Platelet-rich plasma injection versus surgical and medical treatment of mild-moderate carpal tunnel syndrome

Carpal tunnel syndrome (CTS) accounts for approximately 90% of peripheral entrapment neuropathy cases. Treatments of CTS as splinting, corticosteroid injection, and surgery are not 100% effective, and alternative treatments are worth exploring. Surgery indicated in patients with persistent numbness, pain, and motor dysfunction. Empirical evidence indicates that many patients with CTS respond to anti-inflammatory medications. Recently, major attention has been drawn to platelet-rich plasma (PRP) for its possible effects on axon regeneration and neurological recovery. To evaluate the therapeutic efficacy of single ultrasound guided PRP injection of CTS versus surgical procedures and medical treatment in patients with mild-moderate CTS regarding pain relief and function improvement. Thirty patients were injected in the carpal tunnel with single ultrasound-guided PRP (1–2 ml) injections; 30 patients went to surgical procedure, and 30 patients received conventional medical treatment and hand support. They were followed by using VAS (visual analogue scale), Boston questionnaire for CTS, and nerve conduction study for clinical improvement. Both groups of patients who had received PRP injection and who underwent to surgery showed improvements in their scores of evaluation parameters at 6 months post intervention, while the third group that received medical treatment shows insignificant improvement at 6 months post treatment. PRP can be considered as a safe, less invasive, and long-lasting alternative to surgery and effective with one shot session compared to medical treatment in management of mild-moderate CTS. Clinical trial.govID: NCT04235426. Unique protocol ID:1472. Verification date: January 2020.


Introduction
Carpal tunnel syndrome (CTS) accounts for approximately 90% of peripheral entrapment neuropathy cases [1]. Existing evidence-based treatments for carpal tunnel syndrome, splinting, corticosteroid injection, and surgery are not 100% effective, and alternative treatments are worth exploring [2,3]. Surgery indicated in patients with persistent numbness and pain, motor dysfunction with diminished grip or pinch grasping, or thenar eminence flattening [4].
Empirical evidence indicates that many patients with CTS have self-limiting symptoms and respond to nonoperative conservative treatments, including rest, modification of physical behaviors, splinting, nerve-gliding exercises, manual therapy techniques, and anti-inflammatory medications [5].
Platelet-rich plasma (PRP) is a biological product of condensed platelet that contains multiple growth factors and has anti-inflammatory and regenerating effect with subsequently positive impacts on neuronal healing and axon regeneration [6][7][8].
We aim in this study to evaluate the therapeutic efficacy of single ultrasound-guided platelet-rich plasma injection of the carpal tunnel versus surgical procedures and medical treatment and hand support in patients with mildmoderate carpal tunnel regarding pain relief and function improvement during a follow-up period of 6 months.

Material and methods
Ninety patients aged between 20 and 60 years were collected in the period from January 2018 to January 2019 from outpatient clinic of neurosurgery and physical medicine, rheumatology, and rehabilitation department at Menoufia University Hospitals with signs and symptoms of CTS, and a confirmed diagnosis of moderate CTS based on history (paresthesia or dysesthesia and painful swelling of the hand with clumsiness due to weakness that is exacerbated by repetitive use or sleep and improved by shaking the hand), physical examination (sensory loss and numbness in the areas of the hand, innervated by the median nerve (MN), positive Phalen's test, and/or Tinel's test), and electrophysiological studies was included. The severity of CTS was determined according to the electrophysiological classification proposed by Stevens et al. [9]. Mild CTS was defined as sensory latency of longer than 3.6 ms with or without reduced amplitude of sensory nerve action potential; moderate CTS was defined as sensory latency of longer than 3.6 ms plus a prolonged motor latency (4.3-6 ms) with normal motor amplitude, so we selected for the present study mild-moderate CTS patients with sensory latency of longer than 3.6 ms plus a prolonged motor latency (4.3-6 ms) with normal motor and sensory amplitude. All patients were from the Menoufia Governorate. The research protocol was approved by ethical committee in Faculty of Medicine, Menoufia University. An informed written consent was obtained from each patient.
The presenting study excludes pregnancy, history of underlying metabolic diseases (such as diabetes mellitus, thyroid diseases, rheumatoid arthritis), history of local corticosteroid injection in the past 3 months, atrophy of thenar muscles, previous carpal tunnel release surgery, and evidence of concomitant neuropathy or radiculopathy. Patients with PRP contraindications including history of malignancies, autoimmune or hematologic disorders, and non- steroidal anti-inflammatory drugs (NSAID) consumption 2 days prior to injection, treatment with anti-platelet and anticoagulant agents, Hb level under 12 g/dl, and platelet count under 150,000 in milliliter were also excluded. All patients were subjected to demographic data recording, history taking, and clinical examination including general examination and local examination of the hand, and all have done complete blood count (CBC), erythrocyte sedimentation rate (ESR), c-reactive protein (CRP), hepatitis C virus antibody (HCV), and serum uric acid by ELISA. The pain severity was determined by the patients, on a scale of 0 (no pain) to 10 (agonizing pain) according to the VAS [10,11].
Electrophysiological parameters before and after intervention including the peak latency (PL) and the onset latency (OL) of sensory nerve action potential (SNAP) and distal motor latency of the compound muscle action potential (CMAP) were measured for all patients using a NIHON KOHDEN apparatus for electrophysiological study (nerve conduction study and electromyography) Launches Neuropack® S3 Electrodiagnostic System Offering Unparalleled Clean Waveforms Multimodality Diagnostic Platform Designed to Streamline Workflow for Better Clinical Care (Figs. 1 and 2).
Patient evaluation before and after intervention by clinical interaction by means of the Italian version of the Boston Carpal Tunnel Questionnaire (BCTQ). This is a validated questionnaire with two scales: symptoms (SYMP) and function (FUNC). The scores range from 1 to 5 points, with 1 indicating best health and 5 representing worst health [12].
Patients of the study group were divided into three groups as they were randomized to receive PRP or medical treatment or went to surgery in an equal ratio using a computer-generated code: Thirty patients were injected single ultrasound-guided PRP in the carpal tunnel (Figs. 3, 4 and 5); thirty patients went to surgical procedure, and thirty patients received medical treatment and hand support.  Platelet-rich plasma prepared by taken 10 ml of venous blood sample from every patient and was collected in sterile sodium citrated tubes. Then, the tubes with citrated blood were centrifuged at 3500 rpm (revolutions per minute) for 9 min to separate erythrocytes and produce about 1-2 ml of PRP for injection [13].
The data collected were tabulated and analyzed by SPSS (statistical package for the social science software) statistical package version 16 on IBM compatible computer [14].

Results
Patients of the present study divided into 3 groups; the first group included 30 patients with mild-moderate CTS, and they received single ultrasound-guided PRP (1-2 ml) injection treatments to the carpal tunnel. The second group included 30 patients with mild-moderate CTS went to surgical procedure, and the third group of patients with mild-moderate CTS received medical treatment and hand support. They were evaluated at a baseline and at 6 months post intervention with comparing the results of all groups regarding improvement of pain, symptoms severity scale, functional state, visual analogue scale (VAS), Boston Carpal Tunnel Questionnaire (BCTQ), and the electrophysiological results.
There was insignificant difference in the patients of the three study groups regarding age and sex as in Table 1.
Our study revealed a significant improvement of pain at 6 months post-injection in the 30 patients who underwent autologous PRP injection compared to the baseline, as VAS score was (8.53 ± 1.04) at baseline before injection, and it showed improvement at 6 months (1.97 ± 0.72) as in Table 2.
There was a significant improvement of median nerve peak sensory latency post-injection as it was 5.10 ± 0.96 at baseline, and at 6 months post-injection became 2.95 ± 0.56 and median nerve distal motor latency as it was before injection (5.47 ± 0.58), and at 6 months post-injection became 3.86 ± 0.37 as in Table 2.
At the end of 6 months, post-injection symptoms severity scale was 1.0 ± 0.0 compared to baseline parameters that was 3.17 ± 0.38; also, functional state at the end of 6 months post-injection was 1.4 ± 0.03 compared to the baseline parameters that was 2.93±0.22 in the 1 st group, so there was a significant improvement of symptoms severity scale and functional state at 6 months post-injection in the 1st group of patients regarding Boston Carpal Tunnel Questionnaire (BCTQ) as in Table 2.
There was a significant improvement of visual analogue scale after surgery as it was 8.03 ± 1.2, while at 6 months post-operation it became 2.4 ± 0.85 in the 2 nd group of patients who went to surgery as in Table 3. There was significant improvement of median nerve peak sensory latency and distal motor latency at 6 months post-operation compared to baseline as p value was 0.001 as in Table 3.
There was a gradual improvement of symptoms severity scale at 6 months post-operation as it was 1.0 ± 0.0 compared to the baseline parameters which was 3.17 ± 0.38, and gradual improvement of the functional state at 6 months post-operation as it was 1.07 ± 0.05 compared to the baseline parameter which was 2.96 ± 0.33 in the 2nd group as in Table 3.
There was a significant improvement of pain regarding visual analogue scale at 6 months post medical treatment and hand support in the 3rd group of patients as in Table 4.  There was insignificant improvement of median nerve peak sensory latency and distal motor latency, symptoms severity scale, and functional state at 6 months postmedical treatments compared to baseline as in Table 4.
There were insignificant differences between the three groups before intervention and significant statically differences of pain and function and electrophysiological parameters at 6 months post intervention by comparing both first and second groups with the third group while the first and second groups were comparable Table 5.

Discussion
Our study evaluates the role of platelet-rich plasma injection in patients with mild-moderate carpal tunnel syndrome compared to surgical and medical procedure; we recruited a large sample of patients and rely on a longer period of follow-up (6 months), and the injection was ultrasound guided not blind that provide accurate findings compared to other similar studies; our results rely on an subjective and objective methods of assessment as electrophysiological study regarding motor and sensory conductive study for more accurate findings.
Our study revealed a significant improvement of pain and function at 6 months post-injection of platelet-rich plasma in the 1st and post-surgery in the 2nd group of patients compared to the baseline regarding VAS and Boston questionnaire of CTS.
In agreement to our results, Malahias et al. and Yung-Tsan et al. [15,16] and their colleague reported a significant improvement of pain regarding VAS and function regarding QDASH (quick Disabilities of the Arm, Shoulder and Hand) score in patients with mild-moderate carpal tunnel syndrome who received single-dose injection of PRP and throughout 3 months of follow-up post-injection compared to baseline parameters.
There was a significant improvement of median nerve peak sensory latency and distal motor latency at 6 months post-injection compared to the baseline in the 1st and 2nd groups of patients compared to their baseline parameters.
This comes in agreement with Yung-Tsan et al. [16] and Zheng et al. [4] and their teams as they revealed a similar results, and they reported the gradual sustained improvement of electrophysiological parameters regarding median nerve peak sensory latency and distal motor latency in patients with mild-moderate CTS at 6 months post-injection with platelet-rich plasma and explain that by the role of PRP in facilitation of Schwann cell proliferation, production of neurotrophic, and nerve growth factors with subsequent improvement of nerve electrophysiological parameters.
In accordance to our results, Piskin et al. [17] reported that PRP has not a role in axonal regeneration of peripheral nerve healing, and its role limited to regeneration of Table 2 Visual analogue scale, Boston questionnaire of CTS and electrophysiological parameters of median nerve in the first group of patients at 6 months post-injection compared to baseline parameters Group  There is significant improvement of pain, function, and electrophysiological parameters regarding median peak sensory and distal motor latency at 6 months post-injection M mean, SD standard deviation, VAS visual analogue scale Table 3 Visual analogue scale, Boston questionnaire of CTS and electrophysiological parameters of median nerve in the second group of patients at 6 months post-surgery compared to baseline parameters   There is significant improvement of pain and insignificant improvement of function and electrophysiological parameters regarding median peak sensory and distal motor latency at 6 months post-medication M mean, SD standard deviation, VAS visual analogue scale There were insignificant differences between the three groups before intervention and significant statically differences of pain and function and electrophysiological parameters at 6 months post intervention by comparing both first and second groups with the third group while the first and second groups were comparable LSD least significant difference = mean, SD standard deviation, 0=at baseline, 6= at 6 months post-intervention. VAS Visual Analogue Scale myelin sheath with subsequent improvement of demyelinating neuropathy regarding peak sensory latency and distal motor latency in electrophysiological study such as in cases of mild-moderate CTS. Gerritsen et al. [18] reported the significant improvement of pain and function in patients with mildmoderate CTS after surgery and documented that the optimal way of management of moderate CTS is the standard open carpal tunnel release surgery OCTR that is preferred than other non-surgical lines of treatment regarding lower risk of complications and of added costs.
The present study revealed significant improvement of pain and insignificant improvement of function, median nerve peak sensory latency, and distal motor latency at 6 months post-medical treatment and hand support in the 3rd group of patients compared to the baseline regarding electrophysiological study and Boston questionnaire of CTS.
There was a significant statically improvement of function and electrophysiological parameters of the first and second groups of patients compared to the third group at 6 months post intervention regarding median nerve distal motor, peak sensory latency, symptoms severity index, and functional state of Boston questionnaire of CTS.
In agreement with our results, Uzun et al. [19] reported a significant improvement of pain and function regarding VAS and BCTQ in patients with mildmoderate CTS who receiving PRP injection at 3 months post-treatment compared with patient group receiving steroid injection and medical treatment.
In another line Piazzini et al. [20] reported the efficacy of local and oral steroids, splints, NSAIDs, and diuretic medications in pain relief and improvement of function in patients with mild-moderate CTS.
Finally, O'Connor et al. [21] Carlson et al. [22] reported that non-surgical maneuvers as oral treatment, casting, and steroid injection have short-term relief of CTS symptoms and improvement of function.

Conclusion
Platelet-rich plasma can be considered as a safe, less invasive, and long-lasting alternative to surgery and effective with one shot session compared to medical treatment and hand support in management of patients with mild-moderate carpal tunnel syndrome.