Functional Electrical Stimulation and Neuromuscular Electrical Stimulation

Number: 0677

Policy
Applicable CPT / HCPCS / ICD-10 Codes
Background
References

Policy

Scope of Policy

This Clinical Policy Bulletin addresses functional electrical stimulation and neuromuscular electrical stimulation.

Medical Necessity

Aetna considers the following interventions medically necessary:
1. Functional electrical stimulation (FES) (e.g., Parastep I System) as durable medical equipment (DME) to enable members with spinal cord injury (SCI) to ambulate when all of the following criteria are met:
  1. Member has intact lower motor units (L1 and below) (both muscle and peripheral nerve); and
  2. Member has joint stability to bear weight on upper and lower extremities, and has balance and control to maintain an upright posture independently; and
  3. Member demonstrated brisk muscle contraction to neuromuscular electrical stimulation and has sensory perception of electrical stimulation sufficient for muscle contraction; and
  4. Member has the cognitive ability to use such devices for walking and is highly motivated to use the device long term; and
  5. Member can transfer independently and stand for at least 3 minutes; and
  6. Member possesses hand and finger function to manipulate the controls; and
  7. Member is at least 6 months post recovery of spinal cord injury and restorative surgery; and
  8. Member does not have hip and knee degenerative disease and has no history of long bone fracture secondary to osteoporosis; and
  9. The member has successfully completed a training program, which consists of at least 32 physical therapy sessions with the device over a 3-month period; and
  10. The member has none of the following contraindications. Functional electrical stimulation for walking (Parastep I System) is spectifically contraindicated and has no proven value for members with SCI with any of the following:
    1. Members with cardiac pacemakers; or
    2. Members with severe scoliosis or severe osteoporosis; or
    3. Members with skin disease or cancer at area of stimulation; or
    4. Members with irreversible contracture; or
    5. Members with autonomic dysreflexia.
  Aetna considers replacement of a FES for walking medically necessary if the original FES met criteria as medically necessary and is no longer under warranty and cannot be repaired.
  
  Note: These criteria are adapted from the Food and Drug Administration (FDA) labeling for Parastep I System as well as information provided in published studies.
2. Neuromuscular electrical stimulators (NMES) as DME for disuse atrophy where the nerve supply to the muscle is intact and the member has any of the following non-neurological reasons for disuse atrophy:
  1. Contractures due to burn scarring, or
  2. Major knee surgery (e.g., total knee replacement) when there is failure to respond to physical therapy, or
  3. Previous casting or splinting of a limb (arm or leg) when there is failure to respond to physical therapy, or
  4. Recent hip replacement surgery before physical therapy begins (NMES is considered medically necessary until physical therapy begins).
  NMES are specifically contraindicated and considered unproven in persons with cardiac pacemakers.
  
  Note: More than 2 hours of NMES per day is considered not medically necessary; protocols reported in the literature recommend no more than 2 hours of NMES treatment within a 24-hour period.
3. A form-fitting conductive garment as DME only when it has been approved for marketing by the FDA, has been prescribed by a physician for use in delivering NMES that is considered medically necessary, and any of the following criteria is met:
  1. The member can not manage without the conductive garment due to the large area or the large number of sites to be stimulated, and the stimulation would have to be delivered so frequently that it is not feasible to use conventional electrodes, adhesive tapes, and lead wires; or
  2. The member has a skin problem or other medical conditions that precludes the application of conventional electrodes, adhesive tapes, and lead wires; or
  3. The member requires electrical stimulation beneath a cast to treat disuse atrophy, where the nerve supply to the muscle is intact; or
  4. The member has a medical need for rehabilitation strengthening following an injury where the nerve supply to the muscle is intact.
  NMES devices that incorporate a form-fitting conductive garment (e.g., Empi Phoenix, KneeHab devices) are considered medically necessary where the criteria for both NMES and a form-fitting conductive garment are met. Note: Devices that incorporate NMES via a form fitting-conductive garment into a knee brace (e.g., QB1) must also meet medical necessity criteria for knee braces.
  
  Aetna considers form-fitting conductive garments experimental and investigational for all other indications because its effectiveness for indications other than the ones listed above has not been established.
4. Diaphragmatic/phrenic pacing (e.g., the Mark IV™ Breathing Pacemaker System, NeuRx DPS Diaphragm Pacing System, and the NeuRx DPS RA/4 Respiratory Stimulation System) for the following indications:
  1. For improvement of ventilatory function in stable, non-acute members with SCI when all of the following criteria are met:
    1. Member has high quadriplegia at or above C-3; and
    2. There are viable phrenic nerves; and
    3. Member's diaphragm and lung function are adequate; and
    4. Diaphragmatic pacing will allow the individual to breathe without the assistance of a mechanical ventilator for at least four continuous hours a day;
  2. For the treatment of central alveolar hypoventilation when all of the following criteria are met:
    1. Age of 18 years and older; and
    2. Have intact phrenic nerve function; and
    3. Have diaphragm movement with stimulation;
  3. For individuals with amyotrophic lateral sclerosis who meet the following criteria:
    1. Age of 21 years old or older; and
    2. Experiencing chronic hypoventilation; and
    3. Have intact phrenic nerve function; and
    4. Have diaphragm movement with stimulation; and
    5. Diaphragmatic pacing is used as an alternative to mechanical ventilation.
  Aetna considers replacement of a diaphragmatic/phrenic stimulation system medically necessary if the original diaphragmatic/phrenic stimulation system met criteria as medically necessary and is no longer under warranty and cannot be repaired.
5. Electrical stimulation of the sacral anterior roots (by means of an implanted stimulator, the Vocare Bladder System) in conjunction with a posterior rhizotomy for members who have clinically complete spinal cord lesions (American Spinal Injury Association Classification) with intact parasympathetic innervation of the bladder and who are skeletally mature and neurologically stable, to provide urination on demand and to reduce post-void residual volumes of urine. The following selection criteria must be met:
  1. 3 months (female members) after or 9 months (male members) after complete supra-sacral spinal cord injury; and
  2. A phasic detrusor pressure rise of 35 mm H2O (female members) or 50 cm H2O (male members) on cystometry; and
  3. Presence of 3 of the 4 non-vesical sacral segment reflexes (i.e., ankle jerks, bulbo-cavernous reflex, anal skin reflex, and reflex erection).
  Aetna considers electrical stimulation of the sacral anterior roots in conjunction with posterior rhizotomy (Vocare Blader System) experimental and investigational for all other indications because its effectiveness for indications other than the ones listed above has not been established.
  
  Note: The Vocare Bladder System, also known as the implantable Finetech-Brindley stimulator, is different from the InterStim device (sacral nerve neuromodulation. The Vocare Bladder System is patient-activated and is designed to elicit functional contraction of the innervated muscles. Implantation of the Vocare device is frequently performed in conjunction with a dorsal rhizotomy. The rhizotomy results in an areflexive bladder, limiting incontinence and autonomic hyperreflexia.
6. Phrenic nerve stimulation (e.g., the Remede System) for the treatment of adults with moderate-to-severe central sleep apnea who have failed supplemental oxygen therapy, pharmacotherapy (e.g., acetazolamide or theophylline), and masked-based therapies (e.g., bi-level positive airway pressure or continuous positive airway pressure).
Experimental and Investigational

Aetna considers the following interventions experimental and investigational because the effectiveness of these approaches has not been established:
1. FES of the upper extremities (e.g., NESS H200 Handmaster NMS1 System) for all indications, including improvement of muscle strength, reduction of spasticity and atrophy, and facilitation of functional motor movement due to any of the following conditions:
  1. Spinal cord injury; or
  2. Stroke (cerebrovascular accident/CVA); or
  3. Traumatic brain injury; or
  4. Other upper motor neuron disorders (e.g., Parkinson's disease);
2. FES and NMES experimental and investigational for all other indications, including any of the following for indications other than the ones listed above as medically necessary:
  1. Bell's palsy; or
  2. Cardiac conditioning; or
  3. Cerebral palsy; or
  4. Chronic obstructive pulmonary disease; or
  5. Congestive heart failure; or
  6. Erectile dysfunction, or
  7. Foot drop in cerebral palsy, stroke, and for all other indications; or
  8. General muscle strengthening in healthy individuals; or
  9. Improving ambulatory function and muscle strength for progressive diseases (e.g., cancer, chronic heart failure, chronic obstructive pulmonary disease, multiple sclerosis) in persons without spinal cord injury; or
  10. Improvement of functional capacity and quality of life after cardiac surgery; or
  11. Masseter muscle oral dysfunction after stroke: or
  12. Muscle atrophy after stroke; or
  13. Pain caused by necrosis of the femoral head; or
  14. Treatment of denervated muscles; or
  15. Treatment of knee osteoarthritis; or
  16. Upper extremity hemiplegia;
3. Wearable NMES device (e.g., geko T-3 and geko W-3 devices) for enhancement of blood circulation/microcirculation, reduction of edema, and prevention of venous thrombosis in the lower limb with venous insufficiency and/or ischemia because of insufficient evidence;
4. Diaphragmatic/phrenic pacing for all other indications, including for improved outcomes in lung transplant recipients, use in individuals whose phrenic nerve, lung or diaphragm function are not sufficient to achieve adequate diaphragm movement from the electrical stimulation;
5. Sacral nerve stimulation for the treatment of chronic constipation;
6. Transurethral electrical stimulation for the management of neurogenic bladder dysfunction and all other indications;
7. Peroneal nerve stimulators (e.g., the ODFS Dropped Foot Stimulator (Odstock), the WalkAide device, the NESS L300 Foot Drop System, and the NESS L300 Plus) for persons with foot drop in cerebral palsy, multiple sclerosis, traumatic brain injury, stroke or an incomplete spinal cord injury and for all other indications because of insufficient evidence to support their use;
8. Threshold (or therapeutic) electrical stimulation for the management of knee osteoarthritis, cerebral palsy and other motor disorders;
9. NMES for the treatment of dysphagia including, but not limited to, Guardian dysphagia dual chamber unit and VitalStim Therapy devices, patella-femoral pain syndrome, and septic shock;
10. Sequential units, including, but not limited to, RS-4i devices;
  There is a lack of reliable evidence that devices that combine NMES sequentially with interferential stimulation (RS-4i) result in better outcomes than other NMES devices.
11. EMG-triggered NMES, including, but not limited to, Care ETS device;
12. AxioBionics Wearable Therapy NMES for hemiplegia;
13. Neuromuscular stimulation (Electronic Shock Unit) for femoral nerve palsy;
14. The Cala Trio nerve stimulating device for the treatment of essential tremors;
15. Implanted functional electrical stimulation for improvement of gait performance in stroke survivors.
Note: The American Spinal Injury Association (ASIA) Impairment Scale is described in the background section below.
Policy Limitations and Exclusions

Aetna considers the FES exercise devices such as the FES Power Trainer, ERGYS, REGYS, NeuroEDUCATOR, STimMaster Galaxy, RT200 Elliptical, RT300 FES Cycle Ergometer (also referred to as a FES bicycle), RT600 Step and Stand Rehabilitation Therapy System, and SpectraSTIM to be exercise equipment. Most Aetna plans exclude coverage of exercise equipment; please check benefit plan descriptions for details. In addition, these stationary exercise devices are considered experimental and investigational to prevent or reduce muscle atrophy in upper and lower extremities in individuals with hemiplegia or quadriplegia and for all other indications.
Related Policies

Table:
CPT Codes / HCPCS Codes / ICD-10 Codes
Code	Code Description
*Functional Electrical Stimulation (FES) for spinal cord injury (e.g., Parastep I System)*:
CPT codes covered if selection criteria are met:
63655	Laminectomy for implantation of neurostimulator electrodes, plate/paddle, epidural
63685	Insertion or replacement of spinal neurostimulator pulse generator or receiver, direct or inductive coupling
64555	Percutaneous implantation of neurostimulator electrodes; peripheral nerve (excludes sacral nerve)
64575	Incision for implantation of neurostimulator electrodes; peripheral nerve (excludes sacral nerve)
64585	Revision or removal of peripheral neurostimulator electrodes
64590	Insertion or replacement of peripheral or gastric neurostimulator pulse generator or receiver, direct or inductive coupling
64595	Revision or removal of peripheral or gastric neurostimulator pulse generator or receiver
Other CPT codes related to the CPB:
33016 – 33999	Heart and pericardium
HCPCS codes covered if selection criteria are met:
A4556	Electrodes (e.g., apnea monitor), per pair
A4557	Lead wires (e.g., apnea monitor), per pair
A4558	Conductive gel or paste, for use with electrical device (e.g., TENS, NMES), per oz.
A4595	Electrical stimulator supplies, 2 lead, per month, (e.g. TENS, NMES)
E0731	Form-fitting conductive garment for delivery of TENS or NMES (with conductive fibers separated from the patient's skin by layers of fabric)
E0745	Neuromuscular stimulator, electronic shock unit
E0762	Transcutaneous electrical joint stimulation device system, includes all accessories
E0764	Functional neuromuscular stimulator, transcutaneous stimulation of muscles of ambulation with computer control, used for walking by spinal cord injured, entire system, after completion of training program
E0770	Functional electrical stimulator, transcutaneous stimulation of nerve and / or muscle groups, any type, complete system, not otherwise specified
L8680	Implantable neurostimulator electrode, each
L8681	Patient programmer (external) for use with implantable programmable neurostimulator pulse generator
L8682	Implantable neurostimulator radiofrequency receiver
L8683	Radiofrequency transmitter (external) for use with implantable neurostimulator radiofrequency receiver
L8685	Implantable neurostimulator pulse generator, single array, rechargeable, includes extension
L8686	Implantable neurostimulator pulse generator, single array, non-rechargeable, includes extension
L8687	Implantable neurostimulator pulse generator, dual array, rechargeable, includes extension
L8688	Implantable neurostimulator pulse generator, dual array, non-rechargeable, includes extension
L8689	External recharging system for battery (internal) for use with implantable neurostimulator
ICD-10 codes covered if selection criteria are met:
S12.000+ - S12.691+ S12.9xx+ S22.000+ - S22.089+ S32.000+ - S32.2xx+	Fracture of vertebral column with spinal cord injury [not covered for FES of upper extremities]
Numerous options	Spinal cord injury, sequelae [not covered for FES of upper extremities]
S14.0xx+ - S14.159+ S24.0xx+ - S24.159+ S34.01x+ - S34.129+	Spinal cord injury without evidence of spinal bone injury (cervical, thoracic, lumbar) [not covered for FES of upper extremities]
ICD-10 codes not covered for indications listed in the CPB:
C00.0 - C95.92	Malignant neoplasms
G12.20 - G12.9	Motor neuron disease
G20 - G21.9	Parkinson's disease
G35	Multiple sclerosis
G45.0 - G45.2 G45.8 - G46.2 I63.00 - I66.9 I67.89	Occlusion and stenosis of precerebral arteries, occlusion of cerebral arteries, transient cerebral ischemia, and acute, but ill-defined cerebrovascular disease
G47.31	Primary central sleep apnea
G51.0	Bell's palsy (facial palsy) [also not covered for FES of lower extremities]
G56.00 - G56.92 G58.0 - G58.7	Mononeuropathies of upper limb and other mononeuropathies
G71.00 - G72.9 G73.7	Muscular dystrophies and other myopathies
G80.0 - G80.9	Cerebral palsy [also not covered for FES of lower extremities]
I50.1 - I50.9	Heart failure [chronic]
I69.031 - I69.069	Sequelae of cerebrovascular disease, hemiplegia/hemiparesis, monoplegia, or other paralytic syndrome
I69.392	Facial weakness following cerebral infarction [masseter muscle oral dysfunction after stroke]
J40 - J47.9	Chronic lower respiratory diseases
M17.0 - M17.9	Osteoarthritis of knee
M21.371 - M21.379	Foot drop (acquired)
M25.551 - M25.559	Pain in hip [pain caused by necrosis of the femoral head]
M62.50 - M62.59, M62.5A0, M62.5A1, M62.5A2, M62.5A9	Muscle wasting and atrophy, not elsewhere classified [muscle atrophy after stroke]
M87.050 - M87.059	Idiopathic aseptic necrosis of pelvis and femur [pain caused by necrosis of the femoral head]
N52.01 - N52.9	Male erectile dysfunction
P11.3	Birth injury to facial nerve [Facial nerve palsy]
S04.011s - S04.899s	Injury to cranial nerve [traumatic brain injury], sequelae
S06.0X0A - S06.A1XS, S06.0XAA - S06.9XAS	Intracranial injury [traumatic brain injury]
Z48.812	Encounter for surgical aftercare following surgery on the circulatory system
*Neuromuscular Electrical Stimulators (NMES)*:
CPT codes covered if selection criteria are met:
64550	Application of surface (transcutaneous) neurostimulator
64565	Percutaneous implantation of neurostimulator electrodes; neuromuscular
64580	Incision for implantation of neurostimulator electrodes; neuromuscular
Other CPT codes related to the CPB:
33016 – 33999	Heart and pericardium
63190	Laminectomy with rhizotomy; more than two segments
97010 - 97763	Physical Medicine and Rehabilitation
HCPCS codes covered if selection criteria are met:
A4556	Electrodes (e.g., apnea monitor), per pair
A4557	Lead wires (e.g., apnea monitor), per pair
A4558	Conductive gel or paste, for use with electrical device (e.g., TENS, NMES), per oz.
A4595	Electrical stimulator supplies, 2 lead, per month, (e.g. TENS, NMES)
E0731	Form fitting conductive garment for delivery of tens or nmes (with conductive fibers separated from the patient's skin by layers of fabric)
E0745	Neuromuscular stimulator, electronic shock unit
L8680	Implantable neurostimulator electrode, each
L8681	Patient programmer (external) for use with implantable programmable neurostimulator pulse generator
L8682	Implantable neurostimulator radiofrequency receiver
L8683	Radiofrequency transmitter (external) for use with implantable neurostimulator radiofrequency receiver
L8685	Implantable neurostimulator pulse generator, single array, rechargeable, includes extension
L8686	Implantable neurostimulator pulse generator, single array, non-rechargeable, includes extension
L8687	Implantable neurostimulator pulse generator, dual array, rechargeable, includes extension
L8688	Implantable neurostimulator pulse generator, dual array, non-rechargeable, includes extension
L8689	External recharging system for battery (internal) for use with implantable neurostimulator
HCPCS codes not covered for indications listed in the CPB :
AxioBionics Wearable Therapy - no specific code:
ICD-10 codes covered if selection criteria are met:
G71.8, M62.50 - M62.59, M62.5A0 - M62.5A9, M62.84. M79.7	Muscular wasting and disuse atrophy, not elsewhere classified [see criteria] [not covered for muscle atrophy after stroke]
ICD-10 codes not covered for indications listed in the CPB (for FES or NMES):
C00.0 - C95.92	Malignant neoplasms
G35	Multiple sclerosis
G47.31	Primary central sleep apnea
G51.0	Bell's palsy (facial palsy)
G57.20 - G57.23	Lesion of femoral nerve [femoral nerve palsy]
G80.0 - G80.9	Cerebral palsy [also not covered for FES of lower extremities]
G81.00 - G81.94	Hemiplegia
I50.1, I50.22, I50.32, I50.42, I50.9	Chronic heart failure
I69.051 - I69.059, I69.151 - I69.159, I69.251 - I69.259	Hemiplegia and hemiparesis following nontraumatic subarachnoid/intracerebral/intracranial hemorrhage
I69.351 - I69.359	Hemiplegia and hemiparesis following cerebral infarction
I69.392	Facial weakness following cerebral infarction [masseter muscle oral dysfunction after stroke]
I69.851 - I69.859, I69.951 - I69.959	Hemiplegia and hemiparesis following other and unspecified cerebrovascular disease.
J40 - J47.9	Chronic lower respiratory diseases
M22.2x1 - M22.2x9	Patellofemoral disorders [patella-femoral pain syndrome]
M25.551 - M25.559	Pain in hip [pain caused by necrosis of the femoral head]
M87.050 - M87.059	Idiopathic aseptic necrosis of pelvis and femur [pain caused by necrosis of the femoral head]
R65.12	Severe sepsis with septic shock
P11.3	Birth injury to facial nerve [facial nerve palsy]
R65.12	Severe sepsis with septic shock
T81.12xA - T81.12xS	Postprocedural septic shock
Z48.812	Encounter for surgical aftercare following surgery on the circulatory system
*Form-fitting Conductive Garment*:
HCPCS codes covered if selection criteria are met:
E0731	Form-fitting conductive garment for delivery of TENS or NMES (with conductive fibers separated from the patient's skin by layers of fabric)
ICD-10 codes covered if selection criteria are met:
G71.8, M62.50 - M62.59, M62.5A0 - M62.5A9, M79.7	Muscular wasting and disuse atrophy, not elsewhere classified
Z51.89	Encounter for other specified aftercare
Wearable NMES device (e.g., geko T-3 and geko W-3 devices):
HCPCS codes not covered for indications listed in the CPB:
A4560	Neuromuscular electrical stimulator (nmes), disposable, replacement only
ICD-10 codes not covered for indications listed in the CPB:
I87.2	Venous insufficiency (chronic) (peripheral)
R60.9	Edema, unspecified
Z86.718	Personal history of other venous thrombosis and embolism [lower limb]
*Diaphragmatic/phrenic Pacing*:
CPT codes covered if selection criteria are met:
33277	Insertion of phrenic nerve stimulator transvenous sensing lead (List separately in addition to code for primary procedure)
33278	Removal of phrenic nerve stimulator, including vessel catheterization, all imaging guidance, and interrogation and programming, when performed; system, including pulse generator and lead(s)
33279	transvenous stimulation or sensing lead(s) only
33280	pulse generator only
33281	Repositioning of phrenic nerve stimulator transvenous lead(s)
33287	Removal and replacement of phrenic nerve stimulator, including vessel catheterization, all imaging guidance, and interrogation and programming, when performed; pulse generator
33288	transvenous stimulation or sensing lead(s)
64580	Incision for implantation of neurostimulator electrodes; neuromuscular
93150	Therapy activation of implanted phrenic nerve stimulator system, including all interrogation and programming
93151	Interrogation and programming (minimum one parameter) of implanted phrenic nerve stimulator system
93152	Interrogation and programming of implanted phrenic nerve stimulator system during polysomnography
Other CPT codes related to the CPB:
94660	Continuous positive airway pressure ventilation (CPAP), initiation and management
HCPCS codes covered if selection criteria are met:
E0745	Neuromuscular stimulator, electronic shock unit
L8680	Implantable neurostimulator electrode, each
L8681	Patient programmer (external) for use with implantable programmable neurostimulator pulse generator
L8682	Implantable neurostimulator radiofrequency receiver
L8683	Radiofrequency transmitter (external) for use with implantable neurostimulator radiofrequency receiver
L8685	Implantable neurostimulator pulse generator, single array, rechargeable, includes extension
L8686	Implantable neurostimulator pulse generator, single array, non-rechargeable, includes extension
L8687	Implantable neurostimulator pulse generator, dual array, rechargeable, includes extension
L8688	Implantable neurostimulator pulse generator, dual array, non-rechargeable, includes extension
L8689	External recharging system for battery (internal) for use with implantable neurostimulator
L8696	Antenna (external) for use with implantable diaphragmatic/phrenic nerve stimulation device, replacement, each
Other HCPCS codes related to the CPB:
J1120	Injection, acetazolamide sodium, up to 500 mg
J2810	Injection, theophylline, per 40 mg
ICD-10 codes covered if selection criteria are met:
G12.21	Amyotrophic lateral sclerosis
G47.31	Primary central sleep apnea
G47.34	Idiopathic sleep related nonobstructive alveolar hypoventilation
G47.35	Congenital central alveolar hypoventilation syndrome
G82.51 - G82.52	Quadriplegia C1-C4 complete/incomplete
S12.000+ - S12.391+	Fracture of vertebral column with spinal cord injury (cervical, C1-C4)
S14.101+ - S14.104+ S14.111+ - S14.114+ S14.121+ - S14.124+ S14.131+ - S14.134+ S14.141+ - S14.144+ S14.151+ - S14.154+	Spinal cord injury without evidence of spinal bone injury (cervical, C1-C4)
Numerous options	Spinal cord injury,sequelae [not covered for FES of upper extremities]
ICD-10 codes not covered for indications listed in the CPB:
Z94.2	Lung transplant status
*Electrical Stimulation of Sacral Anterior Roots*:
CPT codes covered if selection criteria are met:
63185	Laminectomy with rhizotomy; one or two segments
63190	more than two segments
63655	Laminectomy for implantation of neurostimulator electrodes, plate/paddle, epidural
64561	Percutaneous implantation of neurostimulator electrode array; sacral nerve (transforaminal placement) including image guidance, if performed
64581	Incision for implantation of neurostimulator electrode array; sacral nerve (transforaminal placement)
HCPCS codes covered if selection criteria are met:
A4290	Sacral nerve stimulation test lead, each
E0745	Neuromuscular stimulator, electronic shock unit
L8680	Implantable neurostimulator electrode, each
L8681	Patient programmer (external) for use with implantable programmable neurostimulator pulse generator
L8682	Implantable neurostimulator radiofrequency receiver
L8684	Radiofrequency transmitter (external) for use with implantable sacral root neurostimulator receiver for bowel and bladder management, replacement
L8685	Implantable neurostimulator pulse generator, single array, rechargeable, includes extension
L8686	Implantable neurostimulator pulse generator, single array, non-rechargeable, includes extension
L8687	Implantable neurostimulator pulse generator, dual array, rechargeable, includes extension
L8688	Implantable neurostimulator pulse generator, dual array, non-rechargeable, includes extension
L8689	External recharging system for battery (internal) for use with implantable neurostimulator
ICD-10 codes covered if selection criteria are met:
N31.9	Neuromuscular dysfunction of bladder
ICD-10 codes not covered for indications listed in the CPB (not all-inclusive):
K59.00 - K59.09	Constipation [chornic]
*Transurethral electrical stimulation*:
No specific code
ICD-10 codes not covered for indications listed in the CPB (not all-inclusive):
G83.4	Cauda equina syndrome
N31.9	Neuromuscular dysfunction of bladder, unspecified
*Peroneal Nerve Stimulators*:
No specific code
HCPCS codes not covered for indications listed in the CPB :
E0770	Functional electrical stimulator, transcutaneous stimulation of nerve and / or muscle groups, any type, complete system, not otherwise specified
ICD-10 codes not covered for indications listed in the CPB (not all-inclusive):
M21.071 - M21.079 M21.371 - M21.379 M21.6x1- M21.6x9	Other acquired deformities of ankle and foot
*Threshold electrical stimulation*:
HCPCS codes not covered for indications listed in the CPB:
E0745	Neuromuscular stimulator, electronic shock unit
ICD-10 codes not covered for indications listed in the CPB (not all-inclusive):
A52.11	Tabes dorsalis
F51.8	Other sleep disorders not due to a substance or known physiological condition
F95.0 - F95.9	Tic disorder
F98.4	Stereotyped movement disorders
G11.0 - G11.9	Hereditary ataxia
G20 - G21.9	Parkinson's disease
G23.0 - G26	Extrapyramidal movement disorders
G47.61 - G47.69	Sleep related movement disorders
G52.7	Disorders of multiple cranial nerves
G80.0 - G80.9	Cerebral palsy
M17.0 - M17.9	Osteoaratthritis of knee
M62.40 - M62.49	Contracture of muscle
R25.0 - R25.9	Abnormal involuntary movements
R26.0 - R26.9	Abnormalities of gait and mobility
R27.0 - R27.9	Other lack of coordination
*Remede System*:
CPT codes covered if selection criteria are met:
0424T - 0427T	Insertion or replacement of neurostimulator system for treatment of central sleep apnea
HCPCS codes covered if selection criteria are met:
C1823	Generator, neurostimulator (implantable), non-rechargeable, with transvenous sensing and stimulation leads
ICD-10 codes covered if selection criteria are met:
G47.31	Primary central sleep apnea
*Cala Trio Nerve Stimulation Device*:
HCPCS codes not covered for indications listed in the CPB (not all-inclusive):
A4542	Supplies and accessories for external upper limb tremor stimulator of the peripheral nerves of the wrist
E0734	External upper limb tremor stimulator of the peripheral nerves of the wrist
ICD-10 codes not covered for indications listed in the CPB:
G25.0	Essential tremor

Background

Spinal cord injury can (SCI) cause various degrees of neurological impairment depending on the location and severity of the injury. One method of categorizing the degree of injury is by a neurological examination that explores the segments of the cord which are still functional. The most caudal segment of the cord with normal sensory and motor functions is denoted as the neurological level of injury. The American Spinal Injury Association (ASIA) Impairment Scale is a classification system used to describe the extent of SCI.

Table: The ASIA Impairment Scale
Grade	Extent of SCI
A	Complete: No motor or sensory function is preserved in the sacral segments S4 - S5
B	Incomplete: Sensory but not motor function is preserved below the neurological level and includes the sacral segments S4 - S5
C	Incomplete: Motor function is preserved below the neurological level, and more than half of key muscles below the neurological level have a muscle grade less than 3
D	Incomplete: Motor function is preserved below the neurological level, and at least half of key muscles below the neurological level have a muscle grade of 3 or more
E	Normal: Motor and sensory function are normal

Another factor that influences the severity of impairment is the neurological extent of injury, namely the degree of tissue trauma to the spinal cord at the level of injury. If the spinal cord is seriously damaged at the injury site, there is complete loss of sensation and voluntary muscle control below the level of lesion. On the other hand, if the damage is not complete, some sensory and/or motor functions may still be preserved. Thus, a complete injury to the cervical spine will result in quadriplegia, while an incomplete injury to the cervical spine will result in quadriparesis. Similarly, a complete lesion in the thoracic or lumbar spine will produce paraplegia, whereas an incomplete lesion at these levels will produce paraparesis. Spinal cord injury can result in damage to upper motor neurons (UMN), lower motor neurons (LMN), or a combination of both. The cell bodies of UMN originate from the primary motor area of the cerebral cortex and the brain stem, with their axons descending downward and terminating at each segmental level throughout the entire length of the spinal column to synapse with LMN that arise in the spinal cord and connect to a muscle or organ. The brain, through the UMN, exerts an inhibitory influence on the LMN so that they do not become hyperactive to local stimuli. The cell bodies of LMN are located in the central gray matter throughout the entire length of the spinal column, and their axons extend out via the spinal nerve roots and peripheral nerve branches to innervate skeletal muscles throughout the body.

Neuromuscular electrical stimulation (NMES) can be grouped into 2 categories:

stimulation of muscles to treat muscle atrophy, and
enhancement of functional activity in neurologically impaired individuals.

These devices use electrical impulses to activate paralyzed or weak muscles in precise sequence and have been utilized to provide SCI patients with the ability to walk (e.g., The Parastep I System). Neuromuscular electrical stimulation used in this manner is commonly known as functional electrical stimulation (FES).

Spinal Cord Injury

The Parastep I System, a transcutaneous non-invasive and micro-computerized electrical stimulation system built into a battery-powered unit, is controlled by finger-touch buttons located on a walker's hand-bars for manual selection of stimulation menus. The microcomputer shapes, controls, and distributes trains of stimulation signals that trigger action potentials in selected peripheral nerves. Walker support is used for balance. The patient can don the system in less than 10 minutes. At least 32 training sessions are required.

Klose et al (1997) described performance parameters and effects on anthropometric measures in SCI patients (13 men and 3 women) training with the Parastep I system. Subjects with thoracic (T4 to T11) motor-complete SCI, mean age of 28.8 years, and mean duration post-injury of 3.8 years underwent 32 functional neuromuscular stimulation ambulation training sessions using the Parastep I System. The authors concluded that the Parastep I System enabled persons with thoracic-level SCI to stand and ambulate short distances but with a high-degree of performance variability across individuals. Furthermore, Graupe and Kohn (1998) reported that about 400 patients have used the Parastep I System and essentially all achieved standing and at least 30 feet of ambulation, with a few reaching as much as 1 mile at a time.

Bonaroti et al (1999) compared FES to long leg braces (LLB) as a means of upright mobility for children with motor-complete thoracic level SCI (n = 5). The authors found that FES system generally provided equal or greater independence in seven mobility activities as compared with LLB, provided faster sit-to-stand times, and was preferred over LLB in a majority of cases.

In addition to enhancement of walking abilities in SCI patients, other clinical applications of FES include diaphragmatic/phrenic pacing, and spasticity control. Functional electrical stimulation has had some success in improving ventilatory function in adult patients with SCI (Glenn et al, 1984; Carter et al, 1987; Glenn et al, 1988). Hunt et al (1988) reported that diaphragmatic pacing is also helpful for infants and children who need ventilatory support. Furthermore, in a 1992 review on the rehabilitation of children with SCI, Flett (1992) stated that diaphragmatic/phrenic pacing is indicated for children with quadriplegia at C3 or higher if they have viable phrenic nerves and adequate diaphragm and lung function. Candidates for diaphragmatic pacing should be stable and out of the acute phase of injury. The author stated that this approach of assisting ventilation in these patients resulted in psychological benefits to both the children and their families. Currently, bilateral stimulation at low frequency is more frequently used instead of stimulation of only one hemidiaphragm at a time, and adequate ventilation can be attained with 5 to 9 stimuli per minute.

Diaphragmatic pacing has also been used to treat patients with central alveolar hypoventilation syndrome. Yasuma and associates (1998) noted that the respiratory assistance by the diaphragm pacemaker or the use of a mechanical ventilator as a backup was highly useful for the home care of a patient with central alveolar hypoventilation. Garrido-Garcia and colleagues (1998) presented a series of patients with chronic ventilatory failure treated with electrophrenic respiration: 13 males and 9 females with a mean age of 12 +/- 11.5 years. The etiology was: 13 tetraplegia, 5 sequelae of surgical treatment of intracranial lesions, and 4 central alveolar hypoventilation. The mean duration of the conditioning period was 3 to 4 months. Eighteen patients (81.8 %) achieved permanent, diaphragmatically-paced breathing with bilateral stimulation and in 4 (18.2%) patients, pacing was only during sleep. Five patients died (22.7%): 2 during the hospital stay and 3 at home; 2 deaths had unknown cause and 3 were due respectively to, lack of at-home care, recurrence of an epidermoid tumor, and sequelae of accidental disconnection of the mechanical ventilation before beginning the conditioning period. Two cases were considered failures: 1 patient had transitory neurapraxia lasting 80 days, and the other had an ischemic spinal cord syndrome with progressive deterioration of the left-side response to stimulation. One patient had right phrenic nerve entrapment by scar tissue and 4 suffered infections. These results demonstrated that complete stable ventilation can be achieved using diaphragmatic pacing and that it improves the prognosis and life quality of patients with severe chronic respiratory failure.

Girsch et al (1996) noted that ventilatory insufficiency due to central hypoventilation syndrome and SCI can be treated even in children with diaphragm pacing, provided the indication for implantation, containing medical and social aspects, was made correctly. Additionally, Flageole et al (1995) stated that pediatric surgeons should be aware of congenital central hypoventilation syndrome (CCHS) because it may be treated with surgically implanted electrodes that allow for pacing of the diaphragm. The technique has an acceptable complication rate, and it can greatly decrease the impact of the disease on the lifestyle and activity of the patient. Shaul et al (2002) stated that diaphragmatic pacing can provide chronic ventilatory support for children who suffer from CCHS or cervical SCI.

Chen and Keens (2004) reported that all patients with CCHS require lifelong ventilatory support during sleep but some will be able to maintain adequate ventilation without assistance while awake once past infancy. However, some CCHS patients require ventilatory support for 24 hours/day. Modalities of home mechanical-assisted ventilation include positive pressure ventilation via tracheostomy, non-invasive positive pressure ventilation (bi-level ventilation), negative pressure ventilation and diaphragmatic pacers. Furthermore, Creasey et al (1996) reported that electrical stimulation has been used for over 25 years to restore breathing to patients with high quadriplegia causing respiratory paralysis and patients with central alveolar hypoventilation. Three groups have developed electrical pacing systems for long-term support of respiration in humans. These systems consist of electrodes implanted on the phrenic nerves, connected by leads to a stimulator implanted under the skin, and powered and controlled from a battery-powered transmitter outside the body. The systems differ principally in the electrode design and stimulation waveform. Approximately 1,000 people worldwide have received one of the three phrenic pacing devices, most with strongly positive results: reduced risk of tracheal problems and chronic infection, the ability to speak and smell more normally, reduced risk of accidental interruption of respiration, greater independence, and reduced costs and time for ventilatory care. For patients with partial lesions of the phrenic nerves, intercostal muscle stimulation may supplement respiration.

Neuromuscular respiratory failure is the cause of death in the majority of patients with amyotrophic lateral sclerosis (ALS). Respiratory muscle dysfunction impacts on quality of life and survival. Yun and associates (2007) noted that closed loop systems may facilitate the implementation of diaphragmatic pacing for the treatment of many indications. They may allow for wider adoption of ventilatory support in central sleep apnea and improve quality of life in diseases of chronic hypoventilation, such as ALS.

Onders and colleagues (2009a) summarized the complete worldwide multi-center experience with diaphragm pacing stimulation (DPS) to maintain and provide diaphragm function in ventilator-dependent SCI patients and respiratory-compromised patients with ALS. It high-lighted the surgical experiences and the differences in diaphragm function in these 2 groups of patients. In prospective Food and Drug Administration (FDA) trials, patients underwent laparoscopic diaphragm motor point mapping with intra-muscular electrode implantation. Stimulation of the electrodes ensued to condition and strengthen the diaphragm. From March of 2000 to September of 2007, a total of 88 patients (50 SCI and 38 ALS) were implanted with DPS at 5 sites. Age of patients at implantation ranged from 18 to 74 years. Time from SCI to implantation ranged from 3 months to 27 years. In 87 patients the diaphragm motor point was mapped with successful implantation of electrodes with the only failure the second SCI patient who had a false-positive phrenic nerve study. Patients with ALS had much weaker diaphragms identified surgically, requiring trains of stimulation during mapping to identify the motor point at times. There was no peri-operative mortality even in ALS patients with forced vital capacity (FVC) below 50 % predicted. There was no cardiac involvement from diaphragm pacing even when analyzed in 10 patients who had pre-existing cardiac pacemakers. No infections occurred even with simultaneous gastrostomy tube placements for ALS patients. In the SCI patients, 96 % were able to use DPS to provide ventilation replacing their mechanical ventilators; and in the ALS studies, patients have been able to delay the need for mechanical ventilation up to 24 months. The authors concluded that this multi-center experience has shown that laparoscopic diaphragm motor point mapping, electrode implantation, and pacing can be safely performed both in SCI and in ALS. In SCI patients it allows freedom from ventilator and in ALS patients it delays the need for ventilators, increasing survival.

Onders and co-workers (2009b) summarized the largest series of surgical cases in ALS during multi-center prospective trials of the laparoscopic DPS to delay respiratory failure. The overall strategy outlined includes the use of rapidly reversible short-acting analgesic and amnestic agents with no neuromuscular relaxants. A total of 51 patients were implanted from March 2005 to March 2008 at 2 sites. Age of patients ranged from 42 to 73 years and the percent predicted FVC ranged from 20 % to 87 %. On pre-operative blood gases, Pco(2) was as high as 60. Using this protocol, there were no failures to extubate or 30-day mortalities. The DPS system increase the respiratory system compliance by decreasing posterior lobe atelectasis and can stimulate respirations at the end of each case. The authors concluded that laparoscopic surgery with general anesthesia can be safely performed in patients with ALS undergoing DPS.

It has not been consistently shown that spasticity decreases with long-term FES. Yarkony et al (1992) claimed that no definitive statement can be made regarding the type, the magnitude, or even the direction of the effect of electrical stimulation on the spasticity of patients with SCI. Current management strategy for this condition ranges from rehabilitative physical therapy, re-education therapeutic exercise, oral medications such as Dantrium, Valium, and Lioresal (baclofen), intra-thecal infusion of baclofen, motor point blocks or nerve blocks, to destructive neurosurgical procedures (Merritt 1981).

Functional electrical stimulation exercise training has been claimed to strengthen and increase endurance of muscles paralyzed following UMN injuries, thereby improving physical fitness and health of individuals with SCI. However, fatigue of electrically stimulated muscles is a principal limiting factor in the applications of FES. Glaser (1986) stated that more research is needed to ascertain the mechanisms of fatigue of this type of peripherally induced exercise, and to substantiate the potential fitness and health benefits of FES exercise training. Sipski et al (1989) examined patient perceptions of FES bicycle ergometry. These researchers suggested that future studies should include a placebo control group. They also found that 6 of 9 patients with a history of neurogenic pain reported an increase in this pain which caused them to drop out of the training program. The cause of this intensification of pain was unclear. Leeds et al (1990) reported that bone mineral density did not increase in quadriplegic men who had undergone 6 months of FES cycle ergometry training. Sipski et al (1993) stated that more research is needed to document the benefits, if any, of the use of bicycle ergometry to justify the use of this equipment. Pentland (1993) claimed that much more research in FES techniques and treatment protocols is needed before this approach can be used widely as a means to provide cardiorespiratory fitness for quadriplegics.

Stroke Rehabilitation

The principal goal of stroke rehabilitation is to improve the functional abilities of these patients, thus affording them greater independence in activities of daily living and improving their quality of life. Conventional modalities of stroke rehabilitation comprise various combination of range of motion (ROM) and muscle strengthening exercises, mobilization activities, and compensatory techniques. Other therapies include neurophysiological and/or developmental based methods in which the therapeutic program incorporates neuromuscular re-education techniques. In this regard, FES has been employed in the rehabilitation of stroke patients. It has been utilized to manage contracture of joints, maintain ROM, facilitate voluntary motor control, and reduce spasticity. However, there is insufficient evidence that FES is effective as a rehabilitative tool for patients who suffered strokes. In particular, there are little data supporting the long-term effectiveness of this modality for stroke rehabilitation.

In a review on the clinical applications of FES, Kumar et al (1995) stated that advances in electrode technology and control and command sources activation systems as well as development of close-loop systems are needed if wide patient acceptance of this modality (FES) is to be ensured. The Agency for Health Care Policy and Research's clinical guideline on “Post-stroke Rehabilitation” maintains that neither research evidence nor expert consensus adequately supports recommendation concerning the use of FES in the rehabilitation of stroke patients (Gresham, 1995). Furthermore, Hummelsheim et al (1997) reported that repetitive electrical muscle stimulation did not improve biomechanical or functional motor parameters of the centrally paretic hand and arm of stroke patients.

In a randomized controlled study, Yan and colleagues (2005) evaluated whether FES was more effective in promoting motor recovery of the lower extremity and walking ability than standard rehabilitation alone. A total of 46 patients were assigned randomly to one of three groups receiving standard rehabilitation with FES or placebo stimulation or alone (control). They received treatment for 3 weeks, starting shortly after having the stroke. Outcome measurements included composite spasticity score, maximum isometric voluntary contraction of ankle dorsi-flexors and planter-flexors, and walking ability. After 3 weeks of treatment, those receiving FES plus standard rehabilitation did better on several measures of lower limb functioning compared to the other 2 groups. All patients in the FES group were able to walk after treatment, and 84.6 % of them returned home, in comparison with the placebo (53.3 %) and control (46.2 %) groups. However, these authors stated that generalization of the results from this study should be performed with caution because of subject selection criteria, which did not cover all stroke categories or subjects aged younger than 45 or older than 85 years. Further studies are now needed to see whether FES can work with a wide range of stroke patients.

Although a number of studies suggested that electrical stimulation may be effective for reducing shoulder pain and subluxation or improving the function of wrist and finger extensors following stroke (Chantraine et al, 1999; Wang et al, 2002; and Yozbatrian et al, 2006), more research is needed to validate these findings. Chantraine et al (1999) reported that FES program was significantly effective in reducing the severity of subluxation and pain and possibly may have facilitated recovery of the shoulder function in hemiplegic patients. However, they noted that more research addressing the mechanism of the actions of FES on pain and subluxation of the hemiplegic shoulder is needed.

Chae and Yu (2000) critically evaluated the clinical effectiveness of NMES in treating motor dysfunction in hemiplegia. Three distinct applications were reviewed in the areas of motor relearning, shoulder dysfunction, and neuroprostheses. Assessment of clinical effectiveness and recommendations on clinical implementation were based on the weight of published scientific evidence. With respect to motor relearning, evidence supports the use of NMES to facilitate recovery of muscle strength and coordination in hemiplegia. However, effects on physical disability are uncertain. With respect to shoulder dysfunction, NMES decreases shoulder subluxation, at least in the short term. However, effects on shoulder pain and disability are also uncertain. With respect to neuroprosthesis systems, clinically deployable upper extremity systems must await the development of more sophisticated control methods and greater fundamental understanding of motor dysfunction in hemiplegia. The evidence for clinical feasibility of lower extremity neuroprostheses is stronger, and investigations on clinical effectiveness should be pursued. The authors concluded that the application of NMES for motor relearning and shoulder dysfunction are ready for more rigorous scientific and clinical assessment via large, multi-center, randomized clinical trials.

In a Cochrane review, Price and Pandyan (2000) ascertained the effectiveness of any form of surface ES in the prevention and/or treatment of pain around the shoulder at any time after stroke. These investigators concluded that the evidence from randomized controlled studies so far does not confirm or refute that ES around the shoulder after stroke influences reports of pain, but there do appear to be benefits for passive humeral lateral rotation. A possible mechanism is through the reduction of glenohumeral subluxation. The authors stated that further studies are needed.

Turner-Stokes and Jackson (2002) noted that although a wide variety of physical changes are associated with hemiplegic shoulder pain (HSP), these can be categorized into 2 presentations; (i) "flaccid", and (ii) "spastic". Management should vary accordingly; each presentation requiring different approaches to handling, support and intervention. In the "flaccid" stage, the shoulder is prone to inferior subluxation and vulnerable to soft-tissue damage. The arm should be supported at all times and FES may reduce subluxation and enhance return of muscle activity. In the "spastic" stage, movement is often severely limited. Relieving spasticity and maintaining range requires expert handling; over-head exercise pulleys should never be used. Local steroid injections should be avoided unless there is clear evidence of an inflammatory lesion. The authors concluded that HSP requires coordinated multi-disciplinary management to minimize interference with rehabilitation and optimize outcome. They stated that more research is needed to determine effective prophylaxis and document the therapeutic effect of different modalities in the various presentations.

The New Zealand Guidelines Group's guideline for management of stroke (2003) stated that the use of FES and transcutaneous electrical nerve stimulation for post-stroke patients is not recommended. Furthermore, Van Peppen et al (2004) determined the evidence for physical therapy interventions aimed at improving functional outcome after stroke. These researchers reported that while strong evidence was found regarding NMES for glenohumeral subluxation, no or insufficient evidence in terms of functional outcome was found for FES and NMES aimed at improving dexterity or gait performance; orthotics and assistive devices; and physical therapy interventions for reducing hemiplegic shoulder pain and hand edema. Furthermore, in a review on therapeutic orthosis and ES for upper extremity hemiplegia after stroke, Aoyagi and Tsubahara (2004) stated the longer term effectiveness after discontinuation as well as the motor recovery mechanism of ES or robotic devices remains unclear. More research is needed to determine the evidence-based effectiveness of ES or other devices for stroke survivors.

In a Cochrane review on ES for promoting recovery of movement or functional ability after stroke, Pomeroy et al (2006) concluded that "[a]t present, there are insufficient robust data to inform clinical use of electrostimulation for neuromuscular re-training. Research is needed to address specific questions about the type of electrostimulation that might be most effective, in what dose and at what time after stroke".

In a systematic review and meta-analysis, Eraifej and co-workers (2017) evaluated the effectiveness of post-stroke upper limb FES on activities of daily living (ADL) and motor outcomes. A systematic review of randomized controlled trials (RCTs) from Medline, PsychINFO, EMBASE, CENTRAL, ISRCTN, ICTRP and ClinicalTrials.gov was carried out. Eligibility criteria: included participants greater than 18 years with hemorrhagic/ischemic stroke, intervention group received upper limb FES plus standard care, control group received standard care. Outcomes were ADL (primary), functional motor ability (secondary) and other motor outcomes (tertiary). Quality assessment using GRADE (Grading of Recommendations Assessment, Development and Evaluation) criteria. A total of 20 studies were included. No significant benefit of FES was found for objective ADL measures reported in 6 studies (SMD 0.64; 95 % CI: -0.02 to 1.30]; total participants in FES group (n) = 67); combination of all ADL measures was not possible. Analysis of 3 studies where FES was initiated on average within 2 months post-stroke showed a significant benefit of FES on ADL (SMD 1.24; CI: 0.46 to 2.03]; n = 32). In 3 studies where FES was initiated more than 1 year after stroke, no significant ADL improvements were seen (SMD -0.10; CI: -0.59 to 0.38], n = 35). Quality assessment using GRADE found very low quality evidence in all analyses due to heterogeneity, low participant numbers and lack of blinding. The authors concluded that FES is a promising therapy which could play a part in future stroke rehabilitation . This review found a statistically significant benefit from FES applied within 2 months of stroke on the primary outcome of ADL. However, due to the very low (GRADE) quality evidence of these analyses, firm conclusions cannot be drawn about the effectiveness of FES or its optimum therapeutic window. These researchers stated that there is a need for high quality large-scale RCTs of upper limb FES after stroke.

In a systematic review and meta-analysis, Lee and associates (2017) examined the effectiveness of NMES for the management of shoulder subluxation after stroke including assessment of short (1 hour or less) and long (more than 1 hour) daily treatment duration. Medline, CENTRAL, CINAHL, WOS, KoreaMed, RISS and reference lists from inception to January 2017 were the data sources. These researchers considered RCTs that reported NMES for the treatment of shoulder subluxation post-stroke; 2 reviewers independently selected trials for inclusion, assessed trial quality, and extracted data. A total of 11 studies were included (432 subjects); 7 studies were good quality, 4 were fair. There was a significant treatment effect of NMES for reduction of subluxation for persons with acute and sub-acute stroke (SMD: -1.11; 95 % CI: -1.53 to -0.68) with either short (SMD: -0.91; 95 % CI: -1.43 to -0.40) or long (SMD: -1.49; 95 % CI: -2.31 to -0.67) daily treatment duration. The effect for patients with chronic stroke was not significant (SMD: -1.25; 95 % CI: -2.60 to 0.11). There was no significant effect of NMES on arm function or shoulder pain. The authors concluded that the findings of this meta-analysis suggested a beneficial effect of NMES, with either short or long daily treatment duration, for reducing shoulder subluxation in persons with acute and sub-acute stroke. However, no significant benefits were observed for persons with chronic stroke or for improving arm function or reducing shoulder pain.

Functional Electrical Stimulation of the Upper Extremities

Functional electrical stimulation is being investigated as a means to improve hand and arm function after stroke-related paralysis or spinal cord injury. The NESS H200 hand rehabilitation system (Bioness, Valencia, CA), formerly the Handmaster, is a neuroprosthesis that uses mild ES in an attempt to activate muscle groups in the forearm to produce functional movement patterns in the hand. It is designed to be used as part of a self-administered home-based rehabilitation program for the treatment of upper limb paralysis from hemiplegic stroke, traumatic brain injury or C5 to C6 spinal cord injury. The system contains a custom-fitted orthosis and a control unit. The control unit allows the user to adjust the stimulation intensity and training mode. Exercise sessions can be gradually increased to avoid muscle over-fatigue.

Initial case studies have indicated that the use of FES as an adjunct to physical therapy can improve patient outcomes (Weingarden et al, 1998; Alon et al, 2002; Alon et al, 2003; Berner et al, 2004). However, the studies lacked a control group, involved small study populations with limited periods of follow-up. Thus, it is difficult to ascertain the significance of the treatment effects and their durability.

De Kroon et al (2002) systematically reviewed the evidence for ES to improve motor control and functional abilities of the upper extremity after stroke. The authors reported that "[t]he results suggest that electrical stimulation has a positive effect on motor control, although it is not known if this improvement is clinically relevant." The review stated that "[n]o conclusions can be drawn concerning the effect of electrical stimulation on functional abilities."

Ring and Rosenthal (2005) evaluated the effects of daily neuroprosthetic (NESS Handmaster) FES in sub-acute stroke. Patients were clinically stratified to 2 groups: (i) no active finger movement, and (ii) partial active finger movements, and then were randomized to control and neuroprosthesis groups. Observer blinded evaluations were performed at baseline and completion of the 6-week study. A total of 22 patients with moderate-to-severe upper limb paresis 3 to 6 months after stroke were enrolled in this study. They were in day hospital rehabilitation, receiving physical and occupational therapy 3 times weekly. The neuroprosthesis group used the device at home. The neuroprosthesis group had significantly greater improvements in spasticity, active ROM and scores on the functional hand tests (those with partial active motion). Of the few patients with pain and edema, there was improvement only among those in the neuroprosthesis group. There were no adverse reactions. These investigators concluded that supplementing standard outpatient rehabilitation with daily home neuroprosthetic activation improves upper limb outcomes.

In a systematic review, Meilink et al (2008) evaluated if electromyography-triggered NMES (EMG-NMES) applied to the extensor muscles of the forearm improves hand function after stroke. A total of 8 studies, selected out of 192 hits and presenting 157 patients, were included in quantitative and qualitative analyses. The methodological quality ranged from 2 to 6 points. The meta-analysis revealed non-significant effect sizes in favor of EMG-NMES for reaction time, sustained contraction, dexterity measured with the Box and Block manipulation test, synergism measured with the Fugl-Meyer Motor Assessment Scale and manual dexterity measured with the Action Research Arm test. The authors concluded that no statistically significant differences in effects were found between EMG-NMES and usual care. Most studies had poor methodological quality, low statistical power and insufficient treatment contrast between experimental and control groups. In addition, all studies except 2 investigated the effects of EMG-NMES in the chronic phase after stroke, whereas the literature suggests that an early start, within the time window in which functional outcome of the upper limb is not fully defined, is more appropriate.

In a retrospective cohort study, Meijer et al (2009) evaluated the short-term and long-term use of a hybrid orthosis for NMES of the upper extremity in patients (n = 110) after chronic stroke. The Modified Ashworth Scale (0 to 5) for wrist (primary outcome) and elbow flexor hypertonia, visual analog scale (0 to 10) for pain, edema score (0 to 3), and passive range of wrist flexion and extension (pROM, degrees) were assessed prior to Handmaster orthosis prescription (T0), after 6 weeks try-out (T1) and a subsequent 4 weeks withhold period (T2). Long-term use was evaluated using a questionnaire. Non-parametric analyses and predictive values were used for statistical analyses. Of the 110 patients, 78.2 % were long-term Handmaster orthosis users. Long-term users showed significant short-term (T0 to T1) improvements on all impairment scores and a significant relapse of wrist and elbow Modified Ashworth Scale (T1 to T2). Non-users showed significant short-term effects on elbow Modified Ashworth Scale and visual analog scale only. Positive predictive values of short-term effects for long-term use varied between 75 % and 100 %, with 85 % (95 % confidence interval (CI): 0.72 to 0.93) for wrist Modified Ashworth Scale. Negative predictive values were low (11 to 27 %). The authors concluded that short-term Handmaster orthosis effects were generally beneficial for hypertonia, pain, edema, and pROM, especially in long-term users and that short-term beneficial effects were highly predictive for long-term use, but not for non-use.

The results of these studies are promising, however, these findings need to be validated by further investigation with more patients and follow-up data.

Rehabilitation Following Ligament/Knee Surgery

On the other hand, NMES has been shown to be an effective rehabilitative regimen for patients following ligament/knee surgery. It prevents muscle atrophy associated with knee immobilization, enables patients to ambulate sooner, and reduces the use of pain medication as well as length of hospital stay (Arvidsson, 1986; Lake, 1992; Gotlin et al, 1994; Snyder-Mackler et al, 1995).

Bax et al (2005) systematically reviewed the available evidence for the use of NMES in increasing strength of the quadriceps femoris. The authors concluded that limited evidence suggests that NMES can improve strength in comparison with no exercise, but volitional exercises appear more effective in most situations. The authors' cautious conclusions reflect the general poor quality of the included studies.

Neurogenic Bladder Dysfunction

Neurogenic bladder dysfunction is due to lesions of the innervation either within the central nervous system or in the peripheral nerves of the bladder and urethra. The Lapides Classification is the scheme most frequently used by urologists to classify patients with neuropathic voiding dysfunction. This classification system is divided into 5 categories:

sensory neurogenic bladder,
motor paralytic bladder,
uninhibited neurogenic bladder,
reflex neurogenic bladder, and
autonomous neurogenic bladder.

A sensory neurogenic bladder is caused by diseases that selectively disrupt the sensory fibers between the bladder and spinal cord or the afferent pathways to the brain. This is commonly observed in patients with peripheral neuropathies such as diabetes mellitus, tabes dorsalis, folic acid avitaminosis, and pernicious anemia. A motor paralytic bladder is the consequence of diseases/processes that interrupt the parasympathetic motor innervation of the bladder. It can be produced by extensive pelvic surgery or trauma or herpes zoster. An uninhibited neurogenic bladder is due to the absence of cerebral inhibition of the micturition reflex as a result of injury or disease in the cortico-regulatory tract. Cerebral lesions such as stroke, tumors, arteriosclerosis, and traumatic lesions are the most common causes of this type of voiding disorder. A reflex neurogenic bladder is often observed in the post-spinal shock condition existing following the complete transection of the sensory and motor tracts between the sacral spinal cord and the brain stem. This is often the result of traumatic SCI and transverse myelitis, but may also occur with severe demyelinating disease or tumor. An autonomous neurogenic bladder is caused by complete motor and sensory separation of the bladder from the sacral spinal cord. Diseases that destroy the sacral spinal cord or cause extensive damage to the sacral roots or pelvic nerves can produce this type of disorder. It should be noted that many patients do not exactly fit into one or another of these categories because of gradations of sensory, motor, and mixed lesions. Thus, the patterns produced after different types of peripheral denervation may vary greatly from those that are classically described (Barrett and Wein, 1991).

Neurogenic bladder dysfunction can also be associated with other neurological diseases including cerebellar ataxia, multiple sclerosis, Parkinson's disease, and Shy-Drager syndrome. In children, the common causes of neurogenic bladder dysfunction are sacral agenesis, tethered cord syndrome, and myelomeningocele. The main results of neurogenic bladder dysfunction are renal damage and urinary incontinence (UI). The former is due to either high intravesical pressure or the association of vesicoureteral reflux and infection. The mechanisms for UI are multiple including

overflow incontinence caused by detrusor atonia with a non-relaxing sphincter,
lack of storage capacity caused by hyperreflexia or poor compliance, and
low urethral resistance caused by denervation of the sphincters.

Oftentimes, the causes of UI are mixed (Wein 1992; Fernandes et al, 1994).

The management of patients with neurogenic bladder dysfunction entails clean intermittent catheterization, pharmacotherapy (e.g., oxybutynin, phenoxybenzamine, and anti-cholinergic medications such as tolterodine), and surgical interventions (e.g., urinary diversion or bladder augmentation). Moreover, stimulation of sacral anterior nerve roots in association with posterior rhizotomy has been used in the treatment of patients with suprasacral SCI. The FDA approved the Vocare Bladder System as a humanitarian use device based on a study of 23 patients who received device in association with posterior rhizotomy and were followed for a minimum of 3 months. Comparisons were made with the implanted stimulator turned either on or off; thus patients served as their own controls. The primary outcome measures were improvement in bladder emptying as evidenced by the ability to void more than 200 ml on demand with post-void residual urine volumes of less than 50 ml. Secondary endpoints included reduction in the use of urinary catheters, number and severity of episodes of UI, reduction in incidence of urinary tract infections, and results of a user satisfaction survey.

After 3 months, 90 % of the patients were able to urinate more than 200 ml on demand and 81 % had post-void residual urine volumes of less than 50 ml. A total of 73 % of patients reported fewer urinary tract infections and at 6 months, about 50 % of the patients were using the device exclusively for micturition, and no external devices (e.g., catheters) were needed. The results reported in this study were in agreement with those reported by Van Kerrebroeck et al (1996) as well as Egon et al (1998). The former group of investigators reported on the outcomes of 47 patients who were followed for a minimum of 6 months. Complete continence was observed in 43 of the 47 patients, and 41 of the 47 patients used only the stimulator for bladder emptying. The residual urine volume also decreased to less than 50 ml in 41 patients. The incidence of urinary tract infections also decreased. The latter group of researchers reported on a case series of 93 patients. A total of 83 of the 93 patients used their implants for micturition with residual volumes of less than 50 ml.

Jamil (2001) stated that the Finetech-Brindley stimulator can be recommended to female patients after 3 months and to male patients after 9 months of complete supra-sacral SCI. The presence of 3 of the 4 non-vesical sacral segment reflexes (ankle jerks, bulbo-cavernous reflex, anal skin reflex, and reflex erection) and a phasic detrusor pressure rise of 35 mm H2O in the female and 50 cm H2O in the male on cystometry indicates intact efferent nerve supply to the bladder and consequently the possibility of success of the implanted stimulator.

A less widely used method for the treatment of neurogenic bladder is transurethral electrical bladder stimulation (TEBS). This modality was first introduced in Europe by Katona and Berenyi (1975) to treat patients with myelomeningocele. It was introduced in the United States by Kaplan and Richards (1986). This procedure has been utilized with the theory that bladder stimulation promotes new sensory awareness of bladder filling and a restoration of detrusor contractility (i.e., disappearance of uninhibited bladder contractions and replacement with normal contractions). Briefly, this procedure involves the filling of the bladder to approximately half capacity with normal saline via an electrocatheter under sterile conditions. The catheter is then connected to a pressure recorder for continuous monitoring of bladder pressure. A rectal balloon catheter is employed to subtract abdominal pressure and a ground electrode is placed on the leg. Stimulation parameters are as follow:

voltage - 0.5 to 10 mA,
frequency - 40 to 100 Hz,
duration - 2 to 8 msec, and
interval - 1 to 10 sec.

Patients undergo one or more series of bladder stimulation. The first series of stimulation begins with an evaluation session, which is followed by 10 to 30 90-min daily sessions. Each of these sessions comprises a 15-min period of monitoring of bladder activity followed by 60 mins of bladder stimulation and then another 15 mins of observation of bladder activity. Between series there is a rest period of 3 to 6 months during which no stimulation is given. Following the rest interval, a subsequent series consisting of 5 to 15 daily sessions will commence (Boone et al, 1992; Kaplan and Richards, 1988; Kaplan et al, 1989).

Although earlier reports (Katona and Berenyi, 1975; Kaplan and Richards, 1986; Kaplan and Richards, 1988; Kaplan et al, 1989) claimed that TEBS is effective in treating patients with neurogenic bladder dysfunction, recent studies (Boone et al, 19921; Decter et al, 1992; Lyne and Bellinger, 1993; Decter et al, 1994) have not been able to replicate such findings. The 2 most relevant outcome measures in assessing the effectiveness of TEBS are restoration of normal detrusor contractility and urinary continence. Lyne and Bellinger (1993) treated 17 patients with neurovesical dysfunction with TEBS. Overall, only 5 (41.7 %) of the 12 patients with fully standardized serial cystometry experienced a durable increase in bladder capacity, and no patient achieved volitional voiding. Decter et al (1992) treated 21 patients with neurogenic bladder dysfunction using TEBS. They found that 20 % of the patients showed an increase in bladder capacity and 30 % experienced a decrease in end filling pressures. However, these effects did not significantly change patients' daily voiding regimens. In a follow-up study, Decter et al (1994) stated that TEBS is a time consuming and labor intensive procedure. Additionally, the limited urodynamic benefits attained by patients have not changed their daily routine of bladder management. Because of the afore-mentioned factors, these investigators are not accepting any new patients in their TEBS program. In an earlier study, Nicholas and Eckstein (1975) reported their findings of TEBS in the treatment of 20 patients with neurogenic bladder dysfunction due to spina bifida. No patient attained bladder sensation and the essential pattern of detrusor activity in these patients was unchanged by TEBS.

Boone et al (1992) performed the only prospective, randomized, sham controlled and blinded clinical trial on the use of TEBS in 36 children with myelomeningocele. Patients were allocated to either a 3-week period of TEBS or sham treatment, which was followed by a 3-month rest period, and then all patients were treated with TEBS for an additional 3 weeks. Bladder capacity, sensation, and compliance as well as continence were evaluated. Transurethral electrical bladder stimulation did not produce any beneficial effects even in patients who had undergone a total of 6 weeks of active stimulation.

Van Balken et al (2004) reviewed the literature on the application of various devices and techniques for the ES treatment of lower urinary tract (e.g., bladder) dysfunction with respect to mechanism of action and clinical outcome. These investigators concluded that randomized clinical trials to compare different techniques and evaluate placebo effects are urgently needed, as are further studies to elucidate modes of action to improve stimulation application and therapy results. The introduction of new stimulation methods may provide treatment alternatives as well as help answer more basic questions on ES and neuromodulation.

Cerebral Palsy

Cerebral palsy (CP) refers to a wide variety of non-progressive brain disorders resulting from insults to the central nervous system during the perinatal period. Infants born prematurely and full-term infants with low birth-weight have the highest risk of developing CP. Infants whose birth weights are less than 2,500 g account for approximately 1/3 of all babies who later demonstrate signs of CP. Moreover, the rate of CP is about 30 times higher in babies who weigh less than 1,500 g at birth than in full-term babies with normal weight (Kuban and Leviton, 1994). Traditionally, the adverse effects of spasticity are managed by means of pharmacotherapy, physical therapy, bracing, casting, splinting, orthopedic surgeries, and more recently selective posterior rhizotomy. Various forms of ES have also been employed for the management of patients with CP including NMES, which has been used to increase ROM, decrease spasticity, and enhance muscle rehabilitation.

The exact mechanisms by which NMES might improve motor function in children with CP remain unclear. It may be related to its ability to increase ROM, temporarily decrease spasticity, and enhance muscle rehabilitation. Moreover, Pape et al (1993) suggested that NMES applied during sleep might encourage the differential growth of atrophic non-spastic antagonistic muscles. As a result, the decreased imbalance at the end-organ level might improve motor function.

Pape et al (1993) reported their findings regarding the use of NMES for improving motor deficits in children with CP. Six patients with mild ambulatory spastic hemiplegia or diplegia underwent a study of over-night low intensity sub-threshold transcutaneous ES. Only 5 of the 6 patients completed the study. After 6 months of ES, significant improvement was observed on the Peabody Developmental Motor Scales scores in gross motor, locomotor, and receipt/propulsion skills. However, balance and non-locomotor scores showed no significant changes. On the other hand, when ES was withdrawn for 6 months, there was uniform partial regression in scores. Moreover, re-institution of treatment by ES resulted in additional improvement in total gross motor, balance, locomotor, and receipt/propulsion skills, but not for non-locomotor skills. The authors concluded that in selective cases, especially children with mild CP, over-night ES may be a useful adjunct to conventional rehabilitation services. Although the findings by Pape et al appear to be encouraging, this was an uncontrolled study with 5 children who were 3 to 5 years old, a time when rapid changes are expected in these children. More importantly, no attempt was made to standardize physical therapy throughout the study. All but 1 subject continued to receive rehabilitative procedures which may have a confounding effect on the outcome of the study. It is unclear whether these improvements were translated into improvements in activities of daily living. Additionally, there were no data regarding the long-term effects of this treatment modality.

Hazlewood et al (1994) evaluated the effectiveness of ES in treating children with hemiplegic CP. Ten patients were given ES of the anterior tibial muscles by their parents daily for 1 hour for 35 consecutive days in conjunction with their physical therapy (PT) regimen. Ten patients who were matched for age, severity of gait pattern, and for limitation of range of passive dorsiflexion of the ankle served as controls and continued with their current PT program. Active and passive ranges of movement of the ankle, as well as knee and ankle motion during ambulation were recorded by means of electrogoniometers before and after ES. For passive joint-range measurements, there were no significant changes in the range of ankle plantar-flexion, or dorsiflexion with the knee flexed for patients who received tibial muscles ES. However, there was a significant increase in dorsiflexion of the ankle with the knee extended. The mean ranges of the stimulated group of patients for dorsiflexion with the knee extended increased from 40 to 60 % of the range of the non-affected side. For active joint-range measurements, there was a significant difference in the range of voluntary dorsiflexion when the patient was sitting, comparing the experimental and control groups post-test, but no significant differences comparing the pre-and post-changes of the 2 groups. Furthermore, gait analysis and ankle motion showed little change. The authors concluded that because of the complex and diverse pathology associated with CP, the application of ES for the treatment of children with this disorder requires further investigations to determine which types of CP patients are likely to benefit from ES as well as the desired parameters of stimulation before this modality should be used widely in the clinical setting.

Steinbok et al (1997) concluded that therapeutic ES may be beneficial in children with spastic CP who have undergone a selective posterior rhizotomy more than 1 year ago. However, the authors concluded that more research is needed to confirm these results. More importantly, it must be emphasized that these findings can not be extrapolated to the larger population of children with spastic CP who have not undergone selective posterior rhizotomy.

In a systematic review of the literature on ES for CP, Kerr et al (2004) concluded that "[t]here is more evidence to support the use of NMES than TES [threshold electrical stimulation]. However, the findings should be interpreted with caution as the studies had insufficient power to provide conclusive evidence for or against the use of these modalities." An earlier systematic evidence review by Boyd et al (2001) reached similar conclusions about the paucity of evidence for the use of ES for CP.

Bell's Palsy

Acute idiopathic facial paresis is often known as Bell's palsy. Treatment of idiopathic Bell's palsy is still not well-defined. Conservative approaches entail physiotherapies such as facial exercises, massage, and muscle relaxation, which may support rehabilitation and possibly reduce the production of pathological synkinesia. Medical treatments include botulinum toxin type A (Botox) as well as a combined regimen of cortisone, virostatic agents, hemorrheologic substances, and possibly antibiotics. Moreover, available evidence from RCTs does not show significant benefit from treating Bell's palsy with corticosteroids (Salinas et al, 2002). Surgical decompression of the facial nerve remains controversial.

Adour (1991) stated that decompression of the facial nerve and electrotherapy are not advised for the management of patients with idiopathic (Bell's) palsy. This is in agreement with Wolf who stated that ES should not be used in the treatment of Bell's palsy. Buttress and Herren (2002) reviewed the medical literature to ascertain whether ES had any advantages over facial exercises in promoting recovery after Bell's palsy. Of the 270 papers reviewed by the authors, only 1 presented the best evidence to answer the clinical question. The authors stated that there is no evidence to suggest that either facial exercises or ES is beneficial to patients with acute Bell's palsy. However, evidence does exist to suggest the use of ES in patients with chronic Bell's palsy, although the study design was not rigorous.

Foot Drop

Individuals with stroke, CP, multiple sclerosis, and SCI/traumatic brain injury may exhibit foot drop, a condition caused by weakness or paralysis of the muscles involved in lifting the front part of the foot. The WalkAide is a product of Myo-Orthotics Technology, a term coined by the manufacturer, Innovative Neurotronics (Austin, TX). According to the manufacturer, it represents the convergence of orthotic technology (which braces a limb) and ES (which restores specific muscle function). The WalkAide device is intended to counteract foot drop by producing dorsiflexion of the ankle during the swing phase of the gait. The device attaches to the leg, just below the knee, near the head of the fibula. During a gait cycle, the WalkAide stimulates the common peroneal nerve, which innervates the tibialis anterior and other muscles that produce dorsiflexion of the ankle. The WalkAide is designed to offer persons with foot drop increased mobility, functionality and independence. It was cleared by the FDA through the 510(k) process. However, there is currently insufficient evidence to support its use for foot drop and other indications. Prospective clinical studies of the WalkAide device are necessary to evaluate whether it improves function and reduces disability compared to standard bracing in persons with foot drop.

Sheffler and associates (2007) reported the findings of peroneal nerve stimulation in patients with hemiplegia. Two chronic stroke survivors who utilized an ankle foot orthosis (AFO) prior to study entry were evaluated at baseline and after 4 weeks of daily use of a surface peroneal nerve stimulator. Participants were assessed without their dorsiflexor assistive device, using the modified Emory Functional Ambulation Profile (mEFAP). The participants demonstrated improvement in all 5 components of the mEFAP relative to baseline. These case reports indicated that enhanced functional ambulation may be an important therapeutic effect of peroneal nerve stimulation. The authors stated that controlled trials are needed to demonstrate a cause-and-effect relationship.

Sheffler et al (2006) found equivalent effects of a transcutaneous peroneal nerve stimulator and an ankle foot orthosis in improving functional ambulation in persons with chonic stroke. The investigators compared the efficacy of the Odstock Dropped-Foot Stimulator (ODFS), a transcutaneous peroneal nerve stimulation device, versus an ankle foot orthosis (AFO) in improving functional ambulation of chronic stroke survivors. Fourteen chronic stroke survivors with foot-drop participated in the study. Participants received ambulation training under 3 test conditions:

ODFS,
customized AFO, and
no device.

Each participant was evaluated using the modified Emory Functional Ambulation Profile under the 3 test conditions. All participants were evaluated with a post-evaluation survey to solicit device feedback and preferences. Functional ambulation with the AFO was significantly improved, relative to no device, on the floor (P = 0.000), carpet (P = 0.013), and "up and go" test (P = 0.042). There was a trend toward significance on the obstacle (P = 0.092) and stair (P = 0.067) trials. Functional ambulation with the ODFS was significantly improved, relative to no device, on the carpet(P = 0.004). A trend toward significance on floor (P = 0.081), obstacle (P = 0.092), and stair (P = 0.079) trials was observed. The difference in functional ambulation between the AFO and ODFS showed a trend toward statistical significance on floor (P = 0.065) and up and go (P = 0.082) trials only. Given a choice between the ODFS and AFO for long-term correction of footdrop, participants indicated a preference for the ODFS. The authors concluded that the AFO and the ODFS may be comparable in their effect on improving functional ambulation as compared to no device. Specific characteristics of the ODFS may make it a preferred intervention by stroke survivors. The authors stated that more rigorously controlled trials are needed to confirm these findings.

A randomized controlled study found no therapeutic effect of an implanted peroneal functional electrical stimulator in patients with chronic stroke and foot drop. In a randomized controlled study, Kottink and colleagues (2008) examined the effect of an implantable peroneal nerve stimulator for 6 months versus an AFO in patients with chronic stroke and foot drop (n = 29). The mean time from stroke was 7.3 years (SD = 7.3), and all subjects were community ambulators. The FES group received the implantable stimulation system for correction of their foot drop. The control group continued using their conventional walking device (i.e., AFO, orthopedic shoes, or no walking device). All subjects were measured at baseline and at 4, 8, 12, and 26 weeks in the gait laboratory. The therapeutic effect of FES on the maximum value of the root mean square (RMSmax) of the tibialis anterior (TA) muscle with both flexed and extended knees and walking speed were selected as the primary outcome measures. The RMSmax of the peroneus longus (PL), gastrocnemius (GS), and soleus (SL) muscles with both flexed and extended knees and muscle activity of the TA muscle of the affected leg during the swing phase of gait were selected as secondary outcome measures. A significantly higher RMSmax of the TA muscle with extended knee was found after using FES. No change in walking speed was found when the stimulator was not switched on. A significantly increased RMSmax of the GS muscle with both flexed and extended knees was found after using FES. The authors concluded that functionally, no therapeutic effect of implantable peroneal nerve stimulation was found. However, the significantly increased voluntary muscle output of the TA and GS muscles after the use of FES suggested that there was a certain extent of plasticity in the subjects in this study.

In a randomized trial, Barrett et al (2009) found that exercise provided a greater effect on waking speed and endurance than functional electrical stimulation for people with multiple sclerosis and dropped foot. This two-group randomized trial assessed the effects of single channel common peroneal nerve stimulation on objective aspects of gait relative to exercise therapy for people with secondary progressive multiple sclerosis (SPMS). Forty-four people with a diagnosis of SPMS and unilateral dropped foot completed the trial. Twenty patients were randomly allocated to a group receiving FES and the remaining 24 to a group receiving a physiotherapy home exercise program for a period of 18 weeks. The exercise group showed a statistically significant increase in 10 m walking speed and distance walked in 3 min, relative to the FES group who showed no significant change in walking performance without stimulation. At each stage of the trial, the FES group performed to a significantly higher level with FES than without for the same outcome measures. The investigators concluded that exercise may provide a greater training effect on walking speed and endurance than FES for people with SPMS. FES may provide an orthotic benefit when outcome is measured using the same parameters. The authors stated that more research is required to investigate the combined therapeutic effects of FES and exercise for this patient group.

The NESS L300 Plus is the NESS L300 with a thigh cuff, which supposedly would provide added stability. According to Bioness, the L300 Plus System may help patients develop an even greater sense of confidence1 and allow them to enjoy a variety of daily activities. The BioNESS L300 is a wireless electrical stimulation (ES) unit, used to provide peroneal nerve stimulation to promote ankle dorsiflexion after ‘toe off’ and during the swing phase of gait. The system is used to support functional gait in acute and sub‐acute stroke patients who demonstrate foot drop as a result of first time stroke.

A Queensland Health Technology Assessment team’s Due Diligence (Queensland, 2012) found there is little evidence to suggest that there are major safety concerns related to BioNESS L300, although the long term effects of chronic use of external electrical stimulation devices is unknown. Studies have focused on the use of peroneal nerve stimulation in post-stroke rehabilitation. There were limited available studies that directly compared the new technology with physiotherapist manipulation. The studies that were available were generally not of high quality and often had little statistical power due to small numbers of participants. Of the literature that was assessed, the outcomes were, on the whole more positive than negative. Many studies suggested that more research should be undertaken on larger patient groups to further assess the intervention.

Hausdorff and Ring (2008) reported improved gait and dynamic stability in study of 24 patients experiencing foot drop with chronic hemiparesis. Patients were treated on an outpatient basis with the NESS L300.

van Swigchem et al (2010) evaluated whether community-dwelling chronic stroke patients wearing an ankle-foot orthosis would benefit from changing to FES for the peroneal nerve. Twenty-six patients began wearing the NESS L300. A baseline walking speed was recorded with the original ankle-foot orthosis. Walking speed was also measured at 2 and 8 weeks with both the orthosis and FES. Patients’ satisfaction was assessed with a questionnaire at baseline and at week 8. Results showed patients were more satisfied after the addition of FES. However, measurements of walking speed and physical activity could not objectify the reported benefits of FES. The authors noted additional outcome measures are needed to quantify the FES benefits in this population.

Danino et al (2013) discussed results of 5 hemiplegic patients treated with FES NESS L300 to improve gait. Results found all scores improved when walking with stimulation. However, no significant improvements were noted. At the 1-year follow-up, all patients expressed high satisfaction.

A randomized controlled trial found equivalent improvements with a Bioness L300 foot-drop stimulator and a conventional ankle-foot orthosis for post-stroke rehabilitation (Kluding et al, 2013). Drop foot after stroke may be addressed using an ankle foot orthosis (AFO) or a foot drop stimulator (FDS). The Functional Ambulation: Standard Treatment versus Electric Stimulation Therapy (FASTEST) trial was a multicenter, randomized, single-blinded trial comparing FDS and AFO for drop foot among people ≥ 3 months after stroke with gait speed ≤ 0.8 m/s. Participants (n=197; 79 females and 118 males; 61.14 ± 11.61 years of age; time after stroke 4.55 ± 4.72 years) were randomized to 30 weeks of either FDS or a standard AFO. Eight dose-matched physical therapy sessions were provided to both groups during the first 6 weeks of the trial. There was significant improvement within both groups from baseline to 30 weeks in comfortable gait speed (95% confidence interval for mean change, 0.11-0.17 m/s for FDS and 0.12-0.18 m/s for AFO) and fast gait speed. However, no significant differences in gait speed were found in the between-group comparisons. Secondary outcomes (standard measures of body structure and function, activity, and participation) improved significantly in both groups, whereas user satisfaction was significantly higher in the FDS group than in the control group. The investigators concluded that, using either an FDS or an AFO for 30 weeks yielded clinically and statistically significant improvements in gait speed and other functional outcomes. User satisfaction was higher in the FDS group. Although both groups did receive intervention, this large clinical trial provides evidence that FDS or AFO with initial physical therapy sessions can provide a significant and clinically meaningful benefit even years after stroke.

In a randomized controlled trial, Everaert et al (2013) found that a Walkaide (WA) foot-drop stimulator and a conventional ankle-foot orthosis (AFO) produced equivalent functional gains in walking performance. Individuals with stroke within the previous 12 months and residual foot drop were enrolled in a multicenter, randomized controlled, crossover trial. Subjects were assigned to 1 of 3 parallel arms for 12 weeks (6 weeks/device): arm 1 (WA-AFO), n = 38; arm 2 (AFO-WA), n = 31; arm 3 (AFO-AFO), n = 24. Primary outcomes were walking speed and Physiological Cost Index for the Figure-of-8 walking test. Secondary measures included 10-m walking speed and perceived safety during this test, general mobility, and device preference for arms 1 and 2 for continued use. Walking tests were performed with (On) and without a device (Off) at 0, 3, 6, 9, and 12 weeks. Both WA and AFO had significant orthotic (On-Off difference), therapeutic (change over time when Off), and combined (change over time On vs baseline Off) effects on walking speed. An AFO also had a significant orthotic effect on Physiological Cost Index. The WA had a higher, but not significantly different therapeutic effect on speed than an AFO, whereas an AFO had a greater orthotic effect than the WA (significant at 12 weeks). Combined effects on speed after 6 weeks did not differ between devices. Users felt as safe with the WA as with an AFO, but significantly more users preferred the WA. The investigators concluded that both the WA and AFO produce equivalent functional gains.

A randomized controlled trial found equivalent results with a Walkaide and an ankle foot orthosis in individuals with post-stroke foot drop (Bethoux et al, 2014). In a multi-center RCT, Bethoux et al (2014) compared changes in gait and quality of life between FES and an AFO in individuals with foot drop post-stroke. A total of 495 Medicare-eligible individuals at least 6 months post-stroke wore FES or an AFO for 6 months were included in this study. Primary end-points were 10-meter walk test (10MWT), a composite of the mobility, activities of daily living/instrumental activities of daily living, and social participation subscores on the Stroke Impact Scale (SIS), and device-related serious adverse event rate. Secondary end-points included 6-minute walk test, GaitRite functional ambulation profile (FAP), modified Emory functional ambulation profile (mEFAP), Berg balance scale (BBS), Timed Up and Go, individual SIS domains, and Stroke-Specific Quality of Life measures. Multiply imputed intention-to-treat analyses were used with primary end-points tested for non-inferiority and secondary endpoints tested for superiority. A total of 399 subjects completed the study. Functional electrical stimulation proved non-inferior to the AFO for all primary end-points. Both the FES and AFO groups improved significantly on the 10MWT. Within the FES group, significant improvements were found for SIS composite score, total mFEAP score, individual Floor and Obstacle course time scores of the mEFAP, FAP, and BBS, but again, no between-group differences were found. The authors concluded that use of FES is equivalent to the AFO. They stated that further studies should examine whether FES enables better performance in tasks involving functional mobility, activities of daily living, and balance.

Meilahn (2013) evaluated the tolerability and effectiveness of the WalkAide neuroprosthesis in a small observational study of 10 children (7 to 12 years old) with hemiparetic CP who used an AFO for correction of foot drop. The children tolerated the fitting and wore the device for the first 6 weeks. The mean wear time was 8.4 hours per day in the first 3 weeks and 5.8 hours per day in the next 3 weeks. Seven children (70 %) wore the device for the 3-month study period, with average use of 2.3 hours daily (range of 1.0 to 6.3 hours/day). Six children (60 %) continued to use the WalkAide device after study completion. Gait analysis was performed, but quantitative results were not included in the report. Although 50 % of the children were reported to have improved gait velocity, mean velocity was relatively unchanged with the WalkAide device. The main drawbacks of this study were the small sample size and self-selection of study subjects based on their willingness to try the device.

A study by Damiano et al (2013) found increases in muscle thickness with use of the WalkAide device, but no permanent improvements in voluntary ankle control. The primary goal of this study was to determine whether repetitive FES (WalkAide) for unilateral foot drop increases TA muscle size compared with an untreated baseline and the contralateral side in children with CP. Secondary goals were to determine whether positive changes in muscle size and gait, if found, accumulated during the 3 intervals during which participants used the device. Of 21 participants selected for the study, 7 were excluded because they either did not complete the entire 10-month study (n = 5) or had poor or missing ultrasound data for 1 or more time-points. The analysis was based upon the 14 remaining participants. Participants were independent ambulators with inadequate dorsiflexion in swing, with a mean age of 13.1 years, evaluated before and after the 3-month baseline, 1-month device accommodation, 3-month primary intervention, and 3-month follow-up phases. The FES device (WalkAide) stimulated the common tibial nerve to dorsiflex the ankle and evert the foot; TA muscle ultrasound, gait velocity, and ankle kinematic data for barefoot and device conditions were reported. The authors reported that ultrasound measures of TA anatomic cross-sectional area and muscle thickness increased with the WalkAide compared with the contralateral untreated side. Maximum ankle dorsiflexion decreased at baseline but improved or was maintained during the intervention phase with and without the WalkAide, respectively. Muscle size gains were preserved at follow-up, but barefoot ankle motion returned to baseline values. The authors concluded that the WalkAide device produced evidence of use-dependent muscle plasticity in children with CP, but that permanent improvements in voluntary ankle control after use of the WalkAide were not demonstrated.

In a pilot study, Miller et al (2015) compared the immediate orthotic effect on walking of 2 different devices: the Odstock Dropped Foot Stimulator (ODFS) and WalkAide (WA). A total of 20 people with multiple sclerosis (pwMS) (10 females, 10 males, mean age of 50.4 ± 7.3 years) currently using ODFS were recruited. Participants walked for 5 minutes around an elliptical 9.5-m course at their preferred walking speed; once with ODFS, once with WA and once without FES on the same day of testing. Gait speed, distance and energy cost were measured. There was a statistically significant increase in walking speed for the ODFS (p = 0.043) and a near to significant increase for the WA (p = 0.06) in comparison to without FES. There were no differences between the ODFS and WA in terms of either walking speed (p = 0.596) or energy cost (p = 0.205). The authors concluded that this was the first study to compare the effects of 2 different FES devices on walking. They stated that further research recruiting a larger cohort of FES naive participants is needed. Implications for rehabilitation FES used for foot drop in MS is effective in improving the speed of walking. The Odstock Dropped Foot Stimulator and the WalkAide have similar orthotic effects on the speed and energy cost of walking in people with MS. They stated that further research is needed to compare FES devices, recruiting treatment of naive participants for a fully powered RCT. The authors noted a number of limitations of this study. Subjects were tested for 5 minutes, so that participants in the study only had limited time to adapt to the different modes. This limitation in the study design could have biased the results in favor of ODFS. Bias may also have resulted from an inability to blind participants and investigators to the devices being administered, particularly where a ‘‘new device’’ is being introduced. The authors stated that future studies comparing FES devices should aim to recruit larger number of subjects naive to FES, evaluating the effect over a longer time frame.

Functional electrical stimulation has been used to correct drop foot following stroke or multiple sclerosis; however, previous studies have shown that a significant minority have difficulty identifying correct sites to place the electrodes in order to produce acceptable foot movement. Recently there has been some interest in the use of “virtual electrodes”, the process of stimulating a subset of electrodes chosen from an array, thus allowing the site of stimulation to be moved electronically rather than physically. Prenton et al (2014) examined the feasibility of unsupervised community use of an array-based automated setup (AS) FES system for foot-drop (ShefStim). Participants' gait, total setup (TS) times and satisfaction were evaluated twice in the gait laboratory. Usage, AS times and problems encountered were recorded during a 2-week period of unsupervised use. Participants (n = 7) with diagnosis of unilateral foot-drop of central neurological origin (greater than 6 months), who were regular users of a foot-drop FES system (greater than 3 months). Main outcome measures included logged usage; TS times for both FES systems and logged AS times for the array-based AS FES system; diary recording of problems experienced; Quebec User Evaluation of Satisfaction with assistive Technology (QUEST 2.0) questionnaire; walking speed; ankle angles at initial contact and foot clearance during swing. All participants were able to use the array-based AS FES system. Total setup took longer with it than participants' own FES systems and AS was longer than in a previous study of a similar system. Some problems were experienced but overall participants were as satisfied with this system as their own FES systems. The increase in walking speed (n = 7), relative to no stimulation, was comparable between both systems and appropriate ankle angles at initial contact (n = 7) and foot clearance during swing (n = 5) were greater with the array-based AS FES system. The authors concluded that this study demonstrated, for the first time, that an array-based AS FES system for foot-drop can be successfully used unsupervised. Despite setup taking longer and some problems users are satisfied with it and it would appear as effective, if not better, at addressing the foot-drop impairment. Moreover, they stated that further product development of this unique system, followed by a larger-scale and longer-term study is needed before firm conclusions about its effectiveness can be reached.

In an acute, open-labelled comparative observation trial, Scott et al (2013) examined if the application of FES improves gait kinematics and walking ability in people with MS who experience foot-drop. A total of 12 patients (3 females and 9 males, Expanded Disability Status Scale [EDSS] 2-4) with relapsing remitting multiple sclerosis (RRMS; 47.8 years (S.D. 6.6)) who were new users of FES were included in this study. Gait kinematics was recorded using 3D gait analysis. Walking ability was assessed through the 10-m walk test and the 6-min walk test. All assessments were performed with and without the assistance of FES. The effect of FES was analyzed using paired t-tests. Ankle dorsiflexion at initial contact (p = 0.026), knee flexion at initial contact (p = 0.044) and peak knee flexion during swing (p = 0.011) were significantly greater while walking with FES. The increased peak dorsiflexion in swing of nearly 4 degrees during FES- assisted walking approached significance (p = 0.069). The 10-m walk time was significantly improved by FES (p = 0.004); but the 6-min walk test was not. The authors concluded that the acute application of FES resulted in an orthotic effect through a change in ankle and knee kinematics and increased walking speed over a short distance in people with MS who experienced foot-drop. They stated that “The study is limited by the small sample size, and the large standard deviations of the outcome measures indicating a substantial variation among the participants in both walking pattern and performance. However, the study was sufficiently powered to detect statistically significant differences in both gait kinematics and walking performance between the no FES and FES conditions at group level. Future studies are required to evaluate whether the benefit of FES depends on patient characteristics such as type and progression of MS, neuromuscular properties and gait pattern”. They noted that “Further appropriately powered long-term studies into the effects of prolonged use of FES on the gait kinematics of people with MS are required in order to explain the altered gait mechanisms, which result in the long-term orthotic effects in people with MS”.

In a feasibility study, Taylor et al (2014) examined the effect of FES for dropped foot and hip instability in combination with physiotherapy core stability exercises. A total of 28 patients with secondary progressive MS and unilateral dropped foot participated in a randomized cross-over trial. Group 1 received FES for correction of dropped foot for 6 weeks with the addition of hip extension for a further 6 weeks. In weeks 12 to 18, FES was continued with the addition of 8 sessions of core stability physiotherapy with home-based exercise. Functional electrical stimulation and home-based exercise were continued until weeks 19 to 24. Group 2 received the same physiotherapy intervention over the first 12 weeks, adding FES in the second 12 weeks. Functional electrical stimulation improved walking speed and Rivermead Observational Gait Analysis (ROGA) score, whereas physiotherapy did not. Adding gluteal stimulation further improved ROGA score. Both interventions reduced falls, but adding FES to physiotherapy reduced them further. Functional electrical stimulation had greater impact on Multiple Sclerosis Impact Scale, MSIS-29. The authors concluded that the intervention was feasible; FES for dropped foot may improve mobility and quality of life and may reduce falls. Adding gluteal stimulation further improved gait quality. Adding physiotherapy may have enhanced the effect of FES, but FES had the dominant effect. This was a small (n = 28) feasibility study. The authors noted that “A possible confounding effect on this study was the comparability of Groups 1 and 2. While there was not a significance difference in EDSS between groups at recruitment, there was a greater use of assistive devices by Group 2, suggesting that they may have had a greater degree of disability. However, no correlation could be found between EDSS score and either change in ROGA or walking speed at week 24, suggesting that this discrepancy between the groups did not influence the trial results. There is further need for caution in the interpretation of the results of this study due to the small sample size. The study was not powered to produce definitive results”.

In a case-series study, Street et al (2015) determined the effectiveness of FES on foot-drop in patients with MS using data from standard clinical practice. A total of 187 patients (117 females and 70 males, mean number of years since diagnosis 11.7, range of years 1 to 56, age range of 27 to 80, average age of 55 years) with MS who have foot-drop were included in this study; 166 were still using FES after 20 weeks with 153 patients completing the follow-up measures. Intervention was FES of the common peroneal nerve (178 unilateral, 9 bilateral FES users). Outcome measures were clinically meaningful changes (i.e., greater than 0.05 ms-1 and greater than 0.1ms-1) and functional walking category derived from 10-meter walking speed. An increase in walking speed was found to be highly significant (p < 0.001), both initially where a minimum clinically meaningful change was observed (0.07 ms-1) and after 20 weeks with a substantial clinically meaningful change (0.11 ms-1). After 20 weeks treatment responders displayed a 27 % average improvement in their walking speed. No significant training effect was found. Overall functional walking category was maintained or improved in 95 % of treatment responders. The authors concluded that FES of the dorsiflexors is a well-accepted intervention that enables clinically meaningful changes in walking speed leading to preserved or increased functional walking category. The main drawbacks of this study were the lack of randomization and a control group. The authors also noted that “A further limitation is that the values for a clinically meaningful change in walking speed were derived from a general elderly population. Furthermore, the functional walking categories derived by Perry were from stroke survivors. The cohort from the current study was generally younger and had a disability specific to MS that may have been more profound than that of a general elderly or stroke population. This may suggest that a threshold for a clinically meaningful change may be overestimated in a more disabled population. The final sample consisted of 70 % of those assessed for eligibility, providing an indication of the proportion of patients with MS that the findings may be applied to. Further research using appropriate outcome measures could be used to assess the degree of benefit that patients, who are unable to complete the 10-m walking protocol at baseline, may gain from FES as they progress with their treatment”.

In a systematic review and meta-analysis, Miller and colleagues (2017) reviewed the effectiveness of FES used for foot drop in people with MS on gait speed in short and long walking performance tests. A total of 5 databases (Cochrane Library, CINAHL, Embase, Medline, and PubMed) and reference lists were searched. Studies of both observational and experimental design where gait speed data in patients with MS could be extracted were included. Data were independently extracted and recorded; methodological quality was assessed using the Effective Public Health Practice Project tool. A total of 19 studies (described in 20 articles) recruiting 490 patients with MS were identified and rated as moderate or weak, with none gaining a strong rating. All studies rated weak for blinding. Initial and ongoing orthotic and therapeutic effects were assessed regarding the effect of FES on gait speed in short and long walking tests. Meta-analyses of the short walk tests revealed a significant initial orthotic effect (t = 2.14, p = 0.016), with a mean increase in gait speed of 0.05m/s, and ongoing orthotic effect (t = 2.81, p = 0.003), with a mean increase of 0.08m/s. There were no initial or ongoing effects on gait speed in long walk tests and no therapeutic effect on gait speed in either short or long walk tests. The authors concluded that FES used for foot drop has a positive initial and ongoing effect on gait speed in short walking tests. Moreover, they stated that further fully powered RCTs comparing FES with alternative treatments are needed.

Diabetic Neuropathy

The American Association of Neuromuscular and Electrodiagnostic Medicine, the American Academy of Neurology, and the American Academy of Physical Medicine & Rehabilitation (Bril et al, 2011) developed a scientifically sound and clinically relevant evidence-based guideline for the treatment of painful diabetic neuropathy (PDN). The basic question that was asked was: "What is the efficacy of a given treatment (pharmacological: anticonvulsants, antidepressants, opioids, others; non-pharmacological: electrical stimulation, magnetic field treatment, low-intensity laser treatment, Reiki massage, others) to reduce pain and improve physical function and quality of life (QOL) in patients with PDN"? A systematic review of literature from 1960 to August 2008 was performed, and studies were classified according to the American Academy of Neurology classification of evidence scheme for a therapeutic article. Recommendations were linked to the strength of the evidence. The results indicated that pregabalin is established as effective and should be offered for relief of PDN (Level A). Venlafaxine, duloxetine, amitriptyline, gabapentin, valproate, opioids (morphine sulfate, tramadol, and oxycodone controlled-release), and capsaicin are probably effective and should be considered for treatment of PDN (Level B). Other treatments have less robust evidence, or the evidence is negative. Effective treatments for PDN are available, but many have side effects that limit their usefulness. Few studies have sufficient information on their effects on function and QOL.

Functional Electrical Stimulation / Neuromuscular Electrical Stimulation for Ambulatory Function in Patients with Multiple Sclerosis

In a case-series study, Wahls et al (2010) examined if NMES would improve gait disability in patients with secondary progressive multiple sclerosis (SPMS) or primary progressive multiple sclerosis (PPMS). Participants were treated using NMES coupled with a home-exercise program (HEP) to treat MS-related gait disability. Between June 2007 and June 2009, a licensed physical therapist used NMES coupled with a HEP to work with patients who had SPMS/PPMS and MS-related gait disability. All of the cases in which an NMES test session of NMES was conducted were included in the case series. Data regarding MS symptoms, treatment, gait, and function were abstracted from the PT clinic notes. Results of assessment with the Kurtzke EDSS at presentation and at most recent visit were abstracted from the clinical record by the treating physical therapist. A total of 9 patients (7 with SPMS and 2 with PPMS) met inclusion criteria for review. Mean of years of diagnosis was 10.4 (range of 4 to 15), and mean EDSS score at presentation was 5.9 (range of 4.5 to 6.5). Mean of days of NMES was 140 (range of 22 to 495). Mean EDSS scores improved by 0.78 (range of 0 to 2.0). The authors concluded that NMES was associated with measurable gains in ambulatory function in patients with gait disability associated with SPMS and PPMS. Moreover, they stated that additional studies are needed.

In a systematic review, Springer and colleagues (2017) evaluated the literature describing the orthotic and therapeutic effects of FES on gait in patients with MS. The PubMed, CINAHL, and ProQuest databases were searched. Included were studies that evaluated therapeutic and/or orthotic effects of FES in patients with MS with at least 1 outcome measure related to gait. Methodology was assessed using the Downs and Black checklist. A total of 12 relevant studies were reviewed; their methodological quality ranged from 14 to 21 of 28; 11 studies reported the effects of peroneal stimulation. Most found a significant orthotic effect (measured during stimulation), mainly on walking speed. Only 3 assessed the therapeutic effect (carry-over), which was not significant. The authors concluded that the evidence presented in this review suggested that FES has a positive orthotic effect on walking in patients with MS. Yet, more robust clinical trials are needed to substantiate this finding. They stated that therapeutic effectiveness of FES was not demonstrated, and almost all studies tested a single channel peroneal stimulator; future studies involving FES technological innovations with advanced clinical approaches might contribute to a carry-over effect from FES and increase the percentage of patients with MS who might benefit from this technology.

Pilutti and Motl (2019) noted that there has been substantial interest in the role of exercise for managing impairments, limitations, and disability progression among persons with MS (PwMS). Despite established benefits of exercise training for persons who have mild-to-moderate MS, the ability to deliver exercise to persons who experience higher disability remains challenging. One promising approach for exercise in this population is FES- cycling. These investigators summarized the current evidence for FES-cycling as an exercise training modality in PwMS with respect to prescription, safety, tolerability, and acute and chronic effects. They searched the literature for studies involving FES-cycling exercise in PwMS published in English up until July 2019. A total of 8 studies were retrieved: 2 studies examined acute effects, 2 studies examined chronic effects, and 4 studies reported on both acute and chronic effects of FES-cycling exercise. The overall quality of the studies was low, with only 1 small RCT. There was limited but promising evidence for the application of FES-cycling exercise among PwMS who have moderate-to-severe disability. Subjects were capable of engaging in regular FES-cycling exercise (approximately 30 mins, 2 to 3 times/week), with few, mild AEs experienced. The authors concluded that preliminary evidence from small, mostly uncontrolled trials supported the potential benefits of FES-cycling on physiological fitness, walking mobility, and symptoms of fatigue and pain. Moreover, these researchers stated that high-quality RCTs of FES-cycling exercise are needed for providing recommendations for integrating exercise training in the management of advanced MS.

Scally and colleagues (2020) stated that PwMS are at an increased risk of diseases associated with low levels of physical activity (PA). De-conditioning may lead to an acceleration in the development of secondary complications from MS, impairing physical function and exacerbating disease progression; and FES-cycling may provide a suitable lower limb exercise intervention for PwMS with mobility impairment. The effects of FES-cycling on cardiovascular, musculoskeletal and functional outcomes for PwMS with mobility impairment are yet to be investigated to-date. These researchers examined the outcomes of PwMS with mobility impairment following FES-cycling intervention. They carried out a systematic search of 4 electronic databases (Medline, Web of Science, CINAHL and PEDro) from their inception to January 8, 2019. Inclusion criteria were: subjects with definite diagnosis of MS, participants had to be aged 18 years or older, participants with mobility impairment (determined as an average participant EDSS greater than or equal to 6.0), and evaluation of FES-cycling as an intervention study. Initial searches found 1,163 studies; 9 of which met the full inclusion criteria: 5 pre-post studies with no control group, 2 RCTs, 1 retrospective study and 1 case study; 2 studies had the same participant group and intervention but reported different outcomes. Outcome data were available for n = 76 unique participants, with n = 82 completing a FES-cycling intervention. Of the n = 4 papers with clear drop-out rates, pooled drop-out rate was 25.81 %; 2 papers reported non-significant improvements in aerobic capacity following a FES-cycling intervention; 4 papers reported no change in lower limb strength and 2 papers reported significant reductions in spasticity post-training; 4 studies failed to provide information regarding AEs with the other studies reporting n = 10 AEs across 36 participants. The authors concluded that the findings of this study suggested that FES-cycle training may reduce cardiovascular disease risk alongside trends for a reduction in spasticity post-training, however, the overall study quality was poor, with limitations in study protocols and outcomes, thus precluding any definitive conclusions.

Neuromuscular Electrical Stimulation for Knee Osteoarthritis

Giggins et al (2012) evaluated the effectiveness of surface NMES in the treatment of knee osteoarthritis. A systematic review and meta-analysis of RCTs and controlled clinical trials was performed. Studies were identified from databases (MEDLINE, EMBASE, CINAHL, Sports Discus, PEDro and the Cochrane Library) searched to January 2011 using a battery of keywords. Two reviewers selected studies meeting inclusion criteria. The methodological quality of the included studies was assessed using the Thomas Test and the strength of the evidence was then graded using the Agency for Health Care Policy and Research guidelines. Data were pooled and meta-analyses were performed. A total of 9 RCTs and 1 controlled clinical trial, studying a total of 409 participants (n = 395 for RCTs, and n = 14 for controlled trial) with a diagnosis of osteoarthritis were included. Inconsistent evidence (level D) was found that NMES has a significant impact on measures of pain, function and quadriceps femoris muscle strength in knee osteoarthritis. The authors concluded that the role of NMES in the treatment of knee osteoarthritis is ambiguous. Thus, future work is needed in this field to clearly establish the role of NMES in this population.

Threshold Electrical Stimulation

Threshold electrical stimulation (also known as therapeutic electrical stimulation) entails the use of of low-intensity ES, usually at night. For patients with CP, threshold electrical stimulation (TES) aims to strengthen muscles weakened by non-use and to increase joint mobility, thus, resulting in improved voluntary motor function.

In a randomized, controlled, cross-over trial, Sommerfelt et al (2001) evaluated the effect of TES applied to antagonists of spastic leg muscles on gross motor function in children with spastic diplegic CP. A total of 12 children between 5 and 12 years of age completed a 24-month cross-over study in which 6 were randomly assigned to receive TES for the first 12 months and the remaining 6 for the last 12 months. Physiotherapy and a home training program were not altered. All were evaluated blindly in terms of tests of motor function and video recordings at the start and at 12 and 24 months. At the end of the study parents/carers gave a subjective assessment of the effect of TES. No significant effect of TES on motor or ambulatory function was found on the blinded evaluation, but parents of 11 of the 12 children stated that TES had a significant effect. The authors concluded that it is unlikely that TES has a significant effect on motor and ambulatory function in chilren with spastic diplegia CP.

In a randomized, double-blind, placebo-controlled clinical trial, Dali et al (2002) studied whether a group of stable children with CP (36 boys, 21 girls; mean age of 10 years 11 months with a range of 5 to 18 years) would improve their motor skills after 12 months of TES; 2/3 received active and 1/3 received inactive stimulators. The primary outcome was change in summary indices of the performance measurements in a set of motor function tests. Tests were videotaped and assessed blindly to record qualitative changes that might not be reflected in performance measurements. Fifty-seven of 82 subjects who were able to walk at least with a walker, completed all 12 months of treatment (hemiplegia n = 25; diplegia n = 32). There was no significant difference between active and placebo treatment in any of the tested groups, nor combined. Visual and subjective assessments favored TES (non-significant), whereas objective indices showed the opposite trend. The authors concluded that TES in these patients did not have any significant clinical effect during the test period.

In a randomized placebo-controlled study, Kerr et al (2006) examined the effectiveness of NMES and TES in strengthening the quadriceps muscles of both legs in children with CP. A total of 60 children (38 males, 22 females; mean age of 11 years [SD 3 years 6 months]; age range of 5 to 16 years) were randomized to one of the following groups: NMES (n = 18), TES ( n= 20), or placebo (n = 22). Clinical presentations were diplegia (n = 55), quadriplegia (n = 1), dystonia (n = 1), ataxia (n = 1), and non-classifiable CP (n = 2). Thirty-four children walked unaided, 17 used posterior walkers, 6 used crutches, and the remaining 3 used sticks for mobility. Peak torque of the left and right quadriceps muscles, gross motor function, and impact of disability were assessed at baseline and end of treatment (16 weeks), and at a 6-week follow-up visit. No statistically significant difference was demonstrated between NMES or TES versus placebo for strength or function. Statistically significant differences were observed between NMES and TES versus placebo for impact of disability at the end of treatment, but only between TES and placebo at the 6-week follow-up. The authors concluded that further evidence is needed to show whether NMES and/or TES may be useful as an adjunct to therapy in ambulatory children with diplegia who find resistive strengthening programs difficult.

In a systematic review with meta-analysis of randomized trials, Scianni et al (2009) examined if strengthening interventions increase strength without increasing spasticity and improve activity, and if there is there any carry-over after cessation in children and adolescents with CP? Children with spastic CP between school age and 20 years were included in this analysis. Strengthening interventions involved repetitive, strong, or effortful muscle contractions and progressed as ability changed; and they included biofeedback, ES, and progressive resistance exercise. Strength was measured as continuous measures of maximum voluntary force or torque production. Spasticity was measured as velocity-dependent resistance to passive stretch. Activity was measured as continuous measures, e.g., 10-m Walk Test, or using scales e.g., the Gross Motor Function Measure. A total of 6 studies were identified and 5 had data that could be included in a meta-analysis. Strengthening interventions had no effect on strength (standardized mean difference [SMD] 0.20, 95 % CI: -0.17 to 0.56), no effect on walking speed (MD 0.02 m/s, 95 % CI: -0.13 to 0.16), and had a small statistically-significant but not clinically-worthwhile effect on Gross Motor Function Measure (MD 2 %, 95 % CI: 0 to 4). Only 1 study measured spasticity but did not report the between-group analysis. The authors concluded that in children and adolescents with CP who are walking, the current evidence suggests that strengthening interventions are neither effective nor worthwhile.

Cauraugh et al (2010) performed a systematic review and meta-analysis using the International Classification of Functioning to determine the summary effect of ES on impairment and activity limitations relevant to gait problems of children with CP. These researchers identified 40 CP and ES studies, and 17 gait studies qualified for inclusion. Applying enablement classification methods to walking abnormalities created 2 subgroups: impairment (n = 14) and activity limitations (n = 15). Overall, 238 subjects experienced ES treatments and 224 served as a no stimulation control group. Calculations followed conventional data extraction and meta-analysis techniques:

individual standardized mean differences,
summary effect size,
² heterogeneity test, (
fail-safe N analysis and
moderator variable analyses.

The authors cited reservation about recommending ES as an effective intervention for individuals with CP. Outside of the laboratory-testing experiments, "no quantitative, functional immediate or longitudinal effects beyond the testing situations were reported in the studies. Thus, long-term effects of various types of electrical stimulation on gait challenges in children with cerebral palsy would advance our understanding".

Negm et al (2013) examined if low frequency (less than or equal to 100 Hz) pulsed subsensory TES produced either through pulsed electro-magnetic field (PEMF) or pulsed electrical stimulation (PES) versus sham PEMF/PES intervention is effective in improving pain and physical function at treatment completion in adults with knee osteoarthritis (OA) blinded to treatment. The relevant studies were identified by searching 8 electronic databases and hand search of the past systematic reviews on the same topic till April 5, 2012. These investigators included RCTs of people with knee OA comparing the outcomes of interest for those receiving PEMF/PES with those receiving sham PEMF/PES. Two reviewers independently selected studies, extracted relevant data and assessed quality. Pooled analyses were conducted using inverse-variance random effects models and standardized mean difference (SMD) for the primary outcomes. A total of 7 small trials (459 participants/knees) were included. PEMF/PES improves physical function (SMD = 0.22, 95 % CI: 0.04 to 0.41, p = 0.02, I(2) = 0 %), and does not reduce pain (SMD = 0.08, 95 % CI: -0.17 to 0.32, p = 0.55, I(2) = 43 %). The strength of the body of evidence was low for physical function and very low for pain. The authors concluded that current evidence of low and very low quality suggested that low frequency (less than or equal to 100 Hz) pulsed subsensory TES produced either through PEMF/PES versus sham PEMF/PES is effective in improving physical function but not pain intensity at treatment completion in adults with knee OA blinded to treatment. Moreover, they noted that methodologically rigorous and adequately powered RCTs are needed to confirm these findings.

Improvement of Ambulatory Function/Muscle Weakness in Individuals with Progressive Diseases

Pereira et al (2012) conducted a systematic review on the effectiveness of FES in improving lower extremity function in chronic stroke. Multiple databases (PubMed, CINAHL, EMBASE, and Scopus) were searched for relevant articles. Studies were included for review if

greater than or equal to 50 % of the study population has sustained a stroke,
the study design was a RCT,
the mean time since stroke was greater than or equal to 6 months,
FES or NMES was compared to other interventions or a control group, and
functional lower extremity outcomes were assessed.

Methodological quality was assessed using the PEDro tool. A standardized mean difference (SMD ± SE and 95 % CI) was calculated for the 6-min walk test (6MWT). Pooled analysis was conducted for treatment effect of FES on the 6MWT distance using a fixed effects model. A total of 7 RCTs (PEDro scores 5 to 7) including a pooled sample size of 231 participants met inclusion criteria. Pooled analysis revealed a small but significant treatment effect of FES (0.379 ± 0.152; 95 % CI: 0.081 to 0.677; p = 0.013) on 6MWT distance. The authors concluded that FES may be an effective intervention in the chronic phase post-stroke. However, its therapeutic value in improving lower extremity function and superiority over other gait training approaches remains unclear.

In a Cochrane review, Maddocks et al (2013) evaluated the effectiveness of NMES for improving muscle strength in adults with advanced disease. The secondary objective of this study was to examine the acceptability and safety of NMES, and changes in muscle function (strength or endurance), muscle mass, exercise capacity, breathlessness and health-related quality of life. Studies were identified from searches of The Cochrane Library, MEDLINE, EMBASE, CINAHL and PsycINFO databases to July 2012, citation searches, conference proceedings and previous systematic reviews. These investigators included RCTs in adults with advanced chronic obstructive pulmonary disease (COPD), chronic heart failure, cancer or human immunodeficiency virus/acquired immunodeficiency syndrome (HIV/AIDS) comparing a program of NMES as a sole or adjunct intervention to no treatment, placebo NMES or an active control. They imposed no language restriction. Two review authors independently extracted data on study design, participants, interventions and outcomes. They assessed risk of bias using the Cochrane Collaboration's tool; and calculated mean differences (MD) or standardized mean differences (SMD) between intervention and control groups for outcomes with sufficient data; for other outcomes these researchers described findings from individual studies. A total of 11 studies involving 218 participants met the inclusion criteria across COPD, chronic heart failure and thoracic cancer. Neuromuscular ES significantly improved quadriceps strength by a SMD of 0.9 (95 % CI: 0.33 to 1.46), equating to approximately 25 Newton meters (Nm) (95 % CI: 9 to 41). Mean differences across various walking tests, favoring NMES, were 40 m (95 % CI: -4 to 84) for the 6MWT, 69 m (95 % CI: 19 to 119) for the incremental shuttle walk test and 160 m (95 % CI: 34 to 287) for the endurance shuttle walk test. Limited evidence was available for the assessment of other secondary outcomes. The authors concluded that NMES appears an effective means of improving muscle weakness in adults with progressive diseases such as COPD, chronic heart failure and cancer. Moreover, they stated that further research is needed to clarify its place in clinical practice, by determining the optimal parameters for a NMES program, the patients most likely to benefit, and its impact on morbidity and service use.

Phrenic Nerve Stimulation for Central Sleep Apnea/Ventilator-Dependent Respiratory Failure

In a prospective, multi-center, non-randomized study, Abraham and colleagues (2015) evaluated the safety and effectiveness of chronic, transvenous, unilateral phrenic nerve stimulation (PNS) in the treatment of central sleep apnea (CSA). A total of 57 patients with CSA underwent baseline polysomnography followed by transvenous PNS system implantation and follow-up. Feasibility was assessed by implantation success rate and therapy delivery. Safety was evaluated by monitoring of device- and procedure-related adverse events (AEs). Effectiveness was evaluated by changes in the apnea-hypopnea index (AHI) at 3 months. Quality of life at 6 months was evaluated using a sleepiness questionnaire, patient global assessment, and, in patients with heart failure (HF) at baseline, the Minnesota Living With Heart Failure Questionnaire. The study met its primary end-point, demonstrating a 55 % reduction in AHI from baseline to 3 months (49.5 ± 14.6 episodes/hour versus 22.4 ± 13.6 episodes/hour of sleep; p < 0.0001; 95 % CI for change: -32.3 to -21.9). Central apnea index, oxygenation, and arousals significantly improved. Favorable effects on quality of life and sleepiness were noted. In patients with HF, the Minnesota Living With Heart Failure Questionnaire score significantly improved. Device- or procedure-related serious AEs occurred in 26 % of patients through 6 months post-therapy initiation, predominantly due to lead re-positioning early in the study. Therapy was well-tolerated. Effectiveness was maintained at 6 months. The authors concluded that transvenous, unilateral PNS appeared safe and effective for treating CSA. Moreover, they stated that these findings should be confirmed in a prospective RCT.

Costanzo and associates (2015) stated that the remede System (Respicardia, Minnetonka, MN) is a new physiologic treatment that uses transvenous PNS to contract the diaphragm, thereby stabilizing gas exchange and restoring normal breathing throughout the sleep period. This is a prospective multi-center randomized trial with blinded end-points evaluating the safety and effectiveness of the remede System. Up to 173 patients with CSA will be randomized 1:1 to remede System therapy initiated at 1 month after implantation (treatment) or to an implanted remede System that will remain inactive for 6 months (control). Primary effectiveness end-point is the percentage of patients who experience a reduction in AHI by a greater than or equal to 50 % at 6 months (responder analysis). Primary safety end-point is freedom from serious AEs through 12 months. Secondary end-points include sleep-disordered breathing parameters, sleep architecture, Epworth Sleepiness Scale score, and Patient Global Assessment. The authors stated that this study is the first RCT of the safety and effectiveness of the remede System for the treatment of CSA.

Zhang et al (2017) stated that CSA is common in patients with HF and is associated with poor quality of life and prognosis. Early acute studies using transvenous PNS to treat CSA in HF have shown a significantly reduction of CSA and improvement of key polysomnographic parameters. In a prospective, non-randomized study, these researchers evaluated the safety of and effectiveness of chronic transvenous PNS with an implanted neurostimulator in HF patients with CSA (n = 8). The stimulation lead, which connected to a proprietary neurostimulator, was positioned in either the left peri-cardiophrenic or right brachiocephalic vein. Monitoring during implantation and 6-monthly follow-ups were performed; 6 of the implanted 8 patients completed the study (1 was lost to follow-up; 1 died from pneumonia). Neither side effects nor AEs related to stimulation occurred. During the 6-monthly follow-ups, 1 patient had a lead dislodgement in the first month and the lead was subsequently re-positioned. No additional lead dislodgements occurred. There were no significant changes in sleep habits, appetite, bleeding or infections. Compared with the parameters before stimulator implantation, there were significant improvement in AHI, central apnea index, left ventricular ejection fraction and 6-min walk distance (all p < 0.01). The authors concluded that the use of chronic transvenous PNS appeared to be safe and feasible in HF patients with CSA. Moreover, they stated that large multi-center clinical trials are needed to confirm safety and effectiveness in this population.

Furthermore, an UpToDate review on “Central sleep apnea: Treatment” (Badr, 2015) does not mention phrenic nerve stimulation as a therapeutic option.

Jagielski and colleagues (2016) evaluated the 12-month clinical outcomes of patients with CSA treated with unilateral transvenous PNS in the prospective, multi-center, non-randomized remade System pilot study. A total of 47 patients with CSA were treated with the Remede System for a minimum of 3 months. Sleep-disordered breathing parameters were evaluated by polysomnography (PSG) at 3, 6, and 12-month follow-up. Sleep symptoms and QOL were also evaluated; 41 patients completed all follow-up PSGs and were included in the analysis. At 12 months, there was sustained improvement compared with baseline in the AHI (49.9 ± 15.1 versus 27.5 ± 18.3 events/hour, p < 0.001) and central apnea index (28.2 ± 15.0 versus 6.0 ± 9.2 events/hour, p < 0.001). Sustained improvement in the oxygen desaturation index (46.1 ± 19.1 versus 26.9 ± 18.0 events/hour, p < 0.001), rapid eye movement (REM) sleep (11.4 ± 6.1 % versus 17.1 ± 8.0 %, p < 0.001), and sleep efficiency (69.3 ± 16.9 % versus 75.6 ± 17.1 %, p = 0.024) were also observed. There were also continued favorable effects on sleepiness and QOL; 3 deaths unrelated to remade System therapy and 5 serious AEs occurred over 12 months of follow-up. The authors concluded that the findings of the present study demonstrated that in patients with CSA, unilateral transvenous PNS is associated with sustained improvement in key sleep parameters, sleep symptoms, and QOL over 12 months of follow-up.

In a prospective, multi-center, RCT, Costanzo and co-workers (2016) evaluated the safety and effectiveness of unilateral neurostimulation in patients with CSA. These investigators recruited patients from 31 hospital-based centers in Germany, Poland, and the USA. Participants had to have been medically stable for at least 30 days and have received appropriate guideline recommended therapy, be aged at least 18 years, be expected to tolerate study procedures, and willing and able to comply with study requirements. Eligible patients with an AHI of at least 20 events/hour, tested by PSG, underwent device implantation and were randomly assigned (1:1) by a computer-generated method stratified by site to either stimulation (treatment) or no stimulation (control) for 6 months. The primary effectiveness end-point in the intention-to-treat population was the comparison of the proportions of patients in the treatment versus control groups achieving a 50 % or greater AHI reduction from baseline to 6 months, measured by a full-night PSG assessed by masked investigators in a core laboratory. The primary safety end-point of 12-month freedom from serious AEs related to the procedure, system, or therapy was evaluated in all patients. Between April 17, 2013, and May 28, 2015, these researchers randomly assigned 151 eligible patients to the treatment (n = 73) or control (n = 78) groups. In the analysis of the intention-to-treat population, significantly more patients in the treatment group (35 [51 %] of 68) had an AHI reduction from baseline of 50 % or greater at 6 months than had those in the control group (8 [11 %] of 73; difference between groups 41 %, 95 % CI: 25 to 54, p < 0.0001); 138 (91 %) of 151 patients had no related-serious AEs at 12 months; 7 (9 %) cases of related-serious AEs occurred in the control group and 6 (8 %) cases were reported in the treatment group; 7 patients died (unrelated to implant, system, or therapy), 4deaths (2 in treatment group and 2 in control group) during the 6-month randomization period when PNS was delivered to only the treatment group and was off in the control group, and 3 deaths between 6 months and 12 months of follow-up when all patients received neurostimulation; 27 (37 %) of 73 patients in the treatment group reported non-serious therapy-related discomfort that was resolved with simple system re-programming in 26 (36 %) patients, but was unresolved in 1 (1 %) patient. The authors concluded that transvenous PNS significantly reduced the severity of CSA, including improvements in sleep metrics, and was well-tolerated. The clinically meaningful effects of the therapy were supported by the concordant improvements in oxygenation and QOL, making transvenous PNS a promising therapeutic approach for CSA.

Fox and associates (2017) noted that sleep-disordered breathing (SDB) and Cheyne-Stokes respiration (CSR) are associated with shorter survival in patients with HF. A novel treatment method for this patient group is unilateral PNS by the Remede system, which has recently been studied in a large RCT. Previous literature has shown efficacy and safety of the treatment with this 1st-generation device, but hardly any data are available on long-term clinical parameters, the Remede device's battery lifetime, device exchangeability, lead position stability, surgical accessibility, and manageability. These researchers performed Remede device replacements in consecutive patients for battery depletion, and documented clinical parameters, longevity, operation procedure, complications, and difficulties. All patients were on neurostimulation treatment by PNS when device replacement became necessary; AHI (from 45 ± 4/hour to 9 ± 4/hour), oxygen-desaturation index (from 35 ± 7/hour to 7 ± 6/hour), and time spent with oxygen saturation of less than 90 % (T < 90 % from 5 ± 7 % to 0 ± 0 %) were improved and improvements remained constant throughout the 4-year follow-up. Mean battery life was 4.2 ± 0.2 years and mean replacement procedure time was 25 ± 5.1 minutes. Apart from conventional X-ray documentation of stable lead positions in a long-term setting, no radiation or contrast dye usage was needed and no major complications occurred. In addition, clinical exercise capacity and sleepiness symptoms improved. The authors concluded that the novel Remede device showed sustained therapy efficacy and safety in terms of stable lead positions over 4 years. They stated that long-term PNS therapy for central SDB/CSR appeared feasible in a clinical routine setting.

Germany (2017) stated that CSA is common in HF and contributes to morbidity and mortality. Symptoms are often similar to those associated with HF and a high index of suspicion is needed. Testing is typically done in the sleep laboratory, but home testing equipment can distinguish between central and obstructive events. Treatments are limited. Mask-based therapies have been the primary treatment. Oxygen has some data but lacks long-term studies. Neurostimulation of the phrenic nerve is a new technology that has demonstrated improvement.

On October 6, 2017, the FDA approved the Remede System for adult patients who have been diagnosed with moderate-to-severe CSA. The Remede System is an implantable device that stimulates the phrenic nerve to stimulate breathing. The Remede System is comprised of a battery pack surgically placed subcutaneously in the upper chest area and thin wire leads that are inserted into the veins near the phrenic nerve that stimulates breathing. The system is programmed using an external System Programmer and Programming Wand. It monitors the patient’s respiratory signals during sleep and stimulates the nerve to move the diaphragm and restore normal breathing. The FDA evaluated data from 141 patients to assess the effectiveness of the Remede System in reducing AHI. After 6 months, AHI was reduced by 50 % or more in 51 % of patients with an active Remede System implanted; AHI was reduced by 11 % in patients without an active Remede System implanted. The most common AEs reported included concomitant device interaction, implant site infection, and swelling and local tissue damage or pocket erosion. The Remede System should not be used by patients with an active infection or by patients who are known to require magnetic resonance imaging (MRI). This device is not intended for use in patients with obstructive sleep apnea (OSA).

Examples of NMES devices include Empi 300 PV, NexWave, and R2i muscle stimulator.

Care ETS device is an electromyography (EMG) triggered NMES. This device is designed to detect any EMG signals (nerve impulses from the brain to the muscles) that are supposed to stimulate a muscle contraction but are too weak to do so. When the device detects these signals, it applies stimulation to the muscle and induces a contraction, to purportedly retrain the brain and muscle to properly coordinate contractions and movement. This device is also proposed for use for relaxation of muscle spasms and prevention or retardation of disuse atrophy.

VitalStim Therapy is a type of NMES that uses a mild electrical current that is intended to treat dysphagia by re-educating the muscles and improving swallowing. Guardian dysphagia dual chamber unit is proposed for use for muscle re-education by application of external stimulation for pharyngeal contraction.

Empi Phoenix is a combination NMES and TENS device. QB1 powered muscle stimulator is a combination NMES and TENS device. RS-4i sequential stimulator (also referred to as a combination unit) initially provides an interferential treatment followed by the muscle stimulation. Kneehab XP is a combination NMES and TENS device designed for the knee.

Feil, et al. (2011) reported on a single-center randomized controlled trial comparing the effect of adding traditional neuromuscular electrical stimulation (Polystim) or a novel garment-integrated neuromuscular electrical stimulation (Kneehab) to a standard postoperative rehabilitation program (control). Ninety-six patients, of a total enrolled cohort of 131 patients randomized to 1 of 3 intervention groups, completed a standard rehabilitation program. In addition, the 2 neuromuscular electrical stimulation groups underwent 20-minute sessions of neuromuscular electrical stimulation 3 times a day, 5 days a week, for 12 weeks, in which stimulation was superimposed on isometric volitional contractions. The primary outcome measures of this study were the strength of the knee extensors, the ability to jump on 1 leg (single-legged jump), and the time to complete the shuttle run. Outcome measures were assessed at baseline and at 6 weeks, 12 weeks, and 6 months postoperatively. The Kneehab group achieved significantly better results at each time point compared with the Polystim and control groups (P < .001). Extensor strength of the Kneehab group at speeds of 90 and 180 deg/s increased by 30.2% and 27.8%, respectively, between the preoperative measurements and the 6-month follow-up point in the injured leg. The corresponding changes for Polystim were 5.1% and 5%, whereas for the control group they were 6.6% and 6.7%, respectively. The mean single-legged hop test hop score of the Kneehab group improved by 50% between the 6-week and 6-month follow-up, whereas the corresponding changes for the Polystim and control groups were 26.3% and 26.2%, respectively. Although there was no significant difference between the groups with respect to the Tegner score and the International Knee Documentation Committee 2000 knee examination score, the Kneehab group showed a significant difference in mean improvement for the baseline corrected Lysholm score compared with the control group (P = .01; 95% confidence interval, 1.12-8.59) and with the Polystim group (P < .001; 95% confidence interval, 1.34-9.09) with no significant difference evident between Polystim and control groups (P = .97; 95% confidence interval, -4.23 to 3.51). The investigators concluded that intensive garment-integrated stimulation combined with standard rehabilitation is effective at accelerating recovery after knee surgery.

Walls et al (2010) reported on a pilot study assessing compliance of a home-based, NMES prehabilitation program in patients undergoing total knee arthroplasty (TKA). A portable, battery powered, garment-based stimulator (KneeHAB II) provided the external training stimulus to elicit quadriceps femoral muscle contraction.The investigators evaluated its effect on preoperative and postoperative isometric quadriceps femoris muscle (QFM) strength, QFM cross-sectional area (CSA) and clinical function (subjective and objective). Seventeen subjects were recruited with 14 completing the study (NMES group n = 9; Control group n = 5). Overall compliance with the program was excellent (99%). Preoperative QFM strength increased by 28% (p > 0.05) with associated gains in walk, stair-climb and chair-rise times (p < 0.05). Early postoperative strength loss (approximately 50%) was similar in both groups. Only the NMES group demonstrated significant strength (53.3%, p = 0.011) and functional recovery (p < 0.05) from 6 to 12 weeks post-TKA. QFM CSA decreased by 4% in the NMES group compared to a reduction of 12% in the control group (P > 0.05) at 12 weeks postoperatively compared to baseline. The investigators noted, however, that there were only limited associations found between objective and subjective functional outcome instruments. The investigators concluded that this pilot study has shown that preoperative NMES may improve recovery of quadriceps muscle strength and expedite a return to normal activities in patients undergoing TKA for OA. The investigators noted that, since the sample size is limited with many essential results based on statistical trends, a formal randomized controlled trial is now required to determine if the pre- and postoperative gains in strength and objective functional capacity observed in this clinical trial are reproducible in a larger population.

Maffiuletti et al (2014) noted that neuromuscular electrical stimulation (NMES) with large electrodes and multiple current pathways (m-NMES) has recently been proposed as a valid alternative to conventional NMES (c-NMES) for quadriceps muscle (re)training. The investigators sought to compare discomfort, evoked force and fatigue between m-NMES and c-NMES of the quadriceps femoris muscle in healthy subjects. Ten healthy subjects completed two experimental sessions (c-NMES and m-NMES), that were randomly presented in a cross-over design. Maximal electrically evoked force at pain threshold, self-reported discomfort at different levels of evoked force, and fatigue-induced force declines during and following a series of 20 NMES contractions were compared between c-NMES and m-NMES. The investigators found that m-NMES resulted in greater evoked force (P < 0.05) and lower discomfort in comparison to c-NMES (P < 0.05-0.001), but fatigue time course and magnitude did not differ between the two conditions. The investigators concluded that the use of quadriceps m-NMES appears legitimate for (re)training purposes because it generated stronger contractions and was less discomfortable than c-NMES (due to multiple current pathways and/or lower current density with larger electrodes).

Morf et al (2014) conducted a randomized, single-blind, crossover study to compare maximal evoked torque, discomfort, and fatigue-related outcomes between multipath neuromuscular electrical stimulation (NMES) and conventional NMES of the quadriceps muscle in 20 patients 6 to 12 months after total knee arthroplasty (TKA). The investigators quantified NMES-evoked knee extension torque at the maximally tolerated current intensity, self-reported discomfort, and fatigue induced by NMES intermittent contractions in both conditions. The investigators reported that, compared with conventional NMES, multipath NMES resulted in higher evoked torque (33%, P<.001), lower discomfort scores (-39%, P<.001), and less quadriceps muscle fatigue (P=.034). The investigators concluded that the use of multiple current pathways distributed to large electrodes allowed multipath NMES to generate stronger contractions and reduce discomfort and fatigue compared with conventional NMES. Therefore, multipath NMES has the potential to be more effective than conventional NMES.

Garara and colleagues (2016) noted that intramuscular diaphragmatic stimulation using an abdominal laparoscopic approach has been proposed as a safer alternative to traditional PNS. It has also been suggested that early implementation of diaphragmatic pacing may prevent diaphragm atrophy and lead to earlier ventilator independence. These investigators reviewed the safety and effectiveness of intramuscular diaphragmatic stimulators in the treatment of patients with traumatic high cervical injuries resulting in long-term ventilator dependence, with particular emphasis on the effect of timing of insertion of such stimulators. The Cochrane database and PubMed were searched between January 2000 and June 2015. Reference lists of selected papers were also reviewed. The inclusion criteria used to select from the pool of eligible studies were:

reported on adult patients with traumatic high cervical injury, who were ventilator-dependent,
patients underwent intramuscular diaphragmatic stimulation, and
commented on safety and/or effectiveness.

A total of 12 articles were included in the review. Reported safety issues post insertion of intramuscular electrodes included pneumothorax, infection, and interaction with pre-existing cardiac pacemaker. Only 1 procedural failure was reported. The percentage of patients reported as independent of ventilatory support post-procedure ranged between 40 % and 72.2 %. The mean delay of insertion ranged from 40 days to 9.7 years; of note the study with the average shortest delay in insertion reported the greatest percentage of fully weaned patients. The authors concluded that although evidence for intramuscular diaphragmatic stimulation in patients with high cervical injuries and ventilator-dependent respiratory failure is currently limited, the technique appears to be safe and effective. Earlier implantation of such devices does not appear to be associated with greater surgical risk, and may be more effective. They stated that further high quality studies are needed to examine the impact of delay of insertion on ventilator weaning.

Sieg and associates (2016) noted that case reports, case series and case control studies have examined the use of PNS in the setting of high SCIs and CHS dating back to the 1980s. These researchers evaluated the evidence related to this topic by performing a systematic review of the published literature. Search terms "phrenic nerve stimulation”, "phrenic nerve and spinal cord injury”, and "phrenic nerve and central hypoventilation" were entered into standard search engines in a systematic fashion. Articles were reviewed by 2 study authors and graded independently for class of evidence according to published guidelines. The published evidence was reviewed, and the overall body of evidence was evaluated using the grading of recommendations, assessment, development and evaluations (GRADE) criteria. The initial search yielded 420 articles. There were no class I, II, or III studies; there were 18 relevant class IV articles. There were no discrepancies among article ratings (i.e., kappa = 1). A meta-analysis could not be performed due to the low quality of the available evidence. The overall quality of the body of evidence was evaluated using GRADE criteria and fell within the "very poor" category. The authors concluded that the quality of the published literature for PNS is poor. The available literature suggests that PNS is a safe and effective option for decreasing ventilator dependence in high SCI and central hypoventilation; however, the authors stated that they were left with critical questions that provide crucial directions for future studies.

Functional Electrical Stimulation/Neuromuscular Electrical Stimulation for Chronic Obstructive Pulmonary Disease

In a randomized double-blind, placebo-controlled trial, Maddocks and associates (2017) evaluated the effectiveness of NMES as a home-based exercise therapy for patients with severe COPD. These researchers randomly assigned (1:1) adults with COPD, a forced expiratory volume in 1 s (FEV1) less than 50 % predicted, and incapacitating breathlessness (Medical Research Council dyspnea scale greater than or equal to 4) to receive active or placebo NMES, daily over a 6-week period. Randomization was by an independent system using minimization to balance age, GOLD stage, and quadriceps strength. subjects and outcome assessors were masked to group allocation. The primary end-point was change in 6MWT distance at 6 weeks. Analysis was by intention-to-treat. Between June 29, 2012, and July 4, 2014, these researchers enrolled 73 subjects, of whom 52 participants were randomly assigned; 25 to receive active NMES and 27 to placebo NMES. Change in 6MWT distance was greater in the active NMES group (mean 29.9 [95 % CI: 8.9 to 51.0]) compared with in the placebo group (-5.7 [-19.9 to 8.4]; MD at 6 weeks 35.7 m [95 % CI: 10.5 to 60.9]; p = 0.005). Sensitivity analyses for complete-cases and adjustment for baseline values showed similar results. 6 weeks after stopping the intervention the effect waned (7.3 m [95 % CI: -32.5 to 47.0]; p = 0.50). The proportion of participants who had AEs was similar between groups (5 [20 %] in the active NMES group and nine [33 %] in the placebo group); 2 participants, 1 from each group, reported persistent erythema, which was considered to be possibly related to NMES and the use of adhesive electrodes. The authors concluded that NMES improved functional exercise capacity in patients with severe COPD by enhancing quadriceps muscle mass and function. They stated that these data support the use of NMES in the management of patients unable to engage with conventional pulmonary rehabilitation; however, more work is needed to study how to maintain the effect. They stated that future work should consider trialing longer programs of NMES, potentially those that use improvements in function to dovetail into pulmonary rehabilitation, or add behavioral change and education components to NMES to enhance health status and QOL. Once optimized, the effect of an NMES-based approach on outcomes pertaining to patient independence and health service use could be evaluated.

The authors noted that this study had several drawbacks: These investigators were not able to mask the nurses and physiotherapists who were involved in recording of AE data, although events were classified without unmasking of group allocation. The authors perceived their placebo model to have been successful, but they could not totally rule out an anabolic effect, and incidental features of NMES such as dedicated time for self-management might have affected participant behavior. The sample size was informed by effect estimate data from a pilot study and an established minimally important difference for COPD, and the expected difference of 54 m was not reached. Nonetheless, the homogeneous sample and well standardized assessments contributed to between-group differences that were significant and exceeded updated minimally important differences for the primary end-point. The study was not powered to detect small changes in health status that might be expected following this modest intensity training. These researchers noted a small number of hospital admissions during the short trial period. Although the number of exacerbations, hospital admissions, and courses of oral corticosteroids was higher in the placebo group than in the active group, this was unlikely to account for the differences in functional exercise capacity, which remained stable, and was enhanced following active NMES.

In a meta-analysis, Chen and colleagues (2016) examined the controversial topic of whether NMES is effective in patients with moderate-to-severe COPD. These investigators pooled data from 9 trials published between January 9, 2002 and January 4, 2016 across PubMed, Embase, Cochrane Central Register of Controlled Trials, Google Scholar, and relevant websites for RCTs. In these trials, patients with moderate-to-severe COPD were randomly allocated to receive NMES. Primary outcomes were quadriceps strength and exercise capacity; secondary outcome was health-related QOL. These researchers extracted data from 276 patients; NMES contributed to statistically improved quadriceps strength (SMD 1.12, 95 % CI: 0.64 to 1.59, I2 = 54 %; p < 0.00001) and exercise capacity, including longer exercise distance (WMD 51.53, 95 % CI: 20.13 to 82.93, I2 = 90 %; p = 0.001), and longer exercise endurance (SMD 1.11, 95 % CI: 0.14 to 2.08, I2 = 85 %; p = 0.02). There was no significant difference in St George's Respiratory Questionnaire scores (WMD -0.07, 95 % CI: -2.44 to 2.30, I2 = 56 %; p = 0.95). The authors concluded that NMES appeared to be an effective method of enhancing quadriceps strength and exercise capacity in moderate-to-severe COPD patients. Moreover, they stated that further research is needed to clarify its effect on other outcomes and determine the optimal parameters for an NMES program.

This study had several drawbacks:

the subgroup analysis with small sample size led to insufficient evidence,
the diversity of measurement could have led to heterogeneity correspondingly, and
NMES with different parameter settings or programs may lead to different physiological effects and outcomes.

Sacral Nerve Stimulation for the Treatment of Chronic Constipation

In a Cochrane review, Thaha et al (2015) evaluated the effects of SNS using implanted electrodes for the treatment of FI and constipation in adults. These investigators searched the Cochrane Incontinence Group Specialized Register, which contains trials identified from the Cochrane Central Register of Controlled Trials (CENTRAL), Medline, Medline In-Process, ClinicalTrials.gov, the World Health Organization (WHO) ICTRP and hand-searched journals and conference proceedings (searched February 5, 2015), Embase (January 1, 1947 to 2015 Week 5), and the reference lists of retrieved relevant articles. All randomized or quasi-randomized trials assessing the effects of SNS for FI or constipation in adults. Two review authors independently screened the search results, assessed the methodological quality of the included trials, and undertook data extraction. A total of 6 cross-over trials and 2 parallel group trials were included; 6 trials assessed the effects of SNS for FI. In the parallel group trial conducted by Tjandra, 53 participants with severe FI in the SNS group experienced fewer episodes of FI compared to the control group who received optimal medical therapy (mean difference (MD) -5.20, 95 % confidence interval (CI): -9.15 to -1.25 at 3 months; MD -6.30, 95 % CI: -10.34 to -2.26 at 12 months). Adverse events (AEs) were reported in a proportion of participants: pain at implant site (6 %), seroma (2 %) and excessive tingling in the vaginal region (9 %). In the parallel group trial carried out by Thin, 15 participants with FI in the SNS group experienced fewer episodes of FI compared with the percutaneous tibial nerve stimulation (PTNS) group (MD -3.00, 95 % CI: -6.61 to 0.61 at 3 months; MD -3.20, 95 % CI: -7.14 to 0.74 at 12 months); AEs were reported in 3 participants: mild ipsilateral leg pain during temporary testing (n = 1); and stimulator-site pain following insertion of neurostimulator (n = 2). In the cross-over trial by Leroi, 7 of 34 recruited participants were excluded from the cross-over due mainly to complications or immediate device failure; 24 of the remaining 27 participants while still blinded chose the period of stimulation they had preferred. Outcomes were reported separately for 19 participants who preferred the 'on' and 5 who preferred the 'off' period. For the group of 19, the median (range) episodes of FI per week fell from 1.7 (0 to 9) during the 'off' period to 0.7 (0 to 5) during the 'on' period; for the group of 5, however, the median (range) rose from 1.7 (0 to 11) during the 'off' period compared with 3.7 (0 to 11) during the 'on' period; 4 of 27 participants experienced an AE resulting in removal of the stimulator. In the cross-over trial by Sorensen and colleagues, participants did not experience any FI episodes in either the 1-week 'on' or 'off' periods. In the cross-over trial by Vaizey, participants reported an average of 6, and 1, episodes of FI per week during the 'off' and 'on' periods respectively in 2 participants with FI. Neither study reported AEs. In the cross-over trial by Kahlke, 14 participants with FI experienced significantly lower episodes of FI per week during the stimulator 'on' (1 (SD, 1.7)) compared with the 'off' period (8.4 (SD, 8.7)); AEs reported include: hematoma formation (n = 3); misplacement of tined lead (n = 1); and pain at stimulator site (n = 1). Two trials assessed SNS for constipation. In the Kenefick trial, the 2 participants experienced an average of 2 bowel movements per week during the 'off' cross-over period, compared with 5 during the 'on' period. Abdominal pain and bloating occurred 79 % of the time during the 'off' period compared with 33 % during the 'on' period. No AEs occurred. In contrast, in the trial by Dinning with 59 participants, SNS did not improve frequency of bowel movements and 73 AEs were reported, which included pain at site of the implanted pulse generator (n = 32), wound infection (n = 12), and urological (n = 17) events. The authors concluded that limited evidence from the included trials suggested that SNS can improve continence in a proportion of patients with FI. However, SNS did not improve symptoms in patients with constipation. In addition, AEs occurred in some patients where these were reported. Moreover, they stated that rigorous high quality randomized trials are needed to allow the effects of SNS for these conditions to be assessed with more certainty.

In a pilot study, Iqbal et al (2016) assessed the effectiveness of transcutaneous electrical stimulation directly over the sacral nerve roots in chronic constipation. The study was conducted of transcutaneous sacral stimulation given over a 4-week period for 12 hours a day. Patients were assessed using the Patient Assessment of Constipation Symptoms, the Patient Assessment of Constipation Quality of Life, and the Cleveland constipation tool. A Global Rating of Change measure and a 1-week bowel diary was kept for the final week and compared with baseline. Of the 20 patients recruited (16 women, median age of 38.5 years), 80 % (16) completed the trial; 5 (31 %) patients reported at least a point reduction in the Patient Assessment of Constipation Symptoms score, 4 (25 %) deteriorated, and 7 (44 %) improved by less than 1 point. Median (interquartile range [IQR]) Patient Assessment of Constipation Symptoms scores were 2.33 (2.34) at baseline and 2.08 (2.58) at follow-up (p = 0.074). Median scores for the Patient Assessment of Constipation Quality of Life and Cleveland systems were 3.00 (1.64) and 17.15 (18) at baseline and 2.22 (3.04) and 15.31 (12) at follow-up (p = 0.096 and 0.111); 1/3 of patients reported a positive Global Rating of Change measure, although 68 % required concurrent laxatives during the trial. The authors concluded continuous transcutaneous sacral stimulation in the short-term appeared to be ineffective for chronic constipation. They stated that larger well-powered studies with intermittent stimulation regimens are needed to investigate this further. This was a pilot study and was limited by its small sample size (n = 20).

Patton et al (2016) evaluated the long-term effectiveness of SNS in patients with scintigraphically confirmed slow-transit constipation. At the 1- and 2-year post-randomized controlled trial (RCT), the primary treatment outcome measure was the proportion of patients who reported a feeling of complete evacuation on greater than 2 days per week for greater than or equal to 2 of 3 weeks during stool diary assessment. Secondary outcome was demonstration of improved colonic transit at 1 year. A total of 53 patients entered long-term follow-up, and 1 patient died. Patient dissatisfaction or serious adverse events (AEs) resulted in 44 patients withdrawing from the study because of treatment failure by the end of the 2nd year. At 1 and 2 years, 10 (OR = 18.8 % (95 % CI: 8.3 % to 29.3 %)) and 3 patients (OR = 5.7 % (95 % CI: -0.5 % to 11.9 %)) met the primary outcome measure. Colonic isotope retention at 72 hours did not differ between baseline (OR = 75.6 % (95 % CI: 65.7 % to 85.6 %)) and 1-year follow-up (OR = 61.7 % (95 % CI: 47.8 % to 75.6 %)). The authors concluded that in these patients with slow-transit constipation, SNS was not an effective treatment.

Zerbib et al (2017) stated that open studies have reported favorable results for SNS in the treatment of refractory constipation. These investigators examined its effectiveness in a double-blind cross-over RCT. Patients with at least 2 of the following criteria were included:

fewer than 3 bowel movements per week;
straining to evacuate on more than 25 % of attempts;
or sensation of incomplete evacuation on more than 25 % of occasions.

Response to therapy was defined as at least 3 bowel movements per week and/or more than 50 % improvement in symptoms. Responders to an initial 3-week peripheral nerve evaluation were offered permanent implantation of a pulse generator and were assigned randomly in a cross-over design to two 8-week intervals of active or sham stimulation. At the end of the 2 trial periods, the patients received active stimulation until the final evaluation at 1 year. A total of 36 patients (34 women; mean (s.d.) age of 45(14) years) underwent peripheral nerve evaluation; 20 responded and received a permanent stimulator. A positive response was observed in 12 of 20 and 11 of 20 patients after active and sham stimulation periods respectively (p = 0·746). Pain related to the device occurred in 5 patients and wound infection or hematoma in 3, leading to definitive removal of the pulse generator in 2 patients. At 1 year, 11 of the 20 patients with an implanted device continued to respond. Stimulation had no significant effect on colonic transit time. The authors concluded that these results did not support the recommendation of permanent implantation of a pulse generator in patients with refractory constipation who initially responded to temporary nerve stimulation.

James-Stevenson (2017) stated that FI and constipation are common gastro-intestinal (GI) complaints, but rarely occur concurrently. Management of these seemingly paradoxical processes is challenging, as treatment of one symptom may exacerbate the other. These researchers reported the case of a 51-year old female with lifelong neurogenic bladder secondary to spina bifida occulta who presented with progressive symptoms of daily urge FI as well as hard bowel movements associated with straining and a sensation of incomplete evacuation requiring manual dis-impaction. Pelvic floor testing showed poor ability to squeeze the anal sphincter, which indicated sphincter weakness as a major contributor to her FI symptoms. Additionally, on defecography she was unable to widen her posterior anorectal angle or relax the anal sphincter during defecation consistent with dyssynergic defecation. A sacral nerve stimulator was placed for management of her FI. Interestingly, her constipation also dramatically improved with sacral neuromodulation. The authors concluded that this unique case highlighted the emerging role of SNS in the treatment of complex pelvic floor dysfunction with improvement in symptoms beyond FI in a patient with dyssynergic-type constipation. Moreover, they stated that while SNS is increasingly being used in patients with refractory FI, its role in treatment of refractory constipation is unclear. The findings of this case suggested that SNS may have benefit in the dyssynergic subtype of constipation; further studies evaluating SNS in this specific subset of constipation sufferers are needed.

Chen et al (2017) noted that GI motility disorders are common in clinical settings, including esophageal motility disorders, gastroesophageal reflux disease, functional dyspepsia, gastroparesis, chronic intestinal pseudo-obstruction, post-operative ileus, irritable bowel syndrome, diarrhea and constipation. While a number of drugs have been developed for treating GI motility disorders, few are currently available. Emerging electrical stimulation methods may provide new treatment options for these GI motility disorders. These investigators presented an overview of electrical therapies that have been, and are being developed for GI motility disorders, including gastroesophageal reflux, functional dyspepsia, gastroparesis, intestinal motility disorders and constipation. Various methods of gastrointestinal electrical stimulation were introduced. A few methods of nerve stimulation have also been described, including spinal cord stimulation and SNS. Potentials of electrical therapies for obesity are also discussed. PubMed was searched using keywords and their combinations: electrical stimulation, spinal cord stimulation, sacral nerve stimulation, gastrointestinal motility and functional gastrointestinal diseases. The authors concluded that electrical stimulation is an area of great interest and has potential for treating GI motility disorders. However, further development in technologies (devices suitable for GI stimulation) and extensive clinical research are needed to advance the field and bring electrical therapies to bedside.

Maeda et al (2017) noted that sacral neuromodulation (SNM) has been reported as a treatment for severe idiopathic constipation. These researchers evaluated the long-term effects of sacral neuromodulation by following patients who participated in a prospective, open-label, multi-center study up to 5 years. Patients were followed up at 1, 3, 6, 12, 24, 36, 48 and 60 months. Symptoms and quality of life were assessed using bowel diary, the Cleveland Clinic constipation score and the Short Form-36 quality-of-life scale. A total of 62 patients (7 men, median age of 40 years) underwent test stimulation, and 45 proceeded to permanent implantation; 27 patients exited the study (7 withdrawn consent, 7 loss of efficacy, 6 site-specific reasons, 4 withdrew other reasons, 2 lost to follow-up, 1 prior to follow-up); 18 patients (29 %) attended 60-month follow-up. In 10 patients who submitted bowel diary, their improvement of symptoms was sustained: the number of defecations per week (4.1 ± 3.7 versus 8.1 ± 3.4, mean ± standard deviation, p < 0.001, baseline versus 60 months) and sensation of incomplete emptying (0.8 ± 0.3 versus 0.2 ± 0.1, p = 0.002). In 14 patients (23 %) with Cleveland Clinic constipation score, improvement was sustained at 60 months [17.9 ± 4.4 (baseline) to 10.4 ± 4.1, p < 0.001]. Some 103 device-related AEs were reported in 27 (61 %). The authors concluded that benefit from sacral neuromodulation in the long-term was observed in a small minority of patients with intractable constipation. The results should be interpreted with caution given the high drop-out (69 %; 27 of 45) and complication rate during the follow-up period. Moreover, they stated that the role of SNM within the treatment algorithm and the clinical treatment pathway for chronic constipation in comparison with other options, as well as patient selection criteria, is unclear. Recent randomized double-blind cross-over studies have shown no difference between active and sham stimulations. In both studies, 30 to 60 % of patients had a positive response during sham stimulation, suggestive of either lasting effects of sensory stimulation beyond washout period between sham and active treatment (2 to 3 weeks) or high placebo effects of this treatment. In the light of these results from the well-designed randomized trials, it is difficult to recommend sacral neuromodulation as a treatment within a treatment algorithm of constipation.

Lu et al (2018) evaluated the long-term effectiveness of SNS in children with constipation and describe patient benefit and parent satisfaction. Using a prospective patient registry, these researchers identified patients less than 21 years old with constipation treated with SNS for more than 2 years. They compared symptoms, medical treatment, PedsQL Gastrointestinal Symptom Scale (GSS), Fecal Incontinence Quality of Life Scale (FIQL), and Fecal Incontinence Severity Index (FISI) before SNS and at follow-up. These investigators contacted parents to administer the Glasgow Children's Benefit Inventory (GCBI) and a parent satisfaction questionnaire. They included 25 children (52 % male, median age of 10 years): 16 had functional constipation, 6 anorectal malformation, 2 tethered spinal cord, and 1 Hirschsprung's disease. Defecation frequency did not change after SNS but patients reporting FI decreased from 72 % to 20 % (p < 0.01) and urinary incontinence decreased from 56 % to 28 % (p = 0.04). Patients using laxatives decreased from 64 % to 44 % (ns) and patients using antegrade enemas decreased from 48 % to 20 % (p = 0.03). GSS, most FIQL domains, and FISI were improved at follow-up; 6 (24 %) patients had complications requiring further surgery. Of the 16 parents contacted, 15 (94 %) parents indicated positive health-related benefit and all would recommend SNS to other families. The authors concluded that SNS is a promising and durable treatment for children with refractory constipation, and appeared particularly effective in decreasing FI. Although 25 % of patients experienced complications requiring additional surgery, nearly all parents reported health-related benefit. They stated that future studies to identify predictors of treatment response and complications are needed.

AxioBionics Wearable Therapy NMES for Hemiplegia

Rose et al (2017) stated that cerebral palsy (CP) is the most common childhood motor disability and often results in debilitating walking abnormalities, such as flexed-knee and stiff-knee gait. Current medical and surgical treatments are only partially effective in improving gait abnormalities and may cause significant muscle weakness. However, emerging artificial walking technologies, such as step-initiated, multi-channel neuromuscular electrical stimulation (NMES), can substantially improve gait patterns and promote muscle strength in children with spastic CP. NMES may also be applied to specific lumbar-sacral sensory roots to reduce spasticity. Development of tablet computer-based multi-channel NMES can leverage lightweight, wearable wireless stimulators, advanced control design, and surface electrodes to activate lower-limb muscles. Musculoskeletal models have been used to characterize muscle contributions to unimpaired gait and identify high muscle demands, which can help guide multi-channel NMES-assisted gait protocols. In addition, patient-specific NMES-assisted gait protocols based on 3D gait analysis can facilitate the appropriate activation of lower-limb muscles to achieve a more functional gait: stance-phase hip and knee extension and swing-phase sequence of hip and knee flexion followed by rapid knee extension. NMES-assisted gait treatment can be conducted as either clinic-based or home-based programs. Rigorous testing of multi-channel NMES-assisted gait training protocols will determine optimal treatment dosage for future clinical trials. Evidence-based outcome evaluation using 3D kinematics or temporal-spatial gait parameters will help determine immediate neuroprosthetic effects and longer term neurotherapeutic effects of step-initiated, multi-channel NMES-assisted gait in children with spastic CP. The authors concluded that multi-channel NMES is a promising assistive technology to help children with spastic CP achieve a more upright, functional gait.

Functional Electrical Stimulation for Erectile Dysfunction

Carboni and colleagues (2018) stated that erectile dysfunction (ED) affects approximately 150 million men worldwide; FES has shown a high regenerative capacity for smooth muscle cells and, therefore, is being increasingly adopted. Functional electrical stimulation can be a beneficial therapeutic option when the cause of ED is related to degeneration of cavernous smooth muscle. These researchers evaluated the impact of FES on erectile function in men with ED. A total of 22 patients with ED participated in this randomized clinical trial. Participants were randomly assigned to 2 groups: intervention (IG) or control (CG); IG participants underwent FES therapy (50 Hz/500 µs) for a total of 4 weeks, divided into 2 weekly sessions lasting 15 mins each, with intensity lower than the motor threshold; CG participants were treated with placebo FES and followed the same routine as the IG. Erectile function was assessed by the validated International Index of Erectile Function (IIEF-5) and Erection Hardness Score (EHS), applied before and after treatment, and QOL by the WHOQOL questionnaire. Statistically significant differences in IIEF-5 and EHS were found between the IG and CG after treatment (p < 0.05), as well as a within-group difference in the IG when comparing the post-treatment periods (p < 0.0001). The WHOQOL revealed a significant difference between CG and IG after treatment (p < 0.05), as well as a within-group difference in the IG after treatment (p < 0.0001), except in the environment domain, in which there was no difference between the pre- and post-treatment periods (50.9 ± 2.8 pre versus 52.3 ± 3.1 post). The authors concluded that this trial showed that FES therapy may improve erectile function and QOL in men with ED. These preliminary findings need to be validated by well-designed studies.

Functional Electrical Stimulation for Foot Drop

Moll and colleagues (2017) examined the effect of FES of ankle dorsiflexors in children and adolescents with spastic CP during walking. These researchers carried out a systematic review using the American Academy of Cerebral Palsy and Developmental Medicine methodology and the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. A total of 6 databases were searched for studies applying interventions to patients aged younger than 20 years. Outcomes were classified according to the International Classification of Functioning, Disability and Health (ICF). A total of 708 abstracts were found, 35 articles were fully screened, and 14 articles were used for analysis. Only 5 articles (3 studies) were of level I to III evidence. At ICF participation and activity level, there was limited evidence for a decrease in self-reported frequency of toe-drag and falls. At ICF body structure and function level, there was clear evidence (I-III) that FES increased (active) ankle dorsiflexion angle, strength, and improved selective motor control, balance, and gait kinematics, but decreased walking speed; AEs included skin irritation, toleration, and acceptation issues. The authors concluded that there are insufficient data supporting functional gain by FES on activity and participation level. However, evidence pointed towards a role for FES as an alternative to orthoses in children with spastic CP.

Prenton and associates (2018) compared the RCT evidence for therapeutic effects on walking of FES and ankle foot orthoses for foot drop caused by central nervous system (CNS) conditions. Data sources included Medline, CINAHL, Cochrane Central Register of Controlled Trials, REHABDATA, PEDro, NIHR Centre for Reviews and Dissemination, Scopus and clinicaltrials.gov; 1 reviewer screened titles/abstracts; 2 independent reviewers then screened the full articles; 1 reviewer extracted data, another screened for accuracy. Risk of bias was assessed by 2 independent reviewers using the Cochrane Risk of Bias Tool. A total of 8 papers were eligible; 7 involving participants with stroke and 1 involving participants with CP; 2 papers reporting different measures from the same trial were grouped, resulting in 7 synthesized RCTs (n = 464). Meta-analysis of walking speed at final assessment (p = 0.46), for stroke participants (p = 0.54) and after 4-6 weeks' use (p = 0.49) showed equal improvement for both devices. The authors concluded that FES and ankle foot orthoses have an equally positive therapeutic effect on walking speed in non-progressive CNS diagnoses. The current RCT evidence base does not show whether this improvement translates into the user's own environment or reveal the mechanisms that achieve that change. They stated that future studies should focus on measuring activity, muscle activity and gait kinematics. They should also report specific device details, capture sustained therapeutic effects and involve a variety of CNS diagnoses.

Khamis and co-workers (2018) studied the types of surface FES currently used in a CP population and examined the evidence of its ability to improve gait deviations, functional ability and therapeutic effects. A computerized database search was conducted from inception until June 2016. Included were all clinical trials performing gait analysis of children with CP applying surface FES to any lower leg muscles evaluating the efficiency of the stimulation and any carry-over effect. A total of 15 studies met the inclusion criteria. The most common FES stimulated the dorsi flexors muscles with a positive orthotic effect, improved dorsi flexion during the swing phase and enhanced the foot contact pattern. A smaller positive effect was found for knee extensors stimulation facilitating knee extension during the stance phase and for hip abductors stimulation improving frontal plane knee alignment. No evidence was found to support the use of plantar flexors stimulation in correcting gait deviations. There is scarce evidence of any retention effect. The authors encouraged clinicians to evaluate the use of FES on a case-to-case basis. Moreover, they stated that controlled investigations with larger numbers of subjects are needed to determine the orthotic and therapeutic efficacy of FES.

Neuromuscular Electrical Stimulation for Patello-Femoral Pain Syndrome

Martimbianco and colleagues (2017) examined the effects (benefits and harms) of NMES for people with patella-femoral pain (PFP). These investigators searched the Cochrane Bone, Joint and Muscle Trauma Group Specialized Register, the Cochrane Central Register of Controlled Trials (CENTRAL), Medline, Embase, PEDro, CINAHL, SPORTDiscus, AMED, LILACS, trial registers, conference abstracts, and reference lists. They carried out the search in May 2017. They included RCTs that evaluated the use of NMES for people with PFP. Two review authors independently performed the process of study selection, data extraction, and “risk of bias” assessment in duplicate. The primary outcomes were knee pain, knee function, and AEs. The timing of outcome measurements was up to 3 months (short-term), 3 to 12 months (medium-term), and 12 months and above from trial entry (long-term). These researchers calculated risk ratios (RRs) for dichotomous data and MDs or SMDs for continuous data. Where appropriate, these researchers pooled data using the fixed-effect model. These investigators included 8 randomized clinical trials, reporting results for 345 participants with PFP. The mean ages of trial populations ranged from 25 to 43 years, and the majority (53 % to 100 %) of participants were women. There was a wide duration of symptoms, with the minimum duration of symptoms for trial inclusion ranging from 1 to 6 months. In addition to the study inclusion criteria, studies varied widely in the characteristics of the NMES and its application, and associated co-interventions. These investigators assessed all trials as at high risk of bias in at least one domain, particularly blinding and incomplete outcome data. The results of a laboratory-based trial reporting knee pain immediately after a single 15-min session of NMES were not reported here as these were of questionable clinical relevance. The 7 remaining trials provided evidence for 3 comparisons. These researchers assessed the overall quality of the evidence, using GRADE, for all primary outcomes for all comparisons as very low, thus they were very unsure of the findings; 4 studies compared NMES plus exercise versus exercise alone. Patellar taping was applied as well as exercise to all participants of 1 study, and patellar taping and ice were also applied in another study. Each trial tested a different multiple-session NMES program. Pooled data from 3 studies (118 participants) provided very low-quality evidence that NMES was associated with reduced pain at the end of treatment (ranging from 3 to 12 weeks): MD -1.63, 95 % CI: -2.23 to -1.02; visual analog scale (VAS) 0 to 10; higher scores = worse pain. However, this result may not be clinically relevant since the minimal clinically important difference for VAS during activities (1.5 to 2.0, out of 10 points) lied within the 95 % CI. These investigators found very low-quality evidence from pooled data from 2 trials of little effect of NMES on knee function, as measured by 2 knee function rating systems. The authors found inconclusive and very low-quality evidence from 1 trial (29 participants) of little effect of NMES on pain and function at 1-year follow-up. None of the 4 trials reported on adverse effects of treatment. One study (94 participants) compared NMES, applied 4 hours per day on a daily basis for 4 weeks, with 2 types of exercises (isometric and isokinetic). The study did not report on knee pain or AEs. The study provided very low-quality evidence of no important difference between the 2 groups in knee function at the end of the 4-week treatment. Of note was the potentially onerous NMES schedule in this study, which did not correspond to that typically used in clinical practice; 2 studies compared different types of NMES. Simultaneously delivered high-low frequencies NMES was compared with sequentially delivered high-low frequencies NMES in 1 trial (14 participants) and with fixed frequency NMES in the 2nd trial (64 participants). The studies provided very low-quality evidence of no important differences at the end of the 6-week treatment program between the simultaneous frequencies NMES and the 2 other NMES programs in overall knee pain, knee function, or in quadriceps fatigue (an AE). The authors concluded that this review found insufficient and inconclusive evidence from RCTs to inform on the role of NMES for treating people with PFP in current clinical practice. The very low-quality evidence available meant that the authors were uncertain whether or not a multiple-session program of NMES combined with exercise over several weeks versus exercise alone resulted in clinically important differences in knee pain and function at the end of the treatment period or at 1 year. There were no data on AEs such as muscle fatigue and discomfort. They stated that high-quality randomized clinical trials are needed to inform on the use of NMES for people with PFP. Moreover, professional and stakeholder consensus is needed on prioritization of the research questions for interventions for treating people with PFP, including on the NMES treatment protocol for trials testing NMES.

Neuromuscular Electrical Stimulation for Septic Shock

Lago and colleagues (2018) noted that septic shock is a potentially fatal organ dysfunction caused by an imbalance of the host response to infection. The changes in microcirculation during sepsis can be explained by the alterations in the endothelial barrier function. Endothelial progenitor cells (EPCs) are a potential recovery index of endothelial function and an increase in response to NMES was demonstrated. These researchers examined the effects of NMES in patients with septic shock. It is a study protocol for a randomized cross-over design in an intensive care unit (ICU) of a tertiary University hospital. A total of 31 patients aged 18 to 65 years will be enrolled. The study will be divided in 2 phases: phase-1 will be held in the first 72 hours of septic shock and phase-2 after 3 days of first assessment. Patients will be randomly selected to the intervention protocol (decubitus position with the limbs raised and NMES) and control protocol (decubitus position with the limbs raised without NMES). After this procedure, the patients will be allocated in group 1 (intervention and control protocol) or group 2 (control and intervention protocol) with a wash-out period of 4 to 6 hours between them. The main outcome is mobilization of EPCs; secondary outcome is metabolic and hemodynamic data. A linear mixed model will be used for analysis of dependent variables and estimated values of the mean of the differences of each effect. The authors stated that this work will demonstrate the possible beneficial effects of NMES as evaluated by the mobilization of endothelial progenitor cells in patients with septic shock. It will determine whether NMES can be applied in critically ill patients without causing harmful metabolic and/or hemodynamic changes.

Neuromuscular Stimulation (Electronic Shock Unit) for Femoral Nerve Palsy

Groah and Cifu (1995) stated that the initial diagnoses of associated injuries in patients with traumatic brain injury (TBI) are often over-looked because of the priority given to life-sustaining measures. Pelvic and abdominal injuries comprise less than 5 % each of the concurrent injuries associated with TBI and multiple trauma. This report described a 32-year old man who sustained a moderate TBI with facial, pelvic, and extremity fractures secondary to a fall. His hospital course was complicated by sepsis, acute renal failure, and retro-peritoneal hemorrhage. Admitted to the rehabilitation service 6 weeks after the fall, the patient was found to have a previously undiagnosed profound quadriceps muscle weakness. A diagnosis of femoral neuropathy was confirmed by electro-diagnostic studies and was attributed to compression by pelvic hematomas. Rehabilitation management included use of a solid ankle cushion heel (SACH) wedge, a functional knee brace, a progressive ambulation program, neuromuscular stimulation, and patient and family education with an emphasis on safety. The patient progressed rapidly with his rehabilitation program, improving from moderate assistance in all skills to independence in 3 weeks. The authors concluded that this case illustrated the importance of the physiatrist's role in the early detection of associated injuries in patients with multiple trauma and TBI; it also illustrated some of the rehabilitation techniques that may be employed to aid a patient with a femoral neuropathy to regain junctional ability. This was a single-case study of a TBI patient; and neuromuscular stimulation was a component of the rehabilitation program.

Furthermore, an UpToDate review on “Overview of lower extremity peripheral nerve syndromes” (Rutkove, 2018) does not mention neuromuscular stimulation as a therapeutic option.

Masseter Muscle on Oral Dysfunction After Stroke

Lee and colleagues (2019) examined the effect of NMES in conventional dysphagia therapy on masseter muscle oral dysfunction of patients after subacute stroke. Among subacute stroke patients who were diagnosed as oropharyngeal dysphagia by video-fluoroscopy swallowing study (VFSS), those with oral dysfunction were enrolled. They were randomly assigned to a study group or a control group. The study group received NMES on masseter muscle and suprahyoid muscle simultaneously, while the control group received NMES only on suprahyoid muscle. NMES therapy session was applied for 30 mins each time, twice-daily for a total of 20 sessions. Both groups received conventional dysphagia therapy for 2 weeks. All enrolled patients were evaluated by VFSS after 2 weeks. Oropharyngeal swallowing function was evaluated by Penetration-Aspiration Scale, Functional Dysphagia Scale (FDS), and American Speech-Language-Hearing Association National Outcome Measurement System swallowing scale based on results of VFSS. Patients were randomly assigned to the study group (n = 20) or the control group (n = 20). There were no significant differences in baseline characteristics or initial values between the 2 groups. After 2 weeks of NMES, both groups showed improvement in scores of total FDS and pharyngeal phase FDS. Additionally, the study group showed improvement in oral phase FDS. Changes in all measurements were similar between the 2 groups. The authors concluded that in this preliminary study, NMES for masseter muscle had a therapeutic effect on oral dysfunction of patients after subacute stroke. Moreover, these researchers stated that further studies with larger sample sizes that consider direct chewing function should be conducted in the future to validate these preliminary findings.

The authors stated that this study had several drawbacks. First, oral dysfunction was defined by using sub-scores of FDS; thus, other types such as oral apraxia were excluded. Second, patients with severely deteriorated cognitive function those with oral dysfunction arising from aphasia, apathy, or depression were excluded. Third, the comparison in this study was performed with a relatively small number of patients.

Wang et al (2023) noted that dysphagia is one of the common complications following stroke. It is closely related to lung infection and malnutrition; NMES is often used in the treatment of post-stroke dysphagia. However, the evidence-based medical evidence of NMES is limited; thus, these investigators examined the effectiveness of NMES in patients with post-stroke dysphagia by systematic review and meta-analysis. They searched the CNKI, Wanfang, VIP, SinoMed, PubMed, Embase, Cochrane Library, and Web of Science databases for all RCTs of NMES in the treatment of post-stroke dysphagia from the establishment of the database to June 9, 2022. The risk of bias assessment tool recommended by Cochrane and the GRADE method was used to evaluate the risk of bias and the quality of evidence. RevMan 5.3 was used for statistical analysis. Sensitivity and subgroup analyses were carried out to examine the intervention effect more specifically. A total of 46 RCTs and 3,346 patients with post-stroke dysphagia were included in this study. The meta-analysis showed that NMES combined with routine swallowing therapy (ST) could effectively improve swallowing function in Penetration-Aspiration Scale (MD = -0.63, 95 % CI: -1.15, -0.12, p = 0.01), Functional Oral Intake Scale (MD = 1.32, 95 % CI: 0.81 to 1.83, p < 0.00001), Functional Dysphagia Scale (MD = - 8.81, 95 % CI: -16.48 to -1.15, p = 0.02), the Standardized Swallowing Assessment (MD = -6.39, 95 % CI: -6.56 to -6.22, p < 0.00001), the Videofluoroscopic Swallow Study (MD = 1.42, 95 % CI: 1.28 to 1.57, p < 0.00001) and the Water swallow test (MD = -0.78, 95 % CI: -0.84 to -0.73, p < 0.00001). In addition, it could improve the QOL (MD = 11.90, 95 % CI: 11.10 to 12.70, p < 0.00001), increase the upward movement distance of hyoid bone (MD = 2.84, 95 % CI: 2.28 to 3.40, p < 0.00001) and the forward movement distance of hyoid bone (MD = 4.28, 95 % CI: 3.93 to 4.64, p < 0.00001), reduce the rate of complications (odds ratio [OR] = 0.37, 95 % CI: 0.24 to 0.57, p < 0.00001). Subgroup analyses showed that NMES+ST was more effective at 25 Hz, 7 mA or 0-15 mA, and at courses (4 weeks or less). Moreover, patients with an onset of fewer than 20 days and those older than 60 years appeared to have more positive effects following treatment. The authors concluded that NMES combined with ST could effectively increase the forward and upward movement distance of the hyoid bone, improve the QOL, reduce the rate of complications, and improve the swallowing function of patients with post-stroke dysphagia; however, its safety needs to be further confirmed. Moreover, these researchers stated that due to the small number of included literature and the low quality of evidence, more large-sample, high-quality, multi-center RCTs are needed to prove the effectiveness of NMES + ST in the treatment of post-stroke dysphagia.

The authors stated that this study had several drawbacks. First, the majority of the 46 RCTs included in this study were from China, which may have resulted in regional bias. Second, most of the included clinical trials did not report the blinding method used, which reduced the quality of the methodological study. There may be some placebo effect and observer bias, which may reduce the credibility of the clinical trial results. Third, among the 46 RCTs, only 6 studies reported follow-up visits with the patients; thus, the long-term effectiveness of NMES + ST on post-stroke dysphagia still needs to be further examined. Fourth, AEs were reported in only some studies, which resulted in insufficient evidence to support the safety of NMES + ST treatment. Future studies are needed to strengthen the recording and reporting of AEs. Fifth, due to the high heterogeneity, some results' reliability in the study has been somewhat affected. Sixth, the use of multiple types of ST in different studies resulted in the fact that this study did not perform a subgroup analysis based on the type of ST received by the control group. These researchers stated that they look forward to further investigation in subsequent studies.

Muscle Atrophy after Stroke

Nozoe and colleagues (2017) stated that stroke-related muscle wasting is one of the factors leading to long-term disability and functional dependency; however no study on muscle wasting has reported an effective therapeutic intervention. In a pilot study, these investigators examined the effects of NMES on quadriceps muscle mass preservation in patients with acute moderate or severe stroke by using ultrasonography (US). A total of 20 patients with acute, moderate, or severe stroke were divided into a control group and intervention groups (NMES group). Patients in the NMES group underwent NMES treatment for bilateral quadriceps muscles for 2 weeks in addition to the usual care. Quadriceps muscle thickness was measured on admission and 2 weeks after the 1st measurement. These researchers found that the quadriceps muscle thickness on the paretic and non-paretic sides in the NMES group significantly decreased to a lesser degree than that in the control group (p = 0.04). The authors concluded that NEMS appeared to have preserved the quadriceps muscle mass in patients with moderate or severe acute stroke. These preliminary findings from a pilot study need to be validated by well-designed studies.

Pain Caused by Necrosis of the Femoral Head

In a retrospective study, Ji and colleagues (2019) examined the effectiveness of NMES for pain relief caused by necrosis of femoral head (NFH). A total of 80 cases of patients with NFH were assigned to a treatment group or a control group in this study. Of these, 40 cases in the treatment group received ibuprofen and NMES therapy. The other 40 cases in the control group received ibuprofen alone. Cases in both groups were treated for a total of 6 weeks. The primary outcome of pain intensity was measured by a VAS. The secondary outcome was assessed by Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC). In addition, AEs were also recorded in each case. All outcomes were evaluated before and after the treatment. After treatment, patients in the treatment group experience more pain relief, as measured by VAS (p < 0 .01) and WOMAC sub-pain scale (p < 0.01), except stiffness, as evaluated by WOMAC sub-stiffness scale (p = 0.07), and function, as assessed by WOMAC sub-function scale (p = 0.09), than patients in the control group. Additionally, no significant differences in AEs were detected between 2 groups. The authors concluded that the findings of this study demonstrated that NMES may be helpful for pain relief in patients with NFH.

The authors stated that this study had several drawbacks. First, the treatment duration was quite short with only 6 weeks, which may affect effectiveness of NMES for patients with NFH. Second, the outcomes were not comprehensive; it only assessed pain condition, as well as function and stiffness of the attacked joints. Additional outcomes (e.g., quality of life assessment) would have been beneficial. Lastly, no randomization procedure was applied in this study, a retrospective trial, which may have resulted in high risk of case selection.

Cala Trio Nerve Stimulating Device for the Treatment of Essential Tremors

The Cala Trio nerve stimulating device (Cala Health, Inc., Burlingame, CA) is a non-invasive, wrist-worn stimulator that delivers electrical stimulation to the nerves in the wrist. It has 2 components: a rechargeable stimulator that generates electrical impulses during therapy together with a base station to recharge the stimulator; and a wrist-worn connector that securely attaches the stimulator to the patient’s wrist and assures that electrical impulses are properly targeted to each individual patient’s nerves. Cala Trio is prescribed by a physician for use by patients in their home. It is the only peripherally worn device that is FDA-cleared for the treatment of essential tremor (ET). Cala Trio delivers electrical stimulation to the Central Tremor Network via the peripheral nervous system. On-board sensors are used to measure the patient’s tremor frequency during an initial calibration to individualize the stimulation delivered by the device.

Lin and colleagues (2018) stated that although the precise mechanisms are uncertain, ET is thought to be caused by tremulous activity within a central tremor neural network, which involves the ventral intermediate nucleus (VIM) of the thalamus. Clinical evidence supports targeting the VIM to treat tremor symptoms in ET with various methods. Previous studies have shown that electrical median nerve stimulation evokes activity within the VIM and other regions of the central tremor network. Based on these findings, these researchers hypothesized that median and radial nerve stimulation at the wrist could reduce hand tremor. In a pilot study, these investigators examined the effectiveness of median and radial nerve stimulation as a non-invasive, non-pharmacological treatment to aid in the symptomatic relief of hand tremor in individuals with ET. A total of 23 blinded subjects were examined at a single site under an institutional review board (IRB)‐approved protocol. Subjects were randomized to treatment or sham groups. For stimulation, hydrogel electrodes were positioned on the wrist over the median and radial nerves. Effectiveness was measured as the change in the Tremor Research Group's Essential Tremor Rating Assessment Scale (TETRAS) Archimedes spiral drawing task following stimulation compared with pre-stimulation. The response in the treatment group was significant compared with both baseline and sham. In the treatment group, blinded rater scores significantly improved following stimulation (1.77 ± 0.21) compared with pre-stimulation (2.77 ± 0.22; p = 0.01). This response was achieved without the risks of surgical or pharmacological intervention, such as the risk of hemorrhage or infection with deep brain stimulation (DBS) implantation, or side effects of ET medications, including the 1st‐line therapies propranolol and primidone. In the sham group, scores did not change significantly following stimulation (2.37 ± 0.22) compared with pre-stimulation (2.62 ± 0.14; p = 0.37). The response to treatment corresponded to an estimated hand tremor amplitude reduction of 60 % ± 8.4 % and was significantly greater in the treatment than in the sham group (p = 0.02); 3 subjects experienced transient redness and/or itchiness under the hydrogel electrodes that resolved without intervention. No unanticipated device effects occurred during the study. The authors stated that this was a pilot study with too few subjects for sub-analyses of the effects of age, medication status, or medical history. They stated that future studies should increase the number of subjects, examine the response rate, repeatability, durability, and effects of chronic use, and add assessments of QOL. This therapeutic approach was inspired by the idea that peripheral stimulation evokes central activity in brain regions such as the VIM, a thalamic target widely accepted to improve tremor with DBS. Although these findings support this idea, other potential mechanisms are possible, including circuitry modulated in previous studies demonstrating tremor reduction by manipulation of peripheral sensory input. The authors stated that future studies that could better characterize the precise mechanism may facilitate improvements to therapy. Nonetheless, this randomized, sham‐controlled pilot study suggested that non-invasive neuro-peripheral therapy may offer clinically meaningful symptomatic relief from hand tremor in ET with a favorable side effect profile compared with other available therapies.

In a RCT, Pahwa and associates (2019) examined the safety and effectiveness of a wrist-worn peripheral nerve stimulation (PNS) device in patients with ET in a single in-office session. This trial included 77 ET patients who received either treatment stimulation (n = 40) or sham stimulation (n = 37) on the wrist of the hand with more severe tremor. Tremor was evaluated before and immediately after the end of a single 40-min stimulation session. The primary endpoint compared spiral drawing in the stimulated hand using the TETRAS Archimedes spiral scores in treatment and sham groups. Additional endpoints included TETRAS upper limb tremor scores, subject-rated tasks from the Bain and Findley ADL (BF-ADL) scale before and after stimulation as well as clinical global impression-improvement (CGI-I) rating after stimulation. Subjects who received PNS did not show significantly larger improvement in the Archimedes spiral task compared to sham but did show significantly greater improvement in upper limb TETRAS tremor scores (p = 0.017) compared to sham. Subject-rated improvements in ADLs were significantly greater with treatment (49 % reduction) than with sham (27 % reduction; p = 0.001). A greater percentage of ET patients (88 %) reported improvement in the stimulation group as compared to the sham group (62 %) according to CGI-I ratings (p = 0.019). No significant AEs were reported; 3 % of subjects experienced mild AEs. The authors concluded that PNS in ET may provide a safe, well-tolerated, and effective treatment for transient relief of hand tremor symptoms. Moreover, these researchers stated that these findings were encouraging, and future studies are needed to confirm the effectiveness of this non-invasive therapy over time.

The authors stated that this study had several drawbacks. First, this trial was conducted with a small group of subjects (n = 40 I the treatment group) in whom safety and effectiveness were evaluated immediately after stimulation in a single in clinic session. As a result, these researchers were unable to measure the effect of stimulation over time or implement automated tools to detect tremor in real‐time to optimize therapy. Future studies should examine the durability of the therapeutic effect and the effects of chronic use with enabling technologies to automate tremor measurement over time. Since the device is worn on the wrist, there is potential to incorporate kinematic measurements to provide feedback regarding tremor burden over time to patients and clinicians. Further, due to the immediate therapeutic effect of stimulation, which is unlike other available pharmacologic interventions, kinematic measurements may provide insight into the effect of stimulation on tremor amplitude over time.

Isaacson and colleagues (2020) noted that 2 previous randomized, controlled, single-session trials demonstrated efficacy of non-invasive neuromodulation therapy targeting the median and radial nerves for reducing hand tremor. In a prospective, open-label, post-clearance, single-arm study, these researchers examined the safety and efficacy of the therapy over 3 months of repeated home use. A total of 263 patients enrolled across 26 sites. Patients were instructed to use the therapy twice-daily for 3 months. Pre-specified co-primary endpoints were improvements on clinician-rated TETRAS and patient-rated BF-ADL dominant hand scores. Other endpoints included improvement in the tremor power detected by an accelerometer on the therapeutic device, CGI-I, and Patient Global Impression scores (PGI-I), and QOL in Essential Tremor (QUEST) survey. A total of 205 patients completed the study. The co-primary endpoints were met (p < 0.0001), with 62 % (TETRAS) and 68 % (BF-ADL) of “severe” or “moderate” patients improving to “mild” or “slight”. Clinicians (CGI-I) reported improvement in 68 % of patients, 60 % (PGI-I) of patients reported improvement, and QUEST improved (p = 0.0019). Wrist-worn accelerometer recordings before and after 21,806 therapy sessions showed that 92 % of patients improved, and 54 % of patients experienced greater than or equal to 50 % improvement in tremor power. Device-related AEs (e.g., wrist discomfort, skin irritation, pain) occurred in 18 % of patients. No device-related serious AEs were reported. The authors concluded that the findings of this study suggested that non-invasive neuromodulation therapy used repeatedly at home over 3 months resulted in safe and effective hand tremor reduction in many ET patients. Moreover, these researchers stated that further investigation examining how these clinical trial results would translate into the real-world setting would be valuable.

The authors stated that this study had several drawbacks. First, the open-label, single-arm design limited conclusions reliant on assessment of longitudinal repeated-use sham response. A previous 23-patient blinded, randomized single-session trial using an earlier version of TAPS therapy showed that TETRAS spiral drawing scores had greater improvements with TAPS therapy compared to sham (Lin et al, 2018). A similarly constructed multi-site trial with 77 patients did not reproduce this spiral drawing finding, but found that TAPS therapy resulted in greater improvements compared to sham in the TETRAS scores summed for a lateral postural hold, forward outstretched postural hold, and kinetic finger-nose-finger testing, and improvements in tremor amplitude (Pahwa et al, 2019). However, the latter study’s blinding index of 0.608 suggested it would be challenging to successfully maintain a blind over months of at-home usage. An active sham with altered parameters such as a different stimulation bursting frequency or vibrotactile sensory stimulation could be considered; however, such designs risk activating neural circuitry via alternate pathways and may not provide a true, treatment-free control. These investigators stated that future research to establish robust methods to longitudinally maintain a patient blind for peripheral neuromodulation therapies would be a valuable asset for assessing novel therapies. A sham arm could have also controlled for any improvements due to learning effects as patients grew more comfortable with performing the various tremor tasks. For example, this study found pre-stimulation TETRAS and BF-ADL ratings at Visit 3 were lower than pre-stimulation ratings at Visit 1, which may be partially attributable to learning effects. A post-hoc secondary endpoint analysis that segmented the at-home data into the first, second, and third months of the trial found that acute therapeutic efficacy was similar over time (median improvement ratios of 2.0 in month 1, 2.3 in month 2; and 2.0 in month 3), and substantially greater than the improvement in median pre-stimulation tremor power from month 1 to month 3 (improvement ratio of 1.1). The consistency of response over the three months at home suggests a reproducible therapeutic effect even with task-learning effects. It is possible the cumulative reduction in baseline tremor severity may also be partially attributable to neurophysiological remodeling resulting from repeated use of TAPS therapy. Future studies on longitudinal mechanisms of action of this therapy could be valuable to understand this contribution.

Second, clinical raters were unblinded to the study’s design, which may have introduced bias into the TETRAS ratings (e.g., from pre- to post-stimulation at each of the 3 in-clinic visits). Encouragingly, the objective tremor measurements at the in-clinic visits showed that tremor power decreased with stimulation (median improvement ratio of 1.7 at Visits 1 and 3) and that this decrease was directionally consistent with reductions in clinical TETRAS ratings. The confounding effect of rater-bias could be addressed by using central ratings blinded to the study time-points. While TETRAS rating by video has been validated and successfully used in some acute studies evaluating ET therapies, a recent study on non-invasive pharmacologic therapy suggested methodological concerns with central ratings. Third, while the study found statistically significant reductions across all tremor subtasks in both the TETRAS and BF-ADL ratings, in part due to the study’s unprecedented sample size, the magnitude of those reductions varied between tasks. Across tasks, there were 20 % to 40 % of patients for whom TAPS therapy did not relieve specific tremor symptoms. These researchers expected there were 2 main reasons driving the observed variability in individual and population-level response. Latent patient subtypes may influence the variable treatment response observed with all current ET therapies (i.e., pharmacotherapy, invasive therapy (DBS, magnetic resonance-guided focused ultrasound [MRgFUS]), and non-invasive TAPS therapy). While there is general consensus on the existence of these subtypes (e.g., early-onset versus late-onset ET), the full range of sub-types, their clinical presentation, and their interaction with therapeutic interventions has not been fully characterized. Similarly, patients in this study had diverse symptomatic presentations of tremor. These investigators did not expect TAPS therapy to improve tremor rating in a task that did not elicit tremor for that patient, which created a ceiling on maximum improvement for that patient and accordingly lowered population-level average improvements. To the authors’ knowledge there are no defined standards for what constitutes a clinically meaningful improvement in TETRAS or BF-ADL, although the resolution of the scales (0.5 or 1 point, depending on the scale and task) and the community characterization of intra- and inter-rater reliability for these scales suggested that minimum detectable improvement thresholds defined by the scale’s resolution can be considered clinically meaningful. Encouragingly, tremor improvements in this study were larger and consistently on the order of the task-specific minimum detectable improvements for the subsets of patient who had baseline tremor (i.e., at least a “mild” tremor) in a given subtask.

Finally, the pre-specified primary and secondary endpoints in this study excluded the 58 patients who exited the study early; thus, did not qualify for the pre-specified analyses, which may have biased the study’s reported responder rates; 14 of these 58 patients cited “lack of device benefit” as the reason for withdrawal of consent. A worst-case analysis treating these 14 patients as “non-responders” would lower this study’s reported responder rates by less than 5 %. However, a post-hoc analysis found improvements in TETRAS and BF-ADL were not statistically different between those that completed the study, those withdrew citing lack of benefit, and those that withdrew citing other reasons (e.g., AEs, time commitment). Likewise, these patients’ median at-home improvement ratios were comparable. The similarity in response across these 3 patient cohorts suggested that the study reflected the expected range of therapeutic responses in the ET patient population; and the variability in patient perception despite the similar measured response profiles highlighted opportunities for the field to continue developing patient-centered metrics of meaningful therapeutic improvement.

Yu et al (2020) noted that ET patients often experience hand tremor that impairs daily activities. Non-invasive electrical stimulation of median and radial nerves in the wrist using a recently developed therapy called transcutaneous afferent patterned stimulation (TAPS) has been shown to provide symptomatic tremor relief in ET patients and improve patients' ability to perform functional tasks; however, the duration of tremor reduction is unknown. In an open-label, single-arm study, a total of 15 ET patients carried out 4 hand tremor-specific tasks (postural hold, spiral drawing, finger-to-nose reach, and pouring) from the Fahn-Tolosa-Marin Clinical Rating Scale (FTM-CRS) prior to, during, and 0, 30, and 60 mins following TAPS. At each time-point, tremor severity was visually rated according to the FTM-CRS and simultaneously measured by wrist-worn accelerometers. The duration of tremor reduction was evaluated using improvement in the mean FTM-CRS score across all 4 tasks relative to baseline, as well as reduction in accelerometer-measured tremor power relative to baseline for each task. Patients were labeled as having at least 60 mins of therapeutic benefit from TAPS with respect to each specified metric if all 3 (i.e., 0, 30, and 60 mins) post-therapy measurements were better than that metric's baseline value. The mean FTM-CRS scores improved for at least 60 mins beyond the end of TAPS for 80 % (12 of 15, p = 4.6e-9) of patients. Similarly, for each assessed task, tremor power improved for at least 60 mins beyond the end of TAPS for over 70 % of patients. The postural hold task had the largest reduction in tremor power (median of 5.9-fold peak reduction in tremor power) and had at least 60 mins of improvement relative to baseline beyond the end of TAPS therapy for 73 % (11 of 15, p = 9.8e-8) of patients. Clinical ratings of tremor severity were correlated to simultaneously recorded accelerometer-measured tremor power (r = 0.33-0.76 across the 4 tasks), suggesting tremor power is a valid, objective tremor assessment metric that can be used to track tremor symptoms outside the clinic. The authors concluded these findings suggested that TAPS could provide reductions in upper limb tremor symptoms for at least 1 hour post-therapy in some patients, which may improve patients' ability to perform tasks of daily living.

The authors stated that this study had several drawbacks. First, while most patients showed improvement in tremor with TAPS therapy, the degree of improvement was variable between patients and between tasks. This variability was not surprising given the heterogeneity observed in the ET population and the variability in response to current standard-of-care medications and other treatments. Previous work suggested that the hallmark symptoms of ET (kinetic and postural tremors) are driven by multiple central nervous system pathophysiology and that various tremor tasks may elicit tremor through different sensorimotor pathways. It is possible the variability in these underlying mechanisms affect how each participant and task respond to stimulation. Furthermore, each participant’s stimulation frequency was calibrated to their postural hold tremor frequency. It was possible the increased tremor power reductions observed in the postural hold task were related to this task-specific calibration. Future work to better characterize if and how stimulation therapy should be tuned to ET subtype and task may further improve treatment efficacy. Second, this was a small (n = 15), single-session study with safety and efficacy evaluated out to 60 mins after a single 40-min TAPS therapy session. The observed tremor reduction was still present at 60 mins after end of stimulation for most patients, but longer periods of monitoring or variable duration and amplitude of stimulation are needed to fully characterize the duration of effect. It was also possible that multiple consecutive stimulation sessions (i.e., within and across days) would have an interactive effect on tremor reduction and may alter the duration of effect that was observed with a single isolated stimulation session. Future work to develop passive tremor severity monitoring algorithms using wearable motion sensor data (e.g., from a smartwatch) could enable larger-scale studies to objectively track duration of TAPS therapeutic effect at home. Finally, this study was too small to evaluate the impact of patient characteristics, including age, gender, and medical history, on duration of symptomatic relief following TAPS therapy. All patients in this study remained on their standard-of-care ET treatment. While TAPS has been shown to provide effective symptomatic relief for patients both on and off tremor medication, it was possible the 5 of 15 subjects in this study who were on medication may have ingested medication that could have influenced the measured duration of effect.

Pascual-Valdunciel and co-workers (2021) stated that interventions to reduce tremor in ET and Parkinson's disease (PD) clinical populations often employ pharmacological or surgical therapies. However, there can be significant side effects, decline in effectiveness over time, or clinical contraindications for these interventions; thus, alternative approaches must be considered and developed. Some non-pharmacological strategies include assistive devices, orthoses and mechanical loading of the tremorgenic limb, while others propose peripheral electrical stimulation. Specifically, peripheral electrical stimulation encompasses strategies that activate motor and sensory pathways to evoke muscle contractions and impact sensorimotor function. Many studies reported the efficacy of peripheral electrical stimulation to alter tremor generation, thereby opening new perspectives for both short- and long-term tremor reduction. Therefore, it is timely to examine this promising modality in a comprehensive review. These researchers analyzed 27 studies that reported the use of peripheral electrical stimulation to reduce tremor and discussed various considerations regarding peripheral electrical stimulation: the stimulation strategies and parameters, electrodes, experimental designs, results, and mechanisms hypothesized to reduce tremor. The authors concluded that peripheral electrical stimulation below motor threshold stands as a promising intervention to manage pathological tremor due to its minor adverse effects compared to FES. Usability of peripheral electrical stimulation for regular and/or daily use to reduce pathological tremor has been showcased in 2 novel wrist-worn peripheral nerve stimulation devices. More sophisticated wearable devices and algorithms should be pursued, especially combining both EMG and kinematic based-control to disregard voluntary movement components while reducing tremorgenic activity as well as the potential to focus stimulation at multiple muscles or joints of the tremorous limb.

Brillman et al (2022) noted that transcutaneous afferent patterned stimulation (TAPS) is a prescription, wrist-worn device-delivered, non-invasive neuromodulation therapy for treatment of hand tremor in patients with essential tremor (ET). In a retrospective, observational, post-market, surveillance study, these researchers examined real-world effectiveness of TAPS from patients using therapy on-demand for at least 90 days between August 2019 through June 2021. Demographics were summarized from TAPS prescriptions received from the patient’s healthcare provider. Therapy usage and effectiveness were analyzed from device logs, which included tremor measurements from onboard motion sensors. Tremor history and patient-reported outcomes were assessed from a voluntary survey. A total of 321 patients (average age of 71 years, 32 % women) met the criteria for this analysis, 216 of whom had tremor measurements available for analysis, and 69 of whom completed the survey. Total usage period ranged from 90 to 663 days, with 28 % of patients using the device for over 1 year. Patients used therapy 5.4 ± 4.5 (mean ± 1 standard deviation) times per week. TAPS reduced tremor power by 71 % (geometric mean) across all sessions, with 59 % of patients experiencing greater than 50 % tremor reduction after their sessions; 84 % of patients who returned the voluntary survey reported improvement in at least one of the following activities -- eating, drinking, or writing, and 65 % of patients reported improvement in QOL. Self-reported device-related safety complaints were consistent with AEs in previous clinical trials. The authors concluded that real-world evidence is consistent with previous clinical trials and confirmed that TAPS provided safe and effective tremor control for many patients with ET. Moreover, these researchers stated that further investigations evaluating multi-year safety and effectiveness would be valuable to extend these data.

These researchers stated that potential confounders arising in retrospective, observational, real-world, post-market studies should be noted while interpreting this study’s results. First, the inclusion criteria for the study’s device and patient self-reported usage and effectiveness analyses could have introduced bias. The 90-day inclusion criterion was chosen to allow patients sufficient time to resolve therapy use patterns and to mirror length of a prior clinical trial; but could have biased the study findings towards favorable outcomes. Consistency between this real-world study’s findings and the prior clinical study’s findings suggested this bias may be minimal. Unlike a clinical trial, in this real-world post-market analysis, these investigators did not actively solicit complaints; and AE characterization was presented for completeness but comparison to safety data from clinical trials was limited. Second, only patients who chose to complete the device-prompted postural holds and tremor improvement ratings were included in the analysis, and a substantial number of patients and sessions were not analyzed for effectiveness due to missing or poor-quality data. Treatment effectiveness estimates may be skewed if patient measurement likelihoods were tied to satisfaction of post-therapy tremor. Third, patients were prompted to perform postural holds for measuring tremor only immediately before and after stimulation sessions, and as a result, tremor measurements in this study did not allow characterization of duration of post-stimulation treatment effect. Other clinical studies have estimated this duration to be 1 hour for many patients, and passively monitored at home data may provide means to characterize this more broadly in the future. Fourth, this study captured TAPS effectiveness following 1+ years of repeated use for some patients, which extended the 90-day effectiveness established in previous clinical trials. TAPS became available for healthcare providers prescription in late 2019; as the therapy continues to be available to patients for longer periods of time, future analyses that characterize multi-year safety and effectiveness would be valuable. Fifth, confounding factors such as caffeine, alcohol and medications were not controlled for in real-world usage. A further limitation of the study was that wrist-based accelerometry measures the joint-interaction torques produced by the hand tremor and not the hand tremor itself. The accelerometer on-board the stimulation device measures wrist motion, and not hand or finger tremor. However, previous studies have correlated the wrist-based accelerometer measurements of tremor power with gold-standard TETRAS clinical ratings. Finally, key patient-reported outcomes on ADL were only assessed once and via a voluntary survey, which may be subject to recency and respondent-selection bias.

Shukla (2022) noted that there is growing recognition of peripheral stimulation techniques for controlling arm symptoms in ET. Recently, the FDA gave clearance to the Cala system, a device worn around the wrist to treat arm tremors. The Cala system stimulates the sensory afferents of the peripheral nerves with high-frequency pulses. These pulses are delivered to the median and radial nerves alternately at the tremor frequency of the individual patient. These investigators searched PubMed database using the terms ("Essential Tremor"[Mesh] OR "essential tremor" [Title/Abstract] OR "tremor" [Title/Abstract]) AND ("peripheral arm stimulation" [Title/Abstract] OR "Cala device" [Title/Abstract] OR "sensory afferent stimulation" [Title/Abstract] OR "afferent stimulation" [Title/Abstract] OR "arm stimulation" [Title/Abstract] OR "peripheral nerve stimulation" [Title/Abstract]). The search yielded 54 articles; many studies discussed the rationale and various strategies for peripheral modulation of tremor. While the Cala system was found to be safe and well-tolerated in ET, data on effectiveness revealed mixed findings. In a large randomized, blinded trial (n = 77), the primary outcome evaluated with spiral drawing task did not improve but the secondary outcomes reflected by the arm tremor severity and the ADL score revealed 20 % to 25 % improvements. A subsequent trial (n = 323) found that the in-home use of the Cala device resulted in improvements of similar magnitude lasting for at least 3 months; however, the clinical assessments were open labeled. The authors concluded that peripheral stimulation techniques are promising therapeutic modalities for treating ET symptoms. Stimulation of sensory afferent nerve fibers at the wrist could potentially modulate the peripheral and central components of the tremor network. These researchers stated that although the Cala system is user-friendly, safe, and well-tolerated, the current clinical evidence on the effectiveness is inconsistent and insufficient; thus, further investigation is needed for implementing peripheral nerve stimulation as a standard of care (SOC) for ET.

The ECRI’s clinical evidence assessment on “Cala Trio wrist-worn neuromodulation therapy for essential tremor” (2023) concluded that “Cala Trio is safe and appears to reduce tremor severity and improve activities of daily living (ADLs) after use in some patients with ET at up to 3-month follow-up, based on low-quality evidence from 2 small randomized controlled trials (RCTs) and 2 before-and-after studies. However, study findings do not permit firm conclusions on whether Cala Trio’s clinical benefits are sustained beyond 3 months. No published studies compare Cala Trio with other ET treatments” (Confidence in Evidence = Low for ET severity and ADL; very low for disease improvement).

Furthermore, an UpToDate review on “Essential tremor: Treatment and prognosis” (Deik and Tarsy, 2023) states that “Neuromodulation -- In a randomized, sham-controlled pilot study involving 23 blinded subjects, noninvasive median and radial nerve stimulation resulted in an improvement in the Archimedes spiral drawing task. Subsequent studies, including a larger open-label, single-arm study with 263 patients, suggest that noninvasive neuromodulation therapy used repeatedly at home in 40-minute sessions is safe and effective for hand tremor reduction during use of the device and for up to an hour afterwards”.

Diaphragmatic/Phrenic Pacing in Lung Transplant Recipients

Onders et al (2014) stated that diaphragm dysfunction (DD) can cause sleep abnormalities, dyspnea, atelectasis, and respiratory failure. Historical treatments, including positive pressure ventilation or diaphragm plication, may alleviate symptoms but do not restore physiologic diaphragm function. Diaphragm pacing (DP) is approved for patients with SCI and ALS. These investigators reported a series of DD patients undergoing the use of DP outside of these initial indications. This report entailed a prospective, non-randomized, interventional trial under IRB approval at a single institution. DP involves laparoscopic motor point mapping with implantation of intra-muscular electrodes in each hemi-diaphragm. Post-operatively, diaphragm conditioning ensued. A total of 27 patients were evaluated; all patients had symptomatic and objective hypoventilation for an average of 36 months of symptoms. Causes included idiopathic (n = 13), chest surgery (n = 5), shoulder surgery or trauma (n = 6), and others (n = 3); 17 had bilateral involvement, 6 had non-stimulable diaphragms and were not implanted, and 21 were implanted; 13 (62 %) had substantial clinically relevant respiratory improvements; 4 ventilator patients were weaned completely; 4 had partial improvement, 3 had no improvement, and 1 patient was lost to follow-up for objective analysis. The authors concluded that this was the 1st report of DP being used to treat diverse causes of DD; 81 % of implanted patients experienced improvements. This success suggested a potential for a wider use of DP and areas for future research. There was 1 cardiac transplant subject but no lung transplant recipient in this study.

LoMauro et al (2020) noted that lung transplantation (LTx) is a complex but effective treatment of end-stage pulmonary disease. Among the post-operative complications, phrenic nerve injury, and consequent DD are known to occur but are poorly described. These investigators examined the effect of LTx on diaphragmatic function with a multi-modal approach. A total of 30 patients were studied at 4 time-points: pre-operatively, at discharge after surgery, and after approximately 6 and subsequently 12 months post-surgery. The diaphragmatic function was studied in terms of geometry (assessed by the radius of the diaphragmatic curvature delineated on chest X-ray), weakness (considering changes in forced vital capacity [FVC] when the patient shifted from upright to supine position), force (maximal pressure during sniff), mobility (excursion of the dome of the diaphragm delineated by US), contractility (thickening fraction assessed by US), electrical activity (latency and area of compound muscle action potential during electrical stimulation of phrenic nerve), and kinematics (relative contribution of the abdominal compartment to tidal volume). Despite good clinical recovery (indicated by spirometry and 6MWT), a reduction of the diaphragmatic function was detected at discharge; it persisted 6 months later to recover fully 1 year after transplantation. DD was demonstrated in terms of force, weakness, electrical activity, and kinematics. These findings suggested that the DD was caused by phrenic nerve neurapraxia or moderate axonotmesis, potentially as a consequence of the surgical procedure (i.e., the use of ice and pericardium manipulation). The authors concluded that occurrence of DD in patients with a good clinical recovery indicated that the evaluation of diaphragmatic function should be included in the post-operative assessment following LTx. This study did not provide any clinical data on the use of DP.

In an abstract submitted to the 2020 International ATS Meeting, Hejal et al (2020) presented a retrospective analysis of a prospective, non-randomized interventional experience at a single center for DP in over 600 patients. The authors concluded that DP could play a significant role in patients with symptomatic unilateral DD (UDD). It could be offered as a treatment modality in UDD where the diaphragm can be electrically stimulated before consideration of a plication procedures. There was 1 liver transplant subject in this study, but no LTx recipient.

Onders et al (2021) stated that lung disease and transplantation can lead to DD. These investigators noted that phrenic neuropathy in LTx increases morbidity; DP improves nerve recovery and prevents ventilator-induced diaphragm dysfunction (VIDD). The FDA authorized temporary DP to decrease the burden of mechanical ventilators (MV) during the COVID-19 pandemic. These researchers reported the largest experience of DP in LTx. This was a retrospective analysis of an IRB-approved prospective, non-randomized interventional experience at a single center with 2 DP systems. A chronic DP system was laparoscopically implanted in those with identified (either pre- or post-transplant) phrenic nerve injury. Post-implantation, diaphragm stimulation ensued; and results evaluated radiographically and with diaphragm EMG (dEMG). Transplant recipients had the temporary DP system implanted percutaneously via their chest incision. Diaphragm activity was monitored with the electrodes and stimulation applied for MV weaning. A total of 8 patients used DP with no device AEs; 3 patients with DD, 6 months average post-transplant, had chronic DP implanted. All had evidence of subsequent recovery of diaphragm function; 1 patient had DP pre-transplant for unilateral DD with subsequent diaphragm recovery. At time of unilateral transplant on contralateral side a phrenic nerve injury was identified. DP was employed during the recovery; 4 patients underwent implantation of temporary DP electrodes during LTx; 2 patients had bilateral dEMG identified post-operatively with uneventful recovery and removal of electrodes; 2 patients had no dEMG activity or movement bilaterally post-operatively. Retrospectively, this was a pre-operative condition; 1 recovered diaphragm function at 2 weeks with DP therapy. The 2nd patient was still undergoing DP; 3 patients with phrenic nerve dysfunction post-operatively also had intercostal nerve cryoanalgesia that reduced external intercostal muscles use for respiration. These 3 patients had prolonged ventilation difficulties. The authors concluded that DP was safely used in LTx (n = 8) in identifying and improving recovery of phrenic nerve injuries and preventing VIDD. Intercostal nerve cryo-analgesia should not be used if there is DD; and DP should be considered in all LTx recipients for improved outcomes.

Onders et al (2022) noted that DD is documented following LTx; and could affect up to 62 % patients. DP prevents VIDD while on MV and has been shown via functional electrical stimulation to improve phrenic nerve recovery. Ina retrospective study, these researchers reported the largest experience of DP in LTx recipients. This trial was an IRB-approved prospective, non-randomized interventional experience at a single center with 2 DP systems. A chronic DP system (NeuRx, Synapse Biomedical) was implanted laparoscopically in those with phrenic nerve injury or difficulty with weaning from MV remotely after their transplant. A temporary DP system (TransAeris, Synapse Biomedical) was implanted at the time of transplantation or laparoscopically. In both types of implantation, diaphragm stimulation ensued if needed to wean from MV or for nerve recovery. Results evaluated radiographically and with dEMG. DP was used in16 patients with no device AEs. Of those, 5 patients had chronic DP system: 1 patient 1-year post-transplant showed no recovery of phrenic nerve injury, still pacing; 3 patients showed recovery of phrenic nerve/diaphragm function through pacing; 1 patient 2-year post-transplant sustained hip fracture requiring surgery, developed pneumonia and became tracheostomy MV-dependent; DP allowed complete diaphragm recovery, de-canulation of tracheostomy and removal of DP wires. A total of 11 patients had temporary DP electrodes placed: 1 recipient (2-month post-transplant) had DP use during ECMO for COVID- 19 sepsis and respiratory failure and subsequently expired when family withdrew therapy; 10 implanted at time of LTx. Of those 10, 3 patients had bilateral dEMG identified post-operatively with uneventful recovery and removal of electrodes; 7 patients had diaphragm abnormalities identified post-operatively and underwent DP. Of those 7, 5 showed recovery and DP electrodes removed and 2 were still pacing 1- and 9-month post-transplant. The authors concluded that DP was safely used in LTx to identify and improve recovery of phrenic nerve injuries, wean from MV and prevent VIDD. These researchers stated that DP showed promise in addressing DD following LTx and improving outcomes.

Implanted Functional Electrical Stimulation for Improvement of Gait Performance in Stroke Survivors

Kang et al (2021) stated that the emerging literature suggests that implantable FES may improve gait performance in stroke survivors; however, there is a lack of review providing the possible therapeutic effects of implanted FES on gait performance in stroke survivors. These investigators carried out a web-based, systematic search using PubMed, the Cochrane Library, and Embase. They limited the search results to human subjects and studies published in peer-reviewed journals in English. These researchers did not restrict demographic or clinical characteristics. They included 10 studies in the current systematic review. Across all included studies, these investigators found preliminary evidence of the potential therapeutic effects of FES on walking endurance, walking speed, ankle mobility, and push-off force in stroke survivors. However, due to the heterogeneity between the included studies, small sample size, and lack of RCTs, more studies are needed to confirm if implanted FES could improve gait performance in stroke survivors. Furthermore, these researchers stated that further investigation is needed to examine the effects of implanted FES not only for correcting foot drop (evoking the contraction of dorsiflexor muscles), but also for addressing dysfunction in other muscles or muscle groups in the lower limb that could contribute to overall gait dysfunction following stroke.

The authors stated that this systematic review highlighted a few issues regarding study participants: Small sample size, varied demographic (e.g., age) and clinical characteristics (time since stroke), as well as varied follow-up time-points. In addition, across all studies, these researchers found a lack of measuring possible common co-variates that could mitigate the effect of the experimental intervention such as frailty, fear of falling, and cognitive status. Another drawback of the included papers was the heterogeneity in the type of stroke. Several studies reported mixed results about the effect of other rehabilitation techniques on functional outcomes between ischemic and hemorrhagic patients. However, based on this systematic review, the authors found that the reported effects of implanted FES may have been confounded by different types of strokes included in the patient population studied. It will be important to examine the influence of the type and severity of stroke on functional outcomes after being treated with implanted FES. These investigators also found another drawback regarding the stimulation specifications (i.e., amplitude, frequency, duration), which was found only in 50 % of the included studies. As these specifications may have affected the results of gait performance examined in the included studies, it will be important to report these parameters in future studies. The authors also found issues regarding gait outcome measures. In terms of walking endurance tests (i.e., either 4-min walk distance [4MWD] versus 6MWD), although it may be too early to determine based on the limited number of included studies, given the validity and popularity, the 6MWD may better reflect walking endurance in stroke survivors. additionally, gait speed during level short-distance walking that was reported in 80 % of the included studies may not provide a comprehensive view of gait performance in stroke survivors because this walking condition may not best represent gait performance in natural circumstances. To address this issue, these researchers recommended examining other gait outcomes such as gait stability and gait initiation under various walking conditions (e.g., dual-task walking, changing directions during walking). Furthermore, although a few studies reported ankle mobility during walking, these investigators noticed heterogeneity in the reported outcome variables for ankle mobility. A direct quantitative measure of foot drop, namely, changes in sagittal ankle angle around push-off and the associated compensatory movements like hip hiking is lacking. Also, no studies addressed other types of gait dysfunction besides foot drop, i.e., dysfunction in muscle groups other than the dorsiflexors.

Neuromuscular Electrical Stimulation for Improvement of Functional Capacity and Quality of Life in Patients after Cardiac Surgery

Zhang et al (2022) noted that NMES is a possible adjunctive therapy applied to cardiac surgery patients to improve physical function; however, the results are still controversial. In a systematic review and meta-analysis, these investigators examined the effects of NMES on functional capacity and QOL in cardiac surgery patients. The following databases PubMed, Embase, Medicine, CINAHL, and the Cochrane Central Register of Controlled Trials were searched for the English language from inception up to March 2021. These investigators carried out a systematic targeted literature search examining the effects of NMES on physical function and QOL in cardiac surgery patients. The effect size of NMES was presented as the MD/SMD and its 95 % CI using fixed/random effect models according to heterogeneity. Two reviewers independently screened and appraised each study by using the Cochrane Risk of Bias Tool. A total of 6 studies were included involving 400 cardiac surgery patients. The meta-analysis showed that NMES had effect on knee extensor strength (SMD = 1.68; p = 0.05); but had no effects on 6MWD (MD = 44.08; p = 0.22), walking speed (MD = 0.05; p = 0.24), grip strength (MD = 3.01; p = 0.39), or QOL (SMD = 0.53; p= 0.19). The authors concluded that NMES use in cardiac surgery patients is limited by low-to-moderate quality; existing evidence showed that NMES is safe and effective for improving knee extensor strength. Moreover, these researchers stated that the use of NMES in physical exercise is an emerging field among cardiac surgery patients, the current evidence is limited by adequately powered RCTs. They stated that high-quality RCTs in cardiac surgery patients are needed to examine the effect of NMES and to identify which cardiac patient subgroups might benefit the most and maximize clinical benefit.

The author stated that this systematic review had several drawbacks. First, the sources of the publications were included only in English, potentially introducing publication and language biases. Second, the included studies were of low-to-moderate risk of bias, which limited the usefulness of this review. Third, the lack of homogeneity of the interventions making the comparison impossible or inaccurate. Fourth, due to the original author who could not be contacted, the combined effect of the 6MWD and grip strength in this article has been weakened; therefore, further research, especially large-sample and high-quality RCTs are needed to confirm the effect of NMES on physical capacity and safety among cardiac surgery patients, especially the suitable prescription of NMES for patients after cardiac surgery is crucial.

Wearable NMES Devices (e.g., geko T-3 and geko W-3) for the Treatment of Venous Insufficiency and/or Ischemia in the Lower Limb

The geko devices with OnPulse technology are low-frequency (1-Hz) NMES devices that stimulate the common peroneal nerve activating the calf and foot muscle pumps, resulting in isometric muscle contraction and increased blood flow. The geko device stimulates the motor neurons within the nerve bundle that carry signals to the muscle fibers to cause contraction. Stimulating the common peroneal nerve activates the tibialis, peroneus longus and lateral gastrocnemius muscles. Together, their simultaneous contraction compresses the venous system, efficiently evacuating blood in the deep veins of the calf at a rate equal to 60 % of walking. The device is worn just below the knee on 1 or both legs and is available in two versions; geko T-3 and geko W-3, which can deliver NMES for up to 24 hours per day. The lightweight, battery-operated device has integrated electronics composed of a constant pulse generator with embedded software and a lithium-ion battery enclosed in a molded plastic casing, and embedded electrodes that deliver stimulation via an adhesive surface. The devices deliver multiple stimulation levels that increase the electrical charge, muscle contractions are achieved. The settings address the variation in responsiveness of patients to stimulation due to individual specifics. Two buttons control the on/off function and intensity levels of the device output. Indications include increasing local blood circulation, reduction of edema, prevention of venous thrombosis, and increasing microcirculatory blood flow in lower limb with venous insufficiency and/or ischemia to support wound or tissue healing. The devices can deliver an effective stimulation for up to 24 hours per day, depending on the device selected and the indication for use. After use, the device is removed, discarded and a new device is applied and activated as required. The device is applied to the skin and positioned over the peroneal nerve just below the knee. An indicator line on the device is aligned to the fibula head, for optimal electrode placement. The geko W-3 devices are supplied as 7 single units; the geko T-3 devices are supplied in pairs of devices. The geko T-3 and geko W-3 received the FDA’s 510(k) clearance on May 23, 2018.

However, there is a lack of evidence regarding the clinical value of these wearable NMES devices.

References

The above policy is based on the following references:

Functional Electrical Stimulation for Walking

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Functional Electrical Stimulation of the Upper Extremities

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Neuromuscular Electrical Stimulation for Disuse Atrophy

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Functional Electrical Stimulation / Neuromuscular Electrical Stimulation for Stroke

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Neuromuscular Electrical Stimulation for Spinal Cord Injury

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Diaphragmatic / Phrenic Pacing

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Sacral Nerve Stimulation with Dorsal Rhizotomy (Vocare Bladder System)

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Egon G, Barat M, Columbel P, et al. Implantation of anterior sacral root stimulators combined with posterior sacral rhizotomy in spinal injury patients. World J Urol. 1998;16(5):342-349.
Herbison P, Arnold E. Neuromodulation with implanted electrodes for urinary storage and voiding dysfunction in adults (Protocol for Cochrane Review). Cochrane Database Syst Rev. 2003;(2):CD004202.
Jamil F. Towards a catheter free status in neurogenic bladder dysfunction: A review of bladder management options in spinal cord injury (SCI). Spinal Cord. 2001;39(7):355-361.
Jezernik S, Craggs M, Grill WM, et al. Electrical stimulation for the treatment of bladder dysfunction: Current status and future possibilities. Neurol Res. 2002;24(5):413-430.
U.S. Food and Drug Administration (FDA). Vocare Bladder System. Humanitarian Use Devices. H980005. Rockville, MD: FDA; December 28, 1998.
Van Kerrebroeck PE, Koldewijn EL, Rosier PF, et al. Results of the treatment of neurogenic bladder dysfunction in spinal cord injury by sacral posterior root rhizotomy and anterior sacral root stimulation. J Urol. 1996;155(4):1378-1381.
Wielink G, Essink-Bot M L, van Kerrebroeck PEV, Rutten FFH. Sacral rhizotomies and electrical bladder stimulation in spinal cord injury 2: Cost-effectiveness and quality of life analysis. Eur Urol. 1997;31(4):441-446.
Wyndaele JJ, Madersbacher H, Kovindha A. Conservative treatment of the neuropathic bladder in spinal cord injured patients. Spinal Cord. 2001;39(6):294-300.

Transurethral Electrical Bladder Stimulation

Aslan AR, Kogan BA. Conservative management in neurogenic bladder dysfunction. Curr Opin Urol. 2002;12(6):473-477.
Barrett DM, Wein AJ. Voiding dysfunction: Diagnosis, classification, and management. In: Adult and Pediatric Urology. Vol. 1. 2nd Ed. JY Gillenwater, et al., eds. St. Louis, MO: Mosby Year Book; 1991; Ch. 28B, pp. 1001-1099.
Boone TB, Roehrborn CG, Hurt G. Transurethral intravesical electrotherapy for neurogenic bladder dysfunction in children with myelodysplasia: A prospective, randomized clinical trial. J Urol. 1992;148(2 Pt 2):550-554.
Decter RM, Snyder P, Laudermilch C. Transurethral electrical bladder stimulation: A follow-up report. J Urol. 1994;152(2 Pt 2):812-814.
Decter RM, Snyder P, Rosvanis TK. Transurethral electrical bladder stimulation: Initial results. J Urol. 1992;148(2 Pt 2):651-653, discussion 654.
Fernandes ET, Reinberg Y, Vernier R, Gonzalez R. Neurogenic bladder dysfunction in children: Review of pathophysiology and current management. J Pediatr. 1994;124(1):1-7.
Kaplan WE, Richards I. Intravesical bladder stimulation in myelodysplasia. J Urol. 1988;140(5 Pt 2):1282-1284.
Kaplan WE, Richards I. Intravesical transurethral electrotherapy for the neurogenic bladder. J Urol. 1986;136(1 pt 2):243-246.
Kaplan WE, Richards TW, Richards I. Intravesical transurethral bladder stimulation to increase bladder capacity. J Urol. 1989;142(2 Pt 2):600-602, discussion 603-605.
Katona F, Berenyi M. Intravesical transurethral electrotherapy in meningomyelocele patients. Acta Paed Acad Sci Hung. 1975;16(3-4):363-374.
Lyne CJ, Bellinger MF. Early experience with transurethral electrical bladder stimulation. J Urol. 1993;150(2 Pt 2):697-699.
Nicholas JL, Eckstein HB. Endovesical electrotherapy in treatment of urinary incontinence in spina-bifida patients. Lancet. 1975;2(7948):1276-1277.
van Balken MR, Vergunst H, Bemelmans BL. The use of electrical devices for the treatment of bladder dysfunction: A review of methods. J Urol. 2004;172(3):846-851.
Van Kerrebroeck EV, van der Aa HE, Bosch JL, et al. Sacral rhizotomies and electrical bladder stimulation in spinal cord injury. Part I: Clinical and urodynamic analysis. Dutch Study Group on Sacral Anterior Root Stimulation. Eur Urol. 1997;31(3):263-271.
Wein AJ. Neuromuscular dysfunction of the lower urinary tract. In: Campbell's Urology. Vol. 1. 6th Ed. PC Walsh, et al., eds. Philadelphia, PA: W.B. Saunders Company; 1992; Ch. 13, pp. 573-642.
Wielink G, Essink-Bot ML, van Kerrebroeck PE, Rutten FF. Sacral rhizotomies and electrical bladder stimulation in spinal cord injury. 2: Cost-effectiveness and quality of life analysis. Eur Urol. 1997;31(4):441-446.

Electrical Stimulation for Cerebral Palsy

Atwater SW, et al. Electromyography-triggered electrical muscle stimulation for children with cerebral palsy: A pilot study. Pediatr Phys Ther. 1991;3:190-199.
Boyd RN, Morris ME, Graham HK. Management of upper limb dysfunction in children with cerebral palsy: A systematic review. Eur J Neurol. 2001;8(Suppl 5):150-166.
Carmick J. Clinical use of neuromuscular electrical stimulation for children with cerebral, Part 1: Lower extremity. Phys Ther. 1993;73(8):505-513, discussion 523-527.
Carmick J. Clinical use of neuromuscular electrical stimulation for children with cerebral, Part 2: Upper extremity. Phys Ther. 1993;73(8):514-522, discussion 523-527.
Detrembleur C, Lejeune TM, Renders A, Van Den Bergh PY. Botulinum toxin and short-term electrical stimulation in the treatment of equinus in cerebral palsy. Mov Disord. 2002;17(1):162-169.
Dubowitz L, Finnie N, Hyde SA, et al. Improvement of muscle performance by chronic electrical stimulation in children with cerebral palsy. Lancet. 1988;1(8585):587-588.
Hazlewood ME, Brown JK, Rowe PJ, Salter PM. The use of therapeutic electrical stimulation in the treatment of hemiplegic cerebral palsy. Dev Med Child Neurol. 1994;36(8):661-673.
Kerr C, McDowell B, McDonough S. Electrical stimulation in cerebral palsy: A review of effects on strength and motor function. Dev Med Child Neurol. 2004;46(3):205-213.
Kuban KC, Leviton A. Cerebral Palsy. N Engl J Med. 1994;330(3):188-195.
Lake DA. Neuromuscular electrical stimulation: An overview and its application in the treatment of sports injuries. Sports Medicine. 1992;13(5):320-336.
Pape KE, Kirsch SE, Galil A, et al. Neuromuscular approach to the motor deficits of cerebral palsy: A pilot study. J Pediatr Orthop. 1993;13(5):628-633.
Steinbok P, Reiner A, Kestle JR. Therapeutic electrical stimulation following selective posterior rhizotomy in children with spastic diplegic cerebral palsy: A randomized clinical trial. Dev Med Child Neurol. 1997;39(8):515-520.

Electrical Stimulation for Bell's Palsy

Adour KK. Medical management of idiopathic (Bell's) palsy. Otolaryngol Clin North Am. 1991;24(3):663-673.
Buttress S, Herren K. Towards evidence based emergency medicine: Best BETs from the Manchester Royal Infirmary. Electrical stimulation and Bell's palsy. Emerg Med J. 2002;19(5):428.
Fitzgerald DC. Role of electrical stimulation therapy for Bell's palsy. Am J Otol. 1993;14(4):413-414.
Huizing EH, Mechelse K, Staal A. Treatment of Bell's Palsy. An analysis of the available studies. Acta Otolaryngol. 1981;92(1-2):115-121.
Quinn R, Cramp F. The efficacy of electrotherapy for Bell's palsy: A systematic review. Phys Ther Rev. 2003;8(3):151-164.
Wolf SR. Idiopathic facial paralysis. HNO. 1998;46(9):786-798.

Foot Drop (e.g., Walkaide Device)

Barrett CL, Mann GE, Taylor PN, Strike P. A randomized trial to investigate the effects of functional electrical stimulation and therapeutic exercise on walking performance for people with multiple sclerosis. Mult Scler. 2009;15(4):493-504.
Bethoux F, Rogers HL, Nolan KJ, et al. The effects of peroneal nerve functional electrical stimulation versus ankle-foot orthosis in patients with chronic stroke: A randomized controlled trial. Neurorehabil Neural Repair. 2014;28(7):688-697.
Clinical Access and Redesign Unit, Health Service and Clinical Innovation Division, Queensland Health. Health Technology Assessment Program Annual Report 2011-2012. Brisbane, QLD: Queensland Government; 2012.
Damiano DL, Prosser LA, Curatalo LA, Alter KE. Muscle plasticity and ankle control after repetitive use of a functional electrical stimulation device for foot drop in cerebral palsy. Neurorehabil Neural Repair. 2013;27(3):200-207.
Danino, B., Khamis, S., Hemo, Y., et al. The efficacy of neuroprosthesis in young hemiplegic patients, measured by three different gait indicies: Early results. J Child Orthop. 2013 7(6):537-542.
Everaert DG, Stein RB, Abrams GM, et al. Effect of a foot-drop stimulator and ankle-foot orthosis on walking performance after stroke: A multicenter randomized controlled trial. Neurorehabil Neural Repair. 2013;27(7):579-591.
Hausdorff JM, Ring H. Effects of a new radio frequency-controlled neuroprosthesis on gait symmetry and rhythmicity in patients with chronic hemiparesis. Am J Phys Med Rehabil. 2008;87(1):4-13.
Kido Thompson A, Stein RB. Short-term effects of functional electrical stimulation on motor-evoked potentials in ankle flexor and extensor muscles. Exp Brain Res. 2004;159(4):491-500.
Kluding PM, Dunning K, O'Dell MW, et al. Foot drop stimulation versus ankle foot orthosis after stroke: 30-week outcomes. Stroke. 2013;44(6):1660-1669.
Kottink AI, Hermens HJ, Nene AV, et al. Therapeutic effect of an implantable peroneal nerve stimulator in subjects with chronic stroke and footdrop: A randomized controlled trial. Phys Ther. 2008;88(4):437-448.
Laufer Y, Hausdorff JM, Ring H. Effects of a foot drop neuroprosthesis on functional abilities, social participation, and gait velocity. Am J Phys Med Rehabil. 2009;88(1):14-20.
Laufer Y, Ring H, Sprecher E, Hausdorff JM. Gait in individuals with chronic hemipareisis: One-year follow-up of the effects of a neuroprosthesis that ameliorates foot drop. J Neurol Phys Ther. 2009;33(2):104-110.
Meilahn JR. Tolerability and effectiveness of a neuroprosthesis for the treatment of footdrop in pediatric patients with hemiparetic cerebral palsy. PMR. 2013;5(6):503-509.
Miller L, McFadyen A, Lord AC, et al. Functional electrical stimulation for foot drop in multiple sclerosis: A systematic review and meta-analysis of the effect on gait speed. Arch Phys Med Rehabil. 2017;98(7):1435-1452.
Miller L, Rafferty D, Paul L, Mattison P. A comparison of the orthotic effect of the Odstock Dropped Foot Stimulator and the Walkaide functional electrical stimulation systems on energy cost and speed of walking in multiple sclerosis. Disabil Rehabil Assist Technol. 2015;10(6):482-485.
Prenton S, Kenney LP, Stapleton C, et al. A feasibility study of a take-home array-based functional electrical stimulation system with automated setup for current functional electrical stimulation users with foot-drop. Arch Phys Med Rehabil. 2014;95(10):1870-1877.
Ring H, Treger I, Gruendlinger L, Hausdorff JM. Neuroprosthesis for footdrop compared with an ankle-foot orthosis: Effects on postural control during walking. J Stroke Cerebrovasc Dis. 2009;18(1):41-47.
Scott SM, van der Linden ML, Hooper JE, et al. Quantification of gait kinematics and walking ability of people with multiple sclerosis who are new users of functional electrical stimulation. J Rehabil Med. 2013;45(4):364-369.
Sheffler LR, Hennessey MT, Naples GG, Chae J. Improvement in functional ambulation as a therapeutic effect of peroneal nerve stimulation in hemiplegia: Two case reports. Neurorehabil Neural Repair. 2007;21(4):366-369.
Sheffler LR, Hennessey MT, Naples GG, Chae J. Peroneal nerve stimulation versus an ankle foot orthosis for correction of footdrop in stroke: Impact on functional ambulation. Neurorehabil Neural Repair. 2006;20(3):355-360.
Street T, Taylor P, Swain I. Effectiveness of functional electrical stimulation on walking speed, functional walking category, and clinically meaningful changes for people with multiple sclerosis. Arch Phys Med Rehabil. 2015;96(4):667-672.
Taylor P, Barrett C, Mann G, et al. A feasibility study to investigate the effect of functional electrical stimulation and physiotherapy exercise on the quality of gait of people with multiple sclerosis. Neuromodulation. 2014;17(1):75-84; discussion 84.
Van Swigchem, R., Vloothuis, J., den Boer, J., et al. Is transcutaneous peroneal stimulation beneficial to patients with chronic stroke using an ankle-foot arthosis? A within-subjects study of patients’ satisfaction, walking speed and physical activity level. J Rehabil Med. 2010;42(2):117-121.
Weber DJ, Stein RB, Chan KM, et al. BIONic WalkAide for correcting foot drop. Conf Proc IEEE Eng Med Biol Soc. 2004;6:4189-4192.
Weber DJ, Stein RB, Chan KM, et al. BIONic WalkAide for correcting foot drop. IEEE Trans Neural Syst Rehabil Eng. 2005;13(2):242-246.
Weber DJ, Stein RB, Chan KM, et al. Functional electrical stimulation using microstimulators to correct foot drop: A case study. Can J Physiol Pharmacol. 2004;82(8-9):784-792.

Functional Electrical Stimulation / Neuromuscular Electrical Stimulation for Patients with Multiple Sclerosis

Pilutti LA, Motl RW. Functional electrical stimulation cycling exercise for people with multiple sclerosis. Curr Treat Options Neurol. 2019;21(11):54.
Scally JB, Baker JS, Rankin J, et al. Evaluating functional electrical stimulation (FES) cycling on cardiovascular, musculoskeletal and functional outcomes in adults with multiple sclerosis and mobility impairment: A systematic review. Mult Scler Relat Disord. 2020;101485.
Wahls TL, Reese D, Kaplan D, Darling WG. Rehabilitation with neuromuscular electrical stimulation leads to functional gains in ambulation in patients with secondary progressive and primary progressive multiple sclerosis: A case series report. J Altern Complement Med. 2010;16(12):1343-1349.

Neuromuscular Electrical Stimulation for Knee Osteoarthritis

Giggins OM, Fullen BM, Coughlan GF, et al. Neuromuscular electrical stimulation in the treatment of knee osteoarthritis: A systematic review and meta-analysis. Clin Rehabil. 2012;26(10):867-881.

Threshold Electrical Stimulation

Cauraugh JH, Naik SK, Hsu WH, et al. Children with cerebral palsy: A systematic review and meta-analysis on gait and electrical stimulation. Clin Rehabil. 2010;24(11):963-978.
Dali C, Hansen FJ, Pedersen SA, et al. Threshold electrical stimulation (TES) in ambulant children with CP: A randomized double-blind placebo-controlled clinical trial. Dev Med Child Neurol. 2002; 44(6):364-369.
Kerr C, McDowell B, Cosgrove A, et al. Electrical stimulation in cerebral palsy: A randomized controlled trial. Dev Med Child Neurol. 2006;48(11):870-8766.
Negm A, Lorbergs A, Macintyre NJ. Efficacy of low frequency pulsed subsensory threshold electrical stimulation vs placebo on pain and physical function in people with knee osteoarthritis: Systematic review with meta-analysis. Osteoarthritis Cartilage. 2013;21(9):1281-1289.
Scianni A, Butler JM, Ada L, Teixeira-Salmela LF. Muscle strengthening is not effective in children and adolescents with cerebral palsy: A systematic review. Aust J Physiother. 2009;55(2):81-87.
Sommerfelt K, Markestad T, Berg K, Saetesdal I. Therapeutic electrical stimulation in cerebral palsy: A randomized, controlled, crossover trial. Dev Med Child Neurol. 2001;43(9):609-613.

Improvement of Ambulatory Function / Muscle Weakness in Individuals with Progressive Diseases

Maddocks M, Gao W, Higginson IJ, Wilcock A. Neuromuscular electrical stimulation for muscle weakness in adults with advanced disease. Cochrane Database Syst Rev. 2013;1:CD009419.
Pereira S, Mehta S, McIntyre A, et al. Functional electrical stimulation for improving gait in persons with chronic stroke. Top Stroke Rehabil. 2012;19(6):491-498.

Neuromuscular Electrical Stimulation / Phrenic Nerve Stimulation for Central Sleep Apnea/Ventilator-Dependent Respiratory Failure

Abraham WT, Jagielski D, Oldenburg O, et al; remede Pilot Study Investigators. Phrenic nerve stimulation for the treatment of central sleep apnea. JACC Heart Fail. 2015;3(5):360-369.
Badr MS. Central sleep apnea: Treatment. UpToDate [online serial]. Waltham, MA: UpToDate; reviewed December 2015.
Costanzo MR, Augostini R, Goldberg LR, et al. Design of the remede system pivotal trial: A prospective, randomized study in the use of respiratory rhythm management to treat central sleep apnea. J Card Fail. 2015;21(11):892-902.
Costanzo MR, Ponikowski P, Javaheri S, et al; remedé System Pivotal Trial Study Group. Transvenous neurostimulation for central sleep apnoea: A randomised controlled trial. Lancet. 2016;388(10048):974-982.
Fox H, Bitter T, Horstkotte D, et al. Long-term experience with first-generation implantable neurostimulation device in central sleep apnea treatment. Pacing Clin Electrophysiol. 2017;40(5):498-503.
Germany R. Non-mask-based therapies for central sleep apnea in patients with heart failure. Sleep Med Clin. 2017;12(2):255-264.
Jagielski D, Ponikowski P, Augostini R, et al. Transvenous stimulation of the phrenic nerve for the treatment of central sleep apnoea: 12 months' experience with the remedē® System. Eur J Heart Fail. 2016;18(11):1386-1393.
U.S. Food and Drug Administration (FDA). FDA approves implantable device to treat moderate to severe central sleep apnea. FDA News. Silver Spring, MD: FDA; October 6, 2017.
Zhang X, Ding N, Ni B, et al. Safety and feasibility of chronic transvenous phrenic nerve stimulation for treatment of central sleep apnea in heart failure patients. Clin Respir J. 2017;11(2):176-184.

Functional Electrical Stimulation / Neuromuscular Electrical Stimulation for Chronic Obstructive Pulmonary Disease

Chen RC, Li XY, Guan LL, et al. Effectiveness of neuromuscular electrical stimulation for the rehabilitation of moderate-to-severe COPD: A meta-analysis. Int J Chron Obstruct Pulmon Dis. 2016;11:2965-2975.
Maddocks M, Nolan CM, Man WD, et al. Neuromuscular electrical stimulation to improve exercise capacity in patients with severe COPD: A randomised double-blind, placebo-controlled trial. Lancet Respir Med. 2016;4(1):27-36.
Medrinal C, Prieur G, Combret Y, et al. Functional electrical stimulation - A new therapeutic approach to enhance exercise intensity in chronic obstructive pulmonary disease patients: A randomized, controlled crossover trial. Arch Phys Med Rehabil. 2018;99(8):1454-1461.

Sacral Nerve Stimulation for the Treatment of Chronic Constipation

Chen JD, Yin J, Wei W. Electrical therapies for gastrointestinal motility disorders. Expert Rev Gastroenterol Hepatol. 2017;11(5):407-418.
Iqbal F, Thomas GP, Tan E, et al. Transcutaneous sacral electrical stimulation for chronic functional constipation. Dis Colon Rectum. 2016;59(2):132-139.
Lu PL, Koppen IJN, Orsagh-Yentis DK, et al. Sacral nerve stimulation for constipation and fecal incontinence in children: Long-term outcomes, patient benefit, and parent satisfaction. Neurogastroenterol Motil. 2018;30(2).
Maeda Y, Kamm MA, Vaizey CJ, et al. Long-term outcome of sacral neuromodulation for chronic refractory constipation. Tech Coloproctol. 2017;21(4):277-286.
Patton V, Stewart P, Lubowski DZ, et al. Sacral nerve stimulation fails to offer long-term benefit in patients with slow-transit constipation. Dis Colon Rectum. 2016;59(9):878-885.
Sreepati G, James-Stevenson T. Use of sacral nerve stimulation for the treatment of overlapping constipation and fecal incontinence. Am J Case Rep. 2017;18:230-233.
Thaha MA, Abukar AA, Thin NN, et al. Sacral nerve stimulation for faecal incontinence and constipation in adults. Cochrane Database Syst Rev. 2015;(8):CD004464.
Zerbib F, Siproudhis L, Lehur PA, et al; CONSTIMOD study investigators. Randomized clinical trial of sacral nerve stimulation for refractory constipation. Br J Surg. 2017;104(3):205-213.

Miscellaneous Indications

Barath AS, Rusheen AE, Min HK, et al. Brain metabolic changes with longitudinal transcutaneous afferent patterned stimulation in essential tremor subjects. Tremor Other Hyperkinet Mov (N Y). 2020;10:52.
Brillman S, Colletta K, Borucki S, et al. Real-world evidence of transcutaneous afferent patterned stimulation for essential tremor. Tremor Other Hyperkinetic Mov (N.Y.). 2022;12:27.
Carboni C, Fornari A, Bragante KC, et al. An initial study on the effect of functional electrical stimulation in erectile dysfunction: A randomized controlled trial. Int J Impot Res. 2018;30(3):97-101.
Deik A, Tarsy D. Essential tremor: Treatment and prognosis. UpToDate [online serial]. Waltham, MA: UpToDate; reviewed May 2021; June 2022; April 2023.
ECRI. Clinical Evidence Assessment: Cala Trio wrist-worn neuromodulation therapy (Cala Health, Inc.) for essential tremor. Plymouth Meeting, PA: ECRI; January 2023. .
Feil S, Newell J, Minogue C, Paessler HH. The effectiveness of supplementing a standard rehabilitation program with superimposed neuromuscular electrical stimulation after anterior cruciate ligament reconstruction: A prospective, randomized, single-blind study. Am J Sports Med. 2011;39(6):1238-1247.
Frost J, Robinson HF, Hibberd J. A comparison of neuromuscular electrical stimulation and traditional therapy, versus traditional therapy in patients with longstanding dysphagia. Curr Opin Otolaryngol Head Neck Surg. 2018;26(3):167-173.
Groah SL, Cifu DX. The rehabilitative management of the traumatic brain injury patient with associated femoral neuropathy. Arch Phys Med Rehabil. 1995;76(5):480-483.
Hejal RB, Alonazi A, Elmo M, Onders RP. Unilateral diaphragm paralysis: The evolving role of diaphragm pacing (DP). Am J Respir Critical Care Med. 2020;201:A3261.
Isaacson SH, Peckham E, Tse W, et al. Prospective home-use study on non-invasive neuromodulation therapy for essential tremor. Tremor Other Hyperkinet Mov (N Y). 2020;10:29.
Ji QH, Qiao XF, Wang SF, et al. Effectiveness of neuromuscular electrical stimulation and ibuprofen for pain caused by necrosis of the femoral head: A retrospective study. Medicine (Baltimore). 2019;98(11):e14812.
Kang GE, Frederick R, Nunley B, et al. The effect of implanted functional electrical stimulation on gait performance in stroke survivors: A systematic review. Sensors (Basel). 2021;21(24):8323.
Khamis S, Herman T, Krimus S, Danino B. Is functional electrical stimulation an alternative for orthotics in patients with cerebral palsy? A literature review. Eur J Paediatr Neurol. 2018;22(1):7-16.
Lago AF, de Oliveira AS, de Souza HCD, et al. The effects of physical therapy with neuromuscular electrical stimulation in patients with septic shock: Study protocol for a randomized cross-over design. Medicine (Baltimore). 2018;97(6):e9736.
Lee KW, Kim SB, Lee JH, et al. Effects of neuromuscular electrical stimulation for masseter muscle on oral dysfunction after stroke. Ann Rehabil Med. 2019;43(1):11-18.
Lin PT, Ross EK, Chidester P, et al. Noninvasive neuromodulation in essential tremor demonstrates relief in a sham-controlled pilot trial. Mov Disord. 2018;33(7):1182-1183.
LoMauro A, Righi I, Privitera E, et al. The impaired diaphragmatic function after bilateral lung transplantation: A multifactorial longitudinal study. J Heart Lung Transplant. 2020;39(8):795-804.
Maffiuletti NA, Vivodtzev I, Minetto MA, Place N. A new paradigm of neuromuscular electrical stimulation for the quadriceps femoris muscle. Eur J Appl Physiol. 2014;114(6):1197-1205.
Martimbianco ALC, Torloni MR, Andriolo BN, et al. Neuromuscular electrical stimulation (NMES) for patellofemoral pain syndrome. Cochrane Database Syst Rev. 2017;12:CD011289.
Moll I, Vles JSH, Soudant DLHM, et al. Functional electrical stimulation of the ankle dorsiflexors during walking in spastic cerebral palsy: A systematic review. Dev Med Child Neurol. 2017;59(12):1230-1236.
Morf C, Wellauer V, Casartelli NC, Maffiuletti NA. Acute effects of multipath electrical stimulation in patients with total knee arthroplasty. Arch Phys Med Rehabil. 2015;96(3):498-504.
Cala Health, Inc. Prospective study for symptomatic relief of ET with Cala therapy (PROSPECT). ClinicalTrials.gov. Identifier: NCT03597100. Bethesda, MD: National Library of Medicine; last updated: July 23, 2019.
O'Connor D, Caulfield B, Lennon O. The efficacy and prescription of neuromuscular electrical stimulation (NMES) in adult cancer survivors: A systematic review and meta-analysis. Support Care Cancer. 2018;26(12):3985-4000.
Onders RP, Elgudin Y, Abu-Omar Y, et al. Addressing diaphragm dysfunction in lung transplant patients: The expanding role of diaphragm pacing. J Heart Lung Transplant. 2022;41(4):s431-s432.
Onders RP, Elgudin Y, Abu-Omar Y, et al. Diaphragm pacing in lung transplant patients: To identify and treat diaphragm function abnormalities. J Heart Lung Transplant. 2021;40(4, Supplement):S316-S317.
Onders RP, Elmo M, Kaplan C, et al. Extended use of diaphragm pacing in patients with unilateral or bilateral diaphragm dysfunction: A new therapeutic option. Surgery. 2014;156(4):776-784.
Pahwa R, Dhall R, Ostrem J, et al. An acute randomized controlled trial of noninvasive peripheral nerve stimulation in essential tremor. Neuromodulation. 2019;22(5):537-545.
Pascual-Valdunciel A, Hoo GW, Avrillon S, et al. Peripheral electrical stimulation to reduce pathological tremor: A review. J Neuroeng Rehabil. 2021;18(1):33.
Prenton S, Hollands KL, Kenney LPJ, Onmanee P. Functional electrical stimulation and ankle foot orthoses provide equivalent therapeutic effects on foot drop: A meta-analysis providing direction for future research. J Rehabil Med. 2018;50(2):129-139.
Rose J, Cahill-Rowley K, Butler EE. Artificial walking technologies to improve gait in cerebral palsy: Multichannel neuromuscular stimulation. Artif Organs. 2017;41(11):E233-E239.
Rutkove SB. Overview of lower extremity peripheral nerve syndromes. UpToDate [online serial]. Waltham, MA: UpToDate; reviewed May 2018.
Shukla AW. Rationale and evidence for peripheral nerve stimulation for treating essential tremor. Tremor Other Hyperkinet Mov (N Y). 2022;12:20.
Walls RJ, McHugh G, O'Gorman DJ, et al. Effects of preoperative neuromuscular electrical stimulation on quadriceps strength and functional recovery in total knee arthroplasty. A pilot study. BMC Musculoskelet Disord. 2010 Jun 14;11:119.
Wang H-Y, Chen Y-H, Kuan Y-C, et al. The effectiveness of functional electrical stimulation of the legs in patients with heart failure: A systematic review and meta-analysis of randomized controlled trials. Clin Rehabil. 2022;36(3):303-316.
Wang Y, Xu L, Wang L, et al. Effects of transcutaneous neuromuscular electrical stimulation on post-stroke dysphagia: A systematic review and meta-analysis. Front Neurol. 2023;14:1163045.
Yu JY, Rajagopal A, Syrkin-Nikolau J, et al. Transcutaneous afferent patterned stimulation therapy reduces hand tremor for one hour in essential tremor patients. Front Neurosci. 2020;14:530300.
Zhang X, Peng Y, Zhong F, et al. Effects of neuromuscular electrical stimulation on functional capacity and quality of life among patients after cardiac surgery: A systematic review and meta-analysis. J Cardiol. 2022;79(2):291-298.

Last Review 02/27/2024

Effective: 02/06/2004

Next Review: 07/25/2024
Review History
Definitions

Functional Electrical Stimulation and Neuromuscular Electrical Stimulation

Table Of Contents

Policy

Scope of Policy

Medical Necessity

Experimental and Investigational

Policy Limitations and Exclusions

Related Policies

CPT Codes / HCPCS Codes / ICD-10 Codes

Functional Electrical Stimulation (FES) for spinal cord injury (e.g., Parastep I System):

CPT codes covered if selection criteria are met:

Other CPT codes related to the CPB:

HCPCS codes covered if selection criteria are met:

ICD-10 codes covered if selection criteria are met:

ICD-10 codes not covered for indications listed in the CPB:

Neuromuscular Electrical Stimulators (NMES):

CPT codes covered if selection criteria are met:

Other CPT codes related to the CPB:

HCPCS codes covered if selection criteria are met:

HCPCS codes not covered for indications listed in the CPB :

AxioBionics Wearable Therapy - no specific code:

ICD-10 codes covered if selection criteria are met:

ICD-10 codes not covered for indications listed in the CPB (for FES or NMES):

Form-fitting Conductive Garment:

HCPCS codes covered if selection criteria are met:

ICD-10 codes covered if selection criteria are met:

Wearable NMES device (e.g., geko T-3 and geko W-3 devices):

HCPCS codes not covered for indications listed in the CPB:

ICD-10 codes not covered for indications listed in the CPB:

Diaphragmatic/phrenic Pacing:

CPT codes covered if selection criteria are met:

Other CPT codes related to the CPB:

HCPCS codes covered if selection criteria are met:

Other HCPCS codes related to the CPB:

ICD-10 codes covered if selection criteria are met:

ICD-10 codes not covered for indications listed in the CPB:

Electrical Stimulation of Sacral Anterior Roots:

CPT codes covered if selection criteria are met:

HCPCS codes covered if selection criteria are met:

ICD-10 codes covered if selection criteria are met:

ICD-10 codes not covered for indications listed in the CPB (not all-inclusive):

Transurethral electrical stimulation:

ICD-10 codes not covered for indications listed in the CPB (not all-inclusive):

Peroneal Nerve Stimulators:

HCPCS codes not covered for indications listed in the CPB :

ICD-10 codes not covered for indications listed in the CPB (not all-inclusive):

Threshold electrical stimulation:

HCPCS codes not covered for indications listed in the CPB:

ICD-10 codes not covered for indications listed in the CPB (not all-inclusive):

Remede System:

CPT codes covered if selection criteria are met:

HCPCS codes covered if selection criteria are met:

ICD-10 codes covered if selection criteria are met:

Cala Trio Nerve Stimulation Device:

HCPCS codes not covered for indications listed in the CPB (not all-inclusive):

ICD-10 codes not covered for indications listed in the CPB:

Background

Spinal Cord Injury

Stroke Rehabilitation

Functional Electrical Stimulation of the Upper Extremities

Rehabilitation Following Ligament/Knee Surgery

Neurogenic Bladder Dysfunction

Cerebral Palsy

Bell's Palsy

Foot Drop

Diabetic Neuropathy

Functional Electrical Stimulation / Neuromuscular Electrical Stimulation for Ambulatory Function in Patients with Multiple Sclerosis

Neuromuscular Electrical Stimulation for Knee Osteoarthritis

Threshold Electrical Stimulation

Improvement of Ambulatory Function/Muscle Weakness in Individuals with Progressive Diseases

Phrenic Nerve Stimulation for Central Sleep Apnea/Ventilator-Dependent Respiratory Failure

Functional Electrical Stimulation/Neuromuscular Electrical Stimulation for Chronic Obstructive Pulmonary Disease

Sacral Nerve Stimulation for the Treatment of Chronic Constipation

AxioBionics Wearable Therapy NMES for Hemiplegia

Functional Electrical Stimulation for Erectile Dysfunction

Functional Electrical Stimulation for Foot Drop

Neuromuscular Electrical Stimulation for Patello-Femoral Pain Syndrome

Neuromuscular Electrical Stimulation for Septic Shock

Neuromuscular Stimulation (Electronic Shock Unit) for Femoral Nerve Palsy

Masseter Muscle on Oral Dysfunction After Stroke