Postsurgical Electrical Stimulation Enhances Recovery Following Surgery for Severe Cubital Tunnel Syndrome: A Double-Blind Randomized Controlled Trial.

BACKGROUND: Patients with severe cubital tunnel syndrome often have poor functional recovery with conventional surgical treatment. Postsurgical electrical stimulation (PES) has been shown to enhance axonal regeneration in animal and human studies. OBJECTIVE: To determine if PES following surgery for severe cubital tunnel syndrome would result in better outcomes compared to surgery alone. METHODS: Patients with severe cubital tunnel syndrome in this randomized, double-blind, placebo-controlled trial were randomized in a 1:2 ratio to the control or stimulation groups. Control patients received cubital tunnel surgery and sham stimulation, whereas patients in the stimulation group received 1-h of 20 Hz PES following surgery. Patients were assessed by a blinded evaluator annually for 3 yr. The primary outcome was motor unit number estimation (MUNE) and secondary outcomes were grip and key pinch strength and McGowan grade and compound muscle action potential. RESULTS: A total of 31 patients were enrolled: 11 received surgery alone and 20 received surgery and PES. Three years following surgery, MUNE was significantly higher in the PES group (176 ± 23, mean + SE) compared to controls (88 ± 11, P < .05). The mean gain in key pinch strength in the PES group was almost 3 times greater than in the controls (P < .05). Similarly, other functional and physiological outcomes showed significantly greater improvements in the PES group. CONCLUSION: PES enhanced muscle reinnervation and functional recovery following surgery for severe cubital tunnel syndrome. It may be a clinically useful adjunct to surgery for severe ulnar neuropathy, in which functional recovery with conventional treatment is often suboptimal.

Conditioning electrical stimulation promotes functional nerve regeneration.

Peripheral nerve regeneration following injury is often incomplete, resulting in significant personal and socioeconomic costs. Although a conditioning crush lesion prior to surgical nerve transection and repair greatly promotes nerve regeneration and functional recovery, feasibility and ethical considerations have hindered its clinical applicability. In a recent proof of principle study, we demonstrated that conditioning electrical stimulation (CES) had effects on early nerve regeneration, similar to that seen in conditioning crush lesions (CCL). To convincingly determine its clinical utility, establishing the effects of CES on target reinnervation and functional outcomes is of utmost importance. In this study, we found that CES improved nerve regeneration and reinnervation well beyond that of CCL. Specifically, compared to CCL, CES resulted in greater intraepidermal skin and NMJ reinnervation, and greater physiological and functional recovery including mechanosensation, compound muscle action potential on nerve conduction studies, normalization of gait pattern, and motor performance on the horizontal ladder test. These findings have direct clinical relevance as CES could be delivered at the bedside before scheduled nerve surgery.

Acetyl-L-Carnitine to Enhance Nerve Regeneration in Carpal Tunnel Syndrome: A Double-Blind, Randomized, Controlled Trial.

BACKGROUND: Carpal tunnel syndrome is very common. Although surgery is effective in mild and moderate cases, recovery is often incomplete in severe cases. Therefore, adjuvant therapy to improve nerve regeneration in those patients is much needed. Acetyl-L-carnitine has been shown to be effective in other neuropathies. The goal of this study is to test the hypothesis that acetyl-L-carnitine can promote nerve regeneration and improve function in patients with severe carpal tunnel syndrome. METHODS: In this proof-of-principle, double-blind, randomized, placebo-controlled trial, adults with severe carpal tunnel syndrome were randomized to receive 3000 mg/day of acetyl-L-carnitine orally or placebo following carpal tunnel release surgery for 2 months. Outcomes were assessed at baseline and at 3, 6, and 12 months postoperatively. Symptom severity and functional outcomes were assessed using the Boston Carpal Tunnel Questionnaire and a wide range of physiologic and functional outcome measures. Patient safety was monitored by physical examination, blood work, and serum drug levels. The outcomes were analyzed using repeated measure two-way analysis of variance. RESULTS: Twenty patients with similar baseline characteristics were assigned randomly to the treatment or placebo group in a 1:1 ratio. Sixty percent were women with a mean age ± SD of 59 ± 2. The treatment was safe with no major adverse events reported. Although patients in both groups showed improvements postoperatively, there was no significant difference in any of the outcome measures between the groups. CONCLUSION: Although acetyl-L-carnitine was well tolerated, it did not improve nerve regeneration or functional recovery in patients with severe carpal tunnel syndrome. CLINICAL QUESTION/LEVEL OF EVIDENCE: Therapeutic, II.

Acetyl-L-carnitine (ALCAR) to enhance nerve regeneration in carpal tunnel syndrome: study protocol for a randomized, placebo-controlled trial.

BACKGROUND: Carpal tunnel syndrome (CTS) is the most common form of peripheral nerve injury, affecting approximately 3 % of the population. While surgery is effective in mild and moderate cases, nerve and functional recovery are often not complete in severe cases. Therefore, there is a need for adjuvant methods to improve nerve regeneration in those cases. Acetyl-L-carnitine (ALCAR) is involved in lipid transport, vital for mitochondrial function. Although it has been shown to be effective in various forms of neuropathies, it has not been used in traumatic or compressive peripheral nerve injury. METHODS: In this pilot study we will utilize a double-blind, randomized, placebo-controlled design. Inclusion criteria will include adult patients with severe CTS. This will be confirmed by nerve conduction studies and motor unit number estimation (MUNE). Only those with severe motor unit loss in the thenar muscles (2 standard deviations [SD] below the mean for the age group) will be included. Eligible patients will be randomized to receive 3,000 mg/day of ALCAR orally or placebo following carpal tunnel release surgery for 2 months. The primary outcome will be MUNE with supplementary secondary outcome measures that include: 1) two-point discrimination; 2) Semmes-Weinstein monofilaments for pressure sensitivity; 3) cold and pain threshold for small fiber function; 4) Boston self-assessment Carpal Tunnel Questionnaire and 5) Disabilities of the Arm, Shoulder and Hand (DASH) questionnaire for symptom severity; and 6) Purdue Pegboard Test for hand functional performance. To follow post treatment recovery and monitor safety, patients will be seen at 3 months, 6 months and 1 year. The outcome measures will be analyzed using two-way ANOVA, with treatment assignment and time points being the independent factors. If significant associations are detected, a post hoc analysis will be completed. We aim to recruit ten patients into each of the two groups. Data from this pilot will provide the basis for power calculation for a full-scale trial. DISCUSSION: ALCAR is a physiologic peptide crucial for fatty acid transport. ALCAR has been shown to be effective in neuroprotection in the central nervous system and increase peripheral nerve regeneration. This has been applied clinically to various systemic peripheral neuropathies including diabetic neuropathy, antiretroviral toxic neuropathy, and chemotherapy-induced peripheral neuropathy. While animal evidence exists for the benefit of ALCAR in compression neuropathy, there have been no human studies to date. This trial will represent the first use of ALCAR in peripheral nerve injury/compression neuropathy. TRIAL REGISTRATION: NCT02141035 ; 20 April 2015.

Intraoperative brief electrical stimulation (BES) for prevention of shoulder dysfunction after oncologic neck dissection: study protocol for a randomized controlled trial.

BACKGROUND: Shoulder pain and dysfunction are common after oncologic neck dissection for head and neck cancer (HNC), due to traction, compression, and devascularization injuries to the spinal accessory nerve (SAN). Shoulder pain and dysfunction can hinder postoperative rehabilitation and hygiene, activities of daily living (ADLs), and return to work after treatment for HNC. Due to the rising incidence of human papillomavirus (HPV)-associated oropharyngeal cancer, patients are often diagnosed in the third or fourth decade of life, leaving many potential working years lost if shoulder dysfunction occurs. Brief electrical stimulation (BES) is a novel technique that has been shown to enhance and accelerate neuronal regeneration after injury through a brain-derived neurotrophic growth factor (BDNF)-driven molecular pathway in multiple peripheral nerves in both humans and animals. METHODS/DESIGN: This is a randomized controlled trial testing the effect of intraoperative BES on postoperative shoulder pain and dysfunction. All adult participants with a new diagnosis of HNC undergoing surgery with neck dissection, including Level IIb and postoperative radiotherapy, will be enrolled. Participants will undergo intraoperative BES after completion of neck dissection for 60 min continuously at 20 Hz, 3 to 5 V, in 100-msec pulses. Postoperatively, participants will be evaluated using the Constant-Murley Shoulder Score, a scale that assesses shoulder pain, ADLs, strength, and range of motion. Secondary outcomes measured will include nerve conduction studies (NCS) and electromyographic (EMG) studies, as well as scores on the Oxford Shoulder Score (OSS), the Neck Dissection Impairment Index (NDII), and the University of Washington Quality of Life (UW-QOL) score. Primary and secondary outcomes will be assessed at 6 weeks, 3 months, 6 months, and 12 months. DISCUSSION: The objective of this study is to evaluate the effect of BES on postoperative clinical and objective shoulder functional outcomes and pain after oncologic neck dissection. BES has been shown to be successful in accelerating peripheral nerve regeneration in both animal and human participants in multiple different peripheral nerves. If successful, this technique may provide an adjunctive prevention option for shoulder pain and dysfunction in HNC patients. TRIAL REGISTRATION: NCT02268344: 17 October 2014.

Electrical stimulation enhances sensory recovery: a randomized controlled trial.

OBJECTIVE: Brief postsurgical electrical stimulation (ES) has been shown to enhance peripheral nerve regeneration in animal models following axotomy and crush injury. However, whether this treatment is beneficial in humans with sensory nerve injury has not been tested. The goal of this study was to test the hypothesis that ES would enhance sensory nerve regeneration following digital nerve transection compared to surgery alone. METHODS: Patients with complete digital nerve transection underwent epineurial nerve repair. After coaptation of the severed nerve ends, fine wire electrodes were implanted before skin closure. Postoperatively, patients were randomized to receiving either 1 hour of 20Hz continuous ES or sham stimulation in a double-blinded manner. Patients were followed monthly for 6 months by a blinded evaluator to monitor physiological recovery of spatial discrimination, pressure threshold, and quantitative small fiber sensory testing. Functional disability was measured using the Disability of Arm, Shoulder, and Hand questionnaire. RESULTS: A total of 36 patients were recruited, with 18 in each group. Those in the ES group showed consistently greater improvements in all sensory modalities by 5 to 6 months postoperatively compared to the controls. Although there was a trend of greater functional improvements in the ES group, it was not statistically significant (p > 0.01). INTERPRETATION: Postsurgical ES enhanced sensory reinnervation in patients who sustained complete digital nerve transection. The conferred benefits apply to a wide range of sensory functions.

Functional electrical stimulation and spinal cord injury.

Spinal cord injuries (SCI) can disrupt communications between the brain and the body, resulting in loss of control over otherwise intact neuromuscular systems. Functional electrical stimulation (FES) of the central and peripheral nervous system can use these intact neuromuscular systems to provide therapeutic exercise options to allow functional restoration and to manage medical complications following SCI. The use of FES for the restoration of muscular and organ functions may significantly decrease the morbidity and mortality following SCI. Many FES devices are commercially available and should be considered as part of the lifelong rehabilitation care plan for all eligible persons with SCI.

Novel targeted sensory reinnervation technique to restore functional hand sensation after transhumeral amputation.

We present a case study of a novel variation of the targeted sensory reinnervation technique that provides additional control over sensory restoration after transhumeral amputation. The use of intraoperative somatosensory evoked potentials on individual fascicles of the median and ulnar nerves allowed us to specifically target sensory fascicles to reroute to target cutaneous nerves at a distance away from anticipated motor sites in a transhumeral amputee. This resulted in restored hand maps of the median and ulnar nerve in discrete spatially separated areas. In addition, the subject was able to use native and reinnervated muscle sites to control a robotic arm while simultaneously sensing touch and force feedback from the robotic gripper in a physiologically correct manner. This proof of principle study is the first to demonstrate the ability to have simultaneous dual flow of information (motor and sensory) within the residual limb. In working towards clinical deployment of a sensory integrated prosthetic device, this surgical method addresses the important issue of restoring a usable access point to provide natural hand sensation after upper limb amputation.

Brief post-surgical electrical stimulation accelerates axon regeneration and muscle reinnervation without affecting the functional measures in carpal tunnel syndrome patients.

Electrical stimulation (ES) of injured peripheral nerves accelerates axonal regeneration in laboratory animals. However, clinical applicability of this intervention has never been investigated in human subjects. The aim of this pilot study was to determine the effect of ES on axonal regeneration after surgery in patients with median nerve compression in the carpal tunnel causing marked motor axonal loss. A randomized control trial was conducted to provide proof of principle for ES-induced acceleration of axon regeneration in human patients. Carpel tunnel release surgery (CTRS) was performed and in the stimulation group of patients, stainless steel electrode wires placed alongside the median nerve proximal to the surgical decompression site for immediate 1 h 20 Hz bipolar ES. Subjects were followed for a year at regular intervals. Axonal regeneration was quantified using motor unit number estimation (MUNE) and sensory and motor nerve conduction studies. Purdue Pegboard Test, Semmes Weinstein Monofilaments, and Levine's Self-Assessment Questionnaire were used to assess functional recovery. The stimulation group had significant axonal regeneration 6-8 months after the CTRS when the MUNE increased to 290+/-140 (mean+/-SD) motor units (MU) from 150+/-62 MU at baseline (p<0.05). In comparison, MUNE did not significantly improve in the control group (p>0.2). Terminal motor latency significantly accelerated in the stimulation group but not the control group (p>0.1). Sensory nerve conduction values significantly improved in the stimulation group earlier than the controls. Other outcome measures showed a significant improvement in both patient groups. We conclude that brief low frequency ES accelerates axonal regeneration and target reinnervation in humans.

Accelerating axon growth to overcome limitations in functional recovery after peripheral nerve injury.

OBJECTIVE: Injured peripheral nerves regenerate at very slow rates. Therefore, proximal injury sites such as the brachial plexus still present major challenges, and the outcomes of conventional treatments remain poor. This is in part attributable to a progressive decline in the Schwann cells' ability to provide a supportive milieu for the growth cone to extend and to find the appropriate target. These challenges are compounded by the often considerable delay of regeneration across the site of nerve laceration. Recently, low-frequency electrical stimulation (as brief as an hour) has shown promise, as it significantly accelerated regeneration in animal models through speeding of axon growth across the injury site. METHODS: To test whether this might be a useful clinical tool, we carried out a randomized controlled trial in patients who had experienced substantial axonal loss in the median nerve owing to severe compression in the carpal tunnel. To further elucidate the potential mechanisms, we applied rolipram, a cyclic adenosine monophosphate agonist, to rats after axotomy of the femoral nerve. RESULTS: We demonstrated that effects similar to those observed in animal studies could also be attained in humans. The mechanisms of action of electrical stimulation likely operate through up-regulation of neurotrophic factors and cyclic adenosine monophosphate. Indeed, the application of rolipram significantly accelerated nerve regeneration. CONCLUSION: With new mechanistic insights into the influencing factors of peripheral nerve regeneration, the novel treatments described above could form part of an armament of synergistic therapies that could make a meaningful difference to patients with peripheral nerve injuries.

A new means of transcutaneous coupling for neural prostheses.

Neural prostheses are electronic stimulators that activate nerves to restore sensory or motor functions. Implanted neural prostheses receive command signals and in some cases energy to recharge their batteries through the skin by telemetry. Here, we describe a new approach that eliminates the implanted stimulator. Stimulus pulse trains are passed between two surface electrodes placed on the skin. An insulated lead with conductive terminals at each end is implanted inside the body. One terminal is located under the cathodal surface electrode and the other is attached to a nerve targeted for stimulation. A fraction (10%-15%) of the current flowing between the surface electrodes is routed through the implanted lead. The nerve is stimulated when the amount of routed current is sufficient. The aims of this study were to establish some basic electrical properties of the system and test long-term stability in chronic implants. Stimulation of the nerve innervating the ankle flexors produced graded force over the full physiological range at amplitudes below threshold for evoking muscle contractions under the surface electrodes. Implants remained stable for over 8 mo. The findings provide the basis for a new family of neural prostheses.

BIONic WalkAide for correcting foot drop.

The goal of this study was to test the feasibility and efficacy of using microstimulators (BIONs) to correct foot drop, the first human application of BIONs in functional electrical stimulation (FES). A prototype BIONic foot drop stimulator was developed by modifying a WalkAide2 stimulator to control BION stimulation of the ankle dorsiflexor muscles. BION stimulation was compared with surface stimulation of the common peroneal nerve provided by a normal WalkAide2 foot drop stimulator. Compared to surface stimulation, we found that BION stimulation of the deep peroneal nerve produces a more balanced ankle flexion movement without everting the foot. A three-dimensional motion analysis was performed to measure the ankle and foot kinematics with and without stimulation. Without stimulation, the toe on the affected leg drags across the ground. The BIONic WalkAide elevates the foot such that the toe clears the ground by 3 cm, which is equivalent to the toe clearance in the unaffected leg. The physiological cost index (PCI) was used to measure effort during walking. The PCI is high without stimulation (2.29 +/- 0.37; mean +/- S.D.) and greatly reduced with surface (1.29 +/- 0.10) and BION stimulation (1.46 +/- 0.24). Also, walking speed is increased from 9.4 +/- 0.4 m/min without stimulation to 19.6 +/- 2.0 m/min with surface and 17.8 +/- 0.7 m/min with BION stimulation. We conclude that functional electrical stimulation with BIONs is a practical alternative to surface stimulation and provides more selective control of muscle activation.

Double-blind randomized controlled trial of low-level laser therapy in carpal tunnel syndrome.

Several studies have suggested that low-level laser therapy (LLLT) is effective in patients with carpal tunnel syndrome (CTS). In a double-blind randomized controlled trial of LLLT, 15 CTS patients, 34 to 67 years of age, were randomly assigned to either the control group (n = 8) or treatment group (n =7). Both groups were treated three times per week for 5 weeks. Those in the treatment group received 860 nm galium/aluminum/arsenide laser at a dosage of 6 J/cm2 over the carpal tunnel, whereas those in the control group were treated with sham laser. The primary outcome measure was the Levine Carpal Tunnel Syndrome Questionnaire, and the secondary outcome measures were electrophysiological data and the Purdue pegboard test. All patients completed the study without adverse effects. There was a significant symptomatic improvement in both the control (P = 0.034) and treatment (P =0.043) groups. However, there was no significant difference in any of the outcome measures between the two groups. Thus, LLLT is no more effective in the reduction of symptoms of CTS than is sham treatment.