Jason M. Schwalb

Deep Brain Stimulation for Treatment-Resistant Depression

Treatment-resistant depression is a severely disabling disorder with no proven treatment options once multiple medications, psychotherapy, and electroconvulsive therapy have failed. Based on our preliminary observation that the subgenual cingulate region (Brodmann area 25) is metabolically overactive in treatment-resistant depression, we studied whether the application of chronic deep brain stimulation to modulate BA25 could reduce this elevated activity and produce clinical benefit in six patients with refractory depression. Chronic stimulation of white matter tracts adjacent to the subgenual cingulate gyrus was associated with a striking and sustained remission of depression in four of six patients. Antidepressant effects were associated with a marked reduction in local cerebral blood flow as well as changes in downstream limbic and cortical sites, measured using positron emission tomography. These results suggest that disrupting focal pathological activity in limbic-cortical circuits using electrical stimulation of the subgenual cingulate white matter can effectively reverse symptoms in otherwise treatment-resistant depression.

AAV2-GAD gene therapy for advanced Parkinson's disease: a double-blind, sham-surgery controlled, randomised trial

BACKGROUND Gene transfer of glutamic acid decarboxylase (GAD) and other methods that modulate production of GABA in the subthalamic nucleus improve basal ganglia function in parkinsonism in animal models. We aimed to assess the effect of bilateral delivery of AAV2-GAD in the subthalamic nucleus compared with sham surgery in patients with advanced Parkinsons disease. METHODS Patients aged 30-75 years who had progressive levodopa-responsive Parkinsons disease and an overnight off-medication unified Parkinsons disease rating scale (UPDRS) motor score of 25 or more were enrolled into this double-blind, phase 2, randomised controlled trial, which took place at seven centres in the USA between Nov 17, 2008, and May 11, 2010. Infusion failure or catheter tip location beyond a predefined target zone led to exclusion of patients before unmasking for the efficacy analysis. The primary outcome measure was the 6-month change from baseline in double-blind assessment of off-medication UPDRS motor scores. This trial is registered with ClinicalTrials.gov, NCT00643890. FINDINGS Of 66 patients assessed for eligibility, 23 were randomly assigned to sham surgery and 22 to AAV2-GAD infusions; of those, 21 and 16, respectively, were analysed. At the 6-month endpoint, UPDRS score for the AAV2-GAD group decreased by 8·1 points (SD 1·7, 23·1%; p<0·0001) and by 4·7 points in the sham group (1·5, 12·7%; p=0·003). The AAV2-GAD group showed a significantly greater improvement from baseline in UPDRS scores compared with the sham group over the 6-month course of the study (RMANOVA, p=0·04). One serious adverse event occurred within 6 months of surgery; this case of bowel obstruction occurred in the AAV2-GAD group, was not attributed to treatment or the surgical procedure, and fully resolved. Other adverse events were mild or moderate, likely related to surgery and resolved; the most common were headache (seven patients in the AAV2-GAD group vs two in the sham group) and nausea (six vs two). INTERPRETATION The efficacy and safety of bilateral infusion of AAV2-GAD in the subthalamic nucleus supports its further development for Parkinsons disease and shows the promise for gene therapy for neurological disorders. FUNDING Neurologix.

Bilateral subthalamic nucleus stimulation for Parkinson's disease: A systematic review of the clinical literature

OBJECTIVE: To evaluate the benefits and adverse effects of bilateral subthalamic nucleus stimulation in the treatment of Parkinsons disease (PD) by systematically reviewing the published literature. METHODS: A search of the PubMed database using the key words subthalamic, nucleus, and stimulation yielded 624 articles published between 1966 and December 2003. Only articles that included original, nonduplicated descriptions of patients with PD treated with bilateral subthalamic nucleus stimulation were selected for further analysis. RESULTS: A total of 38 studies from 34 neurosurgical centers in 13 countries were identified for critical review. The outcomes for 471 patients with PD treated with bilateral subthalamic nucleus stimulation were assessed according to the Unified Parkinsons Disease Rating Scale in both on-medication and off-medication conditions. With stimulation, Unified Parkinsons Disease Rating Scale motor scores in the off-medication condition improved by 50% after 6 months, 56% after 12 months, 51% after 2 years, and 49% after 5 years compared with preoperative off-medication scores. At 12 months of subthalamic nucleus stimulation, the mean improvement in tremor was 81%, in rigidity was 63%, in bradykinesia was 52%, in gait was 64%, and in postural instability was 69% when compared with preoperative off-medication subscores. On-medication dyskinesias were reduced by 94%, as assessed 12 months after stimulation using the Unified Parkinsons Disease Rating Scale IV complications of therapy score. There was an overall 52% reduction in the l-dopa-equivalent dose intake after 12 months of stimulation. Most adverse effects were mild to moderate. There was a 1 to 2% incidence of severe adverse effects (death or permanent neurological deficits related to intracerebral hemorrhages). Nineteen percent of the patients had adverse effects related to stimulation that could be reversed by changing stimulation parameters. There was a 9% incidence of adverse effects related to the hardware (infections, lead and pulse generator problems). CONCLUSION: Bilateral subthalamic nucleus stimulation is effective in the treatment of PD. Further refinements in patient selection and surgical technique may lessen the incidence of complications associated with this procedure.

Deep brain stimulation for chronic neuropathic pain: long-term outcome and the incidence of insertional effect.

&NA; We conducted a retrospective analysis of long‐term results of deep brain stimulation (DBS) for the treatment of neuropathic pain. Twenty‐one patients had electrodes implanted in the ventrocaudalis thalamic nucleus (Vc) (n = 13) or in both Vc and periaqueductal/periventricular gray matter (PAG/PVG) (n = 8). After insertion of the electrodes, 9 patients (43%) had a substantial reduction in pain scores in the absence of stimulation (insertional effect). The effects of stimulation were studied right after surgery or upon return of the patients’ pain after electrode insertion (stimulation trials). Patients with a greater than 50% reduction in pain scores were implanted with a pulse generator (IPG). Of interest, patients who had an insertional effect had a trend towards a successful stimulation trial (p = 0.08). Overall, 13 of the 21 patients operated (62%) had a successful stimulation trial and received an IPG (12 with electrodes in Vc and one in both Vc and PAG/PVG). Seven patients (33%) did not benefit from stimulation and had the electrodes removed. One patient experienced a prolonged insertional effect and has not required stimulation. Of the 13 patients that received an IPG, 8 discontinued stimulation during the first year of treatment. Only 5 patients maintained long‐term benefit (4 with stimulation in Vc and one in both Vc and PAG/PVG). The relatively low efficacy of DBS for the treatment of neuropathic pain stresses the need for further investigation and the exploration of new surgical targets.

The history and future of deep brain stimulation

SummaryThe advancement of electrical stimulation of the central nervous system has been a story of fits and bursts with numerous setbacks. In many ways, this history has paralleled the history of medicine and physics. We have moved from anecdotal observation to double-blinded, prospective randomized trials. We have moved from faradic stimulation to systems that lie completely under the skin and can deliver complex electrical currents to discrete areas of the brain while controlled through a device that is not much bigger than a PDA. This review will discuss how deep brain stimulation has developed into its current form, where we see the field going and the potential pitfalls along the way.

Unilateral subdural motor cortex stimulation improves essential tremor but not Parkinson’s disease

Epidural motor cortex stimulation has been reported to be effective in treating some movement disorders. Nevertheless, clinical results have been variable and no double-blinded evaluations have been reported. The aim of this study was to investigate efficacy and safety of unilateral subdural motor cortex stimulation in patients with essential tremor and Parkinsons disease. Six patients with essential tremor and five parkinsonian patients were selected. Craniotomy was performed under local anaesthesia with conscious sedation. A four contact electrode (Resume II model 3587, Medtronic, Inc) was positioned on the motor cortex, after identification of the area with direct monopolar cortical stimulation. Soon after surgery, a variety of different settings of stimulation were assessed using standard rating scales to select the optimal stimulation parameters. The effects of chronic stimulation were evaluated in both groups of patients after 3 months (double-blinded fashion) and 1 year (open fashion). In essential tremor, contralateral hand tremor scores significantly improved (P = 0.04) with stimulation during the double-blinded study, whereas in Parkinsons disease, there were no changes in the OFF medication/on stimulation motor scores compared with off stimulation. At 1 year, tremor was improved by stimulation in two out of three patients with essential tremor available at follow-up, whereas no improvement was observed in the five parkinsonian patients. One parkinsonian patient had a cortical venous infarct. Three other patients had self-limiting seizures with aggressive trials of stimulation in the period of dosage selection. These findings suggest that unilateral subdural motor cortex stimulation may be useful for contralateral hand tremor in selected patients with essential tremor but was not effective in improving parkinsonian signs in our series.

Practice guideline: Idiopathic normal pressure hydrocephalus: Response to shunting and predictors of response: Report of the Guideline Development, Dissemination, and Implementation Subcommittee of the American Academy of Neurology.

Objective: We evaluated evidence for utility of shunting in idiopathic normal pressure hydrocephalus (iNPH) and for predictors of shunting effectiveness. Methods: We identified and classified relevant published studies according to 2004 and 2011 American Academy of Neurology methodology. Results: Of 21 articles, we identified 3 Class I articles. Conclusions: Shunting is possibly effective in iNPH (96% chance subjective improvement, 83% chance improvement on timed walk test at 6 months) (3 Class III). Serious adverse event risk was 11% (1 Class III). Predictors of success included elevated Ro (1 Class I, multiple Class II), impaired cerebral blood flow reactivity to acetazolamide (by SPECT) (1 Class I), and positive response to either external lumbar drainage (1 Class III) or repeated lumbar punctures. Age may not be a prognostic factor (1 Class II). Data are insufficient to judge efficacy of radionuclide cisternography or aqueductal flow measurement by MRI. Recommendations: Clinicians may choose to offer shunting for subjective iNPH symptoms and gait (Level C). Because of significant adverse event risk, risks and benefits should be carefully weighed (Level B). Clinicians should inform patients with iNPH with elevated Ro and their families that they have an increased chance of responding to shunting compared with those without such elevation (Level B). Clinicians may counsel patients with iNPH and their families that (1) positive response to external lumbar drainage or to repeated lumbar punctures increases the chance of response to shunting, and (2) increasing age does not decrease the chance of shunting being successful (both Level C).

Association of Early Imaging for Back Pain With Clinical Outcomes in Older Adults

IMPORTANCE In contrast to the recommendations for younger adults, many guidelines allow for older adults with back pain to undergo imaging without waiting 4 to 6 weeks. However, early imaging may precipitate interventions that do not improve outcomes. OBJECTIVE To compare function and pain at the 12-month follow-up visit among older adults who received early imaging with those who did not receive early imaging after a new primary care visit for back pain without radiculopathy. DESIGN, SETTING, AND PARTICIPANTS Prospective cohort of 5239 patients 65 years or older with a new primary care visit for back pain (2011-2013) in 3 US health care systems. We matched controls 1:1 using propensity score matching of demographic and clinical characteristics, including diagnosis, pain severity, pain duration, functional status, and prior resource use. EXPOSURES Diagnostic imaging (plain films, computed tomography [CT], magnetic resonance imaging [MRI]) of the lumbar or thoracic spine within 6 weeks of the index visit. MAIN OUTCOME AND MEASURES PRIMARY OUTCOME back or leg pain-related disability measured by the modified Roland-Morris Disability Questionnaire (score range, 0-24; higher scores indicate greater disability) 12 months after enrollment. RESULTS Among the 5239 patients, 1174 had early radiographs and 349 had early MRI/CT. At 12 months, neither the early radiograph group nor the early MRI/CT group differed significantly from controls on the disability questionnaire. The mean score for patients who underwent early radiography was 8.54 vs 8.74 among the control group (difference, -0.10 [95% CI, -0.71 to 0.50]; mixed model, P = .36). The mean score for the early MRI/CT group was 9.81 vs 10.50 for the control group (difference,-0.51 [-1.62 to 0.60]; mixed model, P = .18). CONCLUSIONS AND RELEVANCE Among older adults with a new primary care visit for back pain, early imaging was not associated with better 1-year outcomes. The value of early diagnostic imaging in older adults for back pain without radiculopathy is uncertain.

Use of the modified frailty index to predict 30-day morbidity and mortality from spine surgery

OBJECTIVE Limited tools exist to stratify perioperative risk in patients undergoing spinal procedures. The modified frailty index (mFI) based on the Canadian Study of Health and Aging Frailty Index (CSHA-FI), constructed from standard demographic variables, has been applied to various other surgical populations for risk stratification. The authors hypothesized that it would be predictive of postoperative morbidity and mortality in patients undergoing spine surgery. METHODS The 2006-2010 National Surgical Quality Improvement Program (NSQIP) data set was accessed for patients undergoing spine surgeries based on Current Procedural Terminology (CPT) codes. Sixteen preoperative clinical NSQIP variables were matched to 11 CSHA-FI variables (changes in daily activities, gastrointestinal problems, respiratory problems, clouding or delirium, hypertension, coronary artery and peripheral vascular disease, congestive heart failure, and so on). The outcomes assessed were 30-day occurrences of adverse events. These were then summarized in groups: any infection, wound-related complication, Clavien IV complications (life-threatening, requiring ICU admission), and mortality. RESULTS A total of 18,294 patients were identified. In 8.1% of patients with an mFI of 0 there was at least one morbid complication, compared with 24.3% of patients with an mFI of ≥ 0.27 (p < 0.001). An mFI of 0 was associated with a mortality rate of 0.1%, compared with 2.3% for an mFI of ≥ 0.27 (p < 0.001). Patients with an mFI of 0 had a 1.7% rate of surgical site infections and a 0.8% rate of Clavien IV complications, whereas patients with an mFI of ≥ 0.27 had rates of 4.1% and 7.1% for surgical site infections and Clavien IV complications, respectively (p < 0.001 for both). Multivariate analysis showed that the preoperative mFI and American Society of Anesthesiologists classification of ≥ III had a significantly increased risk of leading to Clavien IV complications and death. CONCLUSIONS A higher mFI was associated with a higher risk of postoperative morbidity and mortality, providing an additional tool to improve perioperative risk stratification.

Comparison of dysphagia before and after deep brain stimulation in Parkinson's disease†‡§

Although dysphagia is a common problem for many Parkinsons disease (PD) patients, the effect of deep brain stimulation (DBS) on swallowing is unclear. Fourteen subjects with advanced PD underwent videofluorographic swallowing studies prior to bilateral DBS of the subthalamic nucleus (STN) and at 3 and 12 months postprocedure. They were tested under several stimulation and medication conditions. Subjects completed the Dysphagia Handicap Index at each time. There was a strong trend toward improved swallowing response for solid intake in the medication‐free condition with the stimulator on compared with the stimulator off (P = .0107). Also, there was a trend toward improved oral preparation of thin liquids (P = .0368) in the medication‐free condition when the stimulator was on versus off 12 months later. The remaining swallowing parameters showed no change or worsening of swallowing function regardless of stimulator or medication status. Results of the Dysphagia Handicap Index revealed significant improvement in subject self‐perception of swallowing 3 and 12 months following the procedure compared with baseline on the functional subscale (P = .020 and P = .010, respectively), the emotional subscale (P = .013 and P = .003, respectively), and the total score (P = .025 and P = .003, respectively). These data suggest that bilateral STN‐DBS does not substantively impair swallowing in PD. In addition, it may improve motor sequencing of the oropharyngeal swallow for solid consistencies (which are known to provide increased sensory feedback to assist motor planning of the oropharyngeal swallow). Subjects with advanced PD who are undergoing DBS may perceive significant improvement in swallowing ability despite the lack of objective improvements in swallowing function.