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On April 15, 2003, the Activa® Dystonia Therapy System (Medtronic) received a Humanitarian Device Exemption (HDE) from the FDA for unilateral and bilateral stimulation of the internal globus pallidus or the subthalamic nucleus and is indicated as an aid in the treatment of chronic, medically refractory, primary dystonia, including generalized and segmental dystonia, hemidystonia and cervical dystonia. Activa Dystonia Therapy is limited to use in implanting centers that receive Institutional Review Board (IRB) approval for the procedure. The safety and effectiveness of Activa Dystonia Therapy have not been established through a full PMA study. The therapy is approved for
patients who are seven years of age and older. Available at:
http://www.fda.gov/cdrh/ode/H020007sum.html. Accessed April 2009.
On March 28, 2005, the Activa® Deep Brain Stimulation Therapy System was designated as a Humanitarian Use Device (HUD) for the treatment of chronic, treatment-resistant obsessive compulsive disorder (OCD) in a subset of patients. However, the FDA does not list a Humanitarian Device Exemption (HDE) approval for authorization to market the device.
On February 19, 2009, the ReclaimTM Deep Brain Stimulation Therapy device was designated as an HUD for the treatment of obsessive compulsive disorder (OCD). This device is indicated for bilateral stimulation of the anterior limb of the internal capsule (AIC) as an adjunct to medications and as an alternative to anterior capsulotomy for treatment of chronic, severe, treatment-resistant OCD in adult patients who have failed at least three selective serotonin reuptake inhibitors (SSRIs). See the
following Web site for more information:
http://www.ninds.nih.gov/disorders/dystonias/dystonias.htm. Accessed April 2009.
Deep Brain Stimulation- Commercial Medical Management Guideline
On May 10, 2005, the FDA issued a Public Health Notification regarding MRI-caused injuries in
patients with implanted neurostimulators. Available at:
http://www.fda.gov/cdrh/safety/neurostim.html. Accessed April 2009.
Research Evidence Background Parkinson's disease Parkinson's disease (PD) is a chronic, progressive neurodegenerative disorder which results from the loss of dopamine-producing brain cells. In the United States, an estimated 1.5 million people have this disease. PD is considered idiopathic when the cause is unknown. The primary symptoms of PD are tremor, rigidity, bradykinesia (slowness of movement) and postural instability (impaired balance and coordination). As these symptoms become more pronounced, patients may have difficulty walking, talking, swallowing or completing other simple tasks. PD usually affects people over the age of 50. Medications used to treat PD include levodopa combined with carbidopa, dopamine agonists, catechol-O-methyl-transferase (COMT) inhibitors, monoamine oxidase type B (MAO-B) inhibitors, anticholinergics and amantadine. (NINDS, 2007) Essential tremor Tremor is involuntary muscle movement or trembling involving to-and-fro movements of one or more parts of the body. Essential tremor (ET) is a common movement disorder that affects more than 5 million Americans. Although it may be mild and nonprogressive in some people, in others the tremor is slowly progressive, starting on one side of the body but eventually affecting both sides.
Hand tremor is most common, but the head, arms, voice box (larynx), tongue, legs and trunk may also be involved. The tremors can result in physical limitations with serious adverse effects on activities of daily living (ADL) and quality of life. The cause of ET is unknown; however, it is more common after age 40 and seems to have a genetic connection. For most patients with ET, symptoms can be managed with propanolol or other beta blockers and primidone, an antiseizure medication. If these treatments fail to produce adequate relief, patients with severe ET can be considered as candidates for thalamotomy. (NINDS, 2007) Dystonia Dystonia is characterized by involuntary muscle contractions (sustained or spasmodic) that lead to abnormal body movements or postures. It is the most severe form of a group of movement disorders called dyskinesias and affects more than 300,000 people in North America. The muscle contractions are believed to result from abnormal activity in the basal ganglia of the brain. Dystonia can affect muscle groups in any part of the body, including the arms, legs, trunk, neck or eyelids. Primary dystonia occurs on its own, apart from any illness. Secondary dystonia can occur with illness, after trauma or following exposure to certain medications or toxins. Treatment options include medications (anticholinergics, benzodiazepines, baclofen or dopamine agonists injections of botulinum toxin and surgical procedures, such as myectomy, rhizotomy, pallidotomy or thalamotomy, for severe, refractory cases. (NINDS, 2007)
Deep Brain Stimulation- Commercial Medical Management Guideline
Types of dystonia:
- Generalized - affects multiple areas of the body
- Focal - affects one specific area of the body, such as the neck (cervical dystonia or torticollis), eyelid (blepharospasm) or hand (writer's cramp)
- Segmental - affects two or more adjacent parts of the body
- Multifocal - affects two nonadjacent parts of the body
- Hemidystonia - affects one side of the body Deep brain stimulation Deep brain stimulation (DBS) delivers electrical pulses to the brain via electrodes surgically implanted in the internal globus pallidus (GPi), subthalamic nucleus (STN) or ventral intermediate nucleus (VIM) of the thalamus. The mechanism of action is not completely understood, but the goal of DBS is to interrupt the pathways responsible for the abnormal movements associated with these disorders. The exact location of electrodes depends on the type of movement disorder. Unlike standard surgical ablation, which causes permanent destruction of the targeted area, DBS is reversible and adjustable. The DBS device consists of an implantable pulse generator (IPG) or neurostimulator, an implantable lead with electrodes and a connecting wire. The neurostimulator is approximately the size of a stop watch and is similar to a cardiac pacemaker. Subcutaneous extension wires connect the lead(s) to the neurostimulator which is implanted near the clavicle or, in the case of younger primary dystonia patients, in the abdomen. (Medtronic website) Research Evidence Parkinson's Disease & Essential Tremor Evidence from available published studies indicates that deep brain stimulation (DBS) provides clinically and statistically significant improvements in patients with Parkinson's disease (PD) and essential tremor (ET). The Deep Brain Stimulation for Parkinson's Disease Study Group performed an extensive study involving 134 patients. Patients underwent bilateral subthalamic nucleus (STN) DBS or globus pallidus internus (GPi) DBS electrode implantation. The investigators found the DBS of the STN caused statistically significant improvements in gait, tremor, rigidity, bradykinesia and motor function. PD patients with DBS of the GPi had statistically significant improvements in tremor, motor function, postural stability and activities of daily living on medication. Patients reported that the fraction of the day with good mobility increased from 27% to 74% for the STN group and from 28% to 64% for the GPi group. The medication usage was unchanged for patients who received GPi DBS but a statistically significant decrease of 63% was noted in the STN group at six months. (Deep Brain Stimulation for Parkinson's Disease Study Group, 2001) In a 6-month randomized-pairs trial, Deuschl, et al compared deep brain stimulation plus medication with medical management in 156 patients with advanced Parkinson's disease and severe motor symptoms. Pairwise comparisons showed that neurostimulation, as compared with medication alone, caused greater improvements from baseline to six months in the PDQ-39 (50 of 78 pairs, P=0.02) and Deep Brain Stimulation- Commercial Medical Management Guideline the Unified Parkinson's Disease Rating Scale (UPDRS) III (55 of 78, P In a systematic review and meta-analysis, researchers found that the estimated decreases in absolute Unified Parkinson's Disease Rating Scale (UPDRS) II (activities of daily living) and III (motor) scores after surgery in the stimulation ON/medication off state compared to preoperative medication off state were 13.35 (95% CI: 10.85-15.85; 50%) and 27.55 (95% CI: 24.23-30.87; 52%), respectively. Average reduction in L-dopa equivalents following surgery was 55.9% (95% CI: 50%Average reduction in dyskinesia following surgery was 69.1% (95% CI: 62.0%-76.2%).
Average reduction in daily off periods was 68.2% (95% CI: 57.6%-78.9%). Average improvement in quality of life using PDQ-39 was 34.5% +/- 15.3%. Univariable regression showed improvements in UPDRS III scores were significantly greater in studies with higher baseline UPDRS III off scores, increasing disease duration prior to surgery, earlier year of publication, and higher baseline L-dopa responsiveness. Average baseline UPDRS III off scores were significantly lower (i.e., suggesting milder disease) in later than in earlier studies. In multivariable regression, L-dopa responsiveness, higher baseline motor scores, and disease duration were independent predictors of greater change in motor score. Synthesis of the available literature indicates that STN DBS improves motor activity and activities of daily living in advanced PD. Differences between available studies likely reflect differences in patient populations and follow-up periods. (Kleiner-Fisman, 2006) Weaver, et al. conducted a meta-analysis comparing DBS of the subthalamic nucleus (STN) and the globus pallidus internus (GPI) for treating Parkinson's disease. Motor function improved significantly following stimulation (54% in patients whose STN was targeted and 40% in those whose GPI was stimulated), with effect sizes (ESs) of 2.59 and 2.04, respectively. After controlling for participant and study characteristics, patients who had undergone either STN or GPI DBS experienced comparable improved motor function following surgery (p = 0.094). The performance of activities of daily living improved significantly in patients with either target (40%). Medication requirements were significantly reduced following stimulation of the STN (ES = 1.51) but did not change when the GPI was stimulated (ES = -0.02). (Weaver, 2005) Anderson, et al. studied twenty-three patients with idiopathic PD, levodopa-induced dyskinesia, and response fluctuations were randomized to implantation of bilateral GPi or STN stimulators. Patients and evaluating clinicians were blinded to stimulation site. Off-medication Unified Parkinson's Disease Rating Scale (UPDRS) motor scores were improved after 12 months of both GPi and STN stimulation (39% vs 48%). Bradykinesia tended to improve more with STN than GPi stimulation. No improvement in on-medication function was observed in either group. Levodopa dose was reduced by 38% in STN stimulation patients compared with 3% in GPi stimulation patients (P =.08).
Dyskinesia was reduced by stimulation at both GPi and STN (89% vs 62%). Stimulation of either the GPi or STN improves many features of advanced PD. It is premature to exclude GPi as an appropriate target for DBS in patients with advanced disease. (Anderson, 2005) Researchers at Baylor College of Medicine assessed the long-term safety of deep brain stimulation Deep Brain Stimulation- Commercial Medical Management Guideline (DBS) in a large population of patients with a variety of movement disorders. A total of 319 patients underwent DBS device implantation. Of these 319, 182 suffered from medically refractory Parkinson disease; the other patients had essential tremor (112 patients), dystonia (19 patients), and other hyperkinetic movement disorders (six patients). Intraoperative adverse events (AE) were rare and included vasovagal response in eight patients (2.5%), syncope in four (1.2%), severe cough in three (0.9%), transient ischemic attack in one (0.3%), arrhythmia in one (0.3%), and confusion in one (0.3%). Perioperative AEs included headache in 48 patients (15.0%), confusion in 16 (5.0%), and hallucinations in nine (2.8%). Serious intraoperative/perioperative AEs included isolated seizure in four patients (1.2%), intracerebral hemorrhage in two patients (0.6%), intraventricular hemorrhage in two patients (0.6%), and a large subdural hematoma in one patient (0.3%). Persistent long-term complications of DBS surgery included dysarthria (4.0%), worsening gait (3.8%), cognitive dysfunction (4.0%), and infection (4.4%). Revisions were completed in 25 patients (7.8%) for the following reasons: loss of effect, lack of efficacy, infection, lead fracture, and lead migration.
Hardware-related complications included 12 lead fractures and 10 lead migrations. The authors conclude that in their 10-year experience, DBS has proven to be safe for the treatment of medically refractory movement disorders. (Kenney, 2007) In a randomized (n=34), observer-blind, multicenter trial, Esselink, et al., compared the efficacy of unilateral pallidotomy and bilateral subthalamic nucleus (STN) stimulation in patients with advanced Parkinson disease (PD). The off phase motor Unified Parkinson's Disease Rating Scale (UPDRS) score improved from 46.5 to 37 points in the group of pallidotomy patients and from 51.5 to 26.5 in the STN stimulation patients (p = 0.002). Of the secondary outcome measures, on phase motor UPDRS and dyskinesias UPDRS improved significantly in favor of the STN stimulation patients.
Reduction of antiparkinsonian drugs was greater after STN stimulation than after pallidotomy. The authors concluded that bilateral STN stimulation is more effective than unilateral pallidotomy in reducing parkinsonian symptoms in patients with advanced PD. (Esselink, 2004) Weaver et al. (2009) compared 6-month outcomes for patients with Parkinson's disease who received deep brain stimulation (n=121) or best medical therapy (n=134) in a randomized controlled trial. The investigators found that deep brain stimulation was more effective than best medical therapy in improving motor control without troubling dyskinesias, motor function, and quality of life, but was associated with an increased risk of serious adverse events.