Association between chiropractic spinal manipulation and cauda equina syndrome in adults with low back pain: Retrospective cohort study of US academic health centers

Robert J Trager; Anthony N Baumann; Jaime A Perez; Jeffery A Dusek; Romeo-Paolo T Perfecto; Christine M Goertz

doi:10.1371/journal.pone.0299159

. 2024 Mar 11;19(3):e0299159. doi: 10.1371/journal.pone.0299159

Association between chiropractic spinal manipulation and cauda equina syndrome in adults with low back pain: Retrospective cohort study of US academic health centers

Robert J Trager ^1,^2,^3,^*, Anthony N Baumann ^4,⁵, Jaime A Perez ⁶, Jeffery A Dusek ², Romeo-Paolo T Perfecto ^3,^7,⁸, Christine M Goertz ^7,^8,⁹

Editor: Shabnam ShahAli¹⁰

¹Connor Whole Health, University Hospitals Cleveland Medical Center, Cleveland, Ohio, United States of America

²Department of Family Medicine and Community Health, Case Western Reserve University School of Medicine, Cleveland, Ohio, United States of America

³Department of Biostatistics and Bioinformatics Clinical Research Training Program, Duke University School of Medicine, Durham, North Carolina, United States of America

⁴Department of Rehabilitation, University Hospitals Cleveland Medical Center, Cleveland, Ohio, United States of America

⁵College of Medicine, Northeast Ohio Medical University, Rootstown, Ohio, United States of America

⁶Clinical Research Center, University Hospitals Cleveland Medical Center, Cleveland, Ohio, United States of America

⁷Department of Orthopaedic Surgery, Duke University, Durham, North Carolina, United States of America

⁸Duke Clinical Research Institute, Durham, North Carolina, United States of America

⁹Robert J. Margolis, MD, Center for Health Policy, Duke University, Durham, North Carolina, and Washington, District of Columbia, United States of America

¹⁰Iran University of Medical Sciences, ISLAMIC REPUBLIC OF IRAN

Competing Interests: Robert J. Trager acknowledges that he has received royalties as the author of two texts on the topic of sciatica. The authors have declared no competing interests.

^✉

* E-mail: Robert.Trager@duke.edu

Roles

Robert J Trager: Conceptualization, Data curation, Formal analysis, Investigation, Methodology, Software, Visualization, Writing – original draft, Writing – review & editing

Anthony N Baumann: Conceptualization, Investigation, Methodology, Writing – review & editing

Jaime A Perez: Data curation, Formal analysis, Investigation, Methodology, Resources, Software, Visualization, Writing – review & editing

Jeffery A Dusek: Conceptualization, Project administration, Supervision, Writing – review & editing

Romeo-Paolo T Perfecto: Software, Visualization, Writing – review & editing

Christine M Goertz: Conceptualization, Investigation, Methodology, Project administration, Supervision, Writing – review & editing

Shabnam ShahAli: Editor

PMCID: PMC10927125 PMID: 38466710

Abstract

Background

Cauda equina syndrome (CES) is a lumbosacral surgical emergency that has been associated with chiropractic spinal manipulation (CSM) in case reports. However, identifying if there is a potential causal effect is complicated by the heightened incidence of CES among those with low back pain (LBP). The study hypothesis was that there would be no increase in the risk of CES in adults with LBP following CSM compared to a propensity-matched cohort following physical therapy (PT) evaluation without spinal manipulation over a three-month follow-up period.

Methods

A query of a United States network (TriNetX, Inc.) was conducted, searching health records of more than 107 million patients attending academic health centers, yielding data ranging from 20 years prior to the search date (July 30, 2023). Patients aged 18 or older with LBP were included, excluding those with pre-existing CES, incontinence, or serious pathology that may cause CES. Patients were divided into two cohorts: (1) LBP patients receiving CSM or (2) LBP patients receiving PT evaluation without spinal manipulation. Propensity score matching controlled for confounding variables associated with CES.

Results

67,220 patients per cohort (mean age 51 years) remained after propensity matching. CES incidence was 0.07% (95% confidence intervals [CI]: 0.05–0.09%) in the CSM cohort compared to 0.11% (95% CI: 0.09–0.14%) in the PT evaluation cohort, yielding a risk ratio and 95% CI of 0.60 (0.42–0.86; p = .0052). Both cohorts showed a higher rate of CES during the first two weeks of follow-up.

Conclusions

These findings suggest that CSM is not a risk factor for CES. Considering prior epidemiologic evidence, patients with LBP may have an elevated risk of CES independent of treatment. These findings warrant further corroboration. In the meantime, clinicians should be vigilant to identify LBP patients with CES and promptly refer them for surgical evaluation.

Introduction

The cauda equina is a bundle of nerve roots arising from the spinal cord at the upper lumbar spine [1, 2]. Compression of these nerve roots, typically by a disc herniation [1, 3], can cause cauda equina syndrome (CES). Signs and symptoms of CES include one or more of the following (1) bladder/bowel dysfunction, (2) reduced saddle area sensation or (3) sexual dysfunction [4], and potentially low back pain (LBP) or lower extremity symptoms [4]. CES with neurological deficits is a medical emergency and surgical intervention is recommended within 48 hours to prevent permanent damage [5]. While CES is rare among asymptomatic individuals (0.6 cases per 100,000 per year), it is more common among those with LBP, affecting 270 per 100,000 (0.27%) per year in secondary care settings [6].

CES has given rise to a substantial number of medicolegal cases within both the chiropractic and physical therapy (PT) professions, perhaps because these clinicians commonly manage LBP [7–9]. It is thought that some of these cases occur because clinicians fail to recognize evolving CES features and refer appropriately, leading to a delay in diagnosis and surgery [5, 7–10]. However, in some instances, the degree to which the clinician was negligent is unclear as early identification of CES is compounded by potentially mild or gradually-developing symptoms [10]. For example, a broad review of medicolegal CES cases found that only 27% of patients initially presented with loss of bowel or bladder function [5].

In addition to the possibility of missed CES cases, concerns have been raised regarding documented cases of CES that occurred following chiropractic spinal manipulation (CSM). It has been hypothesized that CSM increases spinal loading, which potentially worsens the type of pre-existing disc injuries that can lead to CES [11, 12]. However, others have suggested that CSM is likely not a meaningful risk factor for CES due to its rarity following CSM when compared to the millions of CSM treatments administered annually [13–15]. In fact, a retrospective study including 54,846 patients of all ages and with various chief complaints found no instances of CES following 960,140 sessions of CSM [16]. However, to the authors’ knowledge, no additional large studies have examined this issue.

Chiropractors are increasingly sought by patients in the US for the treatment of LBP [17]. A recent study based on insurance claims revealed that chiropractors were among the most commonly visited healthcare providers for new episodes of LBP, ranking second only to primary care physicians (25.2% of episodes with primary care versus 24.8% with a chiropractor) [18]. Furthermore, chiropractors use spinal manipulation more frequently than any other type of clinician [18].

Half of chiropractic patients have LBP, [19] with a subset of these patients having lumbar disc herniation [20]. Although CES is a rare event, lumbar disc herniation is its most common cause [2] and is also frequently present among those with LBP [21]. Accordingly, chiropractors may encounter patients who have a heightened risk of developing CES, as these clinicians treat those with LBP and disc disorders [11, 14].

Considering CSM is commonly used for LBP, wherein underlying disc degeneration may pose a risk factor for CES [11, 14], researchers have emphasized the importance of studying the potential association between CSM and CES [14, 22]. Mild adverse events related to CSM, such as transient soreness, are accepted to be common and occur in 23–83% of patients [23]. However, less is known regarding the potential for CSM to cause CES, as the existing literature on the topic is mostly derived from individual case reports [11, 12, 14].

The frequency with which chiropractors encounter undiagnosed CES is unclear. In a retrospective study of 7,221 patients presenting to chiropractors for new-onset LBP, no patients met the criteria for CES [24]. Only a handful of case reports have described chiropractors identifying CES [25–28]. However, one study estimated that 0.1% of 1.6 million patients presenting for PT were recognized as having CES [29]. Given the similarity of chiropractic and PT as conservative, nonpharmacologic secondary care entry points for LBP [18, 30], patients with CES could potentially present to either clinician type.

Given the possibility of harm raised by previous case reports, it is necessary to examine the potential association between receiving CSM and the risk of subsequent CES in adults with LBP. The achieved aim of this project was to test our hypothesis that adults with LBP receiving CSM have no significant increased risk of CES compared to those undergoing PT evaluation without spinal manipulation.

Materials and methods

Study design

This study used a retrospective cohort design with active comparator features to reduce bias [31] and followed a registered protocol [32]. A visual representation of the study design is available in the supplementary material (S1 Fig). Study reporting follows the Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) guideline [33]. We included patients starting 20 years’ prior to the query date (July 30, 2023) to maximize sample size. The inclusion window ended three months prior to the query date to allow identification of CES during follow-up.

This study used fully anonymized, de-identified data and therefore was deemed Not Human Subjects Research by the University Hospitals Institutional Review Board (Cleveland, Ohio, USA, STUDY20230269), which also waived the need for consent. TriNetX is compliant with the Health Insurance Portability and Accountability Act (HIPAA) [34]. TriNetX only contains de-identified data as per the de-identification standard defined in Section §164.514(a) of the HIPAA Privacy Rule. The TriNetX network contains data provided by participating healthcare organizations, each of which represents and warrants that it has all necessary rights, consents, approvals, and authority to provide the data to TriNetX under a Business Associate Agreement, so long as their name remains anonymous as a data source and their data are utilized for research purposes. The data shared through the TriNetX Platform are attenuated to ensure that they do not include sufficient information to facilitate the determination of which health care organization contributed which specific information about a patient.

Setting and data source

Data were obtained from a US research network (TriNetX Inc., Cambridge, Massachusetts, USA) which includes health records data from over 105 million patients. The dataset includes 76 contributing health care organizations which are large, academic medical centers and their affiliated community hospitals and ambulatory offices. The data are routinely collected, related to patient care, include both insured and uninsured patients, and can be searched using standardized nomenclatures such as the International Classification of Diseases, 10^th Edition codes (ICD-10) [34]. A central TriNetX team regularly examines the dataset for conformance, plausibility, and completeness [34]. The TriNetX software interconverts ICD-10 to ICD-9 codes in queries of older medical records [34].

Precise data regarding the characteristics of chiropractors and PTs in the included healthcare organizations (e.g., years of experience, additional training) was not available due to de-identification of the dataset. In general, US chiropractors must complete a doctoral-level degree and pass the National Chiropractic Board of Chiropractic Examiners examinations [35]. In addition, the chiropractic scope of practice is legally regulated [36], and each US state requires continuing education credits [37]. However, evidence suggests that only a minority of chiropractic and PT clinicians in the US are employed in a hospital-based practice setting such as those included in the TriNetX dataset [38, 39]. One study reported that chiropractors in hospital-based settings were a mean 21 years’ post-graduation (minimum: 2 to maximum: 40) [40].

Natural language processing was used to bolster the identification of data items from clinical notes, using machine learning technology available within TriNetX (Averbis, Freiburg im Breisgau, DE). This feature includes mechanisms to understand negation (e.g., absence of a condition), intent, and context, thus aiding us in (1) excluding patients with prior CES as noted in free text in medical records, and (2) identifying new diagnoses of CES during follow-up. Prior studies have demonstrated that this software has acceptable accuracy, reliability, and agreement when compared to manual chart review for extracting clinical concepts related to diagnoses, laboratory values, medications, and symptoms [41, 42].

Participants

Eligibility criteria

Patients were included having either localized or radiating LBP (i.e., radicular pain, sciatica), lumbar disc degeneration, or lumbar disc herniation via any of a combination of commonly used ICD-10 diagnosis codes [43, 44] (S1 Table). Patients were required to be at least 18 years of age, considering that CES is uncommon in the pediatric population [6] and we are unaware of any cases of CES following CSM in pediatric patients [11, 45]. Patients were included on the date of initial CSM or PT evaluation for LBP. Patients receiving CSM were further required to have the presence of a segmental dysfunction code for the thoracic or lumbopelvic regions (i.e., M99.02, M99.03, M99.04, M99.05) indicating that CSM was applied to any of these regions. While CES typically arises from the lumbosacral region, medicolegal reports have documented CES occurring after thoracic CSM [7]. Accordingly, patients receiving only cervical CSM were not included. To help ensure that patients’ medical information was complete, patients were required to have a previous healthcare visit between one week and two years preceding the index date (CSM or PT evaluation).

Patients were excluded who had a previous diagnosis of CES, injury to the cauda equina, neuromuscular dysfunction of the bladder, urinary or fecal incontinence, bladder catheterization, and serious pathology of the lumbar spine (i.e., fracture, malignancy, infection, and bleeding disorders) which may cause CES [1, 4], and congenital abnormalities of the cauda equina such as tethered cord syndrome using an exclusion assessment window of six months (S2 Table). Considering other spinal manipulative therapies resemble CSM, such as manual therapies (e.g., spinal mobilization) and osteopathic manipulation, patients receiving these treatments were excluded from the PT evaluation cohort.

Variables

Cohorts

Patients were divided into two cohorts: (1) CSM; patients identified at the first co-occurrence of CSM (via Current Procedural Terminology codes 98940, 98941, and/or 98942) with a LBP diagnosis and (2) PT evaluation; those receiving a new patient evaluation or re-evaluation for LBP and not receiving any spinal manipulation. Patients in the CSM cohort received CSM in the thoracic, lumbar and/or sacroiliac/pelvic regions. PT evaluations were identified using Current Procedural Terminology codes (i.e., 97161, 97162, 97163, 97164). Current Procedural Terminology and ICD-10 codes used for inclusion and exclusion criteria can be found in the supplementary files (S1 and S2 Tables).

Confounding variables

Propensity score matching was used to reduce bias from confounding variables [31], matching variables present within one year preceding index date of inclusion and having a known association with CES (S3 Table): body mass index [46, 47], constipation [48], demographics (age, sex, race, ethnicity [49]), any emergency department visit [6], epidural steroid injection [50], lumbar/lumbosacral disc herniation with radiculopathy or sciatica [1, 3], lumbar spine advanced imaging [48] (e.g., magnetic resonance imaging or computed tomography), lumbar stenosis and spondylolisthesis [1, 47, 51, 52], and previous spine surgery [53].

Outcome

Considering the potential for a delayed diagnosis [3, 54, 55], identification of occurrences of CES was over a 90-day follow-up window commencing from the index date of CSM or PT evaluation. This duration aligns with a prior study which noted that the median time to CES diagnosis was 11 days (SD = 24), with a maximum of 90 days [55]. The need for a 90-day follow-up was further supported by research suggesting that CES develops gradually in older adults [52], and a review of medicolegal cases of CES after CSM in which CES was only immediate in one case [7]. Assessment included any occurrence of either a diagnosis of CES (ICD-10: G83.4) or injury to the cauda equina (ICD-10: S34.3) [56, 57]. To account for variability in diagnostic coding versus free-text charting, ascertainment of these diagnoses was further refined by natural language processing of narrative text appearing in patients’ clinical charts.

The likelihood of lumbar spine surgery was not examined considering this outcome would not be specific to CES [5]. Other potential CSM-related adverse events were not examined such as spinal fracture or hematoma considering these conditions would require different selection criteria and propensity matched variables.

Statistical methods

Using the TriNetX platform, baseline characteristics were compared using built-in independent-samples t-tests and Pearson chi-squared tests, and propensity score matching used Python’s scikit-learn package (version 3.7 Python Software Foundation, Delaware, USA). Logistic regression was used to calculate propensity scores for patients, and greedy nearest-neighbor matching was performed using a 1:1 ratio with a caliper of 0.1 pooled standard deviations [58]. The risk ratios (RRs) for CES were calculated by dividing the incidence proportion of CES in the CSM cohort by the incidence proportion in the PT evaluation cohort. R (version 4.2.2, Vienna, AT [59]) was used to calculate 95% confidence intervals (CIs) using the normal approximation, and the ggplot2 package [60] was used to plot cumulative incidence (with locally weighted scatterplot smoothing) and propensity score density.

Study size

Given the lack of previous research to estimate the incidence of individuals with LBP receiving CSM developing CES, a required sample size was estimated using broader epidemiologic data [6]. A required sample size of 103,836 was calculated using G*Power (Kiel University, DE) z-tests for examining a difference in incidence proportion between cohorts (0.3% vs. 0.6% for one year, translating to a possible difference of 0.075% vs. 0.150% per our three-month follow-up) using two tails, an alpha error of 0.05, power of 0.95, and allocation ratio of one. Feasibility testing in February 2023, along with previous work using this dataset [61, 62], suggested that this sample size would be attainable.

Results

Participants

Eligible patients were identified from several health care organizations (CSM: 12; PT evaluation: 48). Prior to propensity score matching, the CSM cohort consisted of 67,223 patients, while the PT evaluation cohort consisted of 776,704 patients (Table 1). Following matching, both cohorts consisted of 67,220 patients, with a mean age of 51 years (SD = 17). Before matching, several differences were observed between the CSM cohort and the PT evaluation cohort. Prior to propensity matching, the CSM cohort had a lower mean age, lower proportion of individuals who identified as Asian, Black or African American, and Hispanic or Latino, and lower incidence of several diagnoses and procedures (SMD>0.1 for each). After matching, there were no meaningful differences between the two cohorts for any of the matched variables (SMD <0.1 for each), indicating a successful balancing of the cohorts.

Table 1. Baseline characteristics before and after propensity score matching.

	Before matching			After matching
Variable	CSM	PT evaluation	SMD	CSM	PT evaluation	SMD
Variable	(N = 67,223)	(N = 776,704)	SMD	(N = 67,220)	(N = 67,220)	SMD
Mean age (SD)	50.7(16.9)	60.1(15.8)	0.576	50.7(16.9)	50.7(16.8)	0.002
Age (min-max)	18–89	18–90		18–89	18–90
Female n (%)	39097 (58%)	467378 (61%)	0.052	39097 (58%)	39074 (58%)	0.001
Male n (%)	28125 (42%)	302408 (39%)	0.052	28122 (42%)	28143 (42%)	0.001
Body mass index (kg/m²)	30.2±6.6	30.0±7.0	0.034	30.2±6.6	29.9±6.9	0.039
Race/ethnicity n (%)
Asian	422 (1%)	14519 (2%)	0.113	422 (1%)	452 (1%)	0.006
Black or African American	2458 (4%)	121716 (16%)	0.419	2458 (4%)	2448 (4%)	0.001
Hispanic or Latino	1173 (2%)	51742 (7%)	0.249	1173 (2%)	1195 (2%)	0.002
Not Hispanic or Latino	55422 (82%)	585443 (76%)	0.158	55419 (82%)	55453 (82%)	0.001
White	50766 (76%)	548600 (71%)	0.096	50766 (76%)	50946 (76%)	0.006
Diagnosis n (%)
Constipation	2660 (4%)	107353 (14%)	0.355	2660 (4%)	2604 (4%)	0.004
Disc disorder with radiculopathy, lumbar	602 (1%)	20232 (3%)	0.132	602 (1%)	486 (1%)	0.019
Disc disorder with radiculopathy, lumbosacral	168 (0%)	5990 (1%)	0.074	168 (0%)	124 (0%)	0.014
Lumbago with sciatica	2223 (3%)	59596 (8%)	0.195	2223 (3%)	2185 (3%)	0.003
Postlaminectomy syndrome	341 (1%)	7279 (1%)	0.052	341 (1%)	263 (0%)	0.017
Sciatica	2772 (4%)	43868 (6%)	0.073	2771 (4%)	2674 (4%)	0.007
Spinal stenosis, lumbar	2263 (3%)	74903 (10%)	0.259	2263 (3%)	1998 (3%)	0.023
Spondylolisthesis, lumbar	468 (1%)	26261 (3%)	0.192	468 (1%)	469 (1%)	<0.001
Spondylolisthesis, lumbosacral	180 (0%)	6981 (1%)	0.084	180 (0%)	137 (0%)	0.013
Procedure n (%)
Computed tomography, lumbar	426 (1%)	31821 (4%)	0.231	426 (1%)	384 (1%)	0.008
Emergency department services	11587 (17%)	318884 (41%)	0.551	11587 (17%)	11446 (17%)	0.006
Epidural steroid injection	448 (1%)	8875 (1%)	0.051	448 (1%)	281 (0%)	0.034
Magnetic resonance imaging, spinal canal and contents, lumbar	2941 (4%)	62653 (8%)	0.156	2941 (4%)	2753 (4%)	0.014
Surgical procedures on the spine and spinal cord	1425 (2%)	47350 (6%)	0.204	1425 (2%)	1245 (2%)	0.019
Surgical procedures on the spine	193 (0%)	24623 (3%)	0.224	193 (0%)	240 (0%)	0.012
Transforaminal epidural steroid injection	801 (1%)	11887 (2%)	0.030	801 (1%)	596 (1%)	0.030

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Abbreviations: Kilograms per square meter (kg/m²), standardized mean difference (SMD), standard deviation (SD), physical therapy (PT)

Bold SMD values (>0.1) indicate between-cohort imbalance.

Descriptive data

The mean number of data points per patient per cohort was adequate (CSM: 3,802; PT evaluation: 5,482). After propensity matching, the proportion of ‘unknown’ demographic variables was similar between cohorts: unknown race (CSM: 20%, PT evaluation: 19%, SMD = 0.022), unknown ethnicity (both cohorts 16%, SMD = 0.002), unknown sex (both cohorts 0%, SMD<0.001), and unknown age (both cohorts 0%, SMD<0.001). A propensity score density graph indicated that the cohorts were well-balanced after matching (Fig 1). These findings suggested minimal between-cohort differences relating to data completeness, data density, and covariate balance.

Fig 1 — Propensity score before (A) and after (B) matching, with purple representing the chiropractic spinal manipulation (CSM) cohort and green representing the physical therapy (PT) evaluation cohort. The area of common support improves after matching, as propensity score densities overlap between cohorts, suggesting adequate balance of covariates.

Key results

The incidence of CES over three months’ follow-up from the index date of inclusion was lower in the CSM cohort compared to the PT evaluation cohort both before and after matching, yet 95% CIs overlapped (Table 2 and Fig 2). For the primary outcome, after propensity matching, the incidence of CES in the CSM cohort was 0.07% (95% CI: 0.05–0.09%), compared to 0.11% (95% CI: 0.09–0.14%) in the PT evaluation cohort, yielding an RR of 0.60 (95% CI: 0.42–0.86; p = .0052).

Table 2. Key results before and after propensity score matching.

	Before matching		After matching^*
	CSM	PT evaluation	CSM	PT evaluation
	(N = 67,223)	(N = 776,704)	(N = 67,220)	(N = 67,220)
CES N	46	1,222	46	77
CES % (95% CI)	0.07% (0.05–0.09%)	0.16% (0.15–0.17%)	0.07% (0.05–0.09%)	0.11% (0.09–0.14%)
RR (95% CI)	0.44 (0.32–0.58; p < .0001)	(reference)	0.60 (0.42–0.86; p = .0052)	(reference)

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Abbreviations: Chiropractic spinal manipulation (CSM), risk ratio (RR), 95% confidence intervals (95% CI), physical therapy (PT)

* primary outcome

Fig 2 — CES occurs in a smaller proportion of patients in the CSM cohort (purple) compared to the PT evaluation cohort (green), however, the 95% confidence intervals overlap at 0.09%, indicating a potentially non-meaningful difference.

Sensitivity analysis

A cumulative incidence graph demonstrated that the occurrences of CES increased in a curvilinear manner during the first two weeks of follow-up in both cohorts, suggesting a greater risk of CES immediately following the initial visit of CSM or PT evaluation (Fig 3). The 95% CIs for CES incidence overlapped through most of the follow-up window, indicating a similar time trend in both cohorts.

Fig 3 — Incidence curves in the chiropractic spinal manipulation cohort (CSM, purple) and physical therapy evaluation cohort (PT evaluation, green) are shown over the three-month follow-up window (90 days). Shaded regions indicate 95% confidence intervals.

Discussion

The present study was conducted because prior case reports and medicolegal cases described an onset of CES following CSM [1–4], yet there was no adequately powered and designed study to examine this potential association. The present study tested the hypothesis that there would be no increased risk of CES following CSM, considering limited previous studies suggested this was a rare event and potentially related to pre-existing lumbar disc disorders [1, 8]. The present study results support the hypothesis that there is no increased risk of CES following CSM in adults compared to matched controls receiving PT evaluation without spinal manipulation.

In the present study, the incidence of CES in both cohorts over three months (0.07% to 0.11%) may translate to approximately 0.28% to 0.44% over 12 months, aligning with a previous estimate of CES incidence among individuals with LBP seeking secondary care (0.27% [95% CI: 0.14–0.54%]) [6]. In the present study, while the RR was significant and less than one, potentially indicating reduced CES risk in the CSM cohort, there was an overlap in the 95% CIs for CES incidence between cohorts, suggesting that any risk difference was not meaningful. The similarity of CES incidence to a prior epidemiologic estimate [6], and similar incidence between cohorts, suggest that neither CSM nor PT evaluation influenced the incidence of CES.

A curvilinear increase in CES cumulative incidence in both cohorts was evident over the first two weeks, suggesting the rate of CES is higher when patients first seek care for LBP. This finding aligns with previous evidence that patients with LBP have an inherently higher risk of CES compared to asymptomatic individuals [6]. In addition, this reinforces that clinicians should be vigilant to detect and urgently refer patients with CES symptoms for surgical attention [10].

These present findings contradict the conclusions of prior studies which suggested that an onset of CES after CSM indicated that CSM was causal [12, 63]. However, these prior conclusions were based on case reports, which often highlight atypical situations [64]. In addition, case reports lack a comparator group or a means to account for confounding variables, design elements which were available in the present study.

Our findings are consistent with the hypothesis that patients who develop CES after CSM may have evolving symptoms of CES prior to treatment and/or an already-existing disc herniation [7, 11]. This phenomenon was illustrated in two medicolegal cases of CES wherein chiropractors appeared to overlook symptoms of acute lumbar disc herniation before administering CSM [7]. The present findings show that CES may also arise soon after PT evaluation without manipulation for LBP, suggesting that patients seeking care for LBP are already at a heightened risk of CES and CSM may not be directly causative.

These findings can be compared to population-based studies examining the association between CSM and lumbar disc herniation. A self-controlled case series found that patients who underwent emergency surgery for acute lumbar disc herniation had a similar increase in likelihood of visiting either primary care providers or chiropractors prior to the surgery, suggesting that CSM was not a risk factor for lumbar disc herniation [13]. Another study found that patients with radicular LBP who underwent CSM were less likely to require disc surgery over the subsequent two years compared to matched controls receiving usual medical care [20]. These consistent findings support the notion that CSM is not a meaningful risk factor for disc herniation or CES.

There are multiple reasons why one may suspect that CSM would not contribute to CES. Biomechanically, the lumbar facet joints limit axial rotation during manipulation, thereby protecting the lumbar intervertebral discs [14]. As CSM includes a range of approaches (e.g., high- or low-velocity or force and manual or instrument-assisted manipulations [65]), chiropractors’ ability to customize CSM to patients’ clinical presentations could reduce the likelihood of adverse outcomes. Speculatively, chiropractors could avoid higher-force manipulations on patients with more severe LBP presentations, potentially reducing risk of harm.

Alternate study designs could be considered to corroborate the present findings. A self-controlled case series would use patients as their own controls, minimizing biases with respect to clinical features. A case-control design could be used to compare CES cases with matched non-CES controls and allow for the examination of a potential dose-response relationship between CSM and CES. Alternate comparator groups could be examined, considering different clinician types (e.g., primary care, orthopedic surgeons) may encounter LBP patients of varying complexity and baseline CES risk. Detailed cases from chart reviews, registries, or databases are also needed to understand the clinical presentation and steps to CES diagnosis among patients presenting to chiropractors with LBP.

Strengths and limitations

Strengths of this study include the use of a large, multicenter sample of over 130,000 total patients, a multidisciplinary research team, propensity matching strategy, and use of a registered protocol [32]. The observational design of this study precludes any definitive conclusion regarding the potential for a causal relationship between CSM or PT evaluation and CES, or a lack thereof. Residual confounding related to unmeasured risk factors such as LBP-related disability may have influenced our results. Subtypes of LBP diagnoses may have been incorrect in the medical record due to our lack of requiring previous diagnostic imaging or testing; for example, a label of sciatica includes a broad differential diagnosis encompassing neuropathy and other conditions. Due to the de-identified nature of the dataset, it was not possible to validate CES outcomes via chart review, and false positives or missed diagnoses are possible. Limitations in data granularity prevented the description of parameters of CSM application that may be relevant to CES risk, such as force and type of thrust [65]. The years of chiropractors’ experience and any additional post-graduate training was not feasible to examine in the current study, which could play a role in risk mitigation with SMT. Study results may not be broadly generalizable as treatment of LBP and diagnosis of CES may vary differ in smaller private practice settings as well as regionally with respect to chiropractic and PT approaches outside of the US. In addition, these findings pertain to spinal manipulation administered by trained chiropractors rather than other practitioners or laypersons, considering cases of severe adverse events including spinal fracture and CES have been reported following spinal manipulation by untrained individuals [45, 66–68].

Conclusions

The present study involving over 130,000 propensity-matched patients found that CSM is not a risk factor for CES. The incidence of CES in both CSM and PT evaluation cohorts aligns with previous estimates of CES incidence among patients with LBP, indicating a heightened risk of CES compared to asymptomatic individuals regardless of intervention. Moreover, these findings underscore the increased CES incidence within the first two weeks after either CSM or PT evaluation, emphasizing the need for clinicians’ vigilance in identifying and emergently referring patients with CES for surgical evaluation. Further real-world evidence is needed to corroborate these findings using alternative case-control and case-crossover designs, and different clinician comparators.

Supporting information

S1 Fig. Study design.

(DOCX)

pone.0299159.s001.docx^{(88.6KB, docx)}

S1 Table. Inclusion codes for both cohorts.

(DOCX)

pone.0299159.s002.docx^{(13.3KB, docx)}

S2 Table. Exclusion codes for both cohorts.

(DOCX)

pone.0299159.s003.docx^{(13.3KB, docx)}

S3 Table. Variables controlled for in propensity score matching.

(DOCX)

pone.0299159.s004.docx^{(13.3KB, docx)}

Data Availability

The minimal, de-identified, aggregated data used to describe baseline characteristics, our primary outcome, and plot propensity score density curves and cumulative incidence are available in figshare (https://doi.org/10.6084/m9.figshare.24654396).

Funding Statement

This project was supported by the Clinical and Translational Science Collaborative of Northern Ohio which is funded by the National Institutes of Health, National Center for Advancing Translational Sciences, Clinical and Translational Science Award grant, UM1TR004528. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health.

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PLoS One. doi: 10.1371/journal.pone.0299159.r001

Decision Letter 0

Shabnam ShahAli

25 Jan 2024

PONE-D-23-39784Association between chiropractic spinal manipulation and cauda equina syndrome in adults with low back pain: Retrospective cohort study of US academic health centersPLOS ONE

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Reviewer #1: Please note and correct the following:

1. The words like “we” and “our” were used a lot in this study. It is not common to use such words in scientific articles. It is better to rewrite the sentences in the passive form. Please edit this in the entire text.

2. In the abstract section, the division of patients into two cohort groups is not clear for the reader. Please explain it clearly. If this is what you mean, explain it like this; LBP patients who received manipulation by chiropractors and LBP patients who underwent evaluation and treatment without manipulation by physical therapists.

3. In key word section, is it necessary to use “safety” as a key word? This could show that your search was done with a positivity bias.

4. In the last paragraph of the introduction section, the use of the word “crucial” is not appropriate and again shows a positivity bias towards spinal manipulation.

5. The phrase “Incidence of CES per cohort” is unnecessary and should be removed from the top of the figure 1.

6. The primary outcome was not mentioned in table 2, what is the purpose of the sign * for? It seems better to mention it in the title of the table for example: “score matching for primary outcomes). In addition, it seems that the sign * along with its explanation should be omitted from the table footer 1.

7. Please match the references to the relevant sentences. For example: A) In the third paragraph of the introduction section, it is not possible that the results of article 11 (a systematic review article) is referenced for the two statements that CSM can be a risk factor for CES or not. B) reference 31 seems not to be related to the last sentence of limitation section.

8. The discussion is very poorly written. Logical and scientific justifications were not mentioned for the hypothesis. Please write strong and logical justifications for your hypothesis. Note that the way the discussion is written can be a reason for rejecting or accepting an article.

9. In the discussion section, the sentence “Limitations of such cases include their small sample size and potential confounding factors” is incomprehensible, please explain it clearly.

10. In the limitation section, the sentence “Further research is needed to replicate our findings and assess their consistency” is only a suggestion for future research and not a limitation. Please omit this from this section.

11. In the reference list, the names of the journals should be written in an abbreviated form.

Reviewer #2: The area of investigation has chosen wisely as manipulation is gaining adherents day by day. The manuscript is well written and technically sound. There is only one question from author, how did you include or exclude diabetic patients with neuropathy? please explain your examination and diagnostic tests for confirmation of radicular or sciatic pain.

Reviewer #3: How do you consider 90-day follow-up?

It is important for this study that expert or novice chiropractic does thrust manipulation. Why do you include years of experience of chiropractic?

Method of Abstract: it doesn’t need deception exclusion criteria in abstract

Reviewer #4: Dear authors, I am very happy to be able to write positively. It is evident that you have put a great deal of effort into this project and I want to praise your efforts, Fortunately, the actual contribution from your study is clear and, the manuscript as currently written suggests that it might be suitable for sharing information about this topic, but the manuscript that you reported, needs few minor edits.

General comment: Authors must consider using line numbers in manuscripts.

Abstract

Line: ‘following physical therapy (PT) evaluation’: It can be better written as ‘intervention’, instead of ‘evaluation’.

‘Patients were divided into two cohorts: (1) CSM or (2) PT evaluation without spinal Manipulation’: Did the patients underwent one time evaluation (assessment) or were they on specific physiotherapeutic interventions for any specific time (such as a week, or two)? If they were on intervention(s), the word ‘evaluation’ should be replaced with the word ‘intervention’.

‘Propensity score matching controlled for covariates associated with CES (e.g., body mass index).’: correct the syntax of the sentence.

Lines ‘(mean age 51 years [SD=17]) remained after propensity matching. CES incidence was 0.07% (95% CI: 0.05-0.09%) in the CSM cohort compared to 0.11% (95% CI: 0.09- 0.14%) in the PT evaluation cohort, yielding an RR (95% CI) of 0.60 (0.42-0.86; P=.0052). Both cohorts showed a higher rate of CES during the first two weeks of follow-up.’: Elaborate the abbreviations at first notice.

Introduction: No comments

Materials and Methods

Rephrase the line ‘We included patients starting 20 years ‘prior to the query date (July 30, 2023) to maximize sample size’ for a clearer understanding.

Results

Table 1: Add n (%) for males and females to let the readers understand that the values are in terms of n and its corresponding percentage. Also, add SI units for BMI (kg/m2) and other such variables in the tables.

The level of significance (p) should be written in small italicized letters.

Discussion No comments

Limitations & Conclusions: No comments

Reviewer #5: This study investigated association between chiropractic spinal manipulation and cauda equina syndrome in adults with low back pain. The authors concluded that CSM is not a risk factor for CES. Considering prior epidemiologic evidence, patients with LBP may have an elevated risk of CES independent of treatment. These findings warrant further corroboration. In the meantime, clinicians should be vigilant to identify LBP patients with CES and promptly refer them for surgical evaluation.

Comment#1

The authors should insert low back pain as a keywords.

Comment#2

The authors should provide more explanations about the risk of Cauda equina syndrome following chiropractic spinal manipulation and physiotherapy.

Comment#3

The authors should state more explanations for performing your study.

**********

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Reviewer #1: No

Reviewer #2: Yes: Ghazal Kharaji

Reviewer #3: No

Reviewer #4: No

Reviewer #5: No

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PLoS One. 2024 Mar 11;19(3):e0299159. doi: 10.1371/journal.pone.0299159.r002

Author response to Decision Letter 0

30 Jan 2024

Please see the response document file titled "Response to reviewers" towards the end of the review file PDF - which may be formatted better, although our responses are also copied here:

Overview

We are grateful for the thorough and detailed reviewer comments and have made several revisions to strengthen our manuscript. We have added more detailed justification for conducting the study, focused the discussion on key elements that align with our hypothesis, changed wording to the passive voice, removed unnecessary material from the text and tables, and made formatting and reference style changes, among other edits.

Editorial comments

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• Response: Thank you. See changes:

o We apologize that we were not using the journal abbreviations in the references – which we fixed. They are already in Vancouver style.

o We added continuous line numbers

o We removed the 4th level headings, now we only use level 1 and level 2 headings

o We added SI units for body mass index

o We altered the font sizes, including the heading font sizes, to match the documents you sent.

o Supporting information is already labeled according to S1, S2 etc.

o Please let us know if there is anything we need to do to adhere to the style requirements.

• Response: Thank you. We checked to ensure that our data was shared in a way that matched journal requirements, using an open access repository with an available doi and link. Please let us know if there is anything we need to do to improve this. We inform readers how to access the data in the Data availability statement.

• Response: Thank you. Our study did not include minors, as it was limited to adults (age 18 or older). We updated our statement to explicitly state that the need for consent was waived in the methods section, and mention that data were fully anonymized.

• This study used fully anonymized, de-identified data and therefore was deemed Not Human Subjects Research by the University Hospitals Institutional Review Board (Cleveland, Ohio, USA, STUDY20230269), which also waived the need for consent. TriNetX is compliant with the Health Insurance Portability and Accountability Act (HIPAA) [1]. TriNetX only contains de-identified data as per the de-identification standard defined in Section §164.514(a) of the HIPAA Privacy Rule. The TriNetX network contains data provided by participating healthcare organizations, each of which represents and warrants that it has all necessary rights, consents, approvals, and authority to provide the data to TriNetX under a Business Associate Agreement, so long as their name remains anonymous as a data source and their data are utilized for research purposes. The data shared through the TriNetX Platform are attenuated to ensure that they do not include sufficient information to facilitate the determination of which health care organization contributed which specific information about a patient.

3. If you are reporting a retrospective study of medical records or archived samples, please ensure that you have discussed whether all data were fully anonymized before you accessed them and/or whether the IRB or ethics committee waived the requirement for informed consent. If patients provided informed written consent to have data from their medical records used in research, please include this information.

• Response: Thank you. Please see the updated statement above which mentions these components. Also note that we have an IRB approval / exemption document that we can share with the Editor upon request.

• Response: Thank you. We deleted the previous funding-related text from the acknowledgement section and added it to the funding section. We also added this statement to the online submission form – replacing our previous statement. Please note that the funding statement is also updated and improved as follows:

o This project was supported by the Clinical and Translational Science Collaborative of Northern Ohio which is funded by the National Institutes of Health, National Center for Advancing Translational Sciences, Clinical and Translational Science Award grant, UM1TR004528. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health.

Please include your amended statements within your cover letter; we will change the online submission form on your behalf.

• Response: Thank you. We also inserted the funding statement in the revised cover letter.

• Response: Thank you. We reviewed the reference list and changed a setting so that it now lists the journal abbreviations as recommended. We did not see any retracted articles – and we are using Zotero which has a built-in feature in collaboration with Retractionwatch to alert us if there is any retraction in the cited studies.

Reviewer #1

Please note and correct the following:

• Response: Thank you for this suggestion. We edited the text throughout to remove these terms and now use the passive voice.

• Response: Thank you for pointing out that this description of the cohorts could be clearer. We wish to note that earlier in the abstract “chiropractic spinal manipulation” was already abbreviated as “CSM” and “physical therapy” was abbreviated as “PT” so we can reuse these acronyms here. Also, please note that we did not necessarily require any specific treatment in the PT cohort – simply an evaluation. We took your suggestion and revised this sentence as follows:

o Patients were divided into two cohorts: (1) LBP patients receiving CSM or (2) LBP patients receiving PT evaluation without spinal manipulation.

3. In key word section, is it necessary to use “safety” as a key word? This could show that your search was done with a positivity bias.

• Response: Thank you for this recommendation. We have removed the term “safety” from the keywords. We agree this might give the appearance of a bias. However, please note that we took several steps to minimize bias including having a multidisciplinary team and registering our protocol. We also now do a better job of emphasizing potential risks of CSM in the introduction (see comments for Reviewer #5) to show a better balance in our writing.

4. In the last paragraph of the introduction section, the use of the word “crucial” is not appropriate and again shows a positivity bias towards spinal manipulation.

• Response: Thank you, we agree this term could be changed. We removed the term “crucial” as advised, changing it to a more neutral term of “necessary”. However, please note that this sentence is referring to the possible risks of spinal manipulation from the prior literature and justifying why our study is necessary - to examine potential risks further.

5. The phrase “Incidence of CES per cohort” is unnecessary and should be removed from the top of the figure 1.

• Response. Thank you for this suggestion, we agree completely and feel that removing the title better highlights the data. We believe you mean Figure 2, as there is no title on Figure 1. We removed the title “Incidence of CES per cohort” from the Figure 2 plot area

• Response: Thank you, we agree that this is confusing and unnecessary. We removed the asterisk. The propensity matched cohorts were also used for all outcomes, including our sensitivity analysis so we feel we should keep the title the same, and not try to emphasize which were primary outcomes in this table. The purpose of matching is explained in the Methods section.

• Response: Thank you – we fixed the first potential reference issue as advised by adding a different references supporting spinal manipulation as a potential risk factor for cauda equina syndrome instead of the review article (previously #11 [2]). However, please note that that the original reference was a review of legal / malpractice cases and the author presented both sides to the argument, that CSM might be causative, and it might not be causative of CES. Regardless, the new references may be better for readers [3,4]. The new references are as follows:

o Haldeman, Scott, and Sidney M. Rubinstein. "Cauda equina syndrome in patients undergoing manipulation of the lumbar spine." Spine 17.12 (1992): 1469-1473.

o Tamburrelli, Francesco Ciro, Maurizio Genitiempo, and Carlo Ambrogio Logroscino. "Cauda equina syndrome and spine manipulation: case report and review of the literature." European Spine Journal 20 (2011): 128-131.

• We edited the statement in the limitations section to better match the cited reference and added new references as well. The original sole reference (Hebert et al) review article notes several adverse events such as cauda equina syndrome that occurred after spinal manipulation. Several of the treating clinicians were not chiropractors or they had no known or reported credentials. We are suggesting that our results showing the lack of heightened risk of CES after CSM do not apply to manipulation performed by untrained individuals. Essentially, manipulation may be more dangerous with a lack of training:

o In addition, these findings pertain to spinal manipulation administered by trained chiropractors rather than other practitioners or laypersons, considering cases of severe adverse events including spinal fracture and CES have been reported following manipulation by untrained individuals [5–8].

o Please also note these references are also added to support the original one:

� Yang, Si-Dong, Qian Chen, and Wen-Yuan Ding. "Cauda equina syndrome due to vigorous back massage with spinal manipulation in a patient with pre-existing lumbar disc herniation: a case report and literature review." American Journal of Physical Medicine & Rehabilitation 97.4 (2018): e23-e26.

� Terrett, A. G. "Misuse of the literature by medical authors in discussing spinal manipulative therapy injury." Journal of manipulative and physiological therapeutics 18.4 (1995): 203-210.

� Wenban, Adrian B. "Inappropriate use of the title'chiropractor'and term'chiropractic manipulation'in the peer-reviewed biomedical literature." Chiropractic & Osteopathy 14.1 (2006): 1-7.

• Response. Thank you. We revised the Discussion entirely and are grateful for the opportunity to improve this section. We now realize that several sentences lacked a clear connection to the key points of the study. Our re-write strived for clarity and communicating to a broader audience, while remaining focused and relevant to the main study objectives.

• We trimmed or deleted several sentences and paragraphs to make the Discussion more concise, added a brief recap of the justification for performing the study as advised, reorganized some information, changed the “Limitations” section to “Strengths and limitations” for better organization, and removed some jargon and confusing phrases.

• Please note that while we hypothesized there would be no increased risk of CES after CSM, we were aware (based on our feasibility testing) that we were working with a large sample size, therefore we implemented a 2-tailed alpha in our sample size calculation, ensuring we were adequately powered to test any direction of association (positive, null, or negative). Had there been a positive association between CSM and CES, our sample size and methods would have enabled us to identify this outcome.

• Please see the newly added beginning sentence to the Discussion, which begins with a logical scientific justification for our hypothesis, while you may see several other edits in the revised draft:

o The present study was conducted because prior case reports and medicolegal cases described an onset of CES following CSM [2–5], yet there was no adequately powered and designed study to examine this potential association. The present study tested the hypothesis that there would be no increased risk of CES following CSM, considering limited previous studies suggested this was a rare event and potentially related to pre-existing lumbar disc disorders [2,9]. The present study results support the hypothesis that there is no increased risk of CES following CSM in adults compared to matched controls receiving PT evaluation without spinal manipulation.

• Please note that Reviewer #5 asked for us to add more background information to help justify the study, and we have added much more detail to the Introduction section which highlights the increase in use of CSM for LBP in the US, potential for harm when treating a population with LBP and potentially at risk for CES, and the limited available evidence on the topic. These changes may also help clarify our justification and rationale for conducting the study.

9. In the discussion section, the sentence “Limitations of such cases include their small sample size and potential confounding factors” is incomprehensible, please explain it clearly.

• Response: Thank you for pointing out that this was unclear. We have re-written this entire paragraph for clarity. See below:

o These present findings contradict the conclusions of prior studies which suggested that an onset of CES after CSM indicated that CSM was causal [4,10]. However, these prior conclusions were based on case reports, which often highlight atypical situations [11]. In addition, case reports lack a comparator group or a means to account for confounding variables, design elements which were available in the present study.

• Response: Thank you. We agree and we have removed this sentence from the limitations section.

11. In the reference list, the names of the journals should be written in an abbreviated form.

• Response: Thank you. We modified these accordingly to use journal abbreviations.

Reviewer #2:

The area of investigation has chosen wisely as manipulation is gaining adherents day by day. The manuscript is well written and technically sound. There is only one question from author, how did you include or exclude diabetic patients with neuropathy? please explain your examination and diagnostic tests for confirmation of radicular or sciatic pain.

• Response: Thank you for the positive comments. Note that we required patients to have only one of several diagnosis codes for low back pain, and they were not necessarily required to have radicular or sciatic pain. For example, see in Table 2 that only 4% of each cohort had sciatica on initial presentation. Our broad inclusion of several types of low back pain was done to increase sample size, yet we propensity matched so that cohorts would have a similar composition of each type of LBP.

• We acknowledge that we did not require patients to have any specific diagnostic testing, such as MRI, EMG, NCV, etc. While this may have been helpful, this would have narrowed the cohort sizes as many types of low back pain are diagnosed clinically without any imaging. Our study population generally focuses on patients that are seeking care and therefore may not have had many prior diagnostic tests, as opposed to those who have undergone extensive care already. Note in Table 2 that only 4% of patients per cohort had a prior lumbar spine MRI at presentation, 1% had a CT scan, and at most, 1% had a lumbar epidural steroid injection. The low rate of prior imaging is also expected given the American College of Radiology criteria for imaging for low back pain [12].

• Our study relied on several methods to help define a cohort of patients with low back pain. Aside from inclusion criteria, we excluded patients with several comorbidities including bladder dysfunction, fecal incontinence, and serious spinal pathology who may have already had CES or syndromes that resembled it. In addition, we used natural language processing to further strengthen our selection criteria, using software which has been validated previously. This process was used to refine the query that we used which was mostly based on ICD-10 codes. However, we realize we should have described the natural language processing better because it helps to show a strength of our approach. See the added sentences:

� Prior studies have demonstrated that this software has acceptable accuracy, reliability, and agreement when compared to manual chart review for extracting clinical concepts related to diagnoses, laboratory values, medications, and symptoms [13,14].

o To our knowledge, diabetic neuropathy is not a risk factor for cauda equina syndrome [15–20], although we did control for body mass index, which is a known risk factor .

o However, we agree that it is possible patients had an incorrect diagnosis of one of the subtypes of low back pain that we included, and added a limitation about this:

� Subtypes of LBP diagnoses may have been incorrect in the medical record due to our lack of requiring previous diagnostic imaging or testing; for example, a label of sciatica includes a broad differential diagnosis encompassing neuropathy and other conditions.

Reviewer #3:

How do you consider 90-day follow-up?

• Response: Thank you for this question. In the Methods section we state that “identification of occurrences of CES was over a 90-day follow-up window commencing from the index date of CSM or PT evaluation”. The cumulative incidence graph also shows the days on the X-axis (Figure 3)

• Note that we chose a relatively long 90-day follow-up window because CES did not necessarily develop immediately in prior reports of this condition following CSM, and CES may take time to be identified/diagnosed [21–23]. While much of the literature focuses on this condition being an emergency and recommends prompt surgery, real-world data suggest that it may take up to 90 days to diagnose this condition [23]. Another reason is that we did not want to miss any cases of CES by ending the follow-up window too soon. We also felt that our cumulative incidence graph helps show CES occurrences throughout the 90-day window and could help characterize whether any potential risk window was early, intermediate, or late during this period.

• Please let us know if there is anything you would like us to improve regarding this information.

It is important for this study that expert or novice chiropractic does thrust manipulation.

• Response: Thank you. We added a general disclaimer that chiropractors employed in the study settings typically have multiple years of clinical experience (see our response to your next comment below). We also wish to point out that practicing chiropractic in the US requires a doctoral degree and board examination, which suggests that there is some baseline standardization. However, we agree with your point that the level of experience may matter. We added a limitation as follows:

o The years of chiropractors’ experience and any additional post-graduate training was not feasible to examine in the current study, which could play a role in risk mitigation with SMT.

Why do you include years of experience of chiropractic?

• Response: Thank you for this question. We did not include this data because it was not available in the dataset for which we have access. We agree that years of chiropractic experience could be relevant when considering the likelihood of adverse events such as CES. For example, chiropractors who have more experience might better recognize patients with CES and acknowledge when to refer them for emergency care rather than use spinal manipulation. However, there is not sufficient evidence to substantiate this idea in the context of chiropractic and CES since we are currently conducting the largest study on the topic.

• We edited the Methods section to add more detail regarding potential years of experience and inform readers that the practice setting is relatively unique considering the healthcare organizations included in our study are hospitals and academic institutions. We also should have also noted that there is a standard educational requirement for chiropractic clinicians in the US. Please see the improved section below regarding education, scope of practice, and years of experience:

o Precise data regarding the characteristics of chiropractors and PTs in the included healthcare organizations (e.g., years of experience, additional training) was not available due to de-identification of the dataset. In general, US chiropractors must complete a doctoral-level degree and pass the National Chiropractic Board of Chiropractic Examiners examinations [24]. In addition, the chiropractic scope of practice is legally regulated [25], and each US state requires continuing education credits [26]. However, evidence suggests that only a minority of chiropractic and PT clinicians in the US are employed in a hospital-based practice setting such as those included in the TriNetX dataset [27,28]. One study reported that chiropractors in hospital-based settings were a mean 21 years’ post-graduation (minimum: 2 to maximum: 40) [29].

Method of Abstract: it doesn’t need deception exclusion criteria in abstract

• Response: Thank you. We deleted the specific exclusion criteria examples such as malignancy, fracture, and infection, from the abstract as we agree this phrase was too detailed.

Reviewer #4:

Dear authors, I am very happy to be able to write positively. It is evident that you have put a great deal of effort into this project and I want to praise your efforts, Fortunately, the actual contribution from your study is clear and, the manuscript as currently written suggests that it might be suitable for sharing information about this topic, but the manuscript that you reported, needs few minor edits.

General comment: Authors must consider using line numbers in manuscripts.

• Response: Thank you. We have added line numbers as suggested in the revised document.

Abstract

Line: ‘following physical therapy (PT) evaluation’: It can be better written as ‘intervention’, instead of ‘evaluation’.

• Response: Thank you for this comment. We suspect this term was not clear. Please note that we only required patients who saw a physical therapist (PT) to have an evaluation (e.g., an examination) and we did not require them to have any treatment. We only required the PT patients to not have anything like spinal manipulation or manual therapy which could resemble the chiropractic treatments in the other cohort. The study is based on the receipt of CSM or PT evaluation on the index date of inclusion and we did not track the type of care that the patients received afterwards, during follow-up. We agree that this could have been interesting to track, yet it was beyond the scope of our study. We were most concerned with identifying CES during the follow-up window, rather than characterizing the types of interventions patients received after their initial visit.

• Note that we used the term “evaluation” to be consistent with the definition of the procedural codes that we used in the PT cohort. These are defined using the term “evaluation” so we were hesitant to change it to a similar term or synonym such as “examination” (see example here: https://www.aapc.com/codes/cpt-codes/97161)

‘Propensity score matching controlled for covariates associated with CES (e.g., body mass index).’: correct the syntax of the sentence.

• Response: Thank you. We deleted the text describing this example “(e.g., body mass index)”. We used propensity matching for several variables and it is challenging to try to list them all in the abstract. Similar to your comment above about listing examples of exclusions, we felt it was too detailed to try to include examples of matched variables in the abstract. In exchange, we replaced “covariates” with “confounding variables” for clarity.

• Response: Thank you, we are grateful that you noticed this issue.

o We elaborated on the abbreviation confidence intervals (CI).

o We removed the abbreviation “RR” and now state “risk ratio” because we only used this abbreviation once in the abstract. It is defined again later in the main text.

o We removed the abbreviation SD because it was challenging to fit “standard deviation (SD)” into this section while maintaining a readable style and meeting the word limit requirements. We also feel that the SD for age is not necessary to report in the abstract as it was not a main outcome.

Materials and Methods

Rephrase the line ‘We included patients starting 20 years ‘prior to the query date (July 30, 2023) to maximize sample size’ for a clearer understanding.

• Response: Thank you. We added the apostrophe on years as requested.

Results

• Response: Thank you. We added the nomenclature that you kindly provided to Table 1. We feel this greatly helps with interpretation.

The level of significance (p) should be written in small italicized letters.

• Response: Thank you. We have made this change as advised throughout the manuscript to write “p”

Reviewer #5

This study investigated association between chiropractic spinal manipulation and cauda equina syndrome in adults with low back pain. The authors concluded that CSM is not a risk factor for CES. Considering prior epidemiologic evidence, patients with LBP may have an elevated risk of CES independent of treatment. These findings warrant further corroboration. In the meantime, clinicians should be vigilant to identify LBP patients with CES and promptly refer them for surgical evaluation.

Comment#1

The authors should insert low back pain as a keywords.

• Response: Thank you. We added “low back pain” as a keyword.

Comment#2

The authors should provide more explanations about the risk of Cauda equina syndrome following chiropractic spinal manipulation and physiotherapy.

• Response: Thank you. We added more information in the introduction section as advised which responds to this comment and the comment below. See the added material:

o Chiropractors are increasingly sought by patients in the US for the treatment of LBP [30]. A recent study based on insurance claims revealed that chiropractors were among the most commonly visited healthcare providers for new episodes of LBP, ranking second only to primary care physicians (25.2% of episodes with primary care versus 24.8% with a chiropractor) [31]. Furthermore, chiropractors use spinal manipulation more frequently than any other type of clinician [31].

o Half of chiropractic patients have LBP, [32] with a subset of these patients having lumbar disc herniation [33]. Although CES is a rare event, lumbar disc herniation is its most common cause [34] and is also frequently present among those with LBP [35]. Accordingly, chiropractors may encounter patients who have a heightened risk of developing CES, as these clinicians treat those with LBP and disc disorders [3,9].

o Considering CSM is commonly used for LBP, wherein underlying disc degeneration may pose a risk factor for CES [3,9], researchers have emphasized the importance of studying the potential association between CSM and CES [9,36]. Mild adverse events related to CSM, such as transient soreness, are accepted to be common and occur in 23-83% of patients [37]. However, less is known regarding the potential for CSM to cause CES, as the existing literature on the topic is mostly derived from individual case reports [3,4,9].

• Please note that we are not suggesting physical therapy evaluation may increase or decrease the risk of CES. This is noted in the Discussion.

Comment#3

The authors should state more explanations for performing your study.

• Response: Thank you, we agree. Please see the added paragraphs above. We point out that such a large study has not been conducted yet on the topic, with most of the literature being case reports. Our objectives paragraph at the end of the introduction should now have more context as we provide more thorough background on the topic.

Other changes

1. We added the number of patients (54,846) when describing a study we cite in the introduction. This helps give context, as the study had less patients than ours, and that our study builds upon the past work with having a greater sample size.

2. We deleted a statement from the “Setting and data source” section and combined it with the earlier description of TriNetX in the Methods as it was redundant with our improved ethics statement.

3. We deleted two phrases regarding “claims” data, one in the abstract and another in the Methods in the “Setting and data source” section, as we felt this term was potentially misleading. TriNetX is predominantly based on health records / medical records data. While TriNetX does include claims data as well, our study did not query claims data as we were not focusing on events such as cost.

References (for response document)

1. Topaloglu U, Palchuk MB. Using a federated network of real-world data to optimize clinical trials operations. JCO Clin Cancer Inform. 2018;2:1–10.

2. Boucher P, Robidoux S. Lumbar disc herniation and cauda equina syndrome following spinal manipulative therapy: A review of six court decisions in Canada. J Forensic Leg Med. 2014;22:159–69.

3. Haldeman S, Rubinstein SM. Cauda Equina Syndrome in Patients Undergoing Manipulation of the Lumbar Spine. Spine. 1992;17:1469–73.

4. Tamburrelli FC, Genitiempo M, Logroscino CA. Cauda equina syndrome and spine manipulation: case report and review of the literature. Eur Spine J. 2011;20:128–31.

5. Hebert JJ, Stomski NJ, French SD, Rubinstein SM. Serious adverse events and spinal manipulative therapy of the low back region: a systematic review of cases. J Manipulative Physiol Ther. 2015;38:677–91.

6. Terrett A. Misuse of the literature by medical authors in discussing spinal manipulative therapy injury. J Manipulative Physiol Ther. 1995;18:203–10.

7. Wenban AB. Inappropriate use of the title’chiropractor’and term’chiropractic manipulation’in the peer-reviewed biomedical literature. Chiropr Osteopat. 2006;14:16.

8. Yang S-D, Chen Q, Ding W-Y. Cauda Equina Syndrome Due to Vigorous Back Massage with Spinal Manipulation in a Patient with Pre-Existing Lumbar Disc Herniation: A Case Report and Literature Review. Am J Phys Med Rehabil. 2018;97:e23–6.

9. Oliphant D. Safety of spinal manipulation in the treatment of lumbar disk herniations: a systematic review and risk assessment. J Manip Physiol Ther 2004 Mar-Apr273197-210. 2004;

10. Oppenheim JS, Spitzer DE, Segal DH. Nonvascular complications following spinal manipulation. Spine J Off J North Am Spine Soc. 2005;5:660–6; discussion 666-667.

11. Nissen T, Wynn R. The clinical case report: a review of its merits and limitations. BMC Res Notes. 2014;7:1–7.

12. Hutchins TA, Peckham M, Shah LM, Parsons MS, Agarwal V, Boulter DJ, et al. ACR Appropriateness Criteria® Low Back Pain: 2021 Update. J Am Coll Radiol. 2021;18:S361–79.

13. Pokora RM, Le Cornet L, Daumke P, Mildenberger P, Zeeb H, Blettner M. Validation of Semantic Analyses of Unstructured Medical Data for Research Purposes. Gesundheitswesen Bundesverb Arzte Offentlichen Gesundheitsdienstes Ger. 2020;82:S158–64.

14. Legnar M, Daumke P, Hesser J, Porubsky S, Popovic Z, Bindzus JN, et al. Natural Language Processing in Diagnostic Texts from Nephropathology. Diagnostics. 2022;12:1726.

15. Venkatesan M, Uzoigwe CE, Perianayagam G, Braybrooke JR, Newey ML. Is cauda equina syndrome linked with obesity? J Bone Joint Surg Br. 2012;94-B:1551–6.

16. Cushnie D, Urquhart JC, Gurr KR, Siddiqi F, Bailey CS. Obesity and spinal epidural lipomatosis in cauda equina syndrome. Spine J. 2018;18:407–13.

17. Ahad A, Elsayed M, Tohid H. The accuracy of clinical symptoms in detecting cauda equina syndrome in patients undergoing acute MRI of the spine. Neuroradiol J. 2015;28:438–42.

18. Schoenfeld AJ, Bader JO. Cauda equina syndrome: An analysis of incidence rates and risk factors among a closed North American military population. Clin Neurol Neurosurg. 2012;114:947–50.

19. Vanood A, Singh B, Wheeler K, Patino G. Conus Medullaris Syndrome and Cauda Equina Syndrome after Lumbar Epidural Steroid Injection: A Systematic Review of Literature (4325). Neurology. 2021;96.

20. Kaiser R, Krajcová A, Waldauf P, Srikandarajah N, Makel M, Beneš V. Are There Any Risk Factors Associated with the Presence of Cauda Equina Syndrome in Symptomatic Lumbar Disk Herniation? World Neurosurg. 2020;141:e600–5.

21. Shapiro S. Medical realities of cauda equina syndrome secondary to lumbar disc herniation. Spine. 2000;25:348–52.

22. Korse NS, Pijpers JA, van Zwet E, Elzevier HW, Vleggeert-Lankamp CLA. Cauda Equina Syndrome: presentation, outcome, and predictors with focus on micturition, defecation, and sexual dysfunction. Eur Spine J. 2017;26:894–904.

23. Fuso FAF, Dias ALN, Letaif OB, Cristante AF, Marcon RM, Barros Filho TEP de. Epidemiological study of cauda equina syndrome. Acta Ortop Bras. 2013;21:159–62.

24. Ouzts NE, Himelfarb I, Shotts BL, Gow AR. Current state and future directions of the National Board of Chiropractic Examiners. J Chiropr Educ. 2020;34:31–4.

25. Chang M. The Chiropractic Scope of Practice in the United States: A Cross-Sectional Survey. J Manipulative Physiol Ther. 2014;37:363–76.

26. Bednarz EM, Lisi AJ. A survey of interprofessional education in chiropractic continuing education in the United States. J Chiropr Educ. 2014;28:152–6.

27. Ciolek DE, Hwang W, others. Short-Term Alternatives for Therapy Services (STATS) task order: CY 2008 outpatient therapy utilization report. Baltimore: Centers for Medicare & Medicaid Services. Retrieved from http …; 2010.

28. Himelfarb I, Hyland J, Ouzts N, Russell M, Sterling T, Johnson C, et al. National Board of Chiropractic Examiners: Practice Analysis of Chiropractic 2020 [Internet]. Greeley, CO: NBCE; 2020 [cited 2020 Nov 7]. Available from: https://www.nbce.org/practice-analysis-of-chiropractic-2020/

29. Salsbury SA, Goertz CM, Twist EJ, Lisi AJ. Integration of Doctors of Chiropractic Into Private Sector Health Care Facilities in the United States: A Descriptive Survey. J Manipulative Physiol Ther. 2018;41:149–55.

30. Adams J, Peng W, Cramer H, Sundberg T, Moore C, Amorin-Woods L, et al. The Prevalence, Patterns, and Predictors of Chiropractic Use Among US Adults: Results From the 2012 National Health Interview Survey. Spine. 2017;42:1810–6.

31. Harwood KJ, Pines JM, Andrilla CHA, Frogner BK. Where to start? A two stage residual inclusion approach to estimating influence of the initial provider on health care utilization and costs for low back pain in the US. BMC Health Serv Res. 2022;22:694.

32. Beliveau PJH, Wong JJ, Sutton DA, Simon NB, Bussières AE, Mior SA, et al. The chiropractic profession: a scoping review of utilization rates, reasons for seeking care, patient profiles, and care provided. Chiropr Man Ther. 2017;25:35.

33. Trager RJ, Daniels CJ, Perez JA, Casselberry RM, Dusek JA. Association between chiropractic spinal manipulation and lumbar discectomy in adults with lumbar disc herniation and radiculopathy: retrospective cohort study using United States’ data. BMJ Open. 2022;12:e068262.

34. Lavy C, Marks P, Dangas K, Todd N. Cauda equina syndrome—a practical guide to definition and classification. Int Orthop. 2022;46:165–9.

35. Brinjikji W, Diehn F, Jarvik J, Carr C, Kallmes DF, Murad MH, et al. MRI findings of disc degeneration are more prevalent in adults with low back pain than in asymptomatic controls: a systematic review and meta-analysis. Am J Neuroradiol. 2015;36:2394–9.

36. Funabashi M, French SD, Kranenburg HA (Rik), Hebert JJ. Serious adverse events following lumbar spine mobilization or manipulation and potential associated factors: a systematic review protocol. JBI Evid Synth. 2021;19:1489–96.

37. Swait G, Finch R. What are the risks of manual treatment of the spine? A scoping review for clinicians. Chiropr Man Ther. 2017;25:37.

Attachment

Submitted filename: Response to reviewers_1.2.docx

pone.0299159.s006.docx^{(79.6KB, docx)}

PLoS One. doi: 10.1371/journal.pone.0299159.r003

Decision Letter 1

Shabnam ShahAli

6 Feb 2024

Association between chiropractic spinal manipulation and cauda equina syndrome in adults with low back pain: Retrospective cohort study of US academic health centers

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PLoS One. doi: 10.1371/journal.pone.0299159.r004

Acceptance letter

Shabnam ShahAli

1 Mar 2024

PONE-D-23-39784R1

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Associated Data

This section collects any data citations, data availability statements, or supplementary materials included in this article.

Supplementary Materials

S1 Fig. Study design.

(DOCX)

pone.0299159.s001.docx^{(88.6KB, docx)}

S1 Table. Inclusion codes for both cohorts.

(DOCX)

pone.0299159.s002.docx^{(13.3KB, docx)}

S2 Table. Exclusion codes for both cohorts.

(DOCX)

pone.0299159.s003.docx^{(13.3KB, docx)}

S3 Table. Variables controlled for in propensity score matching.

(DOCX)

pone.0299159.s004.docx^{(13.3KB, docx)}

Attachment

Submitted filename: reviewers report.docx

pone.0299159.s005.docx^{(14.1KB, docx)}

Attachment

Submitted filename: Response to reviewers_1.2.docx

pone.0299159.s006.docx^{(79.6KB, docx)}

Data Availability Statement

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PERMALINK

Association between chiropractic spinal manipulation and cauda equina syndrome in adults with low back pain: Retrospective cohort study of US academic health centers

Robert J Trager

Anthony N Baumann

Jaime A Perez

Jeffery A Dusek

Romeo-Paolo T Perfecto

Christine M Goertz

Roles

Abstract

Background

Methods

Results

Conclusions

Introduction

Materials and methods

Study design

Setting and data source

Participants

Eligibility criteria

Variables

Cohorts

Confounding variables

Outcome

Statistical methods

Study size

Results

Participants

Table 1. Baseline characteristics before and after propensity score matching.

Descriptive data

Fig 1. Propensity score density graph.

Key results

Table 2. Key results before and after propensity score matching.

Fig 2. Incidence of cauda equina syndrome (CES) per cohort after propensity matching.

Sensitivity analysis

Fig 3. Cumulative incidence of cauda equina syndrome.

Discussion

Strengths and limitations

Conclusions

Supporting information

Data Availability

Funding Statement

References

Decision Letter 0

Shabnam ShahAli

Roles

Author response to Decision Letter 0

Decision Letter 1

Shabnam ShahAli

Roles

Acceptance letter

Shabnam ShahAli

Roles

Associated Data

Supplementary Materials

Data Availability Statement

ACTIONS

PERMALINK

RESOURCES

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