Unilateral electrical deep brain stimulation of the thalamus meets primary coverage criteria for effectiveness in improving health outcomes in the treatment of disabling, medically unresponsive tremor due to essential tremor or Parkinson's disease.

 

Unilateral or bilateral deep brain stimulation of the globus pallidus or subthalamic nucleus meets member benefit certificate Primary Coverage Criteria that there be scientific evidence of effectiveness in improving health outcomes in the following patients:

 

 

For contracts without primary coverage criteria, deep brain stimulation for the treatment of other psychiatric or neurologic disorders, including but not limited to multiple sclerosis, post-traumatic dyskinesia, tardive dyskinesia, Tourette syndrome, depression, obsessive compulsive disorder, Alzheimer disease, anorexia nervosa, alcohol addiction, chronic pain, epilepsy and chronic cluster headaches, is considered investigational. Investigational services are specific contract exclusions in most member benefit certificates of coverage.

 

Unilateral electrical deep brain stimulation of the thalamus meets primary coverage criteria for effectiveness in improving health outcomes in the treatment of disabling, medically unresponsive tremor due to essential tremor or Parkinson's disease.

 

Unilateral or bilateral deep brain stimulation of the globus pallidus or subthalamic nucleus meets member benefit certificate Primary Coverage Criteria that there be scientific evidence of effectiveness in improving health outcomes in the following patients:

 

Those with Parkinson’s disease with ALL of the following:

 a good response to levodopa as  manifested by appropriate testing (e.g., UPDRS); AND

 motor complications not controlled by pharmacologic therapy. Patients aged greater than 7 years with chronic, intractable (drug refractory) primary dystonia, including generalized and/or segmental dystonia, hemidystonia, and cervical dystonia (torticollis).  

 

Patients aged greater 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 multiple sclerosis, tardive dyskinesia, and post-traumatic dyskinesia does not meet member benefit certificate Primary Coverage Criteria that there be scientific evidence of effectiveness in improving health outcomes.

 

Deep brain stimulation for the treatment of other psychiatric or neurologic disorders, including but not limited to Tourette Syndrome, depression, obsessive compulsive disorder, epilepsy and chronic cluster headaches does not meet member benefit certificate Primary Coverage Criteria that there be scientific evidence of effectiveness in improving health outcomes.

 

For contracts without primary coverage criteria, deep brain stimulation for other movement disorders, including but not limited to multiple sclerosis, tardive dyskinesia, and post-traumatic dyskinesia, is considered investigational.  

 

Deep brain stimulation for the treatment of other psychiatric or neurologic disorders, including but not limited to Tourette Syndrome, depression, obsessive compulsive disorder, epilepsy and chronic cluster headaches, is considered investigational.  Investigational services are an exclusion in the member certificate of coverage.

 

Tremor suppression was total or clinically significant in 82%–91% of operated sides in 179 patients who underwent implantation of thalamic stimulation devices. Results were durable for up to 8 years, and side effects of stimulation were reported as mild and largely reversible. These results are 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.

 

A wide variety of studies consistently demonstrate that deep brain stimulation of the globus pallidus 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’s 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 is both statistically significant and clinically meaningful. The beneficial treatment effect lasts at least for the 6–12 months observed in most trials. While there is not a great deal of long-term follow-up, the available data are generally positive.

 

Adverse effects and morbidity are similar to those known to occur with thalamic stimulation. Deep brain stimulation possesses advantages to other treatment options. In comparison to pallidotomy, deep brain stimulation can be performed bilaterally. The procedure is non-ablative and reversible.

 

Deep brain stimulation for the treatment of primary dystonia received FDA approval through the Humanitarian Device Exemption (HDE) process. The HDE approval process is available for those conditions that effect less 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 DBS in 201 patients represented in 34 manuscripts.  There were 3 studies that reported at least 10 cases of primary dystonia. In these studies, clinical improvement ranged from 50% to 88%. A total of 21 pediatric patients were studied; 81% were older than 7 years. Among these patients there was about a 60% improvement in clinical scores. As noted in the analysis of risk and probably benefit, the only other treatment options for chronic refractory primary dystonia are neurodestructive procedures. Deep brain stimulation provides a reversible alternative. The FDA Summary of Safety and Probable Benefit states, “Although there are a number of serious adverse events experienced by patients treated with deep brain stimulation, in the absence of therapy, chronic intractable dystonia can be very disabling and in some cases, progress to a life-threatening stage or constitute a major fixed handicap. When the age of dystonia occurs prior to the individual reaching their full adult size, the disease not only can affect normal psychosocial development but also cause irreparable damage to the skeletal system. As the body of the individual is contorted by the disease, the skeleton may be placed under constant severe stresses that may cause permanent disfigurement. Risks associated with deep brain stimulation for dystonia appear to be similar to the risk associated with the performance of stereotactic surgery and the implantation of deep brain stimulation systems for currently approved indications, except when used in either child or adolescent patient groups.”

 

Since the FDA approval, there have been additional published trials of deep brain stimulation for dystonia, which continue to report positive results.  Vidailhet and colleagues reported the results of a prospective multi-institutional case series of 22 patients with primary generalized dystonia. Symptoms were evaluated prior to surgery and at several points up to 1 year of follow-up, in a double-blind fashion with the stimulator turned on and off. Dystonia scores were significantly better with the neurostimulator turned on.

 

Deep brain stimulation of the posterior hypothalamus for the treatment of chronic cluster headaches has been investigated since recent functional studies have suggested cluster headaches have a central hypothalamic pathogenesis. Franzini and colleagues and Leone et al, reported deep brain stimulation with long-term, high-frequency, electrical stimulation of the ipsilateral posterior hypothalamus resulted in long-term pain relief (1–26 months of follow-up) without significant adverse effects in 5–8 patients with chronic cluster headaches.  The results from these reports seem promising; however, the authors note further studies are needed to determine the long-term safety and effectiveness of this treatment.

 

A search of the MEDLINE database for the period of January 2006 to August 2007 identified a number of papers on the topic of deep brain stimulation. A systematic review of 34 studies (921 patients) examined outcomes following subthalamic stimulation for patients with Parkinson’s disease who had failed medical management (e.g., motor fluctuations, dyskinesia, and other medication side effects).  Twenty studies, primarily class IV (uncontrolled cohorts or case series), were included in the meta-analysis. Subthalamic stimulation was found to improve activities of daily living by 50% over baseline as measured by the Unified Parkinson’s Disease Rating Scale (UPDRS) part II (decrease of 13.35 points out of 52). There was a 28-point decrease in the UPDRS III score (out of 108) indicating a 52% improvement in the severity of motor symptoms while the patient was not taking medication. A strong relationship was found between the pre-operative dose response to L-dopa and improvements in both the UPDRS II and III. 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.

 

Two randomized trials assessed the efficacy of subthalamic stimulation for Parkinson’s disease. The German Parkinson Study Group randomized 78 patient pairs with advanced Parkinson’s disease and severe motor symptoms to either subthalamic stimulation or medical management.  Subthalamic stimulation improved severity of symptoms without medication in 55 of 78 pairs (from 48 to 28 on the UPDRS III). Improvements in quality of life were greater than medical management in 50 of 78 pairs (average change from 42 to 32 on the 100 point Parkinson’s Disease Questionnaire), with 24% to 38% improvements in subscales for mobility, activities of daily living, emotional well-being, stigma, and bodily discomfort. Serious adverse events were more common with neurostimulation (13% vs. 4%) and included a fatal intracerebral hemorrhage. Another European multicenter study assessed whether subthalamic stimulation might maintain quality of life and motor function if performed earlier in the course of the disease.  Ten matched patient pairs younger than 55 years of age with mild to moderate motor signs were randomly assigned to deep brain stimulation or medical management. There was no difference in the severity of Parkinsonian motor disability while “on” medication. However, in the medically treated patients both the daily dose of levodopa and the severity of levadopa-induced motor complications increased over the 18 months of the study (12% and 15%, respectively), while in the surgical patients the daily dose of levodopa was reduced by 57% and the severity of levodopa-induced motor complications improved by 83%. Additional studies are needed to determine the long-term effect of subthalamic stimulation in this younger patient population.

 

The Deep-Brain Stimulation for Dystonia Study Group compared bilateral pallidal neurostimulation with sham stimulation in 40 patients with dystonia who had failed medical management (3-month randomized trial with a 6-month open-label extension).  Blinded assessment with the Burke-Fahn-Marsden Dystonia Rating Scale found improvements in the movement score (16 points versus 1.6 points in sham controls), which corresponded to a 39% reduction in symptoms. Disability scores improved by 4 points in the neurostimulation group compared with a 0.8 point improvement in the control subjects (38% improvement). The study found a 30% improvement in quality of life (change of 10 versus 4 points in controls) following stimulation of the globus pallidus. There was high variability in baseline scores and in the magnitude of improvement; 6 patients (17%) were considered to have failed treatment (< 25% improvement), 5 patients (25%) improved by more than 75%. No single factor was found to predict the response to treatment. Independent assessors found similar improvements in the control group after the 6-month open-label extension.

 

Stimulation of the globus pallidus has also been examined as a treatment of tardive dyskinesia in a phase II double-blinded (presence and absence of stimulation) multicenter study.  The trial was stopped early due to successful treatment (greater than 40% improvement) in the first 10 patients. Additional studies with more patients and longer follow-up are needed. Prospective, controlled trials are lacking for other disorders. Stimulation of the posterior hypothalamus was reported to have completely resolved headache in 10 of 16 chronic cluster headache patients and in one patient with neuralgiform headache; treatment failed in 3 of 3 patients who had atypical facial pain.  In addition to the areas of research discussed above, deep brain stimulation is being investigated for the treatment of Tourette syndrome, depression, obsessive compulsive disorder, and epilepsy.  Evidence remains insufficient to evaluate the efficacy of deep brain stimulation for these disorders.

 

The policy was updated with a MEDLINE® search.  Schuurman and colleagues followed 65 patients comparing thalamic stimulation and thalamotomy for treatment of tremor due to Parkinson’s disease (PD) , essential tremor (ET), and multiple sclerosis (MS). After 5 years, 48 patients were available for follow-up.  The primary outcome measure was functional status on the Frenchay Activities Index (FAI); secondary measures were tremor severity, frequency of complications, and patients’ assessment of outcome. The mean difference in FAI scores was 4.4 (95% CI: 1.1–7.7) after 6 months, 3.3 (95% CI: 0.03–6.6) after 2 years and 4.0 (95% CI: 0.3–7.7) after 5 years in favor of stimulation. Tremor suppression was equally effective after both procedures, and stable in PD patients. A diminished effect was observed in half of the patients with ET and MS. Small numbers of patients with ET and MS limit conclusions with respect to these conditions. Neurological adverse effects were higher after thalamotomy. Subjective assessments favored stimulation (Schuurman, 2008).  Hariz et al. evaluated outcomes of thalamic deep brain stimulation in patients with tremor predominant PD who participated in a multicenter European study and reported that, at 6 years post-surgery, tremor was still effectively controlled and appendicular rigidity and akinesia remained stable when compared with baseline (Hariz, 2008).

 

Weaver and colleagues report 6-month outcomes of a multicenter randomized, controlled trial comparing DBS with best medical therapy for patients with advanced PD. Of 278 patients that were screened, 255 were randomized; 134 to best medical therapy and 121 to DBS (61 to stimulation of the globus pallidus and 60 to stimulation of the subthalamic nucleus). By intention-to-treat analysis, patients who received DBS gained a mean of 4.6 hours/day of on time without troubling dyskinesia compared to no hours gained for patients receiving best medical therapy (p<0.001). Seventy-one percent of DBS patients experienced clinically meaningful motor function improvements (i.e., >5 point change in Unified Parkinson Disease Rating Scale of motor function) versus 32% of best medical therapy group. Significantly greater improvements in quality of life measures were achieved by DBS patients. At least one serious adverse event occurred in 49 DBS patients versus 15 in the best medical therapy patients, including 39 related to the surgical procedure and one death secondary to cerebral hemorrhage (Weaver, 2009).

 

Witt et al. performed an ancillary protocol as part of a multicenter randomized, controlled trial (previously reviewed, Deuschl et al., 2006 ) to assess neuropsychiatric consequences of DBS in patients with Parkinson’s disease (Witt, 2008).  One hundred-twenty-three patients with PD and motor fluctuations were randomized to DBS or best medical treatment. Neuropsychological and psychiatric examinations at baseline and 6 months post-implantation were compared. DBS of the subthalamic nucleus did not reduce overall cognition or affectivity. There was a selective decrease in frontal cognitive functions and an improvement in anxiety in patients after treatment that did not affect improvements in quality of life.

 

Appleby et al. report on a meta-analysis focused on adverse events associated with DBS in order to assess the risks and benefits of the treatment as they relate to its potential use in the psychiatric setting (Appleby, 2007).  They concluded that DBS is an effective treatment for PD, dystonia, and essential tremor and rates of depression, cognitive impairment, mania, and behavior change are low. Prevalence of depression was 2–4%, mania 0.9–1.7%, emotional changes 0.1–0.2%, and suicidal ideation/suicide attempt was 0.3–0.7%. The completed suicide rate was 0.16–0.32%. In light of the rate of suicide in patients treated with DBS, particularly with thalamic and globus pallidus interna (GPi) stimulation, the authors argue for prescreening patients for suicide risk.

 

A number of recent papers, mainly case series, focus on the use of DBS for treatment of dystonia. Vidailhet et al. compared outcomes at 3 years with those reported at 1 year for the 22 patients in their study of bilateral, pallidal DBS for generalized dystonia referenced in a previous update (Vidailhet, 2005) and found that the motor improvement observed at 1 year was maintained. At 3 years, measures of cognition and mood were unchanged from baseline and 1 year evaluations (Vidailhet, 2007).  Egidi et al. retrospectively reviewed records of 69 patients treated in multiple Italian centers with DBS implanted in the GPi; 37 patients had primary and 32 had secondary dystonia. Improvement of at least 50% in Burke-Fahn-Marsden severity scale was reached by 45% of primary and 37% of secondary dystonia patients at 3–84 months’ follow-up (longer than 24 months in half of the patients) (Egidi, 2007).  

 

No controlled trials of DBS for seizures were identified. A multicenter, randomized controlled trial of stimulation of the anterior nucleus of the thalamus in epilepsy (SANTE) is in progress. Two small cross-over studies of DBS for Tourette syndrome were identified, one comparing unilateral and bilateral stimulation (5 patients) and the other with 3 patients comparing thalamic, pallidal, simultaneous thalamic and pallidal, and sham stimulation (Maciunas, 2007) (Welter, 2008).  No controlled trials of DBS for tardive dyskinesia or cluster headache were found.

 

A crossover, double-blind, multicenter study of DBS for treatment of refractory obsessive-compulsive disorder (OCD) is reported by Mallet et al (Mallet, 2008).  Eighteen patients were enrolled, one withdrew and one required removal of the stimulator before randomization because of infection. Three months after surgery, 8 patients were randomly assigned to receive active stimulation for 3 months, followed by 1 month of washout, then 3 months of sham stimulation (on-off group). The other group followed the same treatment schedule in reverse (off-on group). New or worsening symptoms were classified as adverse events. It was recommended that medical treatment remain stable and adjustments necessitated by the patient’s psychiatric condition were recorded. Medication was held constant during the 10-month protocol, except for transient increase in benzodiazepine therapy in 3 patients and augmentation of neuroleptic treatment in one patient for exacerbated anxiety. The primary outcome measure was severity of OCD as assessed by the Yale-Brown Obsessive Compulsive Scale (Y-BOCS) measured at the end of each period. The Y-BOCS score was significantly lower at the end of active stimulation than at the end of the sham stimulation (mean score, 19 +/- 8 vs. 28 +/- 7; p=0.01) independent of the group and the period. No significant carryover effect between treatment phases was detected. Patients who had active stimulation first (on-off group) tended to have a larger treatment effect than the off-on group (p=0.06).

 

Outcomes on secondary measures of global health and functioning were significantly better at the end of the stimulation period. Scores on Montgomery and Asberg Depression Scale (MADRS), Brief Scale for Anxiety, neuropsychological ratings, and self-reported disability (Sheehan Disability Scale) did not differ significantly at the end of treatment and sham sessions. Fifteen serious adverse events were reported in 11 patients, the most serious a parenchymal brain hemorrhage. Transient motor and psychiatric symptoms induced by active stimulation resolved spontaneously or with adjustment of stimulation settings. Seven behavioral adverse events were reported in 5 patients during stimulation. Hypomania was the main psychiatric serious adverse event; symptoms resolved with adjustment of stimulation settings. The authors note that the multicenter design might be a limitation of the study because of variation in targeting of stimulation. In addition, in order to preserve blinding, stimulation settings were kept below the threshold known to induce adverse effects and may have been too low to reduce symptoms. They conclude that their finding suggest that DBS may lessen severity of symptoms; however, serious adverse events did occur. Larger studies with longer follow-up are needed including evaluation of quality of life and ability to function in social and work situations (Mallet, 2008).

 

Sachdev and Chen note in a January 2009 review that there has been a shift of interest in psychosurgery away from ablative techniques and toward deep brain stimulation (Sachdev, 2009).  Studies of DBS for depression and obsessive compulsive disorder, however, are few and involve small numbers of subjects and “more data are needed on technical details and outcomes before the possible therapeutic role of DBS can be established.”

 

In summary, these multiple recent publications support current policy; they also reflect interest in DBS as a potential treatment for a growing number of additional clinical indications. The current policy statements are unchanged.