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Yasir A. Syed, Alexandra S. Baer, Gert Lubec, Harald Hoeger, Georg Widhalm and Mark R. Kotter

Object

Promoting repair of central nervous system (CNS) white matter represents an important approach to easing the course of a number of tragic neurological diseases. For this purpose, strategies are currently being evaluated for transplanting cells capable of generating new oligodendrocytes into areas of demyelination and/or enhancing the potential of endogenous stem/precursor cells to give rise to new oligodendrocytes. Emerging evidence, however, indicates that increasing the presence of cells capable of forming new myelin sheaths is not sufficient to promote repair because of unknown inhibitors that accumulate in lesions as a consequence of myelin degeneration and impair the generation of new oligodendrocytes. The aim of the present study was to characterize the nature of the inhibitory molecules present in myelin.

Methods

Differentiation of primary rat oligodendrocyte precursor cells (OPCs) in the presence of CNS and peripheral nervous system myelin was assessed by immunocytochemical methods. The authors further characterized the nature of the inhibitors by submitting myelin membrane preparations to biochemical precipitation and digestion. Finally, OPCs were grown on purified Nogo-A, oligodendrocyte myelin glycoprotein, and myelin-associated glycoprotein, the most prominent inhibitors of axon regeneration.

Results

Myelin membrane preparations induced a differentiation block in OPCs that was associated with down-regulation of expression of the transcription factor Nkx2.2. The inhibitory activity in myelin was restricted to the CNS and was predominantly associated with white matter. Furthermore, the results demonstrate that myelin proteins that are distinct from the most prominent inhibitors of axon outgrowth are specific inhibitors of OPC differentiation.

Conclusions

The inhibitory effect of unknown myelin-associated proteins should be considered in future treatment strategies aimed at enhancing CNS repair.

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Georg Widhalm, Wolfgang Dietrich, Leonhard Müllauer, Berthold Streubel, Werner Rabitsch, Mark R. Kotter, Engelbert Knosp and Karl Roessler

✓ The authors report the unusual case of a 35-year-old woman suffering from left leg numbness and radiculopathy due to multiple lesions in the central nervous system: one right parietal extracranial–intracranial lesion with invasion of the sensory cortex, and two intraspinal, intradural lesions compressing the spinal cord at T3–5 and S1–4. Biopsy sampling of the extracranial part of the parietal lesion led to a diagnosis of myeloid sarcoma. Further examination revealed no evidence of leukemic disease or myeloproliferative disorder. An aggressive multimodal approach to treatment in this patient with a combination of chemotherapy, whole-body radiotherapy, and allogeneic bone marrow transplantation was started immediately. The patient experienced full neurological recovery and complete disappearance of all lesions. At the 7-year follow-up examination, there was no evidence of disease. To the authors’ knowledge, this is the first report of a myeloid sarcoma with both intracranial and intraspinal manifestations in a patient without leukemia.

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Lindsay Tetreault, Jefferson R. Wilson, Mark R. N. Kotter, Aria Nouri, Pierre Côté, Branko Kopjar, Paul M. Arnold and Michael G. Fehlings

OBJECTIVE

The minimum clinically important difference (MCID) is defined as the minimum change in a measurement that a patient would identify as beneficial. Before undergoing surgery, patients are likely to inquire about the ultimate goals of the operation and of their chances of experiencing meaningful improvements. The objective of this study was to define significant predictors of achieving an MCID on the modified Japanese Orthopaedic Association (mJOA) scale at 2 years following surgery for the treatment of degenerative cervical myelopathy (DCM).

METHODS

Seven hundred fifty-seven patients were prospectively enrolled in either the AOSpine North America or International study at 26 global sites. Fourteen patients had a perfect preoperative mJOA score of 18 and were excluded from this analysis (n = 743). Data were collected for each participating subject, including demographic information, symptomatology, medical history, causative pathology, and functional impairment. Univariate log-binominal regression analyses were conducted to evaluate the association between preoperative clinical factors and achieving an MCID on the mJOA scale. Modified Poisson regression using robust error variances was used to create the final multivariate model and compute the relative risk for each predictor.

RESULTS

The sample consisted of 463 men (62.31%) and 280 women (37.69%), with an average age of 56.48 ± 11.85 years. At 2 years following surgery, patients exhibited a mean change in functional status of 2.71 ± 2.89 points on the mJOA scale. Of the 687 patients with available follow-up data, 481 (70.01%) exhibited meaningful gains on the mJOA scale, whereas 206 (29.98%) failed to achieve an MCID. Based on univariate analysis, significant predictors of achieving the MCID on the mJOA scale were younger age; female sex; shorter duration of symptoms; nonsmoking status; a lower comorbidity score and absence of cardiovascular disease; and absence of upgoing plantar responses, lower-limb spasticity, and broad-based unstable gait. The final model included age (relative risk [RR] 0.924, p < 0.0001), smoking status (RR 0.837, p = 0.0043), broad-based unstable gait (RR 0.869, p = 0.0036), and duration of symptoms (RR 0.943, p = 0.0003).

CONCLUSIONS

In this large multinational prospective cohort, 70% of patients treated surgically for DCM exhibited a meaningful functional gain on the mJOA scale. The key predictors of achieving an MCID on the mJOA scale were younger age, shorter duration of symptoms, nonsmoking status, and lack of significant gait impairment.