Novel targets in deep brain stimulation for movement disorders

The neurosurgical treatment of movement disorders, primarily via deep brain stimulation (DBS), is a rapidly expanding and evolving field. Although conventional targets including the subthalamic nucleus (STN) and internal segment of the globus pallidus (GPi) for Parkinson’s disease and ventral intermediate nucleus of the thalams (VIM) for tremor provide substantial benefit in terms of both motor symptoms and quality of life, other targets for DBS have been explored in an effort to maximize clinical benefit and also avoid undesired adverse effects associated with stimulation. These novel targets primarily include the rostral zona incerta (rZI), caudal zona incerta (cZI)/posterior subthalamic area (PSA), prelemniscal radiation (Raprl), pedunculopontine nucleus (PPN), substantia nigra pars reticulata (SNr), centromedian/parafascicular (CM/PF) nucleus of the thalamus, nucleus basalis of Meynert (NBM), dentato-rubro-thalamic tract (DRTT), dentate nucleus of the cerebellum, external segment of the globus pallidus (GPe), and ventral oralis (VO) complex of the thalamus. However, reports of outcomes utilizing these targets are scattered and disparate. In order to provide a comprehensive resource for researchers and clinicians alike, we have summarized the existing literature surrounding these novel targets, including rationale for their use, neurosurgical techniques where relevant, outcomes and adverse effects of stimulation, and future directions for research.

     

Operative and hardware complications of deep brain stimulation for movement disorders

The objective of this investigation was to present the operative and hardware complications encountered during follow-up of patients with in situ deep brain stimulators. The study took the form of a retrospective chart review on a series of consecutive patients who were treated successfully with insertion of deep brain stimulators at a single centre by a single surgeon between 1999 and 2005. During the study period, a total of 60 patients underwent 96 procedures for implantation of unilateral or bilateral DBS electrodes. The mean follow-up period was 43.7 months (range 6-78 months) from the time of the first procedure. No patients were lost to follow-up or died. Eighteen patients (30%) developed 28 adverse events, requiring 28 electrodes to be replaced. Seven patients developed two adverse events and two patients developed three adverse events. The rate of adverse events per electrode-year was 8%. We observed a higher proportion of early complications (<6 months postoperatively) in patients with Parkinson's disease, while dystonic patients had more late complications (>6 months postoperatively) and no early complications. Thirty per cent of our patients developed an adverse event that could potentially lead to revision of the implanted hardware. In patients with Parkinson's disease most of the complications tend to occur during the first 6 months postoperatively, while in dystonic patients most occur between 12 and 24 months postoperatively.     

A prospective study of thalamic deep brain stimulation for the treatment of movement disorders in multiple sclerosis

The place for neurosurgical management of movement disorders in multiple sclerosis is unclear. To evaluate the potential benefits of unilateral thalamic deep brain stimulation (DBS) a prospective study was performed. Fifteen patients with confirmed MS and chronic, severe, drug-resistant movement disorders underwent stereotactic surgery to implant a thalamic DBS electrode using CT image guidance and intra-operative neurophysiological testing. The primary outcome measures were reduction in tremor severity and improvement in tests of hand function when the DBS electrode was turned on, 12 months after surgery. Secondary outcome measures included indices of disability, handicap, neuropsychological function and independence. Thirty-seven patients were assessed for treatment, but only 15 underwent surgery. In the 10 patients in whom implantation of the complete DBS system was carried out there was a significant reduction in the severity of tremor (p = 0.02) and improvement in hand function (p = 0.02). There were no benefits in any of the secondary outcome measures. Two patients had thalamocapsular haemorrhages at the site of electrode implantation and two had seizures in the follow-up period. Thalamic stimulation significantly reduced the tremor associated with MS and improved hand function in the targeted upper limb. However, there can be difficulties with identifying an optimal implantation site during operation, significant procedural morbidity and difficulty in predicting immediate outcome. It is also likely that the insignificant benefits of DBS on disability and handicap reflect persisting cerebeller dysmetria, and both the severity and diffuse nature of the disease process in this patient cohort.     

Costs of thalamic deep brain stimulation for movement disorders in patients with multiple sclerosis

Several studies have shown that thalamic deep brain stimulation (DBS) reduces tremor and improves hand performance in patients with multiple sclerosis (MS). The purpose of this paper is to describe the cost implications of DBS in MS patients and to highlight postoperative medical requirements that can be associated with this therapy. In a prospective study of thalamic DBS in MS patients the mean equipment costs were pounds 4769 (median pounds 7010, Medtronic, 1998 prices); mean neurosurgical inpatient costs per operated patient (n = 15) were pounds 4848 (range pounds 1982-8920, median pounds 5110); and mean in-patient postoperative rehabilitation cost pounds 4602 (range pounds 0-32,225, median pounds 1783). In addition there were transport and follow up costs. Mean neurosurgical inpatient stay following stereotactic DBS implantation was 15 days (median 12 days); and mean inpatient, postoperative rehabilitation stay 54 days (median 25 days). Although there were significant improvements in hand function and tremor reduction at 12 months postoperation, the level of patient performance in activities of daily living, their perception of their handicap and ipse facto the amount of home support required were unchanged from preoperative levels. This study has highlighted significant unforeseen medical requirements and costs that can occur in MS patients who have thalamic DBS surgery.     

Thalamic deep brain stimulation in the treatment of essential tremor: a long-term follow-up

Deep brain stimulation (DBS) of the nucleus ventralis intermedius thalami (Vim) in the treatment of essential tremor (ET) is well documented concerning the acute effects. Reports of the long-term effects are, however, few and the aim of the present study was to analyse the long-term efficacy of this treatment. Nineteen patients operated with unilateral Vim-DBS were evaluated with the Essential Tremor Rating Scale (ETRS) before surgery, and after a mean time of 1 and 7 years after surgery. The ETRS score for tremor of the contralateral hand was reduced from 6.8 at baseline to 1.2 and 2.7, respectively, on stimulation at follow-up. For hand function (item 11 - 14) the score was reduced from 12.7 to 4.1 and 8.2, respectively. Vim-DBS is an efficient treatment for ET, also after many years of treatment. There is, however, a decreasing effect over time, most noticeable concerning tremor of action.     

Neuroethics of deep brain stimulation for mental disorders: brain stimulation reward in humans

The theoretical basis of some deep brain stimulation (DBS) trials undertaken in the early years was the phenomenon of "brain stimulation reward (BSR)," which was first identified in rats. The animals appeared to be rewarded by pleasure caused by the stimulation of certain brain regions (reward system), such as the septal area. "Self-stimulation" experiments, in which rats were allowed to stimulate their own brain by pressing a freely accessible lever, they quickly learned lever pressing and sometimes continued to stimulate until they exhausted themselves. BSR was also observed with DBS of the septal area in humans. DBS trials in later years were undertaken on other theoretical bases, but unexpected BSR was sometimes induced by stimulation of some areas, such as the locus coeruleus complex. When BSR was induced, the subjects experienced feelings that were described as "cheerful," "alert," "good," "well-being," "comfort," "relaxation," "joy," or "satisfaction." Since the DBS procedure is equivalent to a "self-stimulation" experiment, they could become "addicted to the stimulation itself" or "compulsive about the stimulation," and stimulate themselves "for the entire day," "at maximum amplitude" and, in some instances, "into convulsions." DBS of the reward system has recently been applied to alleviate anhedonia in patients with refractory major depression. Although this approach appears promising, there remains a difficult problem: who can adjust their feelings and reward-oriented behavior within the normal range? With a self-stimulation procedure, the BSR may become uncontrollable. To develop DBS to the level of a standard therapy for mental disorders, we need to discuss "Who has the right to control the mental condition?" and "Who makes decisions" on "How much control is appropriate?" in daily life.     

Deep brain stimulation for movement disorders: morbidity and mortality in 109 patients

OBJECT: Deep brain stimulation (DBS) has been advocated as a more highly effective and less morbidity-producing alternative to ablative stereotactic surgery in the treatment of medically intractable movement disorders. Nevertheless, the exact incidence of morbidity and mortality associated with the procedure is not well known. In this study the authors reviewed the surgical morbidity and mortality rates in a large series of DBS operations. METHODS: The authors retrospectively analyzed surgical complications in their consecutive series of 179 DBS implantations in 109 patients performed by a single surgical team at one center between July 1998 and April 2002. The mean follow-up period was 20 months. There were 16 serious adverse events related to surgery in 14 patients (12.8%). There were two perioperative deaths (1.8%), one caused by pulmonary embolism and the second due to aspiration pneumonia. The other adverse events were two pulmonary embolisms, two subcortical hemorrhages, two chronic subdural hematomas, one venous infarction, one seizure, four infections, one cerebrospinal fluid leak, and one skin erosion. The incidence of permanent sequelae was 4.6% (five of 109 patients). The incidence of device-related complications, such as infection or skin erosion, was also 4.6% (five of 109 patients). CONCLUSIONS: There is a significant incidence of adverse events associated with the DBS procedure. Nevertheless, DBS is clinically effective in well-selected patients and should be seriously considered as a treatment option for patients with medically refractory movement disorders.     

Factors involved in long-term efficacy of deep brain stimulation of the thalamus for essential tremor

OBJECT: Although nucleus ventralis intermedius stimulation has been shown to be safe and efficacious in the treatment of essential tremor, there is a subset of patients who eventually lose benefit from their stimulation. Proposed causes for this phenomenon include tolerance, disease progression, and suboptimal location. The goal of this study was to assess the factors that may lead to both stimulation failure, defined as loss of meaningful tremor relief, and less satisfactory outcomes, defined as leads requiring voltages>3.6 V for effective tremor control. METHODS: The authors present their clinical outcomes from 31 leads in 27 patients who had effective tremor control for >1 year following nucleus ventralis intermedius stimulation. All patients postoperatively had a mean decrease in both the writing and drawing subscales of the Fahn-Tolosa-Marin Tremor Rating Scale (p<0.001). RESULTS: After a mean follow-up of 40 months, 22 patients continued to have tremor control with stimulation. Four patients eventually lost efficacy of their stimulation at a mean of 39 months. There was no difference in age, duration of disease, or disease severity between the groups. Examination of perioperative factors revealed that suboptimal anteroposterior positioning as evidenced on intraoperative fluoroscopy occurred significantly more frequently in patients with stimulation failure (p=0.018). In patients with less satisfactory outcomes, no difference was seen between group demographics. Fluoroscopy again revealed suboptimal positioning more frequently in these patients (p=0.005). CONCLUSIONS: This study provides further evidence that suboptimal lead position in combination with disease progression or tolerance may result in less satisfactory long-term outcomes.     

Analysis of hemorrhagic risk factors during deep brain stimulation surgery for movement disorders: comparison of the circumferential paired and multiple electrode insertion methods

Background  

The most serious complication of deep brain stimulation (DBS) surgery is intracranial hemorrhage. The authors have assessed risk factors for hemorrhage in DBS surgery and compared two types of microelectrode insertion technique on hemorrhagic risk.     

Complications of deep brain stimulation surgery

Although technological advances have reduced device-related complications, DBS surgery still carries a significant risk of transient and permanent complications. We report our experience in 86 patients and 149 DBS implants. Patients with Parkinson's disease, essential tremor and dystonia were treated. There were 8 perioperative, 8 postoperative, 9 hardware-related complications and 4 stimulation-induced side effects. Only 5 patients (6%) sustained some persistent neurological sequelae, however, 26 of the 86 patients undergoing 149 DBS implants in this series experienced some untoward event with the procedure. Although there were no fatalities or permanent severe disabilities encountered, it is important to extend the informed consent to include all potential complications.     

Successful long-term deep brain stimulation for hemichorea-hemiballism in a patient with diabetes. Case report

The authors report a case of hemichorea-hemiballism (HC-HB) that was successfully treated using deep brain stimulation (DBS). A 65-year-old right-handed man exhibited a sudden onset of right HC-HB without a diabetic coma. At admission T1-weighted magnetic resonance (MR) images revealed a high-intensity signal in the left striatum, contralateral to the patient's involuntary movements. The HC-HB continued for 5 months after onset of the condition despite medical treatment and a decreased intensity of the signal on T1-weighted MR images. The patient underwent placement of a quadripolar DBS electrode in the left thalamus, including the left ventral oralis (VO) anterior and posterior nuclei (the VO complex). Postoperatively, the right-sided HC-HB disappeared rapidly during electrical stimulation and there were no neurological deficits. The authors demonstrate that DBS can be an effective treatment for medically refractory HC-HB. This is the first case of HC-HB that has been successfully treated with DBS.