L`approccio neurochirurgico nelle lesioni midollari del

L’approccio neurochirurgico nelle
lesioni midollari
del tratto dorsale
Prof. Marco Fontanella
Divisione di Neurochirurgia
Università di Brescia
Cenni anatomici
• Diametro canalare
• Costrutto semirigido
articolazioni intervertebrali
Cenni anatomici
• Diametro canalare
• Costrutto semirigido
• Vascolarizzazione delicata
RadioGraphics September
2003 vol. 23 no. 5 1215-1225
Eziologie
degenerativa
• Osteolegamentosa
Ernia discale dorsale
• Molto più rara di quella lombare (e cervicale)
• Esordio clinico progressivo o dopo sforzo
Ernia discale dorsale
a
Possibili approcci:
a) anteriore
(transtoracico)
b) posteriore
(laminectomia)
c) posterolaterale
(transpeduncolare)
(transtrasversocostale)
c
c
b
Osteoporosi, patologie
autoimmuni
• Esordio generalmente progressivo
• Possibili esacerbazioni cliniche in
caso di cedimenti somatici
Osteoporosi, patologie
autoimmuni
Comuni opzioni di trattamento:
• vertebro-cifoplastica
Osteoporosi, patologie
autoimmuni
Comuni opzioni di trattamento:
• vertebro-cifoplastica
• Decompressione/fissazione
posteriore (casi selezionati)
Eziologie
degenerativa
• Osteolegamentosa
traumatica
Epidemiology of spinal cord injuries:
6 million people affected worldwide
• 2000 cases/year
•
•
•
•
•
Mean age: 37,1 ys
60% cervical spine
20% toraco-lumbar junction
15% thoracic spine
4% lumbosacral junction
Costs in Italy
• Costs / year for medical procedures and
rehabilitation
500.000.000 – 1.000.000.000 Eu/ year
• Costs for each patient
500.000 - 2.000.000 Eu/patient
ASIA
Classificazione fratture toraco-lombari
Magerl et al, A comprehensive classification of
thoracic and lumbar injuries. Eur Spine J (1994)
Classificazione fratture toraco-lombari
Type A (1,2,3)
Magerl et al, A comprehensive classification of
thoracic and lumbar injuries. Eur Spine J (1994)
Classificazione fratture toraco-lombari
Type B
Magerl et al, A comprehensive classification of
thoracic and lumbar injuries. Eur Spine J (1994)
Classificazione fratture toraco-lombari
Type C
Magerl et al, A comprehensive classification of
thoracic and lumbar injuries. Eur Spine J (1994)
Classificazione fratture toraco-lombari
Aebi et al, AO ASIF Princ. Spine Surg (1998)
Timing: indicazioni SINCh
• assenza di deficit neurologici con instabilità
vertebrale conclamata o latente: intervento
chirurgico per precoce mobilizzazione
• deficit neurologico incompleto con compressione
delle strutture nervose sul focolaio lesionale:
intervento chirurgico d’urgenza
• Indispensabile la stabilizzazione delle condizioni
generali
Traumi rachide dorsale
Possibili opzioni chirurgiche:
• posteriore
Traumi rachide dorsale
Possibili opzioni chirurgiche:
• posteriore
laminectomia
stabilizzazione
innesto osseo
viti (approccio intra o
extrapeduncolare)
ganci laminari
Esempio accesso posteriore
Traumi rachide dorsale
Possibili opzioni chirurgiche:
• posteriore
• anterolaterale
Esempio accesso transtoracico
NASCIS (III)
Metilprednisolone 30mg/kg in bolo, poi
5,4mg/kg/h x 23 oppure 48 ore
(a seconda che il trattamento inizi <3 ore o tra 3
e 8 ore dal trauma)
Bracken et al, Administration of methylprednisolone for 24 or 48 hours or tirilazad mesylate for 48
hours in the treatment of acute spinal cord injury. Results of the Third National Acute Spinal Cord
Injury Randomized Controlled Trial. National Acute Spinal Cord Injury Study. JAMA (1997)
NASCIS?
La maggior parte dei clinici -anche in centri di
riferimento per i traumi- somministra il
«protocollo cortisonico» per timore di
rivendicazioni medico-legali pur non essendo
convinti della sua efficacia
Vellman et al, Administration of corticosteroids for acute spinal cord
injury: the current practice of trauma medical directors and emergency
medical sytem physician advisors. Spine (2003)
NASCIS?
• EMG e biopsia muscolare dei pazienti trattati
con steroide mostrano una miopatia non
presente nei controllli.
• il miglioramento neurologico dopo steroide
sarebbe dovuto alla naturale guarigione dalla
miopatia e non ad una reale efficacia dello
steroide
Quian e al, High-dose methylprednisolone may cause myopathy
in acute spinal cord injury patients. Spinal Cord (2004)
NASCIS?
Schröter et al., High-dose corticosteroids after spinal cord injury
reduce neural progenitor cell proliferation. Neuroscience (2009)
Eziologie
• Osteolegamentosa
• Neoplastica
primitiva
metastatica
Eziologie
• Osteolegamentosa
• Neoplastica
epidurale
intradurale extramidollare
intramidollare
Oncotipi primitivi
•
•
•
•
•
•
•
•
•
Glia (astrocitoma, glioblastoma, oligodendroglioma)
Ependima
Meningi
Neurilemma (neurinoma, neurofibroma)
Vasi (emangioblastoma)
Tessuto emopoietico (mieloma, linfoma)
Tessuto connettivo (fibroma, sarcoma)
Tessuto osseo
Tessuto ectopico (dermoide, epidermoide, teratoma)
Oncotipi metastatici
La maggior parte delle lesioni extradurali nel tratto
dorsale sono costituite da tumori secondari
Oncotipi metastatici
La maggior parte delle lesioni extradurali nel tratto
dorsale sono costituite da tumori secondari
Quasi il 10% dei pazienti con neoplasia maligna
presentano sintomi da localizzazione al rachide
Oncotipi metastatici
• Prostata, polmone, mammella, reni e linfomi sono i
primitivi più diffusi
• Le localizzazioni al rachide sono spesso multiple
• La dura madre rappresenta una valida barriera
all’invasione neoplasLca → meno del 5% delle
metastasi sono intradurali
Metastasi
Eziologie
• Osteolegamentosa
• Neoplastica
• Infettiva
Compressioni dorsali infettive
TBC
Spondilodiscite da S aureus
Morbo di Pott
• Incidenza in aumento negli ultimi anni
• Comparsa di ceppi resistenti
• Problema chirurgico della «tenuta» dell’osso
(spesso indicato intervento in 2 tempi)
Patologia vascolare spinale
•
•
•
•
Angiomi cavernosi
Aneurismi
Malformazioni AV
Fistole AV
Patologia vascolare spinale
Eziologie
•
•
•
•
Osteolegamentosa
Neoplastica
Infettivologica
Vascolare
(Neurodegenerativa)
Nota tecnica
Nota tecnica
STEM CELLS
POSSIBLE MECHANISM FOR
FUNCTIONAL RECOVERY
Neurons derived from
transplanted cells relay
ascending signals that had
been disrupted by the injury
Demyelinated axons are remyelinated by tranplanted
cells
Okano,Ogawa, Nakamura, et al, 2003
induced proliferation of the
endogenous neural stem
cells and differentiation into
astrocytes: due to the
microenvironment?
changed microenvironment:
differentiatiation into neurons
and oligodendrocytes
enlarged cystic
cavity and glial
scar formation:
unlikely to lead
to functional
recovery
Okano,Ogawa, Nakamura, et al, 2003
COMMON STRATEGIES TOWARD REGENATION
OF THE DAMAGED SPINAL CORD
Stem cells
Myckatyn, Mackinnon, McDonald, 2004
Neurol Res. 2006 Jul;28(5):500-4.
New strategies for repairing the injured spinal cord: the role of stem cells.
Garbossa D, Fontanella M, Fronda C, Benevello C, Muraca G, Ducati A,
Vercelli A.
Eur J Neurosci. 2009 Sep;30(5):833-46.
Embryonic and adult stem cells promote raphespinal axon outgrowth
and improve functional outcome following spinal hemisection in mice.
Boido M, Rupa R, Garbossa D, Fontanella M, Ducati A, Vercelli A.
Neurosurg Rev. 2012 Jul;35(3):293-311;
Recent therapeutic strategies for spinal cord
injury treatment: possible role of stem cells.
Garbossa D, Boido M, Fontanella M, Fronda C,
Ducati A, Vercelli A.
World Neurosurg. 2012 Sep 25.
Mesenchymal Stem Cell Transplantation Reduces Glial Cyst and Improves
Functional Outcome After Spinal Cord Compression.
Boido M, Garbossa D, Fontanella M, Ducati A, Vercelli A.
The FDA-approved clinical study is a Phase I multi-center trial
designed to assess the safety and tolerability of GRNOPC1 in
patients with complete ASIA (American Spinal Injury
Association) Impairment Scale grade A thoracic spinal cord
injuries.
The first subjects to receive GRNOPC1 under the clinical
protocol will be ASIA grade A injured patients with a thoracic
injury resulting in a neurological level of T3 to T10.
The therapeutic protocol is also limited to subjects with
subacute injuries – injuries that can be treated with GRNOPC1
within seven to 14 days after the injury
• Nel 2009 la FDA ha approvato il primo trial
sull’uomo con trapianto di cellule staminali
embrionali nei traumi midollari (ASIA A).
• Il trial è stato interrotto nel novembre 2011 in
assenza di risultati.
Olfactory Ensheathing Cells
The olfactory bulb houses numerous primitive stem cells (olfactory
ensheathing cells; OECs) which continuously regenerate odordetecting nerves.
Human trials have been carried out in some countries. A Phase I/IIa trial
was conducted in by the National Centre for Adult Stem Cell Research,
Griffith University (Australia). Their main aim was to test the practicability
and safety of transplantation of autologous OECs into the injured spinal
cord in human.
Autologous, cultured OECs were transplanted into the spinal cords of six
patients with complete, thoracic paraplegia for at least two years. The
results showed that the transplant was safe and there were no adverse
findings three years after the transplant; however, no functional or sensory
improvement was noted in the participants.
Olfactory bulb derived from aborted fetus were transplanted in 2006 Huang H, Wang H et al.
(2006) Influence factors for functional improvement after olfactory ensheathing cell transplantation for chronic
spinal cord injury. Zhongguo Xiu Fu Chong Jian Wai Ke Za Zhi 20(4):434-438
Autologous macrophages
A phase I study established safety in acute complete SCI: of 8 enrolled ASIA A patients, 2
improved to ASIA C after 6 months and 3 to ASIA C after 1 year, with some bladder
recovery. In the first cell-based therapy for acute complete SCI multicenter randomized
controlled phase II study (ProCord), enrolling only patients with complete SCI, treated
macrophages promoted recovery from SCI. Phase II was stopped when Proneuron
Biotechnologies, Inc. (Los Angeles, CA), the parent company, found that most patients had
undergone surgery twice, a first time for biomechanical stabilization and a second
approximately 2 weeks after injury, with macrophage injection.
Knoller N et al (2005) Clinical experience using incubated
autologous macrophages as a treatment for complete spinal cord
injury: phase I study results. J Neurosurg Spine 3(3):173-181
Umbilical cord blood stem cells (UCBSCs)
human UCBSCs have been shown to differentiate into neural cells in vivo
and in vitro. Culture of pluripotent cord blood cells with retinoic acid(RA)
and brain-derived neurotrophic factor (BDNF) is recommended for
differentiation along neural lineages.
A case study from the Seoul National University (Korea) has reported transplantation of cord
blood cells in a 37-year-old female patient with SCI at T12 due to a fall causing a fracture at
T11 and T12 vertebrae. The patient was paraplegic after emergency surgery but
transplantation of UCBSCs after 19 years and 6 months improved sensory and motor
function. She was able to maintain an upright posture on post operative day (POD) 13 and
was able to raise her legs by about 1 cm on POD 15. Her hip flexor function gradually
improved till POD 41 and dermatomal somatosensory-evoked potential was recovered to L2
in both legs by POD 41. Approximately 3 million multipotent stem cells were transplanted
into this patient. Such a dramatic improvement almost 20 years after injury, coupled with a
lack of subsequent cases reproducing similar results can be considered anecdotal at best.
Placenta Derived Stem Cells
A recent study showed that human PDSCs cultured with rat brain cells, RA or
1-methyl-3-isobutylxanthine (IBMX) differentiated into neuronal cells. Using a
culture medium including ascorbic acid (AA), along with RA, and IBMX PDSCs
have been differentiated into dopaminergic neurons which expressed
dopaminergic markers and secreted the neurotransmitter.
No animal or human trials have been published yet.
Bone Marrow Stromal Cells
Adult bone marrow is a source of stem cells (Bone Marrow Stem Cells;
BMSCs) that have been shown to differentiate along a variety of cellular
lines, including osteocytes, chondrocytes, myocytes, hepatocytes,
epithelial linings, glia, neurons and Schwan cells.
In a clinical trial in 2004, intravenous injection of autologous BMSCs resulted in a
significant improvement, from American Spinal Injury Association score B to D, in
only one over 9 SCI patients; however, BMSCs were well tolerated during the
observation period.
Recently, the case of a 37-year-old male quadriplegic patient who sustained a SCI at
C4-C5 vertebral level as he fell from a height of 7m has been reported from Kansai
Medical University (Japan). BMSCs were collected from his ileum, on the third day
after injury and cultured for 10 days. BMSCs suspended in saline were infused through
a lumbar puncture on day 13. His ASIA scores for motor and sensory levels showed
some gradual improvement at one and three months after transplantation, but no
further sensory improvement was noticed at six months. The patient is reported to be
gradually improving and able to sit on a wheel chair and drive it slowly by himself. The
investigators recommend that transplantation of BMSCs should be carried out as soon
as possible after injury, and for optimum results should be carried out within three
weeks of injury.
CONCLUSIONI
L’utilizzo di cellule staminali nel trattamento delle lesioni
midollari è una tecnica sperimentale che sini ad ora non ha
portato a risultati significativi nell’uomo.
Il trapianto di cellule staminali deve comunque avvenire tra
i 5 ed i 15 giorni dal momento della sezione midollare.