Neurodynamic Techniques in the Treatment of Mild-to-Moderate Carpal Tunnel Syndrome: A Systematic Review and Meta-Analysis

Carpal tunnel syndrome (CTS) is a condition that affects the main nerves in the wrist area that causes numbness, tingling, and weakness in the hand and arm. CTS affects 5% of the general population and results in pain in the wrist due to repetitive use, most commonly affecting women and office workers. Conservative management of CTS includes neurodynamic modulation to promote median nerve gliding during upper limb movements to maintain normal function. However, evidence for the benefits of neurodynamic modulation found disparities, and hence, the effectiveness of neurodynamic modulation remains unclear. This study aimed to systematically review the current evidence from randomized controlled trials (RCTs) to establish the effectiveness of neurodynamic techniques as a non-surgical treatment option for CTS. Using the PRISMA guidelines, two authors searched four electronic databases, and studies were included if they conformed to pre-established eligibility criteria. Primary outcome measures included outcomes from the Boston carpal tunnel syndrome questionnaire, while secondary outcomes included nerve conduction velocity, pain, and grip strength. Quality assessment was completed using the Cochrane RoB2 form, and a meta-analysis was performed to assess heterogeneity. Twelve RCTs met our inclusion/exclusion criteria with assessments on 1003 participants in the treatment and control arms. High heterogeneity and some risks of bias were observed between studies, but the results of the meta-analysis showed a significant reduction in our primary outcome, the Boston carpal tunnel syndrome questionnaire-symptom severity scale (mean difference = −1.20, 95% CI [−1.72, −0.67], p < 0.00001) and the Boston carpal tunnel syndrome questionnaire-functional severity scale (mean difference = −1.06, 95% CI [−1.53, −0.60], p < 0.00001). Secondary outcomes such as sensory and motor conduction velocity increased significantly, while motor latency was significantly reduced, all positively favoring neurodynamic techniques. Pain was also significantly reduced, but grip strength was not significantly different. Our systematic review demonstrates significant benefits of neurodynamic modulation techniques to treat CTS and specifically that it reduces symptom severity, pain, and motor latency, while at the same time improving nerve conduction velocities. Hence, our study demonstrates a clear benefit of neurodynamic techniques to improve recovery CTS.


Introduction
Carpal tunnel syndrome (CTS) occurs as a result of pressure on the main nerves in the wrist area and is the most common mononeuropathy in the upper limb, accounting for 90% of all peripheral neuropathies [1]. The incidence of CTS is reported to be 3.8-12% with women disproportionately affected than men [1][2][3]. CTS was characterized by sensory and motor symptoms, manifested by numbness, pain, and paresthesia radiating from the wrist to the first three digits. As CTS progresses, muscle atrophy, reduced hand power, and decreased hand dexterity adversely affect the quality of life, activities of daily living, according to the Cochrane Handbook Guide for the systematic review [26] but has not been registered. Filters applied were as follows: randomized controlled trials (RCTs), English language, and human studies. Conference proceedings, reviews, other systematic reviews, registries, and ongoing trials were excluded.
The MeSh search strategy was used with combinations including carpal tunnel syndrome* AND neurodynamic techniques, carpal tunnel syndrome AND exercise* AND physical activity*, carpal tunnel syndrome AND rehabilitation, and carpal tunnel syndrome AND neurodynamic*. All the results of the specified search from the databases were saved in the Microsoft Excel spreadsheet for the complete record and documentation.

Eligibility Criteria
Two authors (S.A.Z and Z.A) assessed the study title and abstracts according to the PICOS framework for the inclusion criteria of the study: (1) population: adult participants (>18 years of age) diagnosed with mild-to-moderate carpal tunnel syndrome were considered; participants who presented with unilateral or bilateral CTS with symptoms reported up to 6 months were also included; (2) intervention: neurodynamic techniques with or without manual therapy; (3) control: placebo, sham, or any other treatment; (4) primary outcome measure was symptom severity and/or functional status scale of Boston carpal tunnel syndrome questionnaire (BCTQ); (5) secondary outcome measures were nerve conduction velocities (NCV), pain, and grip strength; (6) study design: randomized controlled trials (RCTs) from inception to December 2022; (7) setting: hospitals, orthopedic wards and clinics, rehabilitation centers, and out-patient and in-patient departments.

Study Selection and Data Collection
Two authors (S.A.Z and Z.A) independently screened the abstracts and titles of all the searched data based on predetermined selection criteria. De-duplication of the studies was performed through Endnote 20.4 software, and hand searching was also conducted to reduce the reporting bias. Articles were reviewed and selected for full-text reading that matched our inclusion/exclusion criteria. The process was then checked by the senior author (Z.A), and any discrepancies were resolved through discussion. Studies were excluded from the systematic review based on inappropriate population, intervention, comparison, outcome measure, and study design and setting (PICOS framework).
We extracted study characteristics (study author and year, study design, country, age of participants, gender, study's inclusion and exclusion criteria, blinding, intervention, outcome measures, and findings of the study) and data for our primary and secondary outcomes (trial author and year, primary outcome and secondary outcome, experimental and control group, post-intervention median and standard deviations, the effect of therapy, timeframe, follow up, and adverse effects). Intervention type, dosage, and frequency of NM with or without manual therapy versus placebo, sham, or standard therapy were retrieved. Data extraction tables were designed according to the Cochrane Consumer and Communication Review Group's data extraction template in the web-based Google Spreadsheet and Microsoft Word software packages. Four studies were piloted to identify the modifications required in the data extraction table. All of the relevant information was added and stored in the modified versions of the data extraction tables as per the requirement of the eligibility criteria of our study. The trials were re-read and evaluated to extract the important findings, follow-up, frequency of the treatment session, and limitations.
The outcome measures were evaluated by reading the score ranges, baseline characteristics of the participants, and median and standard deviations of the trial's results.
The data of the experimental and control group were compared by identifying trends and differences in the result.

Risk of Bias Assessment
The validity and reliability of each included trial were determined by two authors (S.A.Z) and (Z.A) independently assessing the risk of bias through the Risk of Bias 2 (RoB2) tool by Cochrane recommendations. Disagreements were resolved through discussion among both authors. The overall risk of bias was assessed across five domains including the randomization process, the effect of assignment, missing outcome data, measurement of outcome, and selection of results. The algorithms of ROB 2 were used to analyze the potential risk of bias [27].

Data Synthesis and Statistical Analysis
The data were synthesized qualitatively and quantitatively. We conducted a metaanalysis in Review Manager (RevMan) 5.4 (Cochrane Informatics & Technology, London, UK), using the dichotomous data function employing a random effects model. Mean differences with a 95% confidence interval (CI) were calculated from pre-and post-therapy and used to analyze the effect of the intervention. Cohen's d or Hedge's g were not used for data interpretation as meta-analysis in RevMan 5.4 automatically adds weighting to each study result. Assessment of heterogeneity was performed by examining the differences across studies in the meta-analysis and referring to the Q and I 2 statistics (in percentages). A forest plot was used to graphically represent the results of the meta-analysis.

Study Selection
A total of 326 studies were retrieved from the Cochrane Central Register of Controlled Trials, Ovid Medline, Proquest, and Cinahl database search. After removal of duplicates, 302 articles were screened according to the inclusion/exclusion criteria for full-text reading. After reviewing titles and abstracts, 265 articles were removed, and out of the remaining 36 studies, the full-text reading excluded 24 studies based on the PICOS framework of this systematic review, including inappropriate population, outcome measure, setting, and intervention. No additional studies were found from reference lists in included studies. Twelve studies were included in our final systematic review [10,14,21,25,[28][29][30][31][32][33][34][35], and the PRISMA flow diagram is shown in Figure 1.
The included studies present results from a total of 1003 patients; 549 received NM, and 454 received sham or control treatments. A further 134 patients, 58 allocated to NM and 76 in the control treatment groups, were enrolled but were excluded from the final analysis for various reasons (Table 2). Both males and females aged 18-85 years with unilateral or bilateral CTS were included in the studies. NM was given over a variety of sessions per week, with some treatments lasting for 4 weeks and others for 10 weeks. In general, neurodynamic techniques were applied by a trained physiotherapist in all of the included studies. analysis for various reasons ( Table 2). Both males and females aged 18-85 years with uni lateral or bilateral CTS were included in the studies. NM was given over a variety of ses sions per week, with some treatments lasting for 4 weeks and others for 10 weeks. In gen eral, neurodynamic techniques were applied by a trained physiotherapist in all of the in cluded studies. In five of the 12 included RCTs, BCTQ, split into the functional symptom scale (FSS and symptom severity scale (SSS) were used as the main outcome [14,21,30,31,34]. Tw additional studies also used BCTQ, with one study reporting a single value for BCTQ [10] but the other mentioned the use of BCTQ but did not report anything [33]. Nerve conduc tion velocity studies (NCVs) were performed in five studies [10,14,28,30,31], with thre studies breaking these down to sensory conduction velocity (SCV), motor conduction ve locity (MCV), and motor latency [14,30,31]. Pain was assessed in eight studie [10,14,21,25,28,30,34,35], using either the visual analogue scale (VAS), the numerical pain rating scale (NPRS), or the West Haven-Yale multidimensional pain inventor (WHYMPI).
Grip strength was assessed in six studies [10,14,21,28,31,35], but once again, one study mentioned baseline grip strength, but no data were reported after the intervention [28]; and finally, disabilities of the arm, shoulder, and hand (DASH [21] and Quick DASH [21,33]) was assessed in three studies. In all included studies, the intervention was either NM or control therapy or no intervention. Other outcome measures included 2-point discrimination (2PD) [29], wrist range of motion [21], ultrasound [35], and the West Haven-Yale multidimensional pain inventory (WHYMPI) [35].

Risk of Bias
The overall risk of bias across all domains assessed was low in only 33.3% of the studies, but 50.0% and 16.6% of studies were judged to contain some concerns to high risk of bias, respectively (Figure 2A,B). While most studies included details of randomization, 16.6% of studies raised some concerns due to the extremely small size of participants (7-15 patients in each group) or it was unclear how randomization was achieved (Figure 2A,B). Missing outcome data, bias due to deviations from the intended interventions and bias in the selection of the reported results were all judged to have some risk of bias. Overall, only two studies had no judged risk of bias [21,28], whereas all of the other studies had some bias, ranging from some concerns to high risk of bias. Overall, only two studies had no judged risk of bias [21,28], whereas all of the other studies had some bias, ranging from some concerns to high risk of bias.

Data Synthesis
Overall, of the seven studies that assessed our primary outcome of BCTQ, neurodynamic techniques were effective for the management of symptom severity and functional status in mild-to-moderate CTS (Table 3. For example, BCTQ scores pre-and post-intervention for both SSS and FSS showed the greatest reduction in the NM groups compared to control groups [14,21,30,31,34]. Meta-analysis from the included studies confirmed an overall significant decrease in SSS (mean difference = −1.  (Table 4) demonstrated a significant decrease in overall BCTQ scores (mean difference −0.89, 95% CI [−1.18-0.60], p = 0.00001) ( Figure 3C). These results suggest that BCTQ scores, measured immediately after the intervention, were effective in improving outcomes after NM [10,14,21,30,31,34].
Nerve conduction velocities, broken down to SCV (Table 5) and MVC (Table 6) were only provided in three included studies [14,30,31]. Meta-analysis showed that SCV and MCV were significantly improved after NM compared to control treatment.

Study
Groups Pre-Intervention (Mean ± SD)

Discussion
In this study, we evaluated the effectiveness of NM (gliding and sliding maneuvers) in reducing symptom severity and improving the functional status in adults with mild-to-moderate CTS. Overall, 12 RCTs met our inclusion/exclusion criteria with results for 1003 participants, including 549 of those treated by NM presented in the RCTs [10,14,21,25,[28][29][30][31][32][33][34][35]. Our systematic review showed that BCTQ was significantly improved after NM in patients with CTS, as was sensory and motor conduction velocities with significantly reduced motor latencies. Pain was also significantly reduced, but grip strength remained unaffected. These results support the use of NM for effective management of CTS patients. However, since some of the studies were judged to possess some risk bias, improved quality, well-controlled RCTs with larger numbers of patients could improve the quality of the evidence in support of NM for the treatment of CTS.
All of the included studies suggested that NM was effective in improving symptom severity and functional status in mild-to-moderate CTS, assessed using the BCTQ [10,14,21,30,31,33,34]. However, as with other systematic reviews on NM and CTS clinical management, there were inconsistent methodological issues found in the RCTs included in our study, with studies using a variety of measures for the same thing. For example, some studies broke down BCTQ into BCTQ-SSS and BCTQ-FSS [14,21,30,31,34], while other studies reported only one value for BCTQ [10,33], making the interpretation of the results more difficult. Nerve conduction was also assessed differently with some studies breaking this down to SCV, MCV, and motor latency [14,30,31], while other studies only reported a single nerve conduction value [10,28]. Pain was also assessed using either VAS [10,25,28,34], NPRS [14,21,25,30], or WHYMPI [35], again making the interpretation of the outcome of NM more difficult to compare across studies. Even DASH was assessed by either QuickDASH [21,33] or DASH [28]. Thus, methodological issues in RCTs could weaken the reliability and confidence in the results as studies could be subjected to under-or over-estimation of findings.
One way we reconciled these differences in this systematic review was to calculate the difference pre-and post-NM and use these values to compare the results across the studies. As a precaution, we also assessed individual methods separately. In general, there was good agreement between the individually assessed methods and the combined results except for pain where the use of VAS resulted in a non-significant change by NM, but when combined with NPRS results, there was an overall significant effect. We recommend that future studies are designed with care to trial a design such that a standardized set of measures are assessed in CTS and any potential therapy. Our study shows that BCTQ, broken down into BCTQ-SSS and BCTQ-FSS, nerve conduction studies to assess SCV, MCV, and motor latency, as well as measurement of pain using NPRS might be the most sensitive measures in CTS.
Although other systematic reviews have been performed to evaluate the effectiveness of NM on function in CTS patients, our study evaluated the greatest number of outcomes and found significant differences where others showed no benefits of NM. For example, one systematic review reported no significant effects on symptom severity, distal motor latency, and grip and pinch strength but with low certainty [21]. Another study reported that NM was superior to no treatment on pain and BCTQ but with low quality evidence, while NM did not demonstrate clinical effectiveness [36]. Another study of reported on 13 clinical trials which showed improvements in pain, pressure, and function of CTS after NM, but when compared to other therapies, only two studies reported better results from standard of care, and three studies reported greater and earlier pain relief and function after NM techniques than when compared to conservative techniques [37]. However, most of the studies were deemed low quality [37].
We also found differences in the risk of bias within RCTs, with only 2 of the 12 studies presenting a low risk of bias. The highest risks of bias were judged to be in the treatment of missing outcome data, bias in the measurement of the outcome, bias in the selection of reported results, and bias arising from the randomization process. This means that our study data, despite showing statistically significant benefits of NM in the management of CTS, must be interpreted with caution. Because clinical guidelines play an integral role in clinical decision making [38], the low quality of evidence could be a potential reason why recent clinical guidelines do not, as yet, recommend NM as a conservative treatment option in mild-to-moderate CTS [39]. Our meta-analysis, however, has highlighted significant differences in improvements in different parameters assessed after the application of NM and suggests that further high quality RCTs are required to reach a definitive decision in the management of CTS.
Moreover, NM apparently generated biomechanical, physiological, and neuroimmune responses, but the exact mechanism differed greatly in human and animal studies. For example, NM decreased intra-neural oedema, activated analgesic neuronal pathways, induced anti-inflammatory changes, and desensitized mechanical compression by enhancing the median nerve excursion and nerve diameter [40]. Additionally, a recent systematic review of animal studies reported that NM predisposes a beneficial impact through modulating neurotrophins, neuroinflammation, and opioid systems, leading to decreased mechanical hyperalgesia [40]. In addition, the application of NM on cadavers revealed physiological mechanisms of pain relief, concluding that it enhanced the intraneural dispersion as well as decreasing intra-neural oedema surrounding the tissues [41]. Therefore, the exact mechanism of NM on symptoms and functional status in mild-to-moderate CTS remains unclear.
In the included RCTs, the application of NM varied in dosage, type, and length of treatment. Categorically, gliding enhanced the gliding motion by increasing the length of the nerve bed, whereas the sliding technique released the tension around the median nerve [42]. Studies have also suggested that the sliding technique was more beneficial for CTS [42]. Similarly, to another systematic review [22], we also found inconsistencies in the implementation of NM. Five studies used the same NM technique, dose, and duration of treatment since all of these studies were from the same first author [14,[29][30][31][32]. This presented a potential issue in that there could have been a high risk of bias as it is the same first author; however, to their credit, these studies were multicenter and had the highest numbers of patients. This mitigated some of the initial concerns over these studies.
Other studies used a variety of approaches, with treatment ranging from 60 min weekly to several sessions per week over 3-4 weeks [10,21,28,[33][34][35]. Thus, the inconsistency and variation in dosage of NM not only could have contributed to the overall outcomes, but it also presents a challenging decision for the physical therapist and clinician to select the intervention for achieving optimal outcomes.
The long-lasting effect of NM is also unknown, and several factors may play a key role in determining the duration of NM in mild-to-moderate CTS. We assume that NM imposes short-term relief of symptoms as post-intervention effects in the included RCTs were assessed immediately after the treatment [10,14,21,25,[28][29][30][31][32][33][34][35]. In two studies, a combination of manual therapy and electrotherapy (TENS or ultrasound) was administered along with NM, and this could explain the potential influence on some of the results in these studies [29,30,33]. In agreement with our observations, Barrio et al. [43] also found that there was a lack of follow-up data, due to which the lasting impact of NM could not be established. However, Fernandez-des-Las-Penas et al. [44] reported in a 4-year follow-up study that manual therapy, as well as NM, had similar effectiveness as compared to surgery, with only 15% of women requiring surgical treatment after manual therapy with NM. Hence, the addition of follow-up data would have been useful to establish the long-term effectiveness of NM in recovery from mild-to-moderate CTS.

Limitations
Our study has several limitations. Despite there being a reasonable number of RCTs, the total number of patients included was only 549 with CTS, restricting the generalizability to larger populations. The Cochrane handbook suggests that the wide confidence interval could have resulted due to the high heterogeneity in our included RCTs [45]. We suspected that the high heterogeneity found in both outcome measures might influence the estimation of the effect size. Indeed, it was indicated that the existing RCTs were designed with non-homogenous data, and the concerns with the risk of bias in included studies may limit the value of this systematic review, as the interpretations from our study must be taken with caution.
Secondly, we could not perform a meta-analysis of all of the included RCTs due to the unavailability of homogeneous numerical data for our chosen outcomes across all studies. This made it challenging to interpret the effect of NM on mild-to-moderate CTS. Thirdly, there might be a language or publication bias because we only analyzed studies in the English language, and non-English articles were excluded as per the eligibility criteria.

Future Directions
This systematic review implies that the methodological quality of the RCTs should be improved through robust methodology with numerical data analysis. In future studies, multicenter, large-sample-size, and homogenous data collection across defined assessments in RCTs should be considered to definitively determine the value of NM in the treatment of CTS. Additionally, it would be interesting to find out the duration of the effectiveness of NM in CTS by including a longer-term follow-up in RCTs.
Furthermore, as we have discussed, various underlying pathophysiological mechanisms were generated in response to NM, so future research must quantify, validate, and analyze NM in association with outcome measures. A similar study illustrated that the sciatic nerve movement during neural mobilization could be visualized and quantified [44]. So, in mild-to-moderate CTS, relevant comparisons to assess the effectiveness of each subjective or functional symptom (pain, numbness, muscle strength, ROM, etc.) either as neurophysiological or mechanical change stimulated with the application of NM could be developed in vivo. Eventually, this study design could be helpful to determine which therapeutic mechanisms may be activated by NM.

Conclusions
This systematic review evaluated the therapeutic effectiveness of NM on symptom severity and functional status in mild-to-moderate CTS. Our findings demonstrated significant benefits on several parameters in CTS but found several disparities in methodologies and high heterogeneity, while only 12 RCTs met our inclusion/exclusion criteria, and there were only 549 study participants in the NM group. There is potential for future trials to develop a more robust methodology with homogenous data collection and a much larger cohort to accurately evaluate the effectiveness of NM in the recovery from mild-to-moderate CTS.