Deep Brain Stimulation for Pain in the Modern Era: A Systematic Review.

BACKGROUND: Deep brain stimulation (DBS) has been considered for patients with intractable pain syndromes since the 1950s. Although there is substantial experience reported in the literature, the indications are contested, especially in the United States where it remains off-label. Historically, the sensory-discriminative pain pathways were targeted. More recently, modulation of the affective sphere of pain has emerged as a plausible alternative. OBJECTIVE: To systematically review the literature from studies that used contemporary DBS technology. Our aim is to summarize the current evidence of this therapy. METHODS: A systematic search was conducted in the MEDLINE, EMBASE, and Cochrane libraries through July 2017 to review all studies using the current DBS technology primarily for pain treatment. Study characteristics including patient demographics, surgical technique, outcomes, and complications were collected. RESULTS: Twenty-two articles were included in this review. In total, 228 patients were implanted with a definitive DBS system for pain. The most common targets used were periaqueductal/periventricular gray matter region, ventral posterior lateral/posterior medial thalamus, or both. Poststroke pain, phantom limb pain, and brachial plexus injury were the most common specific indications for DBS. Outcomes varied between studies and across chronic pain diagnoses. Two different groups of investigators targeting the affective sphere of pain have demonstrated improvements in quality of life measures without significant reductions in pain scores. CONCLUSION: DBS outcomes for chronic pain are heterogeneous thus far. Future studies may focus on specific pain diagnosis rather than multiple syndromes and consider randomized placebo-controlled designs. DBS targeting the affective sphere of pain seems promising and deserves further investigation.

Abdominal Versus Standard Placement of the Sacral Nerve Stimulator Implantable Pulse Generator.

OBJECTIVES: To determine patient factors prompting anterior abdominal wall placement of the sacral nerve stimulator implantable pulse generator and investigate revision and infection rates for buttock (standard) and abdominal placement. METHODS: We retrospectively reviewed records of consecutive sacral nerve stimulation procedures by a single surgeon from 2012 to 2017 at a single institution. RESULTS: 75 patients underwent sacral nerve stimulation--60 with standard and 15 with abdominally placed implantable pulse generators. The mean age and body mass index of the standard group was higher than that of the abdominal group and the majority was female. A greater proportion of patients in the abdominal group had a neurological diagnosis and was wheelchair-dependent. Overall, a total of 20 patients underwent 38 revision surgeries. The indications for revision surgery were pain, loss of efficacy, or lead migration. The standard group accounted for more revisions than the abdominal group (34vs 4 cases, P = .048), with no revisions due to pain in the abdominal group. The infection rate (2% vs 13%, P = .10), average time from implantation to revision, and operative duration were not statistically different between groups. CONCLUSION: In a subset of patients who were wheelchair-dependent or lacked gluteal fat, placement of the implantable pulse generator in the anterior abdominal wall resulted in no revisions due to pain. Operative duration and infection rates were similar between abdominal and standard placement. Abdominal placement with extended length leads could be considered as a primary or revision option in these select patients.

Development of a Remote-Controlled Implantable Rat Sacral Nerve Stimulation System.

OBJECTIVES: Sacral nerve stimulation (SNS) is a surgical treatment of urinary and fecal incontinence. Despite its clinical efficacy, the mechanisms of action of SNS are still poorly known. This may be related to the use of acute stimulation models. Up to date, no rodent model of chronic SNS implants has been developed. Therefore, the aim of this study was to create a fully implantable and remotely controllable stimulating device to establish an animal model of chronic SNS. MATERIALS AND METHODS: The stimulating device consisted of an implantable pulse generator linked to a platinum electrode. The communication with the device was made through an inductive link which allowed to adjust the stimulation parameters; that is, to turn the device on and off or check the battery status remotely. Rats underwent two surgical procedures. In the first procedure, we achieved chronic sacral stimulation but the implanted electrode was not fixated. In the second procedure, the electrode was fixated in the sacral foramen using dental resin. In both cases, the correct positioning of the electrode was evaluated by computed tomography (CT) imaging and the presence of tail tremor in response to high intensity stimulation. We only tested the function of implanted electrode with fixation using micturition frequency assessment following bipolar or unipolar SNS for three days after recovery. RESULTS: CT imaging showed that implantation of the electrode required fixation as we found that the second surgical procedure yielded a more precise placement of the implanted electrode. The correct placement of implanted electrode observed with imaging was always correlated with a successful tail tremor response in rats, therefore we pursued our next experiments with the second surgical procedure and only assessed the tail tremor response. We found that both bipolar and unipolar SNS reduced micturition frequency. CONCLUSION: This stimulating device provides an efficient method to perform chronic SNS studies in rats.

Sudden unexpected death in epilepsy in patients treated with brain-responsive neurostimulation.

OBJECTIVE: To study the incidence and clinical features of sudden unexpected death in epilepsy (SUDEP) in patients treated with direct brain-responsive stimulation with the RNS System. METHODS: All deaths in patients treated in clinical trials (N = 256) or following U.S. Food and Drug Administration (FDA) approval (N = 451) through May 5, 2016, were adjudicated for SUDEP. RESULTS: There were 14 deaths among 707 patients (2208 postimplantation years), including 2 possible, 1 probable, and 4 definite SUDEP events. The rate of probable or definite SUDEP was 2.0/1000 (95% confidence interval [CI] 0.7-5.2) over 2036 patient stimulation years and 2.3/1000 (95% CI 0.9-5.4) over 2208 patient implant years. Stored electrocorticograms around the time of death were available for 4 patients with probable/definite SUDEP and revealed the following: frequent epileptiform activity ending abruptly (n = 2), no epileptiform activity or seizures (n = 1), and an electrographic and witnessed seizure with cessation of postictal electrocorticography (ECoG) activity associated with apnea and pulselessness (n = 1). SIGNIFICANCE: The SUDEP rate of 2.0/1000 patient stimulation years among patients treated with the RNS System is favorable relative to treatment-resistant epilepsy patients randomized to the placebo arm of add-on drug studies or with seizures after resective surgery. Our findings support that treatments that reduce seizures reduce SUDEP risk and that not all SUDEPs follow seizures.

[Hypoglossal nerve stimulation in patients with CPAP failure : Evolution of an alternative treatment for patients with obstructive sleep apnea]. / Hypoglossusnervstimulation bei CPAP-Versagen : Evolution einer Alternativbehandlung für Patienten mit obstruktiver Schlafapnoe.

Obstructive sleep apnea (OSA) is a common disease in western industrialized countries with increasing prevalence. Gold standard of therapy is nocturnal positive pressure ventilation by continuous positive airway pressure (CPAP). Due to complications and side effects of ventilation, therapy adherence is limited. Recently an alternative surgical treatment has become available for these patients, which uses established techniques to stimulate the hypoglossus nerve to open the upper airway during sleep. The aim of this work is to provide an overview of the history and current state of scientific knowledge of this therapy in the treatment of OSA. Currently, two systems are available on the market: respiratory-driven hypoglossal nerve stimulation (Inspire Medical Systems) and continuous hypoglossal nerve stimulation (ImThera Medical). For respiratory-driven hypoglossal nerve stimulation, a solid body of evidence is available and the therapy has been investigated in numerous multicenter clinical studies with regard to safety and efficacy. Only a small number of publications is available for continuous hypoglossal nerve stimulation. At the end of the last century, promising clinical results were shown in the first patients treated with hypoglossal nerve stimulation. Consequent technological and scientific development of respiratory-driven hypoglossal nerve stimulation in recent years led to its implementation in today's clinical routine. This therapy significantly broadens the spectrum of therapies in the treatment of OSA, especially for patients with CPAP intolerance.

Long-term effectiveness of sphenopalatine ganglion stimulation for cluster headache.

Objectives The sphenopalatine ganglion (SPG) plays a pivotal role in cluster headache (CH) pathophysiology as the major efferent parasympathetic relay. We evaluated the long-term effectiveness of SPG stimulation in medically refractory, chronic CH patients. Methods Thirty-three patients were enrolled in an open-label follow-up study of the original Pathway CH-1 study, and participated through 24 months post-insertion of a microstimulator. Response to therapy was defined as acute effectiveness in ≥ 50% of attacks or a ≥ 50% reduction in attack frequency versus baseline. Results In total, 5956 attacks (180.5 ± 344.8, range 2-1581 per patient) were evaluated. At 24 months, 45% ( n = 15) of patients were acute responders. Among acute responders, a total of 4340 attacks had been treated, and in 78% of these, effective therapy was achieved using only SPG stimulation (relief from moderate or greater pain or freedom from mild pain or greater). A frequency response was observed in 33% ( n = 11) of patients with a mean reduction of attack frequency of 83% versus baseline. In total, 61% (20/33) of all patients were either acute or frequency responders or both. The majority maintained their therapeutic response through the 24-month evaluation. Conclusions In the population of disabled, medically refractory chronic CH patients treated in this study, SPG stimulation is an effective acute therapy in 45% of patients, offering sustained effectiveness over 24 months of observation. In addition, a maintained, clinically relevant reduction of attack frequency was observed in a third of patients. These long-term data provide support for the use of SPG stimulation for disabled patients and should be considered after medical treatments fail, are not tolerated or are inconvenient for the patients.

Technological innovations in implants used for pain therapies.

The field of pain management has experienced tremendous growth in implantable therapies secondary to the innovations of bioengineers, implanters, and industry. Every aspect of neuromodulation is amenable to innovation from implanting devices to anchors, electrodes, programming, and even patient programmers. Patients with previously refractory neuropathic pain syndromes have new and effective pain management strategies that are a direct result of innovations in implantable devices.

Two-year seizure reduction in adults with medically intractable partial onset epilepsy treated with responsive neurostimulation: final results of the RNS System Pivotal trial.

OBJECTIVE: To demonstrate the safety and effectiveness of responsive stimulation at the seizure focus as an adjunctive therapy to reduce the frequency of seizures in adults with medically intractable partial onset seizures arising from one or two seizure foci. METHODS: Randomized multicenter double-blinded controlled trial of responsive focal cortical stimulation (RNS System). Subjects with medically intractable partial onset seizures from one or two foci were implanted, and 1 month postimplant were randomized 1:1 to active or sham stimulation. After the fifth postimplant month, all subjects received responsive stimulation in an open label period (OLP) to complete 2 years of postimplant follow-up. RESULTS: All 191 subjects were randomized. The percent change in seizures at the end of the blinded period was -37.9% in the active and -17.3% in the sham stimulation group (p = 0.012, Generalized Estimating Equations). The median percent reduction in seizures in the OLP was 44% at 1 year and 53% at 2 years, which represents a progressive and significant improvement with time (p < 0.0001). The serious adverse event rate was not different between subjects receiving active and sham stimulation. Adverse events were consistent with the known risks of an implanted medical device, seizures, and of other epilepsy treatments. There were no adverse effects on neuropsychological function or mood. SIGNIFICANCE: Responsive stimulation to the seizure focus reduced the frequency of partial-onset seizures acutely, showed improving seizure reduction over time, was well tolerated, and was acceptably safe. The RNS System provides an additional treatment option for patients with medically intractable partial-onset seizures.

Peripheral neuromodulation and headaches: history, clinical approach, and considerations on underlying mechanisms.

Implantable peripheral neurostimulation was introduced in 1969 as a potential treatment for certain neuropathic pain syndromes, primarily involving the limbs. While a few early studies included implants for occipital neuralgia, serious interest in its potential as a treatment for head pain came only after our 1999 report of positive findings in a series of patients with occipital neuralgia. Subsequent investigators confirmed these initial findings, and then extended the application to patients with various primary headache disorders, including migraine. While most found a therapeutic response, the degree of that response varied significantly, and analysis suggests that the issue of paresthesia concordancy may be central, both in explaining the data, as well as providing direction for future endeavors. Therefore, while at present peripheral neurostimulation is gaining increasing acceptance as a treatment for chronic headaches, the precise clinical indications and procedures, as well as the underlying neurophysiological mechanisms, are still being worked out.

Challenges for emerging neurostimulation-based therapies for real-time seizure control.

In step with the worthwhile aim of this special issue, two junior investigators impart their insights on the therapeutic challenges imposed by pharmacoresistant epilepsies and offer viable approaches to improvement of treatment outcomes. Sunderam's comprehensive perspective addresses issues of critical importance for the design of efficacious therapies. Talathi delves into the thorny roles of so-called "interictal" spikes in ictio- and epileptogenesis, roles that are central to understanding the dynamics of these phenomena and implicitly of how to prevent them or abort them. First, however, Osorio and co-workers illustrate the complex behavior of the epileptogenic network and point to the importance of real-time intraindividual adaptation and optimization of therapies for seizures originating from the same epileptogenic network.

The future of peripheral nerve stimulation.

The field of peripheral nerve stimulation (PNS) is now experiencing a phase of rapid growth in number of patients, number of implanters, number of indications, and procedure types. This, however, appears to be only a beginning of major developments that could revolutionize the field of PNS. It is expected that the progress in PNS will continue simultaneously in several directions as new indications, new stimulation targets and new device designs evolve in the foreseeable future. Responding to a major need for safe and effective pain treatments and following a general trend toward less-invasive and nondestructive interventions, PNS has the potential of becoming a premier pain-relieving modality that will be used instead of or in combination with existing more established approaches such as spinal cord stimulation and pharmacological pain control. Recent technological advancements are cause for considerable optimism regarding the development of PNS and are likely to be a beginning of a major overhaul in our perception of PNS approaches. Expanding the number of applications will without question strengthen the field of PNS. The turning point, however, will not occur until sufficient scientific evidence is gathered to unequivocally prove its safety, clinical efficacy and cost-effectiveness, and when PNS applications become officially endorsed through regulatory approval of each indication. Such changes will allow implanters to use approved devices for approved indications--instead of the contemporary 'off-label' use--and at the same time give device manufacturers a chance to market these devices and support education on their appropriate use.