Made available in DSpace on 2015-03-26T13:46:57Z (GMT). No. of bitstreams: 1 texto completo.pdf: 3876616 bytes, checksum: c9c4e52759aa0a34b8a0630e1d0ae55e (MD5) Previous issue date: 2011-03-14 / Conselho Nacional de Desenvolvimento Científico e Tecnológico / Effective treatment for spinal cord injury remains subject of several studies. Cell therapy is considered an option promising for lesions of the central nervous system, particularly stem cells after experimental animal models showed the transplantation of bone marrow-derived cells results in amelioration of the functional deficit in various neurological diseases. This work evaluated the effect of an intravenous injection of mesenchymal stem cells (MSCs) in different intervals after compressive spinal cord injury compared to treatment with methylprednisolone (MP) and no treatment. MSCs from rat bone marrow were cultivated and expanded in vitro until transplantation. Spinal cord injury was performed with 2-Fr Fogarty catheter after T9-T10 laminectomy. Animals were randomly divided into five experimental groups with 10 animals each and subjected to different treatments: group (CG), which received only PBS; MP group (GM), who received 30 mg/kg SSMP three hours after injury, group 3 hours (GCT), which received administration of MSCs three hours after induction of injury, group 3 days (G3D), received the MSC after three days of injury; and group 7 days (G7D), received MSC seven days after spinal cord injury. Animals were evaluated weekly using the Basso-Beattie-Bresnahan (BBB) open field locomotor test. 35 days after the lesion was performed histological evaluation. All groups treated with MSC showed better results in the motor recovery. The BBB test revealed no difference between GC and GM. In morphometric analysis, the groups treated with MSC showed minor injury area and a higher percentage of healthy tissue than other groups. No differences were observed between groups in the GM and GC analysis histology. It was found that cell therapy with MSCs contributes positively in clinical recovery and preservation of nervous tissue after compressive spinal cord injury. / O tratamento efetivo para pacientes com lesão medular é motivo de diversas pesquisas. Após a obtenção de resultados satisfatórios em vários modelos experimentais, a terapia celular é considerada uma opção promissora para lesões do sistema nervoso central, sobretudo com a utilização de células-tronco. O presente trabalho avaliou o uso de células-tronco mesenquimais (CTM) indiferenciadas em diferentes intervalos de aplicação endovenosa após lesão medular compressiva e realizou estudo comparativo com succinato sódico de metilprednisolona (SSMP) e nenhum tratamento. As CTM foram obtidas da medula óssea de ratos Wistar, cultivadas, caracterizadas e transplantadas na sexta passagem para animais com lesão medular. A lesão medular foi realizada com a introdução do cateter de Fogarty n.º 2 Fr. no espaço epidural T8 e insuflação do cuff com 50μL de salina por cinco minutos, após laminectomia das vértebras T9 e T10. Os animais foram distribuídos aleatoriamente em cinco grupos experimentais com 10 animais em cada e, submetidos a tratamentos distintos: grupo controle (GC), que recebeu aplicação de PBS; grupo metilprednisolona (GM), que recebeu 30mg/Kg de SSMP três horas após a lesão; grupo 3 horas (GCT), que recebeu administração das CTM três horas após a indução da lesão; grupo 3 dias (G3D), que recebeu as CTM após três dias da lesão; grupo 7 dias (G7D), que recebeu as CTM após sete dias da lesão medular. Foi realizada avaliação motora com a escala de Basso-Beattie-Bresnehan (BBB), semanalmente, até o 35º dia após a lesão. Em seguida, foi realizada avaliação histológica da área de lesão e percentual de área preservada nos fragmentos craniais e caudais à área de lesão macroscópica e no fragmento contendo a lesão macroscópica. Os três grupos tratados com as CTM apresentaram melhores índices de recuperação da função motora na escala de BBB, estatisticamente diferentes dos grupos GC e GM. Não foi observada diferença estatística entre os grupos GC e GM quanto à recuperação motora, através dos índices da escala de BBB. Na avaliação histológica, os grupos tratados com as CTM exibiram menor área de lesão e maior percentual de tecido nervoso preservado que os outros grupos. Não foi observada diferenças entre os grupos GM e GC na análise histológica. Constatou-se que a terapia celular com CTM derivadas da medula óssea de ratos Wistar contribui positivamente na melhora clínica e na preservação do tecido nervoso após lesão medular compressiva.

Une lésion traumatique de la moelle épinière est une affection de la moelle épinière résultant d’un impact direct sur la colonne vertébrale. D’installation brusque par compression, lacération, distraction ou section de la moelle épinière, les lésions médullaires traumatiques entraînent l’interruption partielle ou totale de la transmission de l’influx nerveux et le développement des troubles neurologiques. Ces troubles sont de gravité et de durée variables, limitant significativement la capacité fonctionnelle du patient dans les activités quotidiennes. Il s’agit d’une affection lourde de conséquences à cause de la morbidité et mortalité élevées comparativement à la population générale et d’une qualité de vie amoindrie à la suite de diverses complications à long terme. Ces lésions représentent un fardeau considérable pour le patient, sa famille et le système de santé dans son ensemble. Ceux qui survivent d’une LTME présentent, selon les cas, des évolutions cliniques très variables. Les résultats à long terme vont d’une récupération complète à une incapacité fonctionnelle très sévère. Selon les cas, différents scenarios sont possibles. Certains patients récupèrent considérablement sur le plan neurologique et sur le plan fonctionnel, tandis que d’autres patients ont une récupération très limitée, développant ainsi une invalidité qui les rend totalement dépendants. Au cours des dernières décennies, il y a eu beaucoup d’avancées médicales qui ont permis d’améliorer le diagnostic et la prise en charge rapide dans la phase aiguë. Fort malheureusement, très peu de progrès ont été réalisés sur les thérapies pouvant rétablir la transmission de l’influx nerveux interrompue et entraîner une restitution ad integrum. Tôt après la survenue de la lésion médullaire, la prédiction des résultats neurofonctionnels à long terme reste une préoccupation majeure pour les cliniciens, les patients et leurs familles. Cependant, les résultats à long terme suivant une LTME sont, à l’heure actuelle, difficiles à prédire avec précision à cause de la variabilité observée dans l’évolution clinique et la diversité des facteurs qui influencent ces résultats. Quelques études ont identifié plusieurs prédicteurs de résultats à long terme suivant une lésion médullaire. Cependant, il existe encore des lacunes relatives à la modélisation prédictive dans ce domaine. Ces lacunes sont liées à la sélection des variables indépendantes à utiliser dans la prédiction mais aussi à la pertinence clinique des résultats à prédire. L’objectif général de ce travail a consisté donc à étudier les caractéristiques de la phase d’hospitalisation aigue qui sont susceptibles de prédire les résultats neurofonctionnels à long terme après une LTME, et d’aider les cliniciens dans la prise en charge des patients. Plus précisément, ce travail consistait à (1) identifier les prédicteurs aigus des résultats neurologiques à long terme, (2) déterminer les prédicteurs aigus des résultats fonctionnels tout en établissant leur ordre d’importance et leurs points de coupure, (3) identifier les profils d’amélioration neurologique associés à la récupération fonctionnelle. Dans une première étude, nous avons identifié par une revue systématique de la littérature les variables liées aux caractéristiques du patient, de la lésion et de la prise en charge ayant une valeur prédictive des résultats neurologiques à long terme. Ces prédicteurs ont ensuite été classifiés dans un cadre conceptuel en quatre catégories en fonction de la constance de leur valeur prédictive. Cette étude a permis de mettre en évidence l’existence des prédicteurs émergents comme les biomarqueurs céphalorachidiens, sanguins et radiologiques, qui ont démontré une association significative aux résultats neurologiques bien que non encore suffisamment explorés. Deuxièmement, nous avons déterminé par une étude de cohorte, les prédicteurs aigus des résultats fonctionnels à long terme. Au moyen d’un arbre de régression, nous avons élaboré quatre phénotypes de récupération fonctionnelle en fonction des trois variables issues de l’examen neurologique initial, à savoir la sensibilité à la piqure, le score moteur ASIA des membres inférieurs et le score moteur ASIA des membres supérieurs. Cette étude a permis de déterminer les points de coupure sur ces variables d’intérêt. Enfin, dans une autre étude de cohorte, nous avons déterminé les profils d’amélioration neurologiques associés à la récupération fonctionnelle. La validation externe des résultats de ces deux dernières études dans une large cohorte de blessés médullaires issus d’une population différente est une prochaine étape nécessaire pour la translation clinique de ces algorithmes. En effet, l’identification de profils/phénotypes cliniques pourrait permettre aux cliniciens de mieux orienter et évaluer les stratégies de traitement et de réadaptation pour la clientèle des blessés médullaires. / A traumatic spinal cord injury (SCI) is damage to the spinal cord resulting from a direct impact on the spine. From sudden installation by compression, laceration, distraction, or section of the spinal cord, traumatic SCI causes partial or total interruption of the conduction of nerve impulses and the development of neurological disorders. These disorders vary in severity and duration, significantly limiting the functional capacity of the patient in daily activities. Traumatic SCI is a disease with serious consequences due to high morbidity and mortality compared to the general population, and reduced quality of life because of various long-term complications. These injuries represent a tremendous burden to the patients, their families, and the health care system. Those surviving a SCI present variable clinical evolution, and the long-term outcomes range between a full recovery and a severe functional disability. Depending on the case, different scenarios are possible. Some patients may significantly recover, both neurologically and functionally, while others have very limited recovery, the latter becoming dependent. In recent decades, there have been many medical advances that have improved diagnosis and rapid management in the acute phase. Unfortunately, very little progress has been made on effective therapies to restore the conduction of the interrupted nerve impulses. Early after the onset of a spinal cord injury, predicting long-term neurofunctional outcomes remains a major concern for clinicians, patients, and their families. However, it is currently difficult to accurately predict long-term neurofunctional outcomes, because of the variability in clinical evolution and the diversity of factors influencing these outcomes. A few studies have identified several predictors of long-term outcomes following a SCI. However, there are still gaps in predictive modeling in this area. These gaps are related to the selection of independent variables to be used in prediction but also to the clinical relevance of the results to be predicted. The overall objective of this work was to study the acute predictors of long-term neurofunctional outcomes following a SCI. More specifically, this work consisted of (1) identifying acute predictors of long-term neurological outcomes, (2) determining acute predictors of functional outcomes while determining their relative importance and cut-off, and (3) identifying neurological improvement profiles associated with functional recovery. Firstly, we conducted a systematic review of the literature and identified predictors of long-term neurological outcomes that are related to the patient, SCI, and management characteristics. These predictors were then classified in a new conceptual framework into four categories based on the consistency in the studies and their predictive value. This study highlighted the significant role of the initial neurological variables, as well as the existence of emerging predictors such as cerebrospinal, blood, and radiological biomarkers, which demonstrated a significant association with neurological outcomes although not yet sufficiently studied. Secondly, we conducted a cohort study to determine, the acute predictors of long-term functional outcomes. Using a regression tree, we determined four functional recovery phenotypes based on 3 variables from the initial neurological examination, namely the pinprick sensory score, the lower-extremity ASIA motor score, and the upper-extremity ASIA motor score. This study also defined the cut-off on these variables of interest. Finally, in another cohort study, we identified neurological improvement phenotypes associated with functional recovery. External validation of these results in a large cohort of individuals with SCI from a different population is a necessary next step for the clinical translation of these algorithms. Indeed, the identification of clinical profiles/phenotypes could allow clinicians to better guide and evaluate treatment and rehabilitation strategies for patients with SCI.

Background: The optimal timing of surgical therapy for traumatic spinal cord injury (TSCI) remains unclear. The purpose of this study is to evaluate the impact of “ultra-early” (<4 h) versus “early” (4–24 h) time from injury to surgery in terms of the likelihood of neurologic recovery. Methods: The effect of surgery on neurological recovery was investigated by comparing the assessed initial and final values of the American Spinal Injury Association (ASIA) Impairment Scale (AIS). A post hoc analysis was performed to gain insight into different subgroup regeneration behaviors concerning neurological injury levels. Results: Datasets from 69 cases with traumatic spinal cord injury were analyzed. Overall, 19/46 (41.3%) patients of the “ultra-early” cohort saw neurological recovery compared to 5/23 (21.7%) patients from the “early” cohort (p = 0.112). The subgroup analysis revealed differences based on the neurological level of injury (NLI) of a patient. An optimal cutpoint for patients with a cervical lesion was estimated at 234 min. Regarding the prediction of neurological improvement, sensitivity was 90.9% with a specificity of 68.4%, resulting in an AUC (area under the curve) of 84.2%. In thoracically and lumbar injured cases, the estimate was lower, ranging from 284 (thoracic) to 245 min (lumbar) with an AUC of 51.6% and 54.3%. Conclusions: Treatment within 24 h after TSCI is associated with neurological recovery. Our hypothesis that intervention within 4 h is related to an improvement in the neurological outcome was not confirmed in our collective. In a clinical context, this suggests that after TSCI there is a time frame to get the right patient to the right hospital according to advanced trauma life support (ATLS) guidelines.