Traumatic Spinal Injury: Global Epidemiology and Worldwide Volume

Accepted Manuscript Traumatic spinal injury: global epidemiology and worldwide volume Ramesh Kumar, MD, Jaims Lim, BS, Rania A. Mekary, PhD, Abbas Rattani, MBe, Michael C. Dewan, MD, MSCI, Salman Y. Sharif, MD, Enrique Osorio-Fonseca, MD, Kee B. Park, MD PII:

S1878-8750(18)30303-6

DOI:

10.1016/j.wneu.2018.02.033

Reference:

WNEU 7448

To appear in:

World Neurosurgery

Received Date: 15 October 2017 Revised Date:

5 February 2018

Accepted Date: 6 February 2018

Please cite this article as: Kumar R, Lim J, Mekary RA, Rattani A, Dewan MC, Sharif SY, OsorioFonseca E, Park KB, Traumatic spinal injury: global epidemiology and worldwide volume, World Neurosurgery (2018), doi: 10.1016/j.wneu.2018.02.033. This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.

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Traumatic spinal injury: global epidemiology and worldwide volume

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Ramesh Kumar MD1 Jaims Lim BS2 Rania A. Mekary, PhD3,4 Abbas Rattani, MBe5,6 Michael C. Dewan, MD, MSCI5,7 Salman Y. Sharif, MD8 Enrique Osorio-Fonseca, MD9 Kee B. Park, MD5 1

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Vanderbilt University, School of Medicine, Nashville, TN, USA

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University of Colorado School of Medicine, Department of Neurosurgery, Aurora, CO, USA

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MCPHS University, Department of Pharmaceutical Business and Administrative Sciences, School of Pharmacy, 179 Longwood Ave., Boston MA, USA 4

Cushing Neurosurgical Outcomes Center, Brigham and Women’s Hospital, Department of Neurosurgery, Harvard Medical School, 15 Francis Street, Boston, MA, USA 5

Global Neurosurgery Initiative, Program in Global Surgery and Social Change, Department of Global Health and Social Medicine, Harvard Medical School, Boston, MA, USA 6

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Meharry Medical College, School of Medicine | Nashville, TN, USA

Department of Neurological Surgery Vanderbilt University Medical Center | Nashville, TN, USA

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Department of Neurosurgery Liaquat National Hospital & Medical College, Karachi, Pakistan

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Department of Neurological Surgery Universidad el Bosque| Bogotá, Colombia

Corresponding Author: Jaims Lim Vanderbilt University School of Medicine, Department of Neurosurgery, Nashville, TN, USA Email: [email protected] ph: 551-265-9255 Key Words: epidemiology, global, incidence, traumatic spinal cord injury, traumatic spinal injury, volume Running Head: Global epidemiology of traumatic spinal injury

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ABSTRACT

Background: Traumatic spinal injury (TSI) results from injury to bony, ligamentous and/or neurological

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structures of the spinal column and can cause significant morbidity and mortality. The global burden of TSI is poorly understood, so we performed a systematic review and meta-analysis to estimate the global volume of TSI.

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Methods: We performed a systematic review through PubMed, Embase and Cochrane Databases on TSI studies published from 2000 to 2016. Collected data were used to perform a meta-analysis to estimate

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the annual incidence of TSI across World Health Organization (WHO) regions and World Bank income groups using random effect models. Incorporating global population figures, the annual worldwide volume of TSI was estimated.

Results: A total of 102 studies were included in the systematic review and 19 studies in the meta-

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analysis. The overall global incidence of TSI was 10.5 cases per 100,000 persons, resulting in an estimated 768,473 [95% CI: 597,213 – 939,732] new cases of TSI annually worldwide. The incidence of TSI was higher in low- and middle-income countries (LMICs) (8.72 per 100,000 persons) compared to

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high income countries (HICs) (13.69 per 100,000 persons). Road traffic accidents, followed by falls, were the most common mechanism of TSI worldwide. Overall, 48.8% of patients suffering from TSI required a

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surgery.

Conclusion: TSI is a major source of morbidity and mortality throughout the world. Largely preventable mechanisms, including road traffic accidents and falls, are main causes of TSI globally. Further investigation is needed to delineate local and regional TSI incidences and causes, especially in LMICs.

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INTRODUCTION

Traumatic spinal injury (TSI) includes a multitude of injuries to the spinal cord, nerve roots, osseous

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structures, and disco-ligamentous components of the spinal column.128 Injuries may be secondary to blunt or penetrating trauma and result from both high and low energy mechanisms.17,105 Damage to the spinal column can lead to mechanical instability, pain and impaired mobility, while damage to

neurological structures commonly results in partial or complete paralysis.128,108,88 Spinal Cord injury (SCI)

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holds a more limited definition and specifically pertains to injuries sustained to the spinal cord leading to

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neurological deficits often measured using a clinical score such as the ASIA score.98 Regardless of injury type, TSI has the potential to cause severe disability or death.

Little is known regarding the worldwide volume of TSI. Currently, the incidence of a particular subset of TSI, traumatic spinal cord injury (SCI), is much better understood. Estimated SCI incidences range from 8

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to 246 cases per million people per year.29,31,55 Though very important information, the incidence of SCI represents only a fraction of the worldwide burden of TSI. The magnitude of effect TSI has as a global health issue remains obscure.

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The dearth of available data, especially from low and middle income countries (LMICs), remains an obstacle to the assessment of the global burden of TSI. This lack of knowledge stands as a major

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impediment to the development of national and international agendas focused on injury prevention, training of a capable medical workforce, and the creation of effective medical care delivery systems. The size of the neurosurgical workforce, responsible in large part for the care of TSI, is woefully inadequate in many parts of the world.77 Often, as is the irony with many public health problems, the resources to treat disease and injury are limited where they are needed most. Yet, in the case of TSI, even the most basic epidemiological information is absent, precluding targeted resource allocation. In this study, we

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performed a systematic review and meta-analysis of the TSI literature to estimate the global volume of this heterogeneous group of injuries.

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METHODS

Systematic review

A systematic review was conducted according to the guidelines set forth by the Preferred Reporting

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Items for Systematic Review and Meta-Analyses Statement (PRISMA).65 This consisted of a

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comprehensive search of literature published between January 1, 2000 to October 17, 2016 querying PubMed, Embase, and the Cochrane Database of Systematic Reviews. A full list of search terms can be found in Appendix 1, section A.

Two authors (RK, JL) jointly reviewed all titles, abstracts and manuscripts. The initial list of articles was

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narrowed to pertinent titles by the following exclusion criteria: (1) No available abstract; (2) non-human subjects; (3) study publication before 2000. The cut-off year of 2000 was selected to favor more timely and relevant studies. The titles were then screened and excluded if they were: (1) diagnostic,

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intervention, or outcomes focused; (2) comparative studies (i.e., randomized control trials, cohort, and case control studies); (3) or focused on associations with the disease of interest. Abstracts were then

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reviewed and excluded if they were: (1) not in English; (2) or not pertinent to the epidemiology of TSI. Abstracts selected for further review focused either on the epidemiology (incidence, prevalence, volume, burden) or the descriptive history of TSI. Thus, large population based studies as well a smaller cohort studies were included for further review. Full manuscript review was then performed to deem a study’s merit for inclusion.

From abstract to full manuscript review, a random subset of titles was reviewed by two authors (RK, JL) to ensure concordance in selection of articles. Any differences in the decision to include or exclude an 4

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article were resolved by a tertiary review from two other authors (MD, AR). Studies were excluded at this stage in the review for the following reasons: (1) high income country (HIC) studies based on single institutions; (2) studies with a non-generalizable cohort; (3) studies with poor and/or impertinent data

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reporting; and (4) studies that preluded more current data from the same cohort/population. Studies were considered to have poor and/or impertinent data reporting when basic epidemiological data such as incidence, mechanism of injury or anatomical location of injury were not reported. Full manuscript

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review included the weighting of each article with a score on a 6-point scale. The scale ranged from a lowest assigned score of 0 (small, single institution studies) to a highest of 5 (large, population-based

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studies) (Appendix 1, section B).27 To counter the potential publication bias from high income countries (HICs), a lower threshold for inclusion of studies from LMICs was maintained. A PRISMA diagram was constructed to highlight reasons for inclusion or exclusion of an article at each step of the review process (Figure 1).

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Data reporting

Descriptive data was reported as the proportion of a cohort or the mean and/or median of multiple

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reported proportions. Mortality rates were described as case-fatality rates. Standard deviations, interquartile ranges and confidence intervals were reported where appropriate.

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To coalesce data from countries in similar regions and socioeconomic statuses, we classified countries by income levels and World Health Organization (WHO) regions. WHO member states were divided into six separate regions as follows: Africa (AFR), The Americas (AMR), South-East Asia (SEAR), Europe (EUR), Eastern Mediterranean (EMR), and the Western Pacific (WPR).121 To better discern between the social and economic differences that may influence disease between North America and Central and South America, we divided these regions for the purpose of this study: US and Canada (AMR-US/CAN), Latin

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America (AMR-L). We then classified countries as high income (HIC), middle income (MIC), or low income (LIC) based on the World Bank Country and Lending Groups classification system.122

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Meta-analysis

All studies in which an incidence of TSI could be extracted or calculated were included in the metaanalysis. Data were analyzed with the Comprehensive Meta-Analysis (CMA) Version 3 (Biostat, Inc.,

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Englewood, NJ, USA) and Stata14 software. Overall incidence estimates and 95% confidence intervals (CIs) were obtained using the random-effects model according to the method of DerSimonian and

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Laird,20 which accounted for variation between and within studies for all income levels and WHO regions. As no low income studies met the inclusion criteria for the meta-analysis, LICs and MICs were grouped together as a common incidence (i.e., LMICs). For the WHO regions with fewer than 2 studies included in the meta-analysis, a weighted average of all countries in that region based on the World

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Bank income classification incidence values were used to calculate WHO regional incidence values. The global incidence of TSI was then reported as a range using values calculated from a summation of the incidence of individual WHO regions as well as the global incidence value surmised from the meta-

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analysis.

Forest plots were created to visualize individual and pooled estimates. The Cochran’s Q test (P<0.10)

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was used to evaluate heterogeneity among studies. Thereafter, I-squared was used to measure the proportion of between study heterogeneity. Sub-group analyses by categorical covariates (WHO regions; country income levels) were performed to assess potential sources of heterogeneity. To further explore sources of heterogeneity, meta-regression on study quality was performed for studies included in the meta-analysis, for each WHO region (when possible), and for each income level category. Publication bias was assessed by funnel plots, Egger’s linear regression test, and Begg’s correlation test. A P-value

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<0.05 was considered significant unless otherwise indicated. The statistical analysis was conducted by a statistician who is expert in meta-analysis (RAM).

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RESULTS

Literature yield

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The initial literature search yielded a total of 5,733 articles of which 5,493 were from PubMed, 233 from Embase, and 7 from Cochrane Database of Systematic Reviews. After excluding 5,277 titles, 456

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abstracts remained, of which 165 were selected for full manuscript review (Figure 1). Bibliography review of the selected manuscripts was then performed and yielded 14 additional abstracts for review, none of which were included in the final selection. Thus, there was a total of 102 articles included in the final selection (Table

1).46,84,106,51,104,94,116,67,50,112,107,45,10,3,129,5,80,74,40,18,33,75,79,113,1,111,6,86,89,125,2,76,117,127,22,96,36,17,85,126,14,15,19,99,97,109,13,90,

3,23,91,73,8

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63,64,30,115,34,47,26,68,81,83,4,97,63,130,41,61,43,7,35,60,54,69,52,66,100,101,70,44,38,114,39,93,59,16,95,57,78,110,49,28,58,12,71,72,105,53,62,9,37,102,10

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Articles represented 32 separate countries and all WHO regions. Seven studies were from AFR, 17 from AMR-US/Can, 4 from AMR-L, 11 from SEAR, 32 from EUR, 10 from EMR, and 21 from WPR. The majority

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of source manuscripts included in this review were from HICs (n=50), while several were from MICs (n=46), and only a few from LICs (n=6). Thirty-seven studies were population based, the majority of which were from HICs (81%). No population-based studies were found from LICs. Seventy-three studies covered only SCI, while 29 studied TSI as a whole. The range of subjects within each study varied widely from 4 to 82,720, with a median of 409 subjects (Table 1).

A total of 19 articles were included in the meta-analysis (Figure 2). This included 1 from AFR, 3 from AMR-US/CAN, 2 from EMR, 12 from EUR, 1 from WPR, and none from AMR-L and SEAR. Thirteen 7

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studies were from HICs and 6 were from MICs. No incidence data were available in the LIC studies. Five of the studies included in the meta-analysis focused on TSI in general and 14 focused specifically on SCI. Heterogeneity between studies was high with an I squared value of 99.9% and a P-heterogeneity of

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<0.01. Meta-regression analysis of the Logit event rate on study quality showed a slope of 0.57 (P=0.07 in the RE model and P<0.01 in the fixed effect model) suggesting that higher quality studies tended to have a higher incidence of TSI and may be a potential source of the high level of heterogeneity. This

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positive slope was consistent across studies conducted in Europe (slope=0.83; P=0.15), LMIC

(slope=2.16; P<0.01), and HIC (slope=0.38; P=0.10) although some associations were not statistically

Incidence, demographics, and type of injury

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significant (Appendix, Section C).

The total global incidence for TSI was 10.5 cases per 100,000 persons (95% CI 8.6 – 12.84

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cases/100,000). This resulted in an estimated 768,473 – 790,695 cases of TSI worldwide each year (Table 2). Incidence of TSI, based on WHO region, ranged from 3.4 per 100,000 in EUR (95% CI 1.8-6.6 cases/100,000) to 13.7 per 100,000 in SEAR. When analyzed by income classification according to the

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World Bank Country and Lending Groups, the incidence of TSI was higher in LMICs (13.7 per 100,000 persons, 95% CI 6.4-21.0 cases/100,000) compared to HICs (8.7 per 100,000 persons, 95% CI 6.6-10.9

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cases/100,000) (Figure 3). Worldwide, 37.3% (SD ± 28.3) of patients with TSI suffered a SCI. There was a large difference between the proportion of TSI patients with SCI in HICs (25.27%, SD ± 26.8) compared to MICs (36.6%, SD ± 26.9) and especially LICs (70.4, SD ± 6.0).

Worldwide, the mean age of TSI patients was 39.8 (SD ± 12.2). Patients tended to be the oldest in WPR and the youngest in AMR-US/CAN. However, when average age was analyzed by income classification, low income countries exhibited the youngest average age at time of injury (Figure 4). Males were more commonly affected by TSI, with an average male to female ratio (M:F) of 3.37 worldwide through all 8

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WHO regions and income levels. The highest M:F ratio found was 7.35 in a report of cervical spine injury in Brazil.96 Conversely, only two reports found women to be more commonly affected than men, both of

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which were from WPR.125,115 Overall, the M:F ratio of TSI was higher in LMICs than HICs (Figure 5).

TSI was most commonly involved the cervical spine (46.02%, SD ± 19.2), whereas the lumbosacral spine was the least commonly involved (24.8%, SD ± 17.7). The proportion of cervical spine injuries cases ranged from 39% to 53% in most regions, however, the EMR had a substantially lower rate of cervical

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spine injuries (29.9%, SD ± 20.1) compared to other regions. The EMR and AMR-L were the only regions

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in which thoracic injuries surpassed the reported rate of cervical injuries on average (Figure 6). Road traffic accidents (39.5%, SD ± 16.6) followed by falls (38.8%, SD ± 17.7) were the most common mechanisms for TSI worldwide. Road traffic accidents accounted for 41.6% (SD ± 16.1) of TSI in HICs as opposed to 40.7% (SD ± 18.4) and 27.2% (SD ± 22.6) in MICs and LICs, respectively. Falls were the most common mechanism of injury in LICs (54.7%, SD ± 19.6). Sports-related injuries were relatively rare in

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MICs (2.1%, SD ± 2.8) and LICs (0.6%, SD ± 0.9) as opposed to HICs (8.6%, SD ± 5.8).

Mortality and surgical incidence

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Reported mortality rates attributed to TSI ranged from 0% to 60%. Mean mortality in HICs were 15.4%, as opposed to 3.8% in MICs. Only 1 LIC study from Ethiopia reported a mortality rate of 1.8%.8

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Furthermore, Augutis et al. (2003) reported a mortality rate of 60% within 1 year of injury in children who suffered SCI. This was the only study reporting a mortality rate greater than 50%, which the study attributed to its pediatric-only cohort, inclusion of pre-hospital deaths, and high proportion of traffic accidents.5 The proportion of patients undergoing surgical intervention ranged from 36.4% to 59.1% in the different WHO regions. Data for surgical intervention was again only available from one LIC study in which 18.2% of patients underwent surgery. On average, patients in MICs [54.9% (16.4)] were the more likely to have surgical intervention than patients in HICs ([42.5%, (26.7)]. 9

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An asymmetry to the right of the pooled TSI incidence in the funnel plot suggested the presence of publication bias with studies reporting a higher incidence being potentially missing (Appendix, Section C). However, Begg’s rank correlation test (P=0.20) indicated no publication bias but Egger’s linear

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regression test indicated a statistically significant one (P<0.01). The trim-and-fill method was used to recalculate the pooled incidence by imputing 10 studies to the right of the effect estimate. The analysis suggested that the imputed incidence only slightly increased as compared to the original pooled

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estimate.

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TSI vs SCI

Studies focusing on TSI specifically, as opposed to SCI and TSI combined, were analyzed separately to identify potential epidemiological differences. There were no significant differences in incidence, age at time of injury, mechanism of injury, or gender ratio between TSI and TSI/SCI. Analyses did show

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differences in the mortality rate and percentage of patients receiving surgery post-injury. TSI reports demonstrated a mortality rate of 6.3, half the rate observed in the TSI/SCI analyses. Furthermore, 36.6%

DISCUSSION

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of patients received surgery after a TSI injury, as opposed to 48.8% seen in TSI/SCI patients.

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To the best of our knowledge, this report represents the first attempt to define the volume of TSI worldwide. It encompassed 102 studies from 32 different countries spread out among all the WHO regions. Furthermore, studies from every income stratification of the World Bank Country and Lending Groups Classification system were included in this review.

Neurological trauma remains a significant cause of death and disability worldwide.87,92 These injuries are often due to preventable causes such as falls, road traffic accidents and violence.92 For SCI alone, it has been estimated that up to 226,000 people are affected worldwide each year.55 Much less is known on 10

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the burden of TSI as a whole. Such injuries have significant ramifications for patients and their families, as they commonly lead to death or profound disability. In more remote parts of the world, the diagnosis and treatment of TSI may be inadequate due to a lack of diagnostic equipment and healthcare personnel

resulting in neurological injury, chronic pain or deformity.48

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Current knowledge on the global epidemiology of TSI

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trained in the management of TSI.11 The delay in diagnosis and proper management of TSI can be costly,

This study was the first attempt to estimate the worldwide incidence of TSI stratified by WHO region

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(Figure 7). However, prior to this study, several authors assessed the global incidence of SCI. In 2007, Fitzharris et al. estimated the global incidence of SCI, based on 31 separate studies, to be 23 cases per 1,000,000 persons; the highest rates of which were in SEAR and WPR.29 Furlan et al. reviewed 64 articles published between 1950 and 2012 and found a wide range of reported SCI incidence, from 8 to 246

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cases per million persons. The majority of these studies were from North America and Europe, and none from Africa.31 Based on both actual and extrapolated data, Lee et al. estimated the highest incidence of SCI in North America and the lowest in Australia.55 Furthermore, they estimated a total annual number

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of SCI cases to range from 133 – 226 thousand worldwide.55 Chiu et al. compared the epidemiology of SCI between developed and developing nations and found that people with SCI in developing countries

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suffered much higher mortality rates. The mechanism of injury also differed significantly between the two groups, as road traffic accidents were the leading cause of injury in developed countries, while falls accounted for the majority of injuries in developing nations.118 Rahimi et al. looked specifically at the incidence of SCI in developing countries and found a rate of 25.5 cases per million persons per year.

Though SCI represents a major portion of the burden of TSI, these studies certainly underestimate the magnitude of burden that TSI plays on a global level. Treatment of TSI by trained surgeons often leads to

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improvement or preservation of neurological function in all income stratifications including LMICs such as Ethiopia.56

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Furthermore, surgical care can prevent limited mobility, postural deformities, and chronic pain secondary to unstable fractures which often impede individuals’ abilities to return to work or care for their families. Such conditions can result in severe economic, social and medical consequences for

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persons with TSI.

Some studies have examined the incidence of TSI on a regional or national basis. Yang et al. investigated

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the incidence of hospitalized TSI in Taiwan over several years. They found an average annual incidence of 61.61 cases per 100,000 persons.125 This estimated national incidence of all TSI in Taiwan is significantly higher than the global incidence of SCI reported by Lee et al. (2.3 cases per 100,000 persons.55 The study by Yang et al was relatively stronger as all data was collected from a national

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health insurance database, thus the only cases of TSI that were likely to be missed were those that did not present for hospitalized care. This rather high incidence may represent a much more accurate estimation of the volume of TSI than other studies that lack data from a non-porous catchment system.

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Lastly, they also looked at the rate of spinal cord injury within the TSI population and found a range from 14.5% to 43.9% depending on age group, with younger individuals (age 0 – 19) more likely to have

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suffered a neurological injury.125

Global and regional incidences of TSI

This report estimated the global incidence of TSI to be 10.5 cases per 100,000 persons. Given the worldwide population of over 7 billion people according the World Bank 2015 metadata,82 this accounts for over 700,000 new cases of TSI globally, each year. This annual burden of TSI represents a significant, yet poorly recognized, threat to global public health. The estimated incidence of TSI varied widely 12

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between WHO regions with a low value of 3.4 per 100,000 persons in AMR-L and a high rate of 13.7 per 100,000 persons in WPR. This wide variation may reflect true regional differences in the incidence of TSI,

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but also the quality of studies included in the meta-analysis.

There are several reasons why the incidence figures reported here might underestimate the volume of TSI. First, the paucity of large databases and national health systems capable of identifying all cases of TSI means that many cases of TSI likely go unreported and are not captured in the current literature.

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This is likely more pronounced in LMICs with poor database infrastructure and data reporting. Secondly,

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as the literature is biased towards reporting on SCI and not TSI in general, our incidence calculations are biased towards the incidence of SCI. Comparing the incidences reported in this study to the incidences of SCI reported by Lee et al,55 the global and regional incidences of TSI are expectedly higher than that of SCI. However, the magnitude of difference in volume of TSI and SCI is less than that reported from a large, national study on TSI by Yang et al.125,55 Thirdly, many cases of TSI, especially mild injuries, may

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simply go undiagnosed in LMICS as the availability and access to the necessary diagnostic capabilities is limited. Lastly, this report excluded all osteoporotic fractures, which can occur in the presence or absence of trauma. It is estimated that in the year 2000 there were more than 1.4 million osteoporotic

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vertebral fractures worldwide.42 This adds significantly to the volume of spinal injuries seen worldwide,

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though their etiology is not always traumatic.

There are approximately 33,000 neurosurgeons worldwide, most of which reside in Asia, Europe or North America.24,25 The aforementioned number of neurosurgeons may be higher since these estimates are 7-15 years old and are based on differing criteria for neurosurgeons. The clustering of neurosurgeons and orthopedic surgeons within certain countries around the world creates disparities in the availability of neurosurgical care depending on a person’s country or continent of residence. A stark contrast exists between places like North America, which has approximately 1 neurosurgeon for every

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81,000 residents, and Africa, where there is a single neurosurgeon for every 1,238,000 persons.25,24 Considering the paucity of neurosurgeons on the African continent in light of an estimated 13.6 new cases of TSI for every 100,000 persons in that region, many TSI victims likely struggle with accessibility of

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adequate and affordable neurosurgical care. Lack of accessibility is further highlighted in Dewan et al. (In Press) which found that over five million patients worldwide annually suffer from treatable

neurosurgical conditions, but never receive surgical interventions. The study also found people in Africa

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and South-East Asia are particularly at higher risk due to a low proportion of neurosurgeons to

neurosurgical disease.21 The lack of access to quality neurosurgical care in regions such as AFR, AMR-L

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and SEAR is only worsened by the tendency for neurosurgeons to cluster within urban areas of LMICs, thus making it even more difficult for rural populations to access care in the instance of TSI. With an average of 48.8% (SD ± 22.0) of patients with TSI undergoing surgical intervention, the shortage of global medical personnel capable of caring for TSI stands as a great impediment to the adequate delivery of

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care.

Differences in TSI demographics, injury types, and mechanism of injury

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This report confirmed that TSI affected men much more commonly than women. We found little variation between M:F ratios and country income levels (3.7 in MICs vs. 3.0 in HICs). This universal

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predilection for TSI to affect males may be secondary to unique occupational hazards or riskier behavior which lends them vulnerable to trauma.124

We found the average age of TSI worldwide was 40 years. Overall, we found that TSI victims tended to be slightly older in HICs compared to LMICs. Interestingly, there was a dichotomy between the two major regions (AMR-US/CAN and EUR) that make up a significant portion of HICs, as the average age of injury was more than 14 years higher in EUR compared to AMR-US/CAN.

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Road traffic accidents and falls were the leading causes of TSI worldwide (39.5%, SD ± 16.6 and 38.8%, SD ± 17.7). Similarly, road traffic accidents followed by falls are the most common types of unintentional injuries to cause death worldwide, yet the ratio between the two types of injury for overall mortality is

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greater than two to one in favor of road traffic accidents.120,119 Road traffic accidents leading to TSI were more common in HICs (41.6%, SD ± 16.1) compared to MICs (40.7%, SD ± 18.4) and LICs (27.2%, SD ± 22.6). The higher rate of road traffic injuries leading to TSI in HICs may reflect the fact that HICs have a

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significantly higher number of motor vehicles per capita.123 The significant amount of injuries from road traffic accidents in LMICs, despite a lower number of motor vehicle per capita, are likely secondary to

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poor road infrastructure, poor signage, as well as inadequate safety legislation and law enforcement in those countries.32 Falls were common in both HICs and LMICs, however many falls in HICs tended to occur in the elderly, whereas falls in LMICs were often work-related. A good example of the predominance of work-related falls is from hospital based studies in Pakistan and Nepal, wherein many

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falls occurred while people were working on rooftops, trees or slopes.53,102,103,86 To state that falls in the elderly population were uncommon in LMICs would be misleading, as many LMIC studies reported a high rate of fall-induced injuries in the elderly,116,34 which speaks partly to the increasing life

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expectancies and aging populations seen worldwide. Violence as a cause for TSI was more than double in MICs compared to LICs and HICs. This appears to be due to only a few countries, particularly South

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Africa,105 Mexico,90 Brazil,17 and Botswana,60 reporting a very high level of violence-related injuries and may not clearly represent MICs as a whole.

Globally, just over one-third of patients with TSI suffer SCI. The proportion of SCI in TSI patients varied greatly between income levels, with a much higher proportion of SCI in LMICs compared to HICs. This large difference in the rate of SCI is unlikely to be explained by differences in mechanisms, as road traffic accidents and falls were the most common mechanisms of injury in all income strata. However, the severity of injuries caused by these mechanisms may be higher in LMICs due to poor safety standards 15

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and regulations, thus leading to a higher proportion of SCI. A more plausible explanation is that patients in LMICs with TSI, but without neurological deficit, may be less likely to seek care due to a lack of access to care and obstructive financial costs. As such, patients in HICs with a sole complaint of pain after a

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traumatic event are more likely to seek care and subsequently be diagnosed with a TSI. This

phenomenon could certainly lead to an underestimation of the volume of TSI in LMICs. It may also partly explain the higher rate of surgical intervention seen in LMICs compared to HICs.

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Limitations and future directions

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This study sheds light on the global volume of TSI, however it is not without its limitations. First, as this study does not incorporate primary data, its strength is intimately tied to the strength of the data present in the literature. In this regard, there is a significant bias in the literature to study SCI alone as opposed to TSI. The available literature on global TSI is weakened by a limited number of studies from

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LMICs, extremely heterogeneous data reporting and a preponderance of hospital-based, cohort studies rather than population-based studies, and the limited information reported by the majority of the selected studies in the systematic review. WHO regions with especially low amounts of available data

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included the AMR-L and AFR. As a result, estimates of incidence from these regions are based upon studies from only a few countries or extrapolated by other means. TSI can be viewed as both a local and

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regional phenomenon, where regional/global epidemiological trends are present, yet discrete epidemiological variability exists on a local level. The literature and this paper are inadequate to detect variability on a local level and rather focus on regional and global epidemiology. Secondly, the data presented here are modeled estimates, not true incidences. This introduces the possibility of inaccuracies in estimating of the volume of disease. For example, the incidence of disease may be underestimated in certain regions due to a lack of data, especially in LMICs. Concurrently, data largely derived from hospital-based studies may lend to an estimation of disease incidence that is not

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representative of the country or region as a whole. The exclusion of non-English manuscripts, as the authors were unable to read or translate the text, is another limitation of this study.

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Lastly, in this study we aimed only to estimate the global volume of TSI, not the global burden of disease, which incorporates the extent of morbidity and mortality conferred by a disease. Future studies

incorporating Disability Adjusted Life Years (DALYs), Years Lived with Disability (YLDs), and Years of Life

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Lost (YLLs) are needed to quantify this important healthcare metric.

This study represents an initial step to understanding the global epidemiology of TSI, yet much more

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work is needed. Future investigations should focus on the creation of prospective, multi-institutional, regional and national databases to better characterize local incidences and causes of TSI. Work must also be done to further delineate the actual burden of TSI.

The neurosurgical community must work diligently to advocate for the prevention and treatment of TSI

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and other neurological disorders around the world. Public health policies focused on the effective prevention of TSI should be an upmost priority. Areas of particular public health interest should pertain to increasing road safety and preventing both workplace and domestic falls. To address the current and

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future burden of TSI, we must also focus on the education and training of neurosurgical providers,

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especially in LMICs, and the development of more robust surgical delivery systems around the globe.

CONCLUSION

TSI is a major source of morbidity and mortality throughout the world. It is estimated that 768,473 to 790,695 people will suffer a TSI each year. The proportion of TSI patients with SCI is much higher in LMICs compared to HICs. Partly preventable mechanisms, including road traffic accidents and falls, are the main causes of TSI globally. Further investigation is needed to delineate local and regional incidences and causes of TSI throughout the world, especially in LMICs. Public health initiatives should focus on the 17

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prevention of TSI with programs directed towards improving road safety and decreasing the incidence of falls. For the neurosurgical community, these data support the ever-loudening call for scaling-up of

stronger and more comprehensive surgical delivery systems.

ACKNOWLEDGEMENTS

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global neurosurgical capacity through increased neurosurgical education and training, and building

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We acknowledge the Vanderbilt Medical Scholars Program for providing Abbas Rattani with support on this project.

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129.

130.

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Appendix A: List of terms used for PubMed systematic review

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((("epidemiology" [Subheading] OR "Epidemiology"[Mesh] OR epidemiology[tiab] OR epidemiological[tiab] OR population[tiab] OR population-based[tiab] OR inciden*[tiab] OR prevalen*[tiab] OR burden[tiab] OR DALY[tiab] OR “disability adjusted life year*”[tiab] OR YLL[tiab] OR “years of life lost”[tiab] OR YLD[tiab] OR “years lost to disability”[tiab] or “years lost due to disability”[tiab] OR ratio[tiab] OR QALY[tiab] OR “quality adjusted life year*”[tiab])) AND “spinal injuries”[MESH] OR “spinal cord injuries”[MESH] OR "spinal fractures"[MESH] OR “spinal fracture*”[tiab] OR “spinal fracture dislocation*”[tiab] OR “chance fracture*”[tiab] OR "transverse process fracture*”[tiab] OR "spinous process fracture*"[tiab] OR “burst fracture*”[tiab] OR “vertebral fracture*”[tiab] OR “cervical fracture*”[tiab] OR “thoracic fracture*”[tiab] OR “lumbar fracture*”[tiab] OR “facet fracture*”[tiab] OR “endplate fracture*”[tiab] OR “spinal injury”[tiab] OR “spinal cord injury”[tiab] OR “spinal column injury” OR “spinal injuries”[tiab] OR “spinal cord injuries”[tiab] OR “spinal column injuries” OR ((“spinal ligament”[tiab]) AND (trauma[tiab] OR traumatic[tiab] OR injur*[tiab])) AND ("Africa"[mesh] OR "Asia"[mesh] OR "Central America"[mesh] OR "Developing Countries"[mesh] OR "Geographical Locations Category"[Mesh] OR "Internationality"[Mesh] OR "Latin America"[mesh] OR "South America"[mesh] OR “Dominican Republic”[tiab] OR “Principe”[tiab] OR “Puerto Rico”[tiab] OR “Sao Tome”[tiab] OR “Saudi Arabia”[tiab] OR “Sierra Leone”[tiab] OR “Virgin Islands”[tiab] OR Afghanistan*[tiab] OR Africa*[tiab] OR Albania*[tiab] OR Algeria*[tiab] OR America*[tiab] OR Andorra*[tiab] OR Angola*[tiab] OR Antarct*[tiab] OR Antigua*[tiab] OR Arab Emirate*[tiab] OR Argentin*[tiab] OR Armenia*[tiab] OR Aruba*[tiab] OR Asia*[tiab] OR Atlantic[tiab] OR Australia*[tiab] OR Austria*[tiab] OR Azerbaijan*[tiab] OR Azores Islands[tiab] OR Baham*[tiab] OR Bahra*[tiab] OR Bangladesh*[tiab] OR Barbad*[tiab] OR Barbuda*[tiab] OR Barthelemy[tiab] OR Barthélemy[tiab] OR Belarus*[tiab] OR Belgi*[tiab] OR Belize[tiab] OR Bengali[tiab] OR Benin*[tiab] OR Bermuda*[tiab] OR Bhutan*[tiab] OR Bissau[tiab] OR Bolivia*[tiab] OR Bosnia*[tiab] OR Botswana*[tiab] OR Brazil*[tiab] OR Brunei[tiab] OR Bulgaria*[tiab] OR Burkina Faso[tiab] OR Burma[tiab] OR Burmese*[tiab] OR Burundi*[tiab] OR Cabo Verd*[tiab] OR Caicos[tiab] OR Cambodia*[tiab] OR Cameroon*[tiab] OR Canad*[tiab] OR Cape Verd*[tiab] OR Cayman[tiab] OR Central[tiab] OR Chad*[tiab] OR Chile[tiab] OR China[tiab] OR Chinese[tiab] OR Colombia*[tiab] OR Comoros[tiab] OR Congo*[tiab] OR Costa Rica*[tiab] OR Cote[tiab] OR Cote d'Ivoire[tiab] OR Croatia*[tiab] OR Cuba[tiab] OR Cuban[tiab] OR Cyprus[tiab] OR Czech Republic[tiab] OR Denmark[tiab] OR developing countr*[tiab] OR developing nation*[tiab] OR Djibouti[tiab] OR Dominica*[tiab] OR East[tiab] OR East Timor[tiab] OR Ecuador*[tiab] OR Egypt*[tiab] OR El Salvador*[tiab] OR Eritrea*[tiab] OR Estonia*[tiab] OR Ethiopia*[tiab] OR Europ*[tiab] OR Fiji*[tiab] OR Finland[tiab] OR France[tiab] OR French Guiana[tiab] OR Gabon*[tiab] OR Gambia*[tiab] OR Gaza*[tiab] OR Georgia*[tiab] OR German*[tiab] OR Ghana*[tiab] OR Greece[tiab] OR Grenada*[tiab] OR Grenadines[tiab] OR Guadeloupe[tiab] OR Guatemala*[tiab] OR Guinea*[tiab] OR Guyan*[tiab] OR Haiti*[tiab] OR Herzegovina*[tiab] OR Hondura*[tiab] OR Hungary[tiab] OR Iceland*[tiab] OR income[tiab] OR India[tiab] OR Indian*[tiab] OR Indonesia*[tiab] OR Iran*[tiab] OR Iraq*[tiab] OR Ireland[tiab] OR Israel*[tiab] OR Italian[tiab] OR Italy[tiab] OR Ivory Coast[tiab] OR Jamaica*[tiab] OR Japan*[tiab] OR Jordan*[tiab] OR Kazakh*[tiab] OR Kenya*[tiab] OR Kiribati[tiab] OR Kitts[tiab] OR Korea*[tiab] OR Kosovar*[tiab] OR Kosovo[tiab] OR Kuwait*[tiab] OR Kyrgyz*[tiab] OR Lao[tiab] OR Laos*[tiab] OR Laotian*[tiab] OR latin america[tiab] OR Latvia[tiab] OR Lebanes*[tiab] OR

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Lebanon[tiab] OR lebonese[tiab] OR Lesotho[tiab] OR less developed countr*[tiab] OR less developed nation*[tiab] OR Liberia*[tiab] OR Libya*[tiab] OR Liechtenstein[tiab] OR Lithuania[tiab] OR lmic[tiab] OR lmics[tiab] OR low income countr*[tiab] OR low income nation*[tiab] OR Lucia[tiab] OR Luxembourg[tiab] OR Macedonia*[tiab] OR Madagascar*[tiab] OR Madeira Island[tiab] OR Malawi*[tiab] OR Malaysia*[tiab] OR Maldives[tiab] OR Mali[tiab] OR Malta[tiab] OR Marshall Island*[tiab] OR Martinique[tiab] OR Mauritania*[tiab] OR Mauriti*[tiab] OR Mexican*[tiab] OR Mexico[tiab] OR Micronesia*[tiab] OR middle income countr*[tiab] OR middle income nation*[tiab] OR Moldova[tiab] OR Moldova*[tiab] OR Monaco[tiab] OR Mongolia*[tiab] OR Montenegr*[tiab] OR Montserrat[tiab] OR Morocc*[tiab] OR Mozambique[tiab] OR Myanmar[tiab] OR Namibia*[tiab] OR Nauru[tiab] OR Nepal*[tiab] OR Nevis[tiab] OR New Zealand[tiab] OR Nicaragua*[tiab] OR Niger*[tiab] OR Nigeria*[tiab] OR North[tiab] OR Norway[tiab] OR Oman*[tiab] OR Pacific[tiab] OR Pakistan*[tiab] OR Palau[tiab] OR Palestin*[tiab] OR Panama*[tiab] OR Papua[tiab] OR Paraguay*[tiab] OR Peru*[tiab] OR Philippin*[tiab] OR Poland[tiab] OR poor countr*[tiab] OR poor nation*[tiab] OR Portug*[tiab] OR Principe[tiab] OR Qatar*[tiab] OR Romania*[tiab] OR Russia*[tiab] OR Rwanda*[tiab] OR Saint Lucia[tiab] OR Saint Vincent[tiab] OR Samoa*[tiab] OR San Marino[tiab] OR Sao Tome[tiab] OR Senegal*[tiab] OR Serbia*[tiab] OR Seychelles[tiab] OR Sierra Leone*[tiab] OR Singapore[tiab] OR Slovakia*[tiab] OR Slovenia*[tiab] OR Solomon[tiab] OR Solomon Island*[tiab] OR Somalia*[tiab] OR South [tiab] OR Spain[tiab] OR Sri Lanka[tiab] OR Sudan*[tiab] OR Suriname*[tiab] OR Swaziland*[tiab] OR Swed*[tiab] OR Switzerland[tiab] OR Syria*[tiab] OR Taiwan[tiab] OR Tajik*[tiab] OR Tanzania*[tiab] OR Thai*[tiab] OR third world countr*[tiab] OR third world nation*[tiab] OR Timor Leste[tiab] OR Timor*[tiab] OR Tobago[tiab] OR Togo*[tiab] OR Tonga*[tiab] OR Trinidad*[tiab] OR Tunisia*[tiab] OR Turkey[tiab] OR Turkish[tiab] OR Turkmen*[tiab] OR Turks[tiab] OR Tuvalu*[tiab] OR Uganda*[tiab] OR Ukrain*[tiab] OR under developed countr*[tiab] OR under developed nation*[tiab] OR underdeveloped nation*[tiab] OR underdeveloped nation*[tiab] OR United Kingdom[tiab] OR United States[tiab] OR Uruguay[tiab] OR Uzbeki*[tiab] OR Vanuatu*[tiab] OR Vatican[tiab] OR Venezuela*[tiab] OR Viet nam*[tiab] OR Vietnam*[tiab] OR Vincent[tiab] OR West[tiab] OR West Bank[tiab] OR Yemen*[tiab] OR Zambia*[tiab] OR Zimbabw*[tiab]) NOT ("Animals"[mesh] NOT "Humans"[mesh])

0: Small (<100 patients), single institution-based studies 1: Large (>100patients), single institution-based studies 2: Multiple institution, non-population based and/or trauma registry-based studies 3: Large, population-based studies focused on SCI only 4: Large, population-based studies on TSI, poor methodology 5: Large, population-based studies on TSI, good methodology

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Funnel Plot of Standard Error by Logit event rate 0.0

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0.2

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0.3

0.4 -20

-10

M AN U

Standard Error

0.1

0

Logit event rate

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Table 1. Manuscript Overview Year

Country

WHO Region

Income Level

2008 Japan

WPR

High

Rahimi

2008 Iran

EMR

Middle

Stephan

2015 Germany

EUR

High

Korhonen

2014 Finland

EUR

Smith

2014 Ireland

EUR

Sabre

2015 Estonia

EUR

High

Wang

2012 China

WPR

Middle

Moradi

2011 Iran

Middle

Kokoska

2000 USA

EMR AMRUS/Can

Van Asbeck

2000 Netherlands

Surkin

2000 USA

Karacan

2000 Turkey

Burke

TSI Cases (n)

Study Period

Gender Study design ratio (M:F)

15,640

127

2003-2005

Retrospective

9,006

4

2007-2008

1 Cross-sectional

57,310

4,285

2002-2012

Retrospective

High

5,400,000

372

1970-2011

High

4,581,269

58

2001-2010

391

2005-2007

3,142

2001-2010

16,000

619

2006-2007

High

25,500

408

EUR AMRUS/Can

High

15,100,000

126

Middle

2001 USA

EUR AMRUS/Can

Ali Raja

2001 Pakistan

EMR

Middle

Zhao

2001 China

WPR

Middle

Augutis

2003 Sweden

High

Pickett

2002 Canada

EUR AMRUS/Can

O’Connor

2005 Australia

High

Jackson

2004 USA

WPR AMRUS/Can

Dahlberg

2005 Finland

EUR

Gur

2005 Turkey

EUR

O’Connor

2006 Ireland

High

Pickett

2006 Canada

Vitale

2006 USA

EUR AMRUS/Can AMRUS/Can

Agarwal

2007 India

SEAR

Upendra

2007 India

SEAR

Bajracharya

2007 Nepal

Rathore

2008 Pakistan

High

High

45,784,957

TE D

2

Population Based

3

Other

2

Population Based

4

Retrospective

Hospital Based

2

3.9 Retrospective

Population Based

3

1.9 Retrospective

Hospital Based

2

Population Based

4

Other

2

2.17 Retrospective 1.44 Retrospective

1994

3.3 Retrospective

Population Based

3

4.1 Prospective

Population Based

3

2.5 Cross-sectional

Population Based

3

Other

2

Hospital Based

2

Population Based

3

1992-1994

1992

1993-1998

3 Retrospective

2,654

1995-1999

2.6 Retrospective

1995

7 Cross-sectional

92

1985-1996

1.04 Retrospective

Population Based

3

2,385

1994-1999

2.17 Retrospective

Other

2

2,959

1986-1997

Population Based

3

30,532

1973-2003

4.3 Retrospective

Other

2

3.2 Cross-sectional

Population Based

3

3.4 Retrospective

Hospital Based

2

6.7 Prospective

Hospital Based

2

Hospital Based

2

Population Based

3

Cross-sectional

152

1999

539

1990-1999

46

2000

924,257

151

1997-2001

3 Retrospective

14,000,000

2,909

1997-2000

2.54 Retrospective

Middle

181

2003-2004

3.6 Retrospective

Hospital Based

1

Middle

440

1990-2000

4.58 Retrospective

Hospital Based

1

SEAR

Low

896

1996-2006

3.2 Retrospective

Hospital Based

1

EMR

Middle

83

2006

4.5 Prospective

Hospital Based

0

2007 Ireland

EUR

High

465,000

285

1.58 Retrospective

Hospital Based

2

2008 Taiwan

WPR

High

21,984,415

54,484

2000-2003

0.99 Retrospective

Population Based

4

2008 Finland

EUR

High

1,647

1976-2005

4.8 Retrospective

Hospital Based

2

Obalum

2009 Nigeria

Middle

468

1992-2006

2.34 Retrospective

Hospital Based

1

Wang

2009 USA

AFR AMRUS/Can

2,530

1994-2002

1.3 Retrospective

Population Based

4

Ye

57

1993-2006

3.4 Retrospective

Hospital Based

2

Divanogluo

2009 China WPR sweden/gree 2009 ce EUR

High

Santos

2009 Brazil

AMR-L

Middle

Hagen

2010 Norway

EUR

High

Yang Ahoniemi

Middle

High

EP

AC C

Roche

546,000

Hospital Based

Retrospective

161

246,812

High

High

581

Study Quality

1994-1999

M AN U

High

395

Study Scale

RI PT

Kato

Population at Risk (N)

SC

Author

High

High

20,276

Middle 87/49 2,148,835

2006

7.1/3.3 Prospective

Population Based

3

217

1997-2006

7.35 Prospective

Population Based

5

336

1952-2001

Population Based

3

4.7 Retrospective

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Costacurta

2010 Brazil

AMR-L

Middle

54

2002-2008

Retrospective

Rahimi

2010 Iran

EMR

Middle

496

2008

Yang

2016 China

WPR

Middle

1,340

Chen

2016 China

Middle

Chen

2016 USA

WPR AMRUS/Can

Derakhshaad

2016 Iran

Selassie

1

2.2 Retrospective

Population Based

3

2003-2011

3.5 Retrospective

Hospital Based

2

232

2009-2013

4 Retrospective

Hospital Based

2

30,881

1970-2014

4.2 Cross-sectional

Population Based

3

3.8 Cross-sectional

Hospital Based

1

2.9 Cross-sectional

Population Based

3

2.6 Retrospective

Population Based

4

2.9 Retrospective

Population Based

3

3.6 Retrospective

Hospital Based

1

1.5 Retrospective

Population Based

4

2009-2012

2.2 Retrospective

Population Based

4

2001-2010

0.63 Retrospective

Hospital Based

2

Hospital Based

0

1,137

2011-2015

High

3,365

1998-2012

Thesleff

2015 Finland

EUR

High

2,041

1987-2010

Chamberlain RodríguezMeza MendozaLattes

2015 Switzerland

EUR

High

932

2005-2012

2016 Mexico

Middle

464

2006-2013

2015 USA

AMR-L AMRUS/Can

High

80,167,284

6,191

1997-2009

Fredø

2014 Norway

EUR

High

4,920,000

3,248

Wang

2014 China

WPR

Middle

642

Güzelküçük

2014 Turkey

EUR

Middle

37

2010-2013

Retrospective

Katoh

2014 Japan

WPR

High

91

2011-2012

2.6 Retrospective

Population Based

3

Erdoğan

2013 Turkey

EUR

Middle

409

2007-2011

1.6 Retrospective

Hospital Based

1

New

2011 Australia

High

1,364

2002-2006

2.52 Retrospective

Other

3

Pirouzmand

2010 Canada

WPR AMRUS/Can

12,192

1986-2006

1.94 Retrospective

Hospital Based

1

Puisto

2009 Finland

EUR

High

749

1997-2006

1.04 Retrospective

Population Based

5

Ametefe

2016 Ghana

Low

185

2012-2014

3.2 Retrospective

Hospital Based

1

Saunders

2015 USA

AFR AMRUS/Can

490

1998-2012

2.86 Retrospective

Population Based

3

McCaughey

2016 Scotland

EUR

1994-2013

3.03 Retrospective

Other

3

Zhou

2016 China

354

2009-2014

2.34 Retrospective

Hospital Based

1

Jain

2015 USA

WPR AMRUS/Can

High

3,393

1993-2012

Retrospective

Population Based

0

Majdan

2016 Austria

EUR

High

8,272,469

1,543

2002-2012

1.82 Retrospective

Population Based

3

Joseph

2015 South Africa AFR

Middle

3,860,000

147

2013

5.9 Prospective

Population Based

3

Bellucci

2015 Brazil

348

2012

Hospital Based

1

2015 Botswana

Koskinen Moorin Selvarajah SharifAlhoseini

M AN U 1,100,000

TE D High

5,144,625

Middle

EP

2015 Turkey

Löfvenmark

New

High

776,790

AMR-L

Middle

EUR

Middle

805

242

2009-2013

4.15 Retrospective

Hospital Based

1

AFR

Middle

2,000,000

52

2011-2013

2.5 Prospective

Hospital Based

1

341

2008-2011

5.4 Retrospective

Hospital Based

1

1,364

2002-2006

2.51 Retrospective

Population Based

3

77

2012

2.1 Prospective

Population Based

3

Population Based

3

Other

2

AC C

Güzelküçük

Lalwani

High

RI PT

Middle

2015 USA

EMR AMRUS/Can

SC

High

Hospital Based

5.56 Cross-sectional

2014 India

SEAR

Middle

2015 Australia

WPR

High

2014 Finland

EUR

High

2014 Australia

High

335

2003-2008

2.94 Retrospective

2014 USA

WPR AMRUS/Can

High

6,132

2007-2010

1.2 Retrospective

138

2010-2011

5.57 Retrospective

Hospital Based

2

185

2010

2.85 Retrospective

Other

2

206

2009-2012

Hospital Based

0

3,065,946

2014 Iran

EMR

Middle

Nijendijk

2014 Netherlands

EUR

High

867

Kamravan

2014 Iran

EMR

Middle

Hua

2013 China

WPR

Middle

561

2001-2010

4.1 Retrospective

Hospital Based

1

Wang

2013 China

WPR

Middle

761

2007-2010

3.4 Retrospective

Hospital Based

1

261

3 Cross-sectional

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2013 Malaysia

SEAR

Middle

449

167

2006-2009

3.3 Cross-sectional

Hospital Based

1

Sabre

2013 Estonia

EUR

High

545,533

71

1997-2001

3.4 Retrospective

Population Based

3

Sabre

2013 Norway

EUR

High

1,361,242

244

1997-2001

6 Retrospective

Population Based

3

Liu

2012 China

WPR

Middle

82,720

2001-2007

2.33 Retrospective

Other

2

Chhabra

2012 India

SEAR

Middle

1,138

2002-2010

5.9 Retrospective

Hospital Based

1

Sabre

2012 Estonia

High

1,340,000

595

1997-2007

5.5 Retrospective

Population Based

3

Lenehan

2012 Canada

EUR AMRUS/Can

High

4,200,000

930

1995-2004

4 Prospective

Population Based

3

Pérez

2012 Spain

EUR

High

10,274

2000-2009

2.8 Retrospective

Population Based

3

Tuğcu

2011 Turkey

EUR

Middle

Hospital Based

1

Knútsdóttir

2012 Iceland

EUR

High

Population Based

3

Feng

2011 China

WPR

Hospital Based

1

Li

2011 China

Other

2

Yousefzadeh

2000-2007 1975-2009

Middle

239

1998-2009

WPR

Middle

264

2010 Iran

EMR

Middle

245

Ning

2011 China

WPR

Middle

869

Ning

2016 China

WPR

Middle

Sothmann

2015 South Africa AFR

Middle

lakhey

2005 Nepal

SEAR

Low

Mathur

2015 India

SEAR

Middle

Brolin

2002 Sweden

EUR

High

Heidari

2010 Iran

EMR

Middle

Shrestha

2007 Nepal

SEAR

Low

Shrestha

2014 Nepal

Low

Dryden

2003 Canada

SEAR AMRUS/Can

High

Roohi

2006 Malaysia

SEAR

Middle

Nwadinigwe

2004 Nigeria

AFR

Middle

Biluts

2015 Ethiopia

AFR

Low

385

4.2 Retrospective 3 Retrospective

2005-2006

2.55 Retrospective

Hospital Based

1

2004-2008

5.63 Retrospective

Other

2

554

2009-2013

4.33 Retrospective

Hospital Based

1

2,042

2003-2014

5.25 Retrospective

Hospital Based

1

233

1997-2001

2.64 Retrospective

Hospital Based

1

8,178

2716

2000-2008

4.2 Prospective

Hospital Based

1

1,450,000

4168

1987-1999

1.29 Retrospective

Other

4

16,321

TE D

EP

2.63 Retrospective

2002

1,644

619

1999-2004

2.17 Cross-sectional

Other

2

149

2001-2004

4 Retrospective

Hospital Based

1

381

2008-2011

2.77 Retrospective

Hospital Based

1

450

1997-2000

2.52 Retrospective

Other

2

78

1998

3.76 Retrospective

Hospital Based

0

104

1996-2001

5.5 Retrospective

Hospital Based

1

2008-2012

5.76 Retrospective

Hospital Based

1

TABLE 1. Manuscript Overview. List of Abbreviations: M:F = Male:Female AFR = Africa Region AMR-US/Can = Americas Region-United States and Canada AMR-L = Americas Region-Latin America EMR = Eastern Mediterranean Region EUR = Europe Region SEAR = South-East Asia Region WHO = World Health Organization WPR = Western Pacific Region

AC C

Retrospective

SC

207

M AN U

268,500

RI PT

Ibrahim

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Table 2. Incidence and annual volume of traumatic spinal injury by WHO region WHO Incidence 95% CI - 95% Population # persons affected per Region (per LL CI – annum [95% CI] 100,000) UL* AFR 13.6* 990,267,592 134,676 [***] AMR5.1 1.4 19.0 357,270,594 18,220 [5,002-67,881] US/Can AMR-L 12.6* 630,250,409 79,412 [***] EMR 5.2 1.0 26.3 648,060,427 33,699 [6480-170,440] EUR 3.4 1.8 6.6 914,533,173 31,094 [16,462-60,359] SEAR 13.7* 1,928,530,522 264,209 [***] WPR 12.4* 1,849,874,735 229,385 [***] LMIC 13.69 6.39 20.98 6,160,085,274 843,316 [393,629-1,292,385] HIC 8.72 6.56 10.88 1,163,727,841 101,477 [76,341-126,614] Worldwide 10.5 8.16 12.84 7,318,787,452 768,473 [597,213-939,732]

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Table 2: Worldwide and WHO region incidence per 100,000 persons are described with 95% confidence upper and lower limits. Number of persons affected per annum based on the described incidence and population are also shown.* Incidence values for regions with <2 studies included in the meta-analysis were calculated using a weighted average of the income classification incidence of the countries comprising that region. The worldwide # persons affected per annum reflects a range obtained by calculating the product of the lower and upper limits of the 95% confidence interval and the respective population divided by 100,000. ***Reliable CI estimates not reported given the manner of aggregation of crude incidence rates across income levels List of Abbreviations: AFR = Africa Region AMR-US/Can = Americas Region-United States and Canada AMR-L = Americas Region-Latin America CI – LL = Confidence Interval – Lower Limit CI – UL = Confidence Interval – Upper Limit CI = Confidence Interval EMR = Eastern Mediterranean Region EUR = Europe Region SEAR = South-East Asia Region WHO = World Health Organization WPR = Western Pacific Region

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Figure 1. PRISMA Flowchart

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Figure 1. Flowchart illustrates the exclusion and selection process of the 102 manuscripts included in the final manuscript review.

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Figure 2. Forest plot of event rates for WHO regions

Figure 2: Forest plot represents the incidence per 100,000 persons (95% CI) of traumatic spinal injury by WHO regions from 19 studies. Solid squares represent the point estimate of each study and the diamonds represent the pooled estimate of the incidence for each subgroup. The width of the diamond denotes 95%CIs. The size of the solid squares is proportional to the weight of the study. Weights are from random-effects analysis using the method of DerSimonian and Laird.

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Figure 3: Forest plot of traumatic spinal injury incidence by income level

Figure 3: Forest plot represents the incidence per 100 (95% CI) of traumatic spinal injury by 2 income levels from 19 cross-sectional studies. Solid squares represent the point estimate of each study and the diamonds represent the pooled estimate of the incidence for each subgroup. The width of the diamond denotes 95%CIs. The size of the solid squares is proportional to the weight of the study. Weights are from random-effects analysis using the method of DerSimonian and Laird. The first group represents the high-income level; the second group represents the low/middle.

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Figure 4. Mean age at time of injury

SEAR

36.40

EUR

44.05

EMR

34.80

AMR-US/Can

29.33

AMR-L

30.23

AFR

34.88

Total

39.83

0.00

10.00

20.00

30.00

Figure 4a.

40.00

50.00

SC

46.21

60.00

M AN U

WPR

RI PT

Mean Age by WHO Region

70.00

41.24

Middle

38.83

Low

36.40

Total

39.83

10

AC C

0

EP

High

TE D

Mean Age by Income Level

20

30

40

50

60

Figure 4b.

Figure 4: Mean age at time of injury is illustrated in Figure 4a and 4b by WHO region and income level, respectively.

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Figure 5. Mean gender ratio of TSI victims

3.23

SEAR

3.94

EUR

3.26

EMR

2.96

AMR-US/Can

2.74

AMR-L

5.50

AFR

4.35

TOTAL

3.37 1.00

2.00

3.00

4.00

5.00

6.00

7.00

8.00

M AN U

0.00

SC

WPR

RI PT

Mean Gender Ratio by WHO Region

Figure 5a.

Middle

3.71

Low

3.60

Total

3.37

EP

3.01

AC C

High

TE D

Mean Gender Ratio by Income Level

0.00

1.00

2.00

3.00

4.00

5.00

6.00

Figure 5b.

Figure 5: Mean gender ratio based on WHO region and income level are respectively illustrated in Figure 5a and 5b.

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Figure 6. Anatomic distribution of Injury

SE A R

35.03 26.06 40.19

E U R

23.89 32.68 39.59

E M R

29.37 46.12 29.85

A F R

24.21 24.06 50.08 9.45 51.50 39.10

TE D

19.60 26.11 53.94

T O 24.84 30.68 T 46.02 A… 0

10

20

EP

A M RU… A M RL

SC

27.05 26.75 47.60

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W P R

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Distribution of Injury by WHO Region (%)

30

Lumbosacral

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Figure 6a.

40 Thoracic

50 Cervical

60

70

80

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Middle

26.84 31.77 41.90

Low

29.07 30.19 39.25

Total

24.84 30.68 46.02 0

10

20

SC

22.23 29.22 51.41

30

40

M AN U

High

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Distribution of Injury by Income Level (%)

Lumbosacral

Figure 6b.

Thoracic

50

60

Cervical

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Figure 6: Distribution of injury (lumbosacral, thoracic, or cervical) based on WHO region and income level are respectively illustrated in Figure 6a and 6b.

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Figure 7. Incidence of Traumatic Spinal Injury by WHO Region

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Figure 7: Annual incidence of TSI is illustrated by WHO region on the left. Burden of TSI is illustrated by WHO region and income region on the right.

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Traumatic spinal injury: global epidemiology and worldwide volume Highlight Findings: TSI is a major source of morbidity and mortality throughout the world.

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Males were more likely affected by TSI in all WHO regions and World Bank income levels.

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Preventable mechanisms, including RTAs and falls, are main causes of TSI globally.

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The neurosurgical community must work to strength global neurosurgical capacity to TSI management.

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AFR= Africa AMR-L= Latin American Region AMR-US/CAN= U.S.A. and Canada DALY= Disability Adjusted Life Years EUR= Europe EMR= Eastern Mediterranean Region HIC= High income country LIC= Low income country LMICs= Low and Middle income countries MIC= Middle income country SCI= Traumatic spinal cord injury SEAR= South-East Asia Region TSI= traumatic spinal injury WPR= Western Pacific Region WHO= World Health Organization YLD= Years Lived with Disability YLL= Years of Life Lost

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List of Abbreviations for Manuscript

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Acknowledgements and Disclosures This research received no specific grant from any funding agency in the public, commercial, or not-for-profit sectors.

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The authors report no conflict of interest concerning the materials or methods used in this study or the findings specified in the manuscript.