Richard K. Simpson

Pallidal versus subthalamic deep-brain stimulation for Parkinson's disease

BACKGROUND Deep-brain stimulation is the surgical procedure of choice for patients with advanced Parkinsons disease. The globus pallidus interna and the subthalamic nucleus are accepted targets for this procedure. We compared 24-month outcomes for patients who had undergone bilateral stimulation of the globus pallidus interna (pallidal stimulation) or subthalamic nucleus (subthalamic stimulation). METHODS At seven Veterans Affairs and six university hospitals, we randomly assigned 299 patients with idiopathic Parkinsons disease to undergo either pallidal stimulation (152 patients) or subthalamic stimulation (147 patients). The primary outcome was the change in motor function, as blindly assessed on the Unified Parkinsons Disease Rating Scale, part III (UPDRS-III), while patients were receiving stimulation but not receiving antiparkinsonian medication. Secondary outcomes included self-reported function, quality of life, neurocognitive function, and adverse events. RESULTS Mean changes in the primary outcome did not differ significantly between the two study groups (P=0.50). There was also no significant difference in self-reported function. Patients undergoing subthalamic stimulation required a lower dose of dopaminergic agents than did those undergoing pallidal stimulation (P=0.02). One component of processing speed (visuomotor) declined more after subthalamic stimulation than after pallidal stimulation (P=0.03). The level of depression worsened after subthalamic stimulation and improved after pallidal stimulation (P=0.02). Serious adverse events occurred in 51% of patients undergoing pallidal stimulation and in 56% of those undergoing subthalamic stimulation, with no significant between-group differences at 24 months. CONCLUSIONS Patients with Parkinsons disease had similar improvement in motor function after either pallidal or subthalamic stimulation. Nonmotor factors may reasonably be included in the selection of surgical target for deep-brain stimulation. (ClinicalTrials.gov numbers, NCT00056563 and NCT01076452.)

Randomized, double-blind trial of glial cell line-derived neurotrophic factor (GDNF) in PD

Objective: To assess the safety, tolerability, and biological activity of glial cell line-derived neurotrophic factor (GDNF) administered by an implanted intracerebroventricular (ICV) catheter and access port in advanced PD. Background: GDNF is a peptide that promotes survival of dopamine neurons. It improved 6-OHDA- or MPTP-induced behavioral deficits in rodents and monkeys. Methods: A multicenter, randomized, double-blind, placebo-controlled, sequential cohort study compared the effects of monthly ICV administration of placebo and 25, 75, 150, 300, and 500 to 4,000 μg of GDNF in 50 subjects with PD for 8 months. An open-label study extended exposure up to an additional 20 months and maximum single doses of up to 4,000 μg in 16 subjects. Laboratory testing, adverse events (AE), and Unified Parkinson’s Disease Rating Scale (UPDRS) scoring were obtained at 1- to 4-week intervals throughout the studies. Results: Twelve subjects received placebo and seven or eight subjects were assigned to each of the other GDNF dose groups. “On” and “off” total and motor UPDRS scores were not improved by GDNF at any dose. Nausea, anorexia, and vomiting were common hours to several days after injections of GDNF. Weight loss occurred in the majority of subjects receiving 75 μg or larger doses of GDNF. Paresthesias, often described as electric shocks (Lhermitte sign), were common in GDNF-treated subjects, were not dose related, and resolved on discontinuation of GDNF. Asymptomatic hyponatremia occurred in over half of subjects receiving 75 μg or larger doses of GDNF; it was symptomatic in several subjects. The open-label extension study had similar AE and lack of therapeutic efficacy. Conclusions: GDNF administered by ICV injection is biologically active as evidenced by the spectrum of AE encountered in this study. GDNF did not improve parkinsonism, possibly because GDNF did not reach the target tissues—putamen and substantia nigra.

Vagus nerve stimulation (VNS) for treatment-resistant depressions: A multicenter study

BACKGROUND Vagus Nerve Stimulation (VNS) delivered by the NeuroCybernetic Prosthesis (NCP) System was examined for its potential antidepressant effects. METHODS Adult outpatients (n = 30) with nonpsychotic, treatment-resistant major depressive (n = 21) or bipolar I (n = 4) or II (n = 5; depressed phase) disorders who had failed at least two robust medication trials in the current major depressive episode (MDE) while on stable medication regimens completed a baseline period followed by NCP System implantation. A 2-week, single-blind recovery period (no stimulation) was followed by 10 weeks of VNS. RESULTS In the current MDE (median length = 4.7 years), patients had not adequately responded to two (n = 9), three (n = 2), four (n = 6), or five or more (n = 13) robust antidepressant medication trials or electroconvulsive therapy (n = 17). Baseline 28-item Hamilton Depression Rating Scale (HDRS(28)) scores averaged 38.0. Response rates (> or =50% reduction in baseline scores) were 40% for both the HDRS(28) and the Clinical Global Impressions-Improvement index (score of 1 or 2) and 50% for the Montgomery-Asberg Depression Rating Scale. Symptomatic responses (accompanied by substantial functional improvement) have been largely sustained during long-term follow-up to date. CONCLUSIONS These open trial results suggest that VNS has antidepressant effects in treatment-resistant depressions.

Gene delivery of AAV2-neurturin for Parkinson's disease: a double-blind, randomised, controlled trial

BACKGROUND In an open-label phase 1 trial, gene delivery of the trophic factor neurturin via an adeno-associated type-2 vector (AAV2) was well tolerated and seemed to improve motor function in patients with advanced Parkinsons disease. We aimed to assess the safety and efficacy of AAV2-neurturin in a double-blind, phase 2 randomised trial. METHODS We did a multicentre, double-blind, sham-surgery controlled trial in patients with advanced Parkinsons disease. Patients were randomly assigned (2:1) by a central, computer generated, randomisation code to receive either AAV2-neurturin (5·4 × 10¹¹ vector genomes) injected bilaterally into the putamen or sham surgery. All patients and study personnel with the exception of the neurosurgical team were masked to treatment assignment. The primary endpoint was change from baseline to 12 months in the motor subscore of the unified Parkinsons disease rating scale in the practically-defined off state. All randomly assigned patients who had at least one assessment after baseline were included in the primary analyses. This trial is registered at ClinicalTrials.gov, NCT00400634. RESULTS Between December, 2006, and November, 2008, 58 patients from nine sites in the USA participated in the trial. There was no significant difference in the primary endpoint in patients treated with AAV2-neurturin compared with control individuals (difference -0·31 [SE 2·63], 95% CI -5·58 to 4·97; p=0·91). Serious adverse events occurred in 13 of 38 patients treated with AAV2-neurturin and four of 20 control individuals. Three patients in the AAV2-neurturin group and two in the sham surgery group developed tumours. INTERPRETATION Intraputaminal AAV2-neurturin is not superior to sham surgery when assessed using the UPDRS motor score at 12 months. However, the possibility of a benefit with additional targeting of the substantia nigra and longer term follow-up should be investigated in further studies. FUNDING Ceregene and Michael J Fox Foundation for Parkinsons Research.

Unilateral thalamic deep brain stimulation for refractory essential tremor and Parkinson's disease tremor

Objective: To determine the efficacy and tolerability of unilateral thalamic deep brain stimulation (DBS) for patients with medically refractory essential tremor (ET) and the tremor associated with Parkinsons disease (PD). Background: The tremor of ET and PD may produce functional disability despite optimal medical therapy. Several reports have demonstrated efficacy of thalamic DBS in this scenario. Methods: Preoperative and 3-month postoperative tremor ratings were compared in 33 patients (14 ET and 19 PD) with severe tremor. Evaluations included Unified Parkinsons Disease Rating Scale (UPDRS) scores for PD patients and a modified Unified Tremor Rating Scale in ET patients. Open-label and blinded data (unknown activation status) were obtained. Results: ET patients demonstrated an 83% reduction (p < 0.0001) in observed contralateral arm tremor. All measures of tremor including writing samples, pouring tests, subjective functional surveys, and disability scores improved significantly. PD patients demonstrated an 82% reduction (p < 0.001) i contralateral tremor and significant improvement in disability and global impressions. There was, however, no meaningful improvement in other motor aspects of the disease, and the total UPDRS part II (activities of daily living) score did not change. Adverse events, more common in ET patients, were generally mild and were usually eliminated by adjustment of the device parameters. Conclusions: Thalamic DBS is a safe and effective treatment of ET and the tremor of PD. In PD, its use should be limited to patients in whom high-amplitude tremor results directly in significant functional disability.

Randomized trial of deep brain stimulation for Parkinson disease: Thirty-six-month outcomes

Objectives: Our objective was to compare long-term outcomes of deep brain stimulation (DBS) of the globus pallidus interna (GPi) and subthalamic nucleus (STN) for patients with Parkinson disease (PD) in a multicenter randomized controlled trial. Methods: Patients randomly assigned to GPi (n = 89) or STN DBS (n = 70) were followed for 36 months. The primary outcome was motor function on stimulation/off medication using the Unified Parkinsons Disease Rating Scale motor subscale. Secondary outcomes included quality of life and neurocognitive function. Results: Motor function improved between baseline and 36 months for GPi (41.1 to 27.1; 95% confidence interval [CI] −16.4 to −10.8; p < 0.001) and STN (42.5 to 29.7; 95% CI −15.8 to −9.4; p < 0.001); improvements were similar between targets and stable over time (p = 0.59). Health-related quality of life improved at 6 months on all subscales (all p values significant), but improvement diminished over time. Mattis Dementia Rating Scale scores declined faster for STN than GPi patients (p = 0.01); other neurocognitive measures showed gradual decline overall. Conclusions: The beneficial effect of DBS on motor function was stable and comparable by target over 36 months. Slight declines in quality of life following initial gains and gradual decline in neurocognitive function likely reflect underlying disease progression and highlight the importance of nonmotor symptoms in determining quality of life. Classification of Evidence: This study provides Class III evidence that improvement of motor symptoms of PD by DBS remains stable over 3 years and does not differ by surgical target. Neurology® 2012;79:55–65

GPi deep brain stimulation for Tourette syndrome improves tics and psychiatric comorbidities

Tourette syndrome (TS) is characterized by phonic and motor tics and psychiatric comorbidities including attention-deficit (± hyperactivity) disorder (AD/HD), obsessive-compulsive behavior (OCB), anxiety, depression, and others.1 The efficacy and safety of deep brain stimulation (DBS) in movement disorders are established, and their applicability to neuropsychiatric conditions is expanding. We describe the results of bilateral DBS of the globus pallidus interna (GPi) in a 16-year-old boy with severe, medication-refractory TS. This left-handed boy presented at age 15 years for evaluation of escalating TS. Tics began at age 3, OCB by age 5, and AD/HD, coprolalia, copropraxia, and loud screaming by age 7. Haloperidol, pimozide, fluphenazine, benzodiazepines, guanfacine, selective serotonin reuptake inhibitors, tetrabenazine, and botulinum toxin injections (vocal cords) failed to relieve symptoms, including touching and grabbing others, self-gagging until emesis, eye poking, facial self-excoriations, self-hitting, and screaming until hoarse. Anxiety, depression, hyperactivity, and impulsivity were notable, while inattention and opposition were less problematic. His marked academic and social impairment prompted consideration of DBS surgery. Neuropsychological evaluation assessed suitability …

Transdermal fentanyl as treatment for chronic low back pain

Management of chronic low back pain often includes oral opioid use. The effectiveness of therapy is dependent upon compliance, which in turn is dependent upon response, side effects, access, and convenience. Our hypothesis was that a transdermal fentanyl system would provide more effective pain management than oral opioids. Fifty patients with chronic low back pain were examined. After litration to levels corresponding to current oral opioid use, each patient was maintained on transdermal fentanyl for one month. Oral opioid therapy was then resumed. Their experience was assessed with the a visual analogue scale for pain intensity, a numerical pain score, the Oswestry disability questionnaire, the pain disability index, and the Verran Snyder-Halpern sleep scale. Significant improvement in pain relief and disability was found with transdermal fentanyl compared with oral opioids. Mild opioid side effects were common, but easily controlled. Use of transdermal fentanyl is an effective alternative to oral opioids for managing chronic low back pain.

Treatment of acute penetrating injuries of the spine: a retrospective analysis.

A retrospective review of 160 cases of penetrating spinal injury (PSI) was undertaken to assess the benefits and risks of operative treatment. Criteria for operation included incomplete deficits, worsening neurological status, and associated visceral perforation. Of the 160 cases, 142 had gunshot wounds (GSW) and 18 had stab wounds (SW). Laminectomy, with or without intradural exploration, was undertaken in 23% of cases. No significant differences in outcome were found between the surgical and nonsurgical groups. Meningitis, CSF leakage, and wound infections were complications that occurred more often in the surgically treated group (22%) than the conservatively managed group (7%). It has not been possible to demonstrate a benefit of surgery in PSI in this retrospective study. A prospective study is proposed that would allow better control of the variables affecting outcome.

Gene delivery of neurturin to putamen and substantia nigra in Parkinson disease: A double-blind, randomized, controlled trial

A 12‐month double‐blind sham‐surgery–controlled trial assessing adeno‐associated virus type 2 (AAV2)‐neurturin injected into the putamen bilaterally failed to meet its primary endpoint, but showed positive results for the primary endpoint in the subgroup of subjects followed for 18 months and for several secondary endpoints. Analysis of postmortem tissue suggested impaired axonal transport of neurturin from putamen to substantia nigra. In the present study, we tested the safety and efficacy of AAV2‐neurturin delivered to putamen and substantia nigra.