Efficacy and safety of tibial nerve stimulation using a wearable device for overactive bladder.

OBJECTIVE: To evaluate the efficacy and safety of a wearable, smartphone-controlled, rechargeable transcutaneous tibial nerve stimulation (TTNS) device in patients with overactive bladder (OAB). PATIENTS AND METHODS: This multicentre, prospective, single-blind, randomised clinical trial included eligible patients with OAB symptoms who were randomly assigned to the stimulation group or sham group. The primary efficacy outcome was change from baseline in voiding frequency/24 h after 4 weeks of treatment. The secondary efficacy outcomes included changes in bladder diary outcomes (urgency score/void, nocturia episodes/day, micturition volume/void, and incontinence episodes/day), questionnaires on Overactive Bladder Symptom Score (OABSS), Patient Perception of Bladder Condition (PPBC), and American Urological Association Symptom Index Quality of Life Score (AUA-SI-QoL) at baseline and after 4 weeks of treatment. Device-related adverse events (AEs) were also evaluated. RESULTS: In the full analysis set (FAS), the mean (sd) change of voiding frequency/24 h in the stimulation group and sham group at 4 weeks were -3.5 (2.9) and -0.6 (2.4), respectively (P < 0.01). Similar results were obtained in the per-protocol set (PPS): -3.5 (2.9) vs -0.4 (2.3) (P < 0.01). In the FAS and PPS, micturition volume/void significantly improved at 4 weeks (P = 0.01 and P = 0.02). PPBC improvement almost reached significance in the FAS (P = 0.05), while it was significant in the PPS (P = 0.02). In the FAS and PPS, AUA-SI-QoL significantly improved at 4 weeks in the two groups (P < 0.01 and P < 0.01), whereas there were no significant differences in urgency score/void, nocturia episodes/day or OABSS between the groups. Also, no device-related serious AEs were reported. CONCLUSIONS: The non-invasive neuromodulation technique using the novel ambulatory TTNS device is effective and safe for treating OAB. Its convenience and easy maintenance make it a new potential home-based treatment modality. Future studies are warranted to confirm its longer-term efficacy.

Neuromodulation treatments for migraine: a contemporary update.

PURPOSE OF REVIEW: Neuromodulation approaches have been a part of a revolution in migraine therapies with multiple devices approved or in development. These devices vary in the nerve(s) being targeted, implantable versus noninvasive form factors as well as their effectiveness for acute pain reduction or migraine prevention. This review will summarize these recent advancements and approaches that are being developed which build upon prior work and improved technology that may help enhance the effectiveness as well as the patient experience. RECENT FINDINGS: Both noninvasive and implantable devices primarily targeting cranial nerves have shown the ability to help alleviate migraine symptoms. Multiple prospective and retrospective studies have demonstrated clinically meaningful reductions in headache intensity with noninvasive approaches, while prevention of migraine demonstrates more modest effects. Implantable neuromodulation technologies focusing on occipital and supraorbital stimulation have shown promise in migraine/headache prevention in chronic migraine patients, but there is a need for improvements in technology to address key needs for surgical approaches. SUMMARY: Electrical neuromodulation approaches in the treatment of migraine is undergoing a transformation towards improved outcomes with better technologies that may suit various patient needs on a more individualized basis.

Percutaneous Peripheral Nerve Stimulation (Neuromodulation) for Postoperative Pain: A Randomized, Sham-controlled Pilot Study.

BACKGROUND: Percutaneous peripheral nerve stimulation is an analgesic technique involving the percutaneous implantation of a lead followed by the delivery of electric current using an external pulse generator. Percutaneous peripheral nerve stimulation has been used extensively for chronic pain, but only uncontrolled series have been published for acute postoperative pain. The current multicenter study was undertaken to (1) determine the feasibility and optimize the protocol for a subsequent clinical trial and (2) estimate the treatment effect of percutaneous peripheral nerve stimulation on postoperative pain and opioid consumption. METHODS: Preoperatively, an electrical lead was percutaneously implanted to target the sciatic nerve for major foot/ankle surgery (e.g., hallux valgus correction), the femoral nerve for anterior cruciate ligament reconstruction, or the brachial plexus for rotator cuff repair, followed by a single injection of long-acting local anesthetic along the same nerve/plexus. Postoperatively, participants were randomized to 14 days of either electrical stimulation (n = 32) or sham stimulation (n = 34) using an external pulse generator in a double-masked fashion. The dual primary treatment effect outcome measures were (1) cumulative opioid consumption (in oral morphine equivalents) and (2) mean values of the "average" daily pain scores measured on the 0 to 10 Numeric Rating Scale within the first 7 postoperative days. RESULTS: During the first 7 postoperative days, opioid consumption in participants given active stimulation was a median (interquartile range) of 5 mg (0 to 30) versus 48 mg (25 to 90) in patients given sham treatment (ratio of geometric means, 0.20 [97.5% CI, 0.07 to 0.57]; P < 0.001). During this same period, the average pain intensity in patients given active stimulation was a mean ± SD of 1.1 ± 1.1 versus 3.1 ± 1.7 in those given sham (difference, -1.8 [97.5% CI, -2.6 to -0.9]; P < 0.001). CONCLUSIONS: Percutaneous peripheral nerve stimulation reduced pain scores and opioid requirements free of systemic side effects during at least the initial week after ambulatory orthopedic surgery.

Remote electrical neuromodulation for acute treatment of migraine in adolescents.

OBJECTIVES: Migraine is a common disabling neurological disorder. Current acute treatments for migraine in adolescents are mostly pharmacological and may have limited effectiveness, can cause side effects, and may lead to medication overuse. There is an unmet need for effective and well-tolerated treatments. Remote electrical neuromodulation (REN) is a novel acute treatment of migraine that stimulates upper arm peripheral nerves to induce conditioned pain modulation (CPM)-an endogenous analgesic mechanism. The REN device (Nerivio® , Theranica Bio-Electronics Ltd., Israel) is a FDA-authorized device for acute treatment of migraine in adults. This study assessed the efficacy and safety of REN in adolescents with migraine. DESIGN AND METHODS: This was an open-label, single-arm, multicenter study in adolescents (ages 12-17 years) with migraine. Participants underwent a 4-week run-in phase. Eligible participants continued to an 8-week treatment phase with the device. Pain severity, associated symptoms, and functional disability were recorded at treatment initiation, and 2 and 24 hours post-treatment. The primary endpoints of this study were related to the safety and tolerability of REN. The secondary endpoints were related to device efficacy and included the proportion of participants who achieved pain relief at 2 hours post-treatment and the proportion of participants who achieved pain freedom at 2 hours. The presented results reflect an interim analysis with subsequent stopping of the rest of the study. RESULTS: Sixty participants were enrolled for the study; of these, 14 failed to meet the run-in criteria and 1 was lost to follow-up. Forty-five participants performed at least one treatment, of which 39 participants completed a test treatment with REN. One device-related adverse event (2%) was reported in which a temporary feeling of pain in the arm was felt. Pain relief and pain-free at 2 hours were achieved by 71% (28/39) and 35% (14/39) participants, respectively. At 2 hours, 69% (23/33) participants experienced improvement in functional ability. CONCLUSIONS: REN may offer a safe and effective non-pharmacological alternative for acute treatment in adolescents.

Skin-Mountable Biosensors and Therapeutics: A Review.

Miniaturization of electronic components and advances in flexible and stretchable materials have stimulated the development of wearable health care systems that can reflect and monitor personal health status by health care professionals. New skin-mountable devices that offer seamless contact onto the human skin, even under large deformations by natural motions of the wearer, provide a route for both high-fidelity monitoring and patient-controlled therapy. This article provides an overview of several important aspects of skin-mountable devices and their applications in many medical settings and clinical practices. We comprehensively describe various transdermal sensors and therapeutic systems that are capable of detecting physical, electrophysiological, and electrochemical responses and/or providing electrical and thermal therapies and drug delivery services, and we discuss the current challenges, opportunities, and future perspectives in the field. Finally, we present ways to protect the embedded electronic components of skin-mountable devices from the environment by use of mechanically soft packaging materials.

17-Year Single Center Retrospective Review of Rate, Risk Factors and Outcomes of Lead Breakage during Sacral Neuromodulation Lead Removal.

PURPOSE: One risk of removal of a tined sacral neuromodulation lead is breakage, resulting in a retained lead fragment. We report lead breakage rates, risk factors and outcomes of retained fragments. MATERIALS AND METHODS: We report on 464 tined lead removals from 2002 to 2018. Clinical and surgical factors were reviewed and appropriate statistical analysis performed. Retained fragments were reviewed for fragment description and long-term complications. RESULTS: A total of 464 tined lead removals were included, with 35 lead breaks identified, for a rate of 7.5% (35). Factors associated with breakage included male gender (OR 6.58, 95% CI 2.54-17.01, p=0.001) and diabetes (OR 2.42, 95% CI 1.05-5.58, p=0.019). A shorter time since implantation was protective (OR 0.86, 95% CI 0.76-0.98, p=0.002). There was no difference in breakage rate based on age, weight, history of prior revision, bilateral leads, reason for lead removal, surgical technique or surgeon. Of the 35 breaks 27 had imaging available. Of these 66% (18) broke in the tined region and 81% (22) were ghost leads. Most patients (80%, 28 of 35) with retained lead fragments received another implant. Only 1 patient had a related complication of additional surgery for pain related to the fragment. CONCLUSIONS: There is a low rate of tined lead breakage during lead removal. However, it is higher than the manufacturer estimate. Protective factors include a shorter time between implant and lead revision. The most common location for lead breakage is in the region of the tines, most are ghost fragments and long-term complications are uncommon.

Feasibility and potential effects of using the electro-dress Mollii on spasticity and functioning in chronic stroke.

BACKGROUND: Spasticity after lesions of central motor pathways may be disabling and there is a need for new, cost-effective treatment methods. One novel approach is offered by the electro-dress Mollii®, primarily designed to enhance reciprocal inhibition of spastic muscles by multifocal, transcutaneous antagonist stimulation. METHODS: The Mollii® suit was set individually for 20 participants living with spasticity and hemiplegia after stroke and used in the home setting for 6 weeks. Usability and perceived effects were monitored by weekly telephone interviews. Outcome was assessed by use of the NeuroFlexor™ method for quantification of the neural component (NC) of resistance to passive stretch (spasticity), and the modified Ashworth scale (MAS) for total resistance, Fugl-Meyer Assessment of motor recovery for sensorimotor function in upper (FM-UE) and lower extremities (FM-LE), activity performance with the Action Research Arm Test (ARAT), Berg balance scale, 10 m and 6 min walk tests, and perceived functioning with the Stroke Impact Scale. RESULTS: Compliance was high (mean 19.25 of 21 sessions). Perceived positive effects were reported by 60% and most commonly related to decreased muscle tone (n = 9), improved gait pattern function (n = 7) and voluntary movement in the upper extremity (n = 6). On a group level, the NC decreased significantly in the wrist flexors of the affected hand (p = 0.023) and significant improvements according to FM-UE (p = 0.000) and FM-LE (p = 0.003) were seen after the intervention. No significant difference was detected with MAS or assessed activity performance, except for the ARAT (p = 0.000). FM-UE score change correlated significantly and fairly with the perceived effect in the upper extremity (r 0.498 p = 0.025) and in the corresponding analysis for the FM-LE and perceived effect in the lower extremity (r = 0.469 p = 0.037). CONCLUSION: This study indicates that the Mollii® method is feasible when used in the home setting to decrease spasticity and improve sensorimotor function. The results may guide a larger controlled study combined with rehabilitation interventions to enhance effects on activity and participation domains. TRIAL REGISTRATION: NCT04076878 . Registered 2 September 2019 - Retrospectively registered.

FDA Perspectives on the Regulation of Neuromodulation Devices.

The United States Food and Drug Administration (FDA) ensures that patients in the United States have access to safe and effective medical devices. The division of neurological and physical medicine devices reviews medical technologies that interface with the nervous system, including many neuromodulation devices. This article focuses on neuromodulation devices and addresses how to navigate the FDA's regulatory landscape to successfully bring devices to patients.

Investigating stimulation parameters for preferential small-fiber activation using exponentially rising electrical currents.

Electrical stimulation is widely used in pain research and profiling, but current technologies lack selectivity toward small sensory fibers. Pin electrodes deliver high current density in upper skin layers, and it has been proposed that slowly rising exponential pulses can elevate large-fiber activation threshold and thereby increase preferential small-fiber activation. Optimal stimulation parameters for the combined pin electrode and exponential pulse stimulation have so far not been established, which is the aim of this study. Perception thresholds were compared between pin and patch electrodes using single 1- to 100-ms exponential and rectangular pulses. Stimulus-response functions were evaluated for both pulse shapes delivered as single pulses and pulse trains of 10 Hz using intensities from 0.1 to 20 times perception threshold. Perception thresholds (mA) decreased when duration was increased for both electrodes with rectangular pulses and the pin electrode with exponential pulses. For the patch electrode, perception thresholds for exponential pulses decreased for durations ≤10 ms but increased for durations ≥15 ms, indicating accommodation of large fibers. Stimulus-response curves for single pulses were similar for the two pulse shapes. For pulse trains, the slope of the curve was higher for rectangular pulses. Maximal large-fiber accommodation to exponential pulses was observed for 100-ms pulses, indicating that 100-ms exponential pulses should be applied for preferential small-fiber activation. Intensity of 10 times perception threshold was sufficient to cause maximal pain ratings. The developed methodology may open new opportunities for using electrical stimulation paradigms for small-fiber stimulation and diagnostics.NEW & NOTEWORTHY Selective activation of small cutaneous nerve fibers is pivotal for investigations of the pain system. The present study demonstrated that patch electrode perception thresholds increase with increased duration of exponential currents from 20 to 100 ms. This is likely caused by large-fiber accommodation, which can be utilized to activate small fibers preferentially through small-diameter pin electrodes. This finding may be utilized in studies of fundamental pain mechanisms and, for example, in small-fiber neuropathy.

Remote Electrical Neuromodulation (REN) Relieves Acute Migraine: A Randomized, Double-Blind, Placebo-Controlled, Multicenter Trial.

OBJECTIVE: To assess the efficacy and safety of a remote electrical neuromodulation (REN) device for the acute treatment of migraine. BACKGROUND: There is a significant unmet need for novel effective well-tolerated acute migraine treatments. REN is a novel acute migraine treatment that stimulates upper arm peripheral nerves to induce conditioned pain modulation - an endogenous analgesic mechanism in which conditioning stimulation inhibits pain in remote body regions. A recent pilot study showed that REN can significantly reduce headache. We have conducted a randomized, double-blind, sham-controlled study to further evaluate the efficacy and safety of REN for the acute treatment of migraine. METHODS: This was a randomized, double-blind, sham-controlled, multicenter study conducted at 7 sites in the United States and 5 sites in Israel. Two hundred and fifty-two adults meeting the International Classification of Headache Disorders criteria for migraine with 2-8 migraine headaches per month were randomized in a 1:1 ratio to active or sham stimulation. A smartphone-controlled wireless device was applied for 30-45 minutes on the upper arm within 1 hour of attack onset; electrical stimulation was at a perceptible but non-painful intensity level. Migraine pain levels were recorded at baseline, 2, and 48 hours post-treatment. Most bothersome symptoms (MBS) were also recorded. The primary efficacy endpoint was the proportion of participants achieving pain relief at 2 hours post-treatment (improvement from severe or moderate pain to mild or none, or from mild pain to none). Relief of MBS and pain-free at 2 hours were key secondary endpoints. RESULTS: Active stimulation was more effective than sham stimulation in achieving pain relief (66.7% [66/99] vs 38.8% [40/103]; therapeutic gain of 27.9% [CI95% , 15.6-40.2]; P < .0001), pain-free (37.4% vs 18.4%, P = .003), and MBS relief (46.3% vs 22.2%, P = .0008) at 2 hours post-treatment. The pain relief and pain-free superiority of the active treatment was sustained 48 hours post-treatment. The incidence of device-related adverse events was low and similar between treatment groups (4.8% [6/126] vs 2.4% [3/126], P = .499). CONCLUSIONS: REN provides superior clinically meaningful relief of migraine pain and MBS compared to placebo, offering a safe and effective non-pharmacological alternative for acute migraine treatment.

Electromyographic Responses Across Different Pulse-Widths of Sacral Neuromodulation in Sheep.

OBJECTIVES: In rodents, we reported that short pulse-width (PW) neuromodulation might provide more efficient therapy delivery than traditional 0.21 msec PW. Using fully implanted, commercialized systems in the sheep, the goal of this study was to characterize the relationship of electromyographic (EMG) responses of the external anal sphincter (EAS) to different PWs of sacral neuromodulation (SNM). MATERIALS AND METHODS: In seven sheep, InterStim® quadripolar tined leads were implanted adjacent to the S3 nerve root bilaterally to deliver SNM and two pairs of intramuscular leads were placed on either side of the EAS for EMG sensing. The EMG responses to SNM with different PWs were examined using variable intensities in both anesthetized and conscious conditions. RESULTS: The EMG responses from ipsilateral EAS (IEAS ) and contralateral EAS (CEAS ) were compared. The area under the curve of EMG responses from IEAS were significantly stronger than that from CEAS. The late component EMGs were more sensitive to nerve stimulation with a higher response amplitude in awake sheep. The response threshold-PW relationship from the IEAS as ascertained visually and with EMG in anesthetized and awake sheep were fitted with a monoexponential nonlinear regression; the resulting chronaxies were of 0.05 msec (n = 6), and 0.04 msec (n = 6), and 0.04 msec (n = 8), respectively. CONCLUSIONS: In both anesthetized and awake conditions, a similar motor response may be evoked in the EAS at PWs much shorter (0.04-0.05 msec) than the 0.21 msec typically used with SNM. Potential battery savings manifested by shorter PW would provide more efficient therapy delivery and increased longevity of the stimulator.

Autostimulation in Vagus Nerve Stimulator Treatment: Modulating Neuromodulation.

OBJECTIVES: Until now, the vagus nerve stimulation (VNS) treatment in epilepsy has consisted of two different modes: normal and magnet stimulation. A new vagus nerve stimulator model (106 AspireSR®, LivaNova, Houston, TX, USA) also allows automatic stimulation (AutoStim). The purpose of this study is to examine the effect of autostimulation on seizure frequencies together with energy consumption. MATERIALS AND METHODS: The study material consisted of 14 patients whose former stimulator model (102/103) was replaced with model 106. We calculated the theoretical charge (Q) in Coulombs for one day in both of those groups. We evaluated the follow-up data of the patients' seizure counts, with a mean follow-up time of 18.1 months (SD 8.1). RESULTS: The total charge, "VNS dose," was reduced with model 106 in comparison with models 102 or 103 (p = 0.001, Mann-Whitney test). The average charge (Qtotal ) for one day with AutoStim was 142.56 mC; without AutoStim, it was 321.09 mC. We were able to assess seizure diaries in 11 out of 14 patients. Four patients (36%) had >50% seizure reduction and two patients (18%) experienced a reduction in seizure severity with VNS with autostimulation. Five patients (46%) remained unchanged. In three out of four patients with improved seizure control, the duty cycle was maintained at the original level. The patients whose duty cycle was modified for a more prolonged OFF-time had unchanged seizure frequencies. CONCLUSION: VNS with AutoStim achieves maintenance of prior-established seizure control with markedly less energy consumption and can also improve seizure control as compared to former stimulator model.

Electrical Stimulation and Recovery of Gastrointestinal Function Following Surgery: A Systematic Review.

OBJECTIVES: Postoperative ileus occurs in approximately 5-15% of patients following major abdominal surgery, and poses a substantial clinical and economic burden. Electrical stimulation has been proposed as a means to aid postoperative gastrointestinal (GI) recovery, but no methods have entered routine clinical practice. A systematic review was undertaken to assess electrical stimulation techniques and to evaluate their clinical efficacy in order to identify promising areas for future research. MATERIALS AND METHODS: Literature was searched using MEDLINE, EMBASE, Google Scholar and by assessing relevant clinical trial databases. Studies investigating the use of electrical stimulation for postoperative GI recovery were included, regardless of methods used or outcomes measured. A critical review was constructed encompassing all included studies and evaluating and synthesizing stimulation techniques, protocols, and clinical outcomes. RESULTS: A broad range of neuromodulation strategies and protocols were identified and assessed. Improved postoperative GI recovery following electrical stimulation was reported by 55% of studies (10/18), most commonly those assessing transcutaneous electrical nerve stimulation and electroacupuncture therapy (7/10). Several studies reported shorter time to first flatus and stool, shorter duration of hospital stay, and reduced postoperative pain. However, inconsistent reporting and limitations in trial design were common, compromising a definitive determination of electrical stimulation efficacy. CONCLUSIONS: Electrical stimulation appears to be a promising methodology to aid postoperative GI recovery, but greater attention to mechanisms of action and clinical trial quality is necessary for progress. Future research should also aim to apply validated and standardized gut recovery outcomes and consistent neuromodulation methodologies.

Needle Placement and Position of Electrical Stimulation Inside Sacral Foramen Determines Pelvic Floor Electromyographic Response-Implications for Sacral Neuromodulation.

BACKGROUND: Lead placement within the sacral foramen in sacral neuromodulation patients is guided by visual assessment of the contraction of the pelvic floor musculature (PFM) and/or verbal assessment of the sensation and location of sensation upon stimulation. Generally, lead placement is proceeded by needle probing. This study evaluates which location inside a single sacral foramen would be most ideal for the release of the permanent electrode lead, by measuring electromyographic (EMG) motor responses of the PFM upon stimulation of a peripheral nerve evaluation (PNE) needle. MATERIALS AND METHODS: In eight patients, four standard PNE needles, and in one patient, two PNE needles, were introduced into the same foramen, parallel to the midline and parallel to each other. Position was verified by X-ray. Needles were stimulated (square pulsed waves, 210 µsec, 14 Hz) at increasing amplitudes (1-2-3-5-7-10 mA). PFM EMG was measured using the Multiple Array Probe (MAPLe) placed intravaginally or intrarectally, with 24 derivations. For this study, the mean (normalized) EMG was taken of all electrodes and different positions within the foramen were compared using the Wilcoxon signed rank test. RESULTS: A total of 202 PFM EMG measurements were recorded upon stimulation. EMG motor responses of the PFM for current stimulation = <2 mA showed statistically significant higher mean (normalized) EMG values for needles positioned cranial, medial, and cranial-medial, in comparison to needles positioned caudal, lateral, and caudal-lateral (p = 0.004; p = 0.021; p = 0.002). CONCLUSIONS: Our data suggest stronger PFM contractions are elicit in cranial- and medial-placed PNE needles upon stimulation with clinically relevant current amplitudes (≤ 2 mA). Placement of the lead should aim for this spot in the foramen.

Results of Sacral Neuromodulation Therapy for Urinary Voiding Dysfunction: Five-Year Experience of a Retrospective, Multicenter Study in China.

PURPOSE: This five-year, retrospective, multicenter study evaluated the long-term safety and efficiency of sacral neuromodulation (SNM) in Chinese patients with urinary voiding dysfunction. PATIENTS AND METHODS: This is a Chinese national, multicenter, retrospective study that included 247 patients (51.2% female) who received an implantable pulse generator (IPG) (InterStim, Medtronic, Minneapolis, MN, USA) between 2012 and 2016. Success was considered if the initial ≥50% improvement in any of primary voiding diary variables persisted compared with baseline. The results were further stratified by identifying patients who showed >50% improvement and those although showed <50% improvement but still wanted to receive IPG; these data were collected and analyzed for general improvement. RESULTS: Following test stimulation, 187 patients (43%) declined implantation and 247 (57%) underwent implantation using InterStim®. Among 247 patients, 34 (13.7%) had overactive bladder (OAB), 59 (23.8%) had interstitial cystitis/bladder pain syndrome (IC/BPS), 47 (19%) had idiopathic urinary retention (IUR), and 107 (44.1%) had neurogenic bladder (NB). IPG efficiency rate for OAB, interstitial cystitis/bladder pain syndrome, idiopathic urinary retention, and neurogenic bladder were 42.5, 72.4, 51.6, and 58.8%, respectively. The mean duration of follow-up was 20.1 ± 12.8 months. CONCLUSIONS: SNM appears effective in the long term, with a total IPG implantation rate of approximately 57% (ranging between 42.5 and 72.4% depending on indication). Interstitial cystitis/bladder pain syndrome appear to be the best indication for stage I testing. Chinese neurogenic bladder patients are most inclined to choose SNM. SNM is relatively safe, with low postoperation adverse events of 16.1% and reoperation rate of 3.2% during the follow-up period.

An Acute Randomized Controlled Trial of Noninvasive Peripheral Nerve Stimulation in Essential Tremor.

OBJECTIVE: To evaluate the safety and effectiveness of a wrist-worn peripheral nerve stimulation device in patients with essential tremor (ET) in a single in-office session. METHODS: This was a randomized controlled study of 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-minute stimulation session. The primary endpoint compared spiral drawing in the stimulated hand using the Tremor Research Group Essential Tremor Rating Assessment Scale (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 activities of daily living (ADL) scale before and after stimulation as well as clinical global impression-improvement (CGI-I) rating after stimulation. RESULTS: Subjects who received peripheral nerve stimulation 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 adverse events were reported; 3% of subjects experienced mild adverse events. CONCLUSIONS: Peripheral nerve stimulation in ET may provide a safe, well-tolerated, and effective treatment for transient relief of hand tremor symptoms.

High-Frequency (10 kHz) Electrical Stimulation of Peripheral Nerves for Treating Chronic Pain: A Double-Blind Trial of Presence vs Absence of Stimulation.

OBJECTIVES: The study objectives were to perform a clinical audit of patients implanted with 10 kHz spinal cord (SCS) and peripheral nerve (PNS) stimulators for treating chronic pain and to investigate the effect of 10 kHz PNS on pain and other sensory modalities in a double-blind cross-over trial. METHODS: Pain, disability, and medication status were audited for 12 months after stimulator implantation in 58 SCS patients and in 11 PNS patients with an electrode positioned along a branch of the occipital or trigeminal nerve (four patients), a limb nerve trunk (four patients), or the S1 nerve root, genito-femoral nerve or ileo-inguinal nerve (one patient each). In PNS patients, pain and other sensory modalities were also assessed double-blind before and after the stimulator was switched either ON or OFF for two hours (protocol 1) or four hours (protocol 2). RESULTS: Decreases in pain and disability after stimulator implantation were maintained in both groups at 3-6 months, but these decreases were greater in PNS than SCS patients. In PNS trial patients, pain increased after the system had been turned OFF overnight for at least 12 hours before testing. Pain did not change after two hours of PNS but had decreased significantly after four hours. Other sensory modalities were minimally affected either by two or four hours of stimulation. CONCLUSIONS: These findings suggest that PNS at 10 kHz decreases pain when conducted for at least four hours. Stimulation analgesia does not appear to be due to sensory conduction block.

Selective Decrease in Allodynia With High-Frequency Neuromodulation via High-Electrode-Count Intrafascicular Peripheral Nerve Interface After Brachial Plexus Injury.

OBJECTIVES: Kilohertz high-frequency alternating current (KHFAC) electrical nerve stimulation produces a reversible nerve block in peripheral nerves in human patients with chronic pain pathologies. Although this stimulation methodology has been verified with nonselective extrafascicular electrodes, the effectiveness of producing a selective nerve block with more-selective intrafascicular electrodes has not been well documented. The objective of this study was to examine whether intrafascicular electrodes can block painful stimuli while preserving conduction of other neural activity within the implanted nerve. MATERIALS AND METHODS: We analyzed the effects of various stimulation waveforms delivered through Utah Slanted Electrode Arrays (USEAs) implanted in the median nerve of a male human subject with a left brachial plexus injury. We compared KHFAC stimulation with a sham control. RESULTS: KHFAC stimulation through USEA electrodes produced a reduction in pain sensitivity in the palmar aspect of the left middle finger. KHFAC had limited effects on the patient's ability to feel tactile probing in the same area or move the digits of his left hand. Other tested stimulation parameters either increased or showed no reduction in pain. CONCLUSIONS: KHFAC stimulation in peripheral nerves through intrafascicular electrodes demonstrated a selective reduction in pain sensitivity while preserving other nerve functions. This treatment may benefit patient populations who have chronic pain originating from peripheral nerves, but who do not want to block whole-nerve function in order to preserve sensory and motor function reliant on the implanted nerve. Furthermore, KHFAC may benefit patients who respond negatively to other forms of peripheral nerve stimulation therapy.

The Effect of Peripheral Neuromodulation on Pain From the Sacroiliac Joint: A Retrospective Cohort Study.

OBJECTIVE: To report a retrospective review of the longer-term results of peripheral neuromodulation in 12 patients with significant chronic sacroiliac joint pain who had previously failed multiple conservative and interventional pain therapies. METHODS: To allow for the assessment of meaningful longer-term outcome, implants for all 12 patients had been in place for a minimum of 18 months to a maximum of 36 months prior to the formal review. RESULTS: Compared to the preimplantation baseline, the longer-term follow-up revealed a significant and sustained reduction in visual analog scale pain scores from 8.7T 1.1 to 1.1T 1.0 (p < 0.001), with a 75% reduction in analgesia requirement, and improvement in pain impact on daily function from 94.1% T 5.9% to 5.8% T 6.0% (p < 0.001). CONCLUSION: This initial case series has highlighted that SIJ neuromodulation results in the reduction in pain intensity and improved functionality in patients who have already failed conventional medical management and interventional techniques, including RF denervation. These preliminary results merit a prospective randomized trial of peripheral neuromodulation.

A Randomized Controlled Trial of Subcutaneous Nerve Stimulation for Back Pain Due to Failed Back Surgery Syndrome: The SubQStim Study.

OBJECTIVES: To compare the effectiveness of peripheral nerve stimulation utilizing a subcutaneous lead implant technique-subcutaneous nerve stimulation (SQS) plus optimized medical management (SQS + OMM arm) vs. optimized medical management alone (OMM arm) in patients with back pain due to failed back surgery syndrome. PATIENTS AND METHODS: Patients were recruited from 21 centers, in Europe, Israel, and Australia. Eligible patients were randomized (1:1) to SQS + OMM or OMM arms. Those in the SQS arm were implanted with a neurostimulator and up to two subcutaneous percutaneous cylindrical leads in the area of pain. Patients were evaluated pre-randomization and at one, three, six, and nine months post-randomization. The primary endpoint was the proportion of subjects with a ≥50% reduction in back pain intensity ("responder") from baseline to nine months. Secondary outcomes included proportion of responders with a ≥50% reduction in back pain intensity at six months and ≥30% reduction at nine months, and the mean change from baseline in back pain intensity at six and nine months between the two arms. RESULTS: Due to the slow rate of recruitment, the study was terminated early with 116 subjects randomized. A total of 33.9% (19/56, missing: n = 20 [36%]) of subjects in the SQS + OMM arm and 1.7% (1/60, missing: n = 24 [40%]) in the OMM arm were responders at Month 9 (p < 0.0001). Secondary objectives showed a significant difference in favor of SQS + OMM arm. CONCLUSION: The results indicate that the addition of SQS to OMM is more effective than OMM alone in relieving low back pain at up to nine months.