Medical Policy: 07.01.59
Original Effective Date: November 2000
Reviewed: August 2018
Revised: August 2018
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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) involves the stereotactic placement of an electrode into a central nervous system nucleus (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’s 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).
Deep brain stimulation (DBS) involves the stereotactic placement of an electrode into the brain (i.e. hypothalamus, thalamus, globus pallidus, or subthalamic nucleus). The electrode is initially attached to a temporary transcutaneous cable for short-term stimulation to validate treatment effectiveness. Several days later, the patient returns for permanent subcutaneous surgical implantation of the cable that connects the pulse generator to the implanted electrode. The electrode is typically implanted unilaterally on the side corresponding to the most severe symptoms. However, use of bilateral stimulation using 2 electrode arrays has also been investigated in patients with bilateral, severe symptoms. After implantation, noninvasive programming of the neurostimulator can be adjusted to the patient's symptoms. This feature may be important for patients with Parkinson’s disease (PD), whose disease may progress over time, requiring different neurostimulation parameters. Setting the optimal neurostimulation parameters may involve the balance between optimal symptoms control and appearance of adverse effects of neurostimulation, such as dysarthria, disequilibrium, or involuntary movements.
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’s 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. 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.
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.
A TEC Assessment 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.
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.
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’s 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.
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.
A number of randomized controlled trials (RCTs) and systematic reviews of the literature have been published. A TEC Assessment concluded that studies evaluating deep brain stimulation (DBS) of the globus pallidus internus (GPi) and subthalamic nucleus (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. One RCT compared DBS plus medical therapy with medical therapy alone in patients with levodopa-responsive PD of at least 4 years in duration and uncontrolled motor symptoms. The trial found that QOL (quality of life) at 2 years (e.g., motor disability, motor complications) was significantly higher when DBS was added to medical therapy. Meta-analyses of RCTs comparing GPi and STN have had inconsistent findings and did not conclude that 1 type of stimulation was clearly superior to the other. A new technology in DBS systems, using directional leads, has recently emerged and data evaluating the new technology is expected to be published in 2018.
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, and obsessive-compulsive disorder, 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.
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.
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.
A systematic review identified several RCTs and many observational studies in which DBS was evaluated for the treatment of epilepsy. The largest RCT 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.
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.
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.
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%).
Evidence for the use of deep brain stimulation (DBS) to treat tardive syndromes consists of case series. One study of DBS in patients with tardive dyskinesia included a double-blind evaluation of DBS at 6 months. Symptoms decreased more with the device turned on but the study was small (10 patients were evaluated) and included only patients with DBS for 6 months. Two subsequent case series included 9 and 19 patients, respectively, and reported favorable results with DBS treatment. Additional studies evaluating more patients, especially randomized controlled trials (RCTs) or other controlled studies, are needed to provide greater certainty concerning the efficacy of DBS for this population.
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.
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 and several randomized controlled trials (RCTs) evaluating deep brain stimulation (DBS) in patients with treatment-resistant depression have been published. Two RCTs were terminated for futility (interim analysis demonstrating very low probability of success if the trial was completed as planned). Another RCT did not find a statistically significant difference between groups in the primary outcome (clinical response) and adverse psychiatric events occurred more frequently in the treatment group than in the control group. More recently, a controlled crossover trial randomized patients to active or to sham stimulation after a year of open-label stimulation. There was a greater reduction in symptom scores after active stimulation, but only in patients who were responders in the open-label phase; these findings might not be generalizable.
Several systematic reviews 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.
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.
The literature on deep brain stimulation (DBS) for obsessive compulsive disorder (OCD) consists of several randomized controlled trials (RCTs) and a number of uncontrolled studies. Most studies had small sample sizes. Only 1 of the 5 RCTs identified in a 2015 meta-analysis reported the outcome measure of greatest interest clinically significant change in Yal-Brown Obsessive Compulsive Scale (Y-BOCS) scores. Uncontrolled data have suggested improvements in OCD symptoms after DBS treatment, but have also identified a substantial number of adverse events. Additional blinded controlled studies are needed to draw conclusions about the impact of DBS on the net health benefit.
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.
A number of uncontrolled studies, 4 crossover randomized controlled trials (RCTs), and several systematic reviews have been published. Most studies, including the RCTs had small sample sizes (i.e., ≤15 patients) 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 on use of deep brain stimulation (DBS) for anorexia nervosa/eating disorders, Alzheimer disease/dementias, head or voice tremor, Huntington’s disease, traumatic brain injury (TBI), and chronic pain consists of small case series. These case series provide inadequate evidence on which to assess efficacy.
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. Primary dystonia is defined with dystonia is the only symptom unassociated with other pathology. 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.
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 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.
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.
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) has been investigated in patients with chronic cluster headaches. Cluster headaches occur as episodic attacks of severe pain lasting from 30 minutes to several hours. The pain is usually unilateral and localized to the eye, temple, forehead, and side of the face. Autonomic symptoms that occur with cluster headaches include ipsilateral facial sweating, flushing, tearing, and rhinorrhea. Cluster headaches occur primarily in men and have been classified as vascular headaches associated with, among other things, high blood pressure, smoking and alcohol use. However, the exact pathogenesis of cluster headaches is uncertain. Positron emission tomography scanning and magnetic resonance imaging have shown the hypothalamic region may be important in the pathogenesis of cluster headaches. Alterations in hormonal or serotonergic function may also play a role. Treatment of cluster headaches includes pharmacologic interventions for acute episodes and prophylaxis, sphenopalatine ganglion blockade, and surgical procedures such as percutaneous sphenopalatine ganglion radiofrequency rhizotomy, and gamma knife radiosurgery of the trigeminal nerve.
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.
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.
Several case series and a crossover randomized controlled trial (RCT) hve 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.
For individuals who have essential tremor or tremor in Parkinson’s disease (PD) who receive deep brain stimulation (DBS) of the thalamus, the evidence includes systematic review and case series. The systematic review (BCBSA TEC Assessment) concluded that there was sufficient evidence that DBS of the thalamus resulted 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 net health outcome.
For individuals who have symptoms (e.g. speech, motor fluctuations) associated with Parkinson’s 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 subthalmic nucleus (STN), the evidence includes randomized clinical trials (RCTs) and systematic reviews. One of the systematic reviews (BCBSA TEC Assessment) concluded that studies of 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. An RCT in patients with levodopa-responsive Parkinson’s disease (PD) of at least 4 years in duration and uncontrolled motor symptoms found that quality of life (QOL) at 2 years was significantly higher when DBS was provided in addition to medical therapy. Meta-analyses of RCTs comparing GPi and STN have had 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 a meaningful improvement in net health outcome.
For individuals who have primary dystonia who receive deep brain stimulation (DBS) of the globus pallidus (GPi) or subthalamic nucleus (STN), the evidence includes systematic reviews, a RCT (randomized controlled trial) and case series. 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). A double-blind RCT found that severity scores improved more after active than sham stimulation. The evidence is sufficient to determine that the technology results in a meaningful improvement in net health outcomes for children and adults with disabling primary dystonia who do not respond to pharmacologic therapy or chemodenervation with botulinum toxin or other conservative therapies.
For individuals who have epilepsy who receive deep brain stimulation (DBS), the evidence includes 2 systematic reviews of randomized controlled trials (RCTs) and many observational studies. Two RCTs were identified. The larger study reported that DBS had a positive impact during some parts of the blinded trial phase but not others, and a substantial number of adverse events (in >30% of patients). The smaller RCT (N=16) showed a benefit with DBS. Many small observational studies reported fewer seizures compared with baseline, however, without control groups, interpretation of these results is limited. Additional trials are required to determine the impact of DBS on patient outcomes in the treatment of epilepsy. Also, due to adverse events the risk benefit-ratio is uncertain. The evidence is insufficient to determine the effects of the technology on net health outcomes.
For individuals who have multiple sclerosis (MS) who receive deep brain stimulation (DBS), the evidence includes an RCT (randomized controlled trial). One RCT with 10 MS patients is insufficient evidence on which to draw conclusions about the efficacy of DBS in this population. Additional trials are required. The evidence is insufficient to determine the effects of the technology on net health outcomes.
For individuals who have tardive dyskinesia or tardive dystonia who receive deep brain stimulation (DBS), the evidence includes case series, one of which included a double-blind comparison of outcomes when the DBS device was turned on versus off. Few studies were identified and they had small sample sizes (range, 9-19 patients). Additional studies, especially randomized controlled trials (RCTs) or other controlled studies, are needed. The evidence is insufficient to determine the effects of the technology on net health outcomes.
For individuals who have treatment-resistant depression who receive deep brain stimulation (DBS), the evidence includes randomized controlled trials (RCTs) and systematic reviews. The only double-blind, parallel-group RCT in patients with depression did not find that DBS significantly increased the response rate compared with sham; 2 other RCTs were stopped due to futility (interim analysis demonstrating very low probability of success if the trial was completed as planned). A crossover controlled trial randomized patients to active or to sham stimulation after a year of open-label stimulation. There was a greater reduction in symptom scores after active stimulation, but only in patients who were responders in the open-label phase; these findings might not be generalizable. The evidence is insufficient to determine the effects of the technology on net health outcomes.
For individuals who have obsessive-compulsive disorder (OCD) who receive deep brain stimulation (DBS), the evidence includes randomized controlled trials (RCTs) and systematic reviews. Among the RCTs on DBS for OCD, only one has reported the outcome of greatest clinical interest (therapeutic response rate), and that trial did not find a statistically significant benefit for DBS compared with sham treatment. The evidence is insufficient to determine the effects of the technology on net health outcomes.
For individuals who have Tourette syndrome who receive deep brain stimulation (DBS), the evidence includes crossover randomized controlled trials (RCTs) and systematic reviews. Several small (≤15 patients) crossover trials and a 2015 meta-analysis have suggested that DBS may improve outcomes in patients with Tourette syndrome. However, the optimal target of the brain for DBS is unknown, so additional controlled studies in larger numbers of patients are needed. The evidence is insufficient to determine the effects of the technology on net health outcomes.
For individuals who have anorexia nervosa/eating disorders, Alzheimer disease/dementia, Huntington disease, head or voice tremor, traumatic brain injury (TBI) and chronic pain, the available published peer reviewed medical literature includes case series. These case series provide inadequate evidence on which to assess efficacy. Additional controlled trials with larger number of subjects are needed to evaluate the role of deep brain stimulation (DBS) for these proposed conditions. The evidence is insufficient to determine the effects of the technology on net health outcomes.
For individuals who have primary dystonia who receive deep brain stimulation (DBS) of the globus pallidus internus (GPi) or subthalamic nucleus (STN), the evidence includes systematic reviews, an RCT (randomized controlled trial) and case series. 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). A double-blind RCT found that severity scores improved more after active than after sham stimulation. The evidence is sufficient to determine that the technology results in a meaningful improvement in net health outcomes for children and adults with disabling primary dystonia who do not respond to pharmacologic therapy or chemodenervation with botulinum toxin or other conservative therapies
For individuals who have cluster headaches who receive deep brain stimulation (DBS), the evidence includes a randomized crossover study and case series. In the randomized study, the between-group difference in response rates did not differ significantly between active and sham stimulation phases. Additional randomized controlled trials (RCTs) or other controlled studies are needed. The evidence is insufficient to determine the effects of the technology on net health outcomes.
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 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.
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's 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's 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's 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. Additional randomized controlled trials with larger number of patients are required to evaluate the role and impact of DBS on patient outcomes. 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’s 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’s 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’s disease, and the cause essentially remains unknown. Parkinson’s 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.
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.
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