Effect of Platelet-Rich Plasma Injection on Mild or

Review ArticleEffect of Platelet-Rich Plasma Injection on Mild or ModerateCarpal Tunnel Syndrome: An Updated Systematic Review andMeta-Analysis of Randomized Controlled Trials

Chunke Dong ,1 Yan Sun,2 Yingna Qi,1 Yuting Zhu,2 Hongyu Wei,2 Di Wu ,1

and Chungen Li 1

1Department of Orthopaedics and Traumatology, Beijing Hospital of Traditional Chinese Medicine, Capital Medical University,No. 23, Meishuguan Houjie (Art Gallery Back Street), Dongcheng District, Beijing 100010, China2Beijing University of Chinese Medicine, No. 11, North Third Ring East Road, Chaoyang District, Beijing 100029, China

Correspondence should be addressed to Chungen Li; [email protected]

Received 10 August 2020; Revised 23 October 2020; Accepted 29 October 2020; Published 16 November 2020

Academic Editor: Fabiano Bini

Copyright © 2020 Chunke Dong et al. This is an open access article distributed under the Creative Commons Attribution License,which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

Objective. To evaluate efficacy of platelet-rich plasma (PRP) injection in carpal tunnel syndrome (CTS), we conducted this meta-analysis, as well as proposed a protocol for its application in curative processes. Methods. All randomized controlled trials(RCTs) of PRP for the management of mild or moderate CTS were included in this study. Database search was conducted fromstudy inception to July 2020, including PubMed, Embase, Web of Science, and Cochrane Library. We used visual analoguescores (VAS) and the Boston Carpal Tunnel Questionnaire (BCTQ) as evaluation tools for primary outcomes. Second outcomescomprised cross-sectional area (ΔCSA) and electrophysiological indexes including distal motor latency (DML), sensory peaklatency (SPL), motor nerve conduction velocity (MNCV), sensory nerve conduction velocity (SNCV), compound muscle actionpotential (CMAP), and sensory nerve action potential (SNAP). The pooled data were analyzed using RevMan 5.3. Subgroup andsensitivity analyses were conducted with the evidence of heterogeneity. Egger’ test was used to investigate publication bias.Results. 9 RCTs were finally screened out with 434 patients included. Control groups comprised corticosteroid injection in 5trials, saline injection in 1 trial, and splint in 3 trials. At the 1st month after follow-up, only ΔCSA between the PRP group andthe control group showed significant difference (P < 0:05). In the 3rd month, there were statistically significant differences inVAS, BCTQ, SPL, SNCV, and ΔCSA between two groups (P < 0:05), while no statistically significant differences were found inthe remaining outcomes. In the 6th month, there were statistically significant differences at BCTQ (P < 0:05) in primaryoutcomes and ΔCSA (P < 0:05) in secondary outcomes between two groups. As to adverse events in PRP injection, only onestudy reported increased pain sensation within 48 h after injections. Conclusion. This systematic review and meta-analysisdemonstrates that the PRP could be effective for mild to moderate CTS and superior to traditional conservative treatments inimproving pain and function and reducing the swelling of the median nerve for a mid-long-term effect. To some extent, theelectrophysiological indexes also improved after PRP injection compared with others conservative treatments.

1. Introduction

Carpal tunnel syndrome (CTS) is one of the most disturbingentrapment neuropathy in upper limbs [1] affecting up to 5%of the adult population [2]. Due to the pathogenesis of themedian nerve (MN) compression, which passes through thecarpal tunnel, CTS is characterized by representative symp-toms such as paresthesia and pain in areas innervated by

the MN. More seriously, motor deficit or atrophy of theinnervated muscles emerges in severe CTS [3] which strikesa huge impact on quality of life.

CTS therapies usually include conservative and surgicalmanagement. Surgical therapy is best documented scientifi-cally, but it is not without flaws; therefore, in mild and mod-erate CTS, conservative therapy is often preferred [4, 5].More recently, Wolny and Linek [6, 7] assessed the effective-

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ness of neurodynamic techniques in conservative therapy ofCTS, but the conclusions are not definitive. A community-based cohort revealed that approximately 60% to 70% ofpatients who underwent conservative treatment did nothave symptom relief at the 18-month follow-up, whichindicated limited long-term efficacy [8]. Corticosteroidshave been utilized for perineural injection as early as1980 and achieved a definite effect including CTS,although a Cochrane Review stated that corticosteroidinjections only provided symptomatic benefit at 1-monthfollow-up. Moreover, steroid application may be associatedwith adverse events, e.g., neurotoxicity and degenerativetendon rupture [9, 10]. As for patients with severe CTS,surgical treatment became a desired trial [1, 11]; however,the decision should be cautious in view of the failure ratein surgery ranging 7-75% as reported [12]. Thus, it isnecessary to seek a novel noninvasive and cost-effectiveconservative treatment.

Since 2014, platelet-rich plasma (PRP) has graduallyemerged in neuropathy, with admissible success rates [13,14]. PRP is an autologous blood product collected andcentrifuged from the patient’s blood and comprises a highconcentration of platelets. In addition, several high concen-trations of growth factors are believed to play crucial rolesin tissue regeneration and healing. When PRP is injected topatients themselves, the aforementioned ingredients pro-mote wound healing and angiogenesis and improves axonalregeneration in the entrapment area. Recently, the profitregarding nerve fiber regeneration was also demonstrated inan animal study [15]. Nevertheless, long-term clinical out-come of PRP remains unknown. What is more, it is reportedthat the concentrations less than 4 to 6 times or higher than 8times may be ineffective or conversely inhibit the healingprocess [16, 17]. Indeed, the argument did exist about thecentrifugation technique and the enrichment percentages ofblood [18–20].

So far, several RCTs compared PRP injection to varietiesof other conservative treatments with different assessments.To provide better evidence of efficacy and safety of PRP injec-tion in CTS, we conducted this meta-analysis, as well as pro-posed a protocol for its application in curative processes.

2. Materials and Methods

The present meta-analysis was conducted based on the Pre-ferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) statement [21]. The protocol for our sys-tematic review was registered on INPLASY (2020100077)and available from doi: 10.37766/inplasy2020.10.0077.

2.1. Criteria for including Studies. All RCTs of PRP injectionfor the management of more than 10 participants pergroup with mild or moderate CTS were included in thisstudy. The primary outcomes will be assessment of painsymptom using the VAS and BCTQ [22, 23], which wasdesigned definitely for CTS. BCTQ contains 2 distinctscales, the Symptom Severity Scale (BCTQs) and the Func-tional Status Scale (BCTQf). Secondary outcomes involvedΔCSA and clinical results of nerve electrophysiology

related to motor and sensory nerves. Articles that reportedat least one outcome were included.

2.2. Criteria for excluding Studies. Articles without the out-come measures of interest were excluded. Non-RCTs, retro-spective studies, cross-sectional studies, animal studies,in vitro biomechanical studies, case reports, comments, let-ters, editorials, and reviews were excluded.

2.3. Database Searches. Electronic databases includingPubMed, Embase, Cochrane Library, and Web of Sciencewere searched up to July 2020 for RCTs involving PRP inthe management of mild or moderate CTS. The search strat-egy for PubMed was as follows: The keywords for the studyobject (MeSHwords or free words) included (“Carpal TunnelSyndrome” OR “Carpal Tunnel Syndromes” OR “Syndrome,Carpal Tunnel” OR “Syndromes, Carpal Tunnel” OR“Amyotrophy, Thenar, Of Carpal Origin” OR “Median Neu-ropathy, Carpal Tunnel” OR “Compression Neuropathy,Carpal Tunnel” OR “Entrapment Neuropathy, Carpal Tun-nel”). For the intervention strategy, the keywords were“Platelet-Rich Plasma” OR “Plasma, Platelet-Rich” OR “Platelet Rich Plasma “. For the study design strategy, the key-words were “Randomized Controlled Trial” OR “Random-ized” OR “Placebo”. We only included English-languagearticles. In addition, the reference lists of selected articlesand relevant reviews were manually searched for any addi-tional trials.

2.4. Data Extraction and Quality Assessment. The resultswere managed with Endnote X7 software, and duplicatestudies were automatically deleted. Next, two authors(CK.D. and Y.S.) independently reviewed all titles andabstracts related to the eligibility criteria described above.The full text of the literature was reviewed thoroughly for afinal inclusion. All disagreements were resolved by reachinga consensus with the third author (YN.Q.).

Data were extracted by two authors (CK.D. and YN.Q.)from selected studies independently using a standardizedform. Information for each eligible study included authorinformation, publication year, method of randomizationand blinding, data sources, sample sizes, demographic data-base, parameters of concentration and centrifugation,detailed interventions, treatment course, outcomes, follow-up duration, and adverse events. When a 100-point NRSscore was used, it was converted to a 10-point VAS score[24]. Data in median, interquartile range, and mean ± 95%confidence interval (95% CI) were converted to mean ±standard deviation (SD) according to the Cochrane Hand-book [25]. We extracted data by manual measurements fromthe published figures when not reported numerically. If nec-essary, we contacted the relevant authors in trials for moreoriginal data.

Two authors (YT.Z. and HY.W.) independentlyassessed the risk of bias of the included studies based onthe Cochrane Collaboration’s tool according to six items:random sequence generation, allocation concealment,blinding of participants and personnel, incomplete outcome

2 BioMed Research International

https://doi.org/10.37766/inplasy2020.10.0077

data, selective reporting, and other biases. Disagreementwas resolved by the third author (D.W.).

2.5. Statistical Analysis. Meta-analysis was performed usingsoftware RevMan 5.3. Continuous data were expressed asmean ± SD and calculated through the mean difference(MD) or standardized mean difference (SMD) with 95% CI.Heterogeneity across included studies was assessed with theCochran Q test (the level of significance was set at 0.1) [26].The I2 score was also used to determine the degree of hetero-geneity (I2 < 50%, no obvious heterogeneity; I2 > 50%, largeor extreme heterogeneity) [26]. A random-effect model wasused for heterogeneous statistical data. Otherwise, a fixed-effect model was performed. Sensitive analysis or subgroupanalysis was used to investigate the source of heterogeneity.Meta-analysis results were also assessed using forest plots,and P < 0:05 was considered statistically significant.

3. Results

3.1. Literature Search. In total, 34 citations were identifiedafter an initial systematic search. Afterwards, we reviewedabstracts and titles of included studies, selected the relevantinformation, and removed duplication independently, and

20 studies were selected. Finally, 9 RCTs were screened outafter reading the full text (Figure 1).

3.2. Characteristics and Risk of Bias of Included Studies. Atotal of 9 RCTs published with 434 patients were finallyincluded in this meta-analysis. Characteristics of all studiesare shown in Table 1. All studies compared clinical outcomesof PRP injection versus other conservative treatments formanagement of mild to moderate CTS. Besides, controlgroups comprised corticosteroid injection in 5 trials [13,27–30], saline injection in 1 trial [31], and a splint in 3 trials[32–34]. Of the 9 included studies, 7 studies were consideredto have a low risk of bias, while the 2 remaining studies werefound to have a high risk of bias. Random sequence genera-tion was found in 5 studies. Allocation concealment wasfound in 8 studies, and blinding of participants and person-nel were found in 6 studies. Blinding of outcome assessmentwas found in 7 studies. As shown in Figure 2, incomplete out-come data and selective reports were not found in 9 studies.

3.3. Comparative Analysis of PRP and Other ConservativeTherapies. After carefully reading and summarizing theincluded RCTs, we used VAS and BCTQ as evaluation toolsfor primary outcomes. Second outcomes comprised ΔCSA[35] and electrophysiological indexes including DML, SPL,

Records identified throughdatabase searching (n = 34)

(PubMed: 8, Web of Science: 9,Embase: 13, Cochrane Library: 4)

Iden

tifica

tion

Scre

enin

gEl

igib

ility

Inclu

ded

Ana

lysis

Additional records identifiedthrough other sources (n = 0)

Records a�er duplicatesremoved (n = 20)

Records screened(n = 20)

Removed based on titles/abstracts(n = 8)

Full-text articles removed(n = 3)

Non-PRP study: 4Non-RCTs: 4

Review/opinion: 2Meta-analysis: 1

Full-text articles assessedfor eligibility (n = 12)

Studies included inqualitative synthesis (n = 9)

Studies included inquantitative synthesis

(meta-analysis)(n = 9)

Figure 1: Flow diagram of the study selection process for the meta-analysis.

3BioMed Research International

Table1:Characteristics

ofallthe

trialsinclud

edin

themeta-analysis.

Stud

yCou

ntry

Sample

size

Age

(years)

Gender

(M/F)

Characteristics

ofCTS

Therapy

inintervention

grou

pTherapy

incontrolgroup

IC

IC

IC

Hashim

(2020)

Egypt

2020

48:8±6:6

249:1±6:06

3/17

2/18

Mild

tomod

erate

PRPinjection,

1ml

Methylpredn

isolon

eacetate

Shen

(2019)

China

2026

56:8±1:7

58:5±2:1

2/18

1/25

Mod

erate

PRPinjection,

3ml

5%dextrose

injection

Senn

a(2019)

Egypt

4342

38:3±6:4

40:7±9:4

8/35

6/36

Mild

tomod

erate

PRPinjection,

2ml

Methylpredn

isolon

eacetate

Malahias(2018)

Greece

2624

60:46±

14:39

57:17

±16:14

NR

Mild

tomod

erate

PRPinjection

(ultrasou

ndguided),2ml

0.9%

norm

alsalin

einjection

Esam

(2019)

Egypt

1818

38:5±8

36:6±8:8

2/16

2/16

Mild

tomod

erate

PRPinjection(ultrasoun

dguided),2ml

Methylpredn

isolon

eacetate

Uzun(2016)

Turkey

2020

48:8±5:8

48:5±6:1

4/16

4/16

Mild

PRPinjection,

2ml

Triam

cino

lone

aceton

ide

Wu(2017)

China

3030

57:87±

1:51

54:27

±1:34

3/27

5/25

Mild

tomod

erate

PRPinjection(ultrasou

ndguided),3ml/nightsplin

tSplin

t

Serdar

(2018)

Turkey

1812

47.5(28-63)

50(31-56)

1/17

1/11

Mild

tomod

erate

PRPinjection(ultrasoun

dguided),1ml

Splin

tandacetam

inop

hen

Raeissadat(2018)

Iran

2120

51:2±9:8

247:23

±7:11

0/21

0/20

Mild

tomod

erate

PRPinjection,

1ml/splin

tSplin

t

I:PRPinjectiongrou

p;C:con

trol

grou

p;NR:n

otrepo

rted.


MCV, SNCV, CMAP, and SNAP. Meanwhile, we conducteda subgroup analysis at different follow-up times (at 1, 3, and 6months). Besides, the difference of MD and SD (ΔCSA andSNCV) between baseline and follow-up was compared inthe subgroup analysis for ΔCSA and SNCV.

3.3.1. First Month after Follow-Up. At the first month afterfollow-up, a total of five component studies [27–29, 33, 34],including 707 and 1237 subjects, provided data on primaryoutcomes and secondary outcomes, respectively. As reportedin Figures 3 and 4, only ΔCSA between the PRP group andthe control group showed significant difference (P < 0:0001,Figure 4(e)) with no additional significance of heterogeneity.However, there were no significant differences in remainingoutcomes (P > 0:05).

3.3.2. ThreeMonths after Follow-Up. In the 3rd month, a totalof 907 and 1347 subjects provided data on primary outcomes[13, 28–31, 33] and secondary outcomes [13, 27–31, 33],respectively. There were statistically significant difference atVAS, BCTQs, BCTQf, SPL, SNCV, and ΔCSA between twogroups (P = 0:004, Figure 5(a); P = 0:0003, Figure 5(b);P < 0:00001, Figure 5(c); P < 0:00001, Figure 6(b); P = 0:01,Figure 6(d); and P < 0:00001, Figure 6(e)). No statistically

significant differences were found in the remaining indexes.The fixed-effect model was preformed when I2 < 50%. Other-wise, a random-effect model was performed. We conducted asubgroup analysis based on different control treatmentmethods, and the SNCV during the 3-month follow-upcompared to corticosteroid injection was statisticallydifferent (P = 0:01).

3.3.3. Six Months after Follow-Up. In the 6th month, a total ofthree component studies [13, 27, 33], including 304 and 264subjects, provided data on primary outcomes and secondaryoutcomes, respectively. There were statistically significantdifferences at BCTQs (P = 0:01, Figure 7(a)) and BCTQf(P = 0:0008, Figure 7(b)) in primary outcomes and ΔCSA(P < 0:0001, Figure 8(b)) in secondary outcomes betweentwo groups. On the contrary, no statistically significant dif-ferences were found in DML (P = 0:48, Figure 8(a)). Thefixed-effect model was preformed due to no heterogeneity.

3.4. Publication Bias. Funnel plots of 1-month BCTQs andBCTQf were generated for evaluation of publication biasbecause both were the main indicators and had enough rele-vant studies. As observed, the data indicated moderate publi-cation bias by uncertainty (Figure 9). Afterwards, Egger’s test

+

+

+

+

+

+

? ? ? ? ? ? ? ? ??

?????

?

+

+

+

+

+

+

+

+

+

+

+

+

+

+

+

+

+ + + + + +

+

+ +

+ +

+ +

+ +

+ + +

+ + + +

Esam

(201

9)

Uzu

n (2

017)

Mal

ahia

s (20

18)

Senn

a (20

19)

Has

him

(202

0)Se

rdar

(201

8)

Wu

(201

7)

Shen

(201

9)

Random sequence generation (selection bias)Allocation concealment (selection bias)Blinding of participants and personnel (performance bias)Blinding of outcome assessment (detection bias)Incomplete outcome data (attrition bias)Selective reporting (reporting bias)Other bias

(a)

Random sequence generation (selection bias)

Allocation concealment (selection bias)

Blinding of participants and personnel (performance bias)

Blinding of outcome assessment (detection bias)

Incomplete outcome data (attrition bias)

Selective reporting (reporting bias)

Other biases

Low risk of biasUnclear risk of biasHigh risk of bias

0 % 25 % 50 % 75 % 100 %

(b)

Figure 2: The methodological quality of the included studies. Risk of bias summary (a) and risk of bias graph (b): +: low risk of bias; −: highrisk of bias; ?: bias unclear.


was conducted and showed no evidence of publication biasfor 1-month BCTQs (P = 0:703, Figure 10(a)) and 1-monthBCTQf (P = 0:635, Figure 10(b)).

3.5. Sensitivity Analysis. Sensitivity analysis was performedby omitting 1 study in each turn to investigate the influenceof a single study on the overall outcome. 1-month BCTQfshowed substantive difference compared to the original anal-ysis when removing the study of Senna et al. (P = 0:02, I2= 0%). When Uzun et al.’s study [13] was removed, BCTQsat 3rd-month follow-up was P < 0:00001, I2 = 1% withoutadditional heterogeneity. Similarly, there was no heterogene-ity in DML after removing Hashim et al.’s study [30](P = 0:91, I2 = 0%). Besides, the results did not show sub-stantive difference compared to the original analysis inremaining indicators.

4. Discussion

As a disturbing entrapment neuropathy with a high inci-dence, current treatments have shown limitations, and moreattempts at conservative treatment for CTS are needed toeffectively relieve symptoms and avoid disease progression

and surgery. In recent years, PRP has aroused wide concernfor efficacy and safety on neurosurgery and orthopedics [36,37], and PRP injection was gradually used for managementof CTS. Previous meta-analysis by Catapano et al. [38] con-cluded promising but confounded results limited by thesmall number of studies available (4 studies), short-term fol-low-up, and high heterogeneity. Therefore, selection biasand completeness of outcome data may affect reliability ofresults. In the present analysis, 9 high-level studies wereincluded. In addition, comprehensive nerve function indica-tors relating to motor and sensory were pooled and calcu-lated under the same follow-up month. Thus, we aimed tofurther evaluate efficacy and safety of PRP injection inCTS, as well as proposing a protocol for its application incurative process.

In the last years, PRP was clinically applied for eliminat-ing pain in muscle injuries and chronic neuropathic pain.Moreover, Kuffler [39] stated that PRP may take effect byeliminating inflammation and initiating a series of biologicalprocesses such as tissue remodeling, wound repair, andaxonal regeneration. In this analysis, we found promisingoutcomes in BCTQ at 3 and 6mo follow-up and VAS at3mo follow-up in the PRP group. The BCTQs evaluated

Study or subgroupEsam (2019)Senna (2019)Wu (2017)

Total (95% CI)Heterogeneity: chi2 = 3.55, df = 2 (P = 0.17); I2 = 44% Test for overall effect: Z = 0.35 (P = 0.72)

2.12.443.89

2.60.730.28

184330

3.52.593.88

2.350.830.28

184230

0.6%15.3%84.1%

91 90 100.1%

–1.40 [–3.02, 0.22]–0.15 [–0.48, 0.18]

0.01 [–0.13, 0.15]

–0.02 [–0.15, 0.11]

MeanExperimental Control

SD Total Mean SD Total Weight IV, fixed, 95% CIMean difference

IV, fixed, 95% CIMean difference

–4 –2

Favours [experimental] Favours [control]

0 2 4

(a)

Esam (2019)Senna (2019)Serdar (2018)Shen (2019)Wu (2017)

18.626.418.717.6

17.17

10.76.66.6

5.613.45

1843182630

22.327.517.619.8

18.43

7.45.55.5

5.615.09

1842122630

5.1%27.6%

9.7%19.7%37.9%

135 128 100.0%

–3.70 [–9.71, 2.31]–1.10 [–3.68, 1.48]

1.10 [–3.26, 5.46]–2.20 [–5.25, 0.85]–1.26 [–3.46, 0.94]

–1.30 [–2.65, 0.06]Total (95% CI)

Study or subgroup MeanExperimental Control



–10 –5


0 5 10Heterogeneity: chi2 = 2.14, df = 4 (P = 0.71); I2 = 0% Test for overall effect: Z = 1.88 (P = 0.06)

(b)


11.924.814.413.6

12.24

5.33.24.8

4.083.01

1843182630

3.83.24.8

4.083.83

1842122630

14.2%29.1%11.6%20.2%24.9%

135 128 100.0%

13.924

13.614.414.4

–2.00 [–5.01, 1.01]0.80 [–0.56, 2.16]0.80 [–2.71, 4.31]

–0.80 [–3.02, 1.42]–2.16 [–3.90, –0.42]

–0.66 [–2.07, –0.76]




–10 –5


0 5 10

Total (95% CI)Heterogeneity: tau2 = 1.31; chi2 = 8.54, df = 4 (P = 0.07); I2 = 53% Test for overall effect: Z = 0.91 (P = 0.36)

(c)

Figure 3: Forest plot of primary outcomes at 1 month of follow-up. They are VAS (a), BCTQs (b), and BCTQf (c).





–4 –2Favours [experimental] Favours [control]

0 2 4



4.34.54.45.6

5.28

0.650.60.6

1.531.26

1843182630

4.54.64.55.4

4.96

0.680.60.6

1.531.2

1842122630

17.7%51.4%17.4%

4.8%8.6%

135 128 100.0%

–0.20 [–0.63, 0.23]–0.10 [–0.36, 0.16]–0.10 [–0.54, 0.34]

0.20 [–0.63, 1.03]0.32 [–0.30, 0.94]

–0.07 [–0.25, 0.12]

(a)


SD Total Mean SD Total Weight IV, random, 95% CIMean difference

IV, random, 95% CIMean difference

–4 –2


0 2 4


Esam (2019)Senna (2019)

3.94.2

0.50.8

1843

4.34.1

0.40.6

1842

50.1%49.9%

61 60 100.0%

–0.40 [–0.70, –0.10]0.10 [–0.20, 0.40]

–0.15 [–0.64, 0.34]

(b)




–10 –5


0 5 10


1.40 [–1.38, 4.18]–2.60 [–3.83, –1.37]

–0.80 [–4.70, 3.10]

Esam (2019)Senna (2019)

5857.1

4.51.9

1843

56.659.7

43.6

1842

44.9%55.1%

61 60 100.0%

(c)




–10 –5


0 5 10



8.118.6

2.51.3

2.26

6.952.236.142.040.99

1843182630

1842122630

1.6%33.6%

1.9%24.3%38.6%

135 128 100.0%

5.917.2

0.51.4

2.39

6.242.214.912.042.25

2.20 [–2.11, 6.51]1.40 [0.46, 2.34]

2.00 [–1.97, 5.97]–0.10 [–1.21, 1.01]–0.13 [–1.01, 0.75]

–0.47 [–0.08, 1.02]

(d)




–10 –5


0 5 10


Senna (2019)Serdar (2018)Shen (2019)Wu (2017)

–2.7–1.5–1.9

–2.15

1.254.712.041.31

43182630

117

1.472.111.531.15

42122630

110

44.0%2.4%

15.4%38.1%

100.0%

–2–0.6–1.3

–1.19

–0.70 [–1.28, –0.12]–0.90 [–3.38, 1.58]–0.60 [–1.58, 0.38]

–0.96 [–1.58, –0.34]

–0.79 [–1.17, –0.40]

(e)

Figure 4: Continued.






0 5 10


Esam (2019)Senna (2019)

11.28.6

7.82.1

1843

8.79.3

5.63

1842

5.8%94.2%

–0.51 [–1.58, 0.56]

2.50 [–1.94, 6.94]–0.70 [–1.80, 0.40]

61 60 100.0%

(f)





0 5 10


–0.59 [–1.55, 0.36]

–0.40 [–4.82, 4.02]–0.60 [–1.58, 0.38]

Esam (2019)Senna (2019)

20.319.1

6.22.3

1843

20.719.7

7.32.3

1842

4.7%95.3%

61 60 100.0%

(g)

Figure 4: Forest plot of secondary outcome at 1 month of follow-up. They are DML (a), SPL (b), MNCV(c), SNCV (d), ΔCSA (e), CMAP (f),and SNAP (g).


0 5 10




Total (95% CI)

Esam (2019)Malahias (2018)Senna (2019)Hashim (2020)Wu (2017)

3.42.852.18

2.62.91

2.093.2

0.651.841.26

1826434030

5.24.292.52

43.36

1.93.340.711.651.42

1824422030

157 134

12.7%7.8%

35.4%19.2%25.0%

100.0%

–1.80 [–3.10, –0.50]–1. 4 [–3.26, 0.38]

–0.34 [–0.63, –0.05]–1.40 [–2.32, –0.48]–0.45 [–1.13, –0.23]

–0.84 [–1.41, –0.28]Heterogeneity: tau2 = 0.21; chi2 = 9.70, df = 4 (P = 0.005); I2 = 59% Test for overall effect: Z = 2.92 (P = 0.004)

(a)


0 25 50





Esam (2019)Uzun (2017)Senna (2019)Hashim (2020)Wu (2017)

21.514.52

2214.8215.76

10.22.42

7.73.262.74

1820434030

1820422030

12.9%23.3%19.6%21.4%22.8%

6.84.07

7.75.775.59

28.623.43

26.419

18.13

151 130 100.0% –5.29 [–8.12, –2.45]

–7.10 [–12.76, –1.44]–8.91 [–10.99, –6.83]

–4.40 [–7.67, –1.13]–4.18 [–6.90, –1.46]–2.37 [–4.60, –0.14]

(b)


0 10 20





Esam (2019)Uzun (2017)Senna (2019)Hashim (2020)Wu (2017)

13.38.9616.89.19

10.79

4.82.96

4.81.3

2.19

1820434030

1820422030

5.7%15.0%11.5%47.0%20.8%

42.84.8

2.113.62

16.713.52

2011.0613.63

151 130 100.0% –2.72 [–3.41, –2.02]

–3.40 [–6.29, –0.51]–4.56 [–6.35, –2.77]–3.20 [–5.24, –1.16]–1.87 [–2.88, –0.86]–2.84 [–4.35, –1.33]

(c)

Figure 5: Forest plot of primary outcomes at 3 months of follow-up. They are VAS (a), BCTQs (b), and BCTQf (c).



0 2 4




Total (95% CI)

Esam (2019)Uzun (2017)Senna (2019)Hashim (2020)Shen (2019)Wu (2017)

4.53.56

4.42.44

5.45.26

0.670.11

0.61.021.531.37

182043402630 30

177

4.73.55

4.53.65

5.44.98

0.70.10.8

0.931.531.21

1820422026

156

17.0%25.2%20.8%15.3%

9.4%12.4%

100.0%

–0.20 [–0.65, 0.25]0.01 [–0.06, 0.08]

–0.10 [–0.40, 0.20]–1.21 [–1.73, –0.69]

0.00 [–0.83, 0.83]–0.28 [–0.37, 0.92]

–0.20 [–0.52, 0.12]Heterogeneity: tau2 = 0.11; chi2 = 22.93, df = 5 (P = 0.0003); I2 = 78% Test for overall effect: Z = 1.24 (P = 0.21)

(a)


0 2 4




–0.50 [–0.85, –0.15]–0.30 [–0.62, 0.02]

–0.51 [–0.73, –0.29]

–0.45 [–0.63, –0.29]

Esam (2019)Senna (2019)Hashim (2020)

43.8

3.63

0.560.8

0.35

184340

184220

21.6%25.4%53.0%

101 80 100.0%

4.54.1

4.14

0.50.7

0.44

Total (95% CI)Heterogeneity: chi2 = 1.21, df = 2 (P = 0.55); I2 = 0% Test for overall effect: Z = 5.53 (P < 0.00001)

(b)


0 5 10




1.10 [–0.91, 3.11]–2.50 [–4.03, –0.97]

–0.76 [–4.29, 2.77]

Esam (2019)Senna (2019)

61 60 100.0%

55.157.4

2.73.5

1843

1842

48.3%51.7%

5459.9

3.43.7


(c)


0 2 4




0.70 [–0.83, 2.23]2.10 [0.91, 3.29]

0.93 [–0.72, 2.58]–0.90 [–4.69, 2.89]

–0.06 [–1.16, 1.04]

0.84 [0.19, 1.48]

Esam (2019)Uzun (2017)Senna (2019)Shen (2019)Wu (2017)

2.4 2.78 20 20 15.3%1.47 2.5319.4 3.12 43 42 29.4%17.3 2.44

2.2 2.55 26 26 17.7%1.5 3.062.64 2.19 30 30 34.6%

137 136 100.0%

2.7 2.14

8.1 5.7 18 18 2.9%9 5.9


(d)


0 2 4


SD Total Mean SD Total Weight IV, fixed, 95% CIStd. mean difference

IV, fixed, 95% CI Std. mean difference

–0.80 [–1.32, –0.27]–0.84 [–1.41, –0.27]–0.49 [–0.92, –0.05]

–0.24 [–0.80, 0.32]

–0.58 [–0.83, –0.32]

Malahias (2018)Senna (2019)Shen (2019)Wu (2017)

–0.016 0.026 26 24 21.1%

125 122 100.0%

–0.009 0.031–3 1.31 43 42 35.1%–2.3 1.54–3 1.53 26 26 20.2%–1.7 1.53

–2.66 1.04 30 30 23.6%–1.68 1.37


(e)

Figure 6: Continued.


symptoms of patients with CTS broadly which comprised thefrequency, duration, and severity of tingling, numbness, andpain. As such, the aforementioned result demonstrated themore effective relief of symptoms in long-term follow-up inPRP injection compared with other conservative treatments.In most of the included studies, corticosteroid injections wereused, and hormones were consistently considered to haveshort-term effects on pain relief. This also explains why therewas no difference between the two groups during the 1mofollow-up. Therefore, PRP injection was also effective inreducing pain symptoms in the short term. Moreover, PRPinjection showed potential long-term benefits in nervefunction as subgroup analysis based on different control

treatment methods showed that the SNCV value during the3-month follow-up with PRP injection was statistically differ-ent compared to that with corticosteroid injection (P = 0:01).

Generally, CTS for mild to moderate is reversible; thus,intervention at this stage is critical which means treatmentsshould focus on not only relief of symptoms but alsoenhancing the regeneration of nerve tissue and completelyeliminate the causes of compression. Indeed, PRP has ahigher concentration of growth factors after centrifugationsuch as insulin-like growth factor, transforming growth fac-tor, fibroblast growth factor, platelet-derived growth factor,and vascular endothelial growth factor [40–42], which wereclosely associated to regeneration of nerve tissue. Moreover,


0 5 10




–0.70 [–1.82, 0.42]2.70 [–1.78, 7.18]

0.28 [–2.74, 3.29]

Esam (2019)Senna (2019)

61 60 100.0%

11.5 8 18 18 28.8%8.8 5.58.8 2.2 43 42 71.2%9.5 3


(f)


0 5 10




–0.70 [–1.64, 0.24]1.40 [–2.21, 5.01]

–0.57 [–1.47, 0.34]

Esam (2019)Senna (2019)

61 60 100.0%

19 4.9 18 18 6.3%17.6 6.118.5 2.2 43 42 93.7%19.2 2.2


(g)

Figure 6: Forest plot of secondary outcomes at 3 months of follow-up. They are DML (a), SPL (b), MNCV(c), SNCV (d), ΔCSA (e), CMAP(f), and SNAP (g).


0 5 10




Total (95% CI)

Uzun (2017)Wu (2017)

26.5114.14

Heterogeneity: chi2 = 0.06, df = 1 (P = 0.81); I2 = 0% Test for overall effect: Z = 2.43 (P = 0.01)

3.962.46

2030

4.624.71

2030

33.7%66.3%

–1.65 [–4.32, 1.02]–2.06 [–3.96, –0.16]

50 50 100.0% –1.92 [–3.47, –0.37]

28.1616.2

(a)


0 5 10





Wu (2017)Shen (2019)

56 56 100.0% –2.21 [–3.50, –0.92]

10.41 2.63 30 3.56 30 66.2% –2.52 [–4.10, –0.94]12.9310.4 4.08 26 4.08 26 33.8% –1.60 [–3.82, 0.62]12

(b)

Figure 7: Forest plot of primary outcomes at 6 months of follow-up. They are BCTQs (a) and BCTQf (b).


evidence was addressed in animal studies. A rat study byPark and Kwon [43] compared dextrose and PRP injectionwith the saline injection, and the results of ΔCSA and

DML were positive. In the present meta-analysis, PRP hada lasting effect on ΔCSA compared to the control groupduring whole follow-up period which indicated that PRP


0 5 10





Uzun (2017)Shen (2019)Wu (2017)

3.59 0.59 20 0.11 20 78.5% 0.02 [–0.24, 0.28]3.575.4 1.53 26 1.53 26 7.5% 0.10 [–0.73, 0.93]5.3

5.18 1.42 30 1.04 30 13.7% 0.44 [–0.19, 1.07]

76 76 100.0% 0.08 [–0.15, 0.32]

4.74

(a)


0 5 10





Shen (2019)Wu (2017)

–3.3 1.53 26 2.04 26 32.1%–1.04 [–1.71, –0.37]–1.40 [–2.38, –0.42]–1.9

–3.08 1.1 30 1.53 30 67.9%

100.0%

–2.04

–1.16 [–1.71, –0.60]56 56

(b)

Figure 8: Forest plot of secondary outcomes at 6 months of follow-up. They are DML (a) and ΔCSA (b).

–10 –5 0 5 10MD5

4

3

2

1

0 SE (MD)

(a)

MD2

1.5

1

0.5

0 SE (MD)

–4 –2 0 2 4

(b)

Figure 9: Funnel plot to detect publication bias: 1-month BCTQs (a) and BCTQf (b). MD: mean difference; SE: standard error.

0–5

0

Stan

dard

ized

effec

t

5

10

2 4 6

(a)

–20

–10

Stan

dard

ized

effec

t

0

10

0 2 4 6

(b)

Figure 10: Egger’s publication bias plot: 1-month BCTQs (a) and BCTQf (b).


injection reduced the swelling of the flexor tenosynovitis.According to Allampallam et al. [44], the flexor retinaculumof individuals with carpal tunnel syndrome is physiologicallyaltered and growth factors resulted in higher mitogenicresponse, stimulation of type III collagen production, andmore alpha 2 than alpha 1 collagen production which wereclosely associated in pathological changes beneficial forCTS. On the other hand, several authors revealed thatplatelet counts might not be the best predictor of plateletbiological activity, and platelet counts were not alwaysproportional to the number of growth factors [45–47]. How-ever, enlargement of the median nerve can be caused by avariety of changes, such as inflammation, fibrosis, intimaor axonal edema, and demyelination or remyelin [1]. Thus,the underlying mechanism has not been understood, andmore studies are needed in the future. Overall, the presentstudy demonstrated the promising effect of PRP injectionon CTS.

Notably, there were significant differences in sensoryelectrophysiological examination (SPL: P < 0:00001; SNCV:P = 0:01) at the 3rd-month follow-up between the PRP injec-tion and control groups which was in accordance with reliefof symptoms. Several authors reported that there may be dif-ference between symptoms and electrophysiological result, asshown in our sensitivity analysis, partly due to large myelin-ated fibers responsible for electrophysiological examinationsinstead of small sensory fibers which are related to symptomsof CTS [48]. Nevertheless, our results shed a light on neuro-logical function improvement which deserved persistentstudies. However, motor nerve function did not improveaccording to MNCV and DML. Indeed, previous studiesshowed that the electrodiagnostic measurement had limita-tions in predicting the curative outcome for conservativetreatments [49, 50]. Furthermore, nerve recovery was arather slow process which might last up to 18 months, andlonger follow-up may be needed in the future to address theissue considering the positive result in BCTQf (3 month:P < 0:00001; 6 months: P = 0:0008).

As to adverse events in PRP injection, only one study bySenna et al. [28] reported increased pain sensation within48 h after injection. Afterwards, patients got symptom reliefby receiving paracetamol and local ice application. Compli-cations were uncommon as surgeons were experienced andultrasound guidance was widely applied to avoid neurovas-cular damage. Of the included studies, 6 out of 9 (66.7%) usedultrasound guidance. More importantly, the blood samplecame from the patients themselves, and antibody responsewas avoided. Above all, PRP injection was safe and welltolerated.

The appropriate PRP preparation and accurate enrich-ment percentages that maintain an optimal balance betweenthe advantages and potential side-effects remain controver-sial. It was reported that the platelets may get prematurelyactivated by excessive concentrations [36] or pipetting [51],and consequently, growth factors were early released. Asmentioned before, the concentrations less than 4 to 6 timesor higher than 8 times may be ineffective or converselyinhibit the healing process [16]. Among the included studies,different concentration processes were used resulting in var-

iable concentrations of platelets and other elements. Unfor-tunately, the enrichment percentages were not reportedexcept for one study by Hashim et al. [30]; however, no sig-nificant results were observed between two PRP groups.Hence, further studies are necessary to address this issue.

4.1. Limitations. The present study had some limitations.Firstly, included studies might result in selective and per-formance biases due to the absence of random allocation,allocation concealment, and blinding. Heterogeneity mayhave been caused by study design, which induced by thedifferent PRP injection doses, and varying interventionmethods in the control group. Secondly, all studies werefollowed up within six months which was relatively shortto get information on long-term effects and side effects.Longer follow-up for 1-2 years may be required. Thirdly,all studies are limited to English which may lead to lan-guage bias. Fourth is the lack of research on effective stud-ies at different PRP doses, and more studies are needed toaddress the issue. Finally, given the limited number of theincluded studies in the analysis, the findings should beconfirmed in future research with more relevant RCTs toobtain more reliable and conclusive data.

5. Conclusions

Although a similar early effect, our study demonstrates thatPRP could be effective for mild to moderate CTS and supe-rior to traditional conservative treatments in improving painand function and reducing the swelling of the median nervefor a mid-long-term effect. To some extent, the electrophys-iological indexes also improved after PRP injection com-pared with other conservative treatments. Overall, PRPinjection was an effective and safe additional therapy forpatients with CTS.

Data Availability

The data used to support the findings of this study are avail-able from the corresponding author upon request.

Conflicts of Interest

The authors declare that they have no conflict of interest.

Authors’ Contributions

Chunke Dong, Yan Sun, and Yingna Qi contributed equallyto this study and should be considered co-first authors.

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