CAM 70163

Deep Brain Stimulation

Category:Surgery   Last Reviewed:June 2020
Department(s):Medical Affairs   Next Review:June 2021
Original Date:January 1998    

Description:
Deep brain stimulation (DBS) involves the stereotactic placement of an electrode into a central nervous system nucleus (eg, hypothalamus, thalamus, globus pallidus, subthalamic nucleus). DBS is used as an alternative to permanent neuroablative procedures for control of essential tremor and Parkinson disease. DBS is also being evaluated for the treatment of a variety of other neurologic and psychiatric disorders.

For individuals who have essential tremor or tremor in Parkinson disease who receive DBS of the thalamus, the evidence includes a systematic review and case series. Therelevant outcomes are symptoms, functional outcomes, quality of life (QOL), and treatment-related morbidity. The systematic review (a TEC Assessment) concluded that there was sufficient evidence that 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 five to six years after DBS. The evidence is sufficient to determine that the technology results in a meaningful improvement in the net health outcome.

For individuals who have symptoms (eg, speech, motor fluctuations) associated with Parkinson disease (advanced or >4 years in duration with early motor symptoms) who receive DBS of the globus pallidus interna (GPi) or subthalamic nucleus (STN), the evidence includes randomized controlled trials (RCTs) and systematic reviews. Therelevant outcomes are symptoms, functional outcomes, QOL, and treatment-related morbidity. 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 (eg, 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 disease of at least four years in duration and uncontrolled motor symptoms found that QOL at two years was significantly higher when DBS was provided in addition to medical 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 a meaningful improvement in the net health outcome.

For individuals who have primary dystonia who receive DBS of the GPi or STN, the evidence includes systematic reviews, RCTs, and case series. Therelevant outcomes are symptoms, functional outcomes, QOL, and treatment-related morbidity. 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). Both double-blind RCTs 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 the net health outcome.

For individuals who have tardive dyskinesia or tardive dystonia who receive DBS, the evidence includes an RCT and case series. Therelevant outcomes are symptoms, functional outcomes, QOL, and treatment-related morbidity. Few studies were identified and they had small sample sizes (range, 9-19 patients). The RCT did not report statistically significant improvement in the dystonia severity outcomes or the secondary outcomes related to disability and QOL but may have been under-powered Additional studies, especially RCTs or other controlled studies, are needed. The evidence is insufficient to determine the effects of the technology on health outcomes.

For individuals who have epilepsy who receive DBS, the evidence includessystematic reviews, RCTs and many observational studies. Therelevant outcomes are symptoms, functional outcomes, QOL, and treatment-related morbidity. Two RCTs with more than 15 patientswere identified. The larger RCT evaluated anterior thalamic nucleus DBS and reported that DBS had a positive impact on seizure frequency during some parts of the blinded trial phase but not others, and a substantial number of adverse events (in >30% of patients). There were no differences between groups in 50% responder rates, Liverpool Seizure Severity Scale , or Quality of Life in Epilepsy scores. Aseven year open-label follow-up of the RCT included 66% of implanted patients; reasons for missing data were primarily related to adverse events or dissatisfaction with the device. Reduction in seizure frequency continued to improve during follow-up among the patients who continued follow-up.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. The evidence is insufficient to determine the effects of the technology on health outcomes. 

For individuals who have Tourette syndrome who receive DBS, the evidence includesobservational studies, RCTs and systematic reviews. Therelevant outcomes are symptoms, functional outcomes, QOL, and treatment-related morbidity..Two RCTs with 15 or more patients have been reported. One RCT found differences in severity of Tourettesyndrome for active vs sham at three months while the other RCT did not. Neither study demonstrated improvements in comorbid symptoms of obsessive-compulsive disorder or depression Both studies reported high rates of serious adverse eventsThe evidence is insufficient to determine the effects of the technology on health outcomes.

For individuals who have cluster headaches or facial pain who receive DBS, the evidence includes a randomized crossover study and case series. Therelevant outcomes are symptoms, functional outcomes, QOL, and treatment-related morbidity. In the randomized study, the between-group difference in response rates did not differ significantly between active and sham stimulation phases. Additional RCTs or controlled studies are needed. The evidence is insufficient to determine the effects of the technology on health outcomes.

For individuals who have treatment-resistant depression who receive DBS, the evidence includes RCTs and systematic reviews. Therelevant outcomes are symptoms, functional outcomes, QOL, and treatment-related morbidity. The only double-blind, parallel-group RCT in patients with depression did not find that DBS significantly increased the response rate compared with sham; two other RCTs were stopped due to futility. 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 health outcomes.

For individuals who have obsessive-compulsive disorder who receive DBS, the evidence includes RCTs and systematic reviews. Therelevant outcomes are symptoms, functional outcomes, QOL, and treatment-related morbidity. Among the RCTs on DBS for obsessive-compulsive disorder, 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 health.

For individuals who have multiple sclerosis who receive DBS, the evidence includes an RCT. Therelevant outcomes are symptoms, functional outcomes, QOL, and treatment-related morbidity. One RCT with ten multiple sclerosis 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 health outcomes.

For individuals who have anorexia nervosa, alcohol addiction, Alzheimer disease, Huntington disease, or chronic pain who receive DBS, the evidence includes case series. Therelevant outcomes are symptoms, functional outcomes, QOL, and treatment-related morbidity. RCTs are needed to evaluate the efficacy of DBS for these conditions. The evidence is insufficient to determine the effects of the technology on health outcomes. 

Background 
Deep Brain Stimulation
Deep brain stimulation involves the stereotactic placement of an electrode into the brain (ie, 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 and a radiofrequency-coupled or battery-powered programmable stimulator. The electrode is typically implanted unilaterally on the side corresponding to the most severe symptoms. However, use of bilateral stimulation using two 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 disease, whose disease may progress over time, requiring different neurostimulation parameters. Setting the optimal neurostimulation parameters may involve the balance between optimal symptom control and appearance of adverse effects of neurostimulation, such as dysarthria, disequilibrium, or involuntary movements.

Regulatory Status
In 1997, the Activa® Tremor Control System (Medtronic) was cleared for marketing by the U.S. Food and Drug Administration (FDA) for DBS. 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.

The original FDA-labeled indications for Activa® were limited to unilateral implantation of the device for the treatment of tremor, but, in 2002, FDA-labeled indications were expanded to include bilateral implantation as a treatment to decrease the symptoms of advanced PD not controlled by medication. In 2003, the labeled indications were further 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 was cleared for marketing by FDA through the humanitarian device exemption process. In 2017, the indications for PD were 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 2009, the Reclaim® device (Medtronic), a DBS device, was cleared for marketing by FDA through the humanitarian device exemption process for the treatment of severe obsessive-compulsive disorder.

In 2014, the Brio Neurostimulation System (now called Infinity; St. Jude Medical Neuromodulation) was cleared for marketing by FDA for the treatment of Parkinsonian tremor.

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.

FDA product code: MHY.

Policy:
Unilateral deep brain stimulation of the thalamus may be considered MEDICALLY NECESSARYin patients with disabling, medically unresponsive tremor due to essential tremor or Parkinson disease. 

Bilateral deep brain stimulation of the thalamus may be considered MEDICALLY NECESSARYin patients with disabling, medically unresponsive tremor in both upper limbs due to essential tremor or Parkinson disease.

Unilateral or bilateral deep brain stimulation of the globus pallidus or subthalamic nucleus may be considered MEDICALLY NECESSARYin the following patients: 

  • Those with Parkinson disease and ALL of the following: 
    • good response to levodopa; AND 
    • motor complications not controlled by pharmacologic therapy; AND 
    • one of the following: 
      • a minimum score of 30 points on the motor portion of the Unified Parkinson Disease Rating Scale when the patient has been without medication for approximately 12 hours OR
      • Parkinson disease for at least 4 years 
  • Patients older than 7 years with chronic, intractable (drug-refractory) primary dystonia, including generalized and/or segmental dystonia, hemidystonia, and cervical dystonia (torticollis). 

Deep brain stimulation for other movement disorders, including but not limited to tardive dyskinesia, multiple sclerosis, and post-traumatic dyskinesia, is investigational and/or unproven and therefore considered NOT MEDICALLY NECESSARY

Deep brain stimulation for the treatment of chronic cluster headaches is considered investigational and/or unproven and therefore considered NOT MEDICALLY NECESSARY .

Deep brain stimulation for the treatment of other psychiatric or neurologic disorders, including but notlimited to epilepsy, Tourette syndrome, depression, obsessive-compulsive disorder, anorexia nervosa, alcohol addiction, Alzheimer disease, and chronic pain, is investigational and/or unproven and therefore considered NOT MEDICALLY NECESSARY .

Policy Guidelines:
Disabling, medically unresponsive tremor is defined as all of the following:

  • tremor causing significant limitation in daily activities
  • inadequate control by maximal dosage of medication for at least 3 months before implant

Contraindications to deep brain stimulation include:

  • patients who are not good surgical risks because of unstable medical problems or because of the presence of a cardiac pacemaker
  • patients who have medical conditions that require repeated magnetic resonance imaging (MRI)
  • patients who have dementia that may interfere with the ability to cooperate
  • patients who have had botulinum toxin injections within the last 6 months

The  CPT coding for deep brain stimulation consists of a series of CPT codes describing the various steps of the procedure; i.e., implantation of the electrodes, implantation of the pulse generator, intraoperative monitoring and programming of the electrodes, and postoperative neuroprogramming.

Implantation of Electrodes
61850: Twist drill or burr hole(s) for implantation of neurostimulator electrodes, cortical

* 61863: Twist drill, burr hole, craniotomy, or craniectomy with stereotactic implantation of neurostimulator electrode array in subcortical site (eg, thalamus, globus pallidus, subthalamic nucleus, periventricular, periaqueductal gray), without use of intraoperative microelectrode recording; first array
* 61864: As above, but with each additional array
* 61867: Twist drill, burr hole, craniotomy, or craniectomy with stereotactic implantation of neurostimulator electrode array in subcortical site (eg, thalamus, globus pallidus, subthalamic nucleus, periventricular, periaqueductal gray), with use of intraoperative microelectrode recording; first array
* 61868: As above, but with each additional array.

* The above 4 codes were introduced in 2004. These codes recognize the option of the implantation of electrodes using microelectrode recording or not. In addition, if the patient is undergoing bilateral implantation of electrodes, one of the “each additional array” codes may be used. In some instances, patients undergo bilateral implantation in a staged procedure.

Implantation of Pulse Generator
61885: Insertion or replacement of cranial neurostimulator pulse generator or receiver, direct or inductive coupling; with connection to a single electrode array; OR
61886: As above, but with connection to 2 or more electrode arrays

Electronic Analysis
95970: Electronic analysis of implanted neurostimulator pulse generator system (eg, rate, pulse amplitude, pulse duration, configuration of wave form, battery status, electrode selectability, output modulation, cycling, impedance and patient compliance measurements); simple or complex brain, spinal cord, or peripheral (ie, cranial nerve, peripheral nerve, sacral nerve, neuromuscular) neurostimulator pulse generator/transmitter, without reprogramming
95978: Electronic analysis of implanted neurostimulator pulse generator system (eg, rate, pulse amplitude and duration, battery status, electrode selectability and polarity, impedance, and patient compliance measurements), complex deep brain neurostimulator pulse generator/transmitter, with initial or subsequent programming; first hour
95979: each additional 30 minutes after first hour

Neurostimulator analysis and programming is classified as either simple or complex. CPT codes 95978 and 95979 are time based. Simple neurostimulators are defined as those affecting 3 or fewer neurostimulatory parameters (eg, pulse amplitude, duration, frequency, number of electrode contacts) while a complex device affects more than 3 parameters. In the setting of deep brain stimulation for tremor control, it is anticipated that the neuroprogramming and analysis would be classified as simple. However, deep brain stimulation of the globus pallidus and subthalamic nucleus stimulation requires intraoperative monitoring of more than 1 clinical feature, (ie, rigidity, dyskinesia, and tremor) and the neuroprogramming would probably be classified as complex.

Over time, patients may undergo several sessions of electronic analysis and programming to find the optimal programming parameters. CPT codes 95970, 95978, and 95979, described here, may be used. 

Benefit Application
BlueCard/National Account Issues
State or federal mandates (e.g., FEP) may dictate that all FDA-approved devices, drugs, or biologics may not be considered investigational, and thus these devices may be assessed only on the basis of their medical necessity.

Rationale
This evidence review was created in January 1998 and has been updated regularly with searches of the PubMed database. The most recent literature update was performed through March 13, 2020. 

Evidence reviews assess the clinical evidence to determine whether the use of technology improves the net health outcome. Broadly defined, health outcomes are the length of life, quality of life, and ability to function, including benefits and harms. Every clinical condition has specific outcomes that are important to patients and managing the course of that condition. Validated outcome measures are necessary to ascertain whether a condition improves or worsens; and whether the magnitude of that change is clinically significant. The net health outcome is a balance of benefits and harms. 

To assess whether the evidence is sufficient to draw conclusions about the net health outcome of technology, two domains are examined: the relevance, and quality and credibility. To be relevant, studies must represent one or more intended clinical uses of the technology in the intended population and compare an effective and appropriate alternative at a comparable intensity. For some conditions, the alternative will be supportive care or surveillance. The quality and credibility of the evidence depend on study design and conduct, minimizing bias and confounding that can generate incorrect findings. The randomized controlled trial (RCT) is preferred to assess efficacy; however, in some circumstances, nonrandomized studies may be adequate. RCTs are rarely large enough or long enough to capture less common adverse events and long-term effects. Other types of studies can be used for these purposes and to assess generalizability to broader clinical populations and settings of clinical practice. 

Essential Tremor and Tremor in Parkinson Disease 
Clinical Context and Therapy Purpose 
Deep brain stimulation has been investigated as an alternative to permanent neuroablative procedures, such as thalamotomy and pallidotomy. Deep brain stimulation has been most thoroughly investigated as an alternative to thalamotomy for unilateral control of essential tumor and tremor associated with Parkinson disease. More recently, there has been research interest in the use of deep brain stimulation of the globus pallidus or subthalamic nucleus as a treatment of other Parkinsonian symptoms, such as rigidity, bradykinesia, and akinesia. Another common morbidity associated with Parkinson disease is the occurrence of motor fluctuations, referred to as “on and off” phenomena, related to the maximum effectiveness of drugs (ie, “on” state) and the nadir response during drug troughs (ie, “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 Parkinson disease may involve a balance between optimal effects on Parkinson disease symptoms and the appearance of drug-induced dyskinesias. The effect of deep brain stimulation on both Parkinson disease symptoms and drug-induced dyskinesias has also been studied. 

The question addressed in this evidence review is: Does deep brain stimulation improve the net health outcome in patients with essential tumor or Parkinson disease? 

The following PICO was used to select literature to inform this review. 

Patients 
The relevant populations of interest are patients with essential tumor or symptoms associated with Parkinson disease. 

Interventionsp
The therapy being considered is deep brain stimulation, unilateral or bilateral stimulation of the thalamus as well stimulation of the internal segment of the globus pallidus interna and subthalamic nucleus.. 

Comparators 
Parkinson disease 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. 

Outcomes 
Key efficacy outcomes include motor scores, mobility, disability, activities of daily living and quality of life.. Key safety outcomes include death, stroke, depression, cognition infection and other device and procedure related events. 

Review of Evidence 
Unilateral Stimulation of the Thalamus 
This section was informed by a TEC Assessment (1997) that focused on unilateral deep brain stimulation of the thalamus as a treatment of tremor.1, The Assessment concluded: 

Tremor suppression was total or clinically significant in 82% to 91% of operated sides in 179 patients who underwent implantation of thalamic stimulation devices. Results were durable for up to eight years, and adverse events of stimulation were reported as mild and largely reversible.

These results were at least as good as those associated with thalamotomy. An additional benefit of deep brain stimulation is that recurrence of tremor may be managed by changes in stimulation parameters. 

Studies identified in subsequent literature searches have supported the conclusions of the TEC Assessment. For example, Schuurman et al (2008) reported on 5-year follow-up of 68 patients comparing thalamic stimulation with thalamotomy for treatment of tremor due to Parkinson disease (45 patients), essential tumor (13 patients), and multiple sclerosis (MS; 10 patients).2, Forty-eight (71%) patients were assessed at 5 years: 32 with Parkinson disease, 10 with essential tumor, and 6 with multiple sclerosis (MS). The Frenchay Activities Index, the primary study outcome measure, was used to assess change in functional status; secondary measures included tremor severity, complication frequency, and patient-assessed outcomes. The mean difference (MD) between interventions, as measured on the Frenchay Activities Index, favored thalamic stimulation at all time points: 4.4 (95% confidence interval [CI], 1.1 to 7.7) at 6 months, 3.3 (95% CI, -0.03 to 6.6) at 2 years, and 4.0 (95% CI, 0.3 to 7.7) at 5 years. The procedures had similar efficacy for suppressing tremors. The effect of thalamic stimulation diminished in half of the patients with essential tumor and multiple sclerosis (MS). Neurologic adverse effects were higher after thalamotomy. Subjective assessments favored stimulation. 

Hariz et al (2008) evaluated outcomes of thalamic deep brain stimulation in patients with tremor-predominant Parkinson disease who participated in a multicenter European study; the authors reported that, at 6 years postsurgery, tremor was still effectively controlled and appendicular rigidity and akinesia remained stable compared with baseline.3, 

Bilateral Stimulation of the Thalamus 
Putzke et al (2005) reported on a series of 25 patients with essential tumor treated with bilateral deep brain stimulation for management of midline tremor (head, voice, tongue, trunk).4, Three patients died of unrelated causes, 1 patient was lost to follow-up due to transfer of care, and 1 patient did not have baseline evaluation; these patients were not included in the analysis. Patients were evaluated at baseline (before implantation of second stimulator), and at 1, 3, 6, 12, 24, and 36 months. At 12 months, evaluations were obtained from 76% of patients; at 36 months, 50% of patients were evaluated. The most consistent improvement on the Tremor Rating Scale during both unilateral and bilateral stimulation was found for head and voice tremor. The incremental improvement over unilateral stimulation through the first 12 months of bilateral stimulation was significant (p<0.01). For bilateral stimulation at months 3 and 12, outcome measures were significantly better than unilateral stimulation at month 3 (p<0.05). Small sample size limited analysis at months 24 and 36. Dysarthria was reported in 6 (27%) patients and disequilibrium in 5 (22%) patients after bilateral stimulation in staged implantations. No patient reported dysarthria and two reported disequilibrium before bilateral stimulation. 

Pahwa et al (2006) reported on long-term follow-up of 45 patients who underwent thalamic deep brain stimulation, 26 of whom had essential tumor; of these patients, 18 had unilateral and 8 had bilateral implantation.5, Sixteen patients with unilateral and 7 with bilateral stimulators completed at least part of the 5 year follow-up evaluations. Patients with bilateral stimulation had a 78% improvement in mean motor tremor scores in the stimulation on state compared with baseline at 5 year follow-up (p=0.02) and 36% improvement in activities of daily living (ADL) scores. Patients with unilateral stimulation improved by 46% on motor tremor scores and 51% on activities of daily living (ADL) scores (p<0.01). Stimulation-related adverse events were reported in more than 10% of patients with unilateral and bilateral thalamic stimulators. Most were mild and were reduced with changes in stimulation parameters. Adverse events in patients with bilateral stimulation (eg, dysarthria and other speech difficulties, disequilibrium or balance difficulties, abnormal gait) persisted, despite optimization of the stimulation parameters. 

Directional Deep Brain Stimulation 
Two new deep brain stimulation systems with directional leads are currently available (approved by the U.S. Food and Drug Administration [FDA] in 2016 and 2017). 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 13.6,7,8,9, The studies showed that patients experienced improved tremor scores and improved quality of life. Compared with historical data from conventional Deep brain stimulation systems, directional deep brain stimulation 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. 

Section Summary: Essential Tremor and Tremor in Parkinson disease 
A TEC Assessment concluded there was sufficient evidence that deep brain stimulation of the thalamus results in clinically significant tremor suppression and that outcomes after deep brain stimulation 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 deep brain stimulation. A new technology in deep brain stimulation systems, using directional leads, has more recently emerged.

Symptoms Associated with Parkinson disease
Advanced Parkinson disease 
Stimulation of the Internal Segment of the Globus Pallidus Interna and Subthalamic Nucleus 
This section was informed by a TEC Assessment (2001) that focused on the use of deep brain stimulation of the internal segment of the globus pallidus interna and subthalamic nucleus for a broader range of Parkinson disease symptoms.10, The Assessment concluded: 

A wide variety of studies have consistently demonstrated that deep brain stimulation of the globus pallidus interna or subthalamic nucleus results in significant improvements, as measured by standardized rating scales of neurologic function. The most frequently observed improvements consist of increased waking hours spent in a state of mobility without dyskinesia, improved motor function during “off” periods when levodopa is not effective, reduction in frequency and severity of levodopa-induced dyskinesia during periods when levodopa is working (“on” periods), improvement in cardinal symptoms of Parkinson disease during periods when medication is not working, and in the case of bilateral deep brain stimulation of the subthalamic nucleus, reduction in the required daily dosage of levodopa and/or its equivalents. The magnitude of these changes were both statistically significant and clinically meaningful.

The beneficial treatment effect lasted at least for the 6 to 12 months observed in most trials. While there was not a great deal of long-term follow-up, the available data were generally positive.

Adverse effects and morbidity were similar to those known to occur with thalamic stimulation.

Deep brain stimulation possesses advantages to other treatment options. Compared with pallidotomy, Deep brain stimulation can be performed bilaterally. The procedure is nonablative and reversible. 

A systematic review of RCTs by Perestelo-Perez et al (2014) compared the impact of deep brain stimulation plus medication with medication alone (or plus sham deep brain stimulation) on Parkinson disease outcomes.11, Six RCTs (total n=1,184 patients) were included in the review. Five trials exclusively involved bilateral stimulation to the subthalamic nucleus and, in the sixth trial, half of the patients received stimulation to the subthalamic nucleus and the other half had stimulation to the globus pallidus interna. Motor function assessment was blinded in 2 trials and the randomization method was described in 4 trials. Five studies reported motor function, measured by the Unified Parkinson’s Disease Rating Scale-III. In the off-medication phase, motor function was significantly higher with deep brain stimulation than with control (weighted mean difference, 15.20; 95% CI, 12.23 to 18.18; standard mean difference, 1.35). In the on-medication phase, there was also significantly greater motor function with deep brain stimulation than with control (weighted mean difference=4.36; 95% CI, 2.80 to 5.92; standard mean difference=0.53). Meta-analyses of other outcomes (eg, activities of daily living (ADLs), quality of life, dementia, depression) also favored the deep brain stimulation group. 

An earlier systematic review by Kleiner-Fisman et al (2006) included both RCTs and observational studies; reviewers examined the literature on subthalamic stimulation for patients with Parkinson disease who had failed medical management.12, Twenty studies, primarily uncontrolled cohorts or case series, were included in the meta-analysis. Subthalamic stimulation was found to improve ADLs by 50% over baseline, as measured by the Unified Parkinson’s Disease Rating Scale-II (decrease of 13.35 points out of 52). There was a 28-point decrease in the Unified Parkinson’s Disease Rating Scale-III score (out of 108), indicating a 52% reduction in the severity of motor symptoms that occurred while the patient was not taking medication. A strong relation was found between the preoperative dose response to levodopa and improvements in both the Unified Parkinson’s Disease Rating Scale-II and -III scores. The analysis found a 56% reduction in medication use, a 69% reduction in dyskinesia, and a 35% improvement in quality of life with subthalamic stimulation. 

A meta-analysis by Appleby et al (2007) found that the rate of suicidal ideation and suicide attempts associated with deep brain stimulation for Parkinson disease ranged from 0.3% to 0.7%.13, The completed suicide rate ranged from 0.16% to 0.32%. In light of the rate of suicide in patients treated with deep brain stimulation, reviewers argued for prescreening for suicide risk. 

Parkinson Disease With Early Motor Complications 
Schuepbach et al (2013) published an RCT evaluating deep brain stimulation in patients with Parkinson disease and early motor complications.14, Key eligibility criteria included age 18 to 60 years, disease duration of at least 4 years, improvement of motor signs of at least 50% with dopaminergic medication, and Parkinson disease disease severity below stage 3 in the on-medication condition. A total of 251 patients enrolled, 124 of whom were assigned to deep brain stimulation plus medical therapy and 127 to medical therapy alone. Analysis was intention to treat and blinded outcome assessment was done at baseline and two years. 

The primary endpoint was mean change from baseline to 2 years in the summary index of the Parkinson Disease Questionnaire, which has a maximum score of 39 points, with higher scores indicating higher quality of life. Mean baseline scores on the Parkinson Disease Questionaire were 30.2 in the deep brain stimulation 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 deep brain stimulation 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 deep brain stimulation 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 Unified Parkinson’s Disease Rating Scale subscales. Regarding medication use, the levodopa-equivalent daily dose was reduced by 39% in the deep brain stimulation plus medical therapy group and increased by 21% in the medical therapy only group. 

Sixty-eight patients in the deep brain stimulation 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 deep brain stimulation group that were surgery- or device-related; reoperation was necessary in 4 patients. 

Globus Pallidus Interna versus Subthalamic Nucleus Stimulation 
A number of meta-analyses have compared the efficacy of globus pallidus interna with subthalamic nucleus stimulation in Parkinson disease patients.15,16,17,18,19,20,21, The meta-analysis by Tan et al (2016) included only RCTs comparing the 2 types of stimulation in patients with advanced Parkinson disease and considered a range of outcomes.17, This review included RCTs evaluating patients with Parkinson disease who were responsive to levodopa, had at least 6 months of follow-up, and reported at least one of the following outcome measures: Unified Parkinson’s Disease Rating Scale-III, Beck Depression Inventory-II (BDI-II), levodopa-adjusted dose, neurocognitive status, or quality of life. Ten RCTs met eligibility criteria and were included in the quantitative synthesis. After 6 months, there were no significant differences in the Unified Parkinson’s Disease Rating Scale-III scores between the globus pallidus interna and subthalamic nucleus groups for patients in the off-medication/on-simulation state (5 studies; MD = -1.39; 95% CI, -3.70 to 0.92) or the on-medication/on-stimulation state (5 studies; MD = -0.37; 95% CI, -2.48 to 1.73). At the 12- and 24-month follow-ups, only 1 to 3 studies reported data on the Unified Parkinson’s Disease Rating Scale-III score. In a pooled analysis of the levodopa-adjusted dose, there was a significant difference between the globus pallidus interna and subthalamic nucleus groups, favoring subthalamic nucleus (6 studies; MD=0.60; 95% CI, 0.46 to 0.74). However, the analysis of Beck Depression Inventory II (BDI-II) scores favored the globus pallidus interna group (4 studies; MD = -0.31; 95% CI, -0.51 to -0.12). Other meta-analyses had similar mixed findings and none concluded that one type of stimulation was clearly better than the other for patients with advanced Parkinson disease.

Section Summary: Symptoms Associated With Parkinson Disease
A number of RCTs and systematic reviews of the literature have been published. A TEC Assessment concluded that studies evaluating deep brain stimulation of the globus pallidus interna or subthalamic nucleus have consistently demonstrated clinically significant improvements in outcomes (eg, neurologic function). Other systematic reviews have also found significantly better outcomes after deep brain stimulation than after a control intervention. One RCT compared deep brain stimulation plus medical therapy with medical therapy alone in patients with levodopa-responsive Parkinson disease of at least 4 years in duration and uncontrolled motor symptoms. The trial found that quality of life at 2 years (eg, motor disability, motor complications) was significantly higher when deep brain stimulation was added to medical therapy. Meta-analyses of RCTs comparing globus pallidus interna and subthalamic nucleus have had inconsistent findings and did not conclude that one type of stimulation was clearly superior to the other.

Dystonia
Clinical Context and Therapy Purpose
Deep brain stimulation has also been investigated in patients with primary and secondary 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 for the treatment of primary dystonia received FDA approval through the humanitarian device exemption process in 2003. The humanitarian device exemption approval process is available for conditions that affect fewer than 4,000 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 deep brain stimulation in 201 patients represented in 34 manuscripts.22, Three studies reported at least 10 cases of primary dystonia. In these studies, clinical improvement with deep brain stimulation 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.

The question addressed in this evidence review is: Does deep brain stimulation improve the net health outcome in patients with primary or secondary dystonia?

The following PICO was used to select literature to inform this review.

Patients 
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.

Interventions
The therapy being considered is deep brain stimulation..

Comparators
Treatment options for dystonia include oral or injectable medications (ie, botulinum toxin) and destructive surgical or neurosurgical interventions (ie, 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. Deep brain stimulation provides a reversible alternative.

Outcomes
Key efficacy outcomes include clincial severity of dystonia and disability as reated using the Burke-Fahn-Marsden Dystonia Rating Scale or Toronto Western Spasmodic Torticollis Rating sacle and quality of life.

The Burke-Fahn-Marsden Dystonia Rating Scale 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 patient’s 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 Burke-Fahn-Marsden Dystonia Rating Scale total score.

Toronto Western Spasmodic Torticollis Rating sacle is most commonly used to assess the status of people with cervical dystonia. The Toronto Western Spasmodic Torticollis Rating sacle 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.

Key safety outcomes include death, stroke, depression, cognition, infection and other device and procedure related events.

Primary Dystonia 
Review of Evidence 
Systematic Reviews 
Moro et al (2017) published a systematic review of literature published through November 2015 on primary dystonia (also known as isolated dystonia).23, Reviewers included studies with at least ten cases. Fifty-eight articles corresponding to 54 unique studies were identified; most involved bilateral deep brain stimulation of the globus pallidus interna. There were only 3 controlled studies, 2 RCTs (Kupschetl al [2006] andVolkmann et al [2014]; described below) and 1 study that included a double-blind evaluation with and without stimulation. Rodrigues et al (2019) performed a Cochrane systematic review of RCTs and identified the same 2 RCTs.24,

Randomized Controlled Trials
The 2 RCTs identified in the systematic reviews are described in Tables 2-5. Kupsch et al (2006) randomized 40 patients with primary segmental or generalized dystonia to deep brain stimulation or sham stimulation for 3 months.25, The primary outcome was change from baseline to 3 months in the severity of symptoms measured by the Burke-Fahn-Marsden Dystonia Rating Scale assessed by blinded reviewers from videotaped sessions. All patients subsequently received open-label deep brain stimulation for six months after blinded treatment. Results are shown in Table 2. In brief, the change from baseline in the mean Burke-Fahn-Marsden Dystonia Rating Scale movement score was significantly greater in the deep brain stimulation group. 

The Volkmann et al (2014) RCT was patient- and observer-blinded evaluation of pallidal neurostimulation in subjects with refractory cervical dystonia.26, The primary outcome was change in the Toronto Western Spasmodic Torticollis Rating sacle severity score at the end of the blinded study period (3 months); thereafter, all patients received open-label active stimulation. Results are shown in Table 3. There was significantly greater improvement in the neurostimulation group than in the sham group on the Toronto Western Spasmodic Torticollis Rating sacle disability score and the Bain Tremor Scale score but not on the Toronto Western Spasmodic Torticollis Rating sacle pain score or the Craniocervical Dystonia Questionnaire-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 (ie, slightly slurred speech), which was not reversible in 6 patients. 

Table 2. Characteristics of RCTs of Deep Brain Stimulation for Primary Dystonia 

Study; Trial Countries Sites Dates Participants Interventions
          Active Comparator
Kupsch (2006);25, NCT00142259 Germany, Norway, Austria 10 2002 to 2004 Patients ages 14 to 75 years with marked disability owing to primary generalized or segmental dystonia despite optimal pharmacologic treatment with disease duration of at least 5 years N=20
GPi DBS
N=20
Sham
Volkmann (2014)26,; NCT00148889 Germany, Norway, Austria 10 2006 to 2008 Adults under age of 75 with idiopathic or inherited isolated cervical dystonia with disease duration 3 years or longer, ≥15 on the TWSTRS, and an unsatisfactory response to botulinum toxin injection and oral medication. N=32
GPi DBS
N=30
Sham

DBS: deep brain stimulation; GPi: globuspallidusinternus; TWSTRS: Toronto Western Spasmodic Torticollis Rating Scale; RCT: randomized controlled trial.

Table 3. Results of RCTs of Deep Brain Stimulation for Primary Dystonia 

Study Dystonia severity Disability Quality of life Depression symptoms Serious Adverse Events
Kupsch (2006)25, Change in BFMDRS movement at 3 months, Mean (SD) Change in BFMDRS disability at 3 months, Mean (SD) Change in SF-36 at 3 months, Mean (SD) Change in BDI at 3 months  
N 40 39 33 30  
DBS -15.8 (14.1) 3.9 (2.9) PCS: 10.1 (7.4)MCS: 5.2 (15.0) -5.1 (8.4) 3 (8%)3 related to lead dislodgement or 1 related to infection requiring hospitalization
Sham -1.4 (3.8) 0.8 (1.2) PCS: 3.8 (8.4)MCS: 0.2 (8.7) -0.5 (10.2)
Treatment effect (95% CI) MD =14.40 (8.0 to 20.80); p<0.01 MD= 3.10 (1.72 to 4.48) PCS MD=6.30 (1.06 to 11.54)MCS MD=5.00 (-2.14 to 12.14) MD=4.60 (-2.06 to 11.26)  
Volkmann (2014)26, Change in TWSTRS severity at 3 months Change in TWSTRS disability at 3 months Change in SF-36 at 3 months Change in BDI at 3 months  
N 62 61 57 61  
DBS -5.1 (5.1) -5.6 (5.6) PCS: 6.6 (21.9)MCS: 11.3 (18.2) -3.5 (5.6) 16 (26%); 11 related to surgery or device, 1 related to medication or stimulation, 4 related to dystonia
Sham -1.3 (2.4) -1.8 (3.8) PCS: 3.6 (19.2)MCS: 8.9 (14.4) -0.4 (3.7)
Treatment effect (95% CI) MD=3.80 (1.84 to 5.76); p<0.01 MD=3.80 (1.41 to 6.19) PCS MD=3.00 (-7.71 to 13.71)MCS MD=2.40 (-6.20 to 11.00) MD=3.10 (0.73 to 5.47)  

BFMDRS: Burke-Fahn-Marsden-Dystonia-Rating-Scale; TWSTRS: Toronto Western Spasmodic Torticollis Rating Scale; MD: Mean difference; BDI: Beck Depression Inventory; SF-36: short form 36 item quality of life survey, PCS: Physical Component Score; MCS Mental component score;
CI: confidence interval; DBS: deep brain stimulation; RCT: randomized controlled trial; SD: standard deviation.

Table 4. Study Relevance Limitations: RCTs of Deep Brain Stimulation for Primary Dystonia

Study Populationa Interventionb Comparatorc Outcomesd Follow-Upe
Kupsch (2006)25,         1: Only 3 months of double-blind study
Volkmann (2014)26,         1: Only 3 months of double-blind study

RCT: randomized controlled trial; DBS: deep brain stimulation.
The study limitations stated in this table are those notable in the current review; this is not a comprehensive limitations assessment.
a Population key: 1. Intended use population unclear; 2. Clinical context is unclear; 3. Study population is unclear; 4. Study population not representative of intended use.
b Intervention key: 1. Not clearly defined; 2. Version used unclear; 3. Delivery not similar intensity as comparator; 4.Not the intervention of interest.
c Comparator key: 1. Not clearly defined; 2. Not standard or optimal; 3. Delivery not similar intensity as intervention; 4. Not delivered effectively.
d Outcomes key: 1. Key health outcomes not addressed; 2. Physiologic measures, not validated surrogates; 3. No CONSORT reporting of harms; 4. Not establish and validated measurements; 5. Clinical significant difference not prespecified; 6. Clinical significant difference not supported.
e Follow-Up key: 1. Not sufficient duration for benefit; 2. Not sufficient duration for harms.

Table 5. Study Design and Conduct Limitations: RCTs of Deep Brain Stimulation for Primary Dystonia

Study Allocationa Blindingb Selective Reportingc Data Completenessd Powere Statisticalf
Kupsch (2006)25,     1: Registered after enrollment was complete      
Volkmann (2014)26,   1,3: Treating physicians not blinded. Primary outcome assessors blinded but secondary outcomes subject to bias        

RCT: randomized controlled trial; DBS: deep brain stimulation.
The study limitations stated in this table are those notable in the current review; this is not a comprehensive limitations assessment.
a Allocation key: 1. Participants not randomly allocated; 2. Allocation not concealed; 3. Allocation concealment unclear; 4. Inadequate control for selection bias.
b Blinding key: 1. Not blinded to treatment assignment; 2. Not blinded outcome assessment; 3. Outcome assessed by treating physician.
c Selective Reporting key: 1. Not registered; 2. Evidence of selective reporting; 3. Evidence of selective publication.
d Data Completeness key: 1. High loss to follow-up or missing data; 2. Inadequate handling of missing data; 3. High number of crossovers; 4. Inadequate handling of crossovers; 5. Inappropriate exclusions; 6. Not intent to treat analysis (per protocol for noninferiority trials).
e Power key: 1. Power calculations not reported; 2. Power not calculated for primary outcome; 3. Power not based on clinically important difference.
f Statistical key: 1. Analysis is not appropriate for outcome type: (a) continuous; (b) binary; (c) time to event; 2. Analysis is not appropriate for multiple observations per patient; 3. Confidence intervals and/or p values not reported; 4.Comparative treatment effects not calculated.

Section Summary: Primary Dystonia
A review prepared for the FDA and systematic reviews have evaluated evidence on deep brain stimulation for primary dystonia. There are numerous small case series and 2 RCTs. Both RCTs 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).

Tardive Dyskinesia and Tardive Dystonia
Review of Evidence
Randomized Controlled Trials
One RCT has been conducted of pallidal deep brain stimulation in patients with tardive dystonia. Characteristics are shown in Table 6 and results are in Table 7. Briefly, Gruber et al (2018) assessed dystonia/dyskinesia severity using the Burke-Fahn-Marsden Dystonia Rating Scale at 3 months between active vs sham deep brain stimulation.27, Twenty-five patients were randomized. In the intention-to-treat analyses, the between group difference of dystonia severity was not significant at three months. Adverse events occurred in 10/25 of patients; 3 of the adverse events were serious. The study was originally powered to include 48 patients but only 25 were randomized and analyses may be underpowered. Study limitations are described in Tables 8 and 9.

Table 6. Characteristics of RCTs of Deep Brain Stimulation for Tardive Dyskinesia and Tardive Dystonia

Study; Trial Countries Sites Dates Participants Interventions
          Active Comparator
Gruber 2018;27, NCT00331669 Germany 15 2006 to 2009 Adults with tardive dystonia disease duration of at least 18 months with marked disability and deterioration of activities of daily living owing totardive dystonia despite medical treatment N=12
Pallidal DBS
N=13
Sham

RCT: randomized controlled trial; DBS: deep brain stimulation.

Table 7. Results of RCTs of Deep Brain Stimulation for TardiveDyskinesia and Tardive Dystonia 

Study Dystonia severity Disability Quality of life Depression symptoms Serious Adverse Events
Gruber 201827, Change in BFMDRS Movement score at 3 mon, Mean (SD) Change in BFMDRS Disability score at 3 mon, Mean (SD) Change in SF-36 at 3 mon, Mean (SD) HAM-D at 3 mon, Mean (SD)  
N 25 25 24 24  
DBS -5.6 (9.1) 0.5 (5.5) PCS: 5.4 (10.0)MCS: 0.5 (10.9) 1.4 (5.5) 3 events (episodes of confusion, worsening of dystonia following gastrointestinal infection, skin erosion)
Sham -5.9 (13.9) -0.3 (1.2) PCS: 1.6 (7.8)MCS: -0.6 (4.8) 2.2 (6.6)
Treatment effect (95% CI) p=0.72 p=0.43 PCS: p=0.17MCS: p=0.53 p=0.69  

BFMDRS: Burke-Fahn-Marsden-Dystonia-Rating-Scale; HAM-D: Hamilton Depression Score; SF-36: short form 36 item quality of life survey, PCS: Physical Component Score; MCS Mental component score; DBS: deep brain stimulation; RCT: randomized controlled trial; SD: standard deviation. 

Table 8. Study Relevance Limitations: RCTs of Deep Brain Stimulation for Tardive Dyskinesia and Tardive Dystonia 
Study Populationa Interventionb Comparatorc Outcomesd Follow-Upe
Gruber 201827,         1. 3 mon follow-up in blinded period

DBS: deep brain stimulation; RCT: randomized controlled trial.
The evidence limitations stated in this table are those notable in the current review; this is not a comprehensive limitations assessment.
Population key: 1. Intended use population unclear; 2. Clinical context is unclear; 3. Study population is unclear; 4. Study population not representative of intended use.
Intervention key: 1. Not clearly defined; 2. Version used unclear; 3. Delivery not similar intensity as comparator; 4.Not the intervention of interest.
Comparator key: 1. Not clearly defined; 2. Not standard or optimal; 3. Delivery not similar intensity as intervention; 4. Not delivered effectively.
Outcomes key: 1. Key health outcomes not addressed; 2. Physiologic measures, not validated surrogates; 3. No CONSORT reporting of harms; 4. Not establish and validated measurements; 5. Clinical significant difference not prespecified; 6. Clinical significant difference not supported.
Follow-Up key: 1. Not sufficient duration for benefit; 2. Not sufficient duration for harms.

Table 9. Study Design and Conduct Limitations: RCTs of Deep Brain Stimulation for Tardive Dyskinesia and Tardive Dystonia 

Study Allocationa Blindingb Selective Reportingc Data Completenessd Powere Statisticalf
Gruber 201827,       1. Study powered to include 48 patients but only 25 patients enrolled    

DBS: deep brain stimulation; RCT: randomized controlled trial.
The evidence limitations stated in this table are those notable in the current review; this is not a comprehensive limitations assessment.
Allocation key: 1. Participants not randomly allocated; 2. Allocation not concealed; 3. Allocation concealment unclear; 4. Inadequate control for selection bias.
Blinding key: 1. Not blinded to treatment assignment; 2. Not blinded outcome assessment; 3. Outcome assessed by treating physician.
Selective Reporting key: 1. Not registered; 2. Evidence of selective reporting; 3. Evidence of selective publication.
Data Completeness key: 1. High loss to follow-up or missing data; 2. Inadequate handling of missing data; 3. High number of crossovers; 4. Inadequate handling of crossovers; 5. Inappropriate exclusions; 6. Not intent to treat analysis (per protocol for noninferiority trials).
Power key: 1. Power calculations not reported; 2. Power not calculated for primary outcome; 3. Power not based on clinically important difference.
Statistical key: 1. Analysis is not appropriate for outcome type: (a) continuous; (b) binary; (c) time to event; 2. Analysis is not appropriate for multiple observations per patient; 3. Confidence intervals and/or p values not reported; 4.Comparative treatment effects not calculated.

Case Series 
Stimulation of the globus pallidus interna was examined as a treatment for tardive dyskinesia in a multicenter case series by Damier et al (2007), with a double-blind evaluation at 6 months (comparison of symptoms in the on and off positions).28, The trial was stopped early due to successful treatment (>40% improvement at 6 months) in the first 10 patients. In the double-blind evaluation of these patients, stimulation was associated with a mean decrease of 50% in the symptom score when the device was on vs off. 

Outcomes on motor function, quality of life, and mood in a series of 9 patients treated with deep brain stimulation of the globus pallidus interna for tardive dystonia were reported by Gruber et al (2009).29, One week, and 3 to 6 months after surgery, Burke-Fahn-Marsden Dystonia Rating Scale motor scores were improved by 56.4% and 74.1%, Burke-Fahn-Marsden Dystonia Rating Scale disability scores by 62.5% and 88.9%, and Abnormal Involuntary Movement Scale scores by 52.3% and 69.5%, respectively. At last follow-up (mean, 41 months; range, 18-90 months), Burke-Fahn-Marsden Dystonia Rating Scale motor scores were reduced compared with presurgical assessment by 83%, Burke-Fahn-Marsden Dystonia Rating Scale disability score by 67.7%, and Abnormal Involuntary Movement Scale scores by 78.7%. 

Pouclet-Courtemanche et al (2016) reported on a case series of 19 patients with severe pharmaco-resistant tardive dyskinesia treated with deep brain stimulation.30, Patients were assessed after 3, 6, and 12 months after the procedure. At 6 months, all patients had experienced greater than 40% reduction in symptoms as measured on the Extrapyramidal Symptoms Rating Scale. At 12 months, the mean decrease in Extrapyramidal Symptoms Rating Scale score was 58% (range, 21%-81%). 

Section Summary: Tardive Dyskinesia and Tardive Dystonia 
Evidence for the use of deep brain stimulation to treat tardive syndromes consists of an RCT with 3 months of blinded follow-up and case series with follow-up of 6 months to approximately four years. The RCT did not report statistically significant improvement in the dystonia severity outcomes or the secondary outcomes related to disability and quality of life for deep brain stimulation compared to sham but the study did not recruit the number of patients for which it was originally powered. Case series reported favorable results with deep brain stimulation treatment. 

Epilepsy 
Clinical Context and Therapy Purpose 
Approximately one-third of patients with epilepsy 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 question addressed in this evidence review is: Does deep brain stimulation improve the net health outcome in patients with epilepsy? 

The following PICO was used to select literature to inform this review. 

Patients 
The relevant population(s) of interest are patients with epilepsy refractory to medical treatment who are not candidates for resective surgery. The International League Against Epilepsy defined drug-resistant as failure of adequate trials of two tolerated, appropriately chosen and administered anti-epileptic drugs, used as monotherapy or in combination, to achieve seizure freedom.31,Patients who are not candidates for resective surgery include those multifocal seizure onset, significant medical comorbidities or generalized-onset epilepsy. 

Interventions 
The therapy being considered is deep brain stimulation. Several areas of the brain have been targeted. 

Comparators 
The treatment for chronic epilepsy consists of anti-epileptic drugs. A ketogenic diet may be used as an adjunctive treatment. For patients with epilepsy that is 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. 

Sham control may be used in RCTs. 

Outcomes 
Key efficacy outcomes include measures 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. The Quality of Live Inventory in Epilepsy (QOLIE-31) is a tool used to assess the imapct of antiepileptic treatment on patients' lives; the minimally important change in patients with treatment-resistant seizures was 5 points.32, 

Key safety outcomes include death, stroke, depression, cognition, infection and other device and procedure related events. 

Study Selection Criteria 
To assess efficacy outcomes, comparative controlled prospective trials were included, with a preference for RCTs.

In the absence of such trials, comparative observational studies, with a preference for prospective studies will be included.

To assess long-term outcomes and adverse effects, single arm studies that captured longer periods of follow-up and/or larger populations may be included.

Studies with duplicative or overlapping populations will be excluded.

Review of Evidence
Systematic Reviews
A Cochrane systematic review on deep brain and cortical stimulation for epilepsy was published in 2017 and included RCTs published through 2016.33, The review included 1 trial on anterior thalamic nucleus deep brain stimulation for multifocal epilepsy (n=109, see discussion in following section), 1 trial on centromedian thalamic deep brain stimulation for multifocal or generalized epilepsy (n=7), and 3RCTs on hippocampal deep brain stimulation for medial temporal lobe epilepsy (n=15). Meta-analyses provided estimates by site of stimulation. The RCT using anterior thalamic nucleus deep brain stimulation will be discussed in the following section.

Two systematic reviews on the use of deep brain stimulation for drug-resistant epilepsy, both published in 2018, assessed many of the same studies.34,35, The larger review, by Li et al (2018), identified 10 RCTs and 48 uncontrolled studies.34, The literature search date was not reported. Meta-analyses were not performed.The largest RCT in which deep brain stimulation targeted the anterior nucleus of the thalamusFisher et al (2010)36, is described below. Reviewers concluded that more robust clinical trials would be needed.

Randomized Controlled Trials
Trials including 15 patients or more will be described in more detail in this section. Study characteristics are in Table 10 and results are in Table 11. Tables 12 and 13 describe study limitations.

Fisher et al (2010) conducted a U.S. multicenter, double-blind, randomized trial, Stimulation of the Anterior Nuclei of the Thalamus for Epilepsy (SANTE) (see Table 1).36, Included were 110 patients, ages 18 to 65 years, who experienced at least 6 partial seizures (including secondarily generalized seizures) per month, but no more than 10 per day. (An additional 47 patients were enrolled in the trial but did not undergo implantation.) 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 deep brain stimulation 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; see Table 10). The publication stated that changes in additional outcome measures did not show significant treatment group differences during the double-blind phase, including 50% responder rates, Liverpool Seizure Severity Scale, quality of lifeIE-31 scores but data were not shown. Data for these outcomes are available in the FDA Summary of Safety and Effectiveness, see Table 10.37,

Troster et al (2017) assessed neuropsychological adverse events from the SANTE trial during the 3-month blinded phase, and at 7-year follow-up during the open-label noncomparative phase (see Table 9).38, At baseline, there were no differences in depression history between groups. During the 3-month blinded phase of the trial, depression was reported in 8 (15%) patients from the stimulation group and in 1 (2%) patient from the no stimulation group (p=0.02). At the 7 year follow-up, after the treatment groups had been combined, there was no statistically significant difference in Profile of Mood State depression score compared with baseline. Memory adverse events also occurred at significantly different rates between the treatment groups during the blinded phase (seven in the active group, 1 in the control group; p=0.03). At the 7 year follow-up, most cognitive function tests did not improve over baseline measurements.

Cukiert et al (2017) conducted a double-blind, placebo-controlled randomized trial evaluating 16 patients with refractory temporal lobe epilepsy (see Table 9).39, All patients underwent deep brain stimulation device implantation, and were followed for 6 months. Patients were seen weekly to receive the treatment or placebo. To maintain double-blind status, programming was performed by a nontreating assistant. Patients kept a seizure diary during the study period. Patients were considered seizure-free if no seizures occurred during the last 2 months of the trial. Responders were defined as patients experiencing a reduction of 50% or more in frequency reduction. Results are summarized in Table 9.

Table 10. Summary of RCT Characteristics for Epilepsy 

Study Country Sites Dates Participants Interventions
          Active Comparator
Fisher et al (2010)36,; Troster et al (2017)38,; SANTE U.S. 17 NR Patients with partial seizures, including secondary generalized seizures, refractory to ≥3 medications 5-V stimulus intensity (n=54) No stimulation (n=55)
Cukiert et al (2017)39, Brazil 1 2014-2016 Patients with temporal lobe epilepsy, refractory to ≥3 medications Weekly 0.4-V to 2-V stimulus intensity (n=8) Weekly impedance testing, no stimulation (n=8)

NR: not reported; RCT: randomized controlled trial; V: volts; SANTE: Stimulation of the Anterior Nuclei of the Thalamus for Epilepsy.

Table 11. Summary of RCT Outcomes for Epilepsy

Study Seizure Reduction, % (p) Responder (50% or more reduction in seizure frequency) Hospitalizations Rescue medication (at least one use) Seizure severity Quality of life Adverse Events
  1 Month 2 Months 3 Months   Mean (SD) annual hospitalizations per patient   Change (SD) in LSSS Change (SD) in QOLIE-31  
Fisher et al (2010)36,; Troster et al (2017)38,; SANTE                  
DBS       30%a 0.08 (0.56)a 22%a -8.2 (17.8)a 2.5 (8.7)a  
Sham       26%a 0.37 (1.17)a 22%a -6.8 (19.6)a 2.8 (8.0)a  
Between-group difference -11% (NS) -11% (NS) -29% (0.002) p=0.83a p=0.11a p=0.87a p=0.70a p=0.55a 3 months: higher rate of depression and memory adverse events in treatment group (difference disappeared in long-term follow-up)
  FIAS at 6 Months            
Cukiert et al (2017)39,              
Stimulation on 4 seizure-free; 3 responders; 1 no response           2 patients with local skin erosions at cranial site of implant, treated with antibiotics
Stimulation off 0 seizure-free; 3 responders; 5 no response            

FIAS: focal impaired awareness seizure; RCT: randomized controlled trial; NS: not statistically significant; SD: standard deviation; LSSS: Liverpool Seizure Severity Scale; QOLIE-31: Quality of Life in Epilepsy Score.

a Not reported in publication but reported in FDA SSED. SANTE: Stimulation of the Anterior Nuclei of the Thalamus for Epilepsy..

Study limitations are described in Tables 11 and 12. The SANTE study included relevant patients and outcomes and had few design and conduct limitations. Both RCTs were missing report of several important outcomes such as quality of life and functional outcomes in the publications although SANTE outcomes are available in the FDA Summary of Safety and Effectiveness. Cukiert et al (2017) did not include information on power/sample size, flow of participants and missing data.

Table 12. Study Relevance Limitations

Study Populationa Interventionb Comparatorc Outcomesd Follow-Upe
Fisher et al (2010)36,; SANTE       1: Responder and freedom from seizure, quality of life outcomes not reported in publication; reported in SSED.  
Cukiert et al (2017)39,       1. Quality of life and functional outcomes not reported  

SSED: Summary of Safety and Effectiveness; SANTE: Stimulation of the Anterior Nuclei of the Thalamus for Epilepsy.
The study limitations stated in this table are those notable in the current review; this is not a comprehensive limitations assessment.
Population key: 1. Intended use population unclear; 2. Clinical context is unclear; 3. Study population is unclear; 4. Study population not representative of intended use.
Intervention key: 1. Not clearly defined; 2. Version used unclear; 3. Delivery not similar intensity as comparator; 4.Not the intervention of interest.
Comparator key: 1. Not clearly defined; 2. Not standard or optimal; 3. Delivery not similar intensity as intervention; 4. Not delivered effectively.
Outcomes key: 1. Key health outcomes not addressed; 2. Physiologic measures, not validated surrogates; 3. No CONSORT reporting of harms; 4. Not establish and validated measurements; 5. Clinical significant difference not prespecified; 6. Clinical significant difference not supported.
Follow-Up key: 1. Not sufficient duration for benefit; 2. Not sufficient duration for harms.

Table 13. Study Design and Conduct Limitations

Study Allocationa Blindingb Selective Reportingc Data Completenessd Powere Statisticalf
Fisher et al (2010)36,; SANTE     2. Several seizure outcomes as well as quality of life collected but not reported in publication; available in SSED.      
Cukiert et al (2017)39,       2. No mention of how missing diary data or other missing data were handled in analysis. No flow of participants described. 1: No power calculations 2: Not clear if analyses were done independently for each time point or if analyses adjusted for multiple observations4: Comparative treatment effects not calculated

SSED: Summary of Safety and Effectiveness; SANTE: Stimulation of the Anterior Nuclei of the Thalamus for Epilepsy..
The study limitations stated in this table are those notable in the current review; this is not a comprehensive limitations assessment.
Allocation key: 1. Participants not randomly allocated; 2. Allocation not concealed; 3. Allocation concealment unclear; 4. Inadequate control for selection bias.
Blinding key: 1. Not blinded to treatment assignment; 2. Not blinded outcome assessment; 3. Outcome assessed by treating physician.
Selective Reporting key: 1. Not registered; 2. Evidence of selective reporting; 3. Evidence of selective publication.
Data Completeness key: 1. High loss to follow-up or missing data; 2. Inadequate handling of missing data; 3. High number of crossovers; 4. Inadequate handling of crossovers; 5. Inappropriate exclusions; 6. Not intent to treat analysis (per protocol for noninferiority trials).
Power key: 1. Power calculations not reported; 2. Power not calculated for primary outcome; 3. Power not based on clinically important difference.
Statistical key: 1. Analysis is not appropriate for outcome type: (a) continuous; (b) binary; (c) time to event; 2. Analysis is not appropriate for multiple observations per patient; 3. Confidence intervals and/or p values not reported; 4.Comparative treatment effects not calculated.

Observational Studies
Long-term outcomes of the SANTE trial were reported by Salanova et al (2015).40, 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 (nonserious) was reported in 30 (27%) patients during the trial, half of whom had a history of the condition.

A 7 year follow-up of SANTE was reported in the FDA Summary of Safety and Effectiveness (Table 14).37, Seventy-three (66% of implanted) patients completed the year 7 visit. Reasons for withdrawals from the study after implantation were: death (6), withdrawal of consent (5), investigator decision (3), therapeutic product ineffective (13), implant site infection or pain (6), other adverse event (7) and elective device removal (1). Fifty patients were included in the year 7 analysis of responder rate; see Table 13. Seventy-four percent of the 50 patients were responders (50% or greater reduction in seizure frequency). quality of lifeIE-31 scores (n=67) improved by a mean of 4.9 (SD=11) points at year 7. Liverpool Seizure Severity Scale scores (n=67) improved by a mean of 18 points (SD=23) at year 7. As the FDA documentation notes, interpretation of the long-term follow-up is limited by several factors: patients were aware they were receiving deep brain stimulation, only 66% of implanted patients completed the year 7 visit and those who did not do well may be more likely to leave the study, and changes in anti-epileptic drugs were allowed in long-term follow-up.

Table 14. 7-Year Outcomes from SANTEa

Outcomes Median seizure frequency (change from BL) Responders (≥50% reduction in seizure frequency) LSSS,Mean (SD) QOLIE-31, ≥5 point improvement Hospitalizations, mean (SD) annual number of hospitalizations per patients Serious device-related adverse event
N 50 50 67 67 80 110
Estimate -75%b 74% -18.1 (23.5) 43% 0.08 (0.28) 34.5%

LSSS: Liverpool Seizure Severity Scale; QOLIE-31: Quality of Life in Epilepsy Score; SD: standard deviation; BL: baseline; SANTE: Stimulation of the Anterior Nuclei of the Thalamus for Epilepsy.
110 patients were implanted with DBS in SANTE
b -39% assuming worst case for missing data.

Kim et al (2017) conducted a retrospective chart review of 29 patients with refractory epilepsy treated with deep brain stimulation.41, Patients’ mean age was 31 years, they had had epilepsy for a mean of 19 years, and had a mean preoperative frequency of tonic-clonic seizures of 27 per month. 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 one symptomatic intracranial hemorrhage, one infection requiring removal and reimplantation, and two lead disconnections.

Section Summary: Epilepsy
A systematic review identified several RCTs and many observational studies in which deep brain stimulation was evaluated for the treatment of epilepsy. Many different targets have been investigated and most of the RCTs included fewer than 15 patients. The largest RCT consisted of a 3 month blinded phase in which patients were randomized to stimulation or no stimulation targeting the anterior nucleus of the thalamus. 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. There were no differences between groups in 50% responder rates, Liverpool Seizure Severity Scale, or quality of lifeIE-31 scores. 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. In addition interpretation of 7 year follow-up of SANTE is limited by high loss to follow-up. Serious adverse events were reported in about one-third of patients. The risk-benefit ratio is uncertain. Deep brain stimulation has not been directly compared to vagus nerve stimulation, another treatment used in patients with drug-refractory epilepsy who are not candidates for resective surgery.

Tourette Syndrome
Clinical Context and Therapy Purpose
Tourette Syndrome is a neurological disorder marked by multiple motor and phonic tics with onset during childhood or early adulthood and which often improve in adulthood. Children with Tourette Syndrome frequently have other comorbid conditions such as attention deficit hyperactivity disorder or obsessive-compulsive disorder (OCD).

The question addressed in this evidence review is: Does deep brain stimulation improve the net health outcome in patients with Tourette Syndrome?

The following PICO was used to select literature to inform this review.

Patients
The population of interest are patients with Tourette Syndrome who have disabling tics that are refractory to optimal medical management.

Interventions
The therapy being considered is deep brain stimulation. Several targets have been investigated such as the medial thalamus at the crosspoint of the centromedian nucleus, substantiaperiventricularis, and nucleus ventro-oralisinternus, subthalamic nucleus, caudate nucleus, globus pallidus interna, and the anterior limb of the internal capsule and nucleus accumbens.

Comparators
Intervention may be initiated when symptoms of Tourette Syndrome are disabling or causing difficulty in functioning. Patients may require a therapy to treat tics as well as comorbid attention deficit hyperactivity disorder or OCD. Medication treatment for tics might include antidopaminergic drugs, alpha adrenergic agonists drugs, topiramateorinjections of botulinum toxin. Behavioral therapy, primarily based on habit reversal therapy is also used.

Outcomes
Key efficacy outcomes include measures of motor impairment, tic severity (Yale Global Tic Severity Scale ), functional ability and disability, medication use and quality of life. The overall score for the Yale Global Tic Severity Scale is on a scale from 0 to 100, with lower scores indicating less sever symptoms, It has a motor tic and verbal tick subscale

Key safety outcomes include death, stroke, depression, cognition, infection and other device and procedure related events.

Study Selection Criteria

  1. To assess efficacy outcomes, comparative controlled prospective trials were included, with a preference for RCTs.
  2. In the absence of such trials, comparative observational studies, with a preference for prospective studies will be included.
  3. To assess long-term outcomes and adverse effects, single arm studies that captured longer periods of follow-up and/or larger populations may be included.
  4. Studies with duplicative or overlapping populations will be excluded.

Review of Evidence
Systematic Reviews
Several systematic reviews of the literature on deep brain stimulation for Tourette Syndrome have been published.42,43,44,45,46, Most recent systematic reviews (ie, those published in 2015-2017) qualitatively described the literature. Only Baldermann et al (2016) conducted pooled analyses of study data.42, That review identified 57 studies on deep brain stimulation for Tourette Syndrome, 4 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 interna anteromedial part (n=44) and post ventrolateral part (n=20). Two of the RCTs used thalamic stimulation, one used bilateral globus pallidus stimulation, and one used both. The primary outcome was the Yale Global Tic Severity Scale. In a pooled analysis of within-subject pre-post data, there was a median improvement of 53% in Yale Global Tic Severity Scale 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 Yale Global Tic Severity Scale score and 54% showed improvements of 50% or more. In addition, data were pooled from the 4 crossover RCTs: 27 patients received deep brain stimulation 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 deep brain stimulation (standard mean difference=0.96; 95% CI, 0.36 to 1.56). Reviewers noted that the effect size of 0.96 would be considered be large.

Randomized Controlled Trials
Trials including 15 patients or more will be described in more detail in this section. Study characteristics are shown in Table 15 and results are shown in Table 16. Study limitations are described in Tables 17 and 18.

The crossover RCT was published by Kefalopoulou et al (2015).47, The double-blind trial included 15 patients with severe medically refractory Tourette syndrome; all received bilateral globus pallidus interna surgery for deep brain stimulation 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 scores were 80.7 in the off-stimulation phase and 68.3 in the on-stimulation phase. The mean difference in Yale Global Tic Severity Scale 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 Yale Global Tic Severity Scale scores for patients randomized to the on-stimulation phase first or second. Three serious adverse events were reported, two related to surgery and one related to stimulation.

Welter et al (2017) reported results of a sham-controlled RCT of 3 months of anterior globus pallidus interna deep brain stimulation in 17 adults with severe Tourette Syndrome. 48, The primary endpoint was difference in Yale Global Tic Severity Scale score between the beginning and end of the 3 month double-blind period. The study was powered to detect a benefit amounting to a 30-point reduction in Yale Global Tic Severity Scale score in the active deep brain stimulation group and may, therefore, have been underpowered to detect smaller changes in Yale Global Tic Severity Scale. There was no significant differences in Yale Global Tic Severity Scale score change between groups (active deep brain stimulation median change 1.1% [interquartile range –23.9 to 38.1] vs sham deep brain stimulation median change 0.0% [–10.6 to 4.8]; p=0.39). There was also no difference between groups in change in co-morbid symptoms of OCD or depression or quality of life. There were 15 serious adverse events in 13 patients: infections in 4 patients, 1 electrode misplacement, 1 episode of depressive signs, and 3 episodes of increased tic severity and anxiety.

Table 15. Characteristics of RCTs of Deep Brain Stimulation for Tourette Syndrome

Study; Trial Countries Sites Dates Participants Interventions
          Active Comparator
Kefalopoulou et al (2015)47,; NCT01647269 United Kingdom 2 2009 to 2013 Adults with Tourette Syndorme with chronic and severe tic, with severe functional impairment (12+ months), had not responded to conventional medical treatment, behavioral intervention had been thought inappropriate or had been unsuccessful Stimulation on (Bilateral globus pallidus interna DBS) Stimulation off
Welter et al (2017);48, NCT00478842 France 8 2007 to 2012 Adults aged 18–60 years with severe, medically refractory TS N=8
anterior internal globus pallidus DBS
N= 9
Sham DBS

DBS: deep brain stimulation; RCT: randomized controlled trial.

Table 16. Results of RCTs of Deep Brain Stimulation for Tourette Syndrome

Study Tic severity Co-morbid symptoms Quality of life Depression symptoms Serious Adverse Events
Kefalopoulou et al (2015)47,a YGTSS, Mean (SD) at 3 months Y-BOC, Mean (SD) at 3 months GTS-QOL, Mean (SD) at 3 months Beck Depression Inventory, Mean (SD) at 3 months  
N 15a 15a 15a 15a 15a
DBS 68.3 (18.6) 12.8 (10.0) 54.3 (28.4) 21.0 (13.8) 3 (20%)
No stimulation 80.7 (12.0) 14.6 (10.3) 62.0 (24.7) 20.5 (14.3)  
Treatment effect (95% CI) 12.4 (0.1–24.7, p=0.05) p=0.98 p=0.04 p=0.13  
Welter et al (2017)48, YGTSS, Mean change (CI) at 3 months Y-BOC, Mean change (CI)at 3 months SF-36 , Mean change (CI) at 3 months MADRS, Mean change at 3 months  
N 16 16 16 16 19
DBS -4.5 (-12.5 to 0.5) –3.5 (–6.8 to 0.3) PCS 6.1 (1.2 to 8.7):
MCS: 10.1 (1.8 to 16.8):
–2.0 (–6.0 to 0.5) 15 serious adverse events (three in patients who withdrew before stimulation and six each in the active and sham stimulation groups) occurred in 13 patients: infections in four patients, one electrode misplacement, one episode of depressive signs , and three episodes of increased tic severity and anxiety
No stimulation 5.0 (-2.5 to 17.5) 0.0 (–1.0 to 0.0) PCS:–0.4 (–3.1 to 16.1)
MCS: –2.6 (–16.7 to 10.0)
0.0 (–2.3 to 1.8)  
Treatment effect (95% CI) p=039 p=0.25 PCS:p>0.99
MCS:p=0.14
p = 0.25  

YGTSS: Yale Global Tic Severity Scale; Y-BOCS: Yale and Brown Obsessive Compulsive Scale; GTS-QOL: Gilles de la Tourette Syndrome Quality of Life scale; MADRS: Montgomery and Asberg Rating Scale; DBS: deep brain stimulation;
CI: confidence interval; SD: standard deviation; RCT: randomized controlled trial; MCS: Mental Component Score; PCS: Physical component Score; SF-36: Short-Form 36 Item Quality of Life Survey.
a Crossover design

Table 17. Study Relevance Limitations: RCTs of Deep Brain Stimulation for Tourette Syndrome

Study Populationa Interventionb Comparatorc Outcomesd Follow-Upe
Kefalopoulou et al (2015)47,         1. 3 months of follow-up
Welter et al (2017)48,         1. 3 months of follow-up

DBS: deep brain stimulation; RCT: randomized controlled trial.
The study limitations stated in this table are those notable in the current review; this is not a comprehensive limitations assessment.
a Population key: 1. Intended use population unclear; 2. Clinical context is unclear; 3. Study population is unclear; 4. Study population not representative of intended use.
b Intervention key: 1. Not clearly defined; 2. Version used unclear; 3. Delivery not similar intensity as comparator; 4.Not the intervention of interest.
c Comparator key: 1. Not clearly defined; 2. Not standard or optimal; 3. Delivery not similar intensity as intervention; 4. Not delivered effectively.
d Outcomes key: 1. Key health outcomes not addressed; 2. Physiologic measures, not validated surrogates; 3. No CONSORT reporting of harms; 4. Not establish and validated measurements; 5. Clinical significant difference not prespecified; 6. Clinical significant difference not supported.
e Follow-Up key: 1. Not sufficient duration for benefit; 2. Not sufficient duration for harms.

Table 18. Study Design and Conduct Limitations: RCTs of Deep Brain Stimulation for Tourette Syndrome

Study Allocationa Blindingb Selective Reportingc Data Completenessd Powere Statisticalf
Kefalopoulou et al (2015)47,         3: Sample size based on “practical considerations”  
Welter et al (2017)48,         3: Powered to detect a 30 point reduction in YGTSS in active DBS group  

DBS: deep brain stimulation; RCT: randomized controlled trial; YGTSS: Yale-Brown Obsessive-Compulsive Scale; Gilles de la Tourette Syndrome Quality.
The study limitations stated in this table are those notable in the current review; this is not a comprehensive limitations assessment.
Allocation key: 1. Participants not randomly allocated; 2. Allocation not concealed; 3. Allocation concealment unclear; 4. Inadequate control for selection bias.
Blinding key: 1. Not blinded to treatment assignment; 2. Not blinded outcome assessment; 3. Outcome assessed by treating physician.
Selective Reporting key: 1. Not registered; 2. Evidence of selective reporting; 3. Evidence of selective publication.
Data Completeness key: 1. High loss to follow-up or missing data; 2. Inadequate handling of missing data; 3. High number of crossovers; 4. Inadequate handling of crossovers; 5. Inappropriate exclusions; 6. Not intent to treat analysis (per protocol for noninferiority trials).
Power key: 1. Power calculations not reported; 2. Power not calculated for primary outcome; 3. Power not based on clinically important difference.
Statistical key: 1. Analysis is not appropriate for outcome type: (a) continuous; (b) binary; (c) time to event; 2. Analysis is not appropriate for multiple observations per patient; 3. Confidence intervals and/or p values not reported; 4.Comparative treatment effects not calculated.

Observational Studies
Martinez-Ramirez et al (2018) reported prospective data from the International Deep Brain Stimulation Database and Registry including 185 consecutive patients with refractory Tourette Syndrome who were treated with deep brain stimulation between 2012 and 2016 at 31 sites in 10 countries in Australia, Europe, Asia and North America. Sixty-four percent of the patients had comorbid OCD and 28% had comorbid attention deficit hyperactivity disorder. The population was 78% male. The mean age at diagnosis was 12 years and mean age at surgery was 29 years. Fixty-seven percent received deep brain stimulation in the centromedian thalamic region, 25% in the anterior internal globus pallidus, 15% in the posterior globus pallidus interna and 3% in the anterior limb of the internal capsule. The Yale Global Tic Severity Scale score improved from a mean (SD) of 75 (18) at baseline to 41 (20) after 1 year of deep brain stimulation. More than one-third (35%) of patients had adverse events. Two patients (1.3%) suffered intracranial hemorrhage, 4 (3.2%) had infections, 1 (0.6%) had lead explantation.49,

Section Summary: Tourette Syndrome
A number of uncontrolled studies,RCTs, and several systematic reviews have been published. Most studies, including the RCTs, had small sample sizes (ie, ≤15 patients) and used a variety of deep brain stimulation targets. Two RCTs with 15 or more patients have been reported. One RCT found differences in severity of Tourette Syndrome for active vs sham at 3 months while the other RCT did not. Neither study demonstrated improvements in comorbid symptoms of OCD or depression. Both studies reported high rates of serious adverse events.

Cluster Headache and Facial Pain
Clinical Context and Therapy Purpose
Deep brain stimulation 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 question addressed in this evidence review is: Does deep brain stimulation improve the net health outcome in patients with cluster headache?

The following PICO was used to select literature to inform this review.

Patients
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.50, A summary of cluster headache based on the International Classification of Headache Disorders criteria are below.

Cluster headaches are primary headaches classified as trigeminal automomiccephalalgias 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 symptoms or signs, ipsilateral to the headache: conjunctival injection and/or lacrimation; nasal congestion and/orrhinorrhoea; eyelid oedema; 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 2 cluster periods lasting from 7 days to 1 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 1 year or more without remission, or with remission of less than 3 months. The age at onset for cluster headaches is generally 20-40 years and men are affected 3 times more often than are women.

Interventions
The therapy being considered is deep brain stimulation.

Comparators
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 attacks 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 nonischemic 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 2 doses per day. Steroids 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 headache, trials with sham deep brain stimulation are most relevant.

Outcomes
The general outcomes of interest are headache intensity and frequency, the effect on function and quality of life 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.

Study Selection Criteria

  1. To assess efficacy outcomes, comparative controlled prospective trials were included, with a preference for RCTs.
  2. In the absence of such trials, comparative observational studies, with a preference for prospective studies will be included.
  3. To assess long-term outcomes and adverse effects, single arm studies that captured longer periods of follow-up and/or larger populations may be included.
  4. Studies with duplicative or overlapping populations will be excluded.

Review of Evidence
Randomized Controlled Trials
Fontaine et al (2010) published the results of a prospective crossover, double-blind, multicenter trial in 11 patients who received deep brain stimulation of the posterior hypothalamus for severe refractory chronic cluster headache.51, The randomized phase compared active with sham stimulation during 1 month periods and was followed by a 1 year open phase. Severity of cluster headache was assessed using the weekly attack frequency (primary outcome), pain intensity, sumatriptan injections, emotional impact, and quality of life (12-Item Short-Form Health Survey). During the randomized phase, no significant changes in primary or secondary outcome measures were observed between active and sham stimulation. At the end of the open phase, 6 of 11 patients reported greater than 50% reduction in the weekly frequency of attacks.

Another research group from Europe published two case series (potentially overlapping) on use of deep brain stimulation for the ipsilateral posterior hypothalamus in patients with chronic cluster headache.52,53, 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.

Section Summary: Cluster Headache and Facial Pain
Several case series and a crossover RCT have been published on use of deep brain stimulation for cluster headache or facial pain. The RCT included 11 patients; there were no significant differences between groups receiving active and sham stimulation. Additional RCTs or controlled studies are needed.

Other Neurologic and Psychiatric Disorders
Clinical Context and Therapy Purpose
The role of deep brain stimulation in treatment of other treatment-resistant neurologic and psychiatric disorders such as major depressive disorders, and obsessive-compulsive disorder (OCD), 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 deep brain stimulation of nodes or targets within neural circuits involved in these disorders. Currently, a variety of target areas are being studied.

The question addressed in this evidence review is: Does deep brain stimulation improve the net health outcome in patients with other neurologic and psychiatric disorders?

The following PICO was used to select literature to inform this review.

Patients
The population of interest are patients with other neurologic and psychiatric disorders such as depression and OCD.

Interventions
The therapy being considered is deep brain stimulation. Several targets have been investigated. Affective limbic structures include the ventral striatum/ventral capsule, anterior limb of the internal capsule, and subgenual cingulate. Memory implicated structures include the fornix and nucleus basalis

Comparators
Alternative treatments vary by condition. Sham deep brain stimulation is an appropriate comparator for RCTs.

Outcomes
Key efficacy outcomes include measures of symptoms severity, functional ability and disability, and quality of life.

Outcomes for major depressive disorder are measured with validated scales, most commonly the Hamilton Depression Rating or the Montgomery-Asberg Depression Rating Scale. Response is considered a 50% or greater reduction in symptoms, while remission is based on achieving a specific threshold on one of the scales.

Key safety outcomes include death, stroke, depression, cognition, infection and other device and procedure related events.

Study Selection Criteria

  1. To assess efficacy outcomes, comparative controlled prospective trials were included, with a preference for RCTs.
  2. In the absence of such trials, comparative observational studies, with a preference for prospective studies will be included.
  3. To assess long-term outcomes and adverse effects, single arm studies that captured longer periods of follow-up and/or larger populations may be included.
  4. Studies with duplicative or overlapping populations will be excluded.

Treatment-Resistant Depression
Review of Evidence
Systematic Reviews
A variety of target areas are being investigated for use of deep brain stimulation for treatment resistant depression. A systematic review by Morishita et al (2014) identified 22 published reports with 6 different approaches or targets, including the nucleus accumbens, ventral capsule/ventral striatum, subgenual cingulate cortex, lateral habenula, inferior thalamic nucleus, and medial forebrain bundle.54, Only 3 identified studies were controlled with sham stimulation periods, and 2 multicenter RCTs evaluating subgenual cingulate cortex and ventral striatum/ventral capsule deep brain stimulation were terminated due to futility (interim analysis demonstrating very low probability of success if the trial was completed as planned). A systematic review by Mosley et al (2015) identified an RCT on deep brain stimulation for depression55,; this trial is described next.

Controlled Trials
Ventral Capsule/Ventral Striatum
An industry-sponsored, double-blind RCT evaluating deep brain stimulation targeting the ventral capsule/ventral striatum in patients with chronic treatment resistant depression was published by Dougherty et al (2015).56, 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) deep brain stimulation, 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 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 deep brain stimulation of the ventral capsule/ventral striatum is effective for treating treatment-resistant depression.

Anterior Limb of the Internal Capsule
A crossover RCT evaluating active and sham phases of deep brain stimulation of the ventral anterior limb of the internal capsule in 25 patients with treatment-resistant depression was published after the systematic review by Bergfeld et al (2016).57, Prior to the randomized phase, all patients received 52 weeks of open-label deep brain stimulation 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 score) and 15 (60%) patients were classified as nonresponders. 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 nonresponders). Nine patients were prematurely crossed over to the other intervention. Among all 16 randomized patients, Hamilton Depression Rating scores were significantly improved at the end of the active stimulation phase (mean Hamilton Depression Rating score, 16.5) compared with the sham stimulation phase (mean Hamilton Depression Rating score, 23.1; p<0.001). Mean Hamilton Depression Rating scores were similar after the active (19.0) and sham phases for initial nonresponders (23.0). Among initial responders, the mean Hamilton Depression Rating 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 deep brain stimulation 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 deep brain stimulation-naive.

Subcallosal Singulate
Crowell et al (2019) reported long-term follow-up of a within-subject trial with 28 participants with treatment resistant depression or bi-polar II disorder who were treated with deep brain stimulation of the subcallosal cingulate.58, Patients were included who had depression for at least 12 months with non-response to at least 3 antidepressant medications, a psychotherapy trial, and electroconvulsive therapy (lifetime). Seventeen of the patients had a 1 month sham-controlled period and 11 patients had a 1 month open label period before the stimulation was turned on. Eight year follow-up was available for 14 of the 28 participants. The primary outcome measure was the Illinois Density Index, which assesses the longitudinal area under the curve for behavioral measures; in this study these included response (>50% decrease from baseline) and remission (score <7) on the Hamilton Depression Rating. More than 50% of patients maintained a response and 30% in remission, over the 8 years of follow-up. The physician-rated Clinical Global Impressions severity score improved from 6.1 (severely ill) at baseline to less than 3 (mildly ill or better) in this open label trial.

Section Summary: Treatment-Resistant Depression
A number of case series and several prospective controlled trials evaluating deep brain stimulation in patients with treatment resistant depression have been published. Two RCTs of deep brain stimulation in the subgenual cingulate cortex and ventral striatum/ventral capsule were terminated for futility. Another RCT of stimulation of the ventral striatum/ventral capsule 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 sham or active stimulation of the anterior limb of the internal capsule 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. A 2019 sham-controlled within-subject study of stimulation of the subcallosal singulate found prolonged response in 50% of patients and remission in 30% of patients with treatment resistant depression. Deep brain stimulation for patients with major depressive disorder who have failed all other treatment options is an active area of research, but brain regions that might be effective for treatment resistant depression have yet to be established.

Obsessive-Compulsive Disorder
Several systematic reviews evaluating deep brain stimulation for OCD have been published.59,60,61,62,63, Two of these reviews included meta-analyses and pooled study findings. Kisely et al (2014) included only double-blind RCTs of active vs sham deep brain stimulation.62, Five trials (total n=50 patients) met eligibility criteria and data on 44 patients were available for meta-analysis. Three were parallel-group RCTs with or without a crossover phase and two were only crossover trials. The site of stimulation was the anterior limb of the internal capsule (3 studies), the nucleus accumbens (one study), and the subthalamic nucleus (one study). Duration of treatment ranged from 2 to 12 weeks. All studies reported scores on the Yale-Brown Obsessive Compulsive Scale, which is a 10-item clinician-rated scale, in which higher ratings reflect more intense symptoms, and a score of 24 or more (of a possible 40) indicates severe illness. Most studies designate a therapeutic response as a reduction in Yale-Brown Obsessive Compulsive Scale score of 35% or more from the pretreatment baseline, with a reduction of 25% to 35% considered a partial response. Only 1 of the 5 studies compared the proportion of responders on the Yale-Brown Obsessive Compulsive Scale as an outcome measure and that study did not find a statistically significant difference between active and sham stimulation groups. All studies reported the outcome measure, mean reduction in Yale-Brown Obsessive Compulsive Scale score. When data from the 5 studies were pooled, there was a statistically significant reduction in the mean Yale-Brown Obsessive Compulsive Scale in the active vs the sham group (MD=-8.49; 95% CI, -12.18 to -4.80). The outcome measure, however, does not permit conclusions on whether the between-group difference is clinically meaningful. Trial authors reported 16 serious adverse events including 1 cerebral hemorrhage and 2 infections requiring electrode removal. Additionally, nonserious transient adverse events were reported, including 13 reports of hypomania, 6 of increase in depressive or anxious symptoms, and 6 of headaches.

A meta-analysis by Alonso et al (2015) included studies of any type (including case reports) evaluating deep brain stimulation for OCD and reporting changes in Yale-Brown Obsessive Compulsive Scale score.61, Reviewers identified 31 studies (total n=116 patients). They did not report study type (ie, 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 deep brain stimulation of striatal areas. Of the remaining studies, 5 (27 patients) addressed subthalamic nucleus 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 (ie, >35% reduction in posttreatment Yale-Brown Obsessive Compulsive Scale 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 deep brain stimulation stimulation but could not draw conclusions about stimulation to any particular region or about the safety or efficacy of deep brain stimulation for OCD compared with sham stimulation or other therapy.

Section Summary: Obsessive-Compulsive Disorder
The literature on deep brain stimulation for OCD consists of several 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, a clinically significant change in Yale-Brown Obsessive Compulsive Scale scores. Uncontrolled data have suggested improvements in OCD symptoms after deep brain stimulation treatment but have also identified a substantial number of adverse events. Additional blinded controlled studies are needed to draw conclusions about the impact of deep brain stimulation on the net health benefit.

Multiple Sclerosis
Schuurman et al (2008) 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 MS.2, 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.

Section Summary: Multiple Sclerosis
One RCT reporting on ten MS patients provides insufficient data for drawing conclusions on the efficacy of deep brain stimulation for this population.

Other Indications
The evidence on use of deep brain stimulation for anorexia nervosa, alcohol addiction, Alzheimer disease, Huntington disease, and chronic pain consists of small case series. These case series provide inadequate evidence on which to assess efficacy. 

Summary of Evidence
For individuals who have essential tremor or tremor in Parkinson disease who receive deep brain stimulation of the thalamus, the evidence includes a systematic review and case series. Relevant outcomes are symptoms, functional outcomes, quality of life, and treatment-related morbidity. The systematic review (a TEC Assessment) concluded that there was sufficient evidence that deep brain stimulation of the thalamus results in clinically significant tremor suppression and that outcomes after deep brain stimulation 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 five to six years after deep brain stimulation. The evidence is sufficient to determine that the technology results in a meaningful improvement in the net health outcome.

For individuals who have symptoms (eg, speech, motor fluctuations) associated with Parkinson disease (advanced or >4 years in duration with early motor symptoms) who receive deep brain stimulation of the globus pallidus interna or subthalamic nucleus, the evidence includes randomized controlled trials (RCTs) and systematic reviews. Relevant outcomes are symptoms, functional outcomes, quality of life, and treatment-related morbidity. One of the systematic reviews (a TEC Assessment) concluded that studies evaluating deep brain stimulation of the globus pallidus interna or subthalamic nucleus have consistently demonstrated clinically significant improvements in outcomes (eg, neurologic function). Other systematic reviews have also found significantly better outcomes after deep brain stimulation than after a control intervention. An RCT in patients with levodopa-responsive Parkinson disease of at least four years in duration and uncontrolled motor symptoms found that quality of life at two years was significantly higher when deep brain stimulation was provided in addition to medical therapy. Meta-analyses of RCTs comparing deep brain stimulation of the globus pallidus interna with deep brain stimulation of the subthalamic nucleus 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 a meaningful improvement in the net health outcome.

For individuals who have primary dystonia who receive deep brain stimulation of the globus pallidus interna or subthalamic nucleus, the evidence includes systematic reviews, RCTs, and case series. Relevant outcomes are symptoms, functional outcomes, quality of life, and treatment-related morbidity. 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). Both double-blind RCTs 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 the net health outcome.

For individuals who have tardive dyskinesia or tardive dystonia who receive deep brain stimulation, the evidence includes an RCT and case series. Relevant outcomes are symptoms, functional outcomes, quality of life, and treatment-related morbidity. Few studies were identified and they had small sample sizes (range, 9-19 patients). The RCT did not report statistically significant improvement in the dystonia severity outcomes or the secondary outcomes related to disability and quality of life but may have been under-powered Additional studies, especially RCTs or other controlled studies, are needed. The evidence is insufficient to determine the effects of the technology on health outcomes.

For individuals who have epilepsy who receive deep brain stimulation, the evidence includes systematic reviews, RCTs and many observational studies. Relevant outcomes are symptoms, functional outcomes, quality of life, and treatment-related morbidity. Two RCTs with more than 15 patients were identified. The larger RCT evaluated anterior thalamic nucleus deep brain stimulation and reported that deep brain stimulation had a positive impact on seizure frequency during some parts of the blinded trial phase but not others, and a substantial number of adverse events (in >30% of patients). There were no differences between groups in 50% responder rates, Liverpool Seizure Severity Scale, or Quality of Life in Epilepsy scores. A 7 year open-label follow-up of the RCT included 66% of implanted patients; reasons for missing data were primarily related to adverse events or dissatisfaction with the device. Reduction in seizure frequency continued to improve during follow-up among the patients who continued follow-up. The smaller RCT (n=16) showed a benefit with deep brain stimulation. 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 deep brain stimulation on patient outcomes. The evidence is insufficient to determine the effects of the technology on health outcomes.

For individuals who have Tourette syndrome who receive deep brain stimulation, the evidence includes observational studies, RCTs and systematic reviews. Relevant outcomes are symptoms, functional outcomes, quality of life, and treatment-related morbidity..Two RCTs with 15 or more patients have been reported. One RCT found differences in severity of Tourette syndrome for active vs sham at three months while the other RCT did not. Neither study demonstrated improvements in comorbid symptoms of obsessive-compulsive disorder or depression Both studies reported high rates of serious adverse events The evidence is insufficient to determine the effects of the technology on health outcomes.

For individuals who have cluster headaches or facial pain who receive deep brain stimulation, the evidence includes a randomized crossover study and case series. Relevant outcomes are symptoms, functional outcomes, quality of life, and treatment-related morbidity. In the randomized study, the between-group difference in response rates did not differ significantly between active and sham stimulation phases. Additional RCTs or controlled studies are needed. The evidence is insufficient to determine the effects of the technology on health outcomes.

For individuals who have treatment resistant depression who receive deep brain stimulation, the evidence includes RCTs and systematic reviews. Relevant outcomes are symptoms, functional outcomes, quality of life, and treatment-related morbidity. A number of case series and several prospective controlled trials evaluating deep brain stimulation in patients with have been published. Two RCTs of deep brain stimulation in the subgenual cingulate cortex and ventral striatum/ventral capsule were terminated for futility. Another RCT of stimulation of the same brain area (ventral striatum/ventral capsule) 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 sham or active stimulation of the anterior limb of the internal capsule 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. Stimulation of the subcallosal (subgenual) cingulate was evaluated in a 2019 sham-controlled within-subject study that found prolonged response in 50% of patients and remission in 30% of patients with treatment resistant depression. Deep brain stimulation for patients with major depressive disorder who have failed all other treatment options is an active area of research, but the brain regions that might prove to be effective for treatment resistant depression have yet to be established.The evidence is insufficient to determine the effects of the technology on health outcomes.

For individuals who have obsessive-compulsive disorder who receive deep brain stimulation, the evidence includes RCTs and systematic reviews. Relevant outcomes are symptoms, functional outcomes, quality of life, and treatment-related morbidity. Among the RCTs on deep brain stimulation for obsessive-compulsive disorder, only one has reported the outcome of greatest clinical interest (therapeutic response rate), and that trial did not find a statistically significant benefit for deep brain stimulation compared with sham treatment. The evidence is insufficient to determine the effects of the technology on health.

For individuals who have multiple sclerosis who receive deep brain stimulation, the evidence includes an RCT. Relevant outcomes are symptoms, functional outcomes, quality of life, and treatment-related morbidity. One RCT with ten multiple sclerosis patients is insufficient evidence on which to draw conclusions about the efficacy of deep brain stimulation in this population.Additional trials are required. The evidence is insufficient to determine the effects of the technology on health outcomes. 

For individuals who have anorexia nervosa, alcohol addiction, Alzheimer disease, Huntington disease, or chronic pain who receive deep brain stimulation, the evidence includes case series. Relevant outcomes are symptoms, functional outcomes, quality of life, and treatment-related morbidity. RCTs are needed to evaluate the efficacy of deep brain stimulation for these conditions. The evidence is insufficient to determine the effects of the technology on health outcomes.

Clinical Input From Physician Specialty Societies and Academic Medical Centers
While the various physician specialty societies and academic medical centers may collaborate with and make recommendations during this process, through the provision of appropriate reviewers, input received does not represent an endorsement or position statement by the physician specialty societies or academic medical centers, unless otherwise noted.

In response to requests, input was received from 2 academic medical centers and 2 physician specialty societies while this policy was under review in 2014. Input supported the use of bilateral deep brain stimulation in patients with medically unresponsive tremor in both limbs.

Practice Guidelines and Position Statements
American Academy of Neurology
Essential Tremor
In 2011, the American Academy of Neurology (AAN) updated its guidelines on the treatment of essential tremor.64, This update did not change the conclusions and recommendations of the AAN (2005) practice parameters on deep brain stimulation for essential tumor.65, The guidelines stated that bilateral deep brain stimulation of the thalamic nucleus may be used to treat medically refractory limb tremor in both upper limbs (level C, possibly effective) but that there were insufficient data on the risk/benefit ratio of bilateral vs unilateral deep brain stimulation in the treatment of limb tremor. There was insufficient evidence to make recommendations on the use of thalamic deep brain stimulation for head or voice tremor (level U, treatment is unproven).

Parkinson Disease
Guidelines from AAN (2006) on the treatment of Parkinson disease with motor fluctuations and dyskinesia found that, although criteria are evolving, patients with Parkinson disease considered candidates for deep brain stimulation include those who are levodopa-responsive, non-demented, and neuropsychiatrically intact patients who have intractable motor fluctuations, dyskinesia, or tremor.66, The AAN concluded that deep brain stimulation of the subthalamic nucleus may be considered a treatment option in Parkinson disease patients to improve motor function and to reduce motor fluctuations, dyskinesia, and medication usage (level C, possibly effective) but found evidence insufficient to make any recommendations about the effectiveness of deep brain stimulation of the globus pallidus or the ventral intermediate nucleus of the thalamus in reducing motor complications or medication usage, or in improving motor function in Parkinson disease patients.

Guidelines from AAN (2010) on the treatment of nonmotor symptoms of Parkinson disease found insufficient evidence for the treatment of urinary incontinence with deep brain stimulation of the subthalamic nucleus.67, The AAN found that deep brain stimulation of the subthalamic nucleus possibly improves sleep quality in patients with advanced Parkinson disease. However, none of the studies performed deep brain stimulation to treat insomnia as a primary symptom, and deep brain stimulation of the subthalamic nucleus is not currently used to treat sleep disorders.

Tardive Syndromes
Guidelines from AAN on the treatment of tardive syndromes were updated in 2018.68, The latest guidelines state that “pallidal deep brain stimulation possibly improves tardive dyskinesia and might be considered as a treatment for intractable tardive dyskinesia (Level C, which indicates that the treatment is possibly effective, based on ≥1 class II study and consistent with ≥2 class III studies).

Tourette Syndrome
Guidelines from AAN (2019) provide recommendations on the assessment for and use of deep brain stimulation in adults with severe, treatment-refractory tics.69, AAN notes that patients with severe Tourette syndrome resistant to medical and behavioral therapy may benefit from deep brain stimulation, but there is no consensus on the optimal brain target. Brain regions that have been stimulated in patients with Tourette Syndrome include the centromedian thalamus, the globus pallidus internus (ventral and dorsal), the globus pallidus externus, the subthalamic nucleus, and the ventral striatum/ventral capsular nucleus accumbens region. AAN concludes that deep brain stimulation of the anteromedial globus pallidus is possibly more likely than sham stimulation to reduce tic severity.

American Society for Stereotactic and Functional Neurosurgery et al
The American Society for Stereotactic and Functional Neurosurgery and the Congress of Neurological Surgeons (2014) published a joint systematic review and guidelines on deep brain stimulation for obsessive-compulsive disorder.60, The document concluded that there was a single level I study supporting the use of bilateral subthalamic nucleus deep brain stimulation for medically refractory obsessive-compulsive disorder and a single level II study supporting bilateral nucleus accumbens deep brain stimulation for medically refractory obsessive-compulsive disorder. It also concluded that the evidence on unilateral deep brain stimulation was insufficient.

Congress of Neurologic Surgeons
In 2018, evidence-based guidelines from the Congress of Neurologic Surgeons compared the efficacy of bi-lateral deep brain stimulation of the subthalamic nucleus and globus pallidus internus for the treatment of patients with Parkinson disease.70,

Table 19. Recommendations of the Congress of Neurologic Surgeons for DBS for Parkinson Disease

Goal Most Effective Area of Stimulation (subthalamic nucleus or globus pallidus internus) Level of Evidence
Improving motor symptoms subthalamic nucleus or globus pallidus internus are similarly effective I
Reduction of dopaminergic medication subthalamic nucleus I
Treatment of "on" medication dyskinesias globus pallidus internus if reduction of medication is not anticipated I
Quality of life no evidence to recommend one over the other I
Lessen impact of DBS on cognitive decline globus pallidus internus I
Reduce risk of depression globus pallidus internus I
Reduce adverse effects insufficient evidence to recommend one over the other Insufficient

DBS: Deep brain stimulation

National Institute for Health and Care Excellence
The United Kingdom's National Institute for Health and Care Excellence (NICE) has published guidance documents on deep brain stimulation, as discussed in the following subsections.

Tremor and Dystonia
In 2006, NICE made the same statements about use of deep brain stimulation for treatment of both tremor and dystonia.71, Unilateral and bilateral stimulation of structures responsible for modifying movements, such as the thalamus, globus pallidus, and the subthalamic nucleus, which interact functionally with the substantia nigra, are included in both guidance statements. The guidance stated: “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.”

Refractory Chronic Pain Syndromes (Excluding Headache)
In 2011, guidance from NICE indicated there is evidence that deep brain stimulation for refractory chronic pain (excluding headache) is associated with serious risks.72, However, the procedure is “efficacious in some patients” refractory to other treatments.” Patients should be informed that deep brain stimulation may not control their chronic pain symptoms and that possible risks associated with this procedure include the small risk of death.

Intractable Trigeminal Autonomic Cephalalgias
In 2011, guidance from NICE indicated that the evidence on the efficacy of deep brain stimulation for intractable trigeminal autonomic cephalalgias (eg, cluster headaches) was “limited and inconsistent, and the evidence on safety shows that there were serious but well-known adverse effects.”73,

Refractory Epilepsy
In 2012, guidance from NICE indicated that the evidence on the efficacy of deep brain stimulation for refractory epilepsy was limited in both quantity and quality: “The evidence on safety showed that there are serious but well-known adverse effects.74,

Parkinson Disease
In 2003, NICE stated that the evidence on the safety and efficacy of deep brain stimulation for treatment of Parkinson disease “appears adequate to support the use of the procedure.”75, The guidance noted that deep brain stimulation should only be offered when Parkinson disease is refractory to best medical treatment.

U.S. Preventive Services Task Force Recommendations
Not applicable.

Ongoing and Unpublished Clinical Trials
Some currently unpublished trials that might influence this review are listed in Table 20. Studies with fewer than 20 participants are not included.

Table 20. Summary of Key Trials 

NCT No. Trial Name Planned Enrollment Completion Date
Ongoing      
Epilepsy      
NCT01521754a Product Surveillance Registry- Deep Brain Stimulation for Epilepsy 191 Mar 2020
NCT02076698 Deep Brain Stimulation of the Anterior Nucleus of the Thalamus in Epilepsy 62 Jun 2021
NCT04181229 Deep Brain Stimulation Post Failed Vagal Nerve Stimulation 50 Nov 2022
NCT04164056 Hippocampal and Thalamic deep brain stimulation for Bilateral Temporal Lobe Epilepsy 80 Sep 2024
NCT03900468a Medtronic Deep Brain Stimulation Therapy for Epilepsy Post-Approval Study (EPAS) 216 Mar 2027
Huntington's Disease      
NCT02535884a Deep Brain Stimulation of the Globus Pallidus (GP) in Huntington’s Disease 50 Oct 2020
Parkinson Disease      
NCT02937688a Deep Brain Stimulation for Parkinson’s Disease International Study (REACH-PD) 264 Apr 2021
NCT00354133 The Effect of Deep Brain Stimulation of the Subthalamic Nucleus on Quality of Life in Comparison to Best Medical Treatment in Patients With Complicated Parkinson's Disease and Preserved Psychosocial Competence (EARLYSTIM-study) 251 Mar 2022
NCT01839396a Implantable Neurostimulator for the Treatment of Parkinson's Disease (INTREPID) 313 Aug 2023
Obsessive-Compulsive Disorder      
NCT01506206 ON/OFF Stimulation and Impulsivity in Patients With Deep Brain Stimulators 60 Dec 2020
NCT01590862 ON/OFF Stimulation and Reward Motivation in Patients With Deep Brain Stimulators 60 Dec 2020
NCT00640133 Effectiveness of Deep Brain Stimulation for Treating People With Treatment Resistant Obsessive-Compulsive Disorder 27 Aug 2020
NCT02773082a Reclaim Deep Brain Stimulation Therapy for Obsessive-Compulsive Disorder (OCD) 50 Apr 2020
NCT04228744 The Efficacy and Mechanism of deep brain stimulation in VIC and NAcc for Refractory OCD 20 Dec 2022
NCT02844049 European Study of Quality of Life in Resistant OCD Patients Treated by subthalamic nucleus deep brain stimulation 60 Dec 2023
Treatment Resistant Depression      
NCT03653858a Controlled Randomized Clinical Trial to Assess Efficacy of Deep Brain Stimulation of the slMFB in Patients With Treatment Resistant Major Depression (FORSEEIII) 47 Jun 2023
NCT01984710 Deep brain stimulation for treatment resistant depression Medtronic Activa PC+S 20 Sep 2023
NCT00367003 Deep Brain Stimulation for Treatment Resistant Depression 40 Nov 2024
Unpublished      
NCT01801319 A Clinical Evaluation of Subcallosal Cingulate Gyrus Deep Brain Stimulation for Treatment-Resistant Depression 40 Dec 2017
(status unknown)
NCT01329133 Deep Brain Stimulation and Obsessive-Compulsive Disorder (STOC2) 31 Apr 2019
(completed)
NCT01973478 Deep Brain Stimulation in Patients With Chronic Treatment Resistant Depression 9 enrolled Jan 2020
(suspended)

NCT: nationa clinical trial.
ª Denotes industry-sponsored or cosponsored trial.  

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Coding Section

Codes Number Description
CPT   See Policy Guidelines
  95976 (effective 01/01/2019)  Electronic analysis of implanted neurostimulator pulse generator/transmitter (eg, contact group[s], interleaving, amplitude, pulse width, frequency [Hz], on/off cycling, burst, magnet mode, dose lockout, patient selectable parameters, responsive neurostimulation, detection algorithms, closed loop parameters, and passive parameters) by physician or other qualified health care professional; with simple cranial nerve neurostimulator pulse generator/transmitter programming by physician or other qualified health care professional 
 

95977 (effective 01/01/2019)  

Electronic analysis of implanted neurostimulator pulse generator/transmitter (eg, contact group[s], interleaving, amplitude, pulse width, frequency [Hz], on/off cycling, burst, magnet mode, dose lockout, patient selectable parameters, responsive neurostimulation, detection algorithms, closed loop parameters, and passive parameters) by physician or other qualified health care professional; with complex cranial nerve neurostimulator pulse generator/transmitter programming by physician or other qualified health care professional 
  95983 (effective 01/01/2019)  Electronic analysis of implanted neurostimulator pulse generator/transmitter (eg, contact group[s], interleaving, amplitude, pulse width, frequency [Hz], on/off cycling, burst, magnet mode, dose lockout, patient selectable parameters, responsive neurostimulation, detection algorithms, closed loop parameters, and passive parameters) by physician or other qualified health care professional; with brain neurostimulator pulse generator/transmitter programming, first 15 minutes face-to-face time with physician or other qualified health care professional 
  95984 (effective 01/01/2019)  Electronic analysis of implanted neurostimulator pulse generator/transmitter (eg, contact group[s], interleaving, amplitude, pulse width, frequency [Hz], on/off cycling, burst, magnet mode, dose lockout, patient selectable parameters, responsive neurostimulation, detection algorithms, closed loop parameters, and passive parameters) by physician or other qualified health care professional; with brain neurostimulator pulse generator/transmitter programming, each additional 15 minutes face-to-face time with physician or other qualified health care professional (List separately in addition to code for primary procedure) 
ICD-9 Procedure 02.93 Implantation of intracranial neurostimulator
ICD-9 Diagnosis 332.0 Paralysis agitans (Parkinson’s disease)
  332.1 Secondary parkinsonism
  333.1 Essential and other specified forms of tremor
  333.6 Idiopathic torsion dystonia
  333.79 Acquired torsion dystonia, other (includes symptomatic torsion dystonia)
  333.83 Spasmodic torticollis
  333.89 Fragments of torsion dystonia, other
HCPCS L8680 Implantable neurostimulator electrode, each
  L8685 Implantable neurostimulator pulse generator, single array, rechargeable, includes extension
  L8686 Implantable neurostimulator pulse generator, single array, nonrechargeable, includes extension
  L8687 Implantable neurostimulator pulse generator, dual array, rechargeable, includes extension
  L8688 Implantable neurostimulator pulse generator, dual array, nonrechargeable, includes extension
ICD-10-CM (effective 10/01/15) G20 Parkinson's disease 
  G21.0-G21.9 Secondary Parkinsonism, code range 
  G24.01-G24.9 Dystonia code range 
  G25.0 Essential tremor 
ICD-10-PCS (effective 10/01/15)

 

ICD-10-PCS codes are only used for inpatient services.
 

00H00MZ, 00H03MZ,
00H04MZ, 00H60MZ,
00H63MZ, 00H64MZ,
00HE0MZ, 00HE3MZ,
00HE4MZ

Surgical, insertion, neurostimulator lead, code by body part (brain, cerebral ventricle, cranial nerve) and approach (open, percutaneous, percutaneous endoscopic)
  00P00MZ, 00P03MZ,
00P04MZ, 00P60MZ,
00P63MZ, 00P64MZ,
00PE0MZ, 00PE3MZ,
00PE4MZ
Surgical, removal, neurostimulator lead, code by body part (brain, cerebral ventricle, cranial nerve) and approach (open, percutaneous, percutaneous endoscopic) 
Type of Service  Surgery   
 Place of Service Inpatient   

Procedure and diagnosis codes on Medical Policy documents are included only as a general reference tool for each policy. They may not be all-inclusive.

This medical policy was developed through consideration of peer-reviewed medical literature generally recognized by the relevant medical community, U.S. FDA approval status, nationally accepted standards of medical practice and accepted standards of medical practice in this community, Blue Cross and Blue Shield Association technology assessment program (TEC) and other non-affiliated technology evaluation centers, reference to federal regulations, other plan medical policies, and accredited national guidelines.

"Current Procedural Terminology © American Medical Association.  All Rights Reserved" 

History From 2014 Forward     

06/09/2020 

Annual review, no change to policy intent. Updating background, rationale and references. 

06/03/2019 

Annual review, no change to policy intent. Updating description, rationale and references. 

12/21/2018 

Updating with additional 2019 codes.  

12/20/2018 

Updating with 2019 codes.  

06/19/2018 

Annual review, no change to policy intent. Updating background, regulatory status, rationale and references. 

06/01/2017

Annual review, no change to policy intent. Updating background, description, guidelines, rationale, references and policy verbage. 

11/28/2016 

Interim review to add the St.Jude Medical Infinity DBS system as an FDA approved device. No other changes made. 

06/01/2016 

Annual review, no change to policy intent. Updating background, description, regulatory status, rationale and references. 

06/02/2015 

Annual review, policy updated to contain "Bilateral deep brainstimulation of the thalamus may be considered MEDICALLY NECESSARY in patients with disabling, medically unresponsive tremor in both limbs due to essential tramor or Parkinson's disease.". Updated background, description, regulatory status, guidelines, rationale and references. Added coding.

06/23/2014

Annual review. Added anorexia nervosa, alcohol addiction, chronic pain as investigational. Updated rationale and references.


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