Medical Policy: 07.01.59
Original Effective Date: November 2000
Reviewed: July 2019
Revised: July 2019
This policy contains information which is clinical in nature. The policy is not medical advice. The information in this policy is used by Wellmark to make determinations whether medical treatment is covered under the terms of a Wellmark member's health benefit plan. Physicians and other health care providers are responsible for medical advice and treatment. If you have specific health care needs, you should consult an appropriate health care professional. If you would like to request an accessible version of this document, please contact customer service at 800-524-9242.
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This Medical Policy document describes the status of medical technology at the time the document was developed. Since that time, new technology may have emerged or new medical literature may have been published. This Medical Policy will be reviewed regularly and be updated as scientific and medical literature becomes available.
Deep brain stimulation (DBS) delivers electrical pulses to select areas of the brain (e.g. hypothalamus, thalamus, globus pallidus, subthalmic nucleus). DBS is used as an alternative to permanent neuroablative procedures for control of essential tremor and Parkinson disease. Deep brain stimulation (DBS) is also being evaluated for the treatment of variety of other neurological and psychiatric disorders, including but not limited to refractory epilepsy, dystonia, other movement disorder, cluster headache, Tourette syndrome, treatment resistant depression, and obsessive compulsive disorder (OCD), drug addition, anorexia nervosa, impulsive or violent behavior and Alzheimer disease/dementias.
Deep brain stimulation (DBS) involves the stereotactic placement of electrodes into the brain (i.e. hypothalamus, thalamus, globus pallidus, or subthalamic nucleus). The mechanism of action is not completely understood, but the goal of DBS is to interrupt the pathways responsible for the abnormal movements associated with movement disorders such as Parkinson disease and essential tremor. The exact location of electrodes depends on the type of disorder being treated, and unlike surgical ablation, which causes permanent destruction of the targeted area, DBS is reversible and adjustable. The DBS device consists of an implantable pulse generator (IPG) or neurostimulator, and implantable lead with electrodes and a connecting wire. Subcutaneous extension wires connect the lead(s) to the pulse generator (neurostimulator) which is implanted near the clavicle or, in the case of younger individuals with primary dystonia, in the abdomen. Conventional deep brain stimulation systems deliver stimulation using cylindrical electrodes or Ring Mode (omnidirectional) stimulation which, stimulates neurons around the entire circumference of the lead, Directional deep brain stimulation uses a directional lead designed to steer electrical current to relevant areas of the brain while avoiding areas that may cause side effects.
A few weeks after the surgery, the pulse generator (neurostimulator) is activated in the doctor’s office using a special remote control. The amount of stimulation is dependent on the condition, and may take as long as four to six months to find the optimal setting. The stimulation can be continuous, 24 hours a day, or the doctor may advise to turn the pulse generator off a night and back on in the morning, depending on the condition being treated. In some situations the doctor may program the pulse generator to let the individual make minor adjustments at home using a special remote control. The battery life of the generator varies with usage and setting. When the battery needs to be replaced, the surgeon will replace the pulse generator during an outpatient procedure.
Deep brain stimulation (DBS) does not cure the disease, if deep brain stimulation (DBS) works, symptoms may improve significantly, but they usually do not go away completely. In some cases, medications may still be needed for certain conditions.
Deep brain stimulation (DBS) has been investigated as an alternative to permanent neuroablative procedures, such as thalamotomy and pallidotomy. DBS has been most thoroughly investigated as an alternative to thalamotomy for unilateral control of essential tremor (ET) and tremor associated with Parkinson Disease (PD). More recently, there has been research interest in the use of DBS of the globus pallidus (GPi) or subthalamic nucleus (STN) as a treatment of other parkinsonian symptoms, such as rigidity, bradykinesia, and akinesia. Another common morbidity associated with PD is the occurrence of motor fluctuations, referred to as “on and off” phenomena, related to the maximum effectiveness of drugs (i.e. “on” state) and the nadir response during drug troughs (i.e. “off” state). In addition, levodopa, the most commonly used anti-Parkinson drug, may be associated with disabling drug-induced dyskinesias (uncontrolled involuntary movement). Therefore, the optimal pharmacologic treatment of PD may involve a balance between optimal effects on PD symptoms and the appearance of drug-induced dyskinesias. The effect of DBS on both PD symptoms and drug-induced dyskinesias has also been studied.
The relevant population(s) of interest are patients with essential tremor (ET) or symptoms associated with Parkinson Disease (PD).
The therapy being considered is deep brain stimulation (DBS), unilateral or bilateral stimulation of the thalamus as well as stimulation of the internal segment of the globus pallidus Internus and subthalmic nucleus.
Parkinson disease (PD) is usually treated with medication. Surgery may be considered in people who respond poorly to medication, have severe side-effects, or have severe fluctuations in response to medication.
Key efficacy outcomes include motor scores, mobility, disability, activities of daily living and quality of life (QOL).
Key safety outcomes include, death, stroke, depression, cognition, infection, and other device and procedure related event.
Blue Cross and Blue Shield Association (BCBSA) TEC assessment completed in 1997 focused on unilateral deep brain stimulation (DBS) of the thalamus as a treatment of tremor. The assessment concluded:
BCBSA TEC assessment found that unilateral DBS of the thalamus for patients with disabling, medically unresponsive tremor due to essential tremor or Parkinson’s disease met the BCBSA Technology Evaluation Center (TEC) criteria. Subsequent studies reporting long term follow up have supported the conclusions of the TEC assessment and found that tremors were effectively controlled 5 to 6 years after DBS.
Putzke et. al. reported on series of 22 patients with essential tremor (ET) treated with bilateral deep brain stimulation for management of midline tremor (head, voice, tongue, trunk). Patients were evaluated at baseline (pre-surgical) and postoperatively at 1, 3 and 12 months, and annually thereafter. The tremor rating scale was the primary outcome measure. Midline tremor showed significant improvement with stimulation "on" at nearly every postoperative interval when compared with stimulation "off" and with baseline tremor. Bilateral stimulation was associated with a significant incremental improvement in midline tremor control compared with unilateral stimulation: average "stimulation on" percentage change in midline tremor from the unilateral to bilateral period was 81%. Head and voice tremor showed the most consistent improvement. Among those requiring a change in stimulation parameters because of side effects, dysarthria, disequilibrium, motor disturbances, and paraesthesiae were the most common. Dysarthria was more common with bilateral (n = 6; 27%) than with unilateral (n = 0) stimulation. Stimulation parameters remained largely unchanged after the first three months. Nine of 44 leads placed (20%) required subsequent repositioning or replacement. The authors concluded thalamic stimulation is generally an effective approach for management of midline tremor associated with essential tremor. Although unilateral stimulation results in improvement, bilateral stimulation offers a significant further increment in midline tremor control. The results tend to be maintained over time and do not require a systematic increase in stimulation parameters. Adverse effects are generally mild and can be controlled by adjustment to the stimulation parameters.
Pahwa et. al. reported on the long term safety and efficacy of deep brain stimulation (DBS) of the ventralis intermedius nucleus (VIM) of the thalamus for Parkinson’s disease (PD) and essential tremor (ET). Thirty-eight of 45 patients enrolled at five sites completed a 5-year follow-up study. There were 26 patients with ET and 19 with PD undergoing 29 unilateral (18 ET/11 PD) and 16 bilateral (eight ET/eight PD) procedures. Patients with ET were evaluated using the Tremor Rating Scale, and patients with PD were evaluated using the Unified Parkinson's Disease Rating Scale. The mean age of patients with ET was 70.2 years and 66.3 years in patients with PD. Unilaterally implanted patients with ET had a 75% improvement of the targeted hand tremor; those with bilateral implants had a 65% improvement in the left hand and 86% in the right compared with baseline. Parkinsonian patients with unilateral implants had an 85% improvement in the targeted hand tremor and those with bilateral implants had a 100% improvement in the left hand and 90% improvement in the right. Common DBS-related adverse events in patients receiving unilateral implants were paresthesia (45%) and pain (41%), and in patients receiving implants bilaterally dysarthria (75%) and balance difficulties (56%) occurred. Device-related surgical revisions other than IPG (implantable pulse generator) replacements occurred in 12 (27%) of the 45 patients. The authors concluded thalamic stimulation is safe and effective for the long-term management of essential and Parkinsonian tremors.
For individuals who have essential tremor or tremor in Parkinson disease who receive deep brain stimulation (DBS) of the thalamus, a TEC Assessment (systematic review) concluded there was sufficient evidence that deep brain stimulation (DBS) of the thalamus results in clinically significant tremor suppression and that outcomes after DBS were at least as good as thalamotomy. Subsequent studies reporting long-term follow-up have supported the conclusions of the TEC Assessment and found that tremors were effectively controlled 5 to 6 years after DBS. The evidence is sufficient to determine that the technology results in a meaningful improvement in the net health outcome.
Blue Cross and Blue Shield Association (BCBSA) TEC assessment completed in 2001 focused on the use of deep brain stimulation (DBS) of the internal segment of the globus pallidus internus (GPi) and subthalmic nucleus (STN) for a broader range of Parkinson’s disease (PD) symptoms. The assessment concluded:
BCBSA TEC assessment found that bilateral deep brain stimulation (DBS) of the subthalmic nucleus (STN) or the globus pallidus internus (GPi) for patients with advanced Parkinson’s disease meets the BCBSA Technology Evaluation Center (TEC) criteria.
A systematic review of randomized controlled trials (RCTs) by Perestelo-Perez et. al. (2014) compared the impact of deep brain stimulation (DBS) plus medication versus medication alone or plus sham DBS in Parkinson’s disease (PD) outcomes. Outcome measures were motor function, waking time on good functioning without troublesome dyskinesias, levodopa-equivalent dose reduction, medication-induced complications, activities of daily living, health-related quality of life, and neurocognitive and psychiatric effects. Six RCTs (n = 1,184) that compared DBS plus medication versus medication alone were included. The results show that DBS significantly improves patients' symptoms, functionality and quality of life. Effects sizes are intense for the reduction of motor signs and improvement of functionality in the off-medication phase, in addition to the reduction of the required medication dose and its associated complications. Moderate effects were observed in the case of motor signs and time in good functionality in the on-medication phase, in addition to the quality of life. Although the number of RCTs obtained is small, the total sample size is relatively large, confirming the efficacy of DBS in the control of motor signs and improvement of patients' functionality and quality of life. More controlled research is required on the neurocognitive and psychiatric effects of DBS.
An earlier systematic review by Kleiner-Fisman et. al. included both randomized controlled trials (RCTs) and observational studies; reviewers examined the literature on subthalamic nucleus (STN) stimulation for patients with Parkinson’s disease (PD) who had failed medical management. Estimates of change in absolute Unified Parkinson's Disease Rating Scale (UPDRS) scores after surgery were generated using random-effects models. Sources of heterogeneity were explored with meta-regression models, and the possibility of publication bias was evaluated. Patient demographics, reduction in medication requirements, change in dyskinesia, daily offs, quality of life, and a ratio of postoperative improvement from stimulation compared to preoperative improvement by medication from each study were tabulated and average scores were calculated. Adverse effects from each study were summarized. Thirty-seven cohorts were included in the review. Twenty-two studies with estimates of standard errors were included in the meta-analysis. The estimated decreases in absolute UPDRS II (activities of daily living) and III (motor) scores after surgery in the stimulation ON/medication off state compared to preoperative medication off state were 13.35 (95% CI: 10.85-15.85; 50%) and 27.55 (95% CI: 24.23-30.87; 52%), respectively. Average reduction in L-dopa equivalents following surgery was 55.9% (95% CI: 50%-61.8%). Average reduction in dyskinesia following surgery was 69.1% (95% CI: 62.0%-76.2%). Average reduction in daily off periods was 68.2% (95% CI: 57.6%-78.9%). Average improvement in quality of life using PDQ-39 was 34.5% +/- 15.3%. Univariable regression showed improvements in UPDRS III scores were significantly greater in studies with higher baseline UPDRS III off scores, increasing disease duration prior to surgery, earlier year of publication, and higher baseline L-dopa responsiveness. Average baseline UPDRS III off scores were significantly lower (i.e., suggesting milder disease) in later than in earlier studies. In multivariable regression, L-dopa responsiveness, higher baseline motor scores, and disease duration were independent predictors of greater change in motor score. No evidence of publication bias in the available literature was found. The most common serious adverse event related to surgery was intracranial hemorrhage in 3.9% of patients. Psychiatric sequelae were common. Synthesis of the available literature indicates that STN DBS improves motor activity and activities of daily living in advanced PD. Differences between available studies likely reflect differences in patient populations and follow-up periods. These data provide an estimate of the magnitude of the treatment effects and emphasize the need for controlled and randomized studies.
Tan et al. (2016) conducted a systematic review and meta-analysis to compare deep brain stimulation (DBS) of globus pallidus internus (GPi) and subthalamic nucleus (STN) which are the most targeted locations for the procedure. Clinical outcomes of motor function, non-motor function, and quality of life (QOL) were collected for the meta-analysis. Ten eligible trials with 1,034 patients were included in the analysis. Unified Parkinson's disease rating scale III (UPDRS-III) scores were collected at 6, 12, and 24 months postsurgery separately to assess the motor function of the patients. A statistically significant effect in favor of the GPi DBS was obtained in the off-medication/on-stimulation phase of UPDRS-III at 12 months. However, GPi DBS showed an opposite result at 24 months. In the on-medication/on-stimulation phase, GPi DBS obtained a worse outcome compared with STN DBS. Compared with STN DBS, increased dosage of levodopa equivalent doses was needed in GPi DBS. Meanwhile, Beck Depression Inventory II scores demonstrated that STN has a better performance. As for neurocognitive phase postsurgery, GPi DBS showed better performance in three of the nine tests, especially in verbal fluency. Use of GPi DBS was associated with a greater effect in eight of the nine subscales of QOL. The authors concluded that GPi and STN DBS significantly improve advanced Parkinson's patients' symptoms, functionality, and QOL. According to the authors, the question regarding which target is superior remains open for discussion. An understanding of the target selection depends on individual symptoms, neurocognitive/mood status, therapeutic goals of DBS (e.g., levodopa reduction), and surgical expertise.
Schuepbach et. al. (2013) published a randomized controlled trial (RCT) evaluating the deep brain stimulation (DBS) in patients with Parkinson’s disease (PD) and early motor complications. Key eligibility criteria included age 18 to 60 years; disease duration of 4 years of more; improvement of motor signs of 50% or more with dopaminergic medication; and a disease severity rating below stage 3 in the on-medication condition. A total of 251 patients were enrolled, 124 whom were assigned to DBS plus medical therapy and 127 to medical therapy alone. Analysis was intention to treat and blind outcome assessment was done at baseline and at 2 years. The primary end point was mean change from baseline to 2 years in the summary index of the Parkinson Disease Questionnaire (PDQ-39), which has a maximum score of 39 points, with higher scores indicating higher QOL (quality of life). Mean baseline scores on the PDQ-39 were 30.2 in the DBS plus medical therapy group and 30.2 in the medical therapy only group. At 2 years, the mean score increased by 7.8 points in the DBS plus medical therapy group and decreased by 0.2 points in the medical therapy only group (mean change between groups, 8.0; p=0.002). There were also significant between-group differences in major secondary outcomes, favoring the DBS plus medical therapy group (p<0.01 on each): severity of motor signs, ADLs, severity of treatment-related complications, and the number of hours with good mobility and no troublesome dyskinesia. The first 3 secondary outcomes were assessed using UPDRS subscales. Regarding medication use, the levodopa-equivalent daily dose was reduced by 39% in the DBS plus medical therapy group and increased by 21% in the medical therapy only group. Sixty-eight patients in the DBS plus medical therapy group and 56 in the medical therapy only group experienced at least 1 serious adverse event. This included 26 serious adverse events in the DBS group that were surgery- or device-related; reoperation was necessary in 4 patients. The authors concluded that neurostimulation was superior to medical therapy alone at a relatively early stage of Parkinson disease (PD), before the appearance of severe disabling motor complications. Neurostimulation may be a therapeutic option for patients at an earlier stage than current recommendations suggest.
A number of meta-analyses have compared the efficacy of globus pallidus internus (GPi) and subthalamic nucleus (STN) deep brain stimulation in Parkinson’s disease (PD) patients.
The meta-analysis of randomized controlled trials (RCTs) by Tan et. al. (2016) compared the efficacy of globus pallidus internus (GPi) and subthalamic nucleus (STN) deep brain stimulation (DBS) for advanced Parkinson’s disease (PD). Ten eligible trials with 1,034 patients were included in the analysis. Unified Parkinson disease rating scale III (UPDRS-III) scores were collected at 6, 12, and 24 months post-surgery separately to assess the motor function of the patients. A statistically significant effect in favor of the GPi DBS was obtained in the off-medication/on-stimulation phase of UPDRS-III at 12 months (mean difference [MD] =6.87, 95% confidence interval [95% CI]: 3.00–10.74, P=0.57, I2=0%). However, GPi DBS showed an opposite result at 24 months (MD =−2.46, 95% CI: −4.91 to −0.02, P=0.05, I2=0%). In the on-medication/on-stimulation phase, GPi DBS obtained a worse outcome compared with STN DBS (MD =−2.90, 95% CI: −5.71 to −0.09, P=0.05, I2=0%). Compared with STN DBS, increased dosage of levodopa equivalent doses was needed in GPi DBS (standardized MD =0.60, 95% CI: 0.46–0.74, P,0.00001, I2=24%). Mean¬while, Beck Depression Inventory II scores demonstrated that STN has a better performance (standardized MD =−0.31, 95% CI: −0.51 to −0.12, P=0.002, I2=0%). As for neurocognitive phase post-surgery, GPi DBS showed better performance in three of the nine tests, especially in verbal fluency. Use of GPi DBS was associated with a greater effect in eight of the nine subscales of QOL (quality of life). The authors concluded globus pallidus (GPi) stimulation and subthalamic nucleus (STN) stimulation significantly improve advanced Parkinson patients’ symptoms, functionality, and QOL (quality of life). Variable therapeutic efficiencies were observed in both procedures, GPi and STN DBS. GPi DBS allowed greater recovery of verbal fluency and provided greater relieve of depression symptoms. Better QOL was obtained using GPi DBS. Meanwhile, GPi DBS was also associated with higher levodopa equivalent doses. The question regarding which target is superior remained open for discussion. An understanding of the target selection still depends on individual symptoms, neurocognitive/mood status, therapeutic goals of DBS (e.g. levodopa reduction) and surgical expertise.
In a meta-analysis, Peng et al. (2018) assessed the long-term efficacy of deep brain stimulation (DBS) of the subthalamic nucleus (STN) and globus pallidus interna (GPi) for Parkinson disease (PD). A total of 5 studies with 890 subjects (437 patients in the STN-DBS group and 453 patients in the GPi-DBS group) were included in the analysis. The study results showed no significant differences between STN-DBS and GPi-DBS in the long-term efficacy of unified Parkinson disease rating scale section (UPDRS) III scores including motor subtypes. The authors concluded that STN-DBS and GPi-DBS improve motor function and activities of daily living for PD.
Two new deep brain stimulation (DBS) systems with directional leads are currently available, approved by the Food and Drug Administration (FDA) in 2016 and 2017. In 2016 the FDA approved the St. Jude Medical Infinity DBS device with directional lead technology designed to allow precise steering of the current towards the desired structural areas to optimize patient outcomes (reducing symptoms) and reduce side effects. In 2017 the FDA approved Vercise Deep Brain Stimulation System (Boston Scientific), this system is used as an adjunctive therapy from reducing motor symptoms of moderate to advanced levodopa responsive Parkinson’s disease (PD) inadequately controlled with medication alone.
DBS device directional leads potentially enable clinicians to target more specific areas of the brain to be treated with the direct current. Published evidence consists of several small observational studies, with sample sizes ranging from 7 to 13. The studies showed that patients experienced improved tremor scores and improved quality of life (QOL). Compared with historical data from conventional deep brain stimulation (DBS) systems, directional DBS widened the therapeutic window and achieved beneficial effects using lower current level. Comparative, larger studies are needed to support the conclusions from these small studies.
In 2017, Dembek et. al. investigated whether deep brain stimulation (DBS) of the subthalamic nucleus in Parkinson disease (PD) offers increased therapeutic windows, side-effect thresholds, and clinical benefit. In 10 patients, 20 monopolar reviews were conducted in a prospective, randomized, double-blind design to identify the best stimulation directions and compare them to conventional circular DBS regarding side-effect thresholds, motor improvement, and therapeutic window. In addition, circular and best-directional DBS were directly compared in a short-term crossover. Motor outcome was also assessed after an open-label follow-up of 3 to 6 months. Stimulation in the individual best direction resulted in significantly larger therapeutic windows, higher side-effect thresholds, and more improvement in hand rotation than circular DBS. Rigidity and finger tapping did not respond differentially to the stimulation conditions. There was no difference in motor efficacy or stimulation amplitudes between directional and circular DBS in the short-term crossover. Follow-up evaluations 3 to 6 months after implantation revealed improvements in motor outcome and medication reduction comparable to other DBS studies with a majority of patients remaining with a directional setting. The authors concluded, directional DBS can increase side effect thresholds while achieving clinical benefit comparable to conventional DBS.
For individuals who have symptoms associated with Parkinson disease (PD) (advanced or > 4 years in duration with early motor symptoms) who receive deep brain stimulation (DBS) of the globus pallidus interna (Gpi) or subthalamic nucleus (STN), the evidence includes randomized controlled trials (RCTs) and systematic reviews. One of the systematic reviews (a TEC Assessment) concluded that studies evaluating DBS of the GPi or STN have consistently demonstrated clinically significant improvements in outcomes (e.g. neurologic function). Other systematic reviews have also found significantly better outcomes after DBS than after a control intervention. A randomized controlled trial (RCT) in patients with levodopa-responsive Parkinson disease of at least four years in duration and uncontrolled motor symptoms found that quality of life (QOL) at two years was significantly higher when DBS was provided in addition to meical therapy. Meta-analyses of RCTs comparing DBS of the GPi with DBS of the STN have reported mixed findings and have not shown that one type of stimulation is clearly superior to the other. The evidence is sufficient to determine that the technology results in meaningful improvement in the net health outcome.
The role of deep brain stimulation (DBS) in treatment of other treatment resistant neurologic and psychiatric disorders, particularly epilepsy, multiple sclerosis (MS), Tourette syndrome, major depressive disorders, obsessive-compulsive disorder, anorexia nervosa, drug addiction, impulse or violent behavior, Huntington’s disease, traumatic brain injury (TBI), chronic pain, and Alzheimer disease/dementias is also being investigated. Ablative procedures are irreversible and, though they have been refined, remain controversial treatments for intractable illness. Interest has shifted to neuromodulation through DBS of nodes or targets within neural circuits involved in these disorders. Currently, a variety of target areas are being studied.
The population of interest are patients with other neurologic and psychiatric disorders.
The therapy being considered is deep brain stimulation (DBS). Several target areas have been investigated.
Alternative treatments vary by condition. Sham DBS is an appropriate comparator for randomized controlled trials (RCTs).
Key efficacy outcomes include measures of symptom severity, functional ability and disability, and quality of life (QOL).
Key safety outcomes include death, stroke, depression, cognition, infection and other device and procedure related events.
It is estimated that approximately 30% of epileptic patients do not respond to anti-epileptic drugs and are considered to have drug-resistant epilepsy. Patients with drug-resistant or refractory epilepsy have a higher risk of death as well as a high burden of epilepsy-related disabilities and limitations.
The relevant population(s) of interest are patients with epilepsy refractory to medical treatment who are not candidates for respective surgery. The International League Against Epilepsy defined drug-resistant epilepsy as failure of adequate trials of two tolerated and appropriately chosen and used anti-epileptic drugs (AEDs), used either as monotherapy or in combination, to achieve seizure freedom.
The therapy being considered is deep brain stimulation (DBS). Several areas of the brain have been targeted.
The treatment of chronic epilepsy consists of anti-epileptic drugs. For patients with epilepsy that are refractory to medical treatment, surgery options such as resection or disconnection may be considered.
Vagus nerve stimulation may also be used in patients with drug-refractory epilepsy who are not candidates for resective surgery (see also medical policy 07.01.60 Vagus Nerve Stimulation (VNS) and Vagal Blocking Therapy).
Key efficacy outcomes include measure of seizure frequency or severity, response (reduction in seizure frequency by 50% or more), freedom from seizure, functional ability and disability, medication use, hospitalizations and quality of life (QOL). The Quality of Life Inventory in Epilepsy (QOLIE-31) is a tool used to assess the impact of anti-epileptic treatment on patients’ lives; the minimally important change in patients with treatment-resistant seizures was 5 points.
In 2017, Sprengers et. al. conducted a systematic review on deep brain and cortical stimulation for epilepsy. Despite optimal medical treatment, including epilepsy surgery, many epilepsy patients have uncontrolled seizures. Interest has grown in invasive intracranial neurostimulation as a treatment for these patients. Intracranial stimulation includes deep brain stimulation (DBS) (stimulation through depth electrodes) and cortical stimulation (subdural electrodes). The objective of the systematic review was to assess the efficacy, safety and tolerability of DBS and cortical stimulation for refractory epilepsy based on randomized controlled trials (RCTs). The selection criteria included RCTs comparing deep brain or cortical stimulation versus sham stimulation, resective surgery, further treatment with anti-epileptic drugs or other neurostimulation treatments (including vagus nerve stimulation). Twelve RCTs were identified, eleven of these compared one to three months of intracranial neurostimulation with sham stimulation. One trial was on anterior thalamic DBS (n = 109; 109 treatment periods); two trials on centromedian thalamic DBS (n = 20; 40 treatment periods), but only one of the trials (n = 7; 14 treatment periods) reported sufficient information for inclusion in the quantitative meta-analysis; three trials on cerebellar stimulation (n = 22; 39 treatment periods); three trials on hippocampal DBS (n = 15; 21 treatment periods); one trial on nucleus accumbens DBS (n = 4; 8 treatment periods); and one trial on responsive ictal onset zone stimulation (n =191; 191 treatment periods). In addition, one small RCT (n = 6) compared six months of hippocampal DBS versus sham stimulation. Evidence of selective reporting was present in four trials and the possibility of a carryover effect complicating interpretation of the results could not be excluded in five cross-over trials without any or a sufficient washout period. Moderate-quality evidence could not demonstrate statistically or clinically significant changes in the proportion of patients who were seizure-free or experienced a 50% or greater reduction in seizure frequency (primary outcome measures) after one to three months of anterior thalamic DBS in (multi)focal epilepsy, responsive ictal onset zone stimulation in (multi)focal epilepsy patients and hippocampal DBS in (medial) temporal lobe epilepsy. However, a statistically significant reduction in seizure frequency was found for anterior thalamic DBS (mean difference (MD), -17.4% compared to sham stimulation; 95% confidence interval (CI) -31.2 to -1.0; high quality evidence), responsive ictal onset zone stimulation (MD -24.9%; 95%CI -40.1 to -6.0; high-quality evidence) and hippocampal DBS (MD -28.1%; 95% CI -34.1 to -22.2; moderate-quality evidence). Both anterior thalamic DBS and responsive ictal onset zone stimulation do not have a clinically meaningful impact on quality life after three months of stimulation (high-quality evidence). Electrode implantation resulted in postoperative asymptomatic intracranial hemorrhage in 1.6% to 3.7% of the patients included in the two largest trials and 2.0% to 4.5% had postoperative soft tissue infections (9.4% to 12.7% after five years); no patient reported permanent symptomatic sequelae. Anterior thalamic DBS was associated with fewer epilepsy-associated injuries (7.4 versus 25.5%; P =0.01) but higher rates of self-reported depression (14.8 versus 1.8%; P = 0.02) and subjective memory impairment (13.8 versus 1.8%; P = 0.03); there were no significant differences in formal neuropsychological testing results between the groups. Responsive ictal-onset zone stimulation seemed to be well-tolerated with few side effects. The limited number of patients preclude firm statements on safety and tolerability of hippocampal DBS. With regards to centromedian thalamic DBS, nucleus accumbens DBS and cerebellar stimulation, no statistically significant effects could be demonstrated but evidence is of only low to very low quality. The authors concluded, except for one very small RCT, only short-term RCTs on intracranial neurostimulation for epilepsy are available. Compared to sham stimulation, one to three months of anterior thalamic DBS ((multi)focal epilepsy), responsive ictal onset zone stimulation ((multi)focal epilepsy) and hippocampal DBS (temporal lobe epilepsy) moderately reduce seizure frequency in refractory epilepsy patients. Anterior thalamic DBS is associated with higher rates of self-reported depression and subjective memory impairment. There is insufficient evidence to make firm conclusive statements on the efficacy and safety of hippocampal DBS, centromedian thalamic DBS, nucleus accumbens DBS and cerebellar stimulation. There is a need for more, large and well-designed RCTs to validate and optimize the efficacy and safety of invasive intracranial neurostimulation treatments.
Two systematic reviews on the use of deep brain stimulation (DBS) for drug resistant epilepsy, both published in 2018, assessed many of the same studies. The larger review by Li et. al. identified 10 randomized controlled trials (RCTs) and 48 uncontrolled studies. The literature search date was not reported. Meta-analyses was not performed. Summaries of the studies were discussed by the area of the brain targeted by DBS. A review of the studies showed that DBS might be effective in reducing seizures when DBS targets the anterior nucleus of the thalamus or the hippocampus. Across studies, more than 70% of patients experienced a reduction in seizures by 50% or more. However, there were very few RCTs and the observational studies had small sample sizes. Individual responses varied, depending on seizure syndrome, presence or absence of structural abnormalities, and electrode position. Results were inconclusive when DBS targeted the centromedian nucleus of the thalamus, the cerebellum, and the subthalamic nuclei. Safety data on DBS were limited due to the small population sizes. The RCT in which DBS targeted the anterior nucleus of the thalamus reported paresthesias (23%), implant site pain (21%), and implant site infection (13%). The authors concluded that more large scale clinical trials are needed to explore different stimulation parameters, re-evaluate the indications for DBS and identify robust predictors of patient response.
In a meta-analysis and systematic review by Chang et. al. (2018) identified possible predictors of remarkable seizure reduction (RSR) for deep brain stimulation (DBS) in patients with refractory temporal lobe epilepsy (TLE). The authors conducted a comprehensive search of English-language literature published since 1990 that addressed seizure outcomes in patients who underwent DBS for refractory TLE. A pooled RSR rate was determined for eight included studies. RSR rates were analyzed relative to potential prognostic variables. The pooled RSR rate among 61 DBS-treated patients with TLE from 8 studies was 59%. Higher likelihood of RSR was found to be associated with lateralization of stimulation, lateralized ictal EEG findings, and a longer follow-up period. Seizure semiology, MRI abnormalities, and patient sex were not predictive of RSR rate. The best electrode type for RSR was the Medtronic 3389. Hippocampal and anterior thalamic nuclei (ATN) sites of stimulation had similar odds of producing RSR. The authors concluded, that DBS is an effective therapeutic modality for intractable TLE, particularly in patients with lateralized EEG abnormalities and in patients treated on the ictal side. However, studies with higher levels of evidence and larger populations are needed to determine if DBS is effective for treating epilepsy.
Yan et. al. (2018) conducted a systematic review of deep brain stimulation (DBS) for the treatment of drug-resistant epilepsy (DRE) in childhood. Although deep brain stimulation has been studied in adults with DRE, little evidence is available to guide clinicians regarding the application of this potentially valuable tool in children. This systemic review aimed at understanding the safety and efficacy of DBS for DRE in pediatric populations, emphasizing patient selection, device placement and programming, and seizure outcomes. Inclusion criteria of individual studies were 1) diagnosis of DRE; 2) treatment with DBS; 3) inclusion of at least 1 pediatric patient (age ≤ 18 years); and 4) patient-specific data. Exclusion criteria for the systematic review included 1) missing data for age, DBS target, or seizure freedom; 2) nonhuman subjects; and 3) editorials, abstracts, review articles, and dissertations. This review identified 21 studies and 40 unique pediatric patients (ages 4–18 years) who received DBS treatment for epilepsy. There were 18 patients with electrodes placed in the bilateral or unilateral centromedian nucleus of the thalamus (CM) electrodes, 8 patients with bilateral anterior thalamic nucleus (ATN) electrodes, 5 patients with bilateral and unilateral hippocampal electrodes, 3 patients with bilateral subthalamic nucleus (STN) and 1 patient with unilateral STN electrodes, 2 patients with bilateral posteromedial hypothalamus electrodes, 2 patients with unilateral mammillothalamic tract electrodes, and 1 patient with caudal zona incerta electrode placement. Overall, 5 of the 40 (12.5%) patients had an International League Against Epilepsy class I (i.e., seizure-free) outcome, and 34 of the 40 (85%) patients had seizure reduction with DBS stimulation. The authors concluded, prospective registries and future clinical trials are needed to identify the optimal DBS target, although favorable outcomes are reported with both CM and ATN in children.
Fisher et. al. (2010) conducted a U.S. multicenter, double-blind, randomized trial of bilateral stimulation of the anterior nuclei of the thalamus for localization related epilepsy (SANTE). The study included 110 patients, ages 18 to 65 years, who experienced at least 6 partial seizures (including secondarily generalized seizures) per month, not no more than 10 per day. At least 3 antiepileptic drugs must have failed to produce adequate seizure control before baseline, with 1 to 4 antiepileptic drugs used at the time of study entry. Patients were asked to keep a daily seizure diary during treatment. All patients received DBS device implantation, with half the patients randomized to stimulation (n=54) and half to no stimulation (n=55) during a 3-month blinded phase; thereafter all patients received unblinded stimulation. Baseline monthly median seizure frequency was 19.5. During the first and second months of the blinded phase, the difference in seizure reduction between stimulation on (-42.1%) and stimulation off (-28.7%) did not differ significantly. In the last month of the blinded phase, the stimulated group had a significantly greater reduction in seizures (-40.4%) than the control group (-14.5%; p=0.002). Five deaths occurred and none were from implantation or stimulation. No participant had symptomatic hemorrhage or brain infection. Two participants had acute, transient stimulation-associated seizures. Cognition and mood showed no group differences, but participants in the stimulated group were more likely to report depression or memory problems as adverse events.
Troster et. al. (2017) examined the incidence of memory and depression adverse events (AE) in the SANTE study during the 3 month blinded phase, and at 7 year follow-up during the open label noncomparative phase. No significant cognitive declines or worsening of depression scores were observed through the blinded phase or in open-label at 7-years. Higher scores were observed at 7 years on measures of executive functions and attention. Depression and memory-related AEs were not associated with reliable change on objective measures or 7-year neurobehavioral outcome. The AEs were without significant impact on life quality. Memory and depression AEs were not related to demographic or seizure characteristics, change in seizure frequency, frequency of AE or depression report.
Cukiert et. al. (2017) conducted a prospective, randomized, controlled, double-blind study to evaluate the efficacy of hippocampal deep brain stimulation (Hip-DBS) in patients with refractory temporary lobe epilepsy (TLE). Sixteen adult patients with refractory TLE were studied. Patients were randomized on a 1:1 proportion to an active (stimulation on) or to a control (no stimulation) arm. After implantation, patients were allowed to recover for 1 month, which was followed by a 1-month titration (or sham) period. The 6-month blinded phase started immediately afterward. A postoperative MRI confirmed the electrode's position in all patients. All patients received bipolar continuous stimulation. Stimulus duration was 300 μs and frequency was 130 Hz; final intensity was 2 V. Patients were considered responders when they had at least 50% seizure frequency reduction. All patients had focal impaired awareness seizures (FIAS, complex partial seizures), and 87% had focal aware seizures (FAS, simple partial seizures). Mean preoperative seizure frequency was 12.5 ± 9.4 (mean ± standard deviation) per month. MRI findings were normal in two patients, disclosed bilateral mesial temporal sclerosis (MTS) in three, left MTS in five, and right MTS in six patients. An insertional effect could be noted in both control and active patients. In the active group (n = 8), four patients became seizure-free; seven of eight were considered responders and one was a nonresponder. There was a significant difference regarding FIAS frequency between the two groups from the first month of full stimulation (p < 0.001) until the end of the blinded phase (p < 0.001). This was also true for FAS, except for the third month of the blinded phase. The authors concluded Hip-DBS was effective in significantly reducing seizure frequency in patients with refractory TLE in the active group, as compared to the control group. Fifty-percent of the patients in the active group became seizure-free. The present study is the larger prospective, controlled, double-blind study to evaluate the effects of Hip-DBS published to date.
Long-term outcomes of the SANTE trial were reported by Salanova et. al. (2015). The uncontrolled open-label portion of the trial began after 3 months and, beginning at 13 months, stimulation parameters could be adjusted at the clinician’s discretion. Of the 110 implanted patients, 105 (95%) completed the 13-month follow-up, 98 (89%) completed the 3-year follow-up, and 83 (75%) completed 5 years. Among patients with at least 70 days of diary entries, the median change in seizure frequency from baseline was 41% at 1 year and 69% at 5 years (p<0.001 for both). During the trial, 39 (35%) of 110 patients had a device-related serious adverse event, most of which occurred in the first months after implantation. They included implant-site infection (10% of patients) and lead(s) not within target (8.2% of patients). Seven deaths occurred during the trial and none was considered to be device-related. Depression was reported in 41 (37%) patients following implant; in 3 cases, it was considered device-related. Memory impairment (non-serious) was reported in 30 (27%) patients during the trial, half of whom had a history of the condition. Although some patients appeared to benefit from treatment during the extended follow-up phase, the difference between groups in the blinded portion of the trial, while significant, was modest overall.
Kim et. al. (2017) conducted a retrospective chart review of 29 patients with refractory epilepsy treated with deep brain stimulation (DBS). The patients mean age was 31 years, had epilepsy for a mean of 19 years, and had a mean preoperative frequency of tonic-clonic seizures of 27 per month. The mean follow-up was 6.3 years. Median seizure reduction from baseline was 71% at year 1, 74% at year 2 and ranged from 62% to 80% through 11 years of follow-up. Complications included 1 symptomatic intracranial hemorrhage, 1 infection requiring removal and reimplantation, and 2 lead disconnections.
The evidence includes systematic reviews and meta-analysis, randomized controlled trials (RCTs) and many observational studies in which deep brain stimulation (DBS) was evaluated for the treatment of epilepsy. The largest RCT (SANTE trial) consisted of a 3-month blinded phase in which patients were randomized to stimulation or no stimulation. After the randomized phase, all patients received stimulation and were followed for 13 additional months. Findings in the first 3 months were mixed: patients reported significantly fewer seizures in the third month, but not in the first or second month. In the uncontrolled follow-up period of the RCT and in many small observational studies, patients reported fewer seizures compared with baseline, however, without a control group, interpretation of results is limited. Adverse events, including device-related serious adverse events were reported in about one-third of patients. The risk-benefit ratio is uncertain. Based on systematic reviews of randomized controlled trials, favorable outcomes may have been reported, however, authors concluded further studies are needed with higher levels of evidence and larger populations to determine if DBS is effective for treating epilepsy. The evidence is insufficient to determine that the technology results in a meaningful improvement in net health outcome.
Schuurman et. al. reported on 5-year follow-up for 68 patients in a study that compared thalamic stimulation with thalamotomy for multiple indications, including 10 patients with multiple sclerosis (MS). Trial details are discussed with essential tremor in the section on Unilateral Stimulation of the Thalamus. The small numbers of patients with MS in this trial limits conclusions that can be drawn.
One randomized controlled trial (RCT) reporting on 10 multiple sclerosis (MS) patients provides insufficient data for drawing conclusions on the efficacy of deep brain stimulation (DBS) for this population. The evidence is insufficient to determine that the technology results in a meaningful improvement in net health outcome.
In 2018 Macerolla et. al. completed a systematic review and meta-analysis on the available literature reporting on cases with either tardive dystonia or dyskinesia treated with deep brain stimulation (DBS). Among the broad entity of tardive syndromes, tardive dystonia and classical tardive dyskinesia sometimes require advanced treatments like deep brain stimulation of the globus pallidus internum (Gpi-DBS) or the subthalamic nucleus (STN-DBS). Thirty-four level VI studies and one level II study with 117 patients were included. Level I studies were not identified. Only four of the patients had tardive dyskinesia. All the others had tardive dystonia. The majority had Gpi-DBS (n = 109). Patients had a mean age of 47.4 years. The duration of follow-up was 25.6 months. The Abnormal Involuntary Movement Scale was reported in 51 patients with an improvement of 62 (15%) and the Burke-Fahn-Marsden scale was reported in 67 cases with an improvement of 76 (21%). Reported adverse events were surgery-related in 7 patients, stimulation-induced in 12, and psychiatric in 3 patients. These reports thus suggest favorable effects of DBS and it seems to be relatively safe. DBS can be considered for patients with severe, medication-resistant symptoms. Controlled and randomized studies with blinded outcomes are needed.
Damier et. al. (2007) assessed the efficacy of bilateral deep brain stimulation of the internal part of the global pallidus to treat severe tardive dyskinesia (TD) in a prospective phase 2 multicenter study. Patients with severe TD refractory to medical treatment were studied to evaluate the severity of abnormal involuntary movements before and after 6 months of bilateral globus pallidus deep brain stimulation. A successful outcome was defined as a decrease of more than 40% in the main outcome measure at 6 months. The early stopping rule was invoked if the number of successful outcomes in 10 patients was fewer than 2, or 5 or more. A double-blind evaluation in the presence and absence of stimulation was performed at 6 months after surgery. Main Outcome Measure Change in score on the Extrapyramidal Symptoms Rating Scale. At 6 months after surgery, the Extrapyramidal Symptoms Rating Scale score had decreased compared with baseline by more than 40% (mean improvement, 61%; range, 44%-75%) in the first 10 patients included. In accord with the 2-step open Fleming procedure, we ended the trial at the first step and concluded that pallidal stimulation is an effective treatment for TD. The efficacy of the treatment was confirmed by a double-blind evaluation, with a mean decrease of 50% (range, 30%-66%) (P = .002) in the Extrapyramidal Symptoms Rating Scale score when stimulation was applied compared with the absence of stimulation. There were no marked changes in the patients' psychiatric status. The authors concluded although these results need to be confirmed in a larger group of patients with a longer follow-up, bilateral globus pallidus deep brain stimulation seems to offer a much needed new treatment option for disabling TD.
Gruber et. al. (2009) reported outcomes on motor function, quality of life (QOL) and mood in a series of 9 patients treated with deep brain stimulation (DBS) of the globus pallidus internus (GPi) in patients with tardive dystonia. Patients were assessed at 3 points: 1 week, 3 to 6 months and last follow-up at the mean of 41 (range of 18-80) months after surgery using established and validated movement disorder and neuropsychological scales. Clinical assessment was performed by a neurologist not blinded to the stimulation settings. One week and 3 to 6 months after globus pallidal DBS, Burke-Fahn-Marsden Dystonia Rating Scale (BFMDRS) motor scores were ameliorated by 56.4 +/- 26.7% and 74.1 +/- 15.8%, BFMDRS disability scores by 62.5 +/- 21.0% and 88.9 +/- 10.3%, and Abnormal Involuntary Movement Scale (AIMS) scores by 52.3 +/- 24.1% and 69.5 +/- 27.6%, respectively. At last follow-up, this improvement compared with the pre-surgical assessment was maintained as reflected by a reduction of BFMDRS motor scores by 83.0 +/- 12.2%, BFMDRS disability scores by 67.7 +/- 28.0%, and AIMS scores by 78.7 +/- 19.9%. QOL (quality of life) improved significantly in physical components, and there was a significant improvement in affective state. Furthermore, cognitive functions remained unchanged compared with pre-surgical status in the long-term follow-up. No permanent adverse effects were observed.
Spindler et. al. (2013) complete a case report and review of the literature regarding globus pallidus deep brain stimulation (DBS) for tardive dyskinesia (TD). Tardive dyskinesia (TD) can be a disabling condition and is frequently refractory to medical therapy. Over the past decade there have been many reports of TD patients experiencing significant benefit with deep brain stimulation (DBS) of the globus pallidus interna (GPi). The growing literature on this treatment option for TD consists predominantly of case reports and series. The reported benefit ranges widely, but the majority of cases experienced at least a 50% improvement in symptoms. The anatomical distribution of dyskinesias has not clearly influenced outcome, though fixed postures appear less likely to improve than phasic movements. Onset of benefit can be immediate or take months, and benefit is sustained in most cases, for at least 6 months and up to several years. A wide variety of voltages, frequencies, and pulse widths have demonstrated efficacy. A small number of reports which examined psychiatric symptoms before and after surgery did not find any decline, and in some cases revealed improvement in mood. However, these overall positive results should be interpreted with caution, as the majority of reports lacked blinded assessments, control groups, or standardized therapy parameters.
Pouclet-Courtemanche et. al. (2016) reported on a case series of 19 patients with severe pharmaco-resistant tardive dyskinesia treated with deep brain stimulation (DBS). Patients were assessed after 3, 6 and 12 months after the procedure. At 6 months, all patients had a decrease of more than 40% on the ESRS (Extrapyramidal Symptoms Rating Scale). This improvement was maintained at 12 months ESRS score was 58% (range 21%-81%).
For individuals who have tardive dyskinesia or tardive dystonia who receive deep brain stimulation the evidence consists of case series, case report, randomized controlled trials and systematic reviews. Few studies were identified and they had small sample sizes. While the literature may show some promise in patients with refractory tardive dyskinesia (TD), additional studies are needed to include randomized controlled studies with longer follow-up and more patients to establish the role of DBS for this indication. The evidence is insufficient to determine that the technology results in a meaningful improvement in net health outcome.
In 2011 a comparative effectiveness review was completed by the Agency of Healthcare Research and Quality (AHRQ) regarding nonpharmacologic interventions for treatment resistant depression in adults. The report indicated that clinical trial data on some of the developing nonpharmacologic interventions, such as deep brain stimulation (DBS) were insufficient (from the published literature) to include them in the report. The authors stated that as the evidence bases grow to support the efficacy of such nonpharmacologic interventions, the newer strategies should be included in comparative effectiveness study designs.
A variety of target areas are being investigated for use of deep brain stimulation (DBS) for treatment-resistant depression. A systematic review by Morishita et. al. (2014) identified 22 clinical research papers with 5 unique DBS approaches using different targets, including nucleus accumbens, ventral striatum/ventral capsule (VC/VS), subgenual cingulate cortex (SCC), lateral habenula, inferiorthalamic nucleus, and medial forebrain bundle. Among the 22 published studies, only 3 were controlled trials with sham stimulation periods, and 2 multicenter, randomized, controlled trials (RCTs) evaluating the efficacy of subgenual cingulate cortex and ventral striatum/ventral capsule DBS were discontinued owing to inefficacy based on futility analyses (interim analysis demonstrating very low probability of success if the trial was completed as planned). The authors concluded, in total, 6 different targets have been proposed and tried for major depressive disorder (MDD) DBS. Of these, only VC/VS and SCC DBS have been investigated with controlled trials with small sample sizes,and, unfortunately, recent multicenter, prospective, randomized trials have reportedly failed to confirm the efficacy of stimulation at these 2 targets (i.e., VC/VS and SCC). Despite these setbacks, the extraordinary public health burden of MDD and the promising results of various open-label trials warrant further investigation. No class I evidence exists in the literature supporting the efficacy of DBS for MDD, and the optimal DBS target for treatment-resistant depression remains unclear. DBS for MDD should therefore be considered experimental at present; further studies are indicated to clarify the malfunctioning neurocircuitry associated with MDD and to evaluate the efficacy and safety of the various MDD DBS strategies. As always, surgical therapy for the treatment of psychiatric disorders should only be performed in the setting of a multidisciplinary team, which should include, as a minimum, a dedicated psychiatrist, neurologist, neurosurgeon, and neuropsychologist.
Berlim et al. (2014) conducted a systematic review and exploratory meta-analysis to investigate deep brain stimulation (DBS) applied to the subgenual cingulate cortex (SCC) as a potential treatment for severe and chronic treatment-resistant depression (TRD). Data from 4 observational studies were included in the analysis, totaling 66 subjects with severe and chronic TRD. Twelve-month response and remission rates following DBS treatment were 39.9% and 26.3%, respectively. Also, depression scores at 12 months post-DBS were significantly reduced. There was a significant decrease in depression scores between 3 and 6 months, but no significant changes from months 6 to 12. Finally, dropout rates at 12 months were 10.8%. The authors concluded that DBS applied to the SCC seems to be associated with relatively large response and remission rates in the short- and medium- to long-term in patients with severe TRD. Also, its maximal antidepressant effects are mostly observed within the first 6 months after device implantation. According to the authors, these findings are clearly preliminary and future controlled trials should include larger and more representative samples, and focus on the identification of optimal neuroanatomical sites and stimulation parameters.
In a systematic review, Naesstrom et al. (2016) reviewed the current studies on psychiatric indications for deep brain stimulation (DBS), with focus on obsessive-compulsive disorder (OCD) and major depressive disorder (MDD). A total of 52 studies met the inclusion criteria with a total of 286 unique patients treated with DBS for psychiatric indications; 18 studies described 112 patients treated with DBS for OCD in six different anatomical targets, while nine studies included 100 patients with DBS for MDD in five different targets. The authors concluded that DBS may show promise for treatment-resistant OCD and MDD but the results are limited by small sample size and insufficient randomized controlled data. According to the authors, other psychiatric indications are currently of a purely experimental nature.
Kisely et al. (2018) performed a systematic review and meta-analysis on the effectiveness of deep brain stimulation (DBS) in depression. Ten papers from nine studies met inclusion criteria, all but two of which were double-blinded randomized controlled trials (RCTs). The main outcome was a reduction in depressive symptoms. It was possible to combine data for 190 participants. Patients on active, as opposed to sham, treatment had a significantly higher response and reductions in mean depression score. However, the effect was attenuated on some of the subgroup and sensitivity analyses, and there were no differences for most other outcomes. In addition, 84 participants experienced a total of 131 serious adverse effects, although not all could be directly associated with the device or surgery. Finally, publication bias was possible. The authors concluded that DBS may show promise for treatment-resistant depression but remains an experimental treatment until further data are available.
An industry-sponsored, double-blind RCT evaluating deep brain stimulation (DBS) targeting the ventral capsule/ventral striatum (VC/VS) in patients with chronic treatment-resistant depression was published by Dougherty et al (2015). The trial included 30 patients with a major depressive episode lasting at least 2 years and inadequate response to at least 4 trials of antidepressant therapy. Participants were randomized to 16 weeks of active (n=16) or to sham (n=14) DBS, followed by an open-label continuation phase. One patient, who was assigned to active treatment, dropped out during the blinded treatment phase. The primary outcome was clinical response at 16 weeks, defined as 50% or more improvement from baseline on Montgomery-Asberg Depression Rating Scale (MADRS) score. A response was identified in 3 (20%) of 15 patients in the active treatment group and in 2 (14%) of 14 patients in the sham control group (p=0.53). During the blinded treatment phase, psychiatric adverse events occurring more frequently in the active treatment group included worsening depression, insomnia, irritability, suicidal ideation, hypomania, disinhibition, and mania. Psychiatric adverse events occurring more frequently in the sham control group were early morning awakening and purging. Findings of this trial did not support a conclusion that DBS is effective for treating treatment-resistant depression.
A crossover randomized controlled trial (RCT) evaluating active and sham phases of deep brain stimulation (DBS) in 25 patients with treatment-resistant depression was published after the systematic review by Bergfeld et. al. (2016). Prior to the randomized phase, all patients received 52 weeks of open-label DBS treatment with optimization of settings. Optimization ended when patients achieved a stable response of at least 4 weeks or after the 52-week period ended. At the end of the open-label phase, 10 (40%) patients were classified as responders (≥50% decrease in the Hamilton Depression Rating Scale [HAM-D] score) and 15 (60%) patients were classified as non-responders. After the 52 weeks of open-label treatment, patients underwent 6 weeks of double-blind active and sham stimulation. Sixteen (64%) of 25 enrolled patients participated in the randomized phase (9 responders, 7 non-responders). Nine patients were prematurely crossed over to the other intervention. Among all 16 randomized patients, HAM-D scores were significantly improved at the end of the active stimulation phase (mean HAM-D score, 16.5) compared with the sham stimulation phase (mean HAM-D score, 23.1; p<0.001). Mean HAM-D scores were similar after the active (19.0) and sham phases for initial nonresponders (23.0). Among initial responders, the mean HAM-D score was 9.4 after active stimulation and 23 after sham stimulation. Trial limitations included the small number of patients in the randomized phase and potential bias from having an initial year of open-label treatment; patients who had already responded to DBS over a year of treatment were those likely to respond to active than sham stimulation in the double-blind randomized phase; and findings might not be generalizable to patients with treatment-resistant depression who are DBS-naive.
A number of case series, randomized controlled trials (RCTs) and systematic reviews evaluating deep brain stimulation (DBS) in patients with treatment-resistant depression have been published. The literature review may show that DBS may show promise for treatment-resistant depression, however, additional controlled trials are needed and should include larger and more representative samples, and focus on the identification of optimal neuroanatomical sites and stimulation parameters. The evidence is insufficient to determine that the technology results in a meaningful improvement in net health outcome.
Several systematic reviews and randomized controlled trials (RCTs) evaluating deep brain stimulation (DBS) for obsessive-compulsive disorder (OCD) have been published.
Deep brain stimulation (DBS) is increasingly being applied to psychiatric conditions such as obsessive-compulsive disorder (OCD), major depression and anorexia nervosa. Double-blind, randomized controlled trials (RCTs) of active versus sham treatment have been limited to small numbers. Kisely et. al. (2014) undertook a systematic review and meta-analysis of the effectiveness of DBS in psychiatric conditions to maximize study power. They assessed differences in final values between the active and sham treatments for parallel-group studies and compared changes from baseline score for cross-over designs. Inclusion criteria were met by five studies, all of which were of OCD. Forty-four subjects provided data for the meta-analysis. The main outcome was a reduction in obsessive symptoms as measured by the Yale-Brown Obsessive Compulsive Scale (YBOCS). Patients on active, as opposed to sham, treatment had a significantly lower mean score [mean difference (MD) -8.93, 95% confidence interval (CI) -13.35 to -5.76, p < 0.001], representing partial remission. However, one-third of patients experienced significant adverse effects (n = 16). There were no differences between the two groups in terms of other outcomes. The authors concluded DBS may show promise for treatment-resistant OCD but there are insufficient randomized controlled data for other psychiatric conditions. DBS remains an experimental treatment in adults for severe, medically refractory conditions until further data are available.
Hamani et al. (2014) conducted a systematic review of the literature and developed evidence-based guidelines on deep brain stimulation (DBS) for obsessive-compulsive disorder (OCD) that was sponsored by the American Society for Stereotactic and Functional Neurosurgery and the Congress of Neurological Surgeons (CNS) and endorsed by the CNS and American Association of Neurological Surgeons. Of 353 articles identified, 7 were retrieved for full-text review and analysis. The quality of the articles was assigned to each study and the strength of recommendation graded according to the guidelines development methodology of the American Association of Neurological Surgeons/Congress of Neurological Surgeons Joint Guidelines Committee. Of the 7 studies, 1 class I and 2 class II double-blind, randomized, controlled trials reported that bilateral DBS is more effective in improving OCD symptoms than sham treatment. The authors concluded that based on the data published in the literature, the following recommendations can be made: (1) There is Level I evidence, based on a single class I study, for the use of bilateral subthalamic nucleus DBS for the treatment of medically refractory OCD. (2) There is Level II evidence, based on a single class II study, for the use of bilateral nucleus accumbens DBS for the treatment of medically refractory OCD. (3) There is insufficient evidence to make a recommendation for the use of unilateral DBS for the treatment of medically refractory OCD. The authors noted that additional research is needed to determine which patients respond to deep brain stimulation and if specific targets may be more suitable to treat a specific set of symptoms.
A meta-analysis by Alonso et. al. (2015) included studies of any type (including case reports) evaluating deep brain stimulation (DBS) for obsessive compulsive disorder (OCD) and reporting changes in Yale-Brown Obsessive Compulsive Scale (Y-BOCS) score. Reviewers identified 31 studies (total N=116 patients). They did not report study type (i,e,, controlled vs uncontrolled); however, the meta-analysis only included patients who received active treatment. Twenty-four (77%) studies included 10 or fewer patients. Most studies (24, including 83 patients) involved DBS of striatal areas. Of the remaining studies, 5 (27 patients) addressed subthalamic nucleus (STN) stimulation and 2 (6 patients) addressed stimulation of the inferior thalamic peduncle. Twelve studies provided patient-level data and 4 provided pooled data on percentage of responders (i.e., >35% reduction in post-treatment Y-BOCS scores). Pooled analysis yielded a global percentage of responders of 60% (95% CI, 49% to 69%). The most frequent adverse events reported were worsening anxiety (25 patients) and hypomanic symptoms (23 patients). Reviewers reported on the benefits and risks of DBS stimulation but could not draw conclusions about stimulation to any particular region or about the safety or efficacy of DBS for OCD compared with sham stimulation or other therapy. In a systematic review, Naesstrom et al. (2016) reviewed the current studies on psychiatric indications for deep brain stimulation (DBS), with focus on obsessive-compulsive disorder (OCD) and major depressive disorder (MDD). A total of 52 studies met the inclusion criteria with a total of 286 unique patients treated with DBS for psychiatric indications; 18 studies described 112 patients treated with DBS for OCD in six different anatomical targets, while nine studies included 100 patients with DBS for MDD in five different targets. The authors concluded that DBS may show promise for treatment-resistant OCD and MDD but the results are limited by small sample size and insufficient randomized controlled data. According to the authors, other psychiatric indications are currently of a purely experimental nature.
In a systematic review, Vazquez-Bourgon et al. (2017) evaluated the current scientific evidence on the effectiveness and applicability of deep brain stimulation (DBS) for refractory obsessive-compulsive disorder (OCD). The critical analysis of the evidence shows that the use of DBS in treatment-resistant OCD is providing satisfactory results regarding efficacy, with assumable side-effects. However, there is insufficient evidence to support the use of any single brain target over another. The authors concluded that the use of DBS for OCD is still considered to be in the field of research, although it is increasingly used in refractory-OCD, producing in the majority of studies significant improvements in symptomatology, and in functionality and quality of life. According to the authors, it is important to implement random and controlled studies regarding its long-term efficacy, cost-risk analyses and cost/benefit.
The literature on deep brain stimulation (DBS) for obsessive-compulsive disorder (OCD) consists of randomized controlled trials (RCTs), a number of uncontrolled studies and systematic reviews. Based on review of the literature DBS may show promise for treatment-resistant OCD but the results are limited by small sample size and insufficient randomized controlled data. Additional randomized controlled studies are needed to determine which patients respond to deep brain stimulation (DBS) and if specific targets may be more suitable to treat a specific set of symptoms and to determine the long term efficacy. The evidence is insufficient to determine that the technology results in a meaningful improvement in net health outcome.
Several systematic reviews of the literature on DBS for Tourette syndrome have been published.
A systematic review by Piedad et. al. (2012) examined patient and target selection for use of deep brain stimulation (DBS) for subjects with Tourette syndrome. Most clinical trials evaluating DBS for Tourette syndrome have targeted the medial thalamus at the crosspoint of the centromedian nucleus, substantia periventricularis, and nucleus ventro-oralis internus. Other targets investigated have included the subthalamic nucleus (STN), caudate nucleus, globus pallidus internus (GPi), and the anterior limb of the internal capsule and nucleus accumbens. Reviewers found no clear consensus in the literature for which patients should be treated and what the best target is.
Most recent systematic reviews (i.e., those published in 2015-2017) qualitatively described the literature. Only Baldermann et. al. (2016) conducted pooled analyses of study data. That review identified 57 studies on deep brain stimulation (DBS) for Tourette syndrome, four of which were randomized crossover studies. The studies included a total of 156 cases. Twenty-four studies included a single patient and 4 had sample sizes of 10 or more (maximum, 18 patients). Half of the patients (n=78) received thalamus stimulation and the next most common areas of stimulation were the globus pallidus (GPi) anteromedial part (n=44) and post ventrolateral part (n=20). Two of the RCTs used thalamic stimulation, one used bilateral globus pallidus (GPi) stimulation, and one used both. The primary outcome was the Yale Global Tic Severity Scale (YGTSS). In a pooled analysis of within-subject pre-post data, there was a median improvement of 53% in YGTSS score, a decline from a median score of 83 to 35 at last follow-up. Moreover, 81% of patients showed at least a 25% reduction in YGTSS score and 54% showed improvements of 50% or more. In addition, data were pooled from the 4 crossover RCTs: 27 patients received DBS and 27 received a control intervention. Targets included the thalamus and the globus pallidus. In the pooled analysis, there was a statistically significant between-group difference, favoring DBS (SMD=0.96; 95% CI, 0.36 to 1.56). The authors concluded despite small patient numbers, we conclude that DBS for GTS is a valid option for medically intractable patients. Different brain targets resulted in comparable improvement rates, indicating a modulation of a common network. Future studies might focus on a better characterization of the clinical effects of distinct regions, rather than searching for a unique target.
The crossover randomized controlled trial (RCT) with the largest sample size was published by Kefalopoulou et. al. (2015). The double-blind trial included 15 patients with severe medically refractory Tourette syndrome; all received bilateral globus pallidus (GPi) surgery for deep brain stimulation (DBS) and were randomized to the off-stimulation phase first or the on-stimulation phase first for 3 months, followed by the opposite phase for the next 3 months. Of the 15 receiving surgery, 14 were randomized and 13 completed assessments after both on and off phases. For the 13 trial completers, mean Yale Global Tic Severity Scale (YGTSS) scores were 80.7 in the off-stimulation phase and 68.3 in the on-stimulation phase. The mean difference in YGTSS scores indicated an improvement of 12.4 points (95% CI, 0.1 to 24.7 points), which was statistically significant (p=0.048) after Bonferroni correction. There was no significant between-group difference in YGTSS scores for patients randomized to the on-stimulation phase first or second. Three serious adverse events were reported, 2 related to surgery and 1 related to stimulation. Reviewers noted that the most effective target of the brain for DBS in patients with Tourette syndrome needs additional study.
In a randomized, double-blind, controlled trial, Welter et al. (2017) assessed the efficacy of anterior internal globus pallidus (aGPi) DBS for severe Tourette's syndrome. The study included patients aged 18-60 years with severe and medically refractory Tourette's syndrome from eight hospitals specialized in movement disorders. Enrolled patients received surgery to implant bilateral electrodes for aGPi DBS; 3 months later they were randomly assigned (1:1 ratio with a block size of eight; computer-generated pairwise randomization according to order of enrolment) to receive either active or sham stimulation for the subsequent 3 months in a double-blind fashion. All patients then received open-label active stimulation for the subsequent 6 months. Patients and clinicians assessing outcomes were masked to treatment allocation; an unmasked clinician was responsible for stimulation parameter programming, with intensity set below the side-effect threshold. Nineteen patients were enrolled in the trial. The investigators randomly assigned 17 (89%) patients, with 16 completing blinded assessments (seven [44%] in the active stimulation group and nine [56%] in the sham stimulation group). There was no significant difference in YGTSS score change between the beginning and the end of the 3 month double-blind period between groups. During the following 6 month open-label period, stimulation decreased motor and vocal tic severity, with evidence of an improvement in occupational activities and life satisfaction. Fifteen serious adverse events were reported in 13 patients, of which eight events were related to the surgical procedure or hardware. According to the authors, future research is needed to investigate the efficacy of aGPi DBS for patients over longer periods with optimal stimulation parameters and to identify potential predictors of the therapeutic response.
Martinez-Ramirez et al. (2018) assessed the efficacy and safety of deep brain stimulation (DBS) in a multinational cohort of patients with Tourette syndrome using the International Deep Brain Stimulation Database and Registry. The registry included 185 patients with medically refractory Tourette syndrome who underwent DBS implantation from January 1, 2012, to December 31, 2016, at 31 institutions in 10 countries worldwide. These patients received DBS implantation in different regions of the brain depending on their symptoms. The mean (SD) total Yale Global Tic Severity Scale score improved from 75.01 (18.36) at baseline to 41.19 (20.00) at 1 year after DBS implantation. The mean (SD) motor tic subscore improved from 21.00 (3.72) at baseline to 12.91 (5.78) after 1 year, and the mean (SD) phonic tic subscore improved from 16.82 (6.56) at baseline to 9.63 (6.99) at 1 year. The overall adverse event rate was 35.4% (56 of 158 patients. The most common stimulation-induced adverse effects were dysarthria (10 [6.3%]) and paresthesia (13 [8.2%]). The authors concluded that deep brain stimulation was associated with symptomatic improvement in patients with Tourette syndrome but also with important adverse events. Long-term assessments will be necessary to monitor adverse effects and determine if DBS has lasting effects on symptoms.
A number of uncontrolled studies, randomized controlled trials (RCTs), and several systematic reviews have been published. Most studies, including the RCTs had small sample sizes and used a variety of DBS targets. A 2015 meta-analysis suggested that DBS might improve outcomes in patients with Tourette syndrome. However, the optimal target for DBS is not known and additional controlled studies in larger numbers of patients are needed. The evidence is insufficient to determine that the technology results in a meaningful improvement in net health outcome.
Drug addiction represents a significant public health concern that has high rates of relapse despite optimal medical therapy and rehabilitation support. New therapies are needed, and deep brain stimulation (DBS) is being studied for the treatment of drug addiction. In 2018, Wang et. al. reviewed deep brain stimulation for the treatment of drug addiction. The most common target for stimulation has been the nucleus accumbens, a key structure in the mesolimbic reward pathway. In addiction, the mesolimbic reward pathway undergoes a series of neuroplastic changes. Chief among them is a relative hypofunctioning of the prefrontal cortex, which is thought to lead to the diminished impulse control that is characteristic of drug addiction. The prefrontal cortex, as well as other targets involved in drug addiction such as the lateral habenula, hypothalamus, insula, and subthalamic nucleus have also been stimulated in animals, with encouraging results. The published studies for DBS for drug addiction is currently limited to several promising case series or case reports that are not controlled. Further studies are needed to determine what role DBS can play in the treatment of drug addiction. The evidence is insufficient to determine that the technology results in a meaningful improvement in net health outcome.
Deep brain stimulation (DBS) has also been investigated for other disorders including anorexia nervosa/eating disorders, Alzheimer disease/dementias, head or voice tremor, Huntington’s disease, traumatic brain injury (TBI), impulsive or violent behavior and chronic pain. The studies investigating DBS for the treatment of these other conditions are mainly trials with small sample sizes and short-term follow-up. Further well-designed studies are needed to demonstrate benefits of deep brain stimulation (DBS) for these disorders to include stimulation parameters and identify robust predictors of patient response. The evidence is insufficient to determine that the technology results in a meaningful improvement in net health outcome.
Deep brain stimulation (DBS) has also been investigated in patients with primary dystonia, defined as a neurologic movement disorder characterized by involuntary muscle contractions, which force certain parts of the body into abnormal, contorted, and painful movements or postures. Dystonia can be classified according to age of onset, bodily distribution of symptoms, and cause. Age of onset can occur during childhood or during adulthood. Dystonia can affect certain portions of the body (focal dystonia and multifocal dystonia) or the entire body (generalized dystonia). Torticollis is an example of a focal dystonia.
Deep brain stimulation (DBS) for the treatment of primary dystonia received Food and Drug Administration (FDA) approval through the humanitarian device exemption process in 2003. The humanitarian device exemption approval process is available for conditions that affect fewer than 4000 Americans per year. According to this approval process, the manufacturer is not required to provide definitive evidence of efficacy, but only probable benefit. The approval was based on the results of DBS in 201 patients represented in 34 manuscripts. Three studies reported at least 10 cases of primary dystonia. In these studies, clinical improvement with DBS ranged from 50% to 88%. A total of 21 pediatric patients were studied; 81% were older than age 7 years. Among these patients, there was a 60% improvement in clinical scores. As noted in the analysis of risk and probable benefit, the only other treatment options for chronic refractory primary dystonia are neurodestructive procedures. DBS provides a reversible alternative.
The relevant population(s) of interest are patients with primary or secondary dystonia. Primary dystonia is defined when dystonia is the only symptom unassociated with other pathology. Secondary dystonia is a dystonia brought on by an inciting event, such as a stroke, trauma or drugs. Tardive dystonia is a form of drug-induced secondary dystonia.
The therapy being considered is deep brain stimulation (DBS).
Treatment options for dystonia include oral or injectable medications (i.e. botulinum toxin) and destructive surgical or neurosurgical interventions (i.e. thalamotomies or pallidotomies) when conservative therapies fail.
As noted in the FDA humanitarian device exemption analysis of risk and probable benefit, the only other treatment options for chronic refractory primary dystonia are neurodestructive procedures. DBS provides a reversible alternative.
Key efficacy outcomes include clinical severity of dystonia and disability by combining the Burke-Fahn-Marsden Dystonia Rating Scale (BFMDRS) or Toronto Western Spasmodic Torticollis Rating Scale (TWSTRS) and quality of life (QOL)
The Burke-Fahn-Marsden Dystonia Rating Scale (BFMDRS) total score ranges from 0 to 150. It has 2 subscales: a movement sub-scale, based on clinical patient examination, that assesses dystonia severity and provoking factors in different body areas, with a maximum score of 120; and a disability sub-scale, that evaluates the patients’ report of disability in activities of daily living, for a maximum score of 30. Higher scores correspond to greater levels of morbidity. There is currently no established minimally important difference in the BFMDRS total score.
Toronto Western Spasmodic Torticollis Rating Scale (TWSTRS) is most commonly used to assess the status of people with cervical dystonia. The TWSTRS has a total score ranging from 0 to 85. It is a composite of 3 sub-scales: severity which ranges from 0 to 35; disability which ranges from 0 to 30; and pain which ranges from 0 to 20. Higher scores correspond to greater levels of morbidity.
Moro et. al. (2017) published a systematic review and meta-analysis and the aim of this review was to provide strong clinical evidence of the efficacy of deep brain stimulation for the globus pallidus internus (GPi) in primary dystonia (also known as isolated dystonia). Reviewers included studies with at least 10 cases. Fifty-eight articles corresponding to 54 unique studies were identified; most involved bilateral DBS of the GPi. There were only 2 controlled studies, 1 RCT (Volkmann et. al. described above) and 1 study that included a double-blind evaluation with and without stimulation. Twenty-four studies reported data using the Burke-Fahn-Marsden Dystonia Rating Scale (BFMDRS) and were included in a meta-analysis. These studies enrolled a total of 523 patients (mean per study, 22 patients) and had a mean follow-up of 32.3 months (range, 6-72 months). In a pooled analysis of BFMDRS motor scores (scale range, 0-120; higher scores indicate more severe dystonia) from 24 studies, the mean increase in scores at 6 months compared with baseline was 23.8 points (95% CI, 18.5 to 29.1 points). The mean increase in the motor score at last follow-up compared with baseline was 26.6 points (95% CI, 22.4 to 30.9 points). The mean percentage improvement was 59% at 6 months and 65% at last follow-up. Fourteen studies reported BFMDRS disability scores (scale range, 0-30). Compared with baseline, the mean absolute change in the score was 4.8 points (95% CI, 3.1 to 6.6 points) at 6 months and 6.4 points (95% CI, 5.0 to 7.8 points) at last follow-up. The mean percentage improvement was 44% at 6 months and 59% at last follow-up.
The randomized controlled trial (RCT), which was industry sponsored, patient- and observer-blinded evaluation of pallidal neurostimulation in subjects with refractory cervical dystonia, was published by Volkmann et. al. (2014). The trial included 62 adults with cervical dystonia for 3 or more years in duration, a severity score of 15 or more on the Toronto Western Spasmodic Torticollis Rating Scale (TWSTRS), and an unsatisfactory response to botulinum toxin injection and oral medication. Patients were randomized to DBS (n=32) or to sham stimulation (n=30). The primary outcome was change in the TWSTRS severity score at the end of the blinded study period (3 months); thereafter, all patients received open-label active stimulation. After 3 months, mean TWSTRS score improved by 5.1 points (95% CI, 3.5 to 7.0 points) in the neurostimulation group and by 1.3 points (95% CI, 0.4 to 2.2 points) in the sham group. The between-group difference was 3.8 points (95% CI, 1.8 to 5.8 points; p=0.024). Findings were mixed on the prespecified secondary outcomes. There was significantly greater improvement in the neurostimulation group than in the sham group on the TWSTRS disability score and the Bain Tremor Scale score, but not on the TWSTRS pain score or the Craniocervical Dystonia Questionnaireâ€’24 score. During the 3-month blinded study period, 22 adverse events were reported in 20 (63%) patients in the neurostimulation group and 13 adverse events were reported in 12 (40%) patients in the sham group. Of these 35 adverse events, 11 (31%) were serious. Additionally, 40 adverse events, 5 of which were serious, occurred during 9 months of the open-label extension period. During the study, 7 patients experienced dysarthria (i.e., slightly slurred speech), which was not reversible in 6 patients. The authors concluded pallidal neurostimulation for 3 months is more effective than sham stimulation at reducing symptoms of cervical dystonia. Extended follow-up is needed to ascertain the magnitude and stability of chronic neurostimulation effects before this treatment can be recommended as routine for patients who are not responding to conventional medical therapy.
A review prepared for the Food and Drug Administration (FDA) and a 2017 systematic review have evaluated evidence on deep brain stimulation (DBS) for primary dystonia. There are numerous small case series and a randomized controlled trial (RCT). The RCT found that severity scores improved more after active than after sham stimulation. A pooled analysis of 24 studies, mainly uncontrolled, found improvements in motor scores and disability scores after 6 months and at last follow-up (mean, 32 months).
Deep brain stimulation (DBS) for the treatment of primary dystonia received Food and Drug Administration (FDA) approval through the humanitarian device exemption process in 2003.
Deep brain stimulation (DBS) of the posterior hypothalamus for the treatment of chronic cluster headaches has been investigated, because functional studies have suggested cluster headaches have a central hypothalamic pathogenesis.
The relevant population of interest are patients with cluster headache. The International Headache Society’s International Classification of Headache Disorders classifies types of primary and secondary headaches. A summary of cluster headache based on the International Classification of Headache Disorders criteria is below:
Cluster headaches are primary headaches classified as trigeminalautomomiccephalgias that can be either episodic or chronic. The diagnostic criteria for cluster headaches states that these are attacks of severe, unilateral orbital, supraorbital, and/or temporal pain that lasts 15-180 minutes and occurs from once every other day to 8 times a day and further requires for the patient to have had at least 5 such attacks with at least 1 of the following signs or symptoms, ipsilateral to the headache: conjunctival injection and/or lacrimation; nasal congestion and/or rhinorrhea; eyelid edema; forehead and facial sweating; miosis and/or ptosis; or a sense of restlessness or agitation. The diagnostic criteria for episodic cluster headache requires at least two cluster periods lasting from seven days to one year if untreated, and separated by pain free remission periods of > 3 months. The diagnostic criteria for chronic cluster headache requires cluster headaches occurring for one year or more without remission, or with remission of less than three months. The age at onset for cluster headaches is generally 20-40 years and men are affected three times more often than are women.
The therapy being considered is deep brain stimulation (DBS).
The standard of care treatment to stop or prevent attacks of cluster headache or migraine is medical therapy. Guideline recommended treatments for acute cluster headache attaches include oxygen inhalation and triptans (e.g. sumatriptan and zolmitriptan). Oxygen is preferred first-line, if available, because there are no documented adverse effects for most adults. Triptans have been associated with primarily nonserious adverse events; some patients experience non-ischemic chest pain and distal paresthesia. Use of oxygen may be limited by practical considerations and the FDA approved labeling for subcutaneous sumatriptan limits use to two doses per day. Steroid injections may be used to prevent or reduce the frequency of cluster headaches. Verapamil is also frequently used for prophylaxis although the best evidence supporting its effectiveness is a placebo-controlled RCT including 30 patients.
Given the high placebo response rate in cluster headaches, trials with sham DBS are relevant.
The general outcomes of interest are headache intensity and frequency, the effect on function and quality of life (QOL) and adverse events.
The most common outcome measures for prevention of cluster headache are decrease in headache days per month compared with baseline and the proportion of responders to the treatment, defined as those patients who report more than a 50%, 75% or 100% decrease in headache days per month compared to pre-treatment.
Key safety outcomes include death, stroke, depression, cognition, infection and other device and procedure related events.
Fontaine et. al. (2010) published the results of a prospective crossover, double-blind, multicenter study assessing the efficacy and safety of unilateral hypothalamic deep brain stimulation (DBS) in 11 patients with refractory chronic cluster headache (CCH). The randomized phase compared active and sham stimulation during 1-month periods, and was followed by a 1-year open phase. The severity of CCH was assessed by the weekly attacks frequency (primary outcome), pain intensity, sumatriptan injections, emotional impact (HAD) and quality of life. Tolerance was assessed by active surveillance of behavior, homeostatic and hormonal functions. During the randomized phase, no significant change in primary and secondary outcome measures was observed between active and sham stimulation. At the end of the open phase, 6/11 responded to the chronic stimulation (weekly frequency of attacks decrease [50%]), including three pain-free patients. There were three serious adverse events, including subcutaneous infection, transient loss of consciousness and micturition syncopes. No significant change in hormonal functions or electrolytic balance was observed. Randomized phase findings of this study did not support the efficacy of DBS in refractory CCH, but open phase findings suggested long-term efficacy in more than 50% patients, confirming previous data, without high morbidity. Discrepancy between these findings justifies additional controlled studies.
Two case series were published on use of deep brain stimulation (DBS) for the ipsilateral posterior hypothalamus in patients with cluster headaches and atypical facial pain and DBS in craniofacial pain. Stimulation was reported to result in long-term pain relief (1-26 months of follow-up) without significant adverse events in 16 patients with chronic cluster headaches and in 1 patient with neuralgiform headache; treatment failed in the 3 patients who had atypical facial pain.
Case series and a crossover randomized controlled trial (RCT) have been published on the use of deep brain stimulation for cluster headaches. The RCT included 11 patients, there were no significant differences between groups receiving active and sham stimulation. Additional RCTs or controlled studies are needed. The evidence is insufficient to determine that the technology results in a meaningful improvement in net health outcome.
Cerebellar stimulation or pacing is a similar technique to deep brain stimulation (DBS), but works in the cerebellar portion of the brain. Cerebellar stimulation/pacing is electrical stimulation using surgically implanted electrodes on the surface of the cerebellum and has been proposed as one way to treat some neurological disorders. At this time, there is lilttle information available about this technology to make an assessment of the clinical usefulness. The evidence is insufficient to determine the effects of this technology on net health outcomes.
In 2011, the American Academy of Neurology (AAN) published an updated guideline on the treatment of essential tremor (ET). There were no changes from the conclusions and recommendations of the 2005 practice parameters regarding DBS for ET. The guidelines stated bilateral DBS of the thalamic nucleus may be used to treat medically refractory limb tremor in both upper limbs (level C possibly effective), but there were insufficient data regarding the risk/benefit ratio of bilateral versus unilateral DBS in the treatment of limb tremor. There was insufficient evidence to make recommendation regarding the use of thalamic for head or voice tremor (Level U, treatment is unproven). (This guideline was reaffirmed on April 30, 2014)
In 2013, the American Academy of Neurology (AAN) published an evidence based guideline on the treatment of tardive syndromes which indicated: The available evidence which consists of class IV studies comprising of case reports or small case series, is insufficient to support or refute pallidal deep brain stimulation (DBS) for tardive syndromes. (This guideline was reaffirmed on July 16, 2016)
In 2019, the American Academy of Neurology (AAN) published a practice guideline on the treatment of tics in people with Tourette syndrome and chronic tic disorders which includes the following recommendations regarding deep brain stimulation (DBS):
Patients with severe Tourette syndrome (TS), resistant to medical and behavioral therapy, may benefit from the application of deep brain stimulation (DBS). An important challenge and limitation in the evaluation of the evidence around DBS in TS is that, even in expert DBS centers, few operations per year are performed. Furthermore, there is limited information from randomized clinical trials for analysis and interpretation. There is no consensus on the optimal brain target for the treatment of tics, but the following regions have been stimulated in patients with TS: the centromedian thalamus, the globus pallidus internus (ventral and dorsal), the globus pallidus externus, the subthalamic nucleus, and the ventral straitum/ventral capsular nucleus accumbens region. DBS of the anteromedial globus pallidus is possibly more likely than sham stimulation to reduce tic severity. There is insufficient evidence to determine the efficacy of DBS of the thalamus or the centromedian-parafascicular complex region of the thalamus in reducing tic severity. Complications of treatment, including infection and removal of hardware, appear more common with TS than with other neurologic conditions.
Recommendations from the Movement Disorders Society suggest that, when DBS is used in TS, best practices used for other DBS applications are followed, including confirmation of diagnosis, use of multidisciplinary screening, and stabilization of psychiatric comorbidities including of active suicidality. Appropriate patient selection is one of the most important predictors of success of DBS treatment, making multidisciplinary evaluation essential. Because of the complexity of the patient population, centers performing DBS have been encouraged to screen candidates preoperatively and to follow them postoperatively. There has been concern about high risk of suicide and other negative psychiatric sequelae in patients with TS not screened and monitored for depression, anxiety and bipolar tendencies. The largest available randomized trials for DBS have revealed benefits on motor and phonic tics for the ventral globus pallidus internus and the centromedian thalamic region target; however, these studies have raised methodologic concerns that need to be addressed in future trials. There is little information on the effects of DBS on psychiatric comorbidities and the efficacy of DBS in children with TS.
In 2018, the Congress of Neurological Surgeons (AANS) published a systematic review and evidence based guideline on subthalamic nucleus and globus pallidus internus deep brain stimulation for the treatment of patients with Parkinson’s disease: executive summary that included the following recommendations:
In 2007, the American Psychiatric Association practice guideline for the treatment of patients with obsessive compulsive disorder states DBS may be recommended on the basis of individual circumstances.
In 2013, the American Psychiatric Association guideline watch practice parameter for the treatment of patients with obsessive-compulsive disorder states DBS and ablative neurosurgical treatment for OCD should be performed only at sites with expertise in both OCD and these treatment approaches.
In 2010, the American Psychiatric Association guideline on the treatment of major depressive disorder and the 2014 guideline watch, did not mention the use of deep brain stimulation (DBS) for the treatment of major depressive disorder.
The National Institute of Health and Care Excellence (NICE) has published Interventional Procedure Guidance documents on deep brain stimulation (DBS):
In 2017, NICE guideline (NG71) states the following:
In 2006, NICE interventional procedure guidance (IPG188), which states the following: “Current evidence on the safety and efficacy of deep brain stimulation for tremor and dystonia (excluding Parkinson’s disease) appears adequate to support the use of this procedure, provided that normal arrangements are in place for consent, audit and clinical governance."
In 2011 NICE interventional procedure guidance (IPG382) which states the following:
In 2011 an interventional procedures guidance (IPG381) from NICE indicated the evidence on the efficacy of DBS for intractable trigeminal autonomic cephalalgias (e.g. cluster headaches) was limited and inconsistent, and the evidence on safety shows that there are serious but well-known side effects. Therefore, this procedure should only be used with special arrangements for clinical governance, consent, and audit or research.
In 2012 an interventional procedures guidance (IPG416) from NICE indicated that the evidence on the efficacy of the DBS for refractory epilepsy was limited in both quantity and quality. The evidence on safety shows that there are serious but well-known adverse effects. Therefore, this procedure should only be used with special arrangements for clinical governance, consent and audit or research.
In 1997, the Activa® Tremor Control System, manufactured by Medtronic Corp, MN, was cleared for marketing by the FDA for deep brain stimulation. The Activa® Tremor Control System consists of an implantable neurostimulator, a deep brain stimulator lead, an extension that connects the lead to the power source, a console programmer, a software cartridge to set electrical parameters for stimulation, and a patient control magnet, which allows the patient to turn the neurostimulator on and off, or change between high and low settings. While the original 1997 FDA-labeled indications were limited to unilateral implantation of the device for the treatment of tremor, in January 2002, the FDA-labeled indications were expanded to include bilateral implantation as a treatment to decrease the symptoms of advanced Parkinson’s disease that are not controlled by medication.
In April 2003, the FDA labeled indications for the Activa® Tremor Control System, manufactured by Medtronic Corp, MN for deep brain stimulation were expanded to include “unilateral or bilateral stimulation of the internal globus pallidus or subthalamic nucleus to aid in the management of chronic, intractable (drug refractory) primary dystonia, including generalized and/or segmental dystonia, hemidystonia, and cervical dystonia (torticollis) in patients seven years of age or above.” This latter indication received FDA approval through the Humanitarian Device Exemption process.
In 2017 the FDA labeled indications for the Activa® Tremor Control System, manufactured by Medtronic Corp, MN for deep brain stimulation regarding Parkinson’s disease was modified to include “adjunctive therapy in reducing some of the symptoms in individuals with levodopa-responsive Parkinson’s disease of at least 4 years duration that are not adequately controlled with medication.”
In February 2009, the FDA approved deep brain stimulation with the Reclaim® device (Medtronic, Inc.) via the Humanitarian Device Exemption (HDE) process for the treatment of severe treatment resistant obsessive-compulsive disorder (OCD). This device is indicated for bilateral stimulation of the anterior limb of the internal capsule, AIC, as an adjunct to medication and as an alternative to anterior capsulotomy for the treatment of chronic, severe treatment resistant obsessive compulsive disorder (OCD) in adult patients who have failed at least three selective serotonin reuptake inhibitors (SSRIs).
In June 2015, the FDA approved the Brio Neurostimulation System (now called Infinity; St. Jude Medical Neuromodulation) as a PMA (premarket approval) device for the following indications: 1) bilateral stimulation of the subthalmic nucleus (STN) as an adjunctive therapy to reduce some of the symptoms of advanced levodopa-responsive Parkinson’s disease that are not adequately controlled by medications; 2) unilateral or bilateral stimulation of the ventral intermediate (VIM) of the thalamus for the suppression of disabling upper extremity tremor in adult essential tremor patients whose tremor is not adequately controlled by medications and where the tremor constitutes a significant functional disability. This is a rechargeable system.
In 2016, the St. Jude Medical’s Infinity DBS device with directional leads was approved by FDA. The directional leads enable the clinician to “steer” current to different parts of the brain. This tailored treatment reduces side effects. The Infinity system can be linked to Apple’s iPod Touch and iPad Mini.
In December 2017, a second system with directional leads, the Vercise Deep Brain Stimulation System (Boston Scientific), was approved by FDA. This system is to be used as an adjunctive therapy from reducing motor symptoms of moderate-to-advanced levodopa-responsive PD inadequately controlled with medication alone.
In 2018, the FDA approved the Medtronic DBS System for Epilepsy (Medtronic, Inc) through the Premarket Approval process. The pivotal study was the Stimulation of the Anterior Nucleus of the Thalamus for Epilepsy. The intended use is bilateral stimulation of the anterior nucleus of the thalamus as an adjunctive therapy for reducing the frequency of seizures in individuals 18 years of age or older diagnosed with epilepsy characterized by partial-onset seizures, with or without secondary generalization, that are refractory to three or more anti-epileptic medications.
Unilateral or bilateral deep brain stimulation (DBS) of the globus pallidus (GPi) or the subthalmic nucleus (STN) may be considered medically necessary in patients 7 years of age or older with chronic intractable (drug refractory) primary dystonia, including generalized and/or segmental dystonia, hemidystonia and cervical dystonia (torticollis).
Unilateral or bilateral deep brain stimulation (DBS) of the globus pallidus (GPi) or subthalmic nucleus (STN) may be considered medically necessary for an individual with Parkinson disease when ALL of the following are met:
Unilateral deep brain stimulation (DBS) of the thalamus may be considered medically necessary in patients with disabling medically unresponsive tremor due to essential tremor (ET) or Parkinson disease (PD).
Bilateral deep brain stimulation of the thalamus may be considered medically necessary in patients with disabling, medically unresponsive tremor in both upper limbs due to essential tremor (ET) or Parkinson disease (PD).
Note: Disabling, medically unresponsive tremor is defined as all of the following:
Replacement or revision of deep brain stimulator (DBS) generator and/or lead/electrode(s) and/or programmer may be considered medically necessary for an individual that meets the above criteria and the existing generator/lead/electrode(s)/programmer is no longer under warranty and cannot be repaired.
Deep brain Stimulation (DBS) is considered investigational for all other indications, including but not limited to the following because the safety and effectiveness of deep brain stimulation (DBS) cannot be established by review of the available published peer-reviewed literature. More large scale randomized controlled trials with larger number of patients are needed to explore different stimulation parameters, re-evaluate the indications for deep brain stimulation (DBS) and identify robust predictors of patient response. The evidence is insufficient to determine the effects of this technology on net health outcomes:
The use of cerebellar stimulation/pacing is considered investigational for all indications. Based on peer reviewed literature there is little information available about this technology. The evidence is insufficient to determine the safety and effectiveness of this technology on net health outcomes.
UPDRS is a universal scale of Parkinson disease (PD) symptoms and it was created to comprehensively assess and document the exam of the patient with PD and be able to compare it with patient’s future follow up visits, or to communicate about the progression of the PD symptoms in each patient with other neurologists.
The UPDRS is made up of the 1) Mentation, Behavior, and Mood, 2) ADL and 3) Motor sections. These are evaluated by interview. Some sections require multiple grades assigned to each extremity. A total of 199 points are possible. 199 represents the worst (total) disability), 0--no disability.
Uncontrolled shaking or trembling, usually of one or both hands or arms, that worsens when basic movements are attempted. It is caused by abnormalities in areas of the brain that control movement and is not tied to an underlying disease (e.g. Parkinson disease).
Highly variable neurological movement disorder characterized by involuntary muscle contractions. Dystonia results from abnormal functioning of the basal ganglia, a deep part of the brain which helps control coordination of movement. These regions of the brain control the speed and fluidity of movement and prevent unwanted movements. Patients with dystonia may experience uncontrollable twisting, repetitive movements, or abnormal postures and positions. These can affect any part of the body, including the arms, legs, trunk, face and vocal cords. Dystonia can affect young children to older adults of all races and ethnicities.
Dystonia is the only sign, and secondary causes have been ruled out. Most primary dystonias are variable, have adult onset, and are focal or segmental in nature. However, there are specific primary dystonias with childhood or adolescent onset that have been linked to genetic mutations.
Most common form of Parkinson disease, and the cause essentially remains unknown. Parkinson disease is a progressive disorder that is caused by a degeneration of nerve cells in the part of the brain called the substantia nigra, which controls movement. These nerve cells die or become impaired, losing the ability to produce an important chemical called dopamine.
This is a disorder with symptoms similar to Parkinson’s, but is caused by medication side effects, different neurodegenerative disorders, Illness, or brain damage.
To report provider services, use appropriate CPT* codes, Alpha Numeric (HCPCS level 2) codes, Revenue codes, and/or diagnosis codes.
July 2019 - Annual Review, Policy Revised
August 2018 - Annual Review, Policy Revised
August 2017 - Annual Review, Policy Revised
August 2016 - Annual Review, Policy Revised
September 2015 - Annual Review, Policy Revised
February 2015 - Policy Revised
October 2014 - Annual Review, Policy Revised
January 2014 - Annual Review, Revised and New Policy Created
January 2013 - Annual Review, Policy Renewed
January 2012 - Annual Review, Policy Renewed
February 2011 - Interim Review, Policy Revised
October 2010 - Annual Review, Policy Renewed
Wellmark medical policies address the complex issue of technology assessment of new and emerging treatments, devices, drugs, etc. They are developed to assist in administering plan benefits and constitute neither offers of coverage nor medical advice. Wellmark medical policies contain only a partial, general description of plan or program benefits and do not constitute a contract. Wellmark does not provide health care services and, therefore, cannot guarantee any results or outcomes. Participating providers are independent contractors in private practice and are neither employees nor agents of Wellmark or its affiliates. Treating providers are solely responsible for medical advice and treatment of members. Our medical policies may be updated and therefore are subject to change without notice.
*CPT® is a registered trademark of the American Medical Association.