Deep Brain Stimulation

Number: 0208

Policy

  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) Footnotes*, 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.

    Footnotes*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 bilateral stimulation of the anterior nucleus of the thalamus (e.g., the Medtronic DBS System for Epilepsy) medically necessary for adults aged 18 years or older who have partial onset seizures with or without secondary generalization to tonic-clonic activity, and have not responded to 3 or more antiepileptic medications.  (Note: This approach is for individuals who averaged 6 or more seizures per month during the previous 3 months, with no more than 30 days between seizures.  It hasn’t been evaluated in persons whose seizures are less frequent).

  5. 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.

  6. 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.

  • Addiction
  • Alzheimer's disease
  • Anorexia nervosa
  • Autism spectrum disorder
  • Blepharospasm
  • Cerebral palsy
  • Chronic cluster headache
  • Chronic pain syndrome including complex regional pain syndrome/reflex sympathetic dystrophy
  • Chronic vegetative state
  • Depression
  • Disorders of consciousness (e.g., minimally conscious state, unresponsive wakefulness syndrome, and vegetative state)
  • Explosive aggressive behavior
  • Head or voice tremor
  • Huntington's disease
  • Obesity
  • Obsessive-compulsive disorder
  • Orthostatic tremor
  • Parkinson’s disease-related camptocormia, dysarthria/speech deficits, postural instability, restless legs syndrome, and gait disorders (e.g., gait instability and freezing of gait) 
  • Post-traumatic tremor
  • Self-injurious behavior
  • Substance use disorders
  • Tourette syndrome
  • Traumatic brain injury

Note: The average battery life of a non-rechargeable stimulator is 3 to 5 years, depending upon how much stimulation the individual receives each day.  Rechargeable neurostimulators last longer, about 9 years.  The neurostimulator would then need to be replaced as an outpatient procedure, but the leads implanted to the brain do not need to be replaced.

Background

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:
  1. motor symptoms causing a relevant disability in activities of daily living, despite optimal pharmacotherapy;
  2. biological age of the patient;
  3. neurosurgical contraindications; and
  4. 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:
  1. active stimulation of the subthalamic nucleus followed by sham stimulation and
  2. 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".

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:
  1. nucleus accumbens (NAc),
  2. subthalamic nucleus (STN),
  3. dorsal striatum,
  4. lateral habenula,
  5. medial prefrontal cortex (mPFC) and
  6. hypothalamus,

and 11 human studies targeting 2 different target areas:

  1. NAc and
  2. 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.

Lemaire et al (2014) reported that 6 clinical studies of chronic electrical modulation of deep brain circuits published between 1968 and 2010 have reported effects in 55 vegetative or minimally conscious patients.  The rationale stimulation was to activate the cortex through the reticular-thalamic complex, comprising the tegmental ascending reticular activating system and its thalamic targets.  The most frequent intended target was the central intralaminar zone and adjacent nuclei.  Hassler et al also proposed to modulate the pallidum as part of the arousal and wakefulness system.  Stimulation frequency varied from 8 Hz to 250 Hz.  Most patients improved, although in a limited way.  Schiff et al found correlations between central thalamus stimulation and arousal and conscious behaviors.  Other treatments that have offered some clinical benefit include drugs, repetitive magnetic transcranial stimulation, median nerve stimulation, stimulation of dorsal column of the upper cervical spinal cord, and stimulation of the fronto-parietal cortex.  No one treatment has emerged as a gold standard for practice, which is why clinical trials are still on-going.  The authors concluded that further clinical studies are needed to decipher the altered dynamics of neuronal network circuits in patients suffering from severe disorders of consciousness as a step towards novel therapeutic strategies.

Bartsch and Kuhn (2014) reviewed the current state of DBS in the treatment of refractory OCD.  In addition, initial experimental approaches to investigate the potential use of DBS in substance addiction and AN were outlined as both disorders share some common features with OCD.  The present review was based on a keyword literature search (PubMed) while taking into account relevant references and own investigations.  Although the number of clinical trials for treatment of refractory OCD is limited and sample sizes are small, there is some evidence for a substantial improvement, a so-called full response of OCD symptoms under DBS.  However, not all patients benefit from the intervention.  Regarding substance addiction and AN, data are scarce and are only indicative of a potential benefit at most.  The authors concluded that present data regarding the clinical benefits of DBS in OCD are encouraging and open up new avenues for the treatment of therapy refractory patients.  However, several aspects, such as mechanisms of action, predictors and long-term side effect profiles, are incomplete or even unknown.  In the case of addiction and AN, DBS remains purely experimental, at least for the moment.  Hence, clinical trials should remain the gold standard for all three indications.

Kohl et al (2014) noted that OCD is one of the most disabling of all psychiatric illnesses.  Despite available pharmacological and psychotherapeutic treatments about 10 % of patients remain severely affected and are considered treatment-refractory.  For some of these patients DBS offers an appropriate treatment method.  These researchers reviewed the published data and compared different target structures and their effectiveness.  PubMed search, last update June 2013, was conducted using the terms "deep brain stimulation" and "obsessive compulsive disorder".  A total of 25 studies were found that reported 5 DBS target structures to treat OCD:
  1. the anterior limb of the internal capsule (5 studies including 14 patients),
  2. nucleus accumbens (8 studies including 37 patients),
  3. ventral capsule/ventral striatum (4 studies including 29 patients),
  4. subthalamic nucleus (5 studies including 23 patients) and
  5. inferior thalamic peduncle (2 studies including 6 patients). 

Despite the anatomical diversity, DBS treatment results in similar response rates for the first four target structures.  Inferior thalamic peduncle DBS results in higher response rates but these results have to be interpreted with caution due to a very small number of cases.  Procedure and device related adverse events are relatively low, as well as stimulation or therapy related side effects.  Most stimulation related side effects are transient and decline after stimulation parameters have been changed.  The authors concluded that DBS in treatment-refractory OCD seems to be a relatively safe and promising treatment option.  However, based on these studies no superior target structure could be identified.  They stated that more research is needed to better understand mechanisms of action and response predictors that may help to develop a more personalized approach for these severely affected OCD patients.

Kisely et al (2014) performed a systematic review and meta-analysis of the effectiveness of DBS in psychiatric conditions (including OCD) to maximize study power.  These researchers conducted a systematic literature search for double-blind, RCTs of active versus sham treatment using PubMed/Medline and EMBASE up to April 2013.  Where possible, they combined results from studies in a meta-analysis.  They assessed differences in final values between the active and sham treatments for parallel-group studies and compared changes from baseline score for cross-over designs.  Inclusion criteria were met by 5 studies, all of which were of OCD.  A total of 44 subjects provided data for the meta-analysis.  The main outcome was a reduction in obsessive symptoms as measured by the Yale-Brown Obsessive Compulsive Scale (YBOCS).  Patients on active, as opposed to sham, treatment had a significantly lower mean score [mean difference (MD) -8.93, 95 % CI: -13.35 to -5.76, p < 0.001], representing partial remission.  However, 1/3 of patients experienced significant adverse effects (n = 16).  There were no differences between the two groups in terms of other outcomes.  The authors concluded that DBS may show promise for treatment-resistant OCD but there are insufficient randomized controlled data for other psychiatric conditions.  They stated that DBS remains an experimental treatment in adults for severe, medically refractory conditions until further data are available.

Berlim et al (2014) stated that DBS applied to the subgenual cingulate cortex (SCC) has been recently investigated as a potential treatment for severe and chronic treatment-resistant depression (TRD).  Given its invasive and experimental nature, a comprehensive evaluation of its effectiveness and acceptability is of paramount importance.  These investigators conducted a systematic review and exploratory meta-analysis.  They searched the literature for English language prospective clinical trials on DBS of the SCC for TRD from 1999 through December 2012 using MEDLINE, EMBASE, PsycINFO, CENTRAL and SCOPUS, and performed a random effects exploratory meta-analysis using Event Rates and Hedges׳ g effect sizes.  Data from 4 observational studies were included, totaling 66 subjects with severe and chronic TRD.  Twelve-month response and remission rates following DBS treatment were 39.9 % (95 % CI: 28.4 % to 52.8 %) and 26.3 % (95 % CI: 13 % to 45.9 %), respectively.  Also, depression scores at 12 months post-DBS were significantly reduced (i.e., pooled Hedges׳ g effect size=-1.89 [95 % CI: -2.64 to -1.15, p < 0.0001]).  Also, there was a significant decrease in depression scores between 3 and 6 months (Hedges׳ g = -0.27, p = 0.003), but no significant changes from months 6 to 12.  Finally, dropout rates at 12 months were 10.8 % (95 % CI: 4.3 % to 24.4 %).  The authors concluded that DBS applied to the SCC seems to be associated with relatively large response and remission rates in the short- and medium- to long-term in patients with severe TRD.  Also, its maximal anti-depressant effects are mostly observed within the first 6 months after device implantation.  Nevertheless, these findings are clearly preliminary and future controlled trials should include larger and more representative samples, and focus on the identification of optimal neuroanatomical sites and stimulation parameters.  The drawbacks of this meta-analysis included small number of included studies (most of which were open label), and limited long-term effectiveness data.

Parkinson's Disease-Related Camptocormia

Schulz-Schaeffer and colleagues (2015) stated that although some reports on neurostimulation are positive, no effective treatment method for camptocormia in PD is known to-date.  These researchers identified prognostic factors for a beneficial DBS effect on camptocormia.  In an observational cohort study, the authors investigated 25 idiopathic PD patients, who suffered additionally from camptocormia, and underwent bilateral neurostimulation of the STN to improve classical PD symptoms.  A beneficial neurostimulation effect on camptocormia was defined as an improvement in the bending angle of a least 50 %.  In 13 patients, the bending angle of camptocormia improved, in 12 patients it did not.  A multi-factorial analysis revealed a short duration between onset of camptocormia and start of neurostimulation to be the relevant factor for outcome.  All patients with duration of camptocormia up to 1.5 years showed a beneficial effect; patients between 1.5 and approximately 3 years showed mixed results, but none with a duration of more than 40 months improved except for 1 patient whose camptocormia was levodopa-responsive.  The bending angle was not a prognostic factor.  These findings indicated that the main prognostic factor for a beneficial DBS effect on camptocormia is its short duration.  The authors suggested that neurostimulation may improve camptocormia only as long as muscle pathology is limited.  They stated that their findings may help to elucidate the mode of action of neurostimulation; a prospective study is needed.

In a systematic review, Chieng et al (2015) profiled the various reported interventions for camptocormia in PD and gave an overview of the benefits of DBS.  Currently, there is no consensus in the literature regarding this.  Parkinson's disease manifests in several ways and camptocormia is one of the commonly encountered problems for both spine and functional neurosurgeons.  It is a significant forward flexion of the thoraco-lumbar spine that resolves in the recumbent position.  These investigators reviewed the PubMed and Medical Subject Headings database using the phrases "Parkinson's disease" or "Parkinson" in combination with "spinal deformity" or "camptocormia" or "bent spine syndrome" and "deep brain stimulation".  The review was limited to English language literature and these researchers excluded camptocormia of non-PD origin.  The search yielded 361 articles with 131 patients in the pooled data.  The majority (59 %) of patients were women and the age range was 48 to 76 years.  While 50 % of the patients on levodopa (n = 42) saw no improvement of their camptocormia, 71 % of the lidocaine group (n = 27) and 68 % of the DBS group (n = 32) showed significant improvement.  For mean flexion angle, the spinal surgery and DBS group demonstrated profound improvement in the bending angle, 89.9 % and 78.2 %, respectively.  However, major complications following spinal surgery were noted.  The authors concluded that although the results were from a small group of patients, DBS has achieved sustained improvement in camptocormia with low post-operative morbidity, and appeared to be a promising treatment option.  Moreover, they stated that a larger, long-term study is needed to establish comprehensive outcome data.

Postural Instability and Gait Disorder in Parkinson Disease

Golestanirad and associates (2016) stated that pedunculo-pontine nucleus (PPN) has complex reciprocal connections with basal ganglia, especially with internal globus pallidus and substantia nigra, and it has been postulated that PPN stimulation may improve gait instability and freezing of gait.  In this meta-analysis, these investigators evaluated the evidence for PPN-DBS in treatment of gait and motor abnormalities especially focusing on PD patients.  PubMed and Scopus electronic databases were searched for related studies published before February 2014.  Medline (1966 to 2014), Embase (1974 to 2010), CINAHL, Web of Science, Scopus bibliographic, and Google Scholar databases (1960 to 2014) were also searched for studies investigating effect of PPN-DBS in treatment of postural and postural instability; and a total of 10 studies met the inclusion criteria for this analysis.  The results showed a significant improvement in postural instability (p < 0.001) and motor symptoms of PD on and off medications (p < 0.05), but failed to show improvement in freezing of gait.  The authors concluded that despite significant improvement in postural instability observed in included studies, evidence from current literature is insufficient to generalize these findings to the majority of patients.

Wang and colleagues (2017) noted that postural instability and gait disorder (PIGD) in PD has been a great challenge in clinical practice because PIGD is closely linked to major morbidity and mortality in PD; and PPN has been considered as a potential promising target for DBS in the treatment of PIGD.  These researchers performed a meta-analysis of individual patient data to assess the effects of PPN-DBS on PIGD in patients with PD and explored the factors predicting good outcome.  According to the study strategy, these investigators searched PubMed, Embase, and the Cochrane Central Register of Controlled Trials, and other sources.  After searching the literature, 2 investigators independently screened the literature, assessed the quality of the included trials, and extracted the data.  The outcome measures included PIGD, freezing of gait, and falling in PD.  Then, individual patient data were incorporated into SPSS software for statistical analyses across series.  A total of 6 studies reporting individual patient data were included for final analysis; PPN-DBS significantly improved PIGD as well as freezing of gait and falling after PD, which was depending on the duration of follow-up and types of outcome measures.  In addition, patient age, disease duration, levodopa-equivalent dosage, and the choice of unilateral or bilateral stimulation were similar in groups of patients with PD with or without improvement in PIGD after PPN-DBS.  The authors concluded that the findings of this study provided evidence that PPN-DBS may improve PIGD, which should be interpreted with caution; and that these results need further verification before generalization of these findings can be made.

Depression

Narang and colleagues (2016) reviewed the English-language literature published between the years 2010 and 2015 regarding the utility of DBS for patients with treatment-refractory depression.  The literature review revealed that most DBS research is open label, with few large randomized, placebo-controlled trials to confirm results.  Long-term response rates with DBS were between 40 % and 70 %, with clinical effects depending on location of electrode placement.  Improvement was documented to last for months to years.  The authors stated that although DBS is potentially effective and a relatively safe option for patients with treatment resistance, it is invasive, costly, and still considered experimental.  Understanding of the neurobiology of depression, the mechanism of DBS action, and biomarkers that may predict patient response remains obscure.  They stated that future research should contain careful design, including homogenous inclusion criteria and characterization of pre-treatment patient mood, somatic complaints, and cognition; consistent outcome measures; monitoring of depressive symptoms at different brain-positioning targets across an adequate time course; and records of stimulus parameters.

Naesstrom and associates (2016) stated that DBS is a treatment under investigation for a range of psychiatric disorders.  It has shown promising results for therapy-refractory OCD and major depressive disorder (MDD).  Other indications under investigation include Tourette's syndrome, anorexia nervosa and substance use disorders.  These investigators reviewed current studies on psychiatric indications for DBS, with focus on OCD and MDD.  They performed a systematic search in Medline, and the literature was searched to identify studies with DBS for psychiatric disorders.  The identified studies were analyzed based on patient characteristics, treatment results and AEs of DBS.  A total of 52 papers met the inclusion criteria and described a total of 286 unique patients treated with DBS for psychiatric indications; 18 studies described 112 patients treated with DBS for OCD in 6 different anatomical targets, while 9 studies presented 100 patients with DBS for MDD in 5 different targets.  The authors concluded that DBS may show promise for treatment-resistant OCD and MDD; but the results were limited by small sample size and insufficient randomized controlled data.

Bergfeld and associates (2016) stated that patients with TRD do not respond sufficiently to several consecutive treatments for major depressive disorder; and DBS is a promising treatment for these patients, but presently placebo effects cannot be ruled out.  In a randomized clinical trial, these researchers evaluated the effectiveness of DBS of the ventral anterior limb of the internal capsule (vALIC), controlling for placebo effects with active and sham stimulation phases.  A total of 25 patients with TRD from 2 hospitals in the Netherlands were enrolled between March 22, 2010, and May 8, 2014.  Patients first entered a 52-week open-label trial during which they received bilateral implants of 4 contact electrodes followed by optimization of DBS until a stable response was achieved.  A randomized, double-blind, 12-week cross-over phase was then conducted with patients receiving active treatment followed by sham or vice versa.  Response and non-response to treatment were determined using intention-to-treat analyses.  The change in the investigator-rated score of the 17-item Hamilton Depression Rating Scale (HAM-D-17) was the main outcome used in analysis of the optimization phase.  The primary outcome of the cross-over phase was the difference in the HAM-D-17 scores between active and sham DBS.  The score range of this tool is 0 to 52, with higher scores representing more severe symptoms.  Patients were classified as responders to treatment (greater than or equal to 50 % decrease of the HAM-D-17 score compared with baseline) and partial responders (greater than or equal to 25 but less than 50 % decrease of the HAM-D-17 score).  Of 25 patients included in the study, 8 (32 %) were men; the mean (SD) age at inclusion was 53.2 (8.4) years.  Mean HAM-D-17 scores decreased from 22.2 (95 % confidence interval [CI]: 20.3 to 24.1) at baseline to 15.9 (95 % CI: 12.3 to 19.5) (p = 0.001), Montgomery-Asberg Depression Rating Scale scores from 34.0 (95 % CI: 31.8 to 36.3) to 23.8 (95 % CI: 18.4 to 29.1) (p < 0.001), and Inventory of Depressive Symptomatology-Self-report scores from 49.3 (95 % CI: 45.4 to 53.2) to 38.8 (95 % CI: 31.6 to 46.0) (p = 0.005) in the optimization phase.  Following the optimization phase, which lasted 51.6 (22.0) weeks, 10 patients (40 %) were classified as responders and 15 individuals (60 %) as non-responders; 16 patients entered the randomized cross-over phase (9 responders [56 %], 7 non-responders [44 %]).  During active DBS, patients scored significantly lower on the HAM-D-17 scale (13.6 [95 % CI: 9.8 to 17.4]) than during sham DBS (23.1 [95 % CI: 20.6 to 25.6]) (p < 0.001).  Serious adverse events (AEs) included severe nausea during surgery (1 patient), suicide attempt (4 patients), and suicidal ideation (2 patients).  The authors concluded that DBS of the vALIC resulted in a significant decrease of depressive symptoms in 10 of 25 patients (40 %) and was well-tolerated.  The randomized cross-over design corroborated that vALIC DBS causes symptom reduction rather than sham.  The main drawbacks of the afore-mentioned study by Bergfeld et al (2016) were discussed by Youngerman and Sheth (2017); and they stated that future work will no doubt take into consideration the important lessons learned in this study.

Saleh and Hasler (2017) noted that DBS for refractory psychiatric disorders shows promising effects on symptom-reduction, however, little is known regarding the effects of DBS on social outcome.  These researchers performed a PubMed search based on original studies of DBS for psychiatric disorders [TRD, Gilles de la Tourette's syndrome (GTS), and obsessive compulsive disorder (OCD)].  Data on social outcome following surgery were extracted and analyzed.  Social functioning was not a primary outcome measure in the reviewed article.  The literature is incomplete and inconclusive on this variable, however from the reported data, there is some evidence that DBS has the potential to improve social functioning.  The authors concluded that more systematic and detailed data gathering and reporting on social outcome with longer follow-ups are needed to evaluate more exhaustively the role of DBS in refractory psychiatric disorders.

Furthermore, an UpToDate review on “Unipolar depression in adults: Treatment of resistant depression” (Thase and Connolly, 2017) does not mention DBS as a therapeutic option.

Cluster Headaches

In an uncontrolled, open-label, prospective study, Akram and colleagues (2016) presented outcomes in a cohort of medically intractable chronic cluster headache (CCH) patients treated with ventral tegmental area (VTA) DBS.  A total of 21 patients (17 males; mean age of 52 years) with medically refractory CCH were selected for ipsilateral VTA-DBS by a specialist multi-disciplinary team including a headache neurologist and functional neurosurgeon.  Patients had also failed or were denied access to occipital nerve stimulation within the UK National Health Service.  The primary end-point was improvement in the headache frequency; secondary outcomes included other headache scores (severity, duration, headache load), medication use, disability and affective scores, quality of life (QoL) measures, and AEs.  Median follow-up was 18 months (range of 4 to 60 months).  At the final follow-up point, there was 60 % improvement in headache frequency (p = 0.007) and 30 % improvement in headache severity (p = 0.001).  The headache load (a composite score encompassing frequency, severity, and duration of attacks) improved by 68 % (p = 0.002).  Total monthly triptan intake of the group dropped by 57 % post-treatment.  Significant improvement was observed in a number of QoL, disability, and mood scales; AEs included diplopia, which resolved in 2 patients following stimulation adjustment, and persisted in 1 patient with a history of ipsilateral trochlear nerve palsy.  There were no other serious AEs.  The authors concluded that the findings of this study supported that VTA-DBS may be a safe and effective therapy for refractory CCH patients who failed conventional treatments.  (Class IV Evidence).  The main drawbacks of this study were its open-label design (a placebo effect cannot be excluded) and its small sample size (n = 21).  These findings need to be validated by well-designed studies.

Autism Spectrum Disorder and Self-Injurious Behavior

Park and colleagues (2017) examined the clinical outcome of DBS for autism spectrum disorder (ASD) and the functional and structural changes in the brain after DBS.  These researchers presented the case of a 14-year old boy with ASD and self-injurious behavior (SIB) refractory with medical and behavioral therapy.  He was treated by bilateral nucleus accumbens (NAc) DBS.  Remarkable clinical improvement was observed following NAc DBS.  Brain fluorodeoxyglucose-positron emission tomography (FDG-PET) and magnetic resonance imaging (MRI) volumetric studies revealed that the metabolism in the prefrontal and the frontal cortex as well as the occipital cortex was markedly decreased in association with the decreased cortical volumes in those areas 2 years after NAc DBS.  The authors noted the therapeutic potential of NAc DBS for the improvement of patients with ASD and SIB with structural and functional changes after DBS.  These preliminary findings need to be validated by well-designed studies.

Explosive Aggressive Behavior

Giordano et al (2016) stated that intermittent explosive disease (IED) is a psychiatric disorder characterized by intermittent attacks of rage and violence frequently resistant to pharmacological therapy.  Deep brain stimulation of the postero-medial hypothalamus has been applied with fair results and clinical improvement with some surgical morbidity due to neuro-vegetative side effects.  The anterior limb of the internal capsule/ventral capsule/ventral striatum (VC/VS) has never been used alone as a target for this disease.  These researchers evaluated the effectiveness of bilateral DBS of the VC/VS for the treatment of IED.  They performed bilateral DBS of the VC/VS in a 21-year old patient with IED.  This young man had a traumatic birth complicated by hypoxia, and he showed a mild mental impairment.  Different pharmacological treatments were carried out with no results before DBS was proposed to the patient's relatives after multi-disciplinary approval.  After 22 months of high-frequency mono-polar bilateral DBS of the VC/VS, the patient showed a significant improvement.  Post-operative 18F-FDG PET-CT studies ruled out a reduction of the hyper-metabolic areas located in the limbic system previously detected in pre-operative investigations.  The authors concluded that bilateral DBS of the VC/VS may be considered for the treatment of IED without the risk of neuro-vegetative side effects.  These preliminary findings need to be validated by well-designed studies.

Orthostatic Tremor

In a large case-series study, Hassan and associates (2016) evaluated the clinical, electrophysiological, and treatment outcome features of orthostatic tremor (OT).  These investigators performed medical record review of 184 patients who met clinical and electrodiagnostic criteria for OT from 1976 to 2013 at the Mayo Clinic; demographic, clinical, electrophysiological, and treatment data were extracted.  The majority of OT cases were female (63.6 %) and mean age at onset was 59.3 years (range of 13 to 85).  Diagnosis was delayed by a mean of 7.2 years (range of 0 to 44).  The average tremor frequency was 15.7 Hz (range of 12.5 to 20), and transmitted to the arms on weight-bearing (95.5 %).  Patients reported a spectrum of progressive orthostatic leg symptoms, relieved by sitting or leaning.  Falls were reported in 24.1 %.  Co-existent neurologic disorders included essential tremor (22.8 %), other tremor (4.9 %), and Parkinsonism (8.7 %).  Family history of OT was noted in 4.9 %.  Of 46 medications trialed, 24 failed to provide any benefit.  Benzodiazepines provided at least mild benefit in 55.9%, and moderate to marked benefit in 31.5%; β-blockers (31.0%) and anticonvulsants (25.0%) provided mild benefit, and the remainder were largely ineffective. Medication benefit waned over time; DBS was effective in 2 cases.  The authors concluded that OT predominantly affects female seniors, and the diagnosis should be considered with any orthostatic-induced leg symptoms, and confirmed by surface electromyography.  They stated that benzodiazepines are the most effectives treatment, followed by beta-blockers and anti-convulsants; the published experience with DBS for OT is too limited at present to form definite conclusions, DBS should be further explored for treatment.

Post-Traumatic Tremor

Rojas-Medina et al (2016) noted that post-traumatic tremor (PTT) is the most frequent movement disorder secondary to cranioencephalic trauma and can be persistent and disabling.  These investigators reviewed and evaluated the effectiveness of DBS at the VIM/VOP/ZI (ventralis intermedius/ventrooralis posterior/zona incerta) complex level for the treatment of PTT.  During the period from 1999 to 2014, a total of  5 patients diagnosed with PTT were selected who had experienced a major deterioration in their QoL without improvement during medical treatment for more than 1 year.  They underwent surgery for DBS at the VIM/VOP/ZI complex level, and the modified tremor scale before and after surgery was used for their follow-up.  Each patient showed improvements in their symptoms after DBS compared with baseline, which was moderate (II) in 2 cases and marked (III) in the other cases.  All of the improvements were maintained with chronic DBS, without tremor rebound.  The authors concluded that stimulation of the contralateral VIM/VOP/ZI complex resulted in a noticeable improvement in tremor and recovery of independence in basic daily activities in patients with PTT.  These preliminary findings need to be validated by well-designed studies.

Traumatic Brain Injury

Schiff (2016) discussed a general rationale for the use of central thalamic DBS (CT-DBS) to support arousal regulation mechanisms in the severely injured brain.  The organizing role of the anterior forebrain mesocircuit in recovery mechanisms following widespread deafferentation produced by multi-focal structural brain injuries was emphasized.  The mesocircuit model provides the conceptual foundation for the key role of the central thalamus as a privileged node for neuromodulation to support forebrain arousal regulation.  In this context, cellular mechanisms arising at the neocortical, striatal, and thalamic population level are considered in the assessment of an individual patient's capacity for harboring underlying reserve that could be recruited for further recovery.  The author noted that recent pre-clinical studies and pilot clinical results were compared to frame the detailed rationale for CT-DBS.  Application of CT-DBS across the range of outcomes following severe-to-moderate brain injuries was discussed with the aim of improving consciousness and cognition in patients with non-progressive brain injuries.

Disorders of Consciousness

Vanhoecke and Hariz (2017) stated that a treatment for patients suffering from prolonged severely altered consciousness is not available.  The success of DBS in diseases such as dystonia, essential tremor and PD provided a renewed impetus for its application in disorders of consciousness (DoC).  These researchers evaluated the rationale for DBS in patients with DoC, through systematic review of literature containing clinical data and ethical considerations.  Articles from PubMed, Embase, Medline and Web of Science were systematically reviewed.  The outcomes of 78 individual patients reported in 19 articles from 1968 onwards were pooled and elements of ethical discussions were compared.  There is no clear clinical evidence that DBS is a treatment for DoC that can restore both consciousness and the ability to communicate.  In patients who benefitted, the outcome of DBS is often confounded by the time frame of spontaneous recovery from DoC.  Difficult ethical considerations remain, such as the risk of increasing self-awareness of own limitations, without improving overall well-being, and the issues of proxy consent.  The authors concluded that DBS is far from being evident as a possible future therapeutic avenue for patients with DoC.  They stated that double-blind studies are lacking, and many clinical and ethical issues have to be addressed.

Refractory Epilepsy

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.

Sprengers et al (2014) evaluated the efficacy, safety and tolerability of DBS and cortical stimulation for refractory epilepsy based on RCTs.  These investigators searched PubMed (August 6, 2013), the Cochrane Epilepsy Group Specialized Register (August 31, 2013), Cochrane Central Register of Controlled Trials (CENTRAL) (The Cochrane Library 2013, Issue 7 of 12) and reference lists of retrieved articles.  They also contacted device manufacturers and other researchers in the field.  No language restrictions were imposed.  Randomized controlled trials comparing DBS or cortical stimulation to sham stimulation, resective surgery or further treatment with anti-epileptic drugs were selected for analysis.  Four review authors independently selected trials for inclusion.  Two review authors independently extracted the relevant data and assessed trial quality and overall quality of evidence.  The outcomes investigated were seizure freedom, responder rate, percentage seizure frequency reduction, adverse events, neuropsychological outcome and quality of life.  If additional data were needed, the study investigators were contacted.  Results were analyzed and reported separately for different intra-cranial targets for reasons of clinical heterogeneity.  A total of 10 RCTs comparing 1 to 3 months of intra-cranial neurostimulation to sham stimulation were identified.  One trial was on anterior thalamic DBS (n = 109; 109 treatment periods); 2 trials on centro-median thalamic DBS (n = 20; 40 treatment periods), but only one of the trials (n = 7; 14 treatment periods) reported sufficient information for inclusion in the quantitative meta-analysis; 3 trials on cerebellar stimulation (n = 22; 39 treatment periods); 3 trials on hippocampal DBS (n = 15; 21 treatment periods); and 1 trial on responsive ictal onset zone stimulation (n = 191; 191 treatment periods).  Evidence of selective reporting was present in 4 trials and the possibility of a carryover effect complicating interpretation of the results could not be excluded in 4 cross-over trials without any washout period.  Moderate-quality evidence could not demonstrate statistically or clinically significant changes in the proportion of patients who were seizure-free or experienced a 50 % or greater reduction in seizure frequency (primary outcome measures) after 1 to 3 months of anterior thalamic DBS in (multi) focal epilepsy, responsive ictal onset zone stimulation in (multi) focal epilepsy patients and hippocampal DBS in (medial) temporal lobe epilepsy.  However, a statistically significant reduction in seizure frequency was found for anterior thalamic DBS (-17.4 % compared to sham stimulation; 95 % CI: -32.1 to -1.0; high-quality evidence), responsive ictal onset zone stimulation (-24.9 %; 95 % CI: -40.1 to 6.0; high-quality evidence)) and hippocampal DBS (-28.1 %; 95 % CI: -34.1 to -22.2; moderate-quality evidence).  Both anterior thalamic DBS and responsive ictal onset zone stimulation do not have a clinically meaningful impact on quality life after 3 months of stimulation (high-quality evidence).  Electrode implantation resulted in asymptomatic intracranial hemorrhage in 3 % to 4 % of the patients included in the 2 largest trials and 5 % to 13 % had soft tissue infections; no patient reported permanent symptomatic sequelae.  Anterior thalamic DBS was associated with fewer epilepsy-associated injuries (7.4 versus 25.5 %; p = 0.01) but higher rates of self-reported depression (14.8 versus 1.8 %; p = 0.02) and subjective memory impairment (13.8 versus 1.8 %; p = 0.03); there were no significant differences in formal neuropsychological testing results between the groups.  Responsive ictal-onset zone stimulation was well-tolerated with few side effects but SUDEP rate should be closely monitored in the future (4 per 340 [= 11.8 per 1,000] patient-years; literature: 2.2-10 per 1,000 patient-years).  The limited number of patients preclude firm statements on safety and tolerability of hippocampal DBS.  With regards to centro-median thalamic DBS and cerebellar stimulation, no statistically significant effects could be demonstrated but evidence is of only low to very low quality.  The authors concluded that only short-term RCTs on intra-cranial neurostimulation for epilepsy are available.  Compared to sham stimulation, 1 to 3 months of anterior thalamic DBS ((multi) focal epilepsy), responsive ictal onset zone stimulation ((multi) focal epilepsy) and hippocampal DBS (temporal lobe epilepsy) moderately reduce seizure frequency in refractory epilepsy patients.  Anterior thalamic DBS is associated with higher rates of self-reported depression and subjective memory impairment.  SUDEP rates require careful monitoring in patients undergoing responsive ictal onset zone stimulation.  They stated that there is insufficient evidence to make firm conclusive statements on the efficacy and safety of hippocampal DBS, centro-median thalamic DBS and cerebellar stimulation; and there is a need for more, large and well-designed RCTs to validate and optimize the efficacy and safety of invasive intra-cranial neurostimulation treatments.

Salanova et al (2015) reported long-term efficacy and safety results of the SANTE trial investigating DBS of the anterior nucleus of the thalamus (ANT-DBS) for the treatment of drug-resistant partial epilepsy.  This long-term follow-up was a continuation of a previously reported trial of 5- versus 0-V ANT stimulation.  Long-term follow-up began 13 months after device implantation with stimulation parameters adjusted at the investigators' discretion.  Seizure frequency was determined using daily seizure diaries.  The median percent seizure reduction from baseline at 1 year was 41 %, and 69 % at 5 years.  The responder rate (greater than or equal to 50 % reduction in seizure frequency) at 1 year was 43 %, and 68 % at 5 years.  In the 5 years of follow-up, 16 % of subjects were seizure-free for at least 6 months.  There were no reported unanticipated adverse device effects or symptomatic ICH.  The Liverpool Seizure Severity Scale and 31-item Quality of Life in Epilepsy measure showed statistically significant improvement over baseline by 1 year and at 5 years (p < 0.001).  The authors concluded that long-term follow-up of ANT-DBS showed sustained efficacy and safety in a treatment-resistant population.

Piacentino et al (2015) stated that drug-resistant epileptic patients account for 40 % of cases of epilepsy.  Consequently, specific therapeutic options could be surgical resection or, if not indicated, DBS.  These investigators reviewed data from patients affected by drug-resistant complex partial epilepsy with or without generalization treated by ANT-DBS to evaluate the efficacy and potential future applications of this approach as a standard method for palliative seizure control.  A total of 6 patients affected by drug-resistant complex partial seizures underwent AN DBS from March 2007 to February 2011.  The pre-operative tests consisted of electroencephalography (EEG), video EEG, morphologic and functional magnetic resonance imaging (MRI), non-acute positron emission tomography (PET), neuropsychological evaluation, Liverpool seizure scale, and Quality Of Life In Epilepsy (QOLIE).  These tests and a seizure diary were also administered during a follow-up of at least 3 years.  The improvement in terms of decrease of seizures was more than 50 % in patients affected by complex partial seizures strictly related to limbic system origin.  The amelioration was unsatisfactory for patients having anatomical lesions outside the limbic structures with evidence of late diffusion in limbic areas; 1 patient died 40 days after surgery for reasons not concerned with DBS.  The authors concluded that although the small number of enrolled patients limited the reliability of data, the results were in accordance with those found in the recent literature and deserve to be considered for further studies regarding real efficacy, indications, stimulation parameters, side effects, and complications.

Kim et al (2017) evaluated the long-term safety and efficacy of ATN-DBS treatment, as well as predictors of its success, in patients with drug-refractory epilepsy (DRE).  These investigators retrospectively studied clinical outcomes in 29 consecutive refractory epilepsy patients treated by a single DBS team (2 neurosurgeons, 4 neurologists) over an 11-year period, for whom follow-up was performed for up to 137 months (mean of 74.9 months).  The average participant was 30.7 (± 10.4) years old and had epilepsy for 19.3 (± 9.0) years.  The mean pre-operative frequency of disabling partial or generalized tonic-clonic seizures was 27.5 (± 8.6, SE) seizures a month.  The median percent seizure reduction was 71.3 % at 1year, 73.9 % at 2 years, and ranged from 61.8 % to 80.0 % over post-implant years 3 through 11 in the long-term study (overall 70 % median reduction).  In the 11-year study period, 13.8 % (4/29) of subjects were seizure-free for at least 12 months during this time.  There was only 1 symptomatic ICH that happened during follow-up (3.4 %).  Infection requiring removal and later re-implantation of hardware occurred in only 1 of 30 patients (3.3 %), who was subsequently excluded from follow-up assessment.  Hardware malfunction including lead disconnection occurred in 2 of 29 cases (6.9 %).  Revision of lead position to redeem poor clinical response was performed in 3 of 58 implanted leads (5.2 %).  The authors concluded that ATN-DBS can be an effective therapy in a variety of patients with DRE.  They provided evidence that significant therapeutic efficacy can be sustained for up to 11 years.  Neurological complications were rather rare, but long-term hardware-related complications should be closely followed.

Chang and Xu (2018) noted that conflicting conclusions have been reported regarding predictors of DBS outcome in patients with refractory temporal lobe epilepsy (TLE).  The main goal of this meta-analysis study was to identify possible predictors of remarkable seizure reduction (RSR).  These investigators conducted a comprehensive search of English-language literature published since 1990 and indexed in PubMed, Embase, and the Cochrane Library that addressed seizure outcomes in patients who underwent DBS for refractory TLE.  A pooled RSR rate was determined for eight included studies; RSR rates were analyzed relative to potential prognostic variables.  Random- or fixed-effects models were used depending on the presence or absence of heterogeneity.  The pooled RSR rate among 61 DBS-treated patients with TLE from 8 studies was 59 %.  Higher likelihood of RSR was found to be associated with lateralization of stimulation, lateralized ictal EEG findings, and a longer follow-up period.  Seizure semiology, MRI abnormalities, and patient sex were not predictive of RSR rate.  The best electrode type for RSR was the Medtronic 3389.  Hippocampal and anterior thalamic nuclei (ATN) sites of stimulation had similar odds of producing RSR.  The authors concluded that DBS is an effective therapeutic modality for intractable TLE, particularly in patients with lateralized EEG abnormalities and in patients treated on the ictal side.  This meta-analysis provided evidence-based information for determining DBS suitability in pre-surgical counseling and for explaining seizure outcomes.

Bouwens van der Vlis et al (2018) stated that despite the use of 1st-line anti-epileptic drugs and satisfactory seizure outcome rates after resective epilepsy surgery, a considerable percentage of patients do not become seizure-free; and ANT-DBS may provide an alternative therapeutic option in these patients.  These investigators discussed the rationale, mechanism of action, clinical efficacy, safety, and tolerability of ANT-DBS in drug-resistant epilepsy (DRE) patients.  A review using systematic methods of the available literature was performed using relevant databases including Medline, Embase, and the Cochrane Library pertaining to the different aspects ANT-DBS.  ANT-DBS for drug-resistant epilepsy is a safe, effective and well-tolerated therapy, where a special emphasis must be given to monitoring and neuropsychological assessment of both depression and memory function.  Three patterns of seizure control by ANT-DBS are recognized, of which a delayed stimulation effect may account for an improved long-term response rate.  ANT-DBS remotely modulates neuronal network excitability through over-riding pathological electrical activity, decrease neuronal cell loss, through immune response inhibition or modulation of neuronal energy metabolism.  ANT-DBS is an efficacious treatment modality, even when curative procedures or lesser invasive neuromodulative techniques failed.  When compared to VNS, ANT-DBS showed slightly superior treatment response, which urges for direct comparative trials.  Based on the available evidence ANT-DBS and VNS therapies are currently both superior compared to non-invasive neuromodulation techniques such as t-VNS and rTMS.

On April 27, 2018, the FDA approved (via the PMA process) the Medtronic DBS System (bilateral stimulation of the anterior nucleus of the thalamus) as an adjunctive therapy for reducing the frequency of seizures in individuals 18 years of age or older diagnosed with epilepsy characterized by partial-onset seizures, with or without secondary generalization, that are refractory to 3 or more anti-epileptic medications.  The Medtronic DBS System for Epilepsy has demonstrated safety and effectiveness in patients who averaged 6 or more seizures per month over the 3 most recent months prior to implant of the DBS system (with no more than 30 days between seizures).  The Medtronic DBS System for Epilepsy has not been evaluated in patients with less frequent seizures (Voelker, 2018).  Implantation of a DBS system is contraindicated for diathermy, MRI using a full body transmit radio-frequency (RF) coil, a receive-only head coil, or a head transmit coil that extends over the chest area, and transcranial magnetic stimulation.

Klinger and Mittal (2018) noted that anti-epileptic drugs prevent morbidity and death in a large number of patients suffering from epilepsy.  However, it is estimated that approximately 30 % of epileptic patients will not have adequate seizure control with medication alone.  Resection of epileptogenic cortex may be indicated in medically refractory cases with a discrete seizure focus in non-eloquent cortex.  For patients in whom resection is not an option, DBS may be an effective means of seizure control.  Deep brain stimulation targets for treating seizures primarily include the thalamic nuclei, hippocampus, sub-thalamic nucleus, and cerebellum.  A variety of stimulation parameters have been studied, and more recent advances in electrical stimulation to treat epilepsy include responsive neuro-stimulation.  The authors concluded that data suggested that DBS is effective for treating DRE.

Zhou et al (2018) stated that the field of DBS for epilepsy has grown tremendously since its inception in the 1970s and 1980s.  These investigators evaluated all studies published on the topic of open-loop DBS for epilepsy over the past decade (2008 to present).  A PubMed search was conducted to identify all articles reporting clinical outcomes of open-loop DBS for the treatment of epilepsy published since January 1, 2008.  The following composite search terms were used: ("epilepsy" [MeSH] OR "seizures" [MeSH] OR "kindling, neurologic" [MeSH] OR epilep* OR seizure* OR convuls*) AND ("deep brain stimulation" [MeSH] OR "deep brain stimulation" OR "DBS") OR ("electric stimulation therapy" [MeSH] OR "electric stimulation therapy" OR "implantable neurostimulators" [MeSH]).  The authors identified 41 studies that met the criteria for inclusion.  The ANT, centro-median nucleus of the thalamus, and hippocampus were the most frequently evaluated targets.  Among the 41 articles, 19 reported on stimulation of the ANT, 6 evaluated stimulation of the centro-median nucleus of the thalamus, and 9 evaluated stimulation of the hippocampus.  The remaining 7 articles reported on the evaluation of alternative DBS targets, including the posterior hypothalamus, sub-thalamic nucleus, ventral intermediate nucleus (VIN) of the thalamus, nucleus accumbens, caudal zone incerta, mammillo-thalamic tract, and fornix.  The authors evaluated each study for overall epilepsy response rates as well as adverse events (AEs) and other significant, non-epilepsy outcomes.  The authors concluded Level I evidence supports the safety and efficacy of stimulating the ANT and the hippocampus for the treatment of medically refractory epilepsy.  Level III and IV evidence supports stimulation of other targets for epilepsy.

Furthermore, an UpToDate review on “Evaluation and management of drug-resistant epilepsy” (Sirven, 2018) states that “Deep brain stimulation -- In a randomized clinical trial of deep brain stimulation in the anterior nucleus of the thalamus (SANTE trial) in 110 patients with drug-resistant epilepsy, stimulation therapy was associated with a 29 % reduction in seizure frequency compared with sham stimulation at 3 months; 54 % of patients had a seizure reduction of at least 50 % by 2 years in the unblinded phase.  Complex partial and "most severe" seizures were most significantly reduced by stimulation.  Participants in the stimulated group were more likely to report depression (15 versus 2 %) and memory problems (13 versus 2 %) as adverse effects.  There were five asymptomatic hemorrhages (5 %) and 14 implant site infections (13 %).  In a long-term follow-up study of the same trial, the responder rate was 68 % at 5 years in 59 continuing patients with complete seizure diary information.  Measures of seizure severity and quality of life also improved over time.  There were no unanticipated adverse events with extended follow up, and rates of depression, suicidality, and SUDEP were comparable to expected rates in the general refractory epilepsy population.  The device was approved by the US Food and Drug Administration in 2018 as adjunctive therapy for adults with partial-onset seizures who are refractory to 3 or more antiseizure drugs.  It was previously approved for refractory epilepsy elsewhere, including in Europe, Canada, and Australia”.

Parkinson’s Disease-Related Restless Legs Syndrome

Klepitskaya and colleagues (2018) examined the effect of STN-DBS in patients with PD and moderate-to-severe restless legs syndrome (RLS) on their RLS symptoms.  Patients undergoing STN-DBS surgery for PD completed the International RLS Study Group Rating Scale (IRLS) and RLS QoL questionnaires pre-operatively and post-operatively at 6 months, 1 year, and 2 years.  The primary outcome measure was IRLS sum score and subscales (severity and impact) and the secondary measure was RLS QoL scores.  Differences among the mean scores over time were analyzed using mixed model regression.  A total of 22 patients were enrolled.  The pre-operative IRLS sum scores were 19.59 ± 6.95, severity subscale 12.91 ± 4.33, impact subscale 4.45 ± 2.72, and transformed RLS QoL score 68.30 ± 20.26.  The differences between pre-operative and averaged post-operative scores were IRLS sum score -7.80, severity subscale -5.50, impact subscale -1.20, and RLS QoL 4.73.  The overall F tests demonstrated differences among the times for the means of the IRLS sum and subscales: p < 0.05.  There were no correlations between RLS symptoms improvement and PD motor symptoms improvement or reduction in PD medications; half of the patients had at least 50 % improvement and 27 % had resolution of their RLS symptoms (IRLS = 0).  The authors concluded that STN-DBS significantly decreased RLS symptoms in patients with PD despite a decrease in dopaminergic treatment.  This improvement was sustained over a 2-year period.  They stated that these findings suggested that DBS could be effective for treatment of RLS in patients with PD and, possibly, in severe medication-refractory idiopathic RLS as well.  The study underscored the importance of further investigations and provided directions for future research to clarify the effect of DBS on RLS symptoms.  Level of Evidence = IV.  This was a small (n = 22); and its main drawback was the lack of a placebo control group.

Table: CPT Codes / HCPCS Codes / ICD-10 Codes
Code Code Description

Information in the [brackets] below has been added for clarification purposes.   Codes requiring a 7th character are represented by "+":

CPT codes covered if selection criteria are met:

61863 Twist drill, burr hole, craniotomy, or craniectomy with stereotactic implantation of neurostimulator electrode array in subcortical site (e.g., thalamus, globus pallidus, subthalamic nucleus, periventricular, periaqueductal gray), without use of intraoperative microelectrode recording; first array
+ 61864     each additional array (List separately in addition to primary procedure)
61867 Twist drill, burr hole, craniotomy, or craniectomy with stereotactic implantation of neurostimulator electrode array in subcortical site (e.g., thalamus, globus pallidus, subthalamic nucleus, periventricular, periaqueductal gray), with use of intraoperative microelectrode recording; first array
+ 61868     each additional array (List separately in addition to primary procedure)
61880 Revision or removal of intracranial neurostimulator electrodes
61885 Insertion or replacement of cranial neurostimulator pulse generator or receiver, direct or inductive coupling; with connection to a single electrode array
61886     with connection to 2 or more electrode arrays
95836 Electrocorticogram from an implanted brain neurostimulator pulse generator/transmitter, including recording, with interpretation and written report, up to 30 days
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 programming
95971     simple spinal cord, or peripheral (ie, peripheral nerve, sacral nerve, neuromuscular) neurostimulator pulse generator/transmitter, with intraoperative or subsequent programming
95976 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 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
95978 Electronic analysis of implanted neurostimulator pulse generator system (e.g., 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
95983 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 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)

HCPCS codes covered if selection criteria are met:

C1767 Generator, neurostimulator (implantable), nonrechargeable
C1778 Lead, neurostimulator (implantable)
C1816 Receiver and/or transmitter, neurostimulator (implantable)
C1883 Adaptor/ extension, pacing lead or neurostimulator lead (implantable)
C1897 Lead, neurostimulator test kit (implantable)
E0745 Neuromuscular stimulator, electronic shock unit
L8680 Implantable neurostimulator electrode, each
L8681 Patient programmer (external) for use with implantable programmable neurostimulator pulse generator, replacement only
L8682 Implantable neurostimulator radiofrequency receiver
L8683 Radiofrequency transmitter (external) for use with implantable neurostimulator radiofrequency receiver
L8685 Implantable neurostimulator pulse generator, single array, rechargeable, includes extension
L8686 Implantable neurostimulator pulse generator, single array, non-rechargeable, includes extension
L8687 Implantable neurostimulator pulse generator, dual array, rechargeable, includes extension
L8688 Implantable neurostimulator pulse generator, dual array, non-rechargeable, includes extension
L8689 External recharging system for battery (internal) for use with implantable neurostimulator, replacement only
L8695 External recharging system for battery (external) for use with implantable neurostimulator, replacement only

ICD-10 codes covered if selection criteria are met:

G20 Parkinson's disease
G21.0 - G21.9 Secondary Parkinsonism
G24.1 Genetic torsion dystonia
G24.2 - G24.4
G24.8 - G24.9
Other acquired torsion dystonia [intractable primary including generalized and/or segmental, hemidystonia, or cervical - not drug-induced]
G24.3 Spasmodic torticollis
G25.0 - G25.2 Essential and other specified forms of tremor [disabling upper extremity essential] [not covered for orthostatic tremor and post-traumatic tremor]
G40.00 - G40.219 Localization-related (focal) (partial) idiopathic epilepsy and epileptic syndromes with seizures of localized onset

ICD-10 codes not covered for indications listed in the CPB (not all-inclusive):

A00.0 - B99.9 Infectious and parasitic diseases
C71.0 Malignant neoplasm of cerebrum, except lobes and ventricles [focal lesion of basal ganglia, space occupying lesion or lacunae that would negate result]
C79.31 Secondary malignant neoplasm of brain [focal lesion of basal ganglia, space occupying lesion or lacunae that would negate result]
D33.0 - D33.2 Benign neoplasm of brain [focal lesion of basal ganglia, space occupying lesion or lacunae that would negate result]
D43.0 - D43.2
D43.4
Neoplasm of uncertain behavior of brain and spinal cord [focal lesion of basal ganglia, space occupying lesion or lacunae that would negate result]
E66 - E66.9 Overweight and obesity
E70.0 - E88.9 Metabolic disorders
F02.80 - F02.81 Dementia in conditions classified elsewhere with or without behavioral disturbance or with behavioral disturbance
F03.90 - F03.91 Senile and presenile organic psychotic conditions
F10.20 - F10.99 Alcohol related disorders [abuse, dependence, use]
F11.10 - F19.99 Drug related disorders [abuse, dependence, use]
F30.10 - F39 Mood [affective] disorders
F32.81 - F32.89 Other depressive episodes
F34.1 Dysthymic disorder
F42.2 - F42.9 Obsessive-compulsive disorders
F44.4 Conversion disorder with motor symptom or deficit [Parkinson's disease-related camptocormia]
F50.00 - F50.02 Anorexia nervosa
F63.81 Intermittent explosive disorder [explosive aggressive behavior]
F84.0 - F84.9 Pervasive developmental disorders
F95.2 Tourette's disorder
F98.5 Adult onset fluency disorder [Parkinson's diseases-related]
G10 Huntington's chorea
G23.0 - G23.9
G90.3
Other degenerative diseases of the basal ganglia
G24.01 Drug induced subacute dyskinesia
G24.02 Drug induced acute dystonia
G24.5 Blepharospasm
G25.81 Restless legs syndrome
G25.9 Extrapyramidal and movement disorder, unspecified [drug-induced]
G30.0 - G30.9 Alzheimer's disease
G35 Multiple sclerosis
G40.301 - G40.89 Epilepsy and recurrent seizures
G44.021 - G44.029 Chronic cluster headaches
G80.0 - G80.9 Cerebral palsy
G90.50 - G90.59 Complex regional pain syndrome
Q82.0 Meige Syndrome
R22.0 - R22.1
R90
Swelling, mass, or lump in head and neck
R25.0 - R25.9 Abnormal involuntary movements
R26.0 - R26.9 Abnormalities of gait and mobility
R40.0 - R40.4 Alteration of consciousness
R47.81 - R47.89 Other speech disturbance [Parkinson's diseases-related]
R64 Cachexia [invalidism - Hoehn and Yahr Stage V Parkinson's disease]
S04.011S - S04.899S
S06.0x0S - S06.9x9S
S14.101S - S14.9xxS
S24.101S - S24.9xxS
S34.101S - S34.9xxS
S44.00xS - S44.92xS
S54.00xS - S54.92xS
S64.00xS - S64.92xS
S74.00xS - S74.92xS
S84.00xS - S84.92xS
S94.00xS - S94.92xS
Injuries to the nervous system, sequela
S06.0x0+ - S06.9x9+ Intracranial injury
S66.999S Other injury of unspecified muscle, fascia and tendon at wrist and hand level of unspecified hand, sequela
X71.0xxA - X83.8xxS Intentional self-harm
Z74.01 Bed confinement status [invalidism - Hoehn and Yahr Stage V Parkinson's disease]

The above policy is based on the following references:

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  113. Koy A, Hellmich M, Pauls KA, et al. Effects of deep brain stimulation in dyskinetic cerebral palsy: A meta-analysis. Mov Disord. 2013;28(5):647-654.
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  128. Schulz-Schaeffer WJ, Margraf NG, Munser S, et al. Effect of neurostimulation on camptocormia in Parkinson's disease depends on symptom duration. Mov Disord. 2015;30(3):368-372.
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  130. Servello D, Zekaj E, Saleh C, et al. Sixteen years of deep brain stimulation in Tourette's syndrome: A critical review. J Neurosurg Sci. 2016;60(2):218-229.
  131. Golestanirad L, Elahi B, Graham SJ, et al. Efficacy and safety of pedunculopontine nuclei (PPN) deep brain stimulation in the treatment of gait disorders: A meta-analysis of clinical studies. Can J Neurol Sci. 2016;43(1):120-126.
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