1. Aetna considers unilateral or bilateral deep brain stimulators (e.g., stimulation of the ventral intermediate thalamic nucleus, globus pallidus, and subthalamic nucleus) medically necessary durable medical equipment (DME) for the treatment of intractable tremors as a consequence of Parkinson's disease or essential tremor when all of the following criteria are met:

   • Member does not have dementia, severe depression, cerebral atrophy, or Hoehn and Yahr stage V Parkinson's disease (see Note below), and
   • Member does not have other independent diagnoses that could explain the failure to respond to medical treatment, and 
   • Member suffers from disabling upper extremity essential tremor that is not responding satisfactorily to drug therapy or suffers from a disabling tremor of idiopathic Parkinson's disease that is refractory to pharmacotherapy, and
   • There is no focal lesion of the basal ganglia (e.g., a space occupying lesion or lacunae) at the target site that would negate the result of thalamic stimulation, and
   • There is sufficient residual motor function in the upper extremity so that it is reasonable to expect an improvement following the surgery.

   Note: Hoehn and Yahr Stage V individuals exhibit the following characteristics: 

   • Cachectic state
   • Cannot stand or walk (need wheelchair assistance, or are unable to get out of bed
   • Invalidism
   • Requires constant nursing care
     

2. Aetna considers unilateral or bilateral deep brain stimulators (e.g., stimulation of the globus pallidus and subthalamic nucleus) medically necessary DME for the treatment of severe, refractory motor complications of Parkinson's disease when all of the following criteria are met:

   • A minimal score of 30 points on the motor portion of the United Parkinson's Disease Rating Scale (UPDRS) when the member has been off medication for about 12 hours (scores on this scale range from 0 to 108; higher values indicate greater severity of symptoms); and
   • Member does not have dementia, severe depression, cerebral atrophy, or advanced (Hoehn and Yahr stage V) Parkinson's disease; and
   • Member is levodopa responsive with clearly defined “on” periods; and
   • Motor complications that can not be managed with medication; and
   • Presence of at least 2 major symptoms of Parkinsonism (e.g., tremor, rigidity, and bradykinesia). 
      

3. Aetna considers unilateral or bilateral deep brain stimulators (e.g., stimulation of the globus pallidus and subthalamic nucleus) medically necessary DME for the treatment of persons 7 years of age or older with intractable primary dystonia, including generalized and/or segmental dystonia, hemidystonia and cervical dystonia.

4. Aetna considers deep brain stimulation (DBS) for tremor from other causes such as trauma, multiple sclerosis (MS), degenerative disorders, metabolic disorders, infectious diseases, and drug-induced movement disorders experimental and investigational because DBS has not been shown to be effective for treating tremors due to these other causes.

5. Aetna considers DBS experimental and investigational for the following indications (not an all inclusive list), because there is insufficient evidence to support its effectiveness for these indications.

See also CPB 0153 - Thalamotomy, and  CPB 0307 - Parkinson's Disease.

Essential tremor is a common movement disorder afflicting 5 to 10 million Americans.  It is characterized primarily by an action and postural tremor most often affecting the arms, but it can also affect other body parts.  Essential tremor is a progressive neurological disorder and can result in severe disability in some individuals.  Although there is no cure for essential tremor, pharmacotherapy and surgery can provide some relief.  Primidone and propranolol are first-line treatments.  Other medications include benzodiazepines, gabapentin, and topiramate.  Patients with medication-resistant tremor may benefit from thalamotomy or deep brain stimulation (DBS) of the thalamus.  Medical and surgical interventions can provide benefit in up to 80 % of patients with essential tremor.  Deep brain stimulation is also an effective treatment for patients with advanced Parkinson's disease (PD) and motor complications that can no longer be improved by adjustment of medical therapy.  The most common targets for implantation of deep brain stimulators are the subthalamic nucleus and globus pallidus internus.

The American Academy of Neurology's practice parameter on the treatment of PD with motor fluctuations and dyskinesia (Pahwa et al, 2006) stated that pre-operative response to levodopa predicts better outcome after DBS of the subthalamic nucleus.

Deuschl and Bain (2002) noted that the appropriate selection of patients is essential for the outcome of surgical relief of tremors.  The selection criteria should include: (i) motor symptoms causing a relevant disability in activities of daily living, despite optimal pharmacotherapy; (ii) biological age of the patient; (iii) neurosurgical contraindications; and (iv) the patient is neither demented nor severely depressed.

Lyons and Pahwa (2008) stated that DBS has been used to treat various tremor disorders for several decades.  Medication-resistant, disabling essential tremor is the most common tremor disorder treated with DBS.  The treatment has been consistently reported to result in significant benefit in upper extremity, as well as head and voice tremor, all of which were improved more dramatically with bilateral procedures.  These benefits have been demonstrated to be sustained for up to 7 years.  Deep brain stimualtion has also been shown to be beneficial for the tremor associated with multiple sclerosis and post-traumatic tremor; however, fewer cases have been reported and the benefit is less consistent, less dramatic, and more transient than that seen with essential tremor.  The ventral intermediate nucleus of the thalamus is the most common DBS target for tremor disorders, but more recent studies have demonstrated benefits in tremor from DBS of the subthalamic area, primarily the zona incerta.  Surgical complications are relatively uncommon and are generally less frequent than those seen with thalamotomy.  Stimulation-related effects are usually mild and resolve with adjustment of stimulation parameters.  Deep brain stimulation is thus a relatively safe and effective treatment for tremor disorders, particularly for medication-resistant, disabling essential tremor, but may also have some role in medication-resistant, disabling tremor associated with multiple sclerosis and traumatic head injury.

In a randomized controlled trial (RCT), Weaver and colleagues (2009) compared 6-month outcomes for patients with PD who received DBS (bilateral DBS of the subthalamic nucleus [n = 60] or globus pallidus [n = 61]) or best medical therapy.  A total of 255 patients with PD (Hoehn and Yahr stage > or = 2 while not taking medications) were enrolled; 25 % were aged 70 years or older.  Patients receiving best medical therapy (n = 134) were actively managed by movement disorder neurologists.  The primary outcome was time spent in the "on" state (good motor control with unimpeded motor function) without troubling dyskinesia, using motor diaries.  Other outcomes included motor function, quality of life, neurocognitive function, and adverse events.  Patients who received DBS gained a mean of 4.6 h/d of on time without troubling dyskinesia compared with 0 h/d for patients who received best medical therapy (between group mean difference, 4.5 h/d [95 % confidence interval [CI]: 3.7 to 5.4 h/d]; p < 0.001).  Motor function improved significantly (p < 0.001) with DBS versus best medical therapy, such that 71 % of DBS patients and 32 % of best medical therapy patients experienced clinically meaningful motor function improvements (greater than or equal to 5 points).  Compared with the best medical therapy group, the DBS group experienced significant improvements in the summary measure of quality of life and on 7 of 8 PD quality-of-life scores (p < 0.001).  Neurocognitive testing revealed small decrements in some areas of information processing for patients receiving DBS versus best medical therapy.  At least 1 serious adverse event occurred in 49 DBS patients and 15 best medical therapy patients (p < 0.001), including 39 adverse events related to the surgical procedure and 1 death secondary to cerebral hemorrhage.  The authors concluded that in this RCT of patients with advanced PD, DBS was more effective than best medical therapy in improving on time without troubling dyskinesias, motor function, and quality of life at 6 months, but was associated with an increased risk of serious adverse events.

An editorial that accompanied the afore-mentioned article, Deuschl (2009) stated that "[t]he cumulative risk for device-related problems was 10 % at 6 months, and stimulation-related problems, which mostly can be corrected, were even more frequent .... the suicide rate following deep brain stimulation was 13 times higher in the first postoperative year (24/5,311 patients) and doubled after 4 years .... this study, along with previous research on this therapy, shows that such progress cannot be made without costs in terms of adverse effects".

On the other hand, DBS is an investigational therapy in other conditions such as such as trauma, multiple sclerosis (MS), degenerative disorders, metabolic disorders, infectious diseases, and drug-induced movement disorder.  Experience with DBS in the treatment of tremor due to MS is limited to small case series or case reports.  Currently, it is impossible to predict which patients will benefit from this treatment.  Furthermore, frequent stimulator adjustments are needed to maintain optimum limb functions; and long-term effectiveness has not been demonstrated.  Prospective, RCTs with large sample size are needed to ascertain the long-term efficacy of DBS in patients with MS.

The consensus recommendations of the German Deep Brain Stimulation Association on DBS for tremor in MS (Timmermann et al, 2009) noted that the sparse studies on DBS in MS tremor remain controversial regarding the clinical effect on postural and action tremor of hands, trunk and head.  Furthermore, it remains unclear if DBS in MS tremor is superior to thalamotomy and if patients show an overall improvement in quality of life and activities of daily living.

Pallanti et al (2004) stated that more results are needed before the effectiveness of non-pharmacologic treatments (e.g., DBS) for obsessive-compulsive disorder (OCD) can be determined.  Deep brain stimulation has also been examined for the treatment of epilepsy, chronic cluster headache, and Tourette syndrome (TS).  However, there is currently insufficient evidence to support its effectiveness of these indications.

In a prospective cohort study, Porta et al (2009) evaluated the long-term outcome on tics, behavioral symptoms, and cognitive functions of thalamic DBS for TS.  A total of 15 of the original 18 patients were evaluated before and after surgery according to a standardized protocol that included both neuropsychiatric and neuropsychological assessments.  In addition to marked reduction in tic severity (p = 0.001), 24-month follow-up ratings showed improvement in obsessive-compulsive symptoms (p = 0.009), anxiety symptoms (p = 0.001), depressive symptoms (p = 0.001), and subjective perception of social functioning/quality of life (p = 0.002) in 15 of 18 patients.  There were no substantial differences on measures of cognitive functions before and after DBS.  The authors concluded that at 24-month follow-up, tic severity was improved in patients with intractable TS who underwent bilateral thalamic DBS.  Available data from 15 of 18 patients also showed that neuropsychiatric symptoms were improved and cognitive performances were not disadvantaged.  Moreover, they stated that fcontrolled studies on larger cohorts with blinded protocols are needed to verify that this procedure is safe and effective for selected patients with TS.

In a 10-month, cross-over, double-blind, multi-center study, Mallet and colleagues (2008) evaluated the safety and effectiveness of stimulation of the subthalamic nucleus in treating OCD.  A total of 16 patients with highly refractory OCD were randomly assigned to undergo (i) active stimulation of the subthalamic nucleus followed by sham stimulation and (ii) sham stimulation followed by active stimulation.  The primary outcome measure was the severity of OCD, as assessed by the Yale-Brown Obsessive Compulsive Scale (Y-BOCS), at the end of two 3-month periods.  General psychopathologic findings, functioning, and tolerance were assessed with the use of standardized psychiatric scales, the Global Assessment of Functioning (GAF) scale, and neuropsychological tests.  After active stimulation of the subthalamic nucleus, the Y-BOCS score (on a scale from 0 to 40, with lower scores indicating less severe symptoms) was significantly lower than the score after sham stimulation (mean [+/- SD], 19 +/- 8 versus 28 +/- 7; p = 0.01), and the GAF score (on a scale from 1 to 90, with higher scores indicating higher levels of functioning) was significantly higher (56 +/- 14 versus 43 +/- 8, p = 0.005).  The ratings of neuropsychological measures, depression, and anxiety were not modified by stimulation.  There were 15 serious adverse events overall, including 1 intra-cerebral hemorrhage and 2 infections; there were also 23 non-serious adverse events.  The authors concluded that these preliminary findings suggested that stimulation of the subthalamic nucleus may reduce the symptoms of severe forms of OCD but is associated with a substantial risk of serious adverse events.  They noted that the occurrence of severe adverse events, the small number of patients, and the short duration of the study highlight the risks of stimulation of the subthalamic nucleus and the need for larger studies with longer follow-up.

On February 19, 2009, the Food and Drug Administration (FDA), under a humanitarian device exemption, approved DBS for the treatment of patients with severe OCD who have not responded to conventional therapy (e.g., anti-depressant medications).  The approval was based on a review of data from 26 patients with severe treatment-resistant OCD who were treated with the device at 4 sites.  On average, patients had a 40 % reduction in their symptoms after 12 months of therapy.  While all patients reported adverse events, the majority of these events ended after an adjustment was made in the amount of electrical stimulation.  Contraindications for DBS include patients who require electro-convulsive shock therapy, patients who who will undergo magnetic resonance imaging or diathermy.

Although DBS has been approved by the FDA for the treatment of severe OCD, the available evidence is insufficient to support the effectiveness of DBS for this disorder. In a review on OCD, Abramowitz and colleagues (2009) stated that although the initial results of DBS for the treatment of OCD are promising, this intervention should be adequately assessed its safety and effectiveness.

Primary generalized dystonia associated with the early-onset generalized dystonia gene can cause severe disability, affecting a person’s ability to perform activities of daily living.  Pharmacotherapy has been inadequate in alleviating the motor dysfunctions.  Deep brain stimulation of the bilateral globus pallidus internus has been reported to reduce these debilitating motor abnormalities.  The FDA approved DBS for the treatment of primary dystonia via the humanitarian device exemption process, and its summary of safety and probable benefit stated that although there are a number of serious adverse events experienced by patients treated with DBS, 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 afflicted person is contorted by the disease, the skeleton may be placed under constant severe stresses that may cause permanent disfigurement.  Risks associated with DBS for dystonia appear to be similar to the risk associated with the performance of stereotactic surgery and the implantation of DBS systems for currently approved indications, except when used in either child or adolescent patients groups.

In this regard, Eltahawy et al (2004) reported that bilateral pallidal stimulation is effective in management of selected cases of intractable cervical dystonia.  Furthermore, the findings of a recent prospective, controlled, multicenter study (Vidailhet et al, 2005) support the safety and effectiveness of the use of bilateral stimulation of the internal globus pallidus in selected patients with primary generalized dystonia.  However, according to a report by the American Academy of Neurology (Zesiewicz et al, 2005), there is no evidence of a synergistic effect on limb tremor with bilateral DBS, and there are insufficient data regarding the risk:benefit ratios of unilateral versus bilateral DBS.  Furthermore, the report also stated that there is insufficient evidence to make recommendations regarding the use of DBS for head or voice tremor.

There is currently insufficient scientific evidence that DBS is effective in treating patients with PD-related dysarthria/speech deficit.

In a review, Schulz and Grant (2000) examined the different treatment approaches for patients with PD and their effects on speech.  Therapeutic approaches reviewed include speech therapy, pharmacological, and surgical.  The authors stated that research from the 1950s through the 1970s had not shown significant improvements following speech therapy.  On the other hand, recent research has shown that speech therapy (when PD patients are optimally medicated) has proven to be most effective in improving voice and speech function.  Pharmacotherapies in isolation do not appear to significantly improve voice and speech function in PD patients across research studies.  Neurosurgical interventions including pallidotomy and DBS may be significant treatment options which improve voice and speech function in some PD patients.  These investigators stated that future studies should examine the effects of combined treatment approaches.  Perhaps the combination of pharmacological, neurosurgical, and speech treatment will prove superior to treatments combining pharmacological and neurosurgical approaches, or pharmacotherapies and speech therapy in improving the communication abilities of patients with PD.

Pinto et al (2004) stated that dysarthria in PD can be characterized by monotony of pitch and loudness, reduced stress, variable rate, imprecise consonants, and a breathy and harsh voice.  Use of levodopa to replenish dopamine concentrations in the striatum appears to improve articulation, voice quality, and pitch variation, although some studies showed no change in phonatory parameters.  Traditional speech therapy can lead to improvement of dysarthria, and intensive programs have had substantial beneficial effects on vocal loudness.  Unilateral surgical lesions of subcortical structures are variably effective for the alleviation of dysarthria, whereas bilateral procedures typically lead to worsening of speech production (Pinto et al, 2004).  Among DBS procedures, only stimulation of the subthalamic nucleus improves some motor components of speech although intelligibility seems to decrease after surgery.  Due to the variable treatment effects on Parkinsonian speech, management of dysarthria is still challenging for the clinician.

Farrell and colleagues (2005) examined the effects of neurosurgical management of PD, including pallidotomy, thalamotomy, and DBS on perceptual speech characteristics, speech intelligibility, and oromotor function in a group of 22 patients with PD.  The surgical subjects were compared with a group of 25 non-neurologically impaired individuals matched for age and sex. In addition, the study examined 16 patients with PD who did not undergo neurosurgical treatment to control for disease progression.  Results revealed that neurosurgical intervention did not significantly change the surgical subjects' perceptual speech dimensions or oromotor function despite significant post-operative improvements in ratings of general motor function and disease severity.

There is currently insufficient scientific evidence that DBS is effective in treating patients with depression.  Eitan and Lerer (2006) stated that non-pharmacological modalities for the treatment of depression such as magnetic seizure therapy, vagus nerve stimulation, and DBS are at various stages of research development.  The authors reviewed the development and technical aspects of these treatments, their potential role in the treatment of major depression, adverse effects, and putative mechanism of action.  These researchers concluded that although these modalities hold considerable promise, these novel brain stimulation techniques need to be further developed before they achieve clinical acceptability.  Carpenter et al (2006) noted that DBS for severe intractable depression has been studied in two pilot studies with very few patients to date.  They stated that further investigations are currently underway in order to more fully evaluate DBS with the hope of substantially improving the treatment of refractory depression.  These findings are in agreement with that of (Holtzheimer and Nemeroff, 2006) who stated that for the most part, the data on DBS for the treatment of depression are preliminary, and more study is needed to clarify its potential clinical benefit.

In 2001, the Canadian Psychiatric Association and the Canadian Network for Mood and Anxiety Treatments (CANMAT) partnered to produce evidence-based clinical guidelines for the treatment of depressive disorders.  These guidelines were revised by CANMAT in 2008 to 2009 to reflect advances in the field (Kennedy et al, 2009).  The revised guidelines stated that there is emerging evidence that DBS is effective for otherwise treatment resistant depression, but this approach remains an investigational treatment.

Halpern et al (2008) stated that recent evidence suggested that DBS may be effective and safe in the management of various, refractory neuropsychiatric disorders, including obesity.  These researchers reviewed the literature implicating various neural regions in the pathophysiology of obesity, as well as the evidence supporting these regions as targets for DBS, in order to explore the therapeutic promise of DBS in obesity.  The lateral hypothalamus and ventromedial hypothalamus are the appetite and satiety centers in the brain, respectively.  Substantial data support targeting these regions with DBS for the purpose of appetite suppression and weight loss.  However, reward sensation associated with highly caloric food has been implicated in over-consumption as well as obesity, and may in part explain the failure rates of conservative management and bariatric surgery.  Thus, regions of the brain's reward circuitry, such as the nucleus accumbens, are promising alternatives for DBS in managing obesity.  The authors concluded that DBS should be considered as a promising therapeutic option for patients suffering from refractory obesity.

In a report from the Benign Essential Blepharospasm Research Foundation (BEBRF) International Workshop, Hallett et al (2008) stated that "DBS was recently used to treat patients with disabling cranial dystonia, including blepharospasm, who have become refractory to other forms of therapy .... Very few patients have been studied so far, but given the clear utility of DBS for dystonia, further studies for blepharospasm will certainly be undertaken".

Fisher et al (2010) reported a multi-center, double-blind, randomized trial of bilateral stimulation of the anterior nuclei of the thalamus for localization-related epilepsy.  Subjects were adults with medically refractory partial seizures, including secondarily generalized seizures.  Half received stimulation and half no stimulation during a 3-month blinded phase; then all received unblinded stimulation.  A total of 110 subjects were randomized.  Baseline monthly median seizure frequency was 19.5.  In the last month of the blinded phase the stimulated group had a 29 % greater reduction in seizures compared with the control group, as estimated by a generalized estimating equations (GEE) model (p = 0.002).  Unadjusted median declines at the end of the blinded phase were 14.5 % in the control group and 40.4 % in the stimulated group.  Complex partial and "most severe" seizures were significantly reduced by stimulation.  By 2 years, there was a 56 % median percent reduction in seizure frequency; 54 % of patients had a seizure reduction of at least 50 %, and 14 patients were seizure-free for at least 6 months.  Five deaths occurred and none was from implantation or stimulation.  No subject had symptomatic hemorrhage or brain infection.  Two subjects had acute, transient stimulation-associated seizures.  Cognition and mood showed no group differences, but subjects in the stimulated group were more likely to report depression or memory problems as adverse events.  The authors concluded that bilateral stimulation of the anterior nuclei of the thalamus reduces seizures.  Benefit persisted for 2 years of study.  Complication rates were modest.  They stated that DBS of the anterior thalamus is useful for some people with medically refractory partial and secondarily generalized seizures.  More studies are needed to determine whether this approach can result in long-term benefits.  In this regard, it was noted that "[t]he FDA recently requested that the Medtronic Deep Brain Stimulation (DBS) Therapy ... undergo a second phase 3 study, even though a first was positive, and even though an FDA advisory panel recommended the device's outright approval, so they are taking a cautious stance.  There is also a great deal to be learned about selection of the most appropriate patients, and selection of stimulation parameters that would optimize efficacy" (Collins, 2010).

Fountas et al (2010) reviewed the pertinent literature to outline the role of cerebellar stimulation (CS) in the management of medically refractory epilepsy.  The PubMed medical database was systematically searched for the following terms: "cerebellar," "epilepsy," "stimulation," and "treatment," and all their combinations.  Case reports were excluded from this study.  The pertinent articles were categorized into 2 large groups: animal experimental and human clinical studies.  Particular emphasis on the following aspects was given when reviewing the human clinical studies: their methodological characteristics, the number of participants, their seizure types, the implantation technique and its associated complications, the exact stimulation target, the stimulation technique, the seizure outcome, and the patients' psychological and social post-stimulation status.  Three clinical double-blind studies were found, with similar implantation surgical technique, stimulation target, and stimulation parameters, but quite contradictory results.  Two of these studies failed to demonstrate any significant seizure reduction, whereas the third one showed a significant post-stimulation decrease in seizure frequency.  All possible factors responsible for these differences in the findings are analyzed in the present study.  The authors concluded that CS seems to remain a stimulation target worth exploring for defining its potential in the treatment of medically intractable epilepsy, although the data from the double-blind clinical studies that were performed failed to establish a clear benefit in regard to seizure frequency.  They stated that a large-scale, double-blind clinical study is needed for accurately defining the efficacy of CS in epilepsy treatment.

Lyons et al (2010) stated that Meige syndrome is characterized by blepharospasm, cervical dystonia, and facial oromandibular dystonia.  The medical treatment of this condition is largely unsuccessful over time and is a major source of decreased quality of life in those patients suffering from this disease.  Recent advances in the application of DBS surgery techniques for many disorders have prompted several recent reports of DBS for medically refractory cases of Meige syndrome.  While the etiology for this disorder is unknown, it is considered by many investigators to be a form of idiopathic torsion dystonia.  Pallidal stimulation is widely considered to be effective for dystonia.  These researchers reported the long-term results of bilateral globus pallidus internus (GPi) or subthalamic nucleus (STN) stimulation in 3 patients with Meige syndrome and 1 patient with PD and associated craniofacial dystonia treated at their center.  Initial 12-month and long-term follow-up Burke-Fahn-Marsden scores were substantially improved in all 4 patients compared with pre-operative scores.  The authors concluded that bilateral GPi DBS may be an effective and safe treatment for medically refractory Meige syndrome.  The results are comparable with those reported in the literature.  Sustained and long-term improvement in symptoms does appear to be reproducible across reports.  The authors' patient with PD and associated craniofacial dystonia syndrome undergoing bilateral STN DBS noted immediate and sustained improvement in his symptoms.  They stated that further study is required, but these results, along with the other reports, suggest that bilateral GPi DBS is an effective treatment for medically refractory Meige syndrome.

Georgiopoulos et al (2010) performed a systematic review of the proposed medical or surgical treatments in patients in chronic vegetative state (CVS) or minimally conscious state (MCS), as well as of their mechanisms of action and limitations.  These investigators included patients in CVS or MCS having persisted for over 6 months in post-traumatic cases, and over 3 months in non-traumatic cases, before the time of intervention.  Searches were independently conducted by 2 investigators between May 2009 and September 2009 in the following databases: Medline, Web of Science and the Cochrane Library.  The electronic search was complemented by cross-checking the references of all relevant articles.  Overall, 16 papers were eligible for this systematic review.  According to the 16 eligible studies, medical management by dopaminergic agents (levodopa, amantadine), zolpidem and median nerve stimulation, or surgical management by DBS, extradural cortical stimulation, spinal cord stimulation and intrathecal baclofen have shown to improve the level of consciousness in certain cases.  The authors concluded that treatments proposed for disorders of consciousness have not yet gained the level of "evidence-based treatments"; moreover, the studies to date have led to inconclusiveness.  The published therapeutic responses must be substantiated by further clinical studies of sound methodology.

Authors of an article in Health Affairs (Fins et al, 2011) argued that the humanitarian device exemption (HDE) for DBS for OCD should be rescinded since there is little evidence to support its safe and effective use.  Fins et al (2011) stated that DBS is emerging as a treatment of last resort for people diagnosed with neuropsychiatric disorders such as severe OCD.  The FDA granted HDE to allow patients to access this intervention, thereby removing the requirement for a clinical trial of the appropriate size and statistical power.  Bypassing the rigors of such trials puts patients at risk, limits opportunities for scientific discovery, and gives device manufacturers unique marketing opportunities.  The authors argued that Congress and federal regulators should re-visit the HDE to ensure that it is not used to side-step careful research that can offer valuable data with appropriate patient safeguards.

Muller et al (2011) developed a European guideline on DBS by a working group of the European Society for the Study of Tourette Syndrome (ESSTS).  For a narrative review, a systematic literature search was conducted and expert opinions of the guidelines group contributed also to the suggestions.  Of 63 patients reported so far in the literature, 59 had a beneficial outcome following DBS with moderate to marked tic improvement.  However, randomized controlled studies including a larger number of patients are still lacking.  Although persistent serious adverse effects (AEs) have hardly been reported, surgery-related (e.g., bleeding, infection) as well as stimulation-related AEs (e.g., sedation, anxiety, altered mood, changes in sexual function) may occur.  At present time, DBS in TS is still in its infancy.  Due to both different legality and practical facilities in different European countries these guidelines, therefore, have to be understood as recommendations of experts.  However, among the ESSTS working group on DBS in TS there is general agreement that, at present time, DBS should only be used in adult, treatment resistant, and severely affected patients.  It is highly recommended to perform DBS in the context of controlled trials.

Kang et al (2011) noted that DBS has been shown to be effective in the treatment of various movement disorders including PD, essential tremor and dystonia.  However, there is limited information regarding the potential use of DBS in Huntington's disease (HD).  In this study, the authors presented their findings on the long-term motor and neurocognitive results of 2 HD patients (patient 1: 57 years, 42 cytosine-adenine guanine (CAG) repeats; patient 2: 50 years, 41 CAG repeats) who underwent staged bilateral globus pallidus interna DBS surgery.  The patients were evaluated at baseline and at 5 time points throughout a 2-year post-operative during which motoric ratings ((Unified Huntington's Disease Rating Scale), Activities of Daily Living scores (HD-ADL) and neurocognitive testing) were obtained.  Both patients had a sustained decline in chorea  2 and 14 years after initial DBS surgery.  Despite this improvement in chorea, 1 patient has had continuing deterioration in gait, bradykinesia and dystonia scores, which has caused his ability to perform activities of daily living to return to his baseline level of functioning prior to DBS surgery.  Both patients have experienced further gradual decline in neurocognitive functioning, which appears to be independent of DBS and most likely related to disease progression.  The authors concluded that DBS implantation may be a potential treatment option for a subset of HD patients who have significant functional deficits due to chorea.  However, appropriate selection of the best candidates for DBS appears to be challenging, given the difficulty in predicting disease course in HD due to its variable nature.

Halpern et al (2011) noted that the indications for DBS are expanding, and the feasibility and efficacy of this surgical procedure in various neurologic and neuropsychiatric disorders continue to be tested.  This review attempts to provide background and rationale for applying this therapeutic option to obesity and addiction.  These researchers reviewed neural targets currently under clinical investigation for DBS -- the hypothalamus and nucleus accumbens -- in conditions such as cluster headache and OCD.  These brain regions have also been strongly implicated in obesity and addiction.  These disorders are frequently refractory, with very high rates of weight regain or relapse, respectively, despite the best available treatments.  These investigators performed a structured literature review of the animal studies of DBS, which revealed attenuation of food intake, increased metabolism, or decreased drug seeking.  They also reviewed the available radiologic evidence in humans, implicating the hypothalamus and nucleus in obesity and addiction.  The available evidence of the promise of DBS in these conditions combined with significant medical need, support pursuing pilot studies and clinical trials of DBS in order to decrease the risk of dietary and drug relapse.  The authors concluded that well-designed pilot studies and clinical trials enrolling carefully selected patients with obesity or addiction should be initiated.

Luigjes et al (2012) stated that DBS is currently investigated in psychiatry for the treatment of refractory OCD, Tourette syndrome and depressive disorder.  Although recent research in both animals and humans has indicated that DBS may be an effective intervention for patients with treatment-refractory addiction, it is not yet entirely clear which brain areas should be targeted.  The objective of this review was to provide a systematic overview of the published literature on DBS and addiction and outline the most promising target areas using efficacy and adverse event data from both preclinical and clinical studies.  These researchers found 7 animal studies targeting 6 different brain areas: (i) nucleus accumbens (NAc), (ii) subthalamic nucleus (STN), (iii) dorsal striatum, (iv) lateral habenula, (v) medial prefrontal cortex (mPFC) and (vi) hypothalamus, and 11 human studies targeting 2 different target areas: (i) NAc and (ii) STN.  The analysis of the literature suggests that the NAc is currently the most promising DBS target area for patients with treatment-refractory addiction.  The mPFC is another promising target, but needs further exploration to establish its suitability for clinical purposes.  The authors concluded the review with a discussion on translational issues in DBS research, medical ethical considerations and recommendations for clinical trials with DBS in patients with addiction.

Bronte-Stewart (2012) stated that high-frequency DBS is an established therapy for PD, essential tremor, and primary dystonia, and is under investigation for several neuropsychiatric diseases.  Peri-operative risks include hemorrhage and stroke (less than 2 %) and infection (approximately 8 %).  The benefit/risk ratio may be optimized with individualized patient selection and the use of an experienced surgical team.  Bilateral ablations pose an unacceptable risk of speech impairment and disequilibrium.  In a review on “Major depressive disorder: New clinical, neurobiological, and treatment perspectives”, Kupfer et al (2012) noted that DBS is a promising treatment for treatment-resistant depression.

Cruccu et al (2007) stated that pharmacological relief of neuropathic pain is often insufficient.  Electrical neurostimulation is efficacious in chronic neuropathic pain and other neurological diseases.  European Federation of Neurological Societies (EFNS) launched a Task Force to evaluate the evidence for these techniques and to produce relevant recommendations.  These investigators searched the literature from 1968 to 2006, looking for neurostimulation in neuropathic pain conditions, and classified the trials according to the EFNS scheme of evidence for therapeutic interventions.  Spinal cord stimulation (SCS) is efficacious in failed back surgery syndrome and complex regional pain syndrome (CRPS) type I (level B recommendation).  High-frequency transcutaneous electrical nerve stimulation (TENS) may be better than placebo (level C) although worse than electro-acupuncture (level B).  One kind of repetitive transcranial magnetic stimulation (rTMS) has transient efficacy in central and peripheral neuropathic pains (level B).  Motor cortex stimulation (MCS) is efficacious in central post-stroke and facial pain (level C).  Deep brain stimulation (DBS) should only be performed in experienced centers.  Evidence for implanted peripheral stimulations is inadequate.  TENS and r-TMS are non-invasive and suitable as preliminary or add-on therapies.  The authors concluded that further controlled trials are warranted for SCS in conditions other than failed back surgery syndrome and CRPS and for MCS and DBS in general.  These chronically implanted techniques provide satisfactory pain relief in many patients, including those resistant to medication or other means.

The Washington State Department of Labor and Industries' clinical practice guideline on "Work-related complex regional pain syndrome (CRPS): Diagnosis and treatment" (2011) did not mention the use of DBS as a therapeutic option.  Furthermore, UpToDate reviews on "Prevention and management of complex regional pain syndrome in adults" (Abdi, 2012) and "Complex regional pain syndrome in children" (Sherry, 2012) do not mention the use of DBS as a therapeutic option.

Plow et al (2012) noted that chronic neuropathic pain is one of the most prevalent and debilitating disorders.  Conventional medical management, however, remains frustrating for both patients and clinicians owing to poor specificity of pharmacotherapy, delayed onset of analgesia and extensive side effects.  Neuromodulation presents as a promising alternative, or at least an adjunct, as it is more specific in inducing analgesia without associated risks of pharmacotherapy.  These investigators discussed common clinical and investigational methods of neuromodulation.  Compared to clinical SCS, investigational techniques of cerebral neuromodulation, both invasive (DBS and MCS) and non-invasive (rTMS and transcranial direct current stimulation), may be more advantageous.  By adaptively targeting the multi-dimensional experience of pain, subtended by integrative pain circuitry in the brain, including somatosensory and thalamocortical, limbic and cognitive, cerebral methods may modulate the sensory-discriminative, affective-emotional and evaluative-cognitive spheres of the pain neuromatrix.  Despite promise, the current state of results alludes to the possibility that cerebral neuromodulation has thus far not been effective in producing analgesia as intended in patients with chronic pain disorders.  These techniques, thus, remain investigational and off-label.  These researchers discussed issues implicated in inadequate efficacy, variability of responsiveness, and poor retention of benefit, while recommending design and conceptual refinements for future trials of cerebral neuromodulation in management of chronic neuropathic pain.

Marks and colleagues (2012) noted that cerebral palsy (CP) is the most common cause of pediatric-onset dystonia.  Deep brain stimulation is gaining acceptance for treating dystonias in children.  There is minimal reported experience regarding the effectiveness of DBS in CP.  A total of 14 patients, including 8 younger than 16 years, received bilateral implants (13 patients) or a unilateral implant (1 patient) of the internal globus pallidus and were observed in a non-controlled, non-blinded study for at least 6 months.  Motor function was assessed using the Burke-Fahn-Marsden Dystonia Movement and Disability scales and the Barry Albright Dystonia Scale.  By 6 months, significant improvement was observed in the Burke-Fahn-Marsden Dystonia Movement scale (p = 0.004), the Burke-Fahn-Marsden Dystonia Disability scale (p = 0.027), and the Barry Albright Dystonia Scale (p = 0.029) for the whole cohort (n = 14) and in the patients treated before skeletal maturity (group 1; n = 8): Burke-Fahn-Marsden Dystonia Movement scale, p = 0.012; Burke-Fahn-Marsden Dystonia Disability scale, p = 0.020; and Barry Albright Dystonia Scale, p = 0.027.  The authors concluded that DBS may offer an effective treatment option for CP-related dystonia, especially in those treated before skeletal maturity.  The findings of this small, non-controlled, and non-blinded study need to be validated by well-designed studies.

Koy et al (2013) stated that secondary dystonia encompasses a heterogeneous group with different etiologies.  Cerebral palsy is the most common cause.  Pharmacological treatment is often unsatisfactory.  There are only limited data on the therapeutic outcomes of DBS in dyskinetic CP.  The published literature regarding DBS and secondary dystonia was reviewed in a meta-analysis to re-evaluate the effect on CP.  The Burke-Fahn-Marsden Dystonia Rating Scale movement score was chosen as the primary outcome measure.  Outcome over time was evaluated and summarized by mixed-model repeated-measures analysis, paired Student t-test, and Pearson's correlation coefficient.  A total of 20 articles comprising 68 patients with CP undergoing DBS assessed by the Burke-Fahn-Marsden Dystonia Rating Scale were identified.  Most articles were case reports reflecting great variability in the score and duration of follow-up.  The mean Burke-Fahn-Marsden Dystonia Rating Scale movement score was 64.94 ± 25.40 pre-operatively and dropped to 50.5 ± 26.77 post-operatively, with a mean improvement of 23.6 % (p < 0.001) at a median follow-up of 12 months.  The mean Burke-Fahn-Marsden Dystonia Rating Scale disability score was 18.54 ± 6.15 pre-operatively and 16.83 ± 6.42 post-operatively, with a mean improvement of 9.2 % (p < 0.001).  There was a significant negative correlation between severity of dystonia and clinical outcome (p < 0.05).  The authors concluded that DBS can be an effective treatment option for dyskinetic CP.  Moreover, they stated that i view of the heterogeneous data, a prospective study with a large cohort of patients in a standardized setting with a multi-disciplinary approach would be helpful in further evaluating the role of DBS in CP.

In a pilot study, Lipsman et al (2013) evaluated the safety of DBS to modulate the activity of limbic circuits and examined how this might affect the clinical features of anorexia nervosa (AN).  These researchers performed a phase I, prospective trial of subcallosal cingulate DBS in 6 patients with chronic, severe, and treatment-refractory AN.  Eligible patients were aged 20 to 60 years, had been diagnosed with restricting or binge-purging AN, and showed evidence of chronicity or treatment resistance.  Patients underwent medical optimization pre-operatively and had baseline body-mass index (BMI), psychometric, and neuroimaging investigations, followed by implantation of electrodes and pulse generators for continuous delivery of electrical stimulation.  Patients were followed-up for 9 months after DBS activation, and the primary outcome of adverse events associated with surgery or stimulation was monitored at every follow-up visit.  Repeat psychometric assessments, BMI measurements, and neuroimaging investigations were also done at various intervals.  Deep brain stimulation was associated with several adverse events, only one of which (seizure during programming, roughly 2 weeks after surgery) was serious.  Other related adverse events were panic attack during surgery, nausea, air embolus, and pain.  After 9 months, 3 of the 6 patients had achieved and maintained a BMI greater than their historical baselines.  Deep brain stimulation was associated with improvements in mood, anxiety, affective regulation, and AN-related obsessions and compulsions in 4 patients and with improvements in quality of life in 3 patients after 6 months of stimulation.  These clinical benefits were accompanied by changes in cerebral glucose metabolism (seen in a comparison of composite PET scans at baseline and 6 months) that were consistent with a reversal of the abnormalities seen in the anterior cingulate, insula, and parietal lobe in the disorder.  The authors concluded that subcallosal cingulate DBS seems to be generally safe in this sample of patients with chronic and treatment-refractory AN.  The effectiveness of DBS in the treatment of patients with AN needs to be validated by well-designed studies.

Wu and colleagues (2013) stated that AN is a complex and severe, sometimes life-threatening, psychiatric disorder with high relapse rates under standard treatment.  After decades of brain-lesioning procedures offered as a last resort, DBS has come under investigation in the last few years as a treatment option for severe and refractory AN.  In this jointly written article, Sun et al (the Shanghai group) reported an average of 65 % increase in body weight in 4 severe and refractory patients with AN after they underwent the DBS procedure (average follow-up of 38 months).  All patients weighed greater than 85 % of expected body weight and thus no longer met the diagnostic criteria of AN at last follow-up.  Nuttin et al (the Leuven group) described other clinical studies that provided evidence for the use of DBS for AN; and further discussed patient selection criteria, target selection, and adverse event of this evolving therapy.  The authors concluded that preliminary results from the Shanghai group and other clinical centers showed that the use of DBS to treat AN may be a valuable option for weight restoration in otherwise-refractory and life-threatening cases.  The nature of this procedure, however, remains investigational and should not be viewed as a standard clinical treatment option.  They stated that further scientific investigation is essential to determine the long-term and safety and effectiveness of DBS for AN.