ADEM - Azienda Ospedaliera S.Camillo

Transcription

Sclerosi Multipla Pediatrica:
Problematiche di diagnosi differenziale e
approccio terapeutico
Claudio Gasperini
Ospedale San Camillo Forlanini – Roma
Roma 24 Settembre 2014
S.D, sesso maschile, 15 anni
Anamnesi Familiare, Fisiologica, Pat. Remota: N.d.R.
AN. PATOLOGICA PROSSIMA
Agosto 2014:
Il bambino giunge alla nostra osservazione il 26 agosto per
comparsa da alcuni giorni di cefalea, nausea e disturbo
dell’equilibrio caratterizzato da tendenza alla latero pulsione
destra.
L’obiettivita’ all’ingresso evidenziava una modesta atassia nella
deambulazione con tendenza alla latero pulsione destra
Durante la degenza completa regressione della sintomatologia
senza terapia specifica
Esami Ematochimici:
- Assetto autoanticorpale: nella norma
- Assetto coagulopatico: nella norma
- Sierologia per Borrellia: negativa
- Sierologia per Bartonella : negativa
- Tampone faringeo e nasale: nella norma
- PCR per Enterovirus, Herpes, Influenza, CMV,
Mycoplasma: negativa
Esami Strumentali:
-RMN Encefalo (25/8/14): “sporadiche aree parcellari iperintense
in sostanza bianca periventricolare destra, centro semiovale
sinistro, periventricolare sinistro ed emisfero cerebellare sinistro
e cerebellare medio destro.
-RMN Midollo (26/8/14): non alterazioni della corda midollare
-Non veniva descritto potenziamento delle lesioni dopo mdc
-La lesione cerebellare destra presentava nelle sequenze in DWI
caratteristiche di restrizione della diffusivita’ e riduzione in ADC
come per ischemia in fase acuta o infiammatoria
- Angio RMN cerebrale (25/8/14): nella norma
Esami Strumentali:
- ECG: nella norma
- Ecocardiogramma per ricerca PFO: nella norma
- Ecocolor Doppler Epiaortico: nella norma
- Capillaroscopia periungueale: nella norma
- EEG: sporadiche anomalie irritative e lesionali, prevalenti in
emisfero sx
Rachicentesi:
-Citochimico: Cellule 24 (<10), Proteine 0.68 (0.20-0.40),
Glucosio 0.62 (0.500.80). BEE alterata
-Isoelettrofocusing: BO presenti, Link 0.82
-PCR enterovirus, herpes, CMV, EBV : negativa
Esami Strumentali:
-RMN Encefalo (01/9/14): Invariate per numero e localizzazione
le aree di iperintensita’ della sostanza bianca descritte nel
precedente esame del 25/8/14.
-Sfumato potenziamento dopo mdc nelle areole localizzate a
livello periventricolare destro e capsulare destra
Caso clinico – A.S.
•
•
•
•
M,17enne
Remota: ndr
Fisiologica: “saltuario uso di cannabis”
Famigliare: zia con SM
• Dalla seconda metà di giugno 2014 tosse secca con episodiche
febbricole serali
• Dal 07/07/14 –
– progressivo malessere generale
– Rallentamento psicomotorio
– astenia
• 15/07/14 – ricovero in PS
– Marcata compromissione livello di coscienza
– Emiparesi sin, babinski sin
– Afebbrile, lieve leucocitosi neutrofila
• 15/07/14 – ricovero in PS
– Marcata compromissione livello di coscienza
– Emiparesi sin con segni piramidali bilaterali
– Afebbrile, lieve leucocitosi neutrofila
– Intubazione, sedazione farmacologica
– TC-total body negativa
– RM-encefalo – “diffuse,rilevanti e numerose areole lesionali di disomogenea
iperintensita' (morfoogia a bersaglio), lesioni di dimensioni variabili da parcellari a
similnodulari con max diam. di circa 2,4 cm - ,distribuite nella sostanza bianca
periventricolare -centro ovale -sottocorticale e anche con lesioni corticali. -Alcune lesioni
corticali particolarmente nelle regioni frontoparietali e in sede nucleobasale -capsulare
e regioni giunzionali corticosottocorticali. Alcune leioni ,di iperintensita' piu' tenue, in
sede cerebellare bil.”
– Liquor – lieve iperproteinorrachia e 15 leucociti, negativo per coltura,
virus neurotropi
•
16/07/14 – ricovero in T.I.
– Bolo steroideo ev alte dosi
– Ceftriaxone e Acyclovir
– Valutazione neurologica
• Ridotta interazione con mondo circostante
• Tono flaccido ai 4 arti, Babinski bil.
• Disconiugazione movimenti oculari
– RM-encefalo (22/07/14) – “lieve incremento nel numero e soprattutto nella intensita' del 'pattern' di segnale in seq.FLAIRT2 dip e DWI –diffusione, relativamente alle numerose lesioni descritte al precedente esame RM del 16‐7‐2014”
– EEG – tracciato encefalopatico
•
04/08/14 – trasferimento in Neurologia
– Prosegue Terapia cortisonica (tapering)
– Valutazione neurologica –
•
•
•
•
•
Rimossa l’assistenza respiratoria
Miglioramento livello di interazione
Afasia prettamente espressiva, disartria
Disfagia
Tetraparesi più marcata a sin
– RM-encefalo (6/8/14) – “Più estese e numerose le alterazioni focali
evidenziate ai precedenti controlli; la distribuzione è bilaterale ed asimmetrica, con
interessamento sparso sopra e sottotentoriale di fibre iuxtacorticali, sostanza bianca
sottocorticale e periventricolare, gangli della base e talami. Al controllo attuale
pressochè tutte le lesioni mostrano potenziamento, alcune con morfologia anulare
incompleta, anche con cercine marginale di restrizione alla diffusività.”
•
In Neurologia
– Prosegue Terapia cortisonica
– Esegue ciclo di Plasmaferesi
– Valutazione neurologica –
•
•
•
•
Significativo recupero del livello di interazione
Miglioramento su disfagia e afasia
Mantiene posizione seduta
Movimenti oculari normali
– RM-encefalo (13/8/14) – “lievissima riduzione dimensionale di almeno due focolai
lesionali in sede frontale dx e periventricolare dx, con lieve riduzione dell'edema associato a
diverse delle lesioni suddette.
– - non e' in sostanza rilevabile, all'oderno esame RM, alcun evidente potenziamento patol delle
lesioni dopo mdc param.
– Trasferimento in Riabilitazione
Paediatric MS, update in diagnosis and management
Key points
1.Epidemiology and clinical aspects 2.Diagnosis
3.Treatment
Paediatric MS, update in diagnosis and management
Key points
1.Epidemiology and clinical aspects 2.Diagnosis
3.Treatment
Frequency of MS cases < 16 years. Published data review
•
Duquette et al. 1987 125 subjects:
2.7 %
•
Sindern et al. 1992
31 subjects:
5.0 %
•
Ghezzi et al. 1997 149 subjects: 4.4 %
•
Boiko et al. 2002 116 subjects: 3.6 %
•
Simone et al. 2002
83 subjects: 10.8 %
•
Ozakbas et al. 2003
36 subjects:
4.0 %
•
Deryck et al. 2006
49 subjects:
1.7%
•
Renoux et al. 2007
394 subjects:
2.2 %
… approximately 3-5% of the whole MS population
female/male ratio in relation to age of MS onset
f/m ratio: 2.3
f/m ratio = 4.2 for age 13-15y
In subjects with age of onset < 12 years, f/m ratio = 1.2
Ghezzi A. Neurol. Sci. 2004
Peculiar clinical features in very young subjects
First attack features
Other features of MS course
Banwell et al. 2007 Lancet Neurology
Conversion to CP2 course
Years from onset of MS to
conversion to CP2-MS
Age at conversion to CP2-MS
10 years later (28.1 vs. 18.8)
10 years younger (41.4 vs. 52.1)
Renoux et al. 2007
Key points
•Epidemiology
•Diagnosis
•Treatment
2010 Revised McDonald Criteria
Dissemination in Space (DIS): one or more T2
lesions in at least two of four areas of the CNS:
1- Periventricular,
2- Juxtacortical,
3- Infratentorial,
4- Spinal cord.
Dissemination in Time (DIT):
1- New T2 lesions on serial scan(s),
2 or simultaneous presence of a clinically-silent
gadolinium-enhancing lesion and a nonenhancing lesion on a single baseline scan.
Brain MRI and MS: dissemination in space
Multiple T2-hyperintense lesions are present in 95% of patients
Periventricular
asymmetrical
lesions
Juxtacortical lesions
Infratentorial lesions
Spinal lesions
Ovoid shape, Transverse diameter <3 mm
McDonald Criteria 2010

Alta sensibilità e specificità per la diagnosi di SMP quando applicati
a bambini di età superiore agli 11 anni e senza caratteristiche
.
suggestive di ADEM
RISCHIO di SM in pz con primo Episodio ADEM Like se:
1)Assenza di un pattern diffuso bilaterale
2)Presenza dei Black Holes
3)Presenza di 2 o più lesioni periventricolari
Callen et al, Neurology 2009
1. Paediatric Acute Disseminated Encephalomyelitis Syndrome
(ADEM)
2. Paediatric Clinically Isolated Syndrome (CIS)
3. Paediatric MS
4. Paediatric Neuromyelitis optica (NMO)
PAEDIATRIC MS CRITERIA (can be satisfied by any of the following)
> 30
days
With
+
DIS
>3
months
DIT
+ DIS
With DIS +
DIT
Krupp et al MSJ 2013
ADEM: definition
Acute disseminated encephalomyelitis is
an immune-mediated inflammatory and
demyelinating disorder with acute or
subacute onset affecting multifocal areas
of the CNS.
ADEM clinical presentation:
•must be polysimtomatic
•must include encepahalopathy
Encepahalopahy is defined as one or more of the following:
• Behavioral change (e.g., confusion, excessive irritability)
• Alteration in consciousness (e.g., lethargy, coma)
unexplained by fever
[Krupp L et al. Neurology 2007, Mult Scler 2013]
Focus on Encephalopathy
Encepahalopahy is defined as one or more of the following:
• Behavioral change (e.g., confusion, excessive irritability)
• Alteration in consciousness (e.g., lethargy, coma)
unexplained by fever
42-83% of pediatric
ADEM
Although consensus criteria might be restrictive for the diagnosis
of ADEM, it is very useful to identify patients with a higher risk for
multiple sclerosis.
[Krupp L et al. Mult Scler 2013]
ADEM: epidemiology
ADEM is age-related
Male predominance
Seasonal distribution
9 More common in Children (>3 yrs)
9 The mean age at presentation in children
ranges from 5 to 8 years
9 0.4/100000/year among persons less
than 20 years old
In pediatric cohort: F:M ratios of 0.6-0.8
winter and spring months
Post-infection
Post-vaccination encephalomyelitis
rarely following application of immune sera
77%
of
patients
reported infection or
vaccination
in
the
preceding few weeks
[Tenembaum S et al. Neurology 2007, Wender J Neuroimmunol 2011]
ADEM: disease course
>3 months after the
first ADEM event
Now resumed in
multiphasic ADEM
New event of ADEM 3
months or more after the
initial event that can be
associated with new or
re-emergence of prior
clinical and MRI
findings
[Krupp L et al. Neurology 2007]
ADEM: disease course
• Event should be followed by improvement, either clinically,
on MRI, or both, but there may be residual deficits
Among multiphasic ADEM, in 80% of individuals
the second event occurs within two years of the
initial episode.
Relapsing disease following ADEM that occurs
beyond a second encephalopathic event is no
longer consistent with multiphasic ADEM but rather
indicates a chronic disorder, most often leading to
the diagnosis of MS or NMO
Follow-up:
At least two additional MRI studies after the
first normal MRI, over a period of 5 years from
the initial episode
[Tenembaum S et al. Neurology 2007]
ADEM: Brain MRI
Patchy
Symmetrical
Poorly marginated
Variable from 30
to 100% of cases
Brain MRI reveals large (>1 to 2 cm in size) multifocal, T2hyperintense lesions located in the supratentorial or infratentorial
white matter regions. T1-hypointense lesions are rare.
Gray matter, especially basal ganglia and thalamus, is frequently
involved
[Krupp L et al. Neurology 2007, Mult Scler 2013]
ADEM: Spinal MRI
• Spinal cord MRI may show confluent
intramedullary lesion(s)
• Often swelling lesions
• Predominantly affects the thoracic
region.
• Variable
enhancement
(patchy
or
pheripheral)
Role of MRI in the differentiation of ADEM from MS in children
Callen et al. Neurology 2008
ADEM: MRI
• Complete resolution of MRI abnormalities
after treatment has been described in 37% to
75%
• Partial resolution in 25% to 53% of patients
ADEM: CSF features
[Krupp L et al. Neurology 2007]
[Brilot et al., 2009]
ADEM: criteria summary
Paediatric MS, update in diagnosis and management,
Key points
1.Epidemiology
2.Diagnosis
3.Treatment
THREE COMMON QUESTIONS IN CLINICAL PRACTICE
1.Why should we consider the possibility to use DMDs in paed-MS?
2.Are data available on the use of DMDs in paed-MS?
3.What to do in non-responders?
May 2014
THREE COMMON QUESTIONS IN CLINICAL PRACTICE
1.Why should we consider the possibility to use DMDs in paed-MS?
2.Are data available on the use of DMDs in paed-MS?
3.What to do in non-responders?
May 2014
Disease modifying drugs (DMDs) in paed-MS
There are many evidences showing that DMDs are safe,
well tolerated and useful in paed-MS
There are many reasons suggesting that
immunomodulatory treatment should be useful in paed-MS
1.
2.
3.
4.
5.
6.
The course is RR in most cases
Relapse rate is high in initial phases of the disease
Relapse rate is correlated to a bad prognosis
Progression is slower, compared to adults, but moderate-severe
disability are reached at a lower age
The time to shift from moderate to severe disability is short (mean 7
yrs) compared to the time to reach moderate disability (mean 17
yrs)
Cognitive impairment is frequent and with a negative impact on
social activities and school performances
The treatment of paediatric multiple sclerosis
- Many observational studies providing data on treatment options efficacy, safety
and tolerability in paediatric MS patients
- Two recent consensus papers have critically reviewed the experience of
treatment with DMDs in paed-MS and delineated the best strategies:
Mult Scler. 2010 16:1258-67.
Mult Scler. 2012 Jan;18(1):116-27
The use of immunomodulators in paed-MS (Chitnis 2012)
IFNB - Side Effects in MS children
Frequency: similar to
that observed in
adults
What to do
•
Flu-like symptoms
8% to 71 %
•
iInection skin reaction
7% to 75%
•
Headache
8% to 28%
•
Myalgia
5% to 17%
•
Fatigue
3% to 6%
•
Nausea
3% to 10%
•
Increased liver enzyme
6% to 33%
•
Thyroid dysfunction
8% (transient in 4%)
•
Abnormal blood count
1% to 39%
•
Paracetamol, ibuprofen, education
•
Initiation at 25-50% of adult dose, escalation to full
dose within 1-3 months
•
Blood cell count, liver enzymes, bilirubin: month 0, 1,
3, every 3 months in the 1st year, every 6 months
•
Thyroid function assessment: yearly
Ghezzi et al, The management of multiple sclerosis in children: a European view. Mult Scler 2010
Use of first-line therapies in pediatric MS (where available) is generally
accepted as the standard care. Based on these findings, the IPMSSG
recommends that all pediatric patients with MS, as defined by Krupp et
al., should be considered for treatment with either a beta-interferon or
glatiramer acetate as first line therapy
Mult Scler. 2012 Jan;18(1):116-27
About 30% of paediatric MS cases do not adequately respond to
first line medications
IFNB 1a 30 ug
30%
IFNB high dose/freq
64%
GA
36%
Ghezzi et al Neurol. Sci. 2009, 30:193
Yeh et al. Arch. Neurol., 68:473
SECOND LINE THERAPY:
•Natalizumab
•Mitoxantrone
•Cyclophosphamide
•Fingolimod
•Natalizumab
•Mitoxantrone
•Cyclophosphamide
•Fingolimod
5
4,1
prepost-
4
3
2,6
3
1,9
2
No relapses during the whole
follow up (p<0.001). Only 1
subject continued to deteriorate
during the 1st infusion
1
0,1
0
0
RR
EDSS
Gd +
Reduction of the
mean EDSS, from
2.6 ±1.0 to 1.9 ±1.0
(p< 0.001)
No Gd+
lesions
during the
follow up
By at least 0.5 score
in 6 pts, by at least 1
score in 8 pts
(RM every 6
months)
(p=0.008)
Anti-JCV antibodies
Anti-JCV-Ab have been found in 39% of cases
Ghezzi et al MSJ 2013
May 2014
•Natalizumab
•Mitoxantrone
•Cyclophosphamide
•Fingolimod
Mitoxantrone: Two major adverse events
Cardiomiotoxicity and Leukaemia
In addition to many other side effects (nausea, vomiting, hair loss, infertility, increased risk of
infections, etc.)
Chitnis et al. Mult Scler. 2012 Jan;18(1):116-2
May 2014
•Natalizumab
•Mitoxantrone
•Cyclophosphamide
•Fingolimod
Neurology 2009; 72: 2076–2082.
17 subjects mean age 15 years, mean disease duration 3.1 yrs
Treatment schedule:
•
Induction with 5 doses over 8 days + monthly pulsed treatments
•
Single induction of 5 days in acute relapses
•
Monthly Cy administration 600/1000 mg/m2
Relapse rate
EDSS
Ciclofosfamide in Paediatric MS, Adverse Events (n=17)
SHORT TERM
LONG TERM
•Nausea, vomiting
15
•Lymphopenia
16
•Anemia
10
•Thrombocytopenia
3
•Alopecia
10
•Menstrual disorder
5
•Infections
3
•Fatigue
2
•Hematuria, paresthesias,
urticaria, myalgias,
repeated central line
placement:
1
•Amenorrhea
3
•Sterility
1
•Osteoporosis
•Bladder cancer
2
1
Makhani et al, Neurology 2009; 72: 2076–2082
May 2014
•Natalizumab
•Mitoxantrone
•Cyclophosphamide
•Fingolimod
May 2014
•Natalizumab
•Mitoxantrone
•Cyclophosphamide
•Fingolimod
ADEM: therapy
High doses steroids (tapering for 3 weeks?)
Plasmapheresis
Iv Immunoglobulins
[Wender et al. 11, Alper et al. 2012]
Grazie per l’attenzione