State of the Art in Degenerative Cervical Myelopathy: an Update on Current Clinical Evidence

DEGENERATIVE DISEASE

State of the Art in Degenerative Cervical Myelopathy: An Update on Current Clinical Evidence

∗ Jefferson R. Wilson, MD, PhD Degenerative cervical myelopathy (DCM) is a common cause of spinal cord dysfunction ‡ Lindsay A. Tetreault, PhD that confronts clinicians on a daily basis. Research performed over the past few decades has Downloaded from https://academic.oup.com/neurosurgery/article-abstract/80/3S/S33/3045012 by guest on 29 July 2019 Jun Kim, MD§ provided improved insight into the diagnosis, evaluation, and treatment of this disorder. Mohammed F. Shamji, MD, We aim to provide clinicians with an update regarding the state of the art in DCM, focusing on more recent research pertaining to pathophysiology, natural history, treatment, consid- PhD‡ eration of the minimally symptomatic patient, surgical outcome prediction, and outcome ¶ James S. Harrop, MD measurement. Current concepts of pathophysiology focus on the combination of static Thomas Mroz, MD|| and dynamic elements leading to breakdown of the blood–spinal cord barrier at the Samuel Cho, MD§ site of compression resulting in local inflammation, cellular dysfunction, and apoptosis. Michael G. Fehlings, MD, PhD∗ With respect to treatment, although there is a dearth of high-quality studies comparing surgical to nonoperative treatment, several large prospective studies have recently ∗Department of Surgery, Division of associated surgical management with clinically and statistically significant improvement Neurosurgery, St. Michael’s Hospital, in functional, disability, and quality of life outcome at long-term follow-up. When selecting University of Toronto, Toronto, Canada; ‡Department of Surgery, Division of the specific surgical intervention for a patient with DCM, anterior (discectomy, corpectomy, Neurosurgery, Toronto Western Hospital, hybrid discectomy/corpectomy), posterior (laminectomy and fusion, laminoplasty), and University of Toronto, Toronto, Canada; combined approaches may be considered as options depending on the specifics of the §Department of Orthopedic Surgery, Icahn School of Medicine, New York, patient in question; evidence supporting each of these approaches is reviewed in detail. New York; ¶Division of Neurosurgery Recently developed clinical prediction models allow for accurate forecasting of postoper- and Orthopedics, Thomas Jefferson ative outcomes, permitting enhanced communication and management of patient expec- University Hospital, Thomas Jefferson University, Philadelphia, Pennsylvania; tations in the preoperative setting. Finally, an overview of outcome measures recom- ||Division of Neurosurgery, Cleveland mended for use in the assessment of DCM patients is provided. Clinic, Cleveland, Ohio KEY WORDS: Degenerative cervical myelopathy, Cervical spondylotic myelopathy, Surgery, Pathophysiology, Correspondence: Natural history, Outcome prediction, Outcome measures, Review Michael G. Fehlings, MD, PhD, FRCSC, Toronto Western Hospital, Neurosurgery 80:S33–S45, 2017 DOI:10.1093/neuros/nyw083 www.neurosurgery-online.com West Wing 4th floor, 399 Bathurst Street, Toronto, ON M5T 2S8, Canada. E-mail: [email protected] egenerative cervical myelopathy (DCM) by gait imbalance, loss of hand dexterity, represents a collection of pathological and sphincter dysfunction.1 Although epidemi- Received, August 15, 2016. D entities, which individually, or in combi- ological studies are sparse in the literature, DCM Accepted, September 22, 2016. nation, cause compression of the cervical spinal is one of the most common causes of spinal cord cord, resulting in a clinical syndrome typified dysfunction internationally, with an estimated Copyright C 2016 by the annual incidence of 41 per million in North Congress of Neurological Surgeons America; from a surgical perspective, DCM ABBREVIATIONS: ACDF, anterior cervical ranks amongst the most common of indications discectomy and fusion; BSCB, blood–spinal for surgery on the cervical spine.2-4 cord barrier; CI, confidence interval; CSM, In this review, we provide an overview of cervical spondylotic myelopathy; DCM, Degen- the state of the art in DCM, with a focus erative cervical myelopathy; DTI, diffusion tensor imaging; FA, fractional anisotropy; JOA, Japanese on updating the modern day spine surgeon Orthopaedic Association; mJOA, modified JOA; on the current evidence surrounding patho- MCID, minimally clinical important difference; MRI, physiology, natural history, imaging, outcome magnetic resonance imaging; NDI, Neck Disability measures, and outcome prediction tools. Further, Index; OPLL, ossification of the posterior longi- with respect to treatment, we provide an tudinal ligament; RCT, randomized control trial; overview of the evidence for surgical vs nonop- RR, relative risk; SI, signal intensity; WI, weighted erative management, a summary of the liter- images ature surrounding the most commonly employed

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FIGURE. Artist depiction of anatomic and pathological changes that may occur in the setting of DCM. Reused with permission from Nouri A, Tetreault L, Singh A, Karadimas SK, Fehlings MG. Degenerative cervical myelopathy: epidemiology, genetics, and pathogenesis. Spine. 2015;40:E675-E693.

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ological and, in the setting of degenerative subluxation, patho- TABLE 1. Overview of the Factors involved in the Pathophysiology of logical motion of the cervical spine.8 DCM5,8 When considering injury to the spinal cord itself, there is histopathological evidence to suggest that in addition to physical Static factors compression, there is a reduction in blood supply leading to 1) Spondylosis 8 2) Disk degeneration considerable ischemia within the cord. Pathological features 3) Ossification of the posterior longitudinal ligament of DCM include gray and white matter degeneration, anterior 4) Ossification of the ligamentum flavum horn cell loss, cystic cavitation, and Wallerian degeneration of 5) Congenital stenosis the posterior columns adjacent to the site of compression. In

Dynamic Factors rat models, Karadimas et al9 demonstrated decreased capillary Downloaded from https://academic.oup.com/neurosurgery/article-abstract/80/3S/S33/3045012 by guest on 29 July 2019 1) Degenerative spondylolisthesis density in the compressed spinal cord compared to controls, 2) Physiological narrowing of canal diameter with neck extension 3) Strain and stretch forces placed on spinal cord with physiological thereby indicating blood–spinal cord barrier (BSCB) disruption neck movements in the setting of progressive stenosis from DCM. This correlated Biomolecular factors with a progression from a narrow-based normal gait to a broad- 1) Ischemic injury due to chronic compression of spinal cord based gait with chronic compression in rat models. In the setting vasculature and break down of blood–spinal cord barrier of such vascular insufficiency, local ischemia can lead to neuronal 2) Increased local inflammatory response ionic imbalance and cellular dysfunction resulting in excitotoxic 3) Increased local expression of CX3CR1 glutamate release and an expanded zone of neural tissue injury.9,10 4) Glutamate-mediated excitotoxicity 5) Oligodendrocyte and neuronal apoptosis In addition to the above, with breakdown of the normal BSCB, a secondary cascade of neuroinflammation consisting of microglia activation and macrophage recruitment occurs at the site of mechanical compression within the spinal cord. In the noncompressed nonmyelopathic spinal cord, the BSCB is surgical approaches and a description of novel and less accepted isolated from the peripheral immune system; however, chronic surgical techniques. compression renders the cord susceptible to cell infiltration that may be involved in neural degeneration. Recent liter- Terminology ature has delved into the inflammatory pathways implicated in DCM is used to describe myelopathy resulting from degener- DCM. Specifically, with respect to gene expression, increased ative pathology in the cervical spine including spondylosis, degen- local expression of CX3CR1 has been associated with increased erative disk disease, ossification of the posterior longitudinal microglia and macrophage accumulation at compression sites.11 ligament (OPLL), and ossification of the ligamentum flavum Current research is focused on further defining the role of the (Figure).3 While each of these pathological entities may immune response, as well as the specific inflammatory pathways, be discussed individually (ie, the term cervical spondylotic underlying the pathobiology of DCM. myelopathy [CSM] may be used when considering spondy- In addition to the above, with respect to OPLL, substantial lotic disease alone), when considering these entities together, the progress has been made in understanding the genetics and patho- term DCM is increasingly preferred and employed throughout biology underlying this disorder. The reader is referred to one of the literature. Throughout this manuscript, unless discussing several recent reviews on this topic.12 evidence pertinent to specific pathology (CSM or OPLL alone), the term DCM will be used. NATURAL HISTORY PATHOPHYSIOLOGY Traditionally, the natural history of patients presenting with The pathogenesis of DCM is composed of static and dynamic myelopathy was thought to be marked by near uniform decline factors.5 Table 1 provides a summary of the pathophysiology of in neurological and functional status. In their description of DCM. Static factors result from congenital stenosis or acquired 120 patients with cervical myelopathy, Clarke and Robinson13 stenosis secondary to spondylosis and disk degeneration. Specif- described the natural history as proceeding according to one of ically, age-related desiccation of the disk secondary to a change several patterns: 5% had a rapid onset of symptoms followed in its proteoglycan composition initiates a cascade of degener- by long periods of remission, 20% had a slow gradual decline ative changes that lead to disk height loss, increased uncover- in function, and 75% had a stepwise decline in function. Over tebral and facet joint stress, resulting in subsequent osteophyte the years, additional studies have documented a highly variable generation, infolding of the ligamentum flavum, and ultimately, natural history; while certain patients remain clinically stable at a reduction in the cross-sectional area of the cervical spinal canal long-term follow-up, a large proportion experience clinical deteri- leading to compression of the spinal cord.5-7 Dynamic factors oration if left untreated. A 2013 systematic review by Karadimas relate to exacerbation of spinal cord compression seen with physi- et al5 sought to more specifically quantify the rate of clinical

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deterioration amongst patients presenting with DCM treated (1.29 points). These results seem to indicate that surgery is most nonoperatively. Amongst the 6 studies that considered Japanese effective in restoring function to those with severe and moderate Orthopaedic Association (JOA) or modified JOA (mJOA) scores, myelopathy at presentation. 20% to 62% of patients experienced clinical deterioration, The subsequently published prospective AOSpine Interna- defined by at least a 1 point reduction in mJOA/JOA compared tional CSM study19 has helped to confirm some of the findings to baseline, at 3- to 6-years follow-up. reported in the North American Study. Namely, when analyzing Acknowledging the often variable natural history of DCM, the 2-year outcomes across 479 patients enrolled at 16 global sites the ensuing challenge is to identify important predictors of between 2007 and 2011, the authors found statistically signif- clinical deterioration for purposes of expediting the evaluation icant improvements in the same functional, disability, and quality and surgical treatment of this patient subgroup. In individual of life-related outcomes evaluated in the North American study. Downloaded from https://academic.oup.com/neurosurgery/article-abstract/80/3S/S33/3045012 by guest on 29 July 2019 studies, clinical and radiological features including increased Further, the mean changes observed surpassed the minimally neck range of motion,14 female sex,14 longer duration of clinical important difference (MCID) threshold values for the symptoms,15 worse functional status at presentation,16 and outcomes considered, indicating that the improvements were magnetic resonance imaging (MRI) evidence of circumferential not only statistically significant, but also clinically important. spinal cord compression17 have been associated with increased These findings are particularly interesting in light of the fact that risk for neurological deterioration over time. In the same there was substantial variation in the demographics, causative systematic review discussed above, these predictor variables were pathology, and surgical approach employed from region to assessed for their robustness considering factors such as study region. Examples of this included a higher proportion of anterior design, length, and percentage of follow-up, as well as the presence cervical approaches within European centers vs Latin American of adjustment using regression techniques.5 Using these criteria, centers (71% vs 33%, respectively) and a higher proportion there was low evidence that the presence of circumferential cord of OPLL amongst patients treated in Asia Pacific centers vs compression was associated with deterioration in mJOA score North American centers (35% vs 12%, respectively). These points at follow-up; there was insufficient evidence to support the provide external validity to the findings of the North American prognostic significance of the remaining variables. study, by replicating the results of that study in several different geographic regions with different practice patterns and distribu- tions of pathology. EFFICACY OF SURGERY IN DCM In addition to the studies discussed above, a number of smaller prospective studies have also commented on the impact of surgical Over the last decade, many studies have emerged investigating treatment on clinical outcomes at follow-up. In presented work, the efficacy of surgery in patients with DCM. When considering a meta-analysis by Shamji et al20 collated the effect of surgery this evidence body, it is useful to divide the discussion according across 32 prospective studies evaluating a variety of surgical proce- to 2 main study types: (1) studies which do not directly compare dures in patients with symptomatic DCM. When considering operative to nonoperative treatment (noncomparative studies), this body of literature, the standard mean difference, or average and (2) studies which directly compare operative to nonoperative improvement at 1-year follow-up, was 1.92 for mJOA/JOA (95% treatment (comparative studies). confidence interval [CI] 1.41-2.43), 18.02 for NDI (95% CI 11.02-25.02), and 1.42 for Nurick (95% CI 1.11-1.74). These Noncomparative Studies Evaluating the Impact pooled estimates, all of which exceed the MCID for the respective of Surgery on Clinical Outcomes outcome measure, are expected to be particularly robust in Published in 2013, the AOSpine CSM North America Study18 estimating postoperative outcomes, given that the studies which remains one of the largest prospective studies performed to were used for their generation involved a variety of surgical proce- date evaluating the impact of surgical management on clinical dures (anterior, posterior, combined, arthroplasty, laminoplasty, outcomes. In this study, investigators at 12 North American etc) and emanate from many geographical locations (Asia Pacific, centers enrolled 278 surgically treated patients with mild, South America, Europe, and North America); hence, the results moderate, and severe myelopathy, with the specifics of surgical should be generalizable. management left to the discretion of the surgeon involved. At Several points are important when considering these 1-year follow-up, across the entire spectrum of injury severity, findings. First, traditionally, there has been substantial nihilism statistically and clinically significant improvements were noted surrounding the potential for functional recovery after surgery for functional outcome (mJOA and Nurick grade), disability for DCM, with preoperative discussions centered principally outcome (Neck Disability Index [NDI]) as well as generic on the central goal of symptom stabilization. To the contrary, health-related quality of life (SF-36). When dissecting the results these findings suggest that, on average, patients will experience depending on initial symptom severity, a statistically significant functional, disability-related, and quality of life improvements difference was noted when considering change in mJOA at 1-year at long-term follow-up. Second, evidence of differential efficacy postop, with severe patients improving the most (4.91 points), depending on preoperative symptoms severity suggests that moderate the second most (2.58 points), and mild the least surgeons should be particularly aggressive in advocating for

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surgical management in the severe subclass of patients. Third, in comparison to the 68 patients originally enrolled. In addition, while the risks of surgery are not zero, rates of serious compli- the postoperative functional outcomes described in this study cation events are low, with the most common complication (0 change in mJOA) are at odds with a substantial number of being postoperative neck pain/discomfort. Finally, however, it is prospective surgical series (described above), which consistently important to remember that while these studies have a number of support clinically significant functional improvements at follow- methodological strengths, due to reasons discussed above, there up, irrespective of the procedure performed. In summary, while were no nonoperative treatment arms, and as a result, it is not representing the best evidence available on the topic of surgical possible to comment on the absolute efficacy or safety of surgery vs nonoperative, in light of the concerns raised, this study cannot in relation to conservative measures based on these studies. be used to justify the routine practice of treating DCM patients

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Studies Comparing Operative to Nonoperative Summary of Surgical Literature and Upcoming Surgical Treatment Guidelines In one of the few randomized studies available on this topic, In summary, a large body of literature has shown operative Kadanka et al21 randomized patients with mild DCM (which ≥ management to result in clinically and statistically significant they defined by an mJOA score of 12 points) to surgery vs gains at long-term follow-up; unfortunately, for the ethical and nonoperative management. Although nonoperative management practical reasons discussed above, the majority of these studies was not standardized in this study (consisted of elements of inter- do not directly compare operative to nonoperative management. mittent bed rest, use of collar, anti-inflammatory medication, However, when combining our knowledge surrounding the and discouragement of high-risk activities), when considering unpredictable and often progressive natural history of DCM the 47 patients available for follow-up at 10 years postrandom- (20%-62% rate of deterioration), with the consistency of ization (25 in the conservative arm and 22 in the operative beneficial effects and safety noted with surgical management arm), there was no significant difference in mean mJOA score across the large number of uncontrolled studies, a compelling (15 in conservative group, 14 in the surgical group), and no case can be made for surgical management regardless of patient significant difference in mean mJOA change score (0 in both symptom severity. conservative and surgical groups) between the treatment arms. In order to summarize the existing evidence, clinical guidelines Similarly, no significant difference was observed between the are currently under development; these guidelines are currently groups when considering the results of the 10-meter walk test undergoing external review, with publication anticipated in early at the 10-year follow-up mark; however, a significant difference 2017. favoring for the nonoperative treatment group was seen at 3 years. In the only other prospective study on this topic, Sampath SURGICAL PROCEDURES et al22 assessed rating of neurological symptoms, activities of daily living, pain, and ability to work amongst 2 cohorts Apart from discussing the efficacy and safety of surgery in a of DCM patients, with 1 cohort treated operatively and the generic fashion, it is also necessary to explore the specific surgical other treated nonoperatively (pharmacological therapy with either options available for the treatment of DCM. When consid- narcotic or nonsteroidal drugs, steroids, bed rest, home exercise, ering these options, the most fundamental distinction is between cervical traction, neck bracing, or spinal injections). Of note, anteriorly and posteriorly directed procedures. Within posterior the functional and neurological outcomes used in this study approaches, the 2 most often discussed and performed proce- were created specifically by the authors for use in this study dures include laminectomy and fusion and laminoplasty. From and relied on a subjective assessment of symptoms across several an anterior treatment perspective, anterior cervical discectomy broad categories. Also, a direct statistical comparison between the and fusion (ACDF), anterior cervical corpectomy and fusion, operative and nonoperative group was not performed; instead, the and corpectomy/discectomy constructs are the most commonly 2 cohorts were considered independently. Independent of these performed. In this section, we review the available evidence 2 shortcomings, compared to baseline, patients treated nonop- comparing these procedures and discuss the role of preoperative eratively had an increased number of neurological symptoms, alignment in operative decision making. Table 2 includes recom- worsened activities of daily living and a more severe pain rating at mendations for use of these approaches, based on previously 11-month follow-up.22 completed evidence based reviews. When considering these studies, several points are relevant. With respect to the Kadanka study,21 the randomized nature Anterior vs Posterior Approaches of this study and the prolonged follow-up achieved are clear The question of the relative suitability of an anterior vs methodological strengths. However, while the authors allude to posterior approach for treatment of DCM remains one of the power calculations performed prior to study commencement, the most fundamental, controversial, and unresolved in all of spine sample size is small with 47 patients available at final follow-up, surgery. Classically, anterior approaches have been preferred in

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TABLE 2. Evidenced-based Recommendations for Specific Surgical Interventions in the context of DCM

Surgical approach Recommendation

Anterior vs posterior approach – Comparative effectiveness and safety between anterior approaches appear similar in patients with multilevel disease. – An individualized approach accounting for pathoanatomical variations is recommended.

– In general: Downloaded from https://academic.oup.com/neurosurgery/article-abstract/80/3S/S33/3045012 by guest on 29 July 2019 – In the presence of ventral pathology, a limited number of stenotic segments (<3) and the presence of kyphotic deformity favor an anterior approach. – In the presence of posterior pathology, a greater number of stenotic segments (≥ 3), maintained cervical lordosis and the presence of OPLL favor a posterior approach.24 Laminectomy and fusion vs laminoplasty – Existing literature suggest both procedures to be safe and effective for the treatment of DCM; no evidence of differential efficacy or safety currently exists. – Choice of procedure to depend on individual preferences and surgeon familiarity.29 Anterior multilevel ACDF vs hybrid vs corpectomy – When performing an anterior approach in the setting of minimal retrovertebral disease, multiple discectomy is recommended over corpectomy or discectomy-corpectomy hybrid procedures. – When performing an anterior approach in the presence of significant retrovertebral disease, discectomy-corpectomy hybrid approaches are preferred when possible over multiple corpectomies.26 Alternative procedures included: skip laminectomy, minimally invasive – Insufficient evidence currently exists to recommend these procedures tubularorendoscopic over the more conventions approaches discussed above

the setting of myelopathy with predominately ventral compressive change in mJOA score from preop to postop, neither approach pathology over a limited number of segments, or in the setting was consistently associated with superior outcomes. For 3 of of cervical kyphosis or hypolordosis. In contrast, posterior the 4 studies that collected neck pain-related data, anterior approaches have been preferred in the case of OPLL, or, in the approach was associated with reduced neck pain at follow-up; setting of predominately dorsal compressive pathology, over a hence, there was “low” level of evidence, according to the grading greater number of segments and preserved cervical lordosis. In system applied, that anterior surgery results in less neck pain. perhaps the largest study to date to evaluate this question, Fehlings All 3 studies evaluating canal diameter associated the posterior et al23 performed a retrospective cohort study using data from approach with increased canal diameter, leading to a “moderate” the AOSpine CSM North America study, to compare clinical level of evidence favoring the posterior group with respect to outcomes and complications amongst 264 patients, with 169 this outcome. In summary, when devising an evidence-based treated anteriorly (ACDF or anterior cervical corpectomy and recommendation based on this body of literature, the authors fusion) and 95 treated posteriorly (laminectomy and fusion 86% recommended “an individualized approach when treating patients or laminoplasty 14%). In the unadjusted analysis, the anterior with CSM accounting for pathoanatomical variations (ventral group experienced reduced functional recovery, with an average vs dorsal, focal vs diffuse, sagittal, dynamic instability), as there of 2.5 points of mJOA improvement at 1 year compared to 3.6 appears to be similar outcomes between the anterior and posterior points in the posterior group (P < .01). However, after adjusting approaches in regards to effectiveness and safety.”24 for preoperative characteristics, including preoperative mJOA, no Although the existing body of evidence seems unable to difference in mJOA recovery was noted. With respect to other definitively provide an answer to the question of anterior vs outcomes, including NDI, SF-36, Nurick, and complications, no posterior surgery, this may be partially due to the method- significant differences were noted between the cohorts. ological limitations of the largely retrospective studies performed To collate the evidence on this topic, Lawrence et al24 on this topic, each fraught with substantial concerns of selection performed a systematic review that summarized the findings of and information bias. To overcome this limitation, a multi- 8 retrospective cohort studies comparing anterior and posterior center, randomized control trial (RCT), the cervical spondylotic surgery for multilevel CSM. In summary, when considering myelopathy surgery trial, is currently underway, aiming to provide

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a definitive answer to the anterior vs posterior question, through lack of a designated primary outcome measure, small study use of the most robust study design available for this purpose.25 population, lack of sample size calculation, and lack of a direct statistical comparison between the treatment groups. Acknowl- Anterior Multilevel ACDF vs Hybrid vs Corpectomy edging these limitations, the authors conclude that the findings When confronted with the patient with multilevel cervical support that DCM patients are likely to benefit from both proce- spondylosis and an anterior approach is decided upon, choice of dures. optimal operative intervention remains controversial. Based on In addition to the discussed prospective randomized study, the individual pathoanatomy, decompression may be achievable several retrospective cohort studies have compared lamino- by multiple discectomies, although the presence of signif- plasty to laminectomy and fusion for DCM, 4 of which were icant retrovertebral disease may require hybrid or corpectomy summarized in a recent systematic review by Yoon et al.29 Downloaded from https://academic.oup.com/neurosurgery/article-abstract/80/3S/S33/3045012 by guest on 29 July 2019 approaches to achieve that objective. In a systematic review of With respect to change in mJOA at follow-up, both of the 10 articles addressing anterior surgical options for the myelo- 2 studies considering this outcome documented improvement pathic patient, Shamji et al26 demonstrated similar trajec- with both surgeries at long-term follow-up. With respect to tories of neurological recovery for patients managed by these neck pain outcomes, in all 4 of the included studies, no signif- various options, although sagittal correction and neck pain scores icant difference was noted between the surgical groups at a were best among the multiple discectomy cohort and worst variety of outcome points. The rate of reoperation was found among the corpectomy cohort. A similar incidence of periop- to be higher in the laminectomy and fusion vs laminoplasty erative complications was noted among the different proce- groups (15% vs 0%, 27% vs 13%, and 5% vs 4%, respectively) dures for pseudoarthrosis, dysphagia, and infection. The strong in 2 out of 3 studies exploring this outcome, with profile of recommendations arising from this systematic review were that cause for reoperation found to differ little between the groups. when pathoanatomically appropriate with minimal retrovertebral The authors concluded: “At present time, the available liter- disease, multiple discectomy should be selected over hybrid or ature supports that both laminectomy and fusion, as well as corpectomy procedures; and when pathanatomically appropriate laminoplasy, can be effective and safe in the treatment of DCM; with significant retrovertebral disease, hybrid should be selected however, no definitive comment can be made about the relative over corpectomy procedure. efficacy of these two approaches. A properly powered RCT will be needed in the coming years to more definitively address Laminoplasty vs Laminectomy and Fusion this question.”29 Although multilevel laminectomy was historically the most popular posterior operation for the treatment of DCM, the documentation of relatively high rates (15%- Minimally Invasive/Alternate Procedures 20%) of postlaminectomy kyphosis27 have led to the gradual In addition to the more commonly performed proce- abandonment of this approach and to the nearly uniform dures outlined above, a number of alternative and, in some adoption of one of 2 procedures when considering a posterior cases, minimally invasive procedures have been described operation: laminectomy and fusion or laminoplasty. Both of throughout the literature. These include skip laminectomies and these operations are commonly employed in the setting of tubular/endoscopic decompressions. DCM wherein there are multiple levels of stenosis (typically ≥3) Skip cervical laminectomy, first described by Shirashi in with preservation of cervical lordosis. Several studies have been 2002,30 involves alternating between standard complete laminec- completed over the last decade comparing these 2 procedures. tomies and partial laminectomies when decompressing the In 2012, surgeons from the University of Miami published a cervical spine from a posterior approach. In theory, this approach small prospective study in which they randomized 16 patients allows for decompression of the spinal cord in regions of greatest with DCM to laminectomy and fusion (7 patients) or lamino- stenosis, while allowing for preservation of the posterior cervical plasty (9 patients).28 With respect to eligibility, investigators tension band, thereby limiting the risk of postlaminectomy included patients older than 35, with clinical myelopathy in the kyphosis, without performing an instrumented fusion. One setting of cervical spondylosis, without kyphosis, and at least prospective study, in which patients were randomly allocated 3 levels of spinal cord compression. At 1-year follow-up, while to treatment arms depending on the month of their presen- the laminectomy and fusion group experienced nonsignificant tation, compared skip laminectomy to double open door lamino- improvements in mJOA, Nurick, NDI, neck pain, and SF-36 plasty.31 Although there were significant methodological issues, scores, the laminoplasty group achieved significant improvement the authors followed 41 patients up to a minimum of 1-year in Nurick, SF-36, and NDI scores, in addition to nonsignificant postop, finding no significant difference in JOA score recovery, improvements in mJOA and neck pain scores at the same time neck pain, cervical range of motion, or complications between point. Those undergoing laminectomy and fusion had signif- the treatment groups. Two other prospective cohort studies icantly greater enlargement in canal diameter but significantly comparing skip laminectomy to laminoplasty have yielded similar reduced cervical range of motion as compared to the lamino- results, with the 1 exception that both of these studies associated plasty group. While significant given the randomized nature of skip laminectomies with improved postoperative cervical range of treatment allocation, this study has several weaknesses including motion as compared to laminoplasty.32,33

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In addition to standard midline open surgical techniques, agents in order to maximize the potential for postoperative minimally invasive techniques, involving a parasagittal muscle recovery. As mentioned above, glutamatergic excitotoxicity is splitting approach, have also been described in recent years. Using an important factor in the pathobiology of DCM, resulting this approach, different authors have described the use of tubular in an expanded zone of neural tissue injury. Riluzole is a dilator systems, classically used for MIS lumbar decompression or sodium channel-blocking drug, FDA approved for the treatment cervical foraminotomies, as well as microendoscopic systems to of amyotrophic lateral sclerosis, which has shown to reduce achieve a posterior decompression of the cervical spinal cord.34,35 glutamatergic excitotoxicity and improve behavioral outcomes While initial series report outcomes that compare favorably in animal DCM models.10,42,43 At present, a phase III multi- to more traditional operations, larger comparative studies are center RCT (CSM Protect trial) is underway, evaluating the necessary to properly evaluate the efficacy and safety of these impact of surgery paired with pre- and postoperative Riluzole Downloaded from https://academic.oup.com/neurosurgery/article-abstract/80/3S/S33/3045012 by guest on 29 July 2019 approaches. administration vs surgery paired with pre- and postoperative placebo, on long-term functional outcomes.44 With a goal to enroll 270 patients, this trial is currently nearing completion of Alignment Considerations enrollment, with final trial results anticipated in 2017. While the goals of surgery in the myelopathic patient have classically been described as decompression and stabilization of the cervical spine, emphasis has more recently been placed NONOPERATIVE MANAGEMENT on actively considering preoperative spinal alignment when making surgical decisions. Indeed, experimental animal models In the absence of strong literature comparing operative to of myelopathy reveal that the impact of cervical kyphosis on the nonoperative care, the effectiveness of nonoperative treatment spinal cord includes demyelination, neuronal loss, and decreased can be evaluated through longitudinal observational studies. Six vascular supply.36 In series of 56 and 124 prospectively followed studies were identified that reported outcomes of structured patients, Smith et al37 and Mohanty et al,38 respectively, showed nonoperative treatment using change in JOA or mJOA scores that myelopathy severity was correlated with worse sagittal from baseline to follow-up (mean: 29-74 months).17,22,45-48 vertical axis, the latter defining this to be most robust for both Treatment protocols differed substantially across studies and clinical myelopathy and cord MRI T2 hyperintensity for the included continuous cervical traction, drug therapy, exercise kyphotic patient. Further, Oshima et al39 have suggested that therapy, thermal therapy, immobilization, cervical bracing, segmental kyphosis does predict patients with myelopathy who nonsteroidal anti-inflammatory drugs, or a combination of these will eventually neurologically progress or reach surgical inter- techniques. Reported improvements following structured nonop- vention. erative management were minimal, with JOA/mJOA change Correction of cervical spine deformity may provide for neuro- scores ranging from 0 to 2.3. The 2 studies that observed logical improvement in the short term by addressing ongoing improvements in excess of the MCID of mJOA included patients ventral cord compression as well as longitudinal tension, and, with myelopathy secondary to soft disk herniation and dynamic in the long term, by addressing the incidence of clinically cervical myelopathy.49,50 These etiologies may respond better to symptomatic adjacent segment degeneration. Shamji et al40 nonoperative care as soft disk herniations may spontaneously reported on a prospective series of patients and demonstrated regress over time, and immobilization may, at least temporarily, that patients with preoperative kyphosis exhibit a lesser degree decrease cord irritation in patients with dynamic injury to the of neurological recovery than those with preoperative lordosis, spinal cord. independent of whether alignment was corrected at the time There are no known harms of nonoperative care besides of surgery. This group deteriorated more frequently as well, myelopathic deterioration. Based on 5 studies, the proportion of particularly if approached by posterior-only surgery. Hansen and patients who ultimately convert to surgical intervention following coworkers41 suggested in a systematic review based on low- a period of structured nonoperative treatment ranged from 23% grade evidence, that postsurgical sagittal imbalance increases the to 54% (mean follow-up: 27-74 months).47,48,51-53 incidence of cervical radiographic adjacent segment degeneration. Indeed, together these findings support the maintenance or restoration of cervical sagittal alignment at time of operative MANAGEMENT OF NONMYELOPATHIC OR intervention for myelopathy. MINIMALLY SYMPORMATIC PATIENTS

A controversial area of management relates to the treatment COMBINED SURGICAL AND of nonmyelopathic or minimally symptomatic patients with PHARMACOLOGICAL TREATMENT imaging evidence of canal stenosis, cord compression, or OPLL. In a systematic review of the literature, Wilson et al54 aimed to At present, efforts are underway to evaluate the efficacy of determine the frequency, and timing of, symptom development surgery combined with pharmacological neuroprotective drug in this patient population. Based on this review, 8% and 22.6% of

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those with evidence of cord compression or canal narrowing, but tively as younger patients.63 Reasons for these discrepancies without clinical evidence of myelopathy, developed myelopathy include that the elderly (1) have reduced physiological reserves at a median of 12 and 44 months, respectively. In patients with and may be less tolerant to the invasiveness of surgery64,65;(2) evidence of OPLL, rates of disease onset ranged from 0% to may have other comorbidities that may impact their ability to 61.5% across 3 studies. perform certain activities of daily living or tasks included in a Another objective of this review was to identify important variety of outcome tools; (3) experience age-related changes to clinical, radiographic, and electrophysiological predictors of their spinal cord, including a decrease in synaptic and dendritic myelopathy development. Significant predictors of myelopathy elements, number of anterior horn cells, gamma-motorneurons development were presence of symptomatic radiculopathy and number of myelinated fibers in the corticospinal tract and (relative risk [RR]: 3.0, 95% CI 2.0-4.4), prolonged posterior funiculus66,67; and/or (4) have more severe degener- Downloaded from https://academic.oup.com/neurosurgery/article-abstract/80/3S/S33/3045012 by guest on 29 July 2019 somatosensory (RR: 2.9, 95% CI 1.7-5.1) and motor-evoked ative pathology and spinal stenosis. Other potential predictors potentials (RR: 3.2, 95% CI 1.9-5.6) and electromyography signs of surgical outcomes include smoking status, rapidity of disease of anterior horn cell lesions (RR: 2.4, 95% CI 1.5-3.9).54 Clinical onset and progression, diabetes, various signs and symptoms and radiographic parameters not predictive of myelopathy devel- (Babinski sign, leg spasticity, hyperreflexia, hand atrophy), and opment included gender, a minor traumatic event, type of number of comorbidities.58,68-70 There is, however, substantial compression (osteophytes and/or herniation), number of stenotic inconsistency in the literature as to whether these factors are levels, pavlov or compression ratio, cross-sectional cervical spinal indeed valuable for outcome prediction. cord area, or cervical cord hyperintensity on MRI. Unfortu- In 2013, Tetreault et al71 developed a clinical prediction rule nately, no studies have examined the effectiveness of prophylactic to quantify a patient’s likely outcome using a combination of surgical intervention vs nonoperative management vs a “wait and routinely collected variables. The model was developed using data see” approach for the treatment of this patient population. As per from 278 North American patients and aimed to distinguish the recommendations in the review discussed above, in patients between patients with mild myelopathy postoperatively (mJOA ≥ with a low risk of developing myelopathy, prophylactic surgery 16) and those with substantial residual neurological impairment should not be offered; instead, patients should be counseled as (mJOA < 16). Based on this study, the most important predictors to potential risks of progression, educated about relevant signs of an mJOA ≥ 16 were younger age, milder preoperative and symptoms of myelopathy and be followed clinically. In myelopathy severity, shorter duration of symptoms, nonsmoking contrast, patients at high risk of disease development (eg, those status, and absence of psychiatric disorders and impaired gait. The with radiculopathy) should be offered surgical intervention or predictive performance of this model was 79% as evaluated by the nonoperative treatment consisting of close serial follow-up or a area under the receiver operating curve, indicating good discrim- supervised trial of structured rehabilitation. inative ability. In a second, international study, Tetreault et al72 validated their clinical prediction rule and reported similar performance in an external sample. OUTCOME PREDICTION Clinical Predictors Imaging Predictors Prediction is extremely valuable in a surgical setting as In a recent systematic review of literature, Tetreault et al73 knowledge of a patient’s likely outcome can help manage expec- summarized findings from studies that evaluated the association tations, facilitate shared decision-making, identify strategies to between imaging characteristics and surgical outcomes. Based on optimize results and standardize care across centers.55 Several their results, there is low-level evidence suggesting that a greater studies have evaluated important clinical predictors of surgical number of high signal intensity (SI) segments on T2-weighted outcomes using a variety of assessment tools.56-61 A longer images (WI), low SI change on T1WI, combined T1/T2 SI, and duration of symptoms, more severe preoperative myelopathy a higher SI ratio are predictors of worse outcomes. In contrast, severity, and older age are often significantly associated with worse SI grade on T2WI, compression ratio and canal diameter are not postoperative outcomes across studies.62 predictive of surgical outcomes. Explanations for these findings Patients with severe, chronic, and longstanding compression include that (1) a high SI on T2WI reflects a broad spectrum experience histological damage to their spinal cord which of histological changes (edema, demyelination or ischemia, or may or may not be reversible through surgical decompression. necrosis, myelomalacia, and cavitation) and a wide range of Furthermore, a longer duration of symptoms increases a patient’s recuperative potentials and (2) multilevel SI, combined T1/T2 risk of neurological progression and worsening. As a result, it is SI and a higher SI ratio are all indicative of severe damage that critical that DCM is diagnosed early; this requires that primary may be irreversible even after surgical decompression. care physicians are able to recognize key signs and symptoms and The diagnostic and predictive value of advanced imaging differentiate between this disease and other mimicking diagnoses. techniques are currently under investigation, including diffusion With respect to age, the elderly may not be able to translate tensor imaging (DTI), functional MRI, magnetization transfer, neurological improvements into functional recovery as effec- magnetic resonance spectroscopy, and myelin water fraction.74

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TABLE 3. Overview of the Best Studied and Most Frequently Utilized Outcomes Measures in the Context of DCM

Description Psychometric properties Other

mJOA Functional impairment: 4 categories for a Demonstrates convergent and divergent Mild = 15-17 total of 18 points. validity Upper-extremity motor function (5 points) Responsive to change (Cohen effect Moderate = 12-14 size = 1)

Lower extremity motor function (7 points) Reliability unknown (inter- and intrarater Severe < 12 Downloaded from https://academic.oup.com/neurosurgery/article-abstract/80/3S/S33/3045012 by guest on 29 July 2019 reliability for the JOA are high, intraclass correlation coefficient (ICC) = 0.826) Sensory function (3 points) Moderate internal consistency (α = 0.63) MCID = but varies based on myelopathy Bladder function (3 points) severity (1 point for mild, 2 points for moderate, and 3 points for severe). Nurick Functional impairment: 6 points Demonstrates validity MCID has not been established. 0: root involvement without spinal cord Insensitive, and based solely on dysfunction (SCD) impairment and employment status I: signs of SCD without difficulty walking II: difficulty with walking without effect on employment III: difficulty with walking with effect on full-time employment IV: can walk only with an aid or walker V: chair bound or bedridden 30-meter Functional impairment: Can effectively distinguish between walking controls and myelopathic patients test Patient begins seated in a chair and is Demonstrates convergent and divergent asked to stand up, walk on a flat surface for validity 15 meters, turn around, and then walk back. High reliability, low variability between The time required to complete this trials distance and the number of steps taken are recorded. Neck Disability: 10 subscales for a total of 100 Demonstrates construct validity MCID is 7.5 in a degenerative spine Disability points. population Index Assesses performance in 10 categories (0 = Fair to moderate test-retest reliability no disability, 5 = complete disability), (ICC = 0.55) including pain intensity, personal care, Responsive to change lifting, reading, headaches, concentration, work, driving, sleeping, and recreation. Total score is multiplied by 2. SF-36v2 General health function: 8 subscales for a Can effectively distinguish between MCID is 4.1 for physical component total of 100 points. controls and myelopathic patients summary (PCS) and 5.7 for mental component summary (MCS) in a degenerative spine population. Assesses general health on 8 subscales, Demonstrates convergent, divergent and including physical functioning, bodily pain, predictive validity physical role limitations, general health, Moderate test-retest reliability for all 8 vitality, social functioning, emotional role subscales (r = 0.60-0.81) limitations and mental health. Subscales, MCS and PCS demonstrate good internal consistency Subscales demonstrate either a floor or ceiling effect

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Three studies have evaluated the association between surgical Disclosure outcomes and DTI features such as fractional anisotropy (FA) The authors have no personal, financial, or institutional interest in any of the and fiber tract ratio.75-77 Across studies, a higher FA was highly drugs, materials, or devices described in this article. correlated with improvements on the NDI but not the Nurick grade,postoperativemJOA,orthementalorphysicalcomponent scores of the SF-36. Furthermore, a higher FA was predictive REFERENCES > of an mJOA recovery rate 50%. This association is likely due 1. Tetreault L, Goldstein CL, Arnold P, et al. Degenerative cervical to the fact that highly anisotropic diffusion (ie, a higher FA) myelopathy: a spectrum of related disorders affecting the aging spine. Neurosurgery. reflects highly oriented axonal membranes, myelin sheaths, and 2015;77(suppl 4):S51-S67. less damage.74 In a third study by Nakamura et al,76 the fiber 2. 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