
A STUDY OF LOBAR ATROPHY AND WHITE MATTER TRACT DAMAGE IN PEDIATRIC PATIENTS
WITH TRAUMATIC BRAIN INJURY
L. Storelli1, M. Rocca1, E. Molteni2, E. Pagani1, G. Boffa1, M. Copetti3, S. Galbiati2, F. Arrigoni2, M. Recla2, A. Bardoni2, S.
Strazzer2, M. Filippi1
1
Neuroimaging Research Unit, INSPE, Division of Neuroscience, San Raffaele Scientific Institute, Vita-Salute San Raffaele
University (Milano); 2Acquired Brain Injury Unit, Scientific Institute "Eugenio Medea" (Bosisio Parini, LC); 3Biostatistics
Unit, IRCCS Casa Sollievo della Sofferenza (San Giovanni Rotondo-FG)
Objectives: To investigate, in patients with pediatric severe and moderate traumatic brain injury (TBI), the presence and
severity of white matter (WM) tract damage and cortical lobar atrophy and their correlation with disease clinical scales.
Methods: Diffusion tensor (DT) and 3D T1-weighted MRI scans were obtained using a 3 Tesla scanner from 22 children
with severe and moderate TBI and 31 age-matched healthy children. Patients were tested with functional scales and the
Wechsler Intelligence Scale for Children (WISC). DT MRI indexes were obtained from the arcuate (AF), inferior
longitudinal (ILF), uncinate (UF) and inferior fronto-occipital (IFO) fasciculi, cerebellar peduncles (CP) and corpus
callosum (CC). Whole brain and lobar volumes (using masks from Harvard-Oxford cortical atlas) were derived.
Comparisons between patients and controls, and between patients in acute (<6 months from the event) vs chronic (>6
months)
conditions
were
performed
(False
Discovery
Rate
correction).
Results: Except for pre- and postcentral gyri and occipital lobe volume, all DT MRI indices and atrophy measures were
abnormal in patients compared to healthy controls. Compared to acute, chronic patients had more severe atrophy of the
temporal lobe and more severe DT MRI abnormalities of the CC, ILF, UF and inferior CP. In TBI patients, significant
correlations were found between: 1) temporal lobe atrophy vs DT MRI abnormalities in several WM tracts; 2) whole brain
atrophy vs WISC performance.
Conclusions: TBI in children is characterized by a widespread WM and lobar damage. In the chronic stage, higher
susceptibility to tissue loss involves the temporal lobe.
This study has been supported by a grant from the Ministry of Health Research, Ricerca Corrente 2010–2012, Scientific
Institute “E. Medea.”
PEDALLING FOR PARKINSON’S: EFFECTS OF A NOVEL HIGH PEDALLING CADENCE FORCED
EXERCISE ON AN ELECTRIC MOTOR-DRIVEN BICYCLE
G. Grazzi1, F. Leprotti1, N. Golfrè Andreasi2, M. Gentile2, E. Groppo2, L. Munari1, G. Mazzoni1, C. Merlo1, N. Sorino1, E.
Cesnik1, I. Casetta1, G. Granieri1, M. Manca3, E. Granieri2
1
Center of Biomedical Studies applied to Sport, University of Ferrara (Ferrara); 2Neurological Clinic, University of Ferrara
(Ferrara); 3Department of Rehabilitative Medicine, Arcispedale S. Anna (Ferrara)
Introduction: Forced exercise resulted in neuroprotective effects and improved functional tasks in people with mild-tomoderate Parkinson’s Disease (PD).(1,2) Simple and effective tools are advocated in order to translate the protocols used in
pag. 152
the research into clinical practice.
Aim: To evaluate the effects of a facility-based high pedalling cadence cycling training on global motor function and
Quality of Life (QoL) in PD patients.
Material: Stationary motor-driven bicycle (Mi. Gi., Monselice, PD, Italy), clamped to an electromagnetic roller simulating
real outdoor cycling (Realaxiom CT, Elite, Italy).
Methods: Twenty-six patients, mean age 69±12 years, (M/F,22/4) with mild-to-moderate PD (Hohen-Yahr stage 2.4±0.5)
volunteered for an 8 weeks exercise intervention integrated with usual medications (dopa equivalent dose 452mg, 95% CI
for the mean 275 to 629 mg/day), consisting of three 40 minute weekly sessions of supervised perceptually-regulated
moderate cycling (11-13 on the 6-20 RPE scale), at the higher sustainable pedalling cadence. Cardiorespiratory fitness,
agility, balance mobility, and QoL were assessed by cardiopulmonary incremental test, tapping test, 10-walking test and
Timed-up-and-go test (TUG), and the PD Questionaire-39 items (PDQ-39), before, and after training period. Motor function
were also evaluated using the Unified Parkinson’s Disease Rating Scale (UPDRS) Part-III.
Results: Mean pedalling cadence, work rate, and heart rate were 78±4 rpm, 47±9 watt, and 93±6 bpm (on the average 62%
of maximal age-predicted heart rate), respectively. Maximal cardiorespiratory fitness did not significantly improve
(1632±410 vs 1660±450 mL/min). Comfortable and maximal walking speed during the 10-m walking test improved from
67±4 to 81±13 (P<0.01) and 89±102 m/min (P<0.01) respectively. These improvements in walking ability were determined
by significant improvements in step cadence and length (P<0.01). Tapping test improved by 24% and 30% for left and right
arm respectively (P<0.01). The TUG test improved from 9.8±1.9 to 8.1±1.8 seconds (-17%, P<0.01). Compared to baseline,
a significant 26%, 32%, and 34% improvement (P<0.05) in mobility, emotional well-being and stigma have been observed
after training, indicating better QoL.
Discussion: Assisted high pedalling cadence-low work rate cycle training of the lower extremities leads to improvements in
walking ability, upper extremities function, balance and QoL in PD patients.
Conclusion: These findings provide further evidence supporting the potential benefits on central motor control processes of
a novel non pharmacological treatment for mild-to-moderate PD patients. High cadence cycling exercise on a motor-driven
bike is a simple and effective tool in order to translate the protocols used in the research into clinical practice.
References:
1. Jay L. Alberts, Susan M. Linder, Amanda L. Penko, Mark J. Lowe, and Micheal Phillips. It Is Not About the Bike,
It Is About the Pedaling: Forced Exercise and Parkinson’s Disease. Exerc. Sport Sci. Rev. (2011);39(4):177-186
2. Angela L. Ridgel, Chul-Ho Kim, Emily J. Fickes, Matthew D. Müller, and Jay L. Alberts. Changes in Executive
Function After Acute Bouts of Passive Cycling in Parkinson's Disease. Journal of Aging and Physical Activity
(2011);19:87-98
YOU DO NOT COUNT IF YOU ARE NOT COUNTED: THE NEW WHO INTERNATIONAL CLASSIFICATION
OF HEALTH INTERVENTIONS (ICHI) AS A CHANCE FOR NEUROLOGISTS TO BE BETTER COUNTED
FOR WHAT THEY DO
A. Martinuzzi1, A. Almborg2, N. Fortune3, M. Cumerlato3, C. Sykes4, R. Madden3
1
Conegliano Research Centre, IRCCS Medea (Conegliano-TV); 2Nordic Centre for Classifications in Health, National
Board of Health and Welfare (Stockholm-S); 3National Centre for Classification in Health, Sydney University (Sydney-A);
4
World Confederation for Physical Therapy (London-UK)
Background: The valorization of the clinical activity necessarily starts by listing and counting the health procedures which
in most countries (including Italy) is currently done using adapted lists from the ICD9cm. These lists are grossly outdated
and poorly detailed especially in the non-surgical (so called “functioning”) interventions which constitute the bulk of the
procedures typically carried on by neurologists in neurorehabilitation. The WHO is committed to fill this gap by developing
the new International Classification of Health Interventions (ICHI) and to this end has constituted in 2006 a technical
working group (TWG).
Objective of this presentation is to inform the Italian neurology community of the ongoing process highlighting the
differences with the present system and the potential benefits of the new one.
Materials & methods: The ICHI TWG defined its strategic work plan which first included the development of the
conceptual model providing the appropriate ontological structure to the new classification. Starting from the procedures
listing in the various countries (Canada, Australia, Sweden, Germany, Thailand, Japan) but substantially enriching their
content, the TWG has developed the ICHI alpha draft. A detailed count and comparison of neurology relevant procedures
was carried out to evaluate the gained detail and the possible further need for granularity.
Results: In ICHI each procedure is identified within a 3 axis model: target (the entity on which the Action is carried out),
action (the deed done by an actor to a Target during a healthcare intervention) and mean (the processes and methods by
pag. 153
which the Action is carried out). Settings, diagnosis, profession of the performer are not classified in ICHI. The present
alpha-ICHI lists 780 non-surgical procedures for which the nervous, the neuromuscular systems and the correlated activities
are the targets. 305 items are diagnostic procedures, 475 are therapeutic procedures, with substantial enrichment in
neurorehabilitative interventions. This compares with 74 non-surgical procedures in the ICD9cm based list used in currently
in Italy. Major enhancement was possible by adopting in the target axis the components of the ICF (body structures, body
functions, activities) as guiding categories.
Discussion & Conclusions: The last ICHI alpha draft provides an order of magnitudo enhancement for the description of
neurology relevant procedures. More refinement, including possibly pruning, will be needed and will be provided via field
testing once the beta draft will be released in the next year. Neurologists need to be engaged in this process to ensure proper
valorization of their activity.
pag. 154
QUALIFICHE PROFESSIONALI E SCIENTIFICHE DEI RELATORI
COGNOME
Abbruzzese
NOME
Giovanni
CITTA'
Genova
LAUREA
Medicina e Chirurgia
SPECIALIZZAZIONE
AFFILIAZIONE
Neurologia, Fisioterapia, Medicina
Università degli Studi di Genova - Dipartimento di Neuroscienze, Oftalmologia e Genetica
dello Sport
Neurologia
Ospedale San Raffaele Milano
Agosta
Federica
Milano
Agostoni
Elio
Milano
Aguglia
Umberto
Reggio Calabria
Neurologia
Albanese
Alberto
Milano
Neurologia e Psichiatria
Amato
Maria Pia
Firenze
Angelini
Corrado
Padova
Neurologia
QUALIFICA
Professore Straordinario Neurologia
Neurologo
Direttore S.C. Neurologia e Stroke Unit Dipartimento di Neuroscienze A.O. Ospedale Niguarda Ca' Granda - Milano
Neurologo
Neurologia, Università Magna Graecia Catanzaro, Centro Regionale Epilessie, presidio Riuniti, Reggio Calabria
Professore Ordinario di Neurologia
Direttore Neurologia I Fondazione IRCCS Istituto Neurologico Carlo Besta
Neurologia
I Clinica Neurologica di Firenze
Professore Universitario di ruolo
Neurologia
Università di Padova
Annesi
Grazia
Catanzaro
medicina e chirurgia
neurologia
CNR
Neurologo
Annunziata
Pasquale
Siena
Neurologia
Università degli Studi di Siena
Professore associato in Neurologia
Antonini
Angelo
Milano
Neurologia
Fondazione "Opera San Camillo" Casa di Cura San Pio X
Direttore UO
Arabia
Gennarina
Catanzaro
Neurologia
Università degli studi "Magna Graecia"di Catanzaro, Clinica Neurologica
Ricercatrice
Arnaldi
Dario
Genova
neurologia
UNIGE
neurologo
Arnao
Valentina
Palermo
neurologia
degli Studi di Palermo
neurologo
Ascoli
Michele
Catanzaro
neurologia
Specializzando
Avolio
Carlo
Foggia
Neurologia
Baldereschi
Marzia
Firenze
neurologia
Magna Graecia
Sezione di Clinica delle Malattie del Sistema Nervoso, Dip. Scienze Mediche e del
Lavoro, Università degli Studi di Foggia
CNR
Baldin
Elisa
Bologna
Neurologia
Unità operativa di Neurologia , Ospedale S.Orsola-Malpighi ,Bologna
Neurologo
Balestri
Martina
Roma
neurologia
Ospedale Bambino Gesà¹
neurologo
Professore associato in Neurologia
neurologo
BALESTRINI
SIMONA
London
neurologia
University College of London
neurologo
Baracchini
Claudio
Padova
Neurologia
Dipartimento di Neuroscienze dell'Università di Padova
Medico Chirurgo - specialista in Neurologia
Barbagallo
Gaetano
Catanzaro
neurologia
University Magna Graecia
neurologo
barca
emanuele
Messina
neurologia
Università di Messina
neurologo
Baroncini
Damiano
Gallarate
neurologia
Università Vita-Salute San Raffaele
neurologo
Barone
Paolo
Salerno
Neurologia
Università di Salerno
Professore Associato di Neurologia
Barp
Andrea
Sospirolo
neurologia
Università degli studi di Padova
neurologo
Barzago
Claudia
Milano
neurologia
Fondazione IRCCS Istituto Neurologico Carlo Besta
neurologo
Basaia
Silvia
Milan
neurologia
Vita-Salute San Raffaele University
neurologo
Bassez
Guillaume
Creteil, F
Neurologia
GHU Henri Mondor - Serzizio di Neurologia
Neurologo
Bassi
Maria Teresa
Bosisio Parini, MI
Neurologia
Laboratorio di Biologia Molecolare IRCCS "E. Medea"
Neurologo
Bassi
Andrea
Roma
Battaglia
Mario
GEnova
Beghi
Ettore
Milano
neurologia
Igiene Orientamento Sanità
Pubblica, Igiene Orientamento
Neurologia
Belelli
Giuseppe
Milano
Gerontologia e Geriatria
Bello
Luca
Padova
neurologia
belvisi
daniele
Pozzilli (Is)
Benedetti
Luana
Genova
Benussi
Alberto
Berardelli
Bergamaschi
I.R.C.C.S. Santa Lucia Foundation - Roma
neurologo
Presidente AISM-FISM
Presidente AISM-FISM
Istituto di Ricerche Farmacologiche Mario Negri - Milano
Professore a contratto di Neuroepidemiologia
Clinica Geriatrica, Dipartimento di Medicina Clinica e Prevenzione Università degli Studi Milano-Bicocca
Geriatra
University of Padova
neurologo
neurologia
Sapienza, Università di Roma
neurologo
neurologia
University of Genova and IRCCS AOU San Martino-IST
neurologo
Brescia
neurologia
University of Brescia
Alfredo
Roma
Neurologia
Dipartimento di Scienze Neurologiche Università degli Studi di Roma La Sapienza
Roberto
Pavia
Neurologia
Dipartimento di Neurologia Generale Fondazione Istituto Neurologico "C. Mondino" - IRCCS
Neurologo
neurologia
bernetti
laura
Perugia
Bertinato
Luigi
Venezia
Economia e Commercio
Bertolotto
Antonio
Torino
Bisecco
Alvino
Napoli
Bocci
Tommaso
Pisa
Boldrini
Paolo
Bologna
Matteo
Bonanni
Laura
Bono
Bono
Bonuccelli
neurologo
neurologo
Ospedale SS.Giovanni e Paolo - Neurologia
Responsabili ufficio relazioni socliali e salute regione Veneto
Neurologia
Neurologia 2 – CRESM: Centro Riferimento Regionale Sclerosi Multipla
Direttore Struttura Complessa
neurologia
Seconda Università degli Studi di Napoli
neurologo
neurologia
Università degli Studi di Pisa
neurologo
Roma
Neurologia
Azienda ULss 9 Treviso
Dirigente medico
Roma
Neurologia
Università La Sapienza di Roma
Assegnista di ricerca
Chieti
Neurologia
Clinica Neurologica Dipartimento di Neuroscienze e Imaging Università "G. D'Annunzio" Chieti - Pescara
Ricercatore confermato in Neurologia (MED/26)
Francesco
Catanzaro
Neurologia
Neurologo
Giorgio
Pavia
Neurologia
Div. Neurologia e Stroke Unit, Università di Insubria, Varese
Ubaldo
Pisa
Neurologia
Direttore UO Neurologia Az.Ospedaliero Universitaria Pisa e della Scuola di Specializzazione in Neurologia
Borzi'
Giuseppe
Catanzaro, Italy
neurologia
University Magna Graecia
neurologo
Bossu'
Paola
roma
Neurologia
Fondazione Santa Lucia - Roma
Dirigente di ricerca
Bozzao
Alessandro
Roma
Radiologia Diagnostica
Università di Pavia
Professore Ordinario in Med/37
Bozzoni
Virginia
Padova
neurologia
Università degli Studi di Padova
Bramanti
Placido
Messina
Neurologia
IRCCS Centro Neurolesi - Messina
Bresolin
Nereo
Specializzando
Professore Ordinario di Scienze Tecniche Mediche Applicate SSD
MED/50
Briani
Chiara
Padova
Neurologia
Dipartimento di Neuroscienze - Università degli Studi di Padova
Professore associato confermato in Neurologia
Bruni
amalia Cecilia
Lamezia Terme
Neurologia
Azienda Sanitaria Provinciale di Catanzaro - Responsabile - Centro Regionale di Neurogenetica
Dirigente Medico di I Livello
Bruschini
Michela
Roma
neurologia
Fondazione Santa Lucia
neurologo
Bugiani
Marianna
Amsterdam, NL
Scienze Biologiche
biologia molecolare
VU University Medical Center, Amsterdam
Biologa
Cagnin
Annachiara
Padova
Neurologia
Azienda Ospedaliera di Padova - Clinica Neurologica
Professore associato in neurologia II Fascia
Callegari
Ilaria
Pavia
neurologia
Università degli Studi di Pavia
neurologo
Caltagirone
Carlo
Roma
Calvo
Andrea
Torino
Neurologia
Candelaresi
Milano
Neurologia
Università degli Studi di Milano Dipartimento di Fisiopatologia Medico-Chirurgica e dei trapianti
I.R.C.C.S. Fondazione Santa Lucia.
Professore Associato Neurologia e Neurochirurgia
Dipartimento di Neuroscienze 'Rita Levi Montalcini' - Università degli Studi di Torino - P.O. Molinette
Ricercatore MED/26 - neurologia
Paolo
Milano
Neurologia
UOC Neurologia e Stroke Unit, AO San Carlo Borromeo
Dirigente Medico I Livello
Cappa
Stefano
Milano
Neurologia
Università Vita-Salute San Raffaele Milano Facoltà di Psicologia
Professore Ordinario di Neuropsicologia
Caratozzolo
Salvatore
Villa Carcina
neurologia
Università degli Studi di Brescia
Neurologo
Carelli
Valerio
Bologna
Neurologia
Dpt di scienze biomediche e neuromotorie - Università di bologna
Piantadosi
Carlo
Roma
neurologia
Carolei
Antonio
L'Aquila
Cartabellotta
Nino
Bologna
Casalena
Alfonsina
Parma
Gastroenterologia e in Medicina
Interna
neurologia
Casali
Carlo
Latina
Caso
Francesca
Cassano
Domenico
Casula
Elias
MILANO
Nocera Inferiore SA
Roma
Cattaneo
Elena
Milano
Farmacia
Professore Associato
San Giovanni-Addolorata Hospital, Rome
neurologo
Medicina clinica, sanità pubblica, scienze della vita e dell'ambiente - Ateneo L'Aquila
Professore Ordinario
Presidente Fondazione GIMBE
Direttore Scientifico
Santo Stefano Rehabilitation Institute
neurologo
Neurologia
Università di Roma La Sapienza Dipartimento di SCIENZE E BIOTECNOLOGIE MEDICO-CHIRURGICHE
neurologia
Vita-Salute San Raffaele Hospital
neurologo
Neurologia
Ambulatorio Territoriale per le Cefalee.
Neurologo
Cavalcante
Paola
Milano
neurologia
Biotecnologie applicate alla
farmacologia
neurologia
Nessuna
neurologo
Facoltà di Scienze Biologiche Università degli Studi di Milano
Professore Associato di Scienze Biologiche
Neurology IV - Neurological Institute 'Carlo Besta'
neurologo
Cavaletti
Guido
Milano
Neurologia
Dipartimento di Neuroscienze e Tecnologie Biomediche Università di Milano Bicocca
Cavallieri
Francesco
neurologia
S. Agostino-Estense Hospital and University of Modena and Reggio Emilia
neurologo
Silvia
Neurologia
‘Centro Ictus’ della U.O. di Neurologia dell’Ospedale di Città di Castello
Responsabile della Struttura Semplice
Centonze
Diego
Modena, Italy
Città di Castello,
PG
Roma
Cenciarelli
Fondazione Santa Lucia IRCCS e dell'Università Tor Vergata di Roma, esperto di Neurofisiologia
Ricercatore
Ceravolo
Roberto
Pisa
Neurologia
Azienda Ospedaliero Universitaria di Pisa
Medico ospedaliero
Cereda
Cristina
Pavia
neurologia
IRCCS, "C. Mondino" National Institute of Neurology Foundation.
neurologo
Chiò
Adriano
Torino
neurologia
Università di Torino
neurologo
Ciccarelli
Olga
Londra - UK
Neurologia
National Hospital for Neurology and Neurosurgery
Professore di neurologia
Ciccone
Alfonso
Lodi
Neurologia
Azienda Ospedaliera Ospedale Niguarda Ca’ Granda
Dirigente medico
Ciceri
Elisa
Verona
Neurologia
Unità Operativa Complessa di Neuroradiologia dell’Istituto IRCCS Neurologico “C. Besta” di Milano
Responsabile della SODS di Neuroradiologia Intervenzionale
Cinque
Paola
Milano
Neurologia
Ospedale San Raffaele Milano
Neurologo
Ciocca
Matteo
Milano
neurologia
U.O. Medicina D'Urgenza, S.S. Neurologia ASST Fatebenefratelli Sacco - Milano
neurologo
Cocco
Eleonora
Cagliari
Neurologia
Dipartimento di Sanita' Pubblica, Medicina Clinica e Molecolare Università degli Studi di Cagliari
Cocito
Dario
Torino
Neurologia
S.O.C. Neurologia con indirizzo di Riabilitazione Funzionale del Dipartimento di Neuroscienze dell’Università di Torino Dirigente II Livello
Coghe
Giancarlo
Cagliari
neurologia
Cagliari
neurologo
5
COGNOME
NOME
CITTA'
LAUREA
SPECIALIZZAZIONE
neurologia
Colombo
Irene
Desio
Colosimo
Carlo
Roma
Comi
Giancarlo
Milano
Comi
Giacomo Pietro
Milano
neurologia
conforti
Francesca Luisa
Cosenza
Contarino
Maria Fiorella
Leiden, D
AFFILIAZIONE
QUALIFICA
Università Milano
Dirigente medico
Neurologia
Dipartimento di Scienze Neurologiche - Univ. La Sapienza
ricercatore
Neurologia
Università Vita-Salute San Raffaele Milano Facoltà di Medicina e Chirurgia
Università di Milano
neurologo
Neurologia
Azienda Ospedaliera di Cosenza – Presidio Ospedaliero dell’Annunziata
ricercatrice
Neurologia
Leiden University Medical Centre
Neurologo
Conte
Amelia
Roma
Neurologia
Policlinico A. Gemelli, Istituto di Neurologia
Ricercatore
Coppola
Antonietta
Napoli
Neurologia
Centro Epilessia Università Federico II
Neurologo
Coppola
Gianluca
Roma
Neurologia
Cortelli
Pietro
Bologna
Neurologia
Dip. Scienze Neurologiche Alma Mater Studiorum - Università degli Studi di Bologna Clinica Neurologica
Cortese
Bitonto
University of Bari
neurologo
Cortese
Francesca
Latina
neurologia
Sapienza University of Rome
neurologo
Cossu
Giovanni
Rosa
Cagliari
Neurologia
neurologia
Azienda Ospedaliera G. Brotzu Cagliari
Dirigente Medico di I Livello
Costa
Paolo
Brescia
neurologia
neurologo
Costa
Cinzia
Perugia
neurologia
Università degli Studi di Perugia
neurologo
Costanzo
Erminio
Catania
Neurologia
Ospedale Cannizzaro - Unità Operativa Complessa di Neurologia
Primario Neurologo
Crespi
Vittorio
Monza
Neurologia
Clinica Neurologica, Ospedale S.Gerardo, Monza - Titolare dell’ambulatorio di Neurologia, EEG, EMG, potenziali evocati Libero Professionale Neurologo
Neurologia
Cruccu
Dip. Scienze Neurologiche Università La Sapienza
Professore Ordinario in Neurologia
Cuzzocrea
Salvatore
Messina
Farmacia
Farmacia
Università degli Studi di Messina Dipartimento di Neuroscienze
Docente Universitario di Farmacologia
Dalla Costa
Gloria
Giorgio
Milan, Italy
Roma
neurologia
San Raffaele Hospital
neurologo
de Falco
Fabrizio
Napoli
Neurologia
Unità operativa di neurologia OSP. LORETO NUOVO, ASL NA 1
Medico Neurologo
De Giuli
Valeria
Brescia
neurologia
neurologo
DE LUCA
ROSARIA
Messina
neurologia
Università degli Studi di Messina
neurologo
De Mase
Antonio
Naples
neurologia
Second University of Naples
neurologo
De Meo
Ermelinda
Milano
neurologia
Specializzando
De Michele
Giuseppe
Napoli
Neurologia
De Rossi
Nicola
Brescia
neurologia
Vita-Salute San Raffaele
Università degli Studi di Napoli “Federico II”, Dipartimento di Neuroscienze e Scienze Riproduttive ed
Odontostomatologiche
CSM Montichiari NA Brescia
De Simoni
Grazia
Milano
Neruologia
Istituto Mario Negri - Milano
ricercatrice
De Stefano
Nicola
Siena
Neruologia
Azienda Ospedaliera di Siena
De Tommaso
Marina
Bari
Neurologia
Defanti
Carlo Alberto
Gazzaniga, BG
Defazio
Giovanni
Bari
Diana
L'Aquila
Degan
Dipartimento di Scienze Mediche di Base, Neuroscienze e Organi di Senso
neurologo
Medico Chirurgo, Neurologo
Centro Alzheimer c/o Ospedale Briolini Gazzaniga - BG
Specializzato in Neurologia e Psichiatria
Neurologia
Department of Neuroscience and Sensory Organs "Aldo Moro" University of Bari
neurologia
Università degli Studi dell'Aquila
neurologo
Del Sette
Massimo
Genova
Neurologia
AUSL 5 Spezzino
Direttore SC neurologia
Dell'Edera
Alessandro
Milan
neurologia
neurologo
Devigili
Grazia
Udine
neurologia
Udine
neurologo
Di Bonaventura
Carlo
Roma
Neurologia
Centro per la Cura dell’Epilessia e presso il Laboratorio di Elettroencefalografia della Clinica Neurologica B
Di Carlo
Antonio
Firenze
neurologia
Consiglio Nazionale delle Ricerche
neurologo
Di Fede
Roberta
Bari
Neurologia
Clinica Neurologica Policlinico di Bari
Neurologo
Di Lazzaro
Vincenzo
Roma
Neurologia
Policlinico Universitario Campus Biomedico di Roma
Professore Associato, Settore scientifico MED/26
Di Lorenzo
Francesco
Roma
neurologia
Tor Vergata
Specializzando
Diodato
Daria
Roma
Neurologia
Unità di Neurogenetica Molecolare,
Neurologo
DOCIMO
RENATO
Napoli
neurologia
SUN - Seconda Università degli studi di Napoli
Neurologo
Donadio
Vincenzo
Bologna
neurologia
bologna
Neurologo
Dotti
Maria Teresa
Siena
Neurologia
Dipartimento di Scienze Neurologiche e del Comportamento dell'Università di Siena
Durelli
Luca
Torino
Neurologia
Dipartimento di Scienze Cliniche e Biologiche Università degli Studi di Torino
Eleopra
Roberto
Udine
Neurologia
SOC di Neurologia Azienda Ospedaliero Universitaria S.Maria della Misericordia Udine
Dirigente Medico II Livello
Evoli
Amalia
Roma
Neurologia
Università Cattolica di Sacro Cuore di Roma
Fabbrini
Giovanni
Roma
Fabi
Massimo
Parma
Falco
Fabrizia
Napoli
Falini
Andrea
Milano
Radiologia e Neurologia
Fasano
Alfonso
Toronto, CAN
Neurologia
Division of Neurology at the University of Toronto.
Fasano
Antonio
Modena
neurologia
Università di Modena e Reggio Emilia
neurologo
Federico
Antonio
Siena
Neurologia
Dipartimento di Scienze Neurologiche e del Comportamento Università degli studi di Siena
Federico
Angela
Verona
neurologia
University of Verona
neurologo
Ferlazzo
Edoardo
Catanzaro
Neurologia
Università Magna Graecia di Catanzaro
Professore Aggregato
Ferrante
Enrico
Milan
neurologia
Niguarda Cà Granda Hospital
neurologo
Ferrarese
Carlo
Milano
Neurologia
Dipartimento di Neuroscienze Ospedale San Gerardo - Monza MI
Ferrari
Sergio
Roma
Clinica Neurologica di Verona Dipartim. Biomedicina e del Movimento
Dirigente Medico
Ferraro
Diana
Modena
neurologia
Modena e Reggio Emilia
ricercatore
Ferri
Raffaele
Troina
Neurologia
Dipartimento di Neurologia - Istituto Oasi
Primario Neurologo
Ferri
Lorenzo
Bologna
neurologia
University of Bologna
Specializzando
Fichera
Mario
Milano
neurologia
Vita-Salute San Raffaele
Specializzando
Medicina
Neurologia
Università degli Studi di Roma Dipartimento di NEUROLOGIA E PSICHIATRIA
Reumatologia - Igiene e Medicina
Direttore Generale dell’Azienda Ospedaliero-Universitaria di Parma
preventiva
neurologia
Napoli
Neurologia e neuropatologia
Divisione di Neuroscienze, Istituto Scientifico San Raffaele
Dirigente di II Livello
Dirigente medico
neurologo
Professore di ruolo II fascia, MED/37 Neuroradiologia
Fierini
Fabio
Florence
neurologia
University of Florence
neurologo
Filippi
Massimo
Milano
Neurologia
Filla
Alessandro
Napoli
Neurologia
Università Federico II Napoli
Filosto
Massimiliano
Neurologia
Azienda Ospedaliera “Spedali Civili”, Brescia
Dirigente Neurologo
Finocchi
Cinzia
Neurologia
IRCCS Azienda Ospedaliera Universitaria S. Martino –IST di Genova
Dirigente medico
Fischer
Maximilian
Brescia
Città di Castello,
PG
Firenze
neurologia
Firenze
neurologo
Forlivesi
Stefano
Verona
neurologia
neurologo
Fragiacomo
Federica
Padova
neurologia
neurologo
Francia
Ada
Roma
Neurologia
Responsabile del Centro di Riferimento di neuroimmunologia clinica riconosciuto dal Policlinico Umberto I di Roma
Dirigente I Livello
Franciotta
Diego
Pavia
Neurologia
Istituto Neurologico Nazionale 'C. Mondino' - Università di Pavia
Dirigente Neurologo
Frisoni
Giovanni
Brescia
Neurologia
Responsabile dell’Unità Operativa di Psicogeriatria all’IRCCS-FB
Medico Neurologo
Fumagalli
Giorgio
Milan
neurologia
University of Milan
neurologo
Furlan
Roberto
Milano
Neurologia
Istituto Scientifico San Raffaele - Divisione di Neurologia
Neurologo
Furling
Denis
Parigi - F
Neurologia
Centre de Recherche en Myologie (UPMC/Inserm/CNRS), Institut de Myologie, Paris
Direttore di ricerca
Fusco
Francesca Romana Roma
Neurologia
Fondazione Santa Lucia IRCCS
Dirigente medico
Gagliardi
Monica
Germaneto
neurologia
CNR
Neurologo
Galimberti
Daniela
Milano
Neurologia
Università di Milano Dipartimento di Fisiopatolgia e dei Trapianti
Professore di Seconda Fascia in Neurologia
Gallo
Antonio
Napoli
Neurologia
II Università di Napoli - Dipartimento di Scienze Mediche, Chirurgiche, Neurologiche, Metaboliche e dell InvecchiamentoRicercatore
Gallo
Paolo
Padova
Neurologia
ULSS 16 clinica Neurologica Università di Padova
Galosi
Eleonora
Roma
neurologia
Università degli studi di Roma "La Sapienza"
Specializzando
Facoltà di Medicina e Chirurgia afferente al Dipartimento di Scienze Mediche dell’Università degli Studi Magna Graecia
di Catanzaro
Dirigente ASL I fascia - Neuroradiologia - Ospedale Gaslini
Professore I Fascia
Gambardella
Antonio
Catanzaro
Neurologia
Gandolfo
Carlo
Genova
Radiodiagnostica
gardinetti
margherita
Bergamo
neurologia
universita milano bicocca
Neurologo
Garibaldi
Matteo
Roma
Neurologia
Università di Roma la Sapienza
Neurologo
Garnero
Martina
Genoa
neurologia
University of Genoa
Neurologo
Gemma
Siano
Foggia
Neurologia
AZIENDA OSPEDALIERA S. GIOVANNI DI DIO E RUGGIERO D'ARAGONA
Professore I Fascia
Giacalone
Fabio
Palermo
neurologia
Università degli Studi di Palermo
Neurologo
Giaccone
Giorgio
Milano
Neurologia
Istituto Neurologico C. Besta Milano
Dirigente medico
Giannini
Giulia
Bologna
neurologia
Department of Biomedical and NeuroMotor Sciences (DiBiNeM), Alma Mater Studiorum
Specializzando
Giannoccaro
Maria Pia
Bologna
neurologia
Università di Bologna
Neurologo
Gigli
Gianluigi
Udine
Neurologia - Psichiatria
Giometto
Bruno
Treviso
Neurologia e Neuropatologia
Giordana
Maria Teresa
Torino
Neurologia
Università degli Studi di Udine
Neurologo
Direttore Responsabile della Struttura Complessa di Neurologia dell'Ospedale Regionale Ca'Foncello di Treviso
Esperto professionale
Department of Neurosciences "Rita Levi Montalcini"
5
LAUREA
SPECIALIZZAZIONE
GIORDANO
COGNOME
ALFONSO
NOME
napoli
CITTA'
neurologia
Seconda Università degli studi di Napoli
AFFILIAZIONE
Neurologo
QUALIFICA
Giordano
Antonino
Milano
neurologia
Neurologo
Giorgio
Antonio
Siena
Neurologia
UOSA Neurologia Sperimentale
Neurologo
Giulietti
Giovanni
Roma
neurologia
IRCCS Fondazione Santa Lucia
Neurologo
Giussani
Giorgio
Milano
Neurochirurgia
Clinica Neurochirurgia, Università degli Studi Milano-Bicocca, Osp. San Gerardo dei Tintori - Monza
ricercatore
Giussani
Giuditta
Lecco
Neurochirurgia
godani
massimiliano
la spezia
neurologia
Dpt Neuroscienze - Ospedale di Lecco
Dirigente medico
Parma
Neurologo
GRANATO
ANTONIO
Trieste
neurologia
University of Trieste
Neurologo
Grazzi
Giovanni
Ferrara
neurologia
Ferrara
Neurologo
Grazzi
Licia
Milano
neurologia
Fondazione IRCCS Istituto Neurologico Carlo Besta
Neurologo
Grisold
Wolfang
Vienna, A
Neruologia
Department of Neurology Ludwig Boltzmann Institute for Neurooncology
Grossi
Dario
Guarnieri
Biancamaria
Napoli
Città Sant'Angelo
PE
Clinica Neurologica Università degli Studi di Napoli Federico II
Neurologia
Centro di Medicina del Sonno (Multidisciplinare) (UO di Neurologia,Casa di Cura accreditata “ Villa Serena” )
Neurologo
Imperiale
Daniele
Torino
Neurologia
S.C. Neurologia Dipartimento Attività Mediche Azienda Sanitaria Locale Torino
Neurologo
Introna
Alessandro
Bari
neurologia
University of Bari "Aldo Moro"
Neurologo
Inzitari
Domenico
Firenze
Malattie Nervose e Mentali
Clinica Neurologica dell'Università di Firenze
Koch
Giacomo
Roma
Neurologia
Fondazione Santa Lucia, IRCCS,Roma
ricercatore
La Bianca
Giuseppe
Palermo
neurologia
Università di Palermo
Neurologo
La Morgia
Chiara
Bologna
Neurologia
Dpt di scienze biomediche e neuromotorie - Università di bologna
ricercatore
Lauria
Giuseppe
Milano
Neurologia
ISTITUTO NEUROLOGICO C. BESTA - MILANO
Lavorgna
Luigi
Napoli
Neurologia
I Clinica Neurologica AOU - Seconda Università di Napoli
Neurologo - Dirigente Medico
Leggio
Maria
Roma
Neurologia
Facoltà di Medicina e Psicologia, Università degli Studi di Roma “La Sapienza”.
Leocani
Letizia
Milano
Neurologia
Neurophysiology Dep.t Hospital San Raffaele
Ricercatore Senior Neurofisiologia
Leonardi
Luca
Latina
neurologia
Roma Sapienza
Neurologo
Lettieri
Christian
Udine
neurologia
Azianda Ospedaliero-Universitaria "S. Maria della Misericordia"
Neurologo
Liberatore
Giuseppe
Milan
neurologia
Neurologo
Linfante
Italo
Miami, USA
Neurologia
Milan University
Medical Director of Interventional Neuroradiology and Endovascular Neurosurgery at Miami Cardiac and Vascular
Institute and Baptist Neuroscience Institute
Lisotto
Carlo
Padova
Neurologia
Headache Centre, Hospital of Pordenone and Headache Centre, Department of Neurosciences, University of Padua
Dirigente Medico
Liuzzi
Daniele
Bari
Neurologia
U.O.C. Neurologia - Ospedale Generale Regionale "F. Miulli"
Neurologo
Logroscino
Giancarlo
Bari
Neurologia
Università Degli Studi Di Bari "Aldo Moro" Dipartimento di Scienze Mediche di Base Neuroscienze e Organi di Senso
Lombardi
Carolina
Milano
Neurofisiopatologia
stituto Auxologico Italiano IRCCS –Ospedale San Luca- Università Milano Bicocca- Milano
Dirigente medico
Lopiano
Leonardo
Torino
Neurologia
Clinica Neurologica I - Dipt. di Neuroscienze
Lorenzano
Svetlana
Rome
neurologia
Neurologo
Lorusso
Lorenzo
Chiari, BS
Neurologia
U.O. Neurologia A.O. Mellino Mellini
Dirigente Medico in Neurologia
Lugaresi
Alessandra
Bologna
Neurologia
Clinica Neurologica Dipartimento di Neuroscienze e Imaging
Luisi
Concetta
Bari
neurologia
Università di Bari
Neurologo
Lupo
Angela
Catanzaro, Italy
neurologia
University Magna Grà¦cia
Neurologo
Maggioni
Ferdinando
Padova
Neurologia
Università degli Studi di Padova - Dipartimento di Neruoscienze
Ricercatore Universitario confermato
Mainardi
Federico
Venezia
Neurologia
Ospedale SS. Giovanni e Paolo-Neurologia
Malagutti
Alberto
Mantova
perito elettronico
INPS
perito elettronico
Mallucci
Giulia
Pavia
neurologia
Università di Pavia
ricercatore
Mancardi
Giovanni Luigi
Genova
Neurologia
Dipartimento di Neuroscienze Oftalmologia genetica - Univ. Di Genova
Mancini
Andrea
Perugia
neurologia
University of Perugia
neurologo
Mandrioli
Jessica
Modena
Neurologia
U.O. Neurologia, Nuovo Ospedale Civile S. Agostino Estense di Modena
Manfredini
Lucia Ilaria
Catanzaro, Italy
neurologia
University of Magna Graecia
neurologo
Mangiafico
Salvatore
Firenze
Neurologia e Radiologia
Dipartimento del cuore e dei vasi del’Azienda Ospedaliera Universitaria di Careggi.
Dirigente medico
Manni
Raffaele
Pavia
Neurologia
Dirigente Medico
Mantegazza
Renato
Milano
Neurologia
marchi
margherita
milano
neurologia
Direttore dell'Unità operativa di medicina del sonno e di epilessia dell'Istituto Mondino di Pavia
Istituto Neurologico C. Besta - Responsabile - UO Complessa Malattie Neuromuscolari e
Neuroimmunologia
Unimi
Marchioni
Enrico
Pavia
Neurologia
Istituto C. Mondino
Neurologo
Marcuccio
Laura
Naples
neurologia
Second University of Naples
neurologo
Marrosu
Maria Giovanna
Cagliari
Neurologia
Centro Sclerosi Multipla Osp Binaghi
Martinuzzi
Andrea
Conegliano
neurologia
Padova
neurologo
Massa
Federico
Genova, Italy
neurologia
University of Genova, IRCCS AOU San Martino-IST
neurologo
Massimini
Marcello
Milano
Fisiologia
Dipartimento di Scienze Biomediche e Cliniche "L. Sacco"
Matarese
Giuseppe
Napoli
Clinica Patologica
University of Naples Federico II, Faculty of Medicine and Surgery
Professore Ordinario di Immunologia e Patologia Generale
Matinella
Angela
Verona
Dirigente Medico
neurologo
Università di Verona
Specializzando
Mattavelli
Daniele
Milan, Italy
neurologia
University of Milan
Specializzando
Mattioli
Flavia
Brescia
neurologia
Spedali Civili, Brescia
neurologo
Mazza
Maria Rosaria
Catanzaro
Neurologia
Univers. Magna Grecia di Catanzaro Dipartim. Scienze Mediche
Specializzanda
Mazzon
Giulia
Trieste
neurologia
University of Trieste
neurologo
Mazzucchi
Anna
Parma
Neurologia
Elias Neuroriabilitazione
Professore Associato in Riabilitazione Neurologica
Mechelli
Rosella
Rome
neurologia
ricercatore
Meletti
STefano
Modena
Neurologia
Melone
MariaRosa AB
Napoli
Neurologia
Facoltà di Medicina e Chirurgia. Università di Modena e Reggio Emilia. Dipartimento di Scienze Biomediche,
Metabolismo, e Neuroscienze
Seconda Università di Napoli - Neurologia
Meneghello
Francesca
Venezia
neurologia
Padova
neurologo
Meola
Giovanni
Milano
Neurologia
UNIVERSITÀ DEGLI STUDI DI MILANO
DIRETTORE UNITÀ OPERATIVA COMPLESSA DI NEUROLOGIA E STROKE-UNIT IRCCS POLICLINICO SAN DONATO
merico
antonio
Lido Venezia
neurologia
FONDAZIONE OSPEDALE SAN CAMILLO - I.R.C.C.S. .. Lido Venezia
neurologo
Merlo
Paola
Bergamo
Neurologia
Humanitas Gavazzeni - Bergamo, Lombardia
Messina
Roberta
Milano
neurologia
neurologo
Metz
Gunther
Germania
Santhera Pharmaceuticals
Dipartimento di Psicologia e Scienze Cognitive
Centro Interdipartimentale Mente/Cervello - CIMEC
IRCCS Fondazione Istituto Neurologico "C. Mondino"
Head of Business Development
Medicina
neurologia
Specializzato in Neurologia
Farmacia
Miceli
Gabriele
Rovereto, TN
Neurologia
Micieli
Giuseppe
Pavia
Neurologia
Responsabile Unità Operativa
Neurologo
Mignarri
Andrea
Siena
neurologia
University of Siena
neurologo
Minicucci
Fabio
Milano
Neurologia
Neurologo
Miniussi
Carlo
Brescia
Neurologia
Mirabella
Massimiliano
Roma
Neurologia
Ospedale San Raffaele Milano - Centro Epilessia e tecniche correlate
Dipartimento di Scienze Cliniche e Sperimentali, sezione di Neuroscienze, Università degli
Studi di Brescia
Istituto di Neurologia, Università Cattolica del Sacro Cuore, Policlinico “A. Gemelli”
Moccia
Marcello
Napoli
neurologia
Moiola
Lucia
Milano
Neurologia
Monasta
Lorenzo
Trieste
statistica
Fidenza
Universita' Federico II
Dipartimento di Neurologia e Centro sclerosi multipla Ospedale San Raffaele –Milano
neurologo
Ircss Materna infantile Burlo garofalo
Dirigente statistico
Dirigente medico primo livello
Montanari
Enrico
Neurologia
UO Neurologia Ospedale di Vaio - Fidenza
Direttore di Dipartimento
Morandi Treu
Paula
roma
Vivi Vejo onlus - Roma
presidente
Morelli
Maurizio
Catanzaro
neurologia
Magna Graecia University
neurologo
Moretto
Giuseppe
Verona
Direttore UO di Neurologia Azienda Ospedaliera Universitaria Integrata - Verona
Neurologo
Letteratura inglese
Motta
Caterina
neurologia
Università degli Studi di Roma Tor Vergata
neurologo
Musicco
Massimo
Roma
Neurologia
Univ. 'TOR VERGATA' - ROMA
Ricercatore (SECS-S/02)
musumeci
olimpia
Messina
neurologia
neurologo
Napoletano
Vito
Bari
Neurologia
Ospedale di Monopoli (Bari) ASL BA
Neurologo
Nicoletti
Ferdinando
Roma
Neurologia
Dipartimento di Fisiologia Umana e Farmacologia, Università di Roma "La Sapienza"
Nisticò
Rita
Catanzaro
neurologia
CNR
neurologo
Nobile Orazio
Edoardo
Milano
Neurologia
2nd Neurology, Dept. Translational Medicine, Milan University, IRCCS Istituto Clinico Humanitas
Professore di Neurologia
Neurologia
Notariello
Marcella
Roma
Professore Ordinario di Neurofisiopatologia
Neurologo
Foggia
ASL di Foggia
Neurologo
Notturno
Francesca
Avezzano
neurologia
neurologo
Novellino
Fabiana
Catanzaro
neurologia
Neuroimaging Research Unit
neurologo
Oppo
Valentina
Milano
Neurologia
ASST Grande Ospedale Metropolitano Niguarda
Neurologo
5
LAUREA
SPECIALIZZAZIONE
Orzi
COGNOME
Francesco
NOME
Roma
CITTA'
Neurologia
AFFILIAZIONE
QUALIFICA
Ottoboni
Linda
Neurologia
Neuroimmunologia Ospedale San Raffaele, Milano
Senior Scientist
Cristina
Neurologia
Area Vasta n.5 Ospedale San Benedetto del Tronto
Neurologo
Paciaroni
Maurizio
Milano
San Benedetto del
Tronto, AP
perugia
Paci
Neurologia
Università di Perugia
Principal investigator
Paciotti
Silvia
Perugia
neurologia
University of Perugia
neurologo
Padovani
Alessandro
Brescia
Neurologia
Università degli Studi di Brescia UO Neurologia 2 - AO Spedali Civili di Brescia
Paladin
Francesco
Venezia
Neurologia
Ospedale SS. Giovanni e Paolo
Neurologo
Pandolfo
Massimo
Bruxelles
Neurologia
ULB – Hôpital Erasme - Service Neurology
Dirigente Medico
Panella
Vincenzo
Roma
Medicina
Igiene
Direttore Regionale Salute e Politiche regione Lazio
Direttore Regione Lazio
Pantoni
Leonardo
Firenze
Neurologia
Azienda Ospedaliero-Universitaria Careggi
Paolicelli
Damiano
Bari
neurologia
Univeristy of Bari Aldo Moro
Ricercatore Universitario
Papagno
Costanza
Milano
Neurologia
Psicologia e Neuroscienze Cognitive - Università di Milano-Bicocca
Professore ordinario di psicologia fisiologica
Parchi
Piero
Bologna
Neurologia
Dipartimento Scienze Biomediche e Neuromotorie, presso IRCCS Istituto delle Scienze Neurologiche
Pardini
Matteo
Genoa
neurologia
University of Genoa
neurologo
Parnetti
Lucilla
Perugia
Neurologia e Geriatria
Università degli Studi di Perugia – Facoltà di Medicina e Chirurgia - Perugia
Docente Universitario
Pasini
Elena
Bologna
neurologia
Bolgona
neurologo
PATTI
FRANCESCO
Catania
neurologia
Policlinico 'Gaspare Rodolico'
professore aggregato di Neurologia
Pazzaglia
Costanza
Milano
neurologia
Fondazione Don C. Gnocchi
neurologo
Pegoraro
Elena
Padova
Neurologia e Genetica Medica
Dipartimento di Neuroscienze NPSRR, e Direttore Scuola di Specializzazione Univ. Padova
Pellegrino
Giovanni
Montreal
neurologia
McGill University
neurologo
Pellerino
Alessia
Torino
neurologia
Università di Torino
neurologo
Pellicciari
Roberta
Bari
Neurologia
Villa Igea - Bari
Neurologo
Perani
Daniela
Milano
Neurologia
Università Vita-Salute San Raffaele Milano
Professore ordinario
Perini
Paola
Padova
Neurologia
U.O. di Neurologia - Ospedale Civile di Padova
Dirigemte medico
Perini
Giulia
Pavia
neurologia
University of Pavia
neurologo
Perna
Alessia
Roma
neurologia
"Sacro Cuore"
neurologo
Pessa
Maria Elena
Udine
neurologia
University of Udine
neurologo
petruzzo
martina
Rome, Italy
neurologia
Sapienza University
neurologo
Piano
Mariangela
Milano
Medicina
Piazza
Fabrizio
Milano
Piccininni
Chiara
Radiodiaagnostica
Biotecnologie applicate alla
farmacologia
neurologia
Neuroradiologia dipartim. Di Neuroscienze Niguarda Milano
Scuola di medicina e chirurgia - Università Milano Bicocca
Principal investigator
Roma
Picco
Agnese
Italy
neurologia
University of Genova
neurologo
Pierelli
Francesco
Roma
Neurologia
Università di Roma La Sapienza Dipartimento di SCIENZE E BIOTECNOLOGIE MEDICO-CHIRURGICHE
Neurologia
Pievani
Michela
Brescia
Università Cattolica del Sacro Cuore
neurologo
Centro San Giovanni di Dio - Fatebenefratelli - Brescia
ricercatrice
Piras
Valentina
Cagliari
Biologia
Università di Cagliari
Biologa
Pisani
Laura Rosa
Messina
neurologia
MEssina
neurologo
Piscaglia
Maria Grazia
Ravenna
Neurologia
Dirigente Medico U.O. Neurologia Aziendale AUSL Ravenna.
Neurologo
Pistoia
Francesca
L'Aquila
neurologia
Università di L'Aquila
neurologo
Pizza
Fabio
Bologna
Neurologia
Dipartimento di Scienze Neurologiche dell’Università di Bologna
Neurologo
Poggesi
Anna
Firenze
neurologia
Università degli Studi di Firenze
neurologo
Pontieri
Ferdinando
Roma
Neurologia
Azienda Ospedaliera Sant'Andrea Integrata con la facoltà di Medicina e psicologia di Sapienza Università di Roma
dirigente medico
Pradotto
Luca Guglielmo
Piancavallo (VB)
neurologia
IRCCS ISTITUTO AUXOLOGICO ITALIANO
neurologo
Protti
Alessandra
Milano
Neurologia
Università di Milano
Neurologo
Provinciali
Leandro
Ancona
Neurologia
Dipt. di Scienze Neurologiche Università di Ancona
Quaranta
Davide
ROma
Neurologia
Policlinico Universitario A.Gemelli
dirigente medico
Quartarone
Angelo
Messina
Neurologia
Università degli Studi di Messina Dipartimento di Neuroscienze
Professore Associato MED/48
Quatrale
Rocco
Udine
Neurologia
Azienda Ulss 12 Veneziana
Diretto Unità Operativa
Quattrone
Aldo
Catanzaro
Neurologia
Querin
Giorgia
Padova
neurologia
Università degli Studi di Padova
neurologo
Razzolini
Lorenzo
Firenze
neurologia
Università degli Studi di Firenze
neurologo
Remuzzi
Giuseppe
Nefrologia
dell’Istituto Mario Negri
Primario di Nefrologia e Dialisi
Ricci
Stefano
Neurologia
Azienda USL n. 2 di Perugia
Dirigente Medico di Struttura Complessa
Ricci
Silvia
Milano
Città di Castello,
PG
Legnago
neurologia
Mater Salutis Hospital
neurologo
Rizzone
Mario Giorgio
Torino
Neurologia
Ricercatore
Rocca
Maria Assunta
Milano
Neurologia
Rodolico
Carmelo
Messina
Neurologia
Department of Neurosciences "Rita Levi Montalcini"
Group Leader, Unità Neuroimaging della sostanza Bianca del SNC, Divisione di Neuroscienze, Ospedale San Raffaele,
Milano
AZIENDA OSPEDALIERA UNIVERSITARIA , VIA C. VALERIA - MESSINA
Romano
Angela
Rome
neurologia
Catholic University of the Sacred Heart
Specializzando
Dirigente Medico
Romoli
Michele
Perugia
neurologia
Azienda Ospedaliero Universitaria di Perugia
neurologo
Rossini
Paolo Maria
Roma
Neurologia
Università Cattolica di Sacro Cuore di Roma
Professore Ordinario in Neurologia
Rovaris
Marco
Milano
Neurologia
IRCCS Santamaria Nascente - Fondazione Don Gnocchi - Milano
Primario
Rozzini
Luca
Brescia
neurologia
University of Brescia
neurologo
Rubino
Elisa
Turin
neurologia
University of Turin
neurologo
Rudà
Roberta
Torino
Neurologia
Cure Neuro-Oncologico (GIC), A.O.U. Città della Salute e della Scienza di Torino
Dirigente Medico di Neurologia I livello
Russello
Alfonso
Lecce
Neurologia
Ambulatorio di Neurologia distretto di Casarano LE
Neurologo
Russo
Antonio
Napoli
Neurologia
Centro Cefalee I Clinica Neurologica SUN
Dottorando di Ricerca in Neuroscienze
Russo
Marco
Parma
Neurologia
Medico Neurologo ASMN Reggio Emilia
Medico Neurologo
Sacco
Simona
L'Aquila
neurologia
neurologo
Salmaggi
Andrea
Milano
Neurologia
Direttore UO Neurooncologia Clinica - Neurologia 2 della Fondazione IRCCS Istituto Neurologico C. Besta - Milano
Neurologo
Saltuari
Leopold
Bolzano
Neurologia
Azienda Sanitaria dell'Alto Adige - Ospedale di Vipiteno - Neuroriabilitazione
Direttore scientifico
Salvadori
Emilia
Firenze
neurologia
University of Florence
neurologo
Salvetti
Santantonio
Marco
Piero
Roma
Roma
UOD Centro Neurologico Terapie Sperimentali (CENTERS)
Igeam - Roma
Amministratore delegato
Santorelli
Filippo
IRCCSFondazione Stella Maris, Calabrone (PI)
Università degli Studi di Napoli Federico II - Dipartimento di Neuroscienze e Scienze riproduttive ed
odontostomatologiche - Napoli
Dirirgente Medico II Livello
Università di Cagliari
Division of Sleep and Movement Disorders, Department of Neurology, Univeristy of Utah, Imaging and Neurosciences
Center
Specializzando
Fisica
Neurologia
Sicurezza e protezione industriale
Pisa
Neurologia
Santoro
Sarasso
Lucio
Napoli
Pediatria e allergologia
Elisabetta
Milano
neurologia
Sarchioto
Marianna
Cagliari
neurologia
Savica
Rodolfo
Rochester, USA
Neurologia
Scarpini
Elio
Milano
Neurologia
Schenone
Angelo
Genova
Neurologia
Dipartimento di Neuroscienze, Oftalmologia e Genetica dell’Universita’ Di Genova
Sciacca
Giorgia
Catania
neurologia
Catania
neurologo
Semplicini
Claudio
Padova
neurologia
neurologo
Sensi
Maria Chiara
Ferrara
Neurologia
Dipartimento di Neuroscienze- Riabilitazione dell’Ospedale S. Anna di Ferrara
Serra
Laura
Rome
neurologia
Santa Lucia Foundation IRCCS
neurologo
Serrati
Carlo
Genova
Siciliano
Gabriele
Pisa
Neurologia
Dipartimento di Medicina Clinica e Sperimentale Università di Pisa
Silvani
Antonio
Milano
Neurologia
Dipt. Di Neuroncologia Fondazione IRCCS Istituto Neurologico Carlo Besta
Dirigente Medico in Neurologia
Clinica della Memoria del Centro di Medicina dell'Invecchiamento – Dipartimento di Geriatria, Neuroscienze e
Neurologo
Ortopedia dell'Università Cattolica del Sacro Cuore
Struttura Organizzativa Dipartimentale Semplice (SODS) Stroke Unit/Dipartimento di Neuroscienze, Azienda OspedalieroProfessore Associato in Neuroscienze
Universitaria Ospedali Riuniti di Ancona
S.O.S.D. Neuroepidemiologia Fondazione IRCCS Istituto Neurologico “C. Besta”
Neurologo
Professore di NEUROLOGIA (MED/26)
neurologo
Ricercatore
Dipartimento di Scienze Neurologiche, Università di Milano, IRCCSFondazione Cà Granda Ospedale Maggiore Policlinico Professore Associato
Neurologia e Farmacologia Clinica Direttore U.O. Complessa Neurologia Genova
Neurologo
Professore Associato Neurologia MED 26
Silveri
Maria Caterina
Roma
Neurologia
Silvestrini
Mauro
Ancona
Neurologia
Solari
Alessandra
Neurologia
Solaro
Carlo
Genova
Neurologia
SC Neurologia Dipartimento Testa-Colla ASL3 Genova
Neurologo
Soraru
Gianni
Padova
neurologia
neurologo
Sorbi
Sandro
Firenze
Neurologia
Dipartimento Scienze Neurologiche e Psichiatriche, Univ. di Firenze
Spandonaro
Federico
Roma
Neurologia
Università degli Studi di Roma Tor Vergata
Professore Aggregato
Spano'
Barbara
Rome
neurologia
IRCSS, Santa Lucia Foundation
ricercatore
Milano
5
COGNOME
NOME
CITTA'
LAUREA
SPECIALIZZAZIONE
neurologia
Roma
Milan
Bologna
Salvatore
Napoli
Taga
Arens
Parma
Tagliavini
Fabrizio
Tamburin
Spinelli
Edoardo Gioele
Milano
Stanzione
Paolo
Storelli
Loredana
Stracciari
Andrea
Striano
AFFILIAZIONE
QUALIFICA
neurologo
Neurologia
Università di Roma Tor Vergata – Dipartimento di Neuroscienze
neurologia
neurologo
Neurologia
Unità Operativa di Neurologia del Policlinico S. Orsola-Malpighi
Neurologia
Università Federico II Napoli
neurologia
Parma
neurologo
Milano
ISTITUTO NEUROLOGICO C. BESTA - MILANO
Dirigente Medico - Neurologo
Stefano
Verona
neurologia
neurologo
Taricco
Mariangela
Bologna
Neurologia
U.O. di Medicina Fisica e Riabilitazione della Azienda Ospedaliero-Universitaria Policlinico S. Orsola Malpighi di Bologna Professore a contratto di Neurologia
Taroni
Franco
Istituto Neurologico C Besta SOSD Genetica delle Malattie Neurodegenerative e Metaboliche
Dirigente Medico
Taveggia
Carla
Milano
Neurologia
Istituto Scientifico San Raffaele Milano
Ricercatore
Tedeschi
Gioacchino
Napoli
Neurologia
II Clinica Neurologica II Univ. Di Napoli
Testa
Giulia
Bergamo
neurologia
University of Bergamo
neurologo
Ticozzi
Nicola
Milano
Neurologia
Dipartimento di Fisiopatologia Medico-Chirurgica e dei Trapianti - Università degli Studi di Milano
Tinazzi
Michele
Milano
Verona
Neurologia
Neurologia
Scienze Neurologiche, Neuropsicologiche, Morfologiche e Motorie Università degli Studi di Verona
Associato confermato
Tinuper
Paolo
Bologna
Neurologia
Università di Bologna. Dipartimento di Scienze Biomediche e Neuromotorie
Professore associato
Todeschini
Alice
Brescia
neurologia
neurologo
Tola
Maria Rosaria
Ferrara
Neurologia
Dipartimento Neuroscienze/Riabilitazione, Azienda OspedalieroUniversitaria S. Anna di Ferrara
Professore associato
Tondo
Giacomo
Novara
neurologia
Università del Piemonte Orientale
neurologo
Toni
Danilo
Roma
Neurologia
Unità di Trattamento Neurovascolare Policlinico Umberto I Roma
Torelli
Paola
Parma
Neurologia
Università degli Studi di Parma Dipartimento di Medicina Clinica e Sperimentale
Torrente
Angelo
Palermo
neurologia
Università degli Studi di Palermo
neurologo
Tortorella
Carla
Bari
Neurologia
Azienda Policlinico Consorziale Bari Clinica Neurologica “L. Amaducci”
Toscano
Antonio
Messina
Neurologia
UOC di Neurologia e Malattie Neuromuscolaro AOu "G. Martino"
Tremolizzo
Lucio
Milano
Neurologia
Clinica Neurologica - Ospedale San Gerardo - Milano
Assegnista di ricerca
Trimboli
Michele
London, UK
neurologia
neurologo
Trojano
Maria
Bari
Neurologia
Guy's and St. Thomas' NHS Foundation Trust
Direttore del Dipartimento di Scienze Mediche di Base, Neuroscienze ed Organi di Senso, Università degli Studi "Aldo
Moro" Bari
Trojsi
Francesca
Napoli
Neurologia
Dipartimento Assistenziale di Medicina Specialistica AOU Seconda Università degli Studi di Napoli - Centro storico
Neurologo
Uccelli
Antonio
Genova
Neurologia
Università di Genova
Uncini
Antonino
Chieti
Neurologia
Università degli Studi G. D'Annunzio -Chieti - Dipartimento di Neuroscienze, Imaging e Scienze Cliniche
Valeriani
Massimiliano
Roma
neurologia
Ospedale Bambino Gesà¹
neurologo
Valzania
Franco
Modena
Neurologia
Università di Modena e Reggio Emilia AUSL di Modena
Dirigente Medico - Neurologo
Van der Knapp
Marjo
Amsterdam, NL
Neurologia pediatrica
VU University Amsterdam
ricercatore
Vecchio
Fabrizio
Rome
neurologia
IRCCS San Raffaele Pisana
neurologo
Vercelli
Liliana
Torino
Neurologia
Università di Torino Dipartimento di Neuroscienze
Dottoranda in neurologia
Vernieri
Fabrizio
Roma
neurologia
Università Campus Bio-Medico di Roma
neurologo
Verrengia
Elena Pinuccia
Milan
neurologia
Pavia University
neurologo
Vidale
Simone
Como
neurologia
Sant'Anna Hospital . Como
neurologo
Villani
Veronica
Roma
Neurologia
Neurologia IFO di Roma
Neurologo
Vita
Giuseppe
Messina
neurologia
Vita
Gian Luca
Messina
neurologia
University Hospital â€œG. Martinoâ€
neurologo
Viticchi
Giovanna
Ancona
neurologia
Marche Polytechnic University
neurologo
Vivacqua
Giorgio
Roma
neurologia
Sapienza Università di Roma
neurologo
Zago
Elisabetta
Milan
neurologia
University of Milan
neurologo
Zaino
Domenica
Siena-Italy
neurologia
University of Siena
Specializzando
Zanchin
Giorgio
Padova
Neurologia
direttore del Centro cefalee presso il dipartimento di neuroscienze dell'università di Padova
Professore Associato Neurologia (MED 26)
Zanini
Sergio
Lecco
Medicina
Pediatria
Dipartim. Di Materna Infantile di Lecco
Direttore/Primario
Zaratin
Paola
Genova
Neurologia
Direttore Ricerca AISM-FISM
Zeviani
Massimo
Milano
Neurologia
Dirigente ASL II fascia - Neurologia IX - Neurogenetica Molecolare
Zibetti
Maurizio
Torino
Neurologia
S.C.D.U. Neurologia IV, Azienda Ospedaliero-Universitaria “San Giovanni Battista di Torino”
Dirigente Medico
Medico Chirurgo - specialista in Endocrinologia Specializzazione
in Neurologia Dottorato in Genetica
Dirigente Medico
Zoccarato
Marco
Padova
Azienda ULSS 9 di Treviso
Medico Specialista Ambulatoriale Interno
Zoli
Alberto
Milano
Neurologia
Igiene e Medicina Preventiva Indirizzo Igiene e Tecnica
Ospedaliera
Azienda Regionale Emergenza Urgenza, Milano
Dirigente Medico
5

file unico viii - Società italiana di neurologia

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