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Neuroprotection and Neuroregeneration of the Injured Spinal Cord: A Focus on Degenerative Cervical Myelopathy – Commentary on “Pharmacological Treatment of Degenerative Cervical Myelopathy: A Critical Review of Current Evidence”

Article information

Neurospine. 2024;21(2):401-403
Publication date (electronic) : 2024 June 30
doi : https://doi.org/10.14245/ns.2448552.276
1Division of Neurosurgery, Krembil Neuroscience Centre, University Health Network, Toronto, ON, Canada
2Institute of Medical Science, University of Toronto, Toronto, ON, Canada
3Division of Neurosurgery and Spine Program, Department of Surgery, University of Toronto, Toronto, ON, Canada
Corresponding Author Michael G. Fehlings Toronto Western Hospital, 399 Bathurst Street, Suite 4WW-449, Toronto, ON, Canada M5T 2S8 Email: Michael.Fehlings@uhn.ca

Degenerative cervical myelopathy (DCM) is the commonest form of spinal cord impairment in adults worldwide [1]. While surgery is largely effective in improving spinal cord function and reducing pain, many patients do harbour residual neurological impairment and/or have residual neuropathic pain [2]. The RECODE-DCM project, supported by AO Spine, identified that the development of neuroprotective and neuroregenerative treatments for DCM was an important priority [3]. Given this, the recent article by Levett et al. [4], which reviewed emerging pharmacological approaches for DCM, is timely. The authors reviewed 18 studies based on a literature review up to April 2022, focusing on pharmacological interventions for DCM. They reported that erythropoietin (EPO) (with methylpredinosolone) showed promising results based on a randomized controlled study utilizing a three-month quality of life (QoL) outcome. The sodium-glutamate antagonist riluzole, based on a Phase 3 multicenter randomized controlled trial (RCT), failed to achieve significance in enhancing the modified Japanese Orthopaedic Association (mJOA) score, largely because of ceiling effects in the outcome measure, but did show signal in a number of secondary outcomes including neck and arm pain. Moreover, as summarized below, a new reanalysis of the cervical spondylotic myelopathy (CSM)-PROTECT RCT using a global statistical approach—an article which came out after the review by Leveltt et al., has shown that riluzole confers a significant benefit to patients with DCM undergoing decompressive surgery [5].

Narrative reviews serve as important repositories of distilled knowledge, but synthesizing information and making recommendations based on this type of literature should be approached with caution. The strength of evidence is more appropriately synthesized through meta-analysis or systematic reviews rather than narrative expositions. In this article, several critical factors require closer examination. For instance, the limaprost study, a prospective, nonrandomized controlled trial, and the cerebrolysin study, which presents conflicting results from Allam et al. [6] and Sharma et al. [7], should receive a lower strength of evidence than the riluzole study. The EPO+methylprednisolone study was graded the highest in terms of evidence; however, this rating should be downgraded due to the inadequacy of the control group (i.e., methylprednisolone only), as it lacked a placebo group (i.e., no intervention) necessary to discern the true treatment effect. Similar concerns apply to the cerebrolysin study by Allam et al. [6], where the treatment combined cerebrolysin and celecoxib, making it impossible to assess the pure effect of the intervention with only a single control group. Additionally, except for the cerebrolysin, glucocorticoid, and riluzole studies, all other clinical trials did not include a formal sample size computation. This raises uncertainties about whether the study populations were sufficient to detect true effect sizes or were merely chosen for convenience. Moreover, the representation of evidence in an inverted pyramid in Fig. 2 distorts the overall picture by combining clinical and pre-clinical studies, the latter of which are not covered by the GRADE approach.

Adverse effect assessments are crucial when evaluating medical interventions for DCM. While extensively reported in the CSM-PROTECT trial, it was noticeably absent in the studies on limparost and EPO+methylprednisolone. The lack of comprehensive adverse effect data in these studies renders a thorough evaluation of both intervention efficacy and safety impossible. Short snippets of these limitations were mentioned in the narrative review but did not adequately reflect the caution necessary when interpreting these results.

The application of the GRADE approach entails evaluating the most critical outcome, which determines the overall quality of evidence. For instance, if QoL is prioritized, the study on EPO provides the best evidence, whereas the cerebrolysin study offers the highest evidence of treatment effect when the mJOA score is considered crucial. This issue presents a fundamental challenge in spinal cord injury trials, as there is no consensus on the most appropriate and comprehensive outcome scale to represent recovery after surgery. Although the mJOA is commonly used for assessing outcomes in DCM, its limitations are well documented. Notably, its tendency to reach a ceiling effect in mild DCM and its inability to represent the multidimensional aspects of recovery make it inadequate as a primary trial endpoint. For example, neck pain, now recognized as a top recovery priority in DCM patients, is not adequately captured by the solitary use of the mJOA [8]. Similarly, QoL and functional recovery remain unrepresented within the criteria of the mJOA.

This challenging issue must be addressed using innovative solutions and alternative analytical approaches. The global statistical test has shown promise in neurology trials by effectively representing multiple outcomes scales in a cohesive analysis [9,10]. This nonparametric test consolidates various outcome measures, providing a comprehensive evaluation of the treatment effect between drug and placebo groups and computes a global summary measure. Its recent application in the reanalysis of the CSM-PROTECT trial demonstrates its feasibility and increased power to detect treatment effects, especially when the treatment positively impacts multiple outcome scales [4]. Alternatively, longitudinal clustering techniques using unsupervised machine learning algorithms (e.g., k-means or hierarchical clustering), growth modelling, or latent class analysis may reveal symptom clusters that better capture the heterogeneity of the DCM population. Implementing these models using big data in DCM shows promise in identifying patient phenotypes with more granular features than those described using the mJOA scale [11].

In our opinion, this narrative review effectively summarizes the current state of knowledge on potential therapeutic options for DCM. However, the heterogenous outcomes, varying followup periods, and the limitation imposed by current outcome scales in DCM necessitate caution when synthesizing data from diverse clinical trials. Emerging therapies, including neuroregenerative strategies (e.g., cell, growth, or small molecule-based) and neuromodulatory techniques (e.g., spinal cord, transcranial or neuromuscular stimulation), also warrant evaluation alongside pharmacologic interventions [3]. Potential genetic modifiers of treatment response, such as the presence of the ApoE4 allele, will enable stratified analysis of interventions in the future [12]. As emphasized in this article, two emerging concepts are anticipated to have a major impact on spine surgery clinical trials: (1) the adaptation of a multivariable approach in assessing outcomes in spine trials and (2) secondary analysis using a global statistical approach to reveal latent beneficial treatment effects. The latter is exemplified by a secondary reanalysis of the CSM-PROTECT trial, in which riluzole has shown a significant global benefit in patients with DCM undergoing surgical treatment [5]. Based on these new data, clinicians may wish to consider the use of riluzole in the management of patients with DCM undergoing surgery to enhance neurological outcomes and reduce pain.

Notes

Conflict of Interest

MGF is supported by the Robert Campeau Family Foundation/Dr. C.H. Tator Chair in Brain and Spinal Cord Research. Except for that, the authors have no conflicts to declare.

References

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