Cynthia S. Kubu

Deep Brain Stimulation of the Ventral Capsule/Ventral Striatum for Treatment-Resistant Depression

BACKGROUND We investigated the use of deep brain stimulation (DBS) of the ventral capsule/ventral striatum (VC/VS) for treatment refractory depression. METHODS Fifteen patients with chronic, severe, highly refractory depression received open-label DBS at three collaborating clinical sites. Electrodes were implanted bilaterally in the VC/VS region. Stimulation was titrated to therapeutic benefit and the absence of adverse effects. All patients received continuous stimulation and were followed for a minimum of 6 months to longer than 4 years. Outcome measures included the Hamilton Depression Rating Scale-24 item (HDRS), the Montgomery-Asberg Depression Rating Scale (MADRS), and the Global Assessment of Function Scale (GAF). RESULTS Significant improvements in depressive symptoms were observed during DBS treatment. Mean HDRS scores declined from 33.1 at baseline to 17.5 at 6 months and 14.3 at last follow-up. Similar improvements were seen with the MADRS (34.8, 17.9, and 15.7, respectively) and the GAF (43.4, 55.5, and 61.8, respectively). Responder rates with the HDRS were 40% at 6 months and 53.3% at last follow-up (MADRS: 46.7% and 53.3%, respectively). Remission rates were 20% at 6 months and 40% at last follow-up with the HDRS (MADRS: 26.6% and 33.3%, respectively). The DBS was well-tolerated in this group. CONCLUSIONS Deep brain stimulation of the VC/VS offers promise for the treatment of refractory major depression.

Three-Year Outcomes in Deep Brain Stimulation for Highly Resistant Obsessive–Compulsive Disorder

Deep brain stimulation (DBS) of the anterior limb of the internal capsule has been shown to be beneficial in the short term for obsessive–compulsive disorder (OCD) patients who exhaust conventional therapies. Nuttin et al, who published the first DBS for OCD series, found promising results using a capsule target immediately rostral to the anterior commissure extending into adjacent ventral capsule/ventral striatum (VC/VS). Published long-term outcome data are limited to four patients. In this collaborative study, 10 adult OCD patients meeting stringent criteria for severity and treatment resistance had quadripolar stimulating leads implanted bilaterally in the VC/VS. DBS was activated openly 3 weeks later. Eight patients have been followed for at least 36 months. Group Yale-Brown Obsessive Compulsive Scale (YBOCS) scores decreased from 34.6±0.6 (mean±SEM) at baseline (severe) to 22.3±2.1 (moderate) at 36 months (p<0.001). Four of eight patients had a ⩾35% decrease in YBOCS severity at 36 months; in two patients, scores declined between 25 and 35%. Global Assessment of Functioning scores improved from 36.6±1.5 at baseline to 53.8±2.5 at 36 months (p<0.001). Depression and anxiety also improved, as did self-care, independent living, and work, school, and social functioning. Surgical adverse effects included an asymptomatic hemorrhage, a single seizure, and a superficial infection. Psychiatric adverse effects included transient hypomanic symptoms, and worsened depression and OCD when DBS was interrupted by stimulator battery depletion. This open study found promising long-term effects of DBS in highly treatment-resistant OCD.

Deep brain stimulation of the ventral internal capsule/ventral striatum for obsessive-compulsive disorder: worldwide experience

Psychiatric neurosurgery teams in the United States and Europe have studied deep brain stimulation (DBS) of the ventral anterior limb of the internal capsule and adjacent ventral striatum (VC/VS) for severe and highly treatment-resistant obsessive-compulsive disorder. Four groups have collaborated most closely, in small-scale studies, over the past 8 years. First to begin was Leuven/Antwerp, followed by Butler Hospital/Brown Medical School, the Cleveland Clinic and most recently the University of Florida. These centers used comparable patient selection criteria and surgical targeting. Targeting, but not selection, evolved during this period. Here, we present combined long-term results of those studies, which reveal clinically significant symptom reductions and functional improvement in about two-thirds of patients. DBS was well tolerated overall and adverse effects were overwhelmingly transient. Results generally improved for patients implanted more recently, suggesting a ‘learning curve’ both within and across centers. This is well known from the development of DBS for movement disorders. The main factor accounting for these gains appears to be the refinement of the implantation site. Initially, an anterior–posterior location based on anterior capsulotomy lesions was used. In an attempt to improve results, more posterior sites were investigated resulting in the current target, at the junction of the anterior capsule, anterior commissure and posterior ventral striatum. Clinical results suggest that neural networks relevant to therapeutic improvement might be modulated more effectively at a more posterior target. Taken together, these data show that the procedure can be successfully implemented by dedicated interdisciplinary teams, and support its therapeutic promise.

A multicentre study on suicide outcomes following subthalamic stimulation for Parkinson's disease

Subthalamic nucleus deep brain stimulation improves motor symptoms and quality of life in advanced Parkinsons disease. As after other life-altering surgeries, suicides have been reported following deep brain stimulation for movement disorders. We sought to determine the suicide rate following subthalamic nucleus deep brain stimulation for Parkinsons disease by conducting an international multicentre retrospective survey of movement disorder and surgical centres. We further sought to determine factors associated with suicide attempts through a nested case-control study. In the survey of suicide rate, 55/75 centres participated. The completed suicide percentage was 0.45% (24/5311) and attempted suicide percentage was 0.90% (48/5311). Observed suicide rates in the first postoperative year (263/100,000/year) (0.26%) were higher than the lowest and the highest expected age-, gender- and country-adjusted World Health Organization suicide rates (Standardized Mortality Ratio for suicide: SMR 12.63-15.64; P < 0.001) and remained elevated at the fourth postoperative year (38/100,000/year) (0.04%) (SMR 1.81-2.31; P < 0.05). The excess number of deaths was 13 for the first postoperative year and one for the fourth postoperative year. In the case-control study of associated factors, 10 centres participated. Twenty-seven attempted suicides and nine completed suicides were compared with 70 controls. Postoperative depression (P < 0.001), being single (P = 0.007) and a previous history of impulse control disorders or compulsive medication use (P = 0.005) were independent associated factors accounting for 51% of the variance for attempted suicide risk. Attempted suicides were also associated (P < 0.05) with being younger, younger Parkinsons disease onset and a previous suicide attempt. Completed suicides were associated with postoperative depression (P < 0.001). Postoperative depression remained a significant factor associated with attempted and completed suicides after correction for multiple comparisons using the stringent Bonferroni correction. Mortality in the first year following subthalamic nucleus deep brain stimulation has been reported at 0.4%. Suicide is thus one of the most important potentially preventable risks for mortality following subthalamic nucleus deep brain stimulation for Parkinsons disease. Postoperative depression should be carefully assessed and treated. A multidisciplinary assessment and follow-up is recommended.

Deep brain stimulation: Neuropsychological and neuropsychiatric issues

Parkinsons disease (PD) is a neurodegenerative disorder characterized by motor, cognitive, neuropsychiatric, autonomic, and other nonmotor symptoms. The efficacy of deep brain stimulation (DBS) for the motor symptoms of advanced PD is well established. However, the effects of DBS on the cognitive and neuropsychiatric symptoms are less clear. The neuropsychiatric aspects of DBS for PD have recently been of considerable clinical and pathophysiological interest. As a companion to the preoperative and postoperative sections of the DBS consensus articles, this article reviews the published literature on the cognitive and neuropsychiatric aspects of DBS for PD. The majority of the observed neuropsychiatric symptoms are transient, treatable, and potentially preventable. Outcome studies, methodological issues, pathophysiology, and preoperative and postoperative management of the cognitive and neuropsychiatric aspects and complications of DBS for PD are discussed.

Deep brain stimulation: postoperative issues.

Numerous factors need to be taken into account when managing a patient with Parkinsons disease (PD) after deep brain stimulation (DBS). Questions such as when to begin programming, how to conduct a programming screen, how to assess the effects of programming, and how to titrate stimulation and medication for each of the targeted sites need to be addressed. Follow‐up care should be determined, including patient adjustments of stimulation, timing of follow‐up visits and telephone contact with the patient, and stimulation and medication conditions during the follow‐up assessments. A management plan for problems that can arise after DBS such as weight gain, dyskinesia, axial symptoms, speech dysfunction, muscle contractions, paresthesia, eyelid, ocular and visual disturbances, and behavioral and cognitive problems should be developed. Long‐term complications such as infection or erosion, loss of effect, intermittent stimulation, tolerance, and pain or discomfort can develop and need to be managed. Other factors that need consideration are social and job‐related factors, development of dementia, general medical issues, and lifestyle changes. This report from the Consensus on Deep Brain Stimulation for Parkinsons Disease, a project commissioned by the Congress of Neurological Surgeons and the Movement Disorder Society, outlines answers to a series of questions developed to address all aspects of DBS postoperative management and decision‐making with a systematic overview of the literature (until mid‐2004) and by the expert opinion of the authors. The report has been endorsed by the Scientific Issues Committee of the Movement Disorder Society and the American Society of Stereotactic and Functional Neurosurgery.

Deep brain stimulation: preoperative issues.

Numerous factors need to be taken into account in deciding whether a patient with Parkinsons disease (PD) is a candidate for deep brain stimulation. Patient‐related personal factors including age and the presence of other comorbid disorders need to be considered. Neuropsychological and neuropsychiatric concerns relate both to the presurgical status of the patient and to the potential for surgery to result in new problems postoperatively. A number of factors related to the underlying PD need to be considered, including the specific parkinsonian motor indications (e.g., tremor, bradykinesia, gait dysfunction), previous medical therapies, including benefit from current therapy and adverse effects, and past surgical treatments. Definable causes of Parkinsonism, particularly atypical Parkinsonisms, should be considered. Finally, methods of evaluating outcomes should be defined and formalized. This is a report from the Consensus on Deep Brain Stimulation for Parkinsons Disease, a project commissioned by the Congress of Neurological Surgeons and the Movement Disorder Society (MDS). The report has been endorsed by the Scientific Issues Committee of the MDS and the American Society of Stereotactic and Functional Neurosurgery. It outlines answers to a series of questions developed to address all aspects of deep brain stimulation preoperative decision‐making.

Hippocampal electrical stimulation in mesial temporal lobe epilepsy

Background: Adjustable, reversible therapies are needed for patients with pharmacoresistant epilepsy. Electrical stimulation of the hippocampus has been proposed as a possible treatment for mesial temporal lobe epilepsy (MTLE). Methods: Four patients with refractory MTLE whose risk to memory contraindicated temporal lobe resection underwent implantation of a chronic stimulating depth electrode along the axis of the left hippocampus. The authors used continuous, subthreshold electrical stimulation (90 μsec, 190 Hz) and a double blind, multiple cross-over, randomized controlled design, consisting of three treatment pairs, each containing two 1-month treatment periods. During each treatment pair the stimulator was randomly turned ON 1 month and OFF 1 month. Outcomes were assessed at monthly intervals in a double blind manner, using standardized instruments and accounting for a washout period. The authors compared outcomes between ON, OFF, and baseline periods. Results: Hippocampal stimulation produced a median reduction in seizures of 15%. All but one patient’s seizures improved; however, the results did not reach significance. Effects seemed to carry over into the OFF period, and an implantation effect cannot be ruled out. The authors found no significant differences in other outcomes. There were no adverse effects. One patient has been treated for 4 years and continues to experience substantial long-term seizure improvement. Conclusion: The authors demonstrate important beneficial trends, some long-term benefits, and absence of adverse effects of hippocampal electrical stimulation in mesial temporal lobe epilepsy. However, the effect sizes observed were smaller than those reported in non-randomized, unblinded studies.

A Randomized Sham-Controlled Trial of Deep Brain Stimulation of the Ventral Capsule/Ventral Striatum for Chronic Treatment-Resistant Depression

BACKGROUND Multiple open-label trials of deep brain stimulation (DBS) for treatment-resistant depression (TRD), including those targeting the ventral capsule/ventral striatum target, have shown encouraging response rates. However, no randomized controlled trials of DBS for TRD have been published. METHODS Thirty patients with TRD participated in a sham-controlled trial of DBS at the ventral capsule/ventral striatum target for TRD. Patients were randomized to active versus sham DBS treatment in a blinded fashion for 16 weeks, followed by an open-label continuation phase. The primary outcome measure was response, defined as a 50% or greater improvement on the Montgomery-Åsberg Depression Rating Scale from baseline. RESULTS There was no significant difference in response rates between the active (3 of 15 subjects; 20%) and control (2 of 14 subjects; 14.3%) treatment arms and no significant difference between change in Montgomery-Åsberg Depression Rating Scale scores as a continuous measure upon completion of the 16-week controlled phase of the trial. The response rates at 12, 18, and 24 months during the open-label continuation phase were 20%, 26.7%, and 23.3%, respectively. CONCLUSION The results of this first randomized controlled study of DBS for the treatment of TRD did not demonstrate a significant difference in response rates between the active and control groups at the end of the 16-week controlled phase. However, a range of 20% to 26.7% of patients did achieve response at any time during the open-label continuation phase. Future studies, perhaps utilizing alternative study designs and stimulation parameters, are needed.

Misuse Of The FDA’s Humanitarian Device Exemption In Deep Brain Stimulation For Obsessive-Compulsive Disorder

Deep brain stimulation-a novel surgical procedure-is emerging as a treatment of last resort for people diagnosed with neuropsychiatric disorders such as severe obsessive-compulsive disorder. The US Food and Drug Administration granted a so-called humanitarian device exemption 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. We argue that Congress and federal regulators should revisit the humanitarian device exemption to ensure that it is not used to sidestep careful research that can offer valuable data with appropriate patient safeguards.