Effectiveness of electrophysical modalities in the sensorimotor rehabilitation of radial, ulnar, and median neuropathies: A meta-analysis

Ena Bula-Oyola; Juan-Manuel Belda-Lois; Rosa Porcar-Seder; Álvaro Page

doi:10.1371/journal.pone.0248484

. 2021 Mar 18;16(3):e0248484. doi: 10.1371/journal.pone.0248484

Effectiveness of electrophysical modalities in the sensorimotor rehabilitation of radial, ulnar, and median neuropathies: A meta-analysis

Ena Bula-Oyola ^1,^2,^*, Juan-Manuel Belda-Lois ^3,⁴, Rosa Porcar-Seder ³, Álvaro Page ^3,⁵

Editor: Leila Harhaus⁶

PMCID: PMC7971482 PMID: 33735212

Abstract

Introduction

People with ulnar, radial or median nerve injuries can present significant impairment of their sensory and motor functions. The prescribed treatment for these conditions often includes electrophysical therapies, whose effectiveness in improving symptoms and function is a source of debate. Therefore, this systematic review aims to provide an integrative overview of the efficacy of these modalities in sensorimotor rehabilitation compared to placebo, manual therapy, or between them.

Methods

We conducted a systematic review according to PRISMA guidelines. We perform a literature review in the following databases: Biomed Central, Ebscohost, Lilacs, Ovid, PEDro, Sage, Scopus, Science Direct, Semantic Scholar, Taylor & Francis, and Web of Science, for the period 1980–2020. We include studies that discussed the sensorimotor rehabilitation of people with non-degenerative ulnar, radial, or median nerve injury. We assessed the quality of the included studies using the Risk of Bias Tool described in the Cochrane Handbook of Systematic Reviews of Interventions and the risk of bias across studies with the GRADE approach described in the GRADE Handbook.

Results

Thirty-eight studies were included in the systematic review and 34 in the meta-analysis. The overall quality of evidence was rated as low or very low according to GRADE criteria.

Low-level laser therapy and ultrasound showed favourable results in improving symptom severity and functional status compared to manual therapy. In addition, the low level laser showed improvements in pinch strength compared to placebo and pain (VAS) compared to manual therapy. Splints showed superior results to electrophysical modalities. The clinical significance of the results was assessed by effect size estimation and comparison with the minimum clinically important difference (MCID).

Conclusions

We found favourable results in pain relief, improvement of symptoms, functional status, and neurophysiological parameters for some electrophysical modalities, mainly when applied with a splint. Our results coincide with those obtained in some meta-analyses. However, none of these can be considered clinically significant.

Trial registration

PROSPERO registration number CRD42020168792; https://www.crd.york.ac.uk/PROSPERO/display_record.php?RecordID=168792.

Introduction

Peripheral neuropathies are common pathologies. The incidence is up to 300,000 cases per year in Europe and approximately 200,000 in the United States [1]. Peripheral nerves can be damaged by autoimmune or metabolic disorders, tumours, thermal, chemical, or mechanical trauma. The leading causes are penetration, crushing, or pulling, and ischemia [2]. Most of them involve the upper limbs [3], with a higher rate of damage to the ulnar nerve, followed by the median and radial nerves [4,5]. Signs and symptoms may include partial or total motor dysfunction of the forearm and hand, loss of muscle tone and strength, hypoesthesia or hyperesthesia, pain, allodynia, or paraesthesia [6].

Rehabilitation of peripheral neuropathies has surgical and conservative alternatives. Generally, conservative treatment is considered the first option for mild to moderate injuries, while surgical treatment is standard for severe injuries or lesions that do not respond adequately to conservative management [7].

Current literature has focused on the efficacy of surgical and pharmacological treatments [8–21]. Regarding conservative treatments, most research evaluates the effects of electrophysical modalities (EM) in carpal tunnel syndrome (CTS) [22–32]. There is a gap in the study of entrapment injuries in other nerves and pathologies that represent a higher degree of disability, such as paralysis. Despite the available studies, there is no consensus about EM’s effects on improving symptoms and function. Therefore, this systematic review aims to provide a comprehensive overview of these therapies’ performance in sensorimotor rehabilitation of ulnar, radial, and median neuropathies compared to placebo, physical therapy, or between them.

Methods

We conducted a systematic review according to PRISMA guidelines (see S1 and S2 Tables). We registered our review in the PROSPERO database for systematic reviews (PROSPERO registration number CRD42020168792) and included the protocol in S1 File.

Eligibility criteria

The eligibility criteria involved studies published in English over the last forty years evaluating the effectiveness of electrophysical modalities to treat radial, ulnar, or median neuropathies. The exclusion criteria left out studies that included surgical or pharmacological treatment, animal testing, electrophysical modalities to treat other neuropathies, degenerative neuropathies, or other diseases of diverse origin with neuropathic or musculoskeletal involvement.

Outcomes measures

The primary outcomes of interest were scores on the pain scale, symptom severity, and functional status. As well as the electrophysiological parameters of the nerves: motor latency, the amplitude of motor action potential, motor conduction velocity, sensory latency, the amplitude of sensory action potential, and sensory conduction velocity. The secondary outcomes were grip and pinch strength.

Search strategy

We carried out the literature review between April and July 2019 and October 2020, using medical topic headings (MeSH) and free-text terms for neuropathies and rehabilitation to identify studies from the following databases: Biomed Central, Ebscohost, Lilacs, Ovid, PEDro, Sage, Scopus, Science Direct, Semantic Scholar, Taylor & Francis, and Web of Science. We also hand-searched the references from the studies included in the review to find other possible relevant studies. We provide an example of the search terms in the S2 File.

Data collection and analysis

Selection of studies and data extraction

Two independent reviewers (JBL, EBO) examined all articles eligible for inclusion. We classified the data in an Excel matrix according to the type of study; nerve examined, type of injury, severity, characteristics of the participants (number, age, and sex), follow-up periods, intervention, and comparator.

Assessment of risk of bias

Two independent reviewers (RPS, AP) assessed the bias of included studies with the Cochrane Risk of Bias tool in five domains: sequence generation, allocation concealment, blinding, incomplete data, and selective information [33]. We resolved disagreements through discussion; in cases where we did not reach a consensus, we consulted a third reviewer (JBL).

Data synthesis

We used R Studio software to perform the meta-analysis. We pooled study results according to interventions, outcome measures, and timing of outcome measures. We did the data synthesis for each comparison group separately. In cases where it was not possible to pool the data in a meta-analysis, we provide a narrative synthesis of the results.

We assessed heterogeneity among studies using the I-squared (I²) test. We define heterogeneity using the following ranges as a guide: 0% to 40% might not be important heterogeneity, 30% to 60% might represent moderate heterogeneity, 50% to 90% might represent substantial heterogeneity, and 75% to 100% might represent considerable heterogeneity [33].

We estimated the pooled effect using standardised mean differences (SMDs) with 95% confidence intervals (CI). We used the random-effects model to perform meta-analysis when I²>50% and the fixed-effects model when I²<50%. We assessed the effect size using Cohen’s d coefficient [34] according to the following parameters: <0.2 = trivial effect; 0.2–0.5 = small effect; 0.5–0.8 = moderate effect; > 0.8 = large effect. We used a funnel plot to evaluate publication bias when we could pool at least ten studies examining the same treatment comparison [33].

We used the GRADE approach to summarise the overall quality of evidence for each outcome [35]. According to the GRADE considerations, we assess the quality of evidence across studies: risk of bias, inconsistency, indirect evidence, imprecision, and other considerations (including publication bias, large effect, plausible confounding, and dose-response gradient). We used GRADEpro GDT software (gradepro.org/) for the assessment and generation of summary tables. We provide footnotes to explain decisions to downgrade or upgrade the quality of evidence. The results of the risk of bias across studies are available in S3 Table.

Results

Search strategy

The search strategy yielded 136 results. After eliminating the duplicates, we identified 99 articles. In obtaining the full texts, we excluded several trials: thirteen per language, 42 because the approach was another therapeutic modality (e.g., acupuncture, peloid, kinesiotaping, and paraffin), three that reviewed post-surgical treatments, one whose comparator was no treatment, and two because they included steroid or vitamin B6 injection among their groups (Fig 1).

Study characteristics

We identified thirty-eight studies evaluating the effectiveness of at least one EM to treat peripheral neuropathies. Thirty-four RCTs (n = 1766) assessed the effects in CTS [36–69], two (n = 93) in ulnar neuropathy at the elbow (UNE) [70,71], one comparative study (n = 19) in radial nerve palsy [72], and another (n = 107) in brachial, median, ulnar, and radial nerve palsy [73]. The characteristics and main outcomes of each study are described in S5 Table.

Assessment of risk of bias

All studies reported that participants were randomly assigned between groups, except one due to diversity between treatments [47]. However, the methods of allocation were not described in some of the studies [36,40,43,44,46,52,59,61,65]. We identified possible performance and detection biases in several studies associated with allocation concealment [37,39,43,44,47,50,51,53,55–57,63,67,68], blinding of participants [37,41–43,46,47,50–52,55–57,62,66–70], blinding of personnel [37,38,41–47,50–53,55–57,60,62,63,66–68,70,71], blinding of outcome assessors [39,42–44,46,49,55,58,60,67] that was unclear or not provided. As well as attrition [36,37,39,40,43,45,48–50,52,54,55,58,60,63,64,70,71] and data reporting biases [48,50,63,65]. In general, all studies had similar baseline characteristics and follow-up times among their groups. The results of the risk of bias assessment of the included studies are available in S4 Table.

Effects of electrophysical interventions

We obtained thirty-four RCTs evaluating CTS, eighteen comparing EMs versus placebo (i.e., LLLT alone [42,43,48,53,62,63], LLLT plus splint [49,59], ESWT plus splint [38,58], continuous US alone [39], continuous and pulsed US plus splint [45], continuous and pulsed SWD plus splint [37], SMF [40,69], PMF [61] or alternate use of both MF [44]). Four studies assessed EMs against manual therapy (MT) (i.e., LLLT [46,47], LLLT plus US [64], US plus splint, and US with MT plus splint [57]).

Six studies compared different EMs (i.e., LLLT vs. TENS [68], LLLT vs. PMF [67], LLLT vs. pulsed US [41,65], LLLT plus splint vs. continuous plus splint [52], ESWT vs. pulsed US vs. Cryo US [66], TENS vs. IFC [51]), and six studies evaluated EM versus splinting (i.e., LLLT plus splint [50,54], TENS and IFC [51], PRF plus splint [52], ESWT plus splint [55], PPNL plus splint [56]).

Two studies evaluated EMs for UNE. One RCT compared LLLT versus continuous US [70] and the other evaluated continuous SWD plus splint versus placebo [71]. Two comparative studies evaluated EMs for the treatment of hand paralysis. One compared LLLT alone versus LLLT plus splint for radial palsy [72], and the other used ultrasound, electrostimulation, thermal and manual therapy in a unified therapeutic protocol for brachial, median, ulnar, and radial palsy [73].

Electrophysical modalities versus placebo

Favourable results for extracorporeal shock-wave therapy plus splint in pain relief, severity of symptoms, functional status, and pinch strength. Only the result for pinch strength was supported by a moderate effect size. Conflicting evidence for low-level laser therapy; favoured in three studies and participants with mild carpal tunnel syndrome. A large effect size showed superiority of placebo over electrophysical modalities. Significant improvement in motor latency, sensory amplitude, and grip strength of low-level laser therapy plus splint (trivial effect size) and inconclusive results for sensory latency, motor amplitude, sensory, and motor conduction velocity.

Lazovic et al. [48] reported pain reduction at the end of treatment in the low-level laser therapy group and expressed the results as percentages. Arikan et al. [61] reported improvements in pain (VAS) and symptom severity in the placebo group and presented their results in ranges (min/max). We did not receive the data from the authors, so we could not include them in the meta-analysis.

We found no significant differences in the remaining modalities for the parameters mentioned. The outcomes and significance are in Table 1, and detailed analyses are presented in Figs 2–12.

Table 1. Outcome measures and significance of electrophysical modalities versus placebo.

Author	Intervention	VAS	SS	FS	ML	SL	MNCV	SNCV	SNAP (A)	CMAP (A)	Grip strength	Pinch strength
Armagan et al.	US + SP	+	+	+	+	+	+	+
Jothi and Bland.	US + SP		+	+	+			+
Oztas et al.	US				+	+	+	+
Wu et al.	ESWT	+	+	+				+				+
Ke et al.	ESWT		+ -	+ -				+ -
Abid Ali et al.	LLLT	+ -	+ -	+ -	+ -	+	+ -	+	+ -	+ -
Jiang et al.	LLLT	+ *	+—*		+ -	+ -
Tascioglu et al.	LLLT	+	+	+	+		+	+			+
Shooshtari et al.	LLLT	+ -			+	+		+			+
Chang et al.	LLLT		+	+ -	+	+					+
Lazovic et al.	LLLT	+ °			+			+ -
Fusakul et al.	LLLT + SP	+ -	+ -	+	+ -	+ -			+ -	+	+ -	+ -
Evcik et al.	LLLT + SP
Boyaci et al.	SWD + SP	+	+	+	+	+		+
Badur et al.	SWD + SP	+
Carter et al.	SMF	+
Colbert et al.	SMF		+	+	+	+			+	+
Weintraub and Cole.	SMF+PMF	+
Arikan et al.	PMF	+ °	+		+	+ -	+	+	+	+

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Abbreviations: VAS: Visual analog scale; SS: Symptom severity; FS: Functional status; ML: Motor latency; SL: Sensory latency; MNCV: Motor nerve conduction velocity; SNCV: Sensory nerve conduction velocity; SNAP (A): Sensory nerve action potential amplitude; CMAP (A): Compound muscle action potential amplitude. Annotation symbols: Measured: +; Statistically significant: -; Not included in the meta-analysis: °; Only in the mild group: *.

Fig 2 — Studies with more than two intervention groups (different modalities, treatment doses, or symptom classification) were numbered as (1) and (2).

Fig 3 — Studies with more than two intervention groups (different modalities, treatment doses, or symptom classification) were numbered as (1) and (2).

Fig 4 — Studies with more than two intervention groups (different modalities, treatment doses, or symptom classification) were numbered as (1) and (2).

Fig 5 — Studies with more than two intervention groups (different modalities, treatment doses, or symptom classification) were numbered as (1) and (2).

Fig 6 — Studies with more than two intervention groups (different modalities, treatment doses, or symptom classification) were numbered as (1) and (2).

Fig 7 — Studies with more than two intervention groups (different modalities, treatment doses, or symptom classification) were numbered as (1) and (2).

Fig 8 — Studies with more than two intervention groups (different modalities, treatment doses, or symptom classification) were numbered as (1) and (2).

Fig 9 — Studies with more than two intervention groups (different modalities, treatment doses, or symptom classification) were numbered as (1) and (2).

Fig 10 — Studies with more than two intervention groups (different modalities, treatment doses, or symptom classification) were numbered as (1) and (2).

Fig 11 — Studies with more than two intervention groups (different modalities, treatment doses, or symptom classification) were numbered as (1) and (2). Modalities delivered with a splint were marked as (SP).

Electrophysical modalities versus manual therapy

We observed a greater improvement (trivial effect size) in pain with low-level laser therapy versus manual therapy. We observed that fascial manipulation was superior to low-level laser therapy for symptom severity and functional status. Favourable results for low-level laser therapy in motor latency. No significant difference for low-level laser therapy plus ultrasound in neurophysiological parameters or strength. The outcomes and significance are in Table 2, and detailed analyses are presented in Figs 13–19.

Table 2. Outcome measures and significance of electrophysical modalities versus manual therapy.

Author	INT	VAS	SS	FS	ML	SL	MNCV	SNCV	Grip strength	Muscle strength
Atya and Mansour	LLLT* vs N/TGE	+ -			+ -	+ -		+ -	+ -
Pratelli et al.	LLLT vs FM*	+ -	+ -	+ -
Milicin & Sîrbu.	US + TT + ES + KT + MM						+			+
Baysal et al.	US + SP vs N/TGE + SP vs N/TGE + US + SP*	+	+	+	+	+			+
Wolny et al.	US + LLLT vs NDT + CBM + MM		+	+		+		+

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Abbreviations: INT: Intervention; VAS: Visual analog scale; SS: Symptom severity; FS: Functional status; ML: motor latency; SL: Sensory latency; MNCV: Motor nerve conduction velocity; SNCV: Sensory nerve conduction velocity; SNAP (A): Sensory nerve action potential amplitude; CMAP (A): Compound muscle action potential amplitude; N/TGE: Nerve and tendon gliding exercises; FM: Fascial manipulation; TT: Thermotherapy; ES: Electrostimulation; KT: Kinesiotherapy; MM: Manual massage; SP: Splint. NDT: Neurodynamic Technique; CBM: Carpal bone mobilisation. Annotation symbols: +, Measured; -, Statistically significant; *, Evidence favours this intervention.

Fig 13 — Studies delivering modalities with a splint were marked as (SP).

Fig 19 — Studies delivering modalities with a splint were marked as (SP).

Fig 16 — Studies delivering modalities with a splint were marked as (SP).

Fig 17 — Studies delivering modalities with a splint were marked as (SP).

Comparison between electrophysical modalities

We found superior results with trivial effect size for pulsed US over low-level laser therapy in pain relief, symptoms, and sensory latency for carpal tunnel syndrome and ulnar neuropathy at the elbow. Favourable results for low-level laser therapy in motor latency and sensory velocity. Grip strength improved with both modalities of ultrasound over low-level laser therapy (large effect size). No significant difference for low-level laser therapy, transcutaneous electrical nerve stimulation, or ultrasound in the remaining parameters. The outcomes and significance are in Table 3, and detailed analyses are presented in Figs 20–26.

Table 3. Outcome measures and significance of the comparison between electrophysical modalities.

Author	Intervention	VAS	SS	FS	ML	SL	MNCV	SNCV	Grip strength	Muscle power
Ozkan et al.	LLLT vs Continuous US*	+	+			+			+
Oshima et al.	LLLT vs LLLT + SP			+						+
Armagan et al.	Pulsed US + SP vs Continuous US + SP	+ -	+	+	+	+	+	+
Boyaci et al.	Pulsed SWD + SP vs Continuous SWD + SP	+	+	+	+	+		+
Casale et al.	LLLT vs TENS	+			+ -			+
Dakowicz et al.	LLLT vs PMF	+ °
Saeed et al.	LLLT vs Pulsed US	+ -	+ -	+	+ +	+ -
Dincer et al.	LLLT+ SP vs Continuous US + SP	+	+	+	+			+
Paoloni et al.	ESWT vs Pulsed US vs Pulsed Cryo US	+	+	+
Koca et al.	TENS vs IFC	+ -	+	+	+			+

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Abbreviations: VAS: Visual analog scale; SS: Symptom severity; FS: Functional status; ML: motor latency; SL: Sensory latency; MNCV: Motor nerve conduction velocity; SNCV: Sensory nerve conduction velocity; SNAP (A): Sensory nerve action potential amplitude; CMAP (A): Compound muscle action potential amplitude; SP: Splint. Annotation symbols: +, Measured; -, Statistically significant; *, Evidence favours this intervention; °, Not included in the meta-analysis.

Ozkan et al. [70] compared low-level laser therapy and ultrasound for ulnar neuropathy at the elbow. They reported a marked reduction in VAS pain at the end of treatment, in the first and third months of follow-up in the ultrasound group, while the low-level laser therapy group only showed improvement in the first month of follow-up. Dakowicz et al. [67] compared low-level laser therapy and pulsed magnetic field for carpal tunnel syndrome. They reported a significant reduction in VAS pain in both groups after each treatment series and six months after the last series. The authors presented their mean values through a graph. We did not receive the data from the authors, so we could not include them in the meta-analysis.

Electrophysical modalities versus splinting

Most of the favourable results correspond to the use of splinting in conjunction with electrophysical modalities. This evidence shows a moderate effect size. We found favourable results for pain relief with pulsed Radiofrequency and low-level laser therapy plus splint and interferential current therapy alone. Significant improvement in symptom severity, functional status, sensory nerve conduction velocity, and motor latency for low-level laser therapy plus splint. No significant differences in the remaining modalities for the parameters mentioned. The outcomes and significance are in Table 4, and detailed analyses are presented in Figs 27–34.

Table 4. Outcome measures and significance of electrophysical modalities versus splinting.

Author	INT	VAS	SS	FS	ML	SL	SNCV	SNAP (A)	CMAP (A)	Pinch strength
Dincer et al.	LLLT + SP vs SP	+ -	+ -	+ -	+ -		+ -
Koca et al.	TENS vs IFC vs SP	+ - *	+	+	+		+ - *
Chen et al.	PRF + SP vs SP	+ -	+ -	+ -			+			+
Raeissadat et al.	PPNL+ SP vs SP	+	+ °	+ °	+ °	+		+ °	+ °
Raissi et al.	ESWT + SP vs SP	+		+ °				+	+ -
Yagci et al.	LLLT + SP vs SP		+	+	+		+			+

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Abbreviations: INT: Intervention; VAS: Visual analog scale; SS: Symptom severity; FS: Functional status; ML: motor latency; SL: Sensory latency; MNCV: Motor nerve conduction velocity; SNCV: Sensory nerve conduction velocity; SNAP (A): Sensory nerve action potential amplitude; CMAP (A): Compound muscle action potential amplitude. SP: Splint. Annotation symbols: +, Measured; -, Statistically significant; *, Evidence favours this intervention; °, Not included in the meta-analysis.

Fig 34 — Studies with more than two intervention groups (different modalities) were numbered as (1) and (2).

Fig 28 — Studies with more than two intervention groups (different modalities) were numbered as (1) and (2).

Fig 32 — Studies with more than two intervention groups (different modalities) were numbered as (1) and (2).

Clinical significance

As suggested by Lemieux et al [74] and Page [75], we calculated the MCID by multiplying the pooled baseline standard deviation values by 0.2, which corresponds to the smallest effect size.

We compare the results of the meta-analysis with the references of the minimal clinically important differences for VAS (MCID of 1.2) [76], FSS (MCID of 0.74) [77], SSS (MCID of 1.04) [78], grip strength (MCID of 2.69 kg) and pinch strength (MCID of 0.68 kg) [79] and did not find any results that could be clinically significant. The overview of MCID estimation is in Table 5.

Table 5. Clinical significance from MCID estimation.

Type of comparison	Outcome	SMD [95%-CI]	^*Effect size	Pooled baseline SD	Estimated MCID	Reference MCID
Electrophysical modalities vs placebo	Pain (VAS)	-0.89 [-1.79; 0.02]	Large	1.6	0.32	1.2
	Symptom Severity (SSS)	-1.01 [-1.65; -0.37]	Large	0.55	0.11	1.04
	Functional Status (FSS)	-0.79 [-1.45; -0.13]	Moderate	0.63	0.13	0.74
	Grip Strength	0.08 [-0.22; 0.37]	Trivial	5.4	1.08 kg	2.69 kg
	Pinch Strength	0.57 [-0.26; 1.41]	Moderate	1	0.20 kg	0.68 kg
Electrophysical modalities vs Manual therapy	Pain (VAS)	0.19 [-2.39; 2.77]	Trivial	2.37	0.47	1.2
	Symptom Severity (SSS)	1.44 [-0.27; 3.15]	Large	4.06	0.81	1.04
	Functional Status (FSS)	0.99 [0.10; 1.89]	Large	0.95	0.19	0.74
	Grip Strength	-0.89 [-2.49; 0.71]	Large	6.11	1.22 kg	2.69 kg
Electrophysical modalities vs Splinting	Pain (VAS)	-0.77 [-1.59; 0.05]	Moderate	1.35	0.27	1.2
	Symptom Severity (SSS)	-0.66 [-1.33; 0.01]	Moderate	2.84	0.57	1.04
	Functional Status (FSS)	-0.55 [-1.20; 0.11]	Moderate	0.77	0.15	0.74
Comparison between electrophysical modalities	Pain (VAS) LLLT vs Other EM	1.11 [-0.52; 2.75]	Large	2.9	0.58	1.2
	Symptom Severity (SSS)–US vs Other EM	-0.11 [-1.05; 0.83]	Trivial	1.39	0.28	1.04
	Functional Status (FSS)–US vs Other EM	-0,04 [-0.34; 0,27]	Trivial	1.16	0.25	0.74
	Grip Strength–LLLT vs US	-1.25 [-2.23; -0.27]	Large	6.1	1.22 kg	2.69 kg

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*Cohen’s d coefficient: <0.2 = trivial effect; 0.2–0.5 = small effect; 0.5–0.8 = moderate effect; > 0.8 = large effect.

Discussion

This review included 38 studies comparing the effects of electrophysical modalities compared to placebo or other non-surgical (non-pharmacological) treatments to manage traumatic peripheral neuropathies. We carried out a detailed analysis assessing the main parameters associated with symptoms, function, strength, and nerve conduction.

We assessed the quality of evidence using the GRADE approach. The quality in most studies was classified as low or very low. Risk of bias varied between studies, but was generally serious in most domains. Heterogeneity was mostly high. All studies were small, ranging from 18 to 140 participants, so it is plausible that any effects may be overestimated.

The results of meta-analysis revealed that ESWT plus splint could improve symptoms and functional parameters in patients with mild or moderate carpal tunnel syndrome. Our findings are similar to the results from Huisstede et al. [80], who reported moderate evidence regarding the effectiveness of radial ESWT compared with placebo ESWT in the short-term. We concur with the results from Kim et al. [81], who noticed effectiveness in the outcomes mentioned above but differed in the electrophysiological parameters’ findings.

The US appears to be more effective than LLLT in improving grip strength, pain, and sensory latency. However, we found no significant differences compared to placebo or manual therapy in line with the results of Page et al. [25], who found effectiveness in the outcomes mentioned above but differed in the electrophysiological findings. We also agree with the authors, who noted there is no evidence that US applied with a splint is more effective than any other non-surgical intervention.

Similar to Huisstede et al. [80], we found limited evidence (from one RCT) that fascial manipulation can improve functional and symptom outcomes. Likewise, LLLT plus splint and PRF plus splint compared to splinting. Besides, our results showed that LLLT plus splint was superior to placebo in terms of improving grip strength in patients with mild to moderate CTS, confirming the findings of Bekhet et al. [23] and Li et al. [28]. For the rest of the parameters, we found conflicting evidence differing from the results obtained by Li et al. [28] and is consistent with those obtained by Burger et al. [30]. We agree with the observation made by Bekhet et al. [23] and Li et al. [28], highlighting the usefulness of orthoses as an agent of influencing the outcomes of peripheral neuropathies.

We found no evidence for the effectiveness of magnetic field therapy in functional and symptom improvement or electrophysiological parameters. Our findings agree with O’Connor et al. [29] and differ from Huisstede et al. [80], who reported conflicting evidence.

We found no evidence of the effectiveness of SWD, PPNL, or TENS. Our results differ from Huisstede et al. [80] for SWD and are similar concerning PPNL. We agree with Gibson et al. [82] regarding TENS. The overview of evidence is in Table 6.

Table 6. Overview of evidence of electrophysical modalities.

Low-level laser therapy	ST	MT	Ultrasound	ST	MT	Magnetic field therapy	ST	MT
LLLT alone vs placebo	±		Continuous US splint vs Pulsed US plus splint vs placebo plus splint	Ø		Pulsed magnetic field vs placebo	+
LLLT plus splint* vs placebo plus splint	+		Continuous US (1.5W/cm² * vs 0.8W/cm² dosage) vs placebo	+		Static magnetic field vs placebo	Ø
LLLT vs Pulsed Magnetic Field °	Ø	Ø	Pulsed US plus splint vs MT plus splint vs pulsed US plus MT plus splint*	+		Static magnetic field (15mT vs 45mT dosage) vs placebo	Ø
LLLT* vs TENS	+		Pulsed US vs Cryo-US vs ESWT*	Ø	Ø	Static + pulsed magnetic field	Ø
LLLT vs Continuous ultrasound*	+		Pulsed US* vs LLLT	+		Polarised polychromatic non-coherent light
LLLT plus splint vs Continuous US plus splint	Ø		Continuous US plus splint* vs splinting	+		PPNL (Bioptron) plus splint vs splinting	Ø
LLLT alone vs LLLT plus splint°	Ø		Extracorporeal short-wave therapy			Short-wave diathermy
LLLT plus splint* vs splinting	+	Ø	ESWT plus splint* vs placebo plus splint	+	Ø	Continuous SWD vs Pulsed SWD vs placebo SWD	Ø
LLLT vs Fascial Manipulation*	+	Ø	ESWT plus splint* vs splinting	+		Pulsed radiofrequency
LLLT* vs Nerve and Tendon gliding exercises	+		ESWT (2 dosages) vs placebo	+	+	Pulsed radiofrequency plus splint* vs splinting	+	+
			Interferential current
			Interferential current* vs TENS vs splint	+

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Abbreviations: ST, Short-term; MT, Mid-term; ±, Conflicting evidence; +, Limited evidence; *, Evidence favours this intervention; Ø, No difference; °, Not included in the meta-analysis.

By contrasting effect sizes we could identify that the results favouring placebo were supported by large (for pain and symptom severity) and moderate (functional status) effect sizes. The only outcomes in favour of electrophysical modalities supported by a large effect size were associated with improvement in symptom severity and functional status in comparison to manual therapy. The superior results of splinting over electrophysical modalities were supported by moderate effect sizes. Likewise a moderate effect favoured electrophysical modalities over placebo in pinch strength. The results favouring ultrasound over the other modalities were supported by trivial effect sizes. Similarly a trivial effect size was associated with grip strength in favour of modalities over placebo and in pain improvement over manual therapy.

We contrasted the results with the minimal clinically important difference (MCID) in order to provide practical evidence to support clinical decision-making in the use of therapeutic alternatives for the management of peripheral neuropathies. We found no clinical significance in any of the pooled results when compared to the MCID.

Strengths and limitations

To our knowledge, this is the first systematic review of the effectiveness of electrophysical modalities to treat traumatic neuropathies of the wrist and hand. We used the protocols and methodological tools that ensured quality and transparency in selecting, screening, and treating data.

One of the main limitations to have a broader picture of all pathologies was the scarce availability of studies evaluating traumatic peripheral neuropathies. We found a predominance of trials studying entrapment injuries (94.7% of these trials assessed CTS), and only two trials assessed hand paralysis [72,73]. We do not include studies published in a language other than English.

Conclusions

Implications for practice

We found favourable results for ESWT and PRF in pain relief, symptom severity, functional status, sensory conduction velocity, motor latency, and motor amplitude in participants with CTS. Conflicting evidence of the effectiveness of LLLT for FSS and neurophysiological parameters in participants with mild to moderate CTS.

Continuous US was superior to LLLT in pain and symptom relief in participants with UNE. We found no evidence of benefit in other modalities and parameters.

Although we found some differences favouring electrophysical modalities, mainly when applied with a splint, none of the results obtained throughout this review can be considered clinically significant.

Implications for research

This review found mainly RCTs assessing entrapment injuries with the prevalence of CTS. More high-quality research is needed to evaluate the effectiveness of the available treatments for brachial, radial, ulnar, and median neuropathies, including those with more considerable complexity and rehabilitation time, such as axonotmesis.

Supporting information

S1 Table. PRISMA checklist.

(DOC)

Click here for additional data file.^{(66KB, doc)}

S2 Table. PICO question.

(DOCX)

Click here for additional data file.^{(12.8KB, docx)}

S3 Table. GRADE summary of findings.

(PDF)

Click here for additional data file.^{(666.4KB, pdf)}

S4 Table. Risk of bias of randomised controlled studies.

(XLSX)

Click here for additional data file.^{(12.5KB, xlsx)}

S5 Table. Measures and outcomes of included studies.

(DOCX)

Click here for additional data file.^{(183KB, docx)}

S1 File. PROSPERO protocol.

(PDF)

Click here for additional data file.^{(91.2KB, pdf)}

S2 File. Search terms.

(DOCX)

Click here for additional data file.^{(151.6KB, docx)}

Data Availability

All relevant data are within the manuscript and its Supporting information files.

Funding Statement

EBO: scholarship from the Colombian Ministry of Science: "Formación de capital humano de alto nivel para las regiones- Atlántico 2018". URL: https://minciencias.gov.co/convocatorias/oportunidades-formacion/formacion-capital-humano-alto-nivel-para-las-regiones The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.

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PLoS One. doi: 10.1371/journal.pone.0248484.r001

Decision Letter 0

Leila Harhaus

30 Sep 2020

PONE-D-20-21315

Effectiveness of electrophysical modalities in the sensorimotor rehabilitation of radial, ulnar, and median neuropathies: a meta-analysis

PLOS ONE

Dear Dr. Bula-Oyola,

Thank you for submitting your manuscript to PLOS ONE. After careful consideration, we feel that it has merit but does not fully meet PLOS ONE’s publication criteria as it currently stands. Therefore, we invite you to submit a revised version of the manuscript that addresses the points raised during the review process.

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We look forward to receiving your revised manuscript.

Kind regards,

Leila Harhaus

Academic Editor

PLOS ONE

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Reviewers' comments:

Reviewer's Responses to Questions

Comments to the Author

1. Is the manuscript technically sound, and do the data support the conclusions?

The manuscript must describe a technically sound piece of scientific research with data that supports the conclusions. Experiments must have been conducted rigorously, with appropriate controls, replication, and sample sizes. The conclusions must be drawn appropriately based on the data presented.

Reviewer #1: Partly

Reviewer #2: Partly

**********

2. Has the statistical analysis been performed appropriately and rigorously?

Reviewer #1: I Don't Know

Reviewer #2: Yes

**********

3. Have the authors made all data underlying the findings in their manuscript fully available?

The PLOS Data policy requires authors to make all data underlying the findings described in their manuscript fully available without restriction, with rare exception (please refer to the Data Availability Statement in the manuscript PDF file). The data should be provided as part of the manuscript or its supporting information, or deposited to a public repository. For example, in addition to summary statistics, the data points behind means, medians and variance measures should be available. If there are restrictions on publicly sharing data—e.g. participant privacy or use of data from a third party—those must be specified.

Reviewer #1: Yes

Reviewer #2: Yes

**********

4. Is the manuscript presented in an intelligible fashion and written in standard English?

PLOS ONE does not copyedit accepted manuscripts, so the language in submitted articles must be clear, correct, and unambiguous. Any typographical or grammatical errors should be corrected at revision, so please note any specific errors here.

Reviewer #1: Yes

Reviewer #2: No

**********

5. Review Comments to the Author

Please use the space provided to explain your answers to the questions above. You may also include additional comments for the author, including concerns about dual publication, research ethics, or publication ethics. (Please upload your review as an attachment if it exceeds 20,000 characters)

Reviewer #1: Thank you for the invitation to review this paper. Our author colleagues have submitted an interesting systematic review with meta-analysis on the efficacy of electrophysical modalities in the rehabilitation of radial, ulnar, and median neuropathies. The paper concludes that there is limited favourable evidence for efficacy of electrophysical modalities in these conditions.

The authors should be commended for the comprehensive and detailed review they have undertaken.

I have some comments for consideration:

Introduction:

1) Opening sentence: ‘Peripheral neuropathies are common injuries’ I suggest use pathologies rather than injury, in case of insidious onset peripheral neuropathies not attributable to trauma.

2) Paragraph 2, sentences 1 and 2: Citations should be provided for these statements ‘Current literature has focused on the efficacy of surgical and pharmacological treatments. Regarding conservative treatments, most studies evaluated the effects of electrophysical modalities in carpal tunnel syndrome.’

Methods:

3) Search strategy – Search was undertaken in April-Jul 2019. This was a while ago, re-running and updating the search should be considered.

4) Search strategy – what is the rationale for using just 2 databases? Also, what was the rationale for limiting it to 2009?

5) Study selection and data extraction – indicate which authors (by initials) did the screening, and same for data extraction. Were disagreements solved by consensus discussion?

6) Study selection and data extraction – were corresponding authors of papers contacted if data were missing or presented in graphs only?

7) Sections of the Method that are included in the Prisma guidelines are missing – the details of the methods used for summary measures, synthesis of results (e.g. meta-analysis, best evidence synthesis) and risk of bias across studies are not described. Looking at the results, meta-analysis to calculate SMD has been performed, and there is mention of limited and moderate evidence. But these have not been defined or described in the method.

8) In line with comment 7 above, meta-analysis was undertaken but there does not appear to be an assessment of the risk of bias across studies or overall confidence of the evidence (e.g. the GRADE approach). This should be done for each meta-analysis comparison to provide insight on the quality of meta-analysis evidence and confidence in the findings.

Results:

9) Paragraph 1 – Science direct and research gate are mentioned here, but were not mentioned in the Method. Were these used as additional databases for the search?

10) Reporting of the Results would be much clearer if it were arranged using the sections defined in the Prisma checklist. For example, the section labelled Evidence Hierarchy appears to detail the Study Characteristics. Risk of Bias of individual studies is currently reported in the Method section, so should be presented in the Results instead. Splitting the reporting of results into sections detailing results of individual studies, then detailing the synthesis of results (i.e. meta-analysis and qualitative synthesis) in accordance with the Prisma guidelines would be a much neater way for arranging the Results.

11) The paper is largely well-written, however there are a few grammatical errors (e.g. LLLT is defined twice on page 6), so I suggest reviewing the manuscript for such issues.

12) Forest plots – suggest adding labels to the X axis to show which direction favours the treatment and which direction favours controls

13) Meta-analysis text results – suggest including I-squared when reporting the SMD meta-analysis results, to show heterogeneity without needing to refer to the supplementary material.

Discussion:

14) The discussion is largely a summary of the results. It would be strengthen the paper to discuss how these findings relate to other studies, consider clinical implications etc.

Reviewer #2: The authors provide a systematic analyses of electrophysical therapy in periveral nerve entrapment injuries. They included all papers fom the course of the last decade and conclude a lack of evidence about the efficacy of electrophysical therapy.

Prisma guidlines were used to prepare the manuscript. I think it is an interesting topic to evaluate non surgical treatment of peripheral nerve entrapments. Unfortunately the manuscript is very exhausting to read. The authors sum up every included study with a lack of detailed discussion (for example is splinting a viable option, etc.) Preclinical data about the efficacy is not discussed and compared to clinical experience.

There is a lot of information included in an enumerated fashion.

I would suggest to rewrite the manuscript to catch the reader's attention more and meet the high standard of the journal

**********

6. PLOS authors have the option to publish the peer review history of their article (what does this mean?). If published, this will include your full peer review and any attached files.

If you choose “no”, your identity will remain anonymous but your review may still be made public.

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Reviewer #1: No

Reviewer #2: No

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PLoS One. 2021 Mar 18;16(3):e0248484. doi: 10.1371/journal.pone.0248484.r002

Author response to Decision Letter 0

11 Dec 2020

Dear editor and reviewers:

Thank you for the opportunity to review our manuscript. We appreciate your accurate comments, which provided useful insights to improve our review. We present our responses in bold after every comment and highlight the changes in the manuscript in blue. We consider that we have further enhanced the clarity and lightness of our manuscript. We hope that this revised version reflects all the comments and is better suited to your journal for publication.

The authors should be commended for the comprehensive and detailed review they have undertaken.

We are grateful for the reviewer's insightful comments. We made every effort to address the reviewer's suggestions throughout the manuscript.

I have some comments for consideration:

Introduction:

1. Opening sentence: ‘Peripheral neuropathies are common injuries’ I suggest use pathologies rather than injury, in case of insidious onset peripheral neuropathies not attributable to trauma.

We replace the term ‘lesions’ with ‘pathologies’ in the Introduction’s opening sentence, on page 2, line 49.

2. Paragraph 2, sentences 1 and 2: Citations should be provided for these statements ‘Current literature has focused on the efficacy of surgical and pharmacological treatments. Regarding conservative treatments, most studies evaluated the effects of electrophysical modalities in carpal tunnel syndrome.’

We provided the missing citations for the statements on page 3, lines 62 and 63.

Methods:

3. Search strategy – Search was undertaken in April-Jul 2019. This was a while ago, re-running and updating the search should be considered.

We reactivate the search on 1/10/2020 and adjust the margin until 31/12/2020.

4. Search strategy – what is the rationale for using just 2 databases? Also, what was the rationale for limiting it to 2009?

Initially, we chose to focus our review on the last decade’s findings in the two databases with the largest number of clinical trials. However, in order to have a broader perspective, we expanded the search to the following databases: Biomed Central, Ebscohost, Lilacs, Ovid, Pedro, Sage, Scopus, Science Direct, Semantic Scholar, Taylor & Francis, and Web of Science. We also adjust the period of publication from 1980 to 2020. The search strategy is on page 4. We provide an example of the search terms in S2 File.

5. Study selection and data extraction – indicate which authors (by initials) did the screening, and same for data extraction. Were disagreements solved by consensus discussion?

As suggested, we include the initials of the authors who did the process. Discrepancies were resolved through discussion and consensus moderated by a third author. Data section, pages 4 and 5.

6. Study selection and data extraction – were corresponding authors of papers contacted if data were missing or presented in graphs only?

We contacted the authors but did not respond.

7. Sections of the Method that are included in the Prisma guidelines are missing – the details of the methods used for summary measures, synthesis of results (e.g. meta-analysis, best evidence synthesis) and risk of bias across studies are not described. Looking at the results, meta-analysis to calculate SMD has been performed, and there is mention of limited and moderate evidence. But these have not been defined or described in the method.

We modified the Methods section following the PRISMA methodology checklist, pages 3, 4, and 5. We also included the information of the heterogeneity analysis in Data synthesis, page 5.

8. In line with comment 7 above, meta-analysis was undertaken but there does not appear to be an assessment of the risk of bias across studies or overall confidence of the evidence (e.g. the GRADE approach). This should be done for each meta-analysis comparison to provide insight on the quality of meta-analysis evidence and confidence in the findings.

We assessed the risk of bias using the Cochrane Risk of Bias Tool, as described on page 5 and S3 Table.

Results:

9. Paragraph 1 – Science direct and research gate are mentioned here, but were not mentioned in the Method. Were these used as additional databases for the search?

We obtained the articles from Science Direct and Research Gate from the references of some studies included in the previous review. However, based on the suggestion of expanding our sources, we have included the Science Direct database in this second review.

10. Reporting of the Results would be much clearer if it were arranged using the sections defined in the Prisma checklist. For example, the section labelled Evidence Hierarchy appears to detail the Study Characteristics. Risk of Bias of individual studies is currently reported in the Method section, so should be presented in the Results instead. Splitting the reporting of results into sections detailing results of individual studies, then detailing the synthesis of results (i.e. meta-analysis and qualitative synthesis) in accordance with the Prisma guidelines would be a much neater way for arranging the Results.

Thanks for the feedback. As suggested, we report our results using the sections of the PRISMA checklist. We present the findings for each type of comparison and then the meta-analysis of each one. Pages 5 to 24.

11. The paper is largely well-written, however there are a few grammatical errors (e.g. LLLT is defined twice on page 6), so I suggest reviewing the manuscript for such issues.

We followed the grammatical suggestions and named the modalities with acronyms only at the beginning.

12. Forest plots – suggest adding labels to the X axis to show which direction favours the treatment and which direction favours controls

We add the label on the x-axis of each forest plot indicating the direction of favourability of the treatments.

13. Meta-analysis text results – suggest including I-squared when reporting the SMD meta-analysis results, to show heterogeneity without needing to refer to the supplementary material.

We included in each forest plot the heterogeneity results of the I2 tests.

Discussion:

14. The discussion is largely a summary of the results. It would be strengthen the paper to discuss how these findings relate to other studies, consider clinical implications etc.

We wrote the discussion in terms of clinical relevance contrasting our findings with recent reviews on the topic.

Reviewer #2:

The authors provide a systematic analyses of electrophysical therapy in peripheral nerve entrapment injuries. They included all papers from the course of the last decade and conclude a lack of evidence about the efficacy of electrophysical therapy.

Prisma guidelines were used to prepare the manuscript. I think it is an interesting topic to evaluate non-surgical treatment of peripheral nerve entrapments. Unfortunately the manuscript is very exhausting to read. The authors sum up every included study with a lack of detailed discussion (for example is splinting a viable option, etc.) Preclinical data about the efficacy is not discussed and compared to clinical experience.

There is a lot of information included in an enumerated fashion.

I would suggest to rewrite the manuscript to catch the reader’s attention more and meet the high standard of the journal

We appreciate your valuable feedback, which allowed us to readjust our review. We describe the results according to the comparison types, clearly stating the findings obtained for all the parameters evaluated and their respective meta-analyses.

We rewrote the discussion contrasting our findings with those obtained in the latest reviews of the topic. We compare all the results with the references of the minimal clinically important differences of each of the evaluated parameters. We rewrote a large part of the manuscript considering the suggestions to catch the reader’s attention and meet the high standard of the journal. We hope that we have succeeded.

Attachment

Submitted filename: Response to Reviewers.doc

Click here for additional data file.^{(58.5KB, doc)}

PLoS One. doi: 10.1371/journal.pone.0248484.r003

Decision Letter 1

Leila Harhaus

30 Dec 2020

PONE-D-20-21315R1

Effectiveness of electrophysical modalities in the sensorimotor rehabilitation of radial, ulnar, and median neuropathies: a meta-analysis

PLOS ONE

Dear Dr. Bula-Oyola,

Please submit your revised manuscript by Feb 13 2021 11:59PM. If you will need more time than this to complete your revisions, please reply to this message or contact the journal office at plosone@plos.org. When you're ready to submit your revision, log on to https://www.editorialmanager.com/pone/ and select the 'Submissions Needing Revision' folder to locate your manuscript file.

Please include the following items when submitting your revised manuscript:

A rebuttal letter that responds to each point raised by the academic editor and reviewer(s). You should upload this letter as a separate file labeled 'Response to Reviewers'.
A marked-up copy of your manuscript that highlights changes made to the original version. You should upload this as a separate file labeled 'Revised Manuscript with Track Changes'.
An unmarked version of your revised paper without tracked changes. You should upload this as a separate file labeled 'Manuscript'.

We look forward to receiving your revised manuscript.

Kind regards,

Leila Harhaus

Academic Editor

PLOS ONE

Reviewers' comments:

Reviewer's Responses to Questions

Comments to the Author

1. If the authors have adequately addressed your comments raised in a previous round of review and you feel that this manuscript is now acceptable for publication, you may indicate that here to bypass the “Comments to the Author” section, enter your conflict of interest statement in the “Confidential to Editor” section, and submit your "Accept" recommendation.

Reviewer #1: (No Response)

Reviewer #2: All comments have been addressed

**********

2. Is the manuscript technically sound, and do the data support the conclusions?

Reviewer #1: Yes

Reviewer #2: Yes

**********

3. Has the statistical analysis been performed appropriately and rigorously?

Reviewer #1: Yes

Reviewer #2: Yes

**********

4. Have the authors made all data underlying the findings in their manuscript fully available?

Reviewer #1: Yes

Reviewer #2: (No Response)

**********

5. Is the manuscript presented in an intelligible fashion and written in standard English?

Reviewer #1: Yes

Reviewer #2: Yes

**********

6. Review Comments to the Author

Reviewer #1: Thank you for the invitation to re-review this manuscript.

I wish to thank the authors for their time and efforts revising the manuscript, I agree that it is substantially improved in its revised form. Overall, this is a thorough and comprehensive piece of work that will make a valuable contribution to the field.

Please see below some comments for consideration:

1) Abstract: ‘We found limited evidence favouring therapies with extracorporeal shock-wave, pulsed radiofrequency, and low-level laser.’ It isn’t clear if this refers to limited quality of evidence, or limited effect size. Please revise to make this more apparent.

2) Abstract: missing full stop from final sentence of conclusion

3) Introduction: ‘Symptoms may include partial or total motor dysfunction of the forearm and hand, loss of muscle tone and strength, hypoesthesia or hyperesthesia, pain, allodynia, or paraesthesia’ A minor point, these are both signs and symptoms, so please start this sentence with ‘Signs and symptoms may include…’

4) Methods: For clarity in the Data Synthesis section, please state explicitly that this refers to the meta-analysis performed. Also, some comment on interpretation of effect sizes (small, large etc) would be good, and this would help with the clinical interpretation of findings, and could be integrated/mentioned through the reporting of results (or at least in the Discussion).

5) Methods: The authors have used Cochrane Risk of Bias Tool for assessment of Risk of bias in individual studies (nicely shown in Table S3), however there is no assessment made of risk of bias across studies (like the GRADE approach) to consider confidence in the findings of the meta-analysis comparisons. This would strengthen the review and the manuscript if possible to include.

6) Results: Table S4 – the authors should be commended on the time and work required to produce this comprehensive summary of the results of all included findings. A minor note, it is a bit confusing having Appendix 1 written inside Table S4, suggest just using the term Table S4 rather than Appendix 1

7) Results: Paragraph 1 in subheading ‘Effects of electrophysical interventions’ – Is there a parenthesis missing somewhere?

8) Results: Forest plots – there are instances of a paper appearing twice within the same forest plot. Why is this? It should be made clearer why this is the case in the caption of each figure.

9) Results: I like the comparison of the meta-analysis findings with MCID, that is a nice way to help convey the clinical significance of the findings. Was this done using the mean differences for the outcomes (rather than SMDs) calculated in the meta-analysis? If so, it would be helpful for these data to be included (even just reported as a range in the text) for the outcomes mentioned in the Clinical Significance paragraph (p25, paragraph 1).

10) Discussion: the Discussion succinctly compares findings of the present review and considers the clinical relevance of findings, with respect to the MCID as per comment 9. As noted in comment 4 above, discussing the effect sizes reflected by the SMDs would be another way to explore the clinical significance of these results (e.g. small effect, large effect etc).

11) Discussion: How much confidence do the authors have in the results of their meta-analysis comparisons? The discussion of the results largely indicate that electrophysical modalities do not produce clinically significant treatment effects. Considering the quality of the studies that comprise the meta-analysis (plus numbers of participants, effect sizes etc), is this ‘good quality’ meta-analysis data? The GRADE approach referred to in comment 5 is a nice way to consider this should the authors elect to utilise it.

12) Figures: there are a lot of figures, but they are well done and clear.

Reviewer #2: The authors made a substantial effort top improve their manuscript. The data presentation and discussion gained readability.

I found some minor potential for improvement:

Line 165n and ongoing paragraph should be written in complete sentences and not only in a abbreviated manner.

Figure 9: All other figures show the sham procedure on the right side of the figure this one on teh left. This might be confusing for the Reader

Figure 12: same

**********

7. PLOS authors have the option to publish the peer review history of their article (what does this mean?). If published, this will include your full peer review and any attached files.

If you choose “no”, your identity will remain anonymous but your review may still be made public.

Do you want your identity to be public for this peer review? For information about this choice, including consent withdrawal, please see our Privacy Policy.

Reviewer #1: No

Reviewer #2: No

PLoS One. 2021 Mar 18;16(3):e0248484. doi: 10.1371/journal.pone.0248484.r004

Author response to Decision Letter 1

13 Feb 2021

February 13, 2021

Reviewers

Plos One

Dear editor and reviewers:

Thank you for this new opportunity to review our manuscript. We appreciate your thoughtful comments which have contributed to the substantial improvement of our revision. We present our responses in bold after each comment and highlight changes to the manuscript in blue. We believe that we have improved the methods of evidence assessment and the discussion of results. We hope that this revised version reflects all comments and is better suited to your journal for publication.

Reviewer #1: Thank you for the invitation to re-review this manuscript.

We are grateful for the reviewer's insightful comments. We made every effort to address the reviewer's suggestions throughout the manuscript.

Please see below some comments for consideration:

As suggested, we describe our results based on effect sizes and MCID.

2) Abstract: missing full stop from final sentence of conclusion

We have included the missing period at the end of the sentence.

We start the paragraph with the phrase ‘Signs and symptoms may include…’

We rewrite the data synthesis section detailing the methods for estimating the effect sizes of the meta-analysis results. This information was also included in the results and discussion.

We assess the quality of the evidence through the GRADE approach. This information was included in the results, the discussion and the summary of the findings are present as supplementary material in Table S3.

We replace the term appendix by the name of the table. (Now is named as Table S5).

7) Results: Paragraph 1 in subheading ‘Effects of electrophysical interventions’ – Is there a parenthesis missing somewhere?

We have included the missing parentheses. Thank you for your willingness to improve the details.

8) Results: Forest plots – there are instances of a paper appearing twice within the same forest plot. Why is this? It should be made clearer why this is the case in the caption of each figure.

We have included the clarifying information as a caption on the image. We list studies that compared more than one treatment modality or dose.

We describe the information about the MCID estimate and include a reference table with the values.

We reinforced the discussion about the clinical significance of the results by contrasting them with effect sizes and MCID

We include the assessment of the quality of the evidence as an opening for the discussion and highlighting its implications in the effect estimation.

12) Figures: there are a lot of figures, but they are well done and clear.

We appreciate your feedback.

Reviewer #2: The authors made a substantial effort to improve their manuscript. The data presentation and discussion gained readability.

Thanks for your valuable comments.

I found some minor potential for improvement:

Line 165n and ongoing paragraph should be written in complete sentences and not only in a abbreviated manner.

We replace abbreviations with full names of treatments and neuropathies.

Figure 9: All other figures show the sham procedure on the right side of the figure this one on the left. This might be confusing for the Reader. Figure 12: same

As suggested, we modify the forest plots (Figure 9 and 12).

Sincerely,

Ena Lucía Bula Oyola

Universidad del Norte

Universitat Politècnica de València

+34 667045622

oyolae@uninorte.edu.co

Attachment

Submitted filename: Response to Reviewers.doc

Click here for additional data file.^{(49.5KB, doc)}

PLoS One. doi: 10.1371/journal.pone.0248484.r005

Decision Letter 2

Leila Harhaus

1 Mar 2021

Effectiveness of electrophysical modalities in the sensorimotor rehabilitation of radial, ulnar, and median neuropathies: a meta-analysis

PONE-D-20-21315R2

Dear Dr. Bula-Oyola,

We’re pleased to inform you that your manuscript has been judged scientifically suitable for publication and will be formally accepted for publication once it meets all outstanding technical requirements.

Within one week, you’ll receive an e-mail detailing the required amendments. When these have been addressed, you’ll receive a formal acceptance letter and your manuscript will be scheduled for publication.

An invoice for payment will follow shortly after the formal acceptance. To ensure an efficient process, please log into Editorial Manager at http://www.editorialmanager.com/pone/, click the 'Update My Information' link at the top of the page, and double check that your user information is up-to-date. If you have any billing related questions, please contact our Author Billing department directly at authorbilling@plos.org.

If your institution or institutions have a press office, please notify them about your upcoming paper to help maximize its impact. If they’ll be preparing press materials, please inform our press team as soon as possible -- no later than 48 hours after receiving the formal acceptance. Your manuscript will remain under strict press embargo until 2 pm Eastern Time on the date of publication. For more information, please contact onepress@plos.org.

Kind regards,

Leila Harhaus

Academic Editor

PLOS ONE

Reviewers' comments:

Reviewer's Responses to Questions

Comments to the Author

Reviewer #1: All comments have been addressed

Reviewer #2: All comments have been addressed

**********

2. Is the manuscript technically sound, and do the data support the conclusions?

Reviewer #1: Yes

Reviewer #2: Yes

**********

3. Has the statistical analysis been performed appropriately and rigorously?

Reviewer #1: Yes

Reviewer #2: Yes

**********

4. Have the authors made all data underlying the findings in their manuscript fully available?

Reviewer #1: Yes

Reviewer #2: Yes

**********

5. Is the manuscript presented in an intelligible fashion and written in standard English?

Reviewer #1: Yes

Reviewer #2: Yes

**********

6. Review Comments to the Author

Reviewer #1: Thank you for the invitation to re-review this paper. The authors have done a great job addressing the second round of review comments. I agree the paper has been substantially improved.

I have no further concerns regarding the manuscript and would like to commend the authors on their comprehensive study. I note however that there are currently two different files named Table S3 (one is a replication of Table S4?), however I imagine this will be sorted out at a later stage in the editing process.

Reviewer #2: I think the authors again made an effort to improve their manuscript which is now publishable from my opinion

**********

7. PLOS authors have the option to publish the peer review history of their article (what does this mean?). If published, this will include your full peer review and any attached files.

If you choose “no”, your identity will remain anonymous but your review may still be made public.

Do you want your identity to be public for this peer review? For information about this choice, including consent withdrawal, please see our Privacy Policy.

Reviewer #1: No

Reviewer #2: No

PLoS One. doi: 10.1371/journal.pone.0248484.r006

Acceptance letter

Leila Harhaus

5 Mar 2021

PONE-D-20-21315R2

Effectiveness of electrophysical modalities in the sensorimotor rehabilitation of radial, ulnar, and median neuropathies: a meta-analysis

Dear Dr. Bula-Oyola:

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Supplementary Materials

S1 Table. PRISMA checklist.

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S2 Table. PICO question.

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S3 Table. GRADE summary of findings.

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S4 Table. Risk of bias of randomised controlled studies.

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S5 Table. Measures and outcomes of included studies.

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Data Availability Statement

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PERMALINK

Effectiveness of electrophysical modalities in the sensorimotor rehabilitation of radial, ulnar, and median neuropathies: A meta-analysis

Ena Bula-Oyola

Juan-Manuel Belda-Lois

Rosa Porcar-Seder

Álvaro Page

Roles

Abstract

Introduction

Methods

Results

Conclusions

Trial registration

Introduction

Methods

Eligibility criteria

Outcomes measures

Search strategy

Data collection and analysis

Selection of studies and data extraction

Assessment of risk of bias

Data synthesis

Results

Search strategy

Fig 1. Flowchart of the study selection process.

Study characteristics

Assessment of risk of bias

Effects of electrophysical interventions

Electrophysical modalities versus placebo

Table 1. Outcome measures and significance of electrophysical modalities versus placebo.

Fig 2. Analysis—Electrophysical modalities versus placebo (pain).

Fig 12. Analysis—Electrophysical modalities versus placebo (pinch strength).

Fig 3. Analysis—Electrophysical modalities versus placebo (symptoms severity).

Fig 4. Analysis—Electrophysical modalities versus placebo (functional status).

Fig 5. Analysis—Electrophysical modalities versus placebo (sensory latency).

Fig 6. Analysis—Electrophysical modalities versus placebo (motor latency).

Fig 7. Analysis—Electrophysical modalities versus placebo (sensory velocity).

Fig 8. Analysis—Electrophysical modalities versus placebo (motor velocity).

Fig 9. Analysis—Electrophysical modalities versus placebo (sensory nerve action potential amplitude).

Fig 10. Analysis—Electrophysical modalities versus placebo (compound muscle action potential amplitude).

Fig 11. Analysis—Electrophysical modalities versus placebo (grip strength).

Electrophysical modalities versus manual therapy

Table 2. Outcome measures and significance of electrophysical modalities versus manual therapy.

Fig 13. Analysis—Electrophysical modalities versus manual therapy (pain).

Fig 19. Analysis—Electrophysical modalities versus manual therapy (grip strength).

Fig 14. Analysis—Electrophysical modalities versus manual therapy (symptoms severity).

Fig 15. Analysis—Electrophysical modalities versus manual therapy (functional status).

Fig 16. Analysis—Electrophysical modalities versus manual therapy (sensory latency).

Fig 17. Analysis—Electrophysical modalities versus manual therapy (motor latency).

Fig 18. Analysis—Electrophysical modalities versus manual therapy (sensory velocity).

Comparison between electrophysical modalities

Table 3. Outcome measures and significance of the comparison between electrophysical modalities.

Fig 20. Analysis—Comparison between electrophysical modalities (pain).

Fig 26. Analysis—Comparison between electrophysical modalities (grip strength).

Fig 21. Analysis—Comparison between electrophysical modalities (symptoms severity).

Fig 22. Analysis—Comparison between electrophysical modalities (functional status).

Fig 23. Analysis—Comparison between electrophysical modalities (sensory latency).

Fig 24. Analysis—Ccomparison between electrophysical modalities (motor latency).

Fig 25. Analysis—Comparison between electrophysical modalities (sensory velocity).

Electrophysical modalities versus splinting

Table 4. Outcome measures and significance of electrophysical modalities versus splinting.

Fig 27. Analysis—Electrophysical modalities plus splint versus splinting (pain).

Fig 34. Electrophysical modalities versus splinting (sensory velocity).

Fig 28. Analysis—Electrophysical modalities alone versus splinting (pain).

Fig 29. Analysis—Electrophysical modalities versus splinting (symptoms severity).

Fig 30. Analysis—Electrophysical modalities versus splinting (functional status).

Fig 31. Analysis—Low-level laser plus splint versus splinting (motor latency).

Fig 32. Analysis—Electrophysical modalities alone versus splinting (motor latency).

Fig 33. Analysis—Electrophysical modalities plus splint versus splinting (sensory velocity).

Clinical significance

Table 5. Clinical significance from MCID estimation.

Discussion

Table 6. Overview of evidence of electrophysical modalities.

Strengths and limitations

Conclusions

Implications for practice

Implications for research

Supporting information

Data Availability

Funding Statement