L approccio neurochirurgico nelle lesioni midollari del tratto dorsale. Prof. Marco Fontanella Divisione di Neurochirurgia Università di Brescia

Transcript

1 L approccio neurochirurgico nelle lesioni midollari del tratto dorsale Prof. Marco Fontanella Divisione di Neurochirurgia Università di Brescia

2 Cenni anatomici Diametro canalare Costrutto semirigido articolazioni intervertebrali

3 Cenni anatomici Diametro canalare Costrutto semirigido Vascolarizzazione delicata RadioGraphics September 2003 vol. 23 no

4 Eziologie Osteolegamentosa degenerativa

5 Ernia discale dorsale Molto più rara di quella lombare (e cervicale) Esordio clinico progressivo o dopo sforzo

6 Ernia discale dorsale Possibili approcci: a) anteriore (transtoracico) b) posteriore (laminectomia) c) posterolaterale (transpeduncolare) (transtrasversocostale) b a c c

7 Osteoporosi, patologie autoimmuni Esordio generalmente progressivo Possibili esacerbazioni cliniche in caso di cedimenti somatici

8 Osteoporosi, patologie autoimmuni Comuni opzioni di trattamento: vertebro-cifoplastica

9 Osteoporosi, patologie autoimmuni Comuni opzioni di trattamento: vertebro-cifoplastica Decompressione/fissazione posteriore (casi selezionati)

10 Eziologie Osteolegamentosa degenerativa traumatica

11 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

12 Costs in Italy Costs / year for medical procedures and rehabilitation Eu/ year Costs for each patient Eu/patient

13 ASIA

14 Classificazione fratture toraco-lombari Magerlet al, A comprehensiveclassificationof thoracicand lumbarinjuries. EurSpine J (1994)

15 Classificazione fratture toraco-lombari TypeA (1,2,3) Magerlet al, A comprehensiveclassificationof thoracicand lumbarinjuries. EurSpine J (1994)

16 Classificazione fratture toraco-lombari TypeB Magerlet al, A comprehensiveclassificationof thoracicand lumbarinjuries. EurSpine J (1994)

17 Classificazione fratture toraco-lombari TypeC Magerlet al, A comprehensiveclassificationof thoracicand lumbarinjuries. EurSpine J (1994)

18 Classificazione fratture toraco-lombari Aebiet al, AO ASIF Princ. Spine Surg(1998)

19 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

20 Traumi rachide dorsale Possibili opzioni chirurgiche: posteriore

21 Traumi rachide dorsale Possibili opzioni chirurgiche: posteriore laminectomia stabilizzazione viti (approccio intra o extrapeduncolare) ganci laminari innesto osseo

22 Esempio accesso posteriore

23 Traumi rachide dorsale Possibili opzioni chirurgiche: posteriore anterolaterale

24 Esempio accesso transtoracico

25 NASCIS (III) Metilprednisolone30mg/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 tirilazadmesylatefor 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)

26 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)

27 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)

28 NASCIS? Schröter et al., High-dose corticosteroids after spinal cord injury reduce neural progenitor cell proliferation. Neuroscience (2009)

29 Eziologie Osteolegamentosa Neoplastica primitiva metastatica

30 Eziologie Osteolegamentosa Neoplastica epidurale intradurale extramidollare intramidollare

31 Oncotipiprimitivi 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)

32 Oncotipimetastatici La maggior parte delle lesioni extradurali nel tratto dorsale sono costituite da tumori secondari

33 Oncotipimetastatici 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

34 Oncotipimetastatici 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 neoplas ca meno del 5% delle metastasi sono intradurali

35 Metastasi

36 Eziologie Osteolegamentosa Neoplastica Infettiva

37 Compressioni dorsali infettive TBC Spondilodiscite da S aureus

38 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)

39 Patologia vascolare spinale Angiomi cavernosi Aneurismi Malformazioni AV Fistole AV

40 Patologia vascolare spinale

41 Eziologie Osteolegamentosa Neoplastica Infettivologica Vascolare (Neurodegenerativa)

42 Nota tecnica

43 Nota tecnica

44 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

45 induced proliferation of the endogenous neural stem cells and differentiation into astrocytes: due to the microenvironment? changedmicroenvironment: differentiatiation into neurons and oligodendrocytes enlarged cystic cavity and glial scar formation: unlikely to lead to functional recovery Okano,Ogawa, Nakamura, et al, 2003

46 COMMON STRATEGIES TOWARD REGENATION OF THE DAMAGED SPINAL CORD Stem cells Myckatyn, Mackinnon, McDonald, 2004

47 Neurol Res Jul;28(5): 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 Sep;30(5): 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.

48 Neurosurg Rev Jul;35(3): ; 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.

49 World Neurosurg 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.

50 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 injuryresultinginaneurologicalleveloft3tot10. The therapeutic protocol is also limited to subjects with subacute injuries injuries that can be treated with GRNOPC1 withinsevento14daysaftertheinjury

51 Nel2009 la FDA ha approvatoilprimo 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.

52 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 ensheathingcell transplantation for chronic spinal cord injury. Zhongguo Xiu Fu Chong Jian Wai Ke Za Zhi 20(4):

53 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. KnollerN et al (2005) Clinical experience using incubated autologousmacrophages as a treatment for complete spinal cord injury: phase I study results. J Neurosurg Spine 3(3):

54 Umbilical cord blood stem cells (UCBSCs) human UCBSCshave been shown to differentiate into neural cells in vivo and in vitro. Culture of pluripotentcord blood cells with retinoic acid(ra) and brain-derived neurotrophicfactor (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.

55 Placenta Derived Stem Cells A recent study showed that human PDSCscultured 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 dopaminergicneurons which expressed dopaminergic markers and secreted the neurotransmitter. No animal or human trials have been published yet.

56 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 autologousbmscsresulted in a significant improvement, from American Spinal Injury Association score B to D, in only one over 9 SCI patients; however, BMSCswere 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 abletositon awheelchairand drive it slowly byhimself.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.

57 CONCLUSIONI L utilizzo di cellule staminali nel trattamento delle lesioni midollari è una tecnica sperimentale che siniad ora non ha portato a risultati significativi nell uomo. Il trapianto di cellule staminali deve comunque avvenire tra i 5ed i 15 giorni dal momento della sezione midollare.