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RESEARCH ARTICLE Open Access

Association between work-related biomechanical risk factors and the occurrence of carpal tunnel syndrome: an overview of systematic reviews and a meta-analysis of current research Agnessa Kozak1*, Grita Schedlbauer2†, Tanja Wirth2†, Ulrike Euler3, Claudia Westermann1 and Albert Nienhaus1,2†

Abstract

Background: Occupational risks for carpal tunnel syndrome (CTS) have been examined in various occupations, and several systematic reviews (SRs) have been published on this topic. There has been no critical appraisal or synthesis of the evidence in the SRs. The aims of this study are (1) to synthesise the observational evidence and evaluate the methodological quality of SRs that assess the effect of biomechanical risk factors on the development of CTS in workers, (2) to provide an update of current primary research on this association, (3) to assess a potential dose-response relationship.

Methods: We searched MEDLINE, EMBASE, CINAHL, the Cochrane Library and the reference lists of articles. The first step covered SRs (1998–2014), and the second step covered current primary studies (2011–2014). The methodological quality of the SRs was evaluated by using the AMSTAR-R tool; primary studies were assessed using a list of 20 items. A qualitative approach was used for synthesising evidence. In addition, we undertook a meta-analysis of the primary studies to determine risk ratios in the dose-response relationship.

Results: We identified ten SRs that covered a total of 143 original studies. Seven primary studies met the criteria for inclusion, of which four provided longitudinal data. We found high quality of evidence for risk factors such as repetition, force and combined exposures. Moderate quality of evidence was observed for vibration, and low quality of evidence was found for wrist postures. An association between computer use and CTS could not be established. Recent primary studies supported the existence of a significant relationship between CTS and repetition, force and combined exposure. The meta-analysis of current research revealed a dose-response relationship between CTS and the American Conference of Governmental Industrial Hygienists’ (ACGIH) threshold limit value (TLV) for hand-activity level (HAL). Those between the action limit and TLV and above TLV had RR of 1.5 (95 % CI 1.02–2.31) and RR 2.0 (95 % CI 1.46–2.82), respectively.

Conclusions: Occupational biomechanical factors play a substantial role in the causation of CTS. Data from current primary studies on dose-response suggest that the risk of CTS increases with the ACGIH TLV levels.

Background Carpal tunnel syndrome (CTS) is a pathophysiological peripheral mononeuropathy, caused by an increase in the tissue pressure in the carpal tunnel. This leads to pressure damage of the N. medianus, linked to sensory and motor failures in the affected area. CTS is the most

frequent compression syndrome of a peripheral nerve. A review of occupational populations showed that the prevalence of CTS varies greatly with the diagnostic cri- teria, population and study type, and it may range from 0.6 to 61 % [1, 2]. In population-based studies, the prevalence rates range from 1 to 6 % [3–6]. CTS mainly affects women and increases with age. In Swedish and Italian population studies, the annual incidence for women was 428 and 506 per 100,000 respectively. This is about three times greater than the corresponding values for men, namely 182 and 139 cases per 100,000

* Correspondence: [email protected] †Equal contributors 1Institute for Health Services Research in Dermatology and Nursing (CVcare), University Medical Center Hamburg-Eppendorf, Hamburg, Germany Full list of author information is available at the end of the article

© 2015 Kozak et al. Open Access This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.

Kozak et al. BMC Musculoskeletal Disorders (2015) 16:231 DOI 10.1186/s12891-015-0685-0

respectively [7, 8]. The causes of CTS may be local (e.g., cysts), regional (e.g., rheumatoid arthritis) or systemic (e.g., diabetes) [9]. There is increasing scientific evidence that development of CTS is promoted by highly repeti- tive manual tasks, involving awkward hand/wrist pos- tures, with flexion and extension of the hands, forceful exertion or hand/arm vibration during work [1, 10]. Some occupational groups are more exposed than others, due to the nature of their work. These are mostly occupations requiring the frequent use of hand-held vibratory tools and high levels of physical exposure, par- ticularly during assembly work, food processing and packaging [11]. As CTS is common in the general popu- lation and is multi-causal, it is legitimate to ask to what extent it is caused by occupational factors. This has been a controversial issue for many years [12–16]. For ex- ample, Thurston [17] argued that occupational factors — such as repetition, vibration or force — are not the primary cause of CTS and that it was more likely that these activities trigger symptoms or exacerbate existing latent symptoms. In a prospective study on the aetiology of CTS in the industrial sector, the authors found out that individual factors, such as age, being overweight, gender, hand anthropometrics and hand dominance play a much greater role in causing CTS than occupational factors, such as force, repetition, duration of employment and type of employment [18–20]. However, early systematic reviews (SRs) concluded that there is sufficient evidence for an association between occupational exposure to biomech- anical factors and the development of CTS [1, 10, 21, 22]. In recent years, several SRs and meta-analyses have been

published on the aetiology of CTS in the occupational context. There has however been no critical evaluation of the SRs or a discussion of the results. The “overview of systematic reviews” represents a new approach to synthe- sising evidence from several SRs [23]. Overviews can po- tentially provide a broad summary of empirical research on a specific issue [24]. The information provided by these overviews is essentially dependent on the validity of the primary studies and the SRs that they include [25]. As SRs may very rapidly become dated, it is advisable to include the most recent publications, too [26, 27]. This overview aims to synthesise and critically eva-

luate the quality of SRs and current primary studies assessing the relationship between occupational bio- mechanical factors and CTS in working populations. Another objective is to quantify the dose-response rela- tionship using the American Conference of Governmental Industrial Hygienists (ACGIH) threshold limit value (TLV) for hand-activity level (HAL) model.

Methods The literature search and analysis took place in two steps. The first step consisted of an explicit search for

SRs. The procedure was based on the methods paper published by the Clearinghouse of Systematic Reviews of the Partnership for European Research in Occupational Safety and Health (PEROSH) [28]. In the second step, pri- mary studies were identified and evaluated. This study was conducted according to the Meta-analysis of Observational Studies in Epidemiology (MOOSE) checklist (see Additional file 1) [29].

Search strategy and study selection An electronic literature search for SRs was performed in the MEDLINE (via Pubmed), EMBASE (via Ovid), CINAHL (via EBSCO) and COCHRANE databases. It covered the publication period from 1998 to 2014 (last update 27.7.14) and used predefined search strings and terms. In order to identify aetiological studies in the oc- cupational context, we employed the sensitive search string developed by Mattioli et al. [30], in combination with the terms for exposure (exposure; physical load; risk factor*; repetiti*; hand-arm vibration; force), outcome (carpal tunnel syndrome; median nerve neuropathy; median nerve entrapment; nerve compression syndrome) and study design (meta-analysis; review; not letter, editorial, com- ment). The search strategy is listed in the Additional file 2. We also searched for additional sources within the refer- ences of relevant publications. The following inclusion and exclusion criteria for SRs were applied:

– Population: employed adults. – Exposure: biomechanical factors in the occupational

context (exclusion: studies on diagnostic testing, treatment or rehabilitation).

– Outcome: CTS as primary outcome (exclusion: CTS as concomitant disease, e.g., in diabetes mellitus).

– Design: SRs and meta-analyses (exclusion: narrative reviews, editorials, commentaries).

To update the analysis, we conducted a primary litera- ture search using MEDLINE, EMBASE and CINAHL databases. The same sensitive search string was employed, except for the partial string for SRs and meta- analyses. The last comprehensive literature search was performed in the meta-analysis published by Spahn et al. [31]. Our search therefore included the period January 2011 to 2014 (last update 31.8.2014). The following in- clusion and exclusion criteria were applied for primary studies:

– Population: employed adults. – Exposure: consideration of at least one

biomechanical exposure factor, giving degrees of association or raw data.

– Outcome: conservative CTS case definition: (a) abnormal findings in the nerve conduction study

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(NCS) that indicated dysfunction of the N. medianus in the carpal tunnel and (b) either clinical signs (a positive Phalen’s or Tinel’s sign) or symptoms indicative of CTS such as paraesthesia, numbness or pain.

– Design: peer review article with case control, cross-sectional and cohort studies.

Six languages (English, German, Italian, Spanish, Portuguese and Russian) were considered. The studies were selected independently by two reviewers (AK, TW). In the event of disagreement, consensus was achieved by discussion. When no consensus could be achieved, a third reviewer (GS) was consulted. Data were extracted by one reviewer (AK). To verify accuracy of extraction, a second and a third reviewer (TW, GS) checked all relevant data for each included SR and primary study. Data extracted from the studies is listed in the Additional file 3.

Degree of overlap between the SRs If primary studies are included in more than a single SR on the same research question, this can lead to bias in the interpretation of the results of the overview. For this reason, it was necessary for the overview to determine the extent to which the primary studies overlapped in the different SRs. This is presented in Table 1. Addition- ally, a calculation was performed of the percentage of primary studies included in more than one SR. A mea- sure of overlap was also calculated — the “Corrected Covered Area” (CCA), using the method proposed by Pieper et al. [26]. The included primary studies were ex- tracted from each SR, documented and calculated in an Excel table (SR x primary studies). CCA can be inter- preted as the overlap area of studies that occur at least twice in SRs, after correction for the first time each

primary study was counted (index publications). The fre- quency of repeated occurrence of index publications in SRs (N) is divided by the product of index publications (r) and reviews (c), minus by the number of index publi- cations (r; see calculation formula). CCA values between 0 and 5 indicate slight overlap; values between 6 and 10 moderate overlap, values between 11 and 15 high over- lap and values above 15 very high overlap [26].

CCA ¼ N−r rc−r

N is the number of publications included (with duplicate counts) in the evidence synthesis of individual SRs; r is the number of index publications (individual primary studies) and c the number of SRs.

Quality assessment The validity of the included SRs was critically and inde- pendently assessed by two reviewers using the Assessment of Multiple Systematic Reviews – Revised (AMSTAR-R), an instrument that was specifically developed to assess the methodological quality of SRs [32]. Between 11 and 44 points could be reached on the AMSTAR-R score. To dif- ferentiate between the SRs, the numerical score was con- verted to quality grades: A = 37–44 (very good); B = 29–36 (good); C = 21–28 (moderate); D = 13–20 (poor) points [33]. The inter-rater reliability between two reviewers was determined with Cohen’s kappa coefficient [34]. The evaluation of the validity of the primary studies

was based on the criteria developed by van Rijn et al. [35] and Ariëns et al. [36] (see Additional file 4). These were adapted to suit the research question and then summarised to a cumulative score with a maximum of 20 points. Quality was rated as methodologically

Table 1 Overlap of original research studies included in the systematic reviews

Author, year 1 2 3 4 5 6 7 8 9 10

1. Abbas et al. 1998 [21] 17 0 9 1 7 10 9 8 3 0

2. Sulsky et al. 2005 [44] 34 12 3 12 14 6 13 0 3

3. Palmer et al. 2007 [22] 38 5 19 18 16 19 4 2

4. Thomsen et al. 2008 [45] 9 4 4 1 3 1 3

5. Lozano-Calderón et al. 2008a [46] 66 18 12 16 5 2

6. van Rijn et al. 2009 [35] 44 21 21 3 3

7. Barcenilla et al. 2012 [41] 37 22 3 0

8. Spahn et al. 2012a [31] 55 2 1

9. You et al. 2014 [43] 8 0

10. Mediouni et al. 2014 [42] 6

Bold numbers are studies included in each SRs aIncluded primary studies that were used for the analysis of occupational risk factors, but which were not listed explicitly, e.g., in the form of an evidence table. Consequently all studies from all tables, figures or text were extracted when they were used for the analysis of occupational factors. This was used to determine overlap

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high (≥14 points), moderate (8 to 13 points) or poor (≤7 points).

Quality of evidence Due to the heterogeneity of the primary studies and the overlap of the study pool of the SRs included, no formal evidence synthesis was possible with the Grades of Rec- ommendation, Assessment, Development and Evaluation (GRADE) approach [37]. We therefore determined the quality of evidence using a qualitative approach for each type of occupational exposure. The assessment of the quality of evidence depended on the methodological val- idity of the SRs (AMSTAR-R score), together with the consistency of the results between the SRs (direction of effect and significance) [38, 39]. We gave greater weight to recently published SRs; older SRs provided supportive evidence [27]. The following classification was specified:

– High – consistent evidence in very good SRs (at least one grade A review).

– Moderate – consistent evidence in good SRs (at least one grade B review).

– Low – one SR of moderate quality (at least grade C) and significant results and/or good SRs (grade B), with some inconsistent results.

– Poor – none of the above conditions were met (i.e., consistent findings in low-quality SRs (grade D), or inconsistent findings in multiple SRs).

The results of the primary studies served to support the assessment of the quality of evidence, as both their methodological validity and their consistency were con- sidered; i.e., when at least two valid primary studies (≥14 points) gave consistent results, the quality of the evi- dence from the SRs was upgraded.

Statistical analyses Comparable primary studies were pooled in the form of quantitative data synthesis and presented as forest plots. The relative risk (RR) was calculated and 95 % confi- dence intervals (CI) were generated. The heterogeneity of individual studies was quantified using the Chi-square (χ2) and I2 statistics. If there was statistically significant heterogeneity (χ2, p <0.10 and I2 > 50 %), then the pooled effect estimate was determined with the random effects model. Otherwise, a fixed effects model was used [40]. The analyses were applied to current primary studies and were conducted using RevMan Version 5.2.

Ethics Ethical approval was not required as the study focused only on analysing secondary literature without any in- volvement of human subjects, tissues or medical records.

Results SRs and meta-analyses A total of ten relevant SRs were included. The flow dia- gram (Fig. 1) shows the selection of SRs identified by the electronic and hand search. The number of primary studies per SR varied from 6 to 66. Taken together, the ten SRs covered a total of 143 primary studies (index publications); these were cited up to 314 times in the SRs. 35 % of the index publications were cited in two to three SRs and about 29 % in four to six SRs (Table 1). The CCA value was 13.3, which indicates a high degree of overlap. Table 2 shows the detailed characteristics of the included SRs. In half of the SRs, a meta-analysis was performed [21, 31, 41–43]. Five of the other SRs pre- sented the results qualitatively in the form of an evi- dence table [22, 35, 44–46]. Two SRs concentrated exclusively on the link between computer use and CTS [42, 45]. A meta-analysis by You et al. [43] only exam- ined the link between non-neutral wrist postures and CTS. The paper by Sulsky et al. [44] is a report from the Occupational Insurance Association for Safety at Work; this was not published as a peer review article. Using AMSTAR-R scoring, three SRs were categorised

as “grade B” [35, 41, 42], five as “grade C” [22, 31, 43–45] and two as “grade D” publications [21, 46]. With a single exception, the inter-rater reliability was good to very good (kappa: 0.38–0.87) (see Additional file 5). SRs used different instruments and methods to assess

the methodological quality of the included studies. The Cochrane Collaboration’s tool for assessing risk of bias was used by only a single meta-analysis [41]. Selective criteria were used in three additional studies, which all considered aspects such as study design, allocation of participants, outcome and exposure assessment, as well as the control of potential confounders [35, 44, 45]. You et al. [43] identified possible bias with sensitivity ana- lyses; Mediouni et al. [42] provided the strengths and limitations of the original studies in an evidence table. Lozano-Calderón et al. [46] developed an assessment scheme in accordance with the Bradford-Hill criteria for causality and used this score to determine the quality and the strength of the evidence for the aetiological link be- tween generally accepted risk factors for CTS (biological, occupational, as well as biological and occupational together). The results from the SRs and meta-analyses are pre-

dominantly based on cross-sectional and case control studies; prospective longitudinal studies were in the mi- nority. Table 3 shows the main results from the SRs.

Current primary studies The selection of the primary studies employed the same selection process as for the SRs. After scrutinising 366 titles and abstracts, we reviewed 49 full texts and

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included a total of seven studies in the evidence synthe- sis (Fig. 2). The main reasons for exclusion were no con- servative CTS definition (n = 20) or no investigation of biomechanical risk factors (n = 13). Of the included studies, four were of high quality and had a prospective design [47–50], although one publication only presented the baseline results [48]. The other three studies were of moderate quality, including one prospective study [51] and two case control studies (see Additional file 4) [52, 53]. In four studies, the exposures were measured with objective methods [47–50]. In two studies, exposures were self- reported [52, 53] and in one study, exposures were assessed with Job Exposure Matrices (JEM, US O*NET Database) [51]. A summary of the characteristics of the in- cluded primary studies along with the main results are shown in Table 4. All four studies of high quality deter- mined the ACGIH TLV for HAL and were incorporated in the meta-analysis to clarify the dose-response relation- ship [47–50]. This score includes the combined exposure from peak force (PF) and repetition (HAL). HAL is based on frequency of exertion and duty cycle of exertion. PF is based on the peak effort exerted by the hand during the regular duty cycle. PF and HAL are combined into a single measure by calculating the ratio PF/(10-HAL). As pro- posed by ACGIH the TLV for HAL score <0.56 is consid- ered below the Action Limit (AL) and is a category for general controls due to low risk. A score >0.78 is con- sidered above the TLV and indicates a high risk. Scores between AL and TLV are considered to be possibly dan- gerous borderline exposures [54]. For the results of the meta-analysis see the paragraph on combined exposures.

Repetition Seven SRs (two grade B, three grade C and two grade D) examined repetition as a risk factor for CTS (Table 3).

On the basis of the highest-quality study available, there is a significant association between repetition and CTS. This association is maintained when only studies that used a conservative CTS case definition [41] are con- sidered. A SR of good quality (grade B) showed that five out of eight studies found a positive association with CTS. The authors concluded that cycles times of <10 s were more harmful than cycles times of <30 s, or when the same movements were performed in >50 % of work- ing time [35]. Another meta-analysis also confirmed this association, though this had not been demonstrated for longitudinal studies [31]. A meta-regression analysis by Abbas et al. [21] showed that country, study population, repetition and force were significant predictors of CTS. Sulsky et al. [44] confirmed that there is consistent evi- dence for a weak positive relationship between CTS and repetition. Palmer et al. [22] also found that there is an increased risk of CTS from highly repetitive flexion and extension of the wrist. Using the Bradford-Hill criteria for causality, Lozano-Calderón et al. [46] found only slight evidence for a causal relationship between repeti- tion and CTS (Bradford-Hill score: 6.5 of 21 points). All of the included primary studies confirm that there is

a positive association between repetition and CTS (Table 4). The baseline results of Burt et al. [48] show an interaction between BMI and the frequency of exertion per minute (≥5 % of the maximal voluntary contraction). High fre- quency of exertion (≥15 times/min.) resulted in a three- fold higher probability of CTS in the obese (BMI ≥30). Obesity doubled the odds for CTS among those with fre- quent exertion per minute. Furthermore, a significant asso- ciation between HAL and CTS was observed for men but not for women (OR 1.4, 95 % CI 1.05–1.81). Bonfiglioli et al. [50] found that HAL was an independent predictor of CTS (IRR 1.4, 95 % CI 1.19–1.57). According to

Fig. 1 Flowchart of the selected systematic reviews

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Table 2 Study characteristics of the included systematic reviews and meta-analyses

Author, year Analysis AMSTAR-R grade Country Years included No. of studies included

Study designs A priori quality criteria The study’s aim was to …

You et al. 2014 [43] MA C US 1980–2012 n = 8 CC = 2; CS = 6 Recognition of bias by sensitivity analysis

… conduct a meta-analysis of existing studies to evaluate the evidence of the relationship between wrist posture at work and CTS

Mediouni et al. 2014 [42] MA B FR 1992–2012 n = 6 C = 2; CS = 4 Strengths and limitations acknowledged

… conduct a systematic review and meta- analysis of the available epidemiological data on the association between computer work exposure and CTS

Barcenilla et al. 2012 [41] MA B AU 1980–2009 n = 37 C = 3; CC = 5; CS = 28 Risk of Bias Tool … examine the association between workplace exposure and CTS by meta-analysis, with respect to exposure to hand force, repetition, vibration and wrist posture

Spahn et al. 2012 (in German) [31]

MA C DE ≤2011 n = 55 n/a n/a … conduct a systematic review and meta- analysis to identify associated and risk factors for CTS in the occupational setting

Van Rijn et al. 2009 [35] SR B NL 1966–2007 n = 44 C = 5; CC = 9; CS = 30 16-item score … provide a quantitative assessment of the exposure-response relationship between work-related physical and psychosocial factors and the occurrence of CTS in occupational populations

Lozano-Calderón et al. 2008 [46]

SR D US ≤2008 n = 51a; n = 33b; (total = 66)

C = 7a; CC = 12a; C = 29a; Other = 3a

Bradford Hill criteria for causation

… evaluate the quality and strength of scientific evidence supporting an aetiological relationship between a disease and a proposed risk factor, using a scoring system based on the Bradford Hill criteria for causal association – example of CTS

Thomsen et al. 2008 [45] SR C DK ≤2004 n = 8 C = 4; CC = 2; CS = 2 Selected criteria (4 main domains)

… conduct a systematic review to examine evidence for an association between computer work and CTS

Palmer et al. 2007 [22] SR C GB ≤2004 n = 38 n/a n/a … conduct a systematic review to assess occupational risk factors for CTS

Sulsky et al. 2005 [44] SR C DE 1997–2003 n = 34 C = 10; CC = 2; CS = 22 Selected criteria (6 main domains)

… clarify the relationship between CTS and occupation using quality based criteria from the epidemiological literature

Abbas et al. 1998 [21] MA D US 1980–1995 n = 17 C = 3; CC = 4; CS = 10 n/a … conduct a meta-analysis on work-related CTS and to identify risk estimates and possible biases influencing the risk estimates

Abbreviations: AMSTAR-R Assessment of Multiple Systematic Reviews – Revised (numeric quality score in grades: A = 37–44; B = 29–36; C = 21-28; D = 13–20 points), C Cohort, CC Case control, CS Cross-sectional, CTS Carpal tunnel syndrome, MA Meta-analysis, SR Systematic review aStudies investigating occupational factors alone bStudies investigating both biological and occupational factors

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Table 3 Main results of the included systematic reviews and meta-analyses stratified by the exposure factors

Author, year, ↓quality Vibration (95 % CI) Repetition (95 % CI) Force (95 % CI) Combined exposure (repetition and force) (95 % CI)

Wrist posture (95 % CI) Computer exposure (95 % CI)

Barcenilla et al. 2012 [41] Grade B

NIOSH CTS def.: OR 2.7 (1.9–3.9); n = 12 studies Conservative CTS def.a: OR 5.4 (3.1–9.3); n = 3/3 (100 %) studiesd

NIOSH CTS def.: OR 2.3 (1.8–3.0); n = 25 studies Conservative CTS def.a: OR 2.3 (1.7–2.9); n = 5/11 (45 %) studiesd

NIOSH CTS def.: OR 2.2 (1.5–3.3); n = 13 studies Conservative CTS def.a: OR 4.2 (1.5–11.7); n = 3/5 (60 %) studiesd

NIOSH CTS def.: OR 2.0 (1.4–2.9); n = 4/9 (44 %) studiesd Conservative CTS def.a: OR 1.9 (1.0–3.5); n = 5 studies

NIOSH CTS def.: OR 2.7 (1.3–5.5); n = 7 studies Conservative CTS def.a: OR 4.7 (0.4–53.3); n = 1/3 (33 %) studiesd

/

Mediouni et al. 2014 [42] Grade B

/ / / / / Computer use: OR 1.7 (0.8-3.6); n = 5 studies; Keyboard/mouse use: OR 1.1 (0.6–2.0); OR 1.9 (0.9–4.2)

Van Rijn et al. 2009 [35] Grade B

OR 2.5–4.8; n = 3/5 (60 %) studiesd

OR 0.5–9.4; n = 5/8 (62 %) studiesd

OR 2.1–9.0; n = 3/7 (43 %) studiesd

OR 3.2–8.4; n = 3/4 (80 %) studiesd

OR 1.3–8.7; n = 4/5 (80 %) studiesd

OR 2.1–4.4; n = 2/7 (29 %) studiesd

You et al. 2014 [43] Grade C

/ / / / Non-neutral wrist postures: RR 2.0 (1.7–2.4); n = 4/8 (50 %) studiesd

/

Spahn et al. 2012 [31] Grade C

OR 2.6 (1.7–4.0); n = 6/9 (