Overall, the categorization models proved far more effective, with one reaching an ROC AUC of 0.92 (sagittal PDw 3d SVM deepseg methodology, not harmonized), with an average ROC AUC of 0.654 for non-harmonized data trained models and 0.612 for CovBatharmonized data trained models. The mild mJOA model proved best overall, followed by the severe mJOA model and, finally, the moderate mJOA model. Models with fewer samples also tended to have higher ROC AUC scores, suggesting some level of overfitting was occurring, as the higher sample count provided more natural noise which the models could erroneously detect as significant. The full results are summarized in Table 6 (non-harmonized) and Table 7 (CovBat-harmonized).

**Table 6.** The attributes of logistic models fit on metric data, which was standardized to a common scale, but not and harmonized by scanner used via CovBat. Severity indicates the class attempting to be distinguished from all others (binary classification), while orientation, contrast, and segmentation represent the acquisition methodology associated with the model. Features contains the list of features used to train the model, as selected by SciKit-Learn's SelectFdr function.

**Table 7.** The attributes of logistic models fit on metric data which was standardized to a common scale and harmonized by scanner used via CovBat. Severity indicates the class attempting to be distinguished from all others (binary classification), while orientation, contrast, and segmentation represent the acquisition methodology associated with the model. Features contains the list of features used to train the model, as selected by SciKit-Learn's SelectFdr function.

#### **4. Discussion and Conclusions**

In this work, we explored predictive outcome modeling using computationally aided MRI analysis. We attempted to extract metrics used by trained surgeons from MRI images of the human cervical spine to predict disease severity. Most of these derived metrics simply lack sufficient differentiation across mJOA score severity. Variation appears to be mostly patient-specific rather than related to DCM severity. This is likely a result of the metrics being sampled across the entirety of the spinal cord, whereas morphological differences related to DCM often only effect a portion of the spinal cord, with the remainder appearing 'healthy'. Although there were some interesting trends within the data, these useful trends appear to be masked by natural inter-individual variance between each of the patients enrolled in this study. As a result, our machine learning systems had difficulty pulling out said meaningful trends, resulting in over-fitting to patient variation and lower overall accuracy.

Non-imaging metrics, such as age, smoking status, and symptom duration have been shown to be important metrics in the development of models to predict patient outcomes after surgical treatment for DCM [32]. MR imaging of the cervical spine plays a vital role in the diagnosis and surgical treatment planning of this patient population. Although this data is vital to a surgeon's decision-making process, most surgeons would not consider treating a patient without and MRI confirmed diagnosis. Efforts to distill a surgeon's acumen into an 'imaging metric' have fallen short in terms of predictive capabilities. Our work, while novel in computational approach, only adds to this body of literature, bringing us closer to integrating advanced imaging metrics with a patient's clinical presentation. Such a reality could greatly improve a surgeon's ability to treat their patients.

The models we presented in this work highlight some key features which we can use to inform future processes. Given the low accuracy of most assessment methodologies, the vast majority of metrics extracted from these segmentations did not correlate strongly with mJOA scores. However, a handful did, showing that assessment methodologies could identify statistically significant correlations. Spinal cord segmentation metrics chosen via feature selection also showed an interesting trend, with the angle and diameter of the spine being selected most commonly, followed by metrics associated with cross-sectional area and spinal cord solidity/eccentricity. This is unsurprising given that pathology of DCM results in compression of the spinal cord (i.e. reduction in diameter, often resulting in a misshapen cross-section), but it nonetheless highlights the potential for a model which focused solely on identifying key variations in these values derived directly from the image itself. It is plausible that finding a way to normalize these metrics relative to the patient's unique spinal cord variations could be incredibly valuable for creating a diagnostic model. These techniques show potential, but appear to be hampered by the natural variance of DCM patients' spinal cords.

There are several limitations to this study. First, all data comes from central-southern Alberta (Figure 1), potentially leading to some implicit demographic attributes of the region influencing the analyses. Second, only relatively simple models (Linear and Logistic re-

gression) were used, whereas more complex models may have proven more useful. Simple models simply cannot capture any significant interaction effects. Given the complexity of DCM, it is extremely likely at least one such severity influencing 'complex' effect exists. We limited our analyses to these simpler models to focus the study on evaluating major trends in the data to inform future model design. Third, only simple measures of accuracy were used (*r*2 simply assesses a model's total explained variance, whereas ROC AUC measures its relative ability to predict true positives over false positives), which are likely to mask important details on how each model functions. More nuanced assessment metrics should be considered for future models aimed at diagnostic application; measurements such as false positive rate vs. false negative rate are likely to be far more significant metrics in these contexts (a false positive will be likely caught and dismissed by a clinician upon review, whereas a false negative could lead to significant health consequences for the patient). Fourth, the cross-validation procedure (5-fold) was chosen for its simple implementation in both linear and logistic regression models. A leave-one-out (linear regression) or leaveone-per-category-out (logistic regression) model would be more appropriate here, as it would replicate how a real-world implementation of similar predictive models would be required to function; with a single new patient record being submitted in varying intervals and predictions made for them. Such cross-validation may result in models more prone to over-fitting noise; however, finding noise-resistant metrics would be a must before this limitation could be resolved. Fifth, we only accounted for metrics directly extracted from MRI images. Prior studies have shown that non-imaging metrics can also influence spinal cord morphometrics within a patient [33], and as a result it is likely some confounding or contributing effect from such non-imaging metrics may have not been accounted for. Finding a way to fold in these metrics could improve future models substantially.

Given these limitations, future studies which aim to model DCM outcomes should aim to identify metrics which are normalized to healthy patient variation. This would reduce the amount new models will overfit to natural patient variation over DCM relevant attributes. Likewise, due in part to the limited number of samples available in our dataset and the fact all were diagnosed with DCM, asymptomatic persons who display traits analogous to those of DCM were not accounted for. Prior work has shown MRI images from asymptomatic persons can appear similar to those taken from DCM patients [34]. Increasing the number of MRIs taken from healthy individuals could reduce the likelihood of future models becoming too liberal with their DCM diagnoses. Finding metrics resilient to these forms of over-fitting is imperative if any resulting model is to be implemented in a fully autonomous manner, as to avoid incorrect diagnostic conclusions which may lead to patient harm.

Several possible solutions exist to address these limitations. First, normalizing metrics to be relative per-patient could greatly mitigate natural patient variance effects. These could include ratio metrics (i.e., minimum over maximum ratio), internal outlier detection (i.e., detecting drastic changes in spinal cord shape relative to the rest of the spine), or even dynamically generated metrics such as those produce by Principle Component Analysis. Such metrics would both provide internal normalization for patients, and (in the case of Principle Component Analysis) would be specifically selected based on their relevance to the DCM severity. Second, experimenting with more complex models stands to capture more nuanced details of DCM, such as those of interaction effects between multiple parameters. This would require said metrics to be refined beforehand, however, as such interaction effects would be particularly prone to natural noise masking true relations. Finally, folding in non-imaging derived metrics could address the issue of 'asymptomatic' false positives mentioned prior. Given these effects would likely need to be considered alongside spinal cord morphology metrics, this should be done after the selection of said morphological metrics and after a suitable model is chosen which can reflect these interactions. The outcome of such research could be particularly enlightening, helping to explain what distinguishes asymptomatic persons from those suffering from DCM, potentially providing improved treatment options for the latter.

Overall, it appears that modern computational methods have unmet potential in diagnostic prediction of DCM severity. With improvement of these models via the integration of external non-imaging derived metrics, deploying additional complex statistical and machine learning models, and improved morphological metric identification, it may be possible to create a system capable of working at least as effectively as the average clinician. The numerous limitations of this study will also need to be addressed should such a system come to fruition, namely the problem of models over-fitting to natural patient variation and other noise rather than DCM specific morphological characteristics. If these challenges are met, such a system being integrated in a fully automated capacity could potentially revolutionize the treatment of DCM. Such a system could allow clinicians to focus on each patient's needs more closely, helping them come to more informed treatment decisions and mitigating risks associated with their chosen treatment. This model could also greatly improve our understanding of DCM, potentially identifying targets for new modes of treatment or discovering novel diagnostic metrics.

**Author Contributions:** Conceptualization, K.O., D.W.C., W.B.J., N.E. and J.C.-A. methodology, K.O., D.W.C., W.B.J., N.E. and J.C.-A. software, K.O. and J.C.-A. validation, K.O., D.A., D.W.C., J.C.-A. formal analysis, K.O.; investigation, K.O., D.W.C., W.B.J. and N.E.; resources, D.W.C., W.B.J. and N.E.; data curation, K.O. and D.W.C.; writing—original draft preparation, K.O.; writing—review and editing, All Authors; visualization, K.O.; supervision, D.W.C. and D.A.; project administration, D.W.C.; funding acquisition, D.W.C. All authors have read and agreed to the published version of the manuscript.

**Funding:** This research was funded in part by the Alberta Spine Foundation, Department of Clinical Neurosciences, Cumming School of Medicine and the Hotchkiss Brain Institute.

**Institutional Review Board Statement:** The study was conducted according to the guidelines of the Declaration of Helsinki. Ethics approval for the following research has been renewed by the Conjoint Health Research Ethics Board (CHREB) at the University of Calgary. The CHREB is constituted and operated in compliance with the Tri-Council Policy Statement: Ethical Conduct for Research Involving Humans (TCPS 2); Health Canada Food and Drug Regulations Division 5; Pact C; ICH Guidance E6: Good Clinical Practice and the provisions and regulations of the Health Information Act, RSA 2000 c H-5. Ethics ID: REB18-1614-REN2 Principal Investigator: David Cadotte. The study was originally approved on December 18, 2018 and renewed on an annual basis thereafter.

**Informed Consent Statement:** Informed consent was obtained from each patient at the initial point of clinical contact.

**Data Availability Statement:** The data are not publicly available due to its sensitive nature, to preserve the privacy of those enrolled in our study. However, anonymized data may be made available in the context of a data-sharing agreement in coordination with the corresponding author and appropriate research ethics approval.

**Acknowledgments:** We would like to acknowledge our funding sources—Alberta Spine Foundation, Department of Clinical Neurosciences, Cumming School of Medicine and the Hotchkiss Brain Institute. There are no conflicts of interest. We would also like to acknowledge the clinicians, imaging technicians, and patients who have improved to our research through their contributions to the Canadian Spine Outcomes and Research project.

**Conflicts of Interest:** The authors declare no conflict of interest.

#### **Abbreviations**

The following abbreviations are used in this manuscript:

#### **References**

*Article*

## **Frailty Is a Better Predictor than Age of Mortality and Perioperative Complications after Surgery for Degenerative Cervical Myelopathy: An Analysis of 41,369 Patients from the NSQIP Database 2010–2018**

**Jamie R. F. Wilson 1,2,3, Jetan H. Badhiwala 2,3, Ali Moghaddamjou 2,3, Albert Yee 2, Je**ff**erson R. Wilson 2 and Michael G. Fehlings 2,3,\***

Received: 22 September 2020; Accepted: 27 October 2020; Published: 29 October 2020

**Abstract:** Background: The ability of frailty compared to age alone to predict adverse events in the surgical management of Degenerative Cervical Myelopathy (DCM) has not been defined in the literature. Methods: 41,369 patients with a diagnosis of DCM undergoing surgery were collected from the National Surgical Quality Improvement Program (NSQIP) Database 2010–2018. Univariate analysis for each measure of frailty (modified frailty index 11- and 5-point; MFI-11, MFI-5), modified Charlson Co-morbidity index and ASA grade) were calculated for the following outcomes: mortality, major complication, unplanned reoperation, unplanned readmission, length of hospital stay, and discharge to a non-home destination. Multivariable modeling of age and frailty with a base model was performed to define the discriminative ability of each measure. Results: Age and frailty have a significant effect on all outcomes, but the MFI-5 has the largest effect size. Increasing frailty correlated significantly with the risk of perioperative adverse events, longer hospital stay, and risk of a non-home discharge destination. Multivariable modeling incorporating MFI-5 with age and the base model had a robust predictive value (0.85). MFI-5 had a high categorical assessment correlation with a MFI-11 of 0.988 (*p* < 0.001). Conclusions and Relevance: Measures of frailty have a greater effect size and a higher discriminative value to predict adverse events than age alone. MFI-5 categorical assessment is essentially equivalent to the MFI-11 score for DCM patients. A multivariable model using MFI-5 provides an accurate predictive tool that has important clinical applications.

**Keywords:** degenerative cervical myelopathy; frailty; age; mortality; complications

#### **1. Introduction**

Degenerative cervical myelopathy (DCM) is characterized by progressive compression of the spinal cord in the cervical canal, producing debilitating neurological deficits in upper limb function, gait instability, sphincteric disturbance, and ultimately spastic quadriparesis. It is the most common cause of adult spinal cord dysfunction worldwide and its prevalence increases significantly with age [1]. With the projected shift in demographics over the next 30 years, the burden of (potentially treatable) neurological dysfunction in the elderly has become a major public health concern of the 21st century [1–4]. The Institute of Medicine has declared that DCM includes 3 of the top 100 national

priorities for comparative effectiveness in research, and efforts to address the rise of disability from DCM have been implemented worldwide, including the establishment of international consensus treatment guidelines [5–7].

DCM is an umbrella term that encompasses a number of degenerative pathologies that include osteoarthritis (spondylosis), ligament disease (ossification of the posterior longitudinal ligament (OPLL), ligament hypertrophy), and degenerative listhesis or instability. These entities have pronounced effects on the functional abilities and quality of life of impaired individuals, which may be comparable to serious health conditions, such as cancer or heart disease [8]. The mainstay of treatment for DCM is decompressive surgery, which arrests the progression of the disease and provides a sustained and meaningful improvement in functional and quality of life measures [2,3,7,9–13]. Clinical factors such as duration of symptoms prior to surgery and severity of baseline functional impairment correlate strongly with the chances of a substantial clinical benefit after intervention [9,11,12,14,15].

Decisions regarding the best application of surgical intervention for DCM have become an important focus of clinical study [3,6]. In the elderly population, this issue becomes complex as the potential impact of preventing neurological disability in the elderly needs to be balanced against the healthcare costs and complication profile [4,6,7,13]. Although increasing age is associated with poorer surgical outcomes, in DCM patients many studies have shown sustained long-term functional and quality of life improvements after surgery [4,10,11,15–17]. Moreover, when elderly patients are matched for co-morbidities and baseline functional impairment, their complication profile is equivalent [3]. This has led to the evolving opinion that age alone has become less relevant for the purpose of estimating perioperative risk profile and prognosis after surgery [18–22].

Efforts to move past age alone as a predictor of outcomes has led to the development of measures of physiological reserve (or 'frailty indices'). The most commonly cited index in spine surgery is the Modified Frailty Index (11-point or 5-point, Table 1) [23–26] which is derived from the original 70-point Canadian Study of Health and Aging Frailty Index (CSHA-FI) [27]. Other measures include the American Society of Anesthesiologists Grading scale (ASA) and the modified Charlson Co-morbidity Index (mCCI). ASA is a well-established subjective estimate of overall illness severity that has an uncertain role in the prediction of perioperative outcomes after spine surgery [18]. The mCCI, like the MFI, is also matched to NSQIP variables but produces different weightings according to increasing age and certain co-morbidities. Although used widely in general surgery, the mCCI has received limited application in spine surgery [19,20,28]. In 2017, Shin et al. published a study of 6965 patients who underwent either anterior cervical discectomy or posterior cervical fusion, and showed frailty (as measured by the 11-point MFI) was associated with an increased risk of adverse events [23]. However, this study did not distinguish between radiculopathy or myelopathy patients, and it has been previously demonstrated that myelopathy patients have a higher risk of perioperative complications compared to patients with purely radicular symptoms [24]. To date, no study exists that models the impact of frailty specifically on surgical DCM patients, or that compares the discriminatory ability of different measures of frailty.

**Table 1.** NSQIP clinical variables matched from the CSHA-FI used to construct the 11- and 5- item modified frailty index (MFI-11, MFI-5), compared with the modified Charlson Co-morbidity Index (mCCI).

NSQIP, National Surgical Quality Improvement Program; CSHA-FI, Canadian Study of Health and Aging Frailty Index; mCCI, modified Charlson Co-morbidity Index; COPD, chronic obstructive pulmonary disease; MFI, modified frailty index; OR, Odds Ratio; TIA, transient ischemic attack.

The objectives of the current study were to (1) define the effect of age on the perioperative outcomes of mortality, unplanned readmission/reoperation, major complication, length of stay and discharge to non-home destination for patients undergoing surgery for DCM, (2) directly compare measures of frailty in the same cohort to determine which factor exhibits a greater influence on the observed outcomes, and (3) define the potential correlation between MFI-5 and MFI-11 in DCM patients. We hypothesize that after adjustment for common surgical factors, frailty is a better predictor of perioperative complications compared to age alone. Frailty as a predictor of perioperative complications would have important implications for the clinical management of elderly patients with DCM.

#### **2. Experimental Section**

#### *2.1. Data Source*

The data source for this study was the American College of Surgeons (ACS) National Surgical Quality Improvement Program (NSQIP) database, for years 2010 through 2018 inclusive. The NSQIP datasets encode surgical procedures by Current Procedural Terminology (CPT) codes and diagnoses by International Classification of Diseases, Ninth/Tenth Revision, Clinical Modification (ICD-9/10-CM) codes. NSQIP collects pre-operative through 30-day post-operative data on randomly assigned patients at participating hospitals. Quality and reliability of the data are ensured through rigorous training of data abstractors and inter-rater reliability audits of participating sites [25].

#### *2.2. Patient Population*

Eligible patients who had a primary diagnosis of DCM (ICD-9-CM 721.1 or 722.71; ICD-10-CM M47.12 or M50.00, M50.01, M50.02, M50.03) and underwent a cervical decompression and fusion operation, including anterior (CPT 22551, 22554, 63081) and/or posterior (CPT 22600, 63051, 63020) approach. ICD-9/10-CM and CPT codes used for this study are summarized in Table 2.

**Table 2.** List of ICD-9, ICD-10, and Current Procedural Terminology (CPT) codes used to determine diagnosis, operative approach and number of operated levels.

ICD, International Classification of Diseases; CM, Clinical Modification; CPT, Current Procedural Terminology.

#### *2.3. Baseline Characteristics*

Data relating to baseline demographic characteristics and comorbidities were extracted. The number of operated levels was determined by searching the "other procedure" fields for CPT add-on codes specifying each additional level fused (CPT 22552, 22614). Surgical approaches were separated into anterior, posterior, or combined as a categorical variable.

#### *2.4. Calculation of Frailty Indices*

The MFI-11 was calculated according to established mapping of existing variables included in the NSQIP database (see Table 1). A total score between zero and one was calculated by dividing the number of variables present (for functional status, partial or complete dependency = 1) by 11. Afterwards, 0.09 was categorized as "Pre-Frail", 0.18 as "Frail", and 0.27 and above as "Severely Frail", in line with previously established standards [26,29]. A modified frailty index (mFI-5) was derived according to the standard methodology described by Searle et al. [30], calculated using NSQIP variables [31]. Specifically, five factors within the NSQIP (functional dependence, diabetes, history of chronic obstructive pulmonary disease (COPD), history of congestive heart failure, and hypertension) map to the original Canadian Study of Health and Aging (CSHA) Frailty Index [27]. For every patient, each of these five factors (deficits) were coded as absent (0) or present (1). The mean score across all deficits was calculated, resulting in an index ranging from 0 (least frail) to 5 (most frail), with a score of

1 as "Pre-Frail", 2 as "Frail", and 3 or more as "Severely Frail" as categorical variables. ASA score was taken directly from the NSQIP database for each patient. The mCCI score was calculated according to previous methods mapped directly from the corresponding NSQIP variables [18], creating a score from 0 to 23 depending on the age and presence of defined co-morbidities.

#### *2.5. Outcomes*

Outcomes evaluated were 30-day mortality, unplanned readmission, unplanned reoperation, and major complication, as well as total hospital length of stay (LOS) and routine discharge (home). Major complication was a composite outcome of pneumonia, deep vein thrombosis (DVT), pulmonary embolism, myocardial infarction, cardiac arrest, wound infection or dehiscence, stroke, and sepsis.

#### *2.6. Statistical Analysis*

All statistical analyses were performed using Stata 16 (Stata Corp, College Station, TX, USA) with an a priori specified significance level of *p* = 0.05 (two-tailed). Descriptive statistics were by mean and standard deviation (SD) for continuous variables as well as count and percentage for categorical variables.

The effect of age, MFI-5, MFI-11, CCI, and ASA were each analyzed by univariate analysis using simple logistic regression for dichotomous outcomes or linear regression for continuous outcomes. Effect sizes were summarized by odds ratio (OR) (dichotomous outcomes) or beta coefficients (continuous outcomes) and associated 95% confidence intervals (95% CI). The independent effect of age and frailty on outcomes was further evaluated by multivariable regression. Again, for each outcome, a logistic or linear regression model was constructed that included both variables and additionally adjusted for sex, type of fusion, and number of levels as covariates. To weigh the relative importance of age versus frailty in predicting each outcome, standardized regression coefficients were calculated and their magnitudes directly compared. The margins of interaction of the final model of age (by decade) and frailty (continuous variable) were calculated for all adverse events to assess how the burden of frailty was affected by increasing age.

To compare the discriminative ability of age and the various indices of frailty, receiver operating characteristics (ROC) curve analysis was performed for each dichotomous outcome reported. This was done first using a base model that included the type of approach, number of operated levels and gender, and then with the addition of age and each index of Frailty, before comparing to the final multivariable model incorporating age, MFI-5, and the base model. The Kappa correlation coefficient was calculated to assess the discriminative ability of the MFI-5 to predict the categorical assessment of frailty compared to the MFI-11 assessment.

#### *2.7. Ethics Approval*

Institutional Review Board approval was not required for this study, which relied on de-identified data derived from a national administrative healthcare dataset.

#### **3. Results**

A total of 41,369 patients with the ICD-9/ICD-10 diagnostic code for DCM were identified from the NSQIP database. The mean age was 56.6 (56.5–56.7) years with a range of 18–90, and 46% of patients were female. The majority of patients were Caucasian, although ethnicity metrics were not captured in 9.84% of patients. Data on the surgical approach, based on validated CPT codes, was available for 34,287 patients. Anterior, posterior and combined anterior-posterior surgical approaches were all included; however, 79.86% of the patients underwent anterior surgery. Furthermore, the study included single and multi-level disease, but the majority of cases were single or two-level pathology (39.24% and 31.64% respectively). The ASA grade and mCCI scores were calculated in all patients, and the median was 3 and 2, respectively. MFI-11 was calculated for 11,758 patients with 39.55% and 37.47% in the "Not Frail" or "Pre-Frail" categories. MFI-5 scores were calculated for 41,140 patients, with 44.68% "Not Frail" and 36.03% "Pre-Frail". Complete descriptive statistics for all indices are listed in Table 3.

**Table 3.** Patient demographics and descriptive statistics.

MFI-5, MFI-11, Modified Frailty Index 5-point or 11-point; mCCI, Modified Charlson Co-morbidity Index; ASA, American Society of Anesthesiology Grade; 95% CI, 95% Confidence Interval.

#### *3.1. Univariate Analysis of Age and Frailty Indices on Outcomes*

Univariate analysis demonstrated that age, frailty (MFI-5 or MFI-11), ASA, and mCCI were significantly predictive of perioperative mortality, major complication, unplanned readmission, unplanned reoperation, length of hospital stay, and discharge to non-home destination (Table 4). The OR effect size of age increases by decade for mortality, major complication, length of stay, and discharge to non-home destination (see Table 5). Based on categorical analysis of frailty tiers, increasing frailty was significantly associated with increased risk of all adverse events, increased length of stay and non-home discharge. The effect size of the MFI-5 index on all outcomes was greater than the MFI-11. Categorical correlation between frailty tiers calculated by the MFI-11 and MFI-5 was strongly significant with a kappa coefficient of 0.96 (97.58% agreement) and a spearman rank correlation of 0.988 (*p* < 0.001).

#### *3.2. Multivariable Analysis Adjusting for Approach, Number of Levels Operated and Gender*

The results from the multivariable regression analysis (adjusting for sex, surgical approach, and number of operated levels) demonstrate that age and/or frailty (as measured by the mFI) both have significant effects on the outcomes of patient mortality, unplanned readmission, unplanned reoperation, major complication, length of stay, and discharge home (see Table 6). Both increasing age and higher frailty index score were significantly associated with an increased risk of mortality (*p* < 0.001), but the effect size (as demonstrated by the beta coefficient) was greater for frailty (0.53) as compared to age (0.30). The effect size of frailty on the risk of a major complication event and length of stay was also greater than age, but increased frailty and increased age demonstrated equivalent effect sizes on the chance of a routine home discharge (−0.30 vs. −0.28). Increased age appeared to have a greater influence on the risk of unplanned readmission (0.17 compared to 0.14), however, age was not found to have any significant influence on the risk of unplanned reoperation (0.03; *p* = 0.676) and the effect size for frailty was of a magnitude 5.6 times greater (0.17; *p* = 0.016). Similar to the univariate analysis, increasing frailty was associated with a significantly increased risk of all outcomes, with 'Severely Frail' patients demonstrating an effect size 4–5 times larger for some outcomes (mortality, major complication, unplanned reoperation).

ROC area under the curve (AUC) analysis demonstrated the discriminative ability of the base model could be improved across all outcomes with the addition of age or an index of frailty (See Table 7). MFI-5 and CCI appeared to provide the best discriminative ability when added to the base model compared to the other measures of frailty. However, the final multivariable model demonstrated superior discriminative ability for all outcomes above all of the individual frailty measures+base models tested with an AUC range from 0.76–0.84.

MFI-5, MFI-11, Modified Frailty Index 5-point or 11-point; mCCI, Modified Charlson Co-morbidity Index; ASA, American Society of Anesthesiology Grade; DVT, deep vein thrombosis; PE, Pulmonary Embolus; MI, Myocardial Infarction; CVA, Cerebrovascular Accident. \* indicates the result is statistically significant (*p* value < 0.05).

Correlation between frailty tiers calculated by the MFI-11 and MFI-5 was strongly significant with a kappa coefficient of 0.96 (97.58% agreement) and a spearman rank correlation of 0.988 (*p* < 0.001). † indicates that this decade was removed from analysis due to collinearity; \* indicates the result is statistically significant (*p* value < 0.05).

MFI-5, MFI-11, Modified Frailty Index 5-point or 11-point. mCCI, Modified Charlson Co-morbidity Index. ASA, American Society of Anesthesiology Grade; indicates the result is statistically significant (*p* value < 0.05).

MFI-5, MFI-11, Modified Frailty Index 5-point or 11-point; mCCI, Modified Charlson Co-morbidity Index; ASA, American Society of Anesthesiology Grade.

#### *J. Clin. Med.* **2020** , *9*, 3491

#### **4. Discussion**

As the burden of age-related degenerative spine conditions becomes an ever-greater public health priority, DCM has the potential to be a major cause of preventable neurological disability and poor quality of life across the world [4,8,16]. Decompressive surgery remains the only treatment proven to arrest or reverse the dysfunction caused by myelopathy and has a proven benefit in the elderly population [3,7,10,32]. The diagnosis of DCM and identification of suitable surgical candidates is therefore of paramount importance, and for this reason, identifying tools to aid risk stratification and predict potential outcomes after surgery is a major focus of clinical research [6,9,13,14].

The evidence for decompressive surgery to improve functional and quality of life impairment in DCM is strong [7,10,32]. Reports on the effect of age on the outcomes after DCM surgery have been variable, with many supporting the notion that increasing age is associated with negative clinical outcomes, whether increased complication rates or functional outcomes [12,13,15,33]. A recent ambispective study has demonstrated a clear and sustained benefit for surgery in DCM for both functional and quality of life outcomes in patients over the age of 70, albeit with an order of magnitude less than their younger surgery- and co-morbidity-matched cohort [3]. The suggested mechanism for this discrepancy has traditionally been the burden of age-related co-morbidities influencing clinical outcomes and reduction of physiological reserve, which has been manifested as measures of frailty or frailty indices in recent years. This hypothesis has been further substantiated with the correlation of worsening frailty to increased complication rate after spine surgery, and poorer recovery after spinal cord injury [28,34,35]. However, despite DCM being the most common indication for cervical spine surgery in North America, the effect of frailty on the outcomes after DCM surgery has not been investigated [16].

This study is one of the most comprehensive investigations of perioperative adverse events after surgery for DCM, and is the first to present a direct comparison of age and frailty indices. Concepts of frailty, although distinct from risk stratification, are increasingly incorporated in the pre-operative assessment as a superior and comprehensive alternative to age alone. Although it is no surprise that increasing age leads to an increased risk of adverse events, it appears the burden of frailty can have an effect up to 28 times the magnitude compared to age alone. On univariate analysis, increasing frailty (MFI-5/MFI-11) had the largest effect size for mortality, major complication and discharge to non-home destination. This effect remained in the multivariable model, but the effect size was largest for mortality and unplanned reoperation. These findings suggest that physiological reserve is much more of a driver of perioperative complications when compared to age alone. This is consistent with previous studies on spine surgical patients, but also other surgical domains [36,37]. The degree to which frailty appears to have an influence on unplanned reoperation rates has a sound pathophysiological basis. Given the usual indications for early reoperation are compressive hematoma, infection, and hardware failure, patients who have a higher mFI score are more likely to develop post-operative infections and a higher risk of osteopenia/osteoporosis.

Frailty significantly affected the risk of perioperative adverse events for patients of all ages, but the burden of frailty becomes greater with increased age. This effect is not linear, as demonstrated by the margins of interaction between age (by decade) and categorical level of frailty (see Figure 1). This effect (for readmission, reoperation, length of stay, and discharge to non-home destination) begins after the age of 60, which is in line with previously reported studies [32,34,35].

**Figure 1.** Predictive margins of the final multivariable model for each frailty level stratified per decade of age, for each outcome studied. Decades of age were removed if co-linearity was present. 95% CI, 95% Confidence Interval.

The mCCI proved a significant predictor of all adverse events on univariate and multivariable analysis, and the effect size remained similar for both. This may suggest that it could be a useful tool in the assessment of DCM patients. However, the role of the mCCI in multivariable modeling is unclear due to the inclusion of age-related modifiers. The mCCI incorporates increasing age as a contributor to the overall score, and therefore does not provide an age-independent measure of frailty. It cannot therefore be a definitive frailty assessment when incorporated into a multivariable model that includes age as a continuous variable. The ASA score also proved to be significantly predictive of adverse events on both univariable and multivariable analysis. However, the ASA score is notoriously subjective and its practical use for pre-operative adverse event prediction modeling has not been substantiated.

There was strong correlation between the MFI-11 and MFI-5 assessment of frailty tiers, which has been echoed in previous articles in other spine pathologies [28]. The effect size of the odds ratio or regression coefficients were larger when the MFI-5 was used compared to the MFI-11 for all dichotomous outcomes and length of hospital stay. This would suggest that to achieve an assessment of "Frail" or "Severely Frail" with the MFI-5 this would indicate a greater degree of frailty compared to the MFI-11 equivalent. This is strong evidence that the use of the MFI-5 is an effective determinant of frailty and further substantiates the MFI-5 as the standard of choice for frailty assessment for DCM patients. This has important implications for the use of MFI-5 in clinical practice and for future studies into the effect of frailty in adult spine surgery.

There are limitations to the current study. The NSQIP database carries metrics regarding peri-operative events, but no long term follow up or outcome measures are included. This restricts the analysis to short term follow up only, and therefore long-term outcomes cannot be extrapolated. However, the validity of short-term complication rates and their use for pre-operative decision-making in spine surgery is well published. In a similar vein, there is no measure of baseline functional impairment and therefore there is no way to eliminate the effect of myelopathy severity on the surgical approach, or other covariates applied to the regression model. Pre-operative neurological function is a key predictor of the functional outcomes of DCM surgery, however its relationship to perioperative adverse events and mortality is less clear. It is known that myelopathy patients have increased perioperative complications compared to radiculopathy [26], but there is a paucity of evidence of the effect of functional impairment on perioperative outcomes in DCM.

There was an observed difference in the number of patients that were able to have the MFI-11 calculated (*n* = 11,758) compared to the MFI-5 (*n* = 41,140). This difference arose arbitrarily due to a

reduction in the demographic information collected by NSQIP from 2015 onwards. This difference in numbers has the potential to skew the effects and effect size of the results presented. The authors argue that given the categorical correlation of frailty was excellent between MFI-5 and MFI-11 (97.58% agreement), the large size of the cohorts, the strength of the a priori statistical frameworks and the levels of significance observed, the risk of statistical inaccuracy is low.

The study is a retrospective analysis of prospectively collected nationwide hospital inpatient registry data. As such, it lacks the protection from confounders and bias from a true prospectively-collected data set. However, uniformity across the data collection and homogeneity amongst the selected cohort does reduce the impact of any latent confounding. The cohort selection relied on ICD-9 & 10 diagnostic codes, and therefore the potential risk of not capturing patients if they were inappropriately coded is present. Patients were removed from the final analysis if no reliable CPT code data could identify the surgical approach or number of levels, which led to a reduction in the overall number of patients in the multivariable model. It is unlikely that these occurrences have affected the findings of the study given the levels of significance seen on univariable and multivariable analysis.

The authors note that DCM carries a significant heterogeneity in presenting symptoms ranging from mild sensory disturbance in the fingers through to gait instability and eventual quadriparesis. Traditional measures of frailty, in particular those based on 5- or 11-point scales as used in this study, may not be as accurate when compared to other pathologies not affecting gait or upper limb function. Therefore, developing more appropriate indices of frailty specific to DCM should be a future research priority. Also, the authors wish to state that the purpose of this study is not to prove patients who have an increased frailty score should not be offered surgical management. In contrast, this study should be used to provide further clarification of the factors that go into informed decision-making, which should be a shared process between the patient and clinician. The concept that frailty could potentially be viewed as a modifiable risk factor is also emerging, however evidence that improving frailty index scores prior to planned spine surgery to reduce perioperative complications is not conclusive at this stage [38].

#### **5. Conclusions**

Increasing frailty appears to have a greater influence on the risk of perioperative mortality, risk of major complication, unplanned readmission, unplanned reoperation, and longer duration of hospital stay when directly compared to age alone for patients undergoing surgery for DCM. The MFI-5 is a robust predictor of adverse outcomes after DCM surgery and is equivalent to the traditional MFI-11 when categorizing patients as 'Pre-Frail', 'Frail', or 'Severely Frail.' Multivariable models incorporating MFI-5 with age, approach, number of levels, and gender provide an accurate and reliable method of predicting outcomes from DCM surgery. Future work should focus on how to delineate the association of frailty with long term functional and quality of life outcomes after DCM surgery.

**Author Contributions:** Conceptualization, J.R.F.W., J.H.B., J.R.W., A.Y. and M.G.F.; methodology, J.R.F.W., J.H.B. and A.M.; formal analysis, J.R.F.W., J.H.B., A.M. and M.G.F.; investigation, J.R.F.W., J.H.B. and A.M.; writing—Original draft, J.R.F.W. and J.H.B.; writing—Review and editing, J.R.W., A.Y. and M.G.F.; supervision and administration, J.R.W., A.Y. and M.G.F. All authors have read and agreed to the published version of the manuscript.

**Funding:** This research received no external funding.

**Acknowledgments:** J.R.F.W. is the recipient of an award from the Neurosurgery Research and Education Fund (NREF) of the American Association of Neurological Surgeons (AANS). M.G.F. acknowledges support from the Gerry and Tootsie Halbert Chair in Neural Repair and Regeneration and the DeZwirek Family Foundation. This work has been produced with patient information from the National Safety Quality Improvement Program (NSQIP) organization and contributing members.

**Conflicts of Interest:** The authors declare no conflict of interest.

#### **References**

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## *Review* **The Role of Magnetic Resonance Imaging to Inform Clinical Decision-Making in Acute Spinal Cord Injury: A Systematic Review and Meta-Analysis**

**Arash Ghaffari-Rafi 1,2, Catherine Peterson 1, Jose E. Leon-Rojas 3,4, Nobuaki Tadokoro 5, Stefan F. Lange 6, Mayank Kaushal 7, Lindsay Tetreault 8, Michael G. Fehlings 8 and Allan R. Martin 1,8,\***

	- Quito 170411, Ecuador<EMAIL_ADDRESS>	- 4 Queen Square Institute of Neurology, University College London, London WC1N 3BG, UK
	- 5 Department of Orthopaedic Surgery, Kochi University, Nankoku 783-0000, Japan<EMAIL_ADDRESS>	- 6 Department of Neurosurgery, University Medical Centre Groningen, 9713 GZ Groningen, The Netherlands<EMAIL_ADDRESS>	- 7 Department of Neurosurgery, Medical College of Wisconsin, Milwaukee, WI 53226, USA<EMAIL_ADDRESS>	- 8 Department of Neurosurgery, Toronto Western Hospital, University of Toronto, Toronto, ON M5T 2S8, Canada<EMAIL_ADDRESS>(L.T<EMAIL_ADDRESS>(M.G.F.)
	- **\*** Correspondence<EMAIL_ADDRESS>
**Abstract:** The clinical indications and added value of obtaining MRI in the acute phase of spinal cord injury (SCI) remain controversial. This review aims to critically evaluate evidence regarding the role of MRI to influence decision-making and outcomes in acute SCI. A systematic review and meta-analysis were performed according to PRISMA methodology to identify studies that address six key questions (KQs) regarding diagnostic accuracy, frequency of abnormal findings, frequency of altered decision-making, optimal timing, and differences in outcomes related to obtaining an MRI in acute SCI. A total of 32 studies were identified that addressed one or more KQs. MRI showed no adverse events in 156 patients (five studies) and frequently identified cord compression (70%, 12 studies), disc herniation (43%, 16 studies), ligamentous injury (39%, 13 studies), and epidural hematoma (10%, two studies), with good diagnostic accuracy (seven comparative studies) except for fracture detection. MRI findings often altered management, including timing of surgery (78%, three studies), decision to operate (36%, 15 studies), and surgical approach (29%, nine studies). MRI may also be useful to determine the need for instrumentation (100%, one study), which levels to decompress (100%, one study), and if reoperation is needed (34%, two studies). The available literature consistently concluded that MRI was useful prior to surgical treatment (13 studies) and after surgery to assess decompression (two studies), but utility before/after closed reduction of cervical dislocations was unclear (three studies). One study showed improved outcomes with an MRI-based protocol but had a high risk of bias. Heterogeneity was high for most findings (I2 > 0.75). MRI is safe and frequently identifies findings alter clinical management in acute SCI, although direct evidence of its impact on outcomes is lacking. MRI should be performed before and after surgery, when feasible, to facilitate improved clinical decision-making. However, further research is needed to determine its optimal timing, effect on outcomes, cost-effectiveness, and utility before and after closed reduction.

**Keywords:** spinal cord injury; SCI; spine trauma; magnetic resonance imaging; MRI

**Citation:** Ghaffari-Rafi, A.; Peterson, C.; Leon-Rojas, J.E.; Tadokoro, N.; Lange, S.F.; Kaushal, M.; Tetreault, L.; Fehlings, M.G.; Martin, A.R. The Role of Magnetic Resonance Imaging to Inform Clinical Decision-Making in Acute Spinal Cord Injury: A Systematic Review and Meta-Analysis. *J. Clin. Med.* **2021**, *10*, 4948. https://doi.org/10.3390/ jcm10214948

Academic Editor: Maria A. Poca

Received: 25 August 2021 Accepted: 15 October 2021 Published: 26 October 2021

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**Copyright:** © 2021 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https:// creativecommons.org/licenses/by/ 4.0/).

#### **1. Introduction**

Traumatic injury to the spine is common and can have devastating consequences when resulting in spinal cord injury (SCI). Acute SCI has an estimated incidence of 750 cases per million annually, often affecting younger individuals and resulting in a substantial impact upon families and society [1]. Evidence-based management of SCI is primarily focused on the acute period, including careful immobilization and transport, avoidance of hypotension and hypoxia, and early surgical decompression [2–5].

Imaging plays a critical role in the initial evaluation of spinal trauma, and computed tomography (CT) has largely supplanted radiography in modern clinical algorithms [6]. CT is widely available and can quickly screen trauma patients for numerous injuries (head, spine, thorax, and abdomen), but the visualization of the spinal soft tissues is poor, including the spinal cord, intervertebral discs, and ligaments. In contrast, magnetic resonance imaging (MRI) provides detailed views of these structures, allowing detection of spinal cord compression, acute disc herniation, ligamentous injury, and epidural hemorrhage. However, MRI has not been widely incorporated into trauma protocols due to concerns over safety, availability, inconvenience, cost, time required, and the argument that MRI findings rarely change clinical decision-making. Surprisingly, in spite of numerous manuscripts investigating MRI in spinal trauma and SCI, high-quality studies that compare clinical decision-making with and without MRI are lacking [6–8]. The American Association of Neurological Surgeons (AANS) and Congress of Neurological Surgeons (CNS) published guidelines for acute cervical spine trauma and SCI in 2002 and updated these in 2013, but offered limited recommendations regarding the use of MRI beyond its utility for cervical collar clearance—no recommendations on the use of MRI in adult patients with SCI were offered [6]. A systematic review performed by Bozzo et al. (2011) [8] took a broader approach in evaluating the clinical utility of MRI, by considering various indirect lines of evidence; based on low-quality evidence, the authors offered a weak recommendation that MRI be performed in all patients with SCI when feasible, to direct management [8]. More recently, a multi-disciplinary group sponsored by AOSpine, AANS/CNS, and Ontario Neurotrauma Foundation developed clinical practice guidelines (CPGs) on five controversial topics in SCI that included a similarly weak recommendation based on very weak evidence that MRI should be used when feasible, to guide clinical decision-making in SCI [9]. However, this CPG was primarily based on expert opinion, as the systematic review that formed its evidentiary basis found only one study that examined MRI for clinical decision-making, and it had a high risk of bias due to methodological issues [7,10]. Overall, the efforts to synthesize the evidence have not provided sufficient guidance on the routine use of MRI in acute SCI; as a result, clinical practice among spinal surgeons and other clinicians remains highly variable.

The overarching aim of this review was to determine if performing an MRI in the acute phase of SCI yields useful clinical information, leading to improvements in patient care and outcomes. However, in view of previous reviews that revealed the paucity of literature directly addressing this question, we aimed to perform a more inclusive review seeking indirect evidence that answers the key questions (KQs) listed in Table 1. Hence, our review aims to synthesize the available direct and indirect evidence regarding the utility of MRI, to guide decision-making in the acute phase of SCI.

#### **Table 1.** Key Questions of Systematic Review.

#### **2. Materials and Methods**

The systematic review was designed in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) and the Cochrane Handbook of Systematic Reviews of Interventions [11–13].

Only studies with human subjects published in the English language were included, with the search confined to randomized controlled trials (RCTs), cohort studies, case series, and case-control studies. Reviews, opinion articles, case reports, and case series with less than ten patients were excluded. A summary of the study's design in PICO format (population, intervention, comparison, outcome), including inclusion and exclusion criteria, is found in Table 2. Studies of interest were those that included adults (16 years or older) with SCI in the acute phase (within 7 days of injury). Relevant studies that also included a small proportion of pediatric patients (<20%) were allowed after consideration by the authors, but were marked with an asterisk (\*) in all tables. Relevant studies were required to utilize MRI in the acute phase (within 7 days) for the purpose of clinical decision-making (Table 1). Investigations that only examined the role of MRI for prognostication were excluded. The outcomes of interest were selected a priori based on previous studies, and are specified as KQs 1–6 listed in Table 1.

For KQ1, studies were only included if they calculated the diagnostic accuracy of MRI in reference to a gold standard measure (e.g., intraoperative findings) for the detection of specific pathological entities (spinal cord compression, disc herniation, ligamentous injury, epidural hematoma, fracture, or a spinal cord lesion/edema/contusion in the context of SCI without radiologic abnormality [SCIWORA]). For KQ2, studies were included that simply reported the frequency of abnormal MRI findings among the entities included in KQ1. For KQ3, studies were included if they examined how often obtaining an MRI alters clinical decision-making in SCI, including if surgery is required, when to operate, surgical approach, the need for instrumentation, which levels to decompress, or the need

for reoperation after surgery. Comparative studies were also included that evaluated differences in decision-making between groups that did and did not undergo MRI. For KQ4, studies were included that reported data on the optimal timing of MRI in acute SCI, including before or after closed reduction, before or after surgery, within a certain time period, or studies that compared differences in timing of MRI between groups. Regarding KQ5, studies that reported the frequency of adverse events when performing MRI in SCI were included. Finally, for KQ6, comparative studies were included that evaluated differences in outcomes (neurological, functional, health-related quality of life) between patients that received an MRI versus those that did not.

**Table 2.** PICO Summary of Inclusion and Exclusion Criteria.

Medical subheadings (MeSH) and text words related to acute spinal cord injury and magnetic resonance imaging were utilized for the search strategy. Medline, Embase, and Cochrane Central Register for Controlled Trials (CENTRAL, Wiley interface) were searched. A first search was performed between 1 January 1980 to 30 April 2016. The project was subsequently postponed, and a second search from 1 January 2016 to 26 August 2020 was completed with some overlap in dates to ensure no relevant studies were missed. The starting year of 1980 for the search was based on the timing of the first clinical MRI manuscripts being published in the 1980s [14]. In relevant literature and reviews, references were manually searched for additional studies, while use of Embase ensured gray literature was also screened. Other than dates, no database search limitations were utilized. The Appendix A provides the search protocols, including keywords. Specific search strategies were developed under guidance of library/information scientists with expertise in systemic review searches. Search results were imported to EndNote (Clarivate Analytics, Philadelphia, PA, USA) for the first search and Covidence (Covidence A/S, Melbourne, Australia) for the second search, to reduce data entry errors and bias (i.e., deduplicating references). All investigation reports were assessed for inconsistencies (e.g., design description, outcome presentation, total patients analyzed).

Two authors independently screened all titles and abstracts based on the eligibility criteria. Two authors reviewed each manuscript in full-text for inclusion, to assess eligibility for final inclusion and data extraction. Any discordances between reviewers during the abstract screening, full-text screening, or data-extraction phases were resolved with discussion and review by a third author. In compliance with recommendations from the Cochrane Handbook for Systematic Reviews of Interventions, the following data were compiled into a Microsoft Excel spreadsheet: author, publication year, journal citation, setting, inclusion and exclusion criteria, study design, study population, KQs addressed, and outcomes.

Data were placed into tables stratified by the KQ, enabling qualitative assessment. For simplicity, studied populations were categorized as SCIWORA when CT or radiographs showed no evidence of traumatic injury; otherwise, they were labeled as SCI (i.e., including cases with fracture or malalignment). For quantitative outcome data that were similarly reported across studies and their populations, a meta-analysis was conducted to calculate pooled results. In these cases, a chi-squared test for heterogeneity was performed and the I 2 statistic was calculated. Analysis was conducted using R v4.0.2 Statistical Software (R Foundation for Statistical Computing, Vienna, Austria) [15].

Two authors independently performed risk of bias assessment according to the National Institutes of Health (NIH) Quality Assessment Tool [16]. Studies appraised as good had minimally low risk of bias, studies appraised as fair had moderately low risk of bias, and those appraised as poor had high risk of bias.

#### **3. Results**

The two electronic database searches yielded a total of 21,323 unique citations (Figure 1). After title and abstract review, 268 manuscripts were selected. Following full-text review, 32 studies were identified that met eligibility criteria and were included in the qualitative synthesis in the form of Tables 3–8. Three studies were prospective, while the remainder were retrospective case series, cohort studies, or case-control studies (Table 9). Risk of bias assessment found a high risk of bias in two studies, moderately low in 17, and minimally low in 13 (Table 9).

**Figure 1.** Frequency of ligamentous injury on MRI in patients with acute spinal cord injury. \* Studies that include pediatric patients (<16) or unspecified age range. \*\* Studies with overlapping cohorts.

**Table 3.** *Cont.*

unspecified age range. \*\* Studies with overlapping cohorts.

*J. Clin. Med.* **2021**, *10*, 4948

cohort with Krappinger et al., 2019.

 **5.** Key Question 3: How often does obtaining an MRI alter clinical decision-making in acute

 SCI.

**Table**

**Table 5.** *Cont.*

cohort with

Papadopoulos

 et al., 2002.

**Table 6.** Key Question 4: When should MRI be performed in acute spinal cord

 injury?

*J. Clin. Med.* **2021**, *10*, 4948

**Table 6.** *Cont.* \* Studies that include pediatric patients (<16) or unspecified age range. \*\* Studies with overlapping cohorts.

cohort with

Papadopoulos

 et al., 2002.

**Table 9.** Risk of bias assessment. Studies arranged alphabetically by the last name of the first author. Risk of bias assessment was performed according to the National Institutes of Health (NIH) Quality Assessment Tool. Studies appraised as good had minimally low risk of bias, studies appraised as fair had moderately low risk of bias, and those appraised as poor had high risk of bias.

#### *3.1. KQ1: Diagnostic Accuracy of MRI*

Seven studies involving SCI were identified that addressed KQ1 (Table 3) [17–23]. Five studies calculated the diagnostic accuracy of MRI in relation to intraoperative findings [17–19,22,23], one compared against flexion/extension radiographs [20], and one against CT myelography [21]. Two studies with overlapping cohorts focused on hyperextension injuries and central cord syndrome [17,18]; both studies investigated detection of ALL injury, demonstrating superior sensitivity of STIR over T2-weighted (T2w) images (88% vs. 61%) [18] and a specialized MRI radiologist over a general radiologist (86% vs. 68%) [17]. In addition, one study also reported improved sensitivity of STIR over T2w images (82% vs. 61%) to identify intervertebral disc injury/herniation [18]. Two studies found 2 and 5 cases, respectively, of acute disc herniation on MRI that were verified by intraoperative findings [22,23]. Another study investigated the diagnostic accuracy of T2w images to detect intramedullary hemorrhage/contusion/edema in patients with SCIWORA compared with direct visualization of the spinal cord, reporting a sensitivity of 100% [19]. One study compared MRI against flexion/extension radiographs for segmental

instability [20]; the MRI finding of ALL injury was present in 23/28 patients with instability (sensitivity: 0.82) and absent in 39/60 patients without instability (specificity: 0.65), while the finding of disc injury was present in 18/28 patients with instability (sensitivity: 0.64) and absent in 41/60 patients without instability (specificity: 0.68). One study found that MRI had only 40% (2/5) sensitivity to detect fracture, but 100% specificity (14/14) compared with CT myelography [21]. Meta-analysis was not possible for KQ1 findings due to the limited data available.

#### *3.2. KQ2: Frequency of Abnormal Findings*

Overall, 28 studies relevant to KQ2 were identified, reporting the frequency of certain pathological MRI findings in various types of SCI (Table 4) [17–21,23–45].

#### 3.2.1. Ligamentous Injury

Thirteen studies provided data on the frequency of ligamentous injury, all in patients with cervical SCI [17,18,20,24–29,34,37,41,43]. Among these studies, nine focused on patients with SCIWORA, in which the frequency of ligamentous injury ranged from 0 to 100% [20,24–28,34,37,41]. The pooled frequency of ligamentous injury in SCIWORA was 36% (145/404 across eight studies excluding [18] due to overlapping cohort with [17]), but heterogeneity across studies was high (I2 = 0.94, *p* < 0.001). Similarly, the pooled frequency of ligamentous injury was 39% in all patients with SCI (190/483 across 12 studies), with high heterogeneity (I2 = 0.93, *p* < 0.001; Figure 1).

#### 3.2.2. Disc Injury/Herniation

Sixteen studies provided data on the frequency of disc herniation and/or injury in SCI, including 15 in cervical injuries and one including all spinal levels [20,21,23,25–28,30–33,37,41–44]. The rate of disc injury ranged from 4% to 42% in studies involving cervical SCIWORA, whereas it was 40% to 88% in other SCI studies [20,21,23,25–28,30–33,37,41–44]. Disc herniation was present in 37% to 100% of patients with SCIWORA, whereas it was present in 24% to 100% in SCI [20,21,23,25–28,30–33,37,41–44]. Disc herniation causing cord compression varied from 3% to 83% in two studies involving SCI [23,30]. In SCIWORA, the aggregate rate of disc injury was 20% (46/230), while disc herniation was more frequent at 45% (102/229); both results showed high heterogeneity across studies (I2 = 0.96, 0.84, respectively, both *p* < 0.001). The pooled frequency of disc injury, disc herniation, and disc herniation causing cord compression across all studies (SCIWORA and SCI) was 26% (71/278), 43% (159/370), and 16% (12/74), respectively, while heterogeneity was high for all analyses (I2 = 0.95, 0.83, and 0.98, respectively, all *p* < 0.001; Figure 2).

**Figure 2.** Frequency of disc injury or herniation on MRI in patients with acute spinal cord injury. \* Studies that include pediatric patients (<16) or unspecified age range.

#### 3.2.3. Cord Compression

Twelve studies reported the frequency of ongoing spinal cord compression in SCI, including nine that included only cervical injuries, two that had sub-axial injuries (C3-T1), and one that included all levels [23–25,29–31,33,34,38,39,41,44]. A cohort examining subaxial SCI found cord compression frequency at 89% (63/71) with a T1w sagittal sequence, but 92% (65/71) with T2w sagittal and 96% (68/71) when either result was positive [38]. In SCIWORA, cord compression was identified in 0% to 100% of patients in five studies [24,25,33,34,41]. In two studies involving cervical dislocations, cord compression was noted in 65% to 83% [30,31]. For fracture-dislocation patients, cord compression frequency was 65% (11/17) pre-traction, but 12% (2/17) post-traction according to one study [31]. The pooled frequency of cord compression across studies in patients with SCIWORA was 41% (47/116), whereas it was 70% (413/589) among all cases of SCI; heterogeneity across studies was high in both groups (I2 = 0.94, 0.95, respectively, both *p* < 0.001; Figure 3).

**Figure 3.** Frequency of cord compression on MRI in patients with acute spinal cord injury. \* Studies that include pediatric patients (<16) or unspecified age range.

#### 3.2.4. Epidural Hematoma

Three investigations in cervical SCI reported epidural hematoma in 3% to 27% of patients, resulting in a pooled frequency of 10% (20/198) [26,39,44]; the results showed high heterogeneity (I2 = 0.92, *p* < 0.001; Figure 4).

#### 3.2.5. Fracture

Two small studies provided data on the frequency of identifying fractures in patients with SCI, with a range of 10% to 20% and a pooled frequency of 15% (6/41) [21,39]; the results were homogeneous across these two studies, with I2 = 0, *p* = 0.61 (Figure 4).

#### 3.2.6. Intramedullary Lesions in SCIWORA

Thirteen studies provided data on the frequency of intramedullary signal change in patients with SCIWORA, including 336 cervical injuries and 44 thoracic injuries [19,24,32–38,40–42,45]. The pooled frequency of simple edema was 40% (74/187), while the rate of any intramedullary lesion (including edema, contusion, hemorrhage, or cavitation) was 77% (291/380) [19,24,32–38,40–42,45]; heterogeneity between studies was high (I2 = 0.90, 0.91 respectively, both *p* < 0.001; Figure 4).

**Figure 4.** Frequency of Epidural Hemorrhage, Fracture, and Intramedullary Lesions (SCIWORA) on MRI in patients with acute spinal cord injury. \* Studies that include pediatric patients (<16) or unspecified age range.

#### *3.3. KQ3: Influence of MRI on Clinical Decision-Making*

Twenty studies provided data relevant to KQ3, regarding if surgery is required, surgical approach, when to operate, determining the need for instrumentation, which levels to decompress, and the need for reoperation after surgery, based upon MRI findings in acute SCI (Table 5) [10,17,21–24,26,28–33,37,40,42,44–47].

#### 3.3.1. If Surgery Is Required

Fifteen studies reported that MRI results directly influenced the decision of whether surgery was required in acute SCI [10,21–24,26,30,32,33,37,40,42,44–46]. Specific MRI findings that reportedly led to the decision for surgical treatment included cord compression, disc herniation, ligamentous injury, instability, and intramedullary edema (in conjunction with cord compression in SCIWORA). The frequency of MRI results reportedly leading to a decision to operate ranged from 3% to 100% across studies, with a pooled average of 36% (223/611) and high heterogeneity across studies (I2 = 0.96, *p* < 0.001).

#### 3.3.2. Surgical Approach

Nine studies reported on theinfluence ofMRI findings on surgical approach[21,23,28–30,33,37,42,44]. Seven studies cited acute disc herniations with cord compression as the rationale for performing anterior surgery, at a rate of 3% to 83% of cases across studies [21,23,30,33,37,42,44]. Two additional studies of SCIWORA noted that MRI dictated surgical approach in all patients requiring surgery (42/211 and 70/70 patients, respectively), listing anterior compression, anterior compression limited to 1–3 segments, and kyphosis as reasons for selecting anterior surgery [28,29]. Overall, MRI was reported to affect the surgical approach in 29% (143/500) of patients in the included studies, with high heterogeneity (I2 = 0.97, *p* < 0.001).

#### 3.3.3. When to Operate

Three investigations examined the role of MRI in determining when to operate [10,31,44]. In two studies with overlapping datasets, 49% to 52% of patients required emergent surgery due to MRI-documented cord compression [10,44]. Two studies found that after traction/closed reduction, 33% to 82% of patients had good decompression and could undergo delayed surgery to perform definitive fixation [10,31]. Meta-analysis found that MRI affected surgical timing in 78% (65/83) of patients, with high heterogeneity (I2 = 0.84, *p* = 0.01).

#### 3.3.4. Need for Instrumentation

One study reported on the need for instrumented fusion due to the finding of segmental instability [17]. This study reported that the level of injury in SCIWORA (showing edema on MRI) and any levels showing ligamentous injury on MRI (19/23 patients) or segmental instability intraoperatively (22/23 patients) would be decompressed and fused.

#### 3.3.5. Which Levels to Decompress

A single study reported that MRI findings of edema and ligamentous injury, and intraoperative findings of instability, dictated which level(s) would be decompressed and fused [17].

#### 3.3.6. Need for Re-Operation after Surgery

Two studies reported the use of post-operative MRI to determine if adequate cord compression had been achieved after SCI [29,47]. One study found that 11/28 patients undergoing anterior surgery had residual cord compression, and this finding led to additional posterior surgical decompression [29]. Another study found that 63/184 patients had inadequate decompression following surgery for acute SCI, highlighting the role of cord swelling and the possible need for multi-level laminectomy and expansile duraplasty [47].

#### *3.4. KQ4: When to Perform MRI*

Sixteen studies provided data addressing KQ4 (Table 6) [10,22–24,26,28–33,43–47]. Fourteen studies concluded that MRI was useful during the initial assessment for the purpose of decision-making (related to one or more aspects of KQ3) [10,22–24,26,28–30,32,33,44–47]. However, two studies found that MRI prior to closed reduction of cervical facet dislocation was of unclear utility, with one study finding that two patients with pre-reduction disc herniation did not deteriorate after closed reduction [43], while another study similarly reported that 11 patients with pre-reduction cord compression did not deteriorate during closed reduction [31]. In contrast, Selden et al. found acute disc herniation in 10/18 patients with cervical dislocations, prompting a decision for immediate anterior surgery as the authors felt that closed reduction was unsafe [44]. Furthermore, Doran et al. reported neurological complications in three patients undergoing closed reduction of cervical dislocations that did not have pre-reduction MRI, and subsequent MRI showed disc herniations in all cases [30]. Three studies yielded data on MRI after closed-reduction, with two finding that it was helpful to identify ongoing spinal cord compression [31,44], whereas the third study found no neurological deterioration in spite of disc herniations in five of nine patients [43]. Two studies with overlapping cohorts reported that post-operative MRI was useful to identify inadequate decompression of the cord for consideration of re-operation [29,47]. No studies specifically recommended MRI within a set time period, but one study found no difference in the time interval from injury to pre-operative MRI between patients that were completely and incompletely decompressed [47].

#### *3.5. KQ5: Frequency of Adverse Events When Performing MRI*

Five investigations reported on frequency of adverse events when performing an MRI in patients with acute SCI (Table 7) [10,22,23,31,44]. Bao et al. examined patients receiving neutral, flexion, and extension MRIs for cervical SCI without fracture and dislocation, and amongst the cohort of 16 patients found no deterioration of neurological functions [22]. Similarly, when closed reduction for cervical dislocation was performed during MRI, no patients (*n* = 12) experienced permanent neurological deterioration or burning sensations at pin sites [31]. Pooled results found a 0% rate of adverse events (0/156 patients, 95% CI: 0% to 2.4%), with homogeneity across studies (I2 = 0, *p* = 1).

#### *3.6. KQ6: Effect of MRI on Outcomes*

One investigation addressed KQ6, evaluating differences in outcome between 66 patients assigned to an MRI-based treatment protocol (including urgent surgery) and 25 who were not assigned (due to a "contraindication to MRI, the need for an emergent surgical procedure, or the bias of specific admitting attending neurosurgeons regarding the 'futility' of emergent surgical treatment") [10]. In patients assigned to the protocol group, Frankel grade improved from admission in 50%, relative to 24% in the non-protocol group (*p* < 0.006). Furthermore, eight of 50 patients from the protocol group presenting with complete motor quadriplegia (grade A or B) improved to independent ambulation (grade D or E), compared with none of the 20 reference patients (*p* = 0.09, Fisher exact test, not reported in original manuscript). MRI protocol patients also had shorter ICU stay (9.9 ± 1.7 days vs. 23.8 ± 3.7 days, *p* < 0.001) and total length of stay (71.4 ± 5.9 days vs. 99.9 ± 13.1 days, *p* = 0.02) [10]. Unfortunately, this study was deemed to have a high risk of bias due to non-random assignment to treatment groups and the confounding effect of more urgent spinal cord decompression in the protocol group compared with the reference group.

#### **4. Discussion**

This systematic review and meta-analysis addressed the role of MRI to inform clinical decision-making for patients with acute SCI, offering several lines of evidence supporting its use in routine practice. First, obtaining an MRI in the acute phase of SCI appears to be safe, with no adverse events reported in greater than 150 patients across five studies. This finding confirms the safety of obtaining an MRI in acute SCI, in spite of limited monitoring, additional transfers, and positioning the patient flat and supine for 30 to 45 min. MRI also demonstrates good diagnostic accuracy for ligamentous injury, instability, disc injury, disc herniation, and intramedullary tissue changes, albeit in a small number of comparative studies. Despite substantial heterogeneity between manuscripts, it is clear based on the large number of subjects and studies included in this meta-analysis that MRI frequently identified important pathological findings in patients with SCI, including spinal cord compression in 70%, disc herniation in 43%, ligamentous injury in 39%, and epidural hematoma in 10%. In patients with SCIWORA, MRI demonstrated intramedullary signal change in 77%, disc herniation in 45%, cord compression in 41%, and ligamentous injury in 36%. In contrast, evidence for the utility of MRI in detecting fractures in acute SCI was limited, with a low frequency of positive findings (15%) and poor diagnostic accuracy.

In terms of clinical decision-making, a large number of studies were identified that consistently reported evidence of clinical utility, influencing the decision to operate in 36% of patients, surgical approach in 29%, and the timing of surgery in 78%. Limited evidence also suggested that MRI is useful to determine the need for instrumentation, which levels to decompress, and if re-operation is needed for inadequate decompression. In terms of timing of MRI, most studies concluded that MRI should be performed on initial evaluation, prior to surgery. However, in cases of cervical dislocations, the utility of MRI prior to and after closed reduction remained unclear, due to conflicting results between studies regarding both the frequency and clinical significance of disc herniations; some reports suggest that MRI may be useful to avoid secondary injury due to a large disc herniation, but this area requires further study to draw conclusions. Finally, the results of this review confirm that evidence is lacking to directly show if obtaining an MRI improves outcomes; the only study addressing this topic had a high risk of bias due to non-randomized selection and a confounding effect of earlier spinal cord decompression in patients in the MRI-protocol group. Overall, the body of literature offers moderate evidence

that (1) MRI is safe in the acute phase of SCI, (2) MRI has good diagnostic accuracy to detect certain features that are potentially useful for decision-making, (3) these features occur frequently, (4) these features often affect clinical decision-making, and (5) MRI should be performed prior to surgical treatment, whenever possible. However, further studies that investigate management decisions and clinical outcomes with and without MRI, the role of MRI in cervical dislocations, the time delay incurred by obtaining an MRI, and the cost-effectiveness of MRI are required to fully define its utility in acute SCI.

The novelty of the current study is that the review was broadly inclusive, looking for both direct and indirect evidence, while focusing narrowly on the topic of the role of MRI to facilitate clinical decision-making in patients with acute SCI. This review involved a comprehensive search of the literature that considered a large number of citations and fulltext articles, and was designed to directly answer a common question that faces surgeons when a patient presents with acute SCI: should I get an MRI first, or just proceed directly to the operating room? The 2002 and 2013 AANS/CNS guidelines for the management of SCI also attempted to address the utility of MRI, but circumvented the main topic with only peripheral recommendations that MRI should be used in pediatric patients to assess SCI, or in adults for collar clearance, for the diagnosis of vertebral artery injury, or to assess patients with ankylosing spondylitis or SCIWORA [6]. Subsequently, AOSpine sponsored an effort to develop five guidelines for controversial topics in SCI, including one on the role of MRI in acute SCI, which provided a weak recommendation that MRI should be used in acute SCI to facilitate improved decision-making and prognostication [9]. These recommendations were based on a systematic review by Kurpad et al. (2017), which was unfortunately hampered by restrictive inclusion criteria yielding only one relevant study (which was deemed to have a high risk of bias) regarding the utility of MRI to guide acute SCI management, thus resulting in a vacuum of relevant evidence [7]. Conversely, Bozzo et al. (2011) utilized liberal inclusion criteria, involving the broader population of all spinal trauma, but was less focused and potentially lacked external validity. Furthermore, the review did not explore how individual studies reported changes in management based on MRI results, nor did it explore the importance of MRI in detection of spinal cord compression, which was the most common entity cited in the current review to affect management. In addition, the vast majority of studies included in both Bozzo et al. (2011) and Kurpad et al. (2017) investigated the use of MRI for prognostication, which we feel is of secondary importance, compared to the imperative task of deciding upon and planning surgical treatment. As a result, a knowledge gap currently exists regarding the optimal use of MRI, with highly variable practice patterns between surgeons. In summary, this systematic review provides a focused synthesis of the literature that clarifies the utility of MRI, while highlighting several areas that require further investigation.

SCI is an inherently difficult condition to study, due to profound heterogeneity in demographics, patterns of injury, timing after injury, neurological presentation, biomechanical stability, comorbidities, concomitant injuries, treatments performed, outcome measures, and MRI methods. The current study performed meta-analyses that clearly reflected this heterogeneity, providing aggregate results that may be helpful to provide general insights, but must be interpreted with caution as the frequency of findings varied with several factors. Complicating matters, the literature uses inconsistent definitions of terms such as SCIWORA, which was originally described in the pediatric population based on radiographs, but has increasingly been used to describe adult SCI without CT evidence of trauma (sometimes dubbed SCIWOCTET). Adult SCIWORA is widely felt to be considerably different than pediatric SCIWORA, with the former frequently involving degenerative spondylosis, ossification of posterior longitudinal ligament, and disc herniations, whereas the latter typically involves ligamentous laxity; therefore, it was not surprising that the SCIWORA results presented in this study also showed high heterogeneity. Furthermore, patients presenting with acute SCI frequently have concomitant injuries, hemodynamic instability, altered mental status, and/or undefined neurological deficits, making it difficult to develop recommendations that are universally applicable. However, the findings of this

study are sufficiently compelling to suggest that MRI should be obtained during initial assessment of most patients with acute SCI, in the absence of a contraindication.

Looking ahead, further investigations should focus on several areas to elucidate the role of MRI in acute SCI. First, studies are needed that directly compare outcomes with and without MRI, while implementing similar management otherwise. However, it is doubtful that a randomized study can be ethically performed, as there was a perceived lack of equipoise expressed by expert clinicians in a recent guidelines effort [9]. Furthermore, emerging evidence suggests that earlier decompression has an hour-by-hour benefit on outcomes for the first 36 h after injury [48], suggesting that delays incurred in obtaining an MRI may counteract the benefits. Thus, future studies should include an analysis of the timing of surgery and the related impact of obtaining an MRI. On this topic, institutional protocols such as a "Code SCI" that streamline the care of SCI patients to minimize delays in imaging and definitive treatment should be developed [10,49], akin to "Code Stroke" protocols that have transformed stroke care. Future research is required that prospectively investigates the utility of MRI to make specific decisions on the need for surgery, surgical approach, the number of levels of decompression, and the need for instrumentation. Aarabi et al. (2019) demonstrated that decompressing more levels (up to five) with laminectomy showed higher rates of complete spinal cord decompression, likely due to greater alleviation of spinal cord swelling and secondary injury [47]; identifying pre-operative MRI features that predict spinal cord swelling could inform the need for additional levels of decompression and/or expansile duraplasty. In addition, the vast majority of previous studies have focused on cervical SCI, while the utility of MRI in thoracolumbar injuries is poorly defined, such as burst fractures with SCI. Evaluation of the cost-effectiveness of MRI is also needed to justify its widespread use, particularly in health systems and regions with scarce resources. Finally, emerging microstructural MRI techniques that measure specific physical properties such as axonal injury, demyelination, and perfusion should be studied for their potential value in prognostication [50].

This study is subject to several limitations. The systematic review involved two separate literature searches that were conducted using different interfaces and software tools, which occurred because the authors paused the initial project; this could have resulted in missed citations, although the literature search was comprehensive and overlapping dates were used to mitigate this risk. The large number of citations and full-text articles that were reviewed could also lead to errors, but we had multiple authors reviewing at each step to avoid errors. After careful consideration, we also modified the original inclusion criteria to allow studies with a small number of pediatric patients, as we felt that exclusion of certain key studies would result in a failure to identify important evidence; however, this decision potentially degrades the internal validity, as the small number of pediatric patients could mildly influence the overall results. There also exists the possibility of publication bias, which may have influenced our results. Our approach also excluded studies of spinal trauma without SCI or those that did not perform subgroup analyses with and without SCI; this approach omitted a large number of studies that offered substantial data on the diagnostic accuracy of MRI to detect ligamentous injury and fractures; however, we felt that it was essential to focus the current study on the specific clinical population of acute SCI.

#### **5. Conclusions**

MRI is safe and frequently identifies important findings with good diagnostic accuracy that alter clinical management in patients with acute SCI of all presentations, and thus, should be utilized when feasible. Therefore, pessimism that some surgeons feel toward obtaining MRI for the purpose of informing decision-making in acute SCI appears to be unjustified. Although the evidence is imperfect and indirect, it confirms the prior CPG recommendation "that MRI be performed in adult patients with acute SCI prior to surgical intervention, when feasible, to facilitate improved clinical decision-making". Future prospective studies are needed to fully define the utility and cost-effectiveness of

MRI in specific types of SCI, to allow for stronger recommendations that improve and standardize clinical practice.

**Author Contributions:** Conceptualization, A.R.M., N.T. and M.G.F.; Methodology, A.R.M. and L.T.; Formal analysis, A.R.M. and A.G.-R.; Investigation, A.G.-R., J.E.L.-R., C.P., N.T., S.F.L. and M.K.; Data curation, A.G.-R., J.E.L.-R., C.P., N.T., S.F.L., M.K. and A.R.M.; Writing—original draft preparation, A.R.M. and A.G.-R.; Writing—review and editing, A.R.M., A.G.-R. and M.G.F.; Supervision, A.R.M.; Project administration, A.R.M. All authors have read and agreed to the published version of the manuscript.

**Funding:** Martin received support from Canadian Institutes of Health Research (CIHR) Fellowship (2016–2017) and Neurosurgery Research and Education Foundation (NREF) Clinical Fellowship (2019–2020). Fehlings was supported by the Halbert Chair in Neural Repair and Regeneration (MGF).

**Institutional Review Board Statement:** Not applicable.

**Informed Consent Statement:** Not applicable.

**Data Availability Statement:** All data supporting reported results can be found within the manuscript.

**Conflicts of Interest:** The authors declare no conflict of interest.

#### **Appendix A**

#### **Pubmed (MEDLINE) Search Strategy**

(((magnetic resonance imaging) OR (MRI)) AND (((((((SCI) OR (spinal cord injury)) OR (spinal trauma)) OR (spine fracture)) OR (spine trauma)) OR (cervical fracture)) OR (cervical trauma))) AND ((((((((outcome) OR (recovery)) OR (management)) OR (decisionmaking)) OR (decision)) OR (surgery)) OR (surgical)) OR (treatment))

#### **Embase Ovid Search Strategy**

(magnetic AND resonance AND imaging OR mri) AND (((((((sci OR spinal) AND cord AND injury OR spinal) AND trauma OR spine) AND fracture OR spine) AND trauma OR cervical) AND fracture OR cervical) AND trauma) AND ((outcome OR recovery OR management OR decision) AND making OR decision OR surgery OR surgical OR treatment)

#### **CENTRAL Search Strategy**

[Magnetic Resonance Imaging] explode all trees OR MRI AND [Spinal Cord Injuries] explode all trees OR spinal cord injury OR SCI OR spinal trauma OR spine trauma OR spine fracture OR cervical fracture OR cervical trauma AND [Outcome Assessment, Health Care] explode all trees OR outcome OR recovery OR management OR MeSH descriptor: [Clinical Decision-Making] explode all trees OR decision-making OR decision OR MeSH descriptor: [General Surgery] explode all trees OR surgery OR surgical OR treatment OR MeSH descriptor: [Therapeutics] explode all trees.

#### **References**

## *Review* **The Relative Merits of Posterior Surgical Treatments for Multi-Level Degenerative Cervical Myelopathy Remain Uncertain: Findings from a Systematic Review**

**Xiaoyu Yang 1,2, Aref-Ali Gharooni 1, Rana S. Dhillon 3, Edward Goacher 4, Edward W. Dyson 5, Oliver Mowforth 1, Alexandru Budu 6, Guy Wynne-Jones 7, Jibin Francis 1, Rikin Trivedi 1, Marcel Ivanov 6, Sashin Ahuja 8, Kia Rezajooi 9, Andreas K. Demetriades 10, David Choi 11, Antony H. Bateman 12, Nasir Quraishi 13, Vishal Kumar 14, Manjul Tripathi 15, Sandeep Mohindra 15, Erlick A. Pereira 16, Giles Critchley 17, Michael G. Fehlings 18, Peter J. A. Hutchinson 1, Benjamin M. Davies 1,\* and Mark R. N. Kotter 1,19**

**Abstract:** Objectives: To assess the reporting of study design and characteristics in multi-level degenerative cervical myelopathy (DCM) treated by posterior surgical approaches, and perform a comparison of clinical and radiographic outcomes between different approaches. Methods: A literature search was performed in Embase and MEDLINE between 1995–2019 using a sensitive search string combination. Studies were selected by predefined selection criteria: Full text articles in English, with >10 patients (prospective) or >50 patients (retrospective), reporting outcomes of

**Citation:** Yang, X.; Gharooni, A.-A.; Dhillon, R.S.; Goacher, E.; Dyson, E.W.; Mowforth, O.; Budu, A.; Wynne-Jones, G.; Francis, J.; Trivedi, R.; et al. The Relative Merits of Posterior Surgical Treatments for Multi-Level Degenerative Cervical Myelopathy Remain Uncertain: Findings from a Systematic Review. *J. Clin. Med.* **2021**, *10*, 3653. https:// doi.org/10.3390/jcm10163653

Academic Editors: Allan R. Martin and Aria Nouri

Received: 4 July 2021 Accepted: 17 August 2021 Published: 18 August 2021

**Publisher's Note:** MDPI stays neutral with regard to jurisdictional claims in published maps and institutional affiliations.

**Copyright:** © 2021 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https:// creativecommons.org/licenses/by/ 4.0/).

multi-level DCM treated by posterior surgical approach. Results: A total of 75 studies involving 19,510 patients, conducted worldwide, were identified. Laminoplasty was described in 56 studies (75%), followed by laminectomy with (36%) and without fusion (16%). The majority of studies were conducted in Asia (84%), in the period of 2016–2019 (51%), of which laminoplasty was studied predominantly. Twelve (16%) prospective studies and 63 (84%) retrospective studies were identified. The vast majority of studies were conducted in a single centre (95%) with clear inclusion/exclusion criteria and explicit cause of DCM. Eleven studies (15%) included patients with ossification of the posterior longitudinal ligament exclusively with cohorts of 57 to 252. The clinical and radiographic outcomes were reported with heterogeneity when comparing laminoplasty, laminectomy with and without fusion. Conclusions: Heterogeneity in the reporting of study and sample characteristics exists, as well as in clinical and radiographic outcomes, with a paucity of studies with a higher level of evidence. Future studies are needed to elucidate the clinical effectiveness of posterior surgical treatments.

**Keywords:** cervical spine; multi-level; myelopathy; laminoplasty; laminectomy; fusion; degenerative cervical myelopathy

#### **1. Introduction**

Degenerative cervical myelopathy (DCM) is a common and disabling condition, caused by arthritic changes in the cervical spine that compress and injure the cervical spinal cord. This results in functional impairment of the spinal cord that progresses at various rates and patterns, most commonly in a stepwise deterioration with periods of stable symptoms [1]. DCM is estimated to affect up to 2.3% [2] of adults and leads to progressive loss of dexterity, gait disturbance, imbalance, bladder disturbance, and occasionally incontinence and tetraplegia [1]. Surgery is currently the only treatment shown to alter the natural history of the disease: removing the mechanical compression on the spinal cord can stop disease progression and typically offer meaningful, albeit incomplete, recovery. There are a number of different surgical approaches and techniques in use. International guidelines currently recommend surgery for moderate (mJOA 12–14) to severe impairment (mJOA ≤ 11) and any progressive disease [3].

These guidelines leave the choice of procedure at the discretion of the operating surgeon, which reflects an uncertainty within scientific evidence over the relative merits and contra/indications for specific procedures [4]. Understanding these nuances is a recognised research priority by AO Spine RECODE DCM (aospine.org/recode) [5]; 'Individualising Surgery', and the need to address specific sub-questions of surgery, for example as is being evaluated in cervical spondylotic myelopathy (CSM) surgery, a randomised controlled trial (RCT) of anterior versus posterior surgery [6].

A further area of uncertainty remains the role of stabilisation or reconstruction after decompression. For DCM treated posteriorly, the typically used techniques are laminectomy, laminoplasty or laminectomy and fusion [7]. These techniques all provide posterior decompression but have differing approaches to stabilisation: laminectomy includes no stabilisation [8], laminoplasty (with several variations) uses a construct to float and retain the dorsal elements posteriorly [9] whilst laminectomy and fusion uses instrumentation to rigidly stabilise the spinal column [10–14]. These techniques therefore represent contrasting views on the contribution of dynamic instability to the pathogenesis of DCM, and the significance and role of retaining range of motion (ROM) versus preventing secondary cervical deformity.

Whether or not this is significant to patients is uncertain [10,15], with conflicting evidence [16–19] and recommendations [8,14,20,21], leading to widespread variation in clinical practice [22,23]. Although widely used, there has been no prospectively powered comparison of these techniques [4]. Furthermore, much of the evidence comes from cohorts including single level disease [24,25]. One assumption is the inherent biomechanical implications for posterior surgery are magnified when treating multiple levels, and this is most likely where any divergence would be most significant. This subgroup of multi-level DCM is therefore underrepresented in DCM literature [24,25] and represents an important knowledge gap in particular given the popularity of a global preference for posterior techniques for multi-level DCM [7].

The objectives of this study were therefore to describe the current evidence for posterior surgical treatment of multi-level DCM in terms of the range of outcome measures and the manner in which they were reported to inform the design of a prospective trial. Furthermore, where possible, to compare the clinical and radiographic outcomes between different posterior approaches.

#### **2. Materials and Methods**

The systematic review was conducted in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses: the PRISMA Statement [26]. Due to heterogenous outcome reporting, a formal meta-analysis was not possible in this study and comparisons were made descriptively [27].

#### *2.1. Literature Search and Selection*

Up to 11th November 2019, the electronic databases Embase [Ovid] and MEDLINE [Ovid] were searched using the search strategies as shown in Table S1. Two of the authors (XY and AG) independently evaluated the articles by title, abstract, or full article, where necessary, to select the studies that met the predefined selection criteria. Selection criteria were stated as follows:

Animal studies, letters and editorials were excluded from this study. Reference screening and citation tracking were performed on the identified articles and as a final check, the reviews found in the search were studied to make sure no relevant articles were missed. Any discrepancy in selection between the two reviewers was resolved by a third reviewer (BD). Descriptive statistics were used to report frequency and proportion of outcome measures. Statistical comparisons were made using the Chi-Squared test, with significance set at *p* = 0.05.

#### *2.2. Data Extraction*

Data extraction was performed by two independent reviewers (XY and AG), using a piloted extraction template covering study characteristics, design, participant characteristics, clinical outcome and radiographic outcome. Extracted data underwent a narrative synthesis and was presented with summary tables.

#### *2.3. Quality Assessment*

Two reviewers (XY and AG) independently appraised each publication according to study design. None of the studies found in our review of the literature were randomised trials. Nonrandomised observational studies were evaluated utilising the New Castle Ottawa Scale to evaluate the validity of each. Discrepancies between the two reviewers were addressed by a joint re-evaluation of the original article.

#### **3. Results**

#### *3.1. Characteristics of Studies*

Of the 1322 articles identified, 1074 original articles were left after removing duplicates. Following abstract and title review, 124 articles were shortlisted. After reviewing the full

text, 75 articles were included in this study, assessing 19,510 patients (Figure 1). Of the 75 included articles, 18 studies reported the comparison between anterior and posterior approach, of which the data regarding posterior approach was extracted and included in this review.

**Figure 1.** PRISMA flow diagram of search strategy.

Laminoplasty was described in 56 studies (75%), whereas laminectomy with fusion in 27 (36%), and laminectomy without fusion in 12 (16%). The majority of studies were conducted in Asia (*n* = 63, 84%), followed by North America (*n* = 8, 11%) and Europe (*n* = 4, 5%) (Figure 2A). The articles were mainly published in the period of 2016–2019 (*n* = 38, 51%) and 2011–2015 (*n* = 26, 35%), of which laminoplasty was studied predominantly (Figure 2B). The sample size ranged from 51 to 1025.

#### *3.2. Data Quality*

The New Castle Ottawa Scale was used to assess the quality of each study due to its high content validity and inter-rater reliability. One study was allotted three stars, three studies four stars, five studies five stars, and two studies were assessed and awarded six stars (Table 1).

**Figure 2.** Location (**A**) and trend (**B**) of published research.

#### *3.3. Study Design, Patient Selection and Reporting Differences*

Twelve (16%) studies were conducted prospectively, and 63 (84%) retrospective studies were identified. The vast majority of studies were conducted in a single centre (*n* = 71, 95%), three were in multiple centres, and the design of the other study is unknown. Of the 75 studies, 45 (60%) documented that ethical approval was obtained, including one study which held the waiver for ethical approval. Clear inclusion and exclusion criteria were defined in 72 (96%) and 59 (79%) studies, respectively. All of the included studies described the cause of cervical myelopathy, of which 11 (15%) studies included patients suffering ossification of the posterior longitudinal ligament (OPLL) exclusively with sample sizes of 57 to 252, while other studies comprised patients with DCM. The number of levels involved in the diagnosis of multi-DCM was specified in 36 studies describing it as two or more than two levels (*n* = 3, 4%), three or more than three levels (*n* = 28, 37%), four levels (*n* = 4, 5%) and five levels (*n* = 1, 1%).

Reporting differences were noted when comparing prospective with retrospective studies (Tables S2–S4). When compared to retrospective studies, prospective studies were more likely to report the duration of symptom (*p* = 0.047) and the result of dynamic X-rays (*p* = 0.023).

#### *3.4. Comparison between Laminoplasty and Laminectomy with Fusion*

Six retrospective studies [28–33] compared laminoplasty to laminectomy with fusion with sample sizes ranging from 56 to 141 patients (Table 2). The surgical treatment was decided based on (1) surgeon's choice: Highsmith et al. [30] chose patients with more facet pathology to undergo laminectomy and fusion, while Yang et al. [33] preferred patients with large anterior osteophytes, facet degeneration, and the continuous type of OPLL to receive laminectomy and fusion; (2) radiographic parameters: Ha et al. [29] preferred laminectomy with fusion for patients with straight or lordotic cervical curvature and segmental instability, and those with severe cord compression caused by OPLL, while Stephens et al. [32] preferred those who demonstrated any amount of C2–7 kyphosis to undergo laminectomy and fusion; or (3) the combination of both (further details were not available) [31]. Of the six studies, two [29,31] included patients with exclusively OPLL, while others comprised patients with DCM.

**Table 2.** Studies describing laminoplasty versus laminectomy with fusion.

NA: Not applicable; CSM: Cervical spondylotic myelopathy; mJOA: Modified Japanese orthopaedic association score; OPLL: Ossification of the posterior longitudinal ligament; NDI: Neck disability index; JOA: Japanese orthopaedic association score; SVA: Sagittal vertical axis; ROM: Range of motion.

Ajiboye et al. [28] reported that there was no difference observed in modified Japanese orthopaedic association (mJOA) score between two groups, while laminectomy with fusion was associated with larger interval regression in disc-osteophyte complex size measured on magnetic resonance imaging (MRI) compared to laminoplasty. Ha et al. [29] observed similar improvements in Health-related quality of life (HRQOL), JOA recovery, and visual analog scale (VAS) in both groups, whilst neck disability index (NDI) improved more significantly in the laminoplasty group. Laminoplasty preserved cervical lordosis, ROM and C2–C7 sagittal vertical axis (SVA) more than laminectomy with fusion group, but the progression of OPLL was suppressed by stabilization using instrumented fusion. Highsmith et al. [30] reported comparable improvements in Nurick scores, mJOA, and Odom outcomes, and comparable radiographic outcomes between groups. They also noted improved VAS neck pain in laminectomy with fusion, though at higher cost (3 times) and increased complications (2 times), compared to laminoplasty. Stephens et al. [32] found that overall pain scores and mJOA improved significantly in both groups. Improved NDI and the loss of lordosis were found in laminoplasty group. Yang et al. [33] reported that the neurological functional recovery (JOA and Nurick scores) was similar between groups. Neck function (NDI and VAS) was worse in the laminectomy and fusion group, although with the achievement of a greater extent of enlargement of the spinal canal and spinal cord drift, compared with laminoplasty. Lee et al. [31] did not report clinical outcome but demonstrated that laminectomy with fusion had the effect of reducing OPLL growth rate compared with motion-preserving laminoplasty.

#### *3.5. Comparison between Laminoplasty and Laminectomy without Fusion*

Three studies [34–36] were conducted retrospectively by comparing laminoplasty to laminectomy alone with the sample sizes ranging from of 67 to 330 (Table 3). The surgeonbased treatment was recorded in only one study (no further details provided) [35]. Two studies [34,35] included patients with CSM and the other [36] enrolled patients with OPLL only.

**Table 3.** Studies describing laminoplasty versus laminectomy alone.

NA: Not applicable; CSM: Cervical spondylotic myelopathy; JOA: Japanese orthopaedic association score; NDI: Neck disability index; ROM: Range of motion; OPLL: Ossification of the posterior longitudinal ligament; SVA: Sagittal vertical axis.

> Chang et al. [34] demonstrated similar clinical outcomes (NDI, JOA and VAS neck pain) between groups. Although shorter operation time and less blood loss was observed in the laminectomy group, Cobb angle and ROM significantly decreased at 1-year follow-up. Li et al. [35] compared laminectomy to French-door and open-door laminoplasty, and demonstrated a significantly improved Nurick score and reduced postoperative ROM in all groups at 1-year follow-up. However, French-door laminoplasty showed a higher bone union rate with smaller increased spinal cord volume compared to the other two groups. Yoo et al. [36] found no difference between laminoplasty and laminectomy in 73 patients

with OPLL, neither on clinical outcomes (NDI and JOA), nor on radiographic outcomes (C2–7 Cobb angle, SVA, and T1 slope).

#### *3.6. Comparison between Laminoplasty, Laminectomy with and without Fusion*

Two retrospective studies reported comparison between laminoplasty, laminectomy with and without fusion, but none of them mentioned the allocation method (Table 4). Du et al. [37] studied 98 patients and reported that an excellent neurological improvement (JOA recovery rates ≥ 75 %) was achieved in patients with laminoplasty and laminectomy with fusion at 7 to 12 years follow-up, whilst a high incidence of axial symptoms (NDI) was found in the laminoplasty and laminectomy alone groups caused by loss of curvature index. In the fusion group, lateral mass screw fixation was demonstrated to effectively prevent loss of postoperative cervical curvature and therefore to reduce the incidence of axial symptoms. Lee et al. [38] investigated sagittal alignment and clinical outcome in 57 patients with CSM and OPLL, and found that cervical lordosis, C2–C7 Cobb angle, and cervical curvature index decreased gradually in all patients at minimum 2-year follow-up, with the exception of SVA which was maintained in laminectomy with fusion group. Clinical outcomes, NDI and VAS, improved in all patients. Neck pain was found to increase in laminoplasty in patients showing SVA more than 40 mm at baseline, and the progression of OPLL was observed more frequently in the laminectomy alone group than the group with fusion.

**Table 4.** Studies describing laminoplasty versus laminectomy with and without fusion.

NA: Not applicable; DCM: Degenerative cervical myelopathy; OPLL: Ossification of the posterior longitudinal ligament; JOA: Japanese orthopaedic association score; NDI: Neck disability index; CSM: Cervical spondylotic myelopathy; ROM: Range of motion; SVA: Sagittal vertical axis.

#### **4. Discussion**

#### *4.1. Summary of Findings*

DCM is a common cause of spinal cord injury, and many patients with DCM go on to develop progressive disease leading to neurological deficits and reduced quality of life.

This study has identified significant heterogeneity in the conduct and reporting of clinical research evaluating posterior surgery for multi-level DCM. This included variation in study design characteristics, such as the reporting of ethics committee approval, clear inclusion/exclusion criteria and population characteristics, such as the definition of multilevel and subtype of DCM. Most studies were conducted in Asia during recent years focusing on laminoplasty. Few studies made direct comparisons of techniques, and no high level of evidence, such as a RCT, was found. Due to the heterogeneous reporting of outcomes, it was a challenge to interpret these results and taken together this confirmed an important knowledge gap for surgeons.

#### *4.2. Comparison between Posterior Approaches*

As the most popular posterior surgical approach described in the literature, laminoplasty was compared to laminectomy with and without fusion. When compared to laminectomy with fusion, with various measurements evaluated, the clinical findings were heterogeneous and contradictory. However, two studies [29,31] reported the superiority of laminectomy with instrumented fusion at suppressing the progression of OPLL when compared with other procedures. One possible explanation is that the decrease in pulsations of the thecal sac and venous plexus after posterior fusion lead to the reduction in thickness of OPLL [39,40]. Another possibility is the removal of mechanical stimulus

for cervical OPLL after posterior fusion possibly suppresses the progression of OPLL [41].  When compared to laminectomy alone, although reported with various measurements, comparable clinical outcomes were demonstrated between groups. Cervical laminoplasty was introduced in Japan in the 1970s, with proposed advantages of protecting the spinal cord and preventing neurological deterioration by preservation of the posterior elements and stability [42,43]. However, this is still a controversial issue. In this systematic review it was not possible to show superior clinical outcomes for any particular posterior surgical procedure used to treat DCM as was the case in previous systematic reviews [44,45]. Although Du et al. [37] demonstrated laminectomy with fusion to have a JOA improvement with less incidence of axial symptoms in the comparison of three surgical approaches, this was not confirmed by Lee et al. [38]. Furthermore, a recent meta-analysis disputes this finding, which concluded that laminoplasty had fewer complications, a lower incidence of C5 palsy, better NDI scores and recovery outcomes compared to laminectomy with fusion [46]. Again, due to limited and heterogenous outcomes, no firm conclusion could be made.

Whilst the evidence base has largely focused on laminoplasty, especially in Asia, it is of note in clinical practice that the use of instrumented fusion has increased significantly. This is acknowledged by Deyo et al., who describe how the adoption of technology within spinal surgery has outstripped its rigorous evaluation [47]. More broadly, this is a recognised problem throughout surgery and underpins the IDEAL framework, and specifically the need to match innovation with evaluation [48].

Of note, CSM-S, a RCT of ventral versus dorsal surgery for DCM has recently reported [49]. In this trial, which randomised patients undergoing surgery for multi-level CSM (i.e., excluding OPLL) in the absence of kyphosis to an anterior or posterior approach in whom there was surgical equipoise, a planned subgroup analysis of laminoplasty (*n* = 28) vs. laminectomy and fusion (*n* = 69) occurred. The decision to perform a laminoplasty versus a laminectomy and fusion was at the surgeon's discretion. In this subgroup, posterior instrumented fusion was associated with significantly higher adverse events (fusion, 29.0% [95% CI, 18.7%–41.2%]; laminoplasty, 10.7% [95% CI, 2.3%–28.2%]), increased opioid use (fusion, 65.2% [95% CI, 52.8%–76.3%]; laminoplasty, 39.3% [95% CI, 21.5%–59.4%]), and worse physical function at 2 years (estimated mean 5.8; 95% CI, 1.5–10.1; *p* = 0.01). This difference is greater than their defined MCID. Furthermore, the rate of recovery from instrumented fusion was slower, the short-term neck disability greater and return to work delayed. In fact, these outcomes amongst the laminoplasty subgroup broadly matched anterior surgical results.

#### *4.3. Designing a Future Comparative Study*

The results of this systematic review indicate that there is no high level of evidence to guide surgeons when considering a posterior surgical approach for patients with multilevel DCM. Although improved outcomes have been reported in laminectomy with fusion, considering the significant costs, additional skill, increased operative time and reduced ROM after surgery, its superior cost-effectiveness compared to laminectomy requires evaluation. Thus, a comparative study is needed to answer this question.

Although, no firm conclusion can be drawn in this review concerning the clinical effectiveness of posterior surgical treatments, it provides useful information which will facilitate the setting up of future comparative studies. All of three posterior approaches were effective when performed for patients with multilevel DCM. However, the indications of each approach were inconsistent, and some were even contradictory [29,32], paving the way for a randomised controlled trial. The majority of previous studies have a follow-up duration within 24 months, which seems to be pragmatic. Furthermore, various outcome measures have been used in previous studies, including clinical (neurological function assessment and neck pain score) and radiological alignment (X-rays).

Ideally, a three-armed RCT would examine the effectiveness of these posterior surgical treatments. Nevertheless, some existing disputes make it difficult to conduct, such as whether a Bonferroni or similar correction factor should be employed to decrease the likelihood of a type I error in the three-armed RCT. Additionally, given that all procedures are effective to some extent and the relative differences to be detected are likely to be small, this would significantly inflate the sample size. Thus, the initial step, to examine the fundamental question of whether or not stabilisation is required after posterior decompression may be an RCT of the two extremes: laminectomy alone versus laminectomy with fusion. Such a trial has been commissioned by the National Institute for Health Research within the UK, in part owing to a very limited use of laminoplasty in UK spinal practice: The POLYFIX-DCM trial (Posterior LaminectomY and FIXation for DCM) aims to offer the first fully powered, randomised evaluation of this question and will commence recruitment in January 2022. International sites and collaborators are sought.

#### *4.4. Limitations*

Due to various definitions of 'multi-level DCM', patients who received short-range decompression may have compared to those who underwent long-range surgeries in this review. However, it is still not clear whether there is a clinical significance between them. Besides, findings in this review were generalised from studies with CSM and OPLL, which are two different pathogenic factors for DCM. Due to the paucity of comparative data, further subgroup analysis was not possible. Furthermore, the follow-up of included studies may be inadequate (mostly 1–2 years), since adjacent segment disease and bony remodelling may take years to occur and is arguably the most important difference between fusion and non-fusion surgery. This study was designed to focus on contemporary and large sample studies, and those articles with non-English language were excluded. The global representation of included studies suggests that the foreign language exclusion is unlikely to be significant. Indeed, the authors propose that assessment of 25 years of published data of large sample studies, is representative of current practice.

#### **5. Conclusions**

Studies evaluating posterior surgery for multi-level DCM demonstrate heterogeneity in the reporting of definitions, sample characteristics, as well as in clinical and radiographic outcomes. To date, no studies with a high level of evidence exist. This represents an important knowledge gap, supporting an individualised approach to DCM surgery, and a current leading research priority as identified by AO Spine RECODE DCM (aospine.org/recode).

**Supplementary Materials:** The following are available online at https://www.mdpi.com/article/10 .3390/jcm10163653/s1, Table S1 Search strategy; Table S2 Differences in reporting characteristics and study design; Table S3 Differences in reporting clinical outcomes; Table S4 Differences in reporting radiographic outcomes.

**Author Contributions:** X.Y. and B.M.D. conceived and wrote the article, X.Y. and A.-A.G. selected articles and extracted data, R.S.D., E.G., E.W.D., O.M., A.B., G.W.-J., J.F., R.T., M.I., S.A., K.R., A.K.D., D.C., A.H.B., N.Q., V.K., M.T., S.M., E.A.P., G.C., M.G.F., P.J.A.H. and M.R.N.K. provided critical feedback and revised the manuscript. All authors read and approved the final manuscript.

**Funding:** The research was supported by the National Institute for Health Research (NIHR) Brain Injury MedTech Co-operative based at Cambridge University Hospitals NHS Foundation Trust and University of Cambridge. The views expressed are those of the author(s) and not necessarily those of the NHS, the NIHR or the Department of Health and Social Care.

**Institutional Review Board Statement:** Not applicable.

**Informed Consent Statement:** Not applicable.

**Data Availability Statement:** Not applicable.

**Acknowledgments:** X.Y. reports grant from Cultural Foundation Grant (Award number 40026482, Prins Bernhard Cultural Foundation, the Netherlands) during the conduct of the study, the grant has no role in the conduction of this research. B.M.D. is supported by a NIHR Clinical Doctoral Research Fellowship. This research aligns with the AO Spine RECODE DCM, James Lind Alliance top research

priority, individualising surgery. For further information on how this process was conducted, why this question was prioritised, and on-going research activity, please visit www.aospine.org/recode/ individualizing-surgery.

**Conflicts of Interest:** The authors declare no conflict of interest.

#### **References**

## *Review* **Degenerative Cervical Myelopathy: Clinical Presentation, Assessment, and Natural History**

**Melissa Lannon and Edward Kachur \***

Division of Neurosurgery, McMaster University, Hamilton, ON L8S 4L8, Canada<EMAIL_ADDRESS>**\*** Correspondence<EMAIL_ADDRESS>
**Abstract:** Degenerative cervical myelopathy (DCM) is a leading cause of spinal cord injury and a major contributor to morbidity resulting from narrowing of the spinal canal due to osteoarthritic changes. This narrowing produces chronic spinal cord compression and neurologic disability with a variety of symptoms ranging from mild numbness in the upper extremities to quadriparesis and incontinence. Clinicians from all specialties should be familiar with the early signs and symptoms of this prevalent condition to prevent gradual neurologic compromise through surgical consultation, where appropriate. The purpose of this review is to familiarize medical practitioners with the pathophysiology, common presentations, diagnosis, and management (conservative and surgical) for DCM to develop informed discussions with patients and recognize those in need of early surgical referral to prevent severe neurologic deterioration.

**Keywords:** degenerative cervical myelopathy; cervical spondylotic myelopathy; cervical decompression

#### **1. Introduction**

Degenerative cervical myelopathy (DCM) is now the leading cause of spinal cord injury [1,2], resulting in major disability and reduced quality of life. While precise prevalence is not well described, a 2017 Canadian study estimated a prevalence of 1120 per million [3].

DCM results from narrowing of the spinal canal due to osteoarthritic changes. This narrowing leads to chronic spinal cord compression and neurologic disability. Symptoms may range from mild dysfunction, including numbness or decreased dexterity in the upper extremities, to severe dysfunction including quadriparesis and incontinence. Importantly, clinicians should note that paresthesia in the extremities may be the first sign and is frequently overlooked by patients and providers due to its mild nature. This variable pattern of presenting symptoms may lead to a delay in diagnosis of up to 2 years [4].

Early diagnosis and surgical management may improve neurologic and overall outcomes for these patients and, importantly, prevent progressive deterioration.

#### **2. Topics**

#### *2.1. Pathophysiology*

Degenerative changes in the spine are considered a normal part of the aging process. The cervical spine is particularly prone to degenerative changes due to the mobility of this region. Typically, the degenerative process that culminates in DCM begins with deterioration of the intervertebral disk [5–7]. The intervertebral disk normally acts to distribute pressure evenly across vertebral endplates and facet joints. Normal aging leads to loss of proteoglycans and dehydration of disks, causing loss of elastic and supportive structure. As the disk collapses, it bulges posteriorly, narrowing the spinal canal and compressing the spinal cord at that level. Resultant decreased disk height produces shortening of the spinal column, ultimately producing abnormal spinal mechanics [1,7]. These altered mechanics further contribute to osteoarthritic and osteophytic changes that may worsen narrowing.

**Citation:** Lannon, M.; Kachur, E. Degenerative Cervical Myelopathy: Clinical Presentation, Assessment, and Natural History. *J. Clin. Med.* **2021**, *10*, 3626. https://doi.org/ 10.3390/jcm10163626

Academic Editors: Allan R. Martin, Aria Nouri and Katharina Schallmoser

Received: 12 July 2021 Accepted: 14 August 2021 Published: 17 August 2021

**Publisher's Note:** MDPI stays neutral with regard to jurisdictional claims in published maps and institutional affiliations.

**Copyright:** © 2021 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https:// creativecommons.org/licenses/by/ 4.0/).

In addition to changes related to disk degeneration, the ligamentum flavum can thicken and buckle anteriorly toward the spinal cord, also resulting in compression. Finally, the posterior longitudinal ligament may contribute to degenerative cervical myelopathy by direct compression of the cord in the event of ossification of the posterior longitudinal ligament (OPLL) [5–7].

As these changes occur, stiffening of affected structures may result. To compensate, adjacent segments of the spine may develop hypermobility, which may further contribute to instability and degeneration as the process progresses.

With these mechanical changes, abnormal repetitive movement of the cervical spine may cause spinal cord irritation and compression. For example, flexion may compress the spinal cord against anterior osteophytes and intervertebral disks, while hyperextension may lead to compression between the posterior aspect of the vertebral bodies anteriorly and hypertrophied ligamentum flavum posteriorly [8].

The aforementioned compressive factors produce vascular changes within the cord, inducing ischemia and inflammation [5,7]. With these changes, chronic compression may lead to demyelination, astrogliosis, and axonal degeneration. Endothelial damage may promote further cellular injury through disruption of the blood–spinal cord barrier [5,7]. Ultimately, this histopathologic pattern leads to cell loss and the subsequent functional decline observed clinically in patients [5,7].

Interestingly, recent studies have shown an association between DCM and cerebral reorganization, seemingly to compensate for functional impairment. The majority of studies have focused on cortical reorganization, however similar changes have been observed in the brainstem [9] and the thalamus [10]. This reorganization has been seen across a number of modalities, including arterial spin labelling functional MRI (fMRI) [11], blood oxygen level dependent (BOLD) fMRI [10,12], and navigated transcranial magnetic stimulation (nTMS) [13].

Congenital cervical spinal stenosis, defined as a sagittal canal diameter less than 13 mm [14] or a Torg-Pavlov (canal diameter/vertebral body diameter) ratio less than 0.82 [15], is recognized for its significant role in predisposing patients to DCM [16–18]. Congenital narrowing of the canal produces a vulnerability in the spinal cord to even minor compression from factors described above. It has been suggested that the narrow canal seen in these patients reduces cerebrospinal fluid volume at stenosed levels, impairing the cushioning effect of kinetic energy in the setting of minor trauma and other dynamic injury mechanisms described here [19]. As such, these patients should be monitored regularly for early onset myelopathic symptoms.

#### *2.2. Presentation*

No pathognomonic sign exists for DCM. Therefore, clinicians must be cognizant of the constellation of symptoms in this variable presentation. Initially, patients with DCM most commonly present with paresthesia in one or more extremities. Patients may also report decreased dexterity, often described as "clumsiness" with buttons and zippers or changes in penmanship. Patients may note changes in mobility or frequent falls.

DCM carries a slow progressive course, so while paresthesia is commonly an early symptom, patients may present at any point along the disease course with any number of symptoms, including weakness, sensory change, decreased dexterity, and gait abnormality. Neck pain may or may not be present. Bowel and bladder symptoms may occur, however clinicians should keep in mind that these symptoms are rare and indicative of severe injury to the spinal cord [7].

Physical examination is an important aspect of diagnosis in DCM. Patients should be thoroughly assessed for weakness, particularly in the intrinsic muscles of the hands. Patients commonly exhibit hyperreflexia, clonus at the ankles and patellae, spasticity, and abnormal Babinski and Hoffmann signs, as well as loss of sensory proprioception [7].

A number of classification systems have been generated to assess severity of DCM. The most commonly utilized is the modified Japanese Orthopaedic Association (mJOA) classification, grading motor dysfunction in both upper and lower extremities as well as sensation and bladder control to characterize patients as mild (mJOA 15–17), moderate (12–14), or severe (0–11) (Table 1) [20].

**Table 1.** The modified Japanese Orthopaedic Association (mJOA) Score (adapted from [21]).