Elektrical Direct Stimulation of Peripheral Nerves to enhance Regeneration - Safety & Feasibility

Despite efforts to enhance peripheral nerve regeneration, there has been little
progress in improving clinical outcomes for patients with a peripheral nerve
lesion. Many different methods were explored in laboratory settings, but until
now, none of these methods were brought to the clinic successfully. Recently, a
method of brief post*surgical low frequency electrical stimulation (ES) of
surgically repaired nerves has been developed. Electrical stimulation was shown
to accelerate axon outgrowth across the repair site and it hastened target
reinnervation. The mechanistic insights and functional impacts of the post*
surgical electrical stimulation have been gained through a large number of
animal studies. Brain*derived neurotrophic factor, cyclic AMP and regeneration*
associated genes play a vital role in expediting the outgrowth of axons across
the injury site. (Gordon 2016)

Electrical stimulation has also been shown to be effective in patients. Until
now, only a few patient series have been published or presented at meetings
that explore the effects of brief electrical stimulation (1 hour 20 Hz) during
or after nerve surgery. (Chan, Curran et al. 2016) These series will be
summarized below.
1. Severe compressive neuropathy: carpal tunnel syndrome. (Gordon 2010)
In a randomized study, 11 patients underwent electrical stimulation of the
median nerve after decompressive surgery. Results were compared to 10 controls.
The stimulation group had significant axonal regeneration 6-8 months after
carpal tunnel operation when the Motor Unit Number Estimation (MUNE, Gooch
2014) increased to 290+/-140 (mean+/-SD) motor units from 150+/-62 motor units
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.
2. Digital nerve repair. (Wong 2015)
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 electrical stimulation 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
(DASH). 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).
3. Peroperative traction injury to the spinal accessory nerve. (Barber 2018)
Shoulder dysfunction is common after neck dissection for head and neck cancer,
resulting from traction injury of the spinal accessory nerve. Adult
participants undergoing neck dissection were recruited. Those in the treatment
group received intraoperative electrical stimulation applied to the spinal
accessory nerve (SAN) after completion of neck dissection, while those in the
control group received no stimulation. The primary outcome measured was the
Constant-Murley Shoulder Score, comparing changes from baseline to 12 months
post-neck dissection. Fifty-four patients were randomized to the treatment or
control group (1:1). Significantly lower shoulder scores were observed in the
ES group at 12 months, indicating better preservation of shoulder function (p*=*
0.007). Only four patients in the ES group compared to 17 patients in the
control groups had a relevant decrease in shoulder function post-operatively (p*
=*0.023). It was concluded that peroperative stimulation had a positive effect
of nerve recovery after stretch lesions.
4. Severe compressive neuropathy: ulnar nerve compression. (Morhart 2018, Power
2019)
In a study regarding decompressive surgery of the ulnar nerve 24 patients were
enrolled to receive post-operative electrical stimulation or sham stimulation.
The presented cohort comprised of 16 patient who received stimulation and 8
controls. Patients were followed 3 years after surgery. In the patients
receiving electrical stimulation MUNE detected a larger number of motor units
in the hypothenar muscle compared with controls (+/- 180 vs 90 respectively).
It was concluded that ES stimulates nerve recovery after decompressive surgery.
5. Nerve transfer to restore biceps function. (Morhart 2018)
Nerve transfer from a fascicle of the ulnar nerve to the musculocutaneous nerve
(Oberlin*s procedure) is applied in patients who have biceps muscle paralysis
following a nerve traction injury. This procedure reliably results in biceps
muscle recovery estimated at Medical Research Council (MRC) grade 4/4+, a
semi-quantitative scale ranging from 0 to 5. The presented cohort included 9
patients who received post-operative stimulation and 9 controls. The median MRC
score was 5 in the stimulation group versus MRC 4+ in the control group. The
quantitative elbow strength was 12 kg (stimulation group) versus 6 kg (control
group). The Disability of Arm Shoulder Hand questionnaire (DASH) decreased from
60 (pre-operatively) to 40 (stimulation group) versus 50 (control group).

In summary, a limited number of patient series have been presented that
describe the benefits of brief electrical stimulation during or after surgery
in patients with compressive neuropathy, nerve repair, and nerve traction
injury. A number of limitations exist on these series. 1) The number of
patients is small in each of the studies 2) The published or presented series
were reported from a single Canadian research consortium. 3) In patients with
other types of nerve lesions were not investigated yet, for instance patients
in whom surgical repair of larger peripheral nerves or repair of proximal
spinal nerves (brachial plexus) was performed, patients with axonal nerve
injury without surgical intervention, pediatric patients, and patients with
lesions of cranial nerves (other than the spinal accessory nerve). The effects
and safety of peri-operative electrical stimulation in these *new* patient
categories are unknown. It is unsure whether the preliminary results in the
describes studies justify to apply electrical stimulation in patients with
other types of nerve lesions.

Barber, B., H. Seikaly, K. Ming Chan, R. Beaudry, S. Rychlik, J. Olson, M.
Curran, P. Dziegielewski, V. Biron, J. Harris, M. McNeely and D. O'Connell
(2018). "Intraoperative Brief Electrical Stimulation of the Spinal Accessory
Nerve (BEST SPIN) for prevention of shoulder dysfunction after oncologic neck
dissection: a double-blinded, randomized controlled trial." J Otolaryngol Head
Neck Surg 47(1): 7.
Chan, K. M., M. W. Curran and T. Gordon (2016). "The use of brief post-surgical
low frequency electrical stimulation to enhance nerve regeneration in clinical
practice." J Physiol 594(13): 3553-3559.
Gooch, C. L., T. J. Doherty, K. M. Chan, M. B. Bromberg, R. A. Lewis, D. W.
Stashuk, M. J. Berger, M. T. Andary and J. R. Daube (2014). "Motor unit number
estimation: a technology and literature review." Muscle Nerve 50(6): 884-893.
Gordon, T. (2016). "Electrical Stimulation to Enhance Axon Regeneration After
Peripheral Nerve Injuries in Animal Models and Humans." Neurotherapeutics
13(2): 295-310.
Gordon, T., N. Amirjani, D. C. Edwards and K. M. Chan (2010). "Brief
post-surgical electrical stimulation accelerates axon regeneration and muscle
reinnervation without affecting the functional measures in carpal tunnel
syndrome patients." Exp Neurol 223(1): 192-202.
Morhart, M. (2018). Electrical Stimulation in the PNS: What*s New and What
Works? American Society of Peripheral Nerve (ASNP annual conference). Phoenix
AZ.
Power, H.A., Morhart M.J., Olson J.L., Chan K.M. (2019) "Postsurgical
Electrical Stimulation Enhances Recovery Following Surgery for Severe Cubital
Tunnel Syndrome: A Double-Blind Randomized Controlled Trial." Neurosurgery.
2019 [Epub ahead of print]
Wong, J. N., J. L. Olson, M. J. Morhart and K. M. Chan (2015). "Electrical
stimulation enhances sensory recovery: a randomized controlled trial." Ann
Neurol 77(6): 996-1006.

The primary objective of the present study is to explore the safety and
feasibility of electrical stimulation in patients with diverse kinds of nerve
lesions. The secondary objective is to make a reasonable estimation of clinical
effect size, which can then be used for the design of a larger randomized trial
in any of the patient categories.

It concerns a prospective randomized trial that includes patients with nerve
lesions that need to be surgically treated according to current standards of
care. Patients will be randomized to receive brief electrical stimulation of
the affected nerve (during or directly after surgery) or no stimulation.

Brief electrical stimulation will be applied to the proximal nerve that was
repaired or decompressed. This will be applied for one hour, with a frequency
of 20 Hz, the same as in previous studies. In most cases the electrical
stimulation will be applied during surgery. In control patients, there will be
no stimulation. In case of compressive neuropathy, electrical stimulation will
take in the recovery room for one hour using electrodes that can be removed
afterwards. In these patients sham stimulation will be performed depending on
the randomization, to guarantee the blinded study setup.

The risk of an adverse effect is estimated to be virtually zero. From a
theoretical point of view, brief electrical stimulation of a nerve will not
result in adverse effect. In the patient series that were published or
presented, no adverse effects were reported. Electrical stimulation was well
tolerated, and no adverse effects were encountered in the experience of the
Canadian group with other patients that were not reported yet (personal
communication with K.M Chan).
The burden of the patient can be divided in the burden of the electrical
stimulation itself, and the burden of taking part in the thorough
post-operative evaluation.
The burden of the electrical stimulation depends on the nature of the nerve
lesion.
- In case the electrical stimulation is performed during their surgery, the
duration of the surgery may be longer. In most cases the time of the electrical
stimulation (one hour) will be used to perform parts of the surgery where the
relevant nerve is not manipulated in the operative field. In many of the
intended surgical procedures, it is necessary to harvest an autologous sural
nerve graft from the patient*s leg, which usually takes the amount of time that
is necessary to complete the electrical stimulation. In a minority of patients,
it may be necessary to extend the time the patient is under general anesthesia.
- In case the electrical stimulation is applied after the surgery, this will
take place in the recovery room. As a result of the electrical stimulation, the
patient may experience a muscle twitch during the electrical stimulation. The
discomfort of the patient will be measured using a Numerical Rating Scale.
After the stimulation or sham stimulation, the fine wire electrodes that were
inserted during surgery, will be taken out, which probably leads to less
discomfort than taking out an intravenous line.
The postoperative follow-up of included patients is intended as more thorough
than in current clinical practice. The patient is subject to a fixed schedule
of postoperative follow-up (the number of visits will be the same as in current
clinical practice), and during the postoperative visits a larger number of
tests may be applied, either during physical examination (which will probably
not exceed 10 minutes extra time during each visit), either with ancillary
investigation (EMG/MUNE). Additionally, patient will be asked to answer a
questionnaire.
The anticipated benefit for the patients who receive electrical stimulation is
that they experience a better nerve regeneration. As such, this may result in a
qualitatively better recovery or recovery earlier in time of biceps muscle
force, hand function, or facial movement depending on the concerned nerve
lesion and repair.