Effects of apomorphine on subthalamic nucleus and globus pallidus internus neurons in patients with Parkinson's disease.

This study examines the effect of apomorphine (APO), a nonselective D(1)- and D(2)-dopamine receptor agonist, on the firing activity of neurons in the subthalamic nucleus (STN) and internal segment of the globus pallidus (GPi) in patients with Parkinson's disease (PD). Single-unit microelectrode recordings were conducted in 13 patients undergoing implantation of deep brain stimulation electrodes in STN and 6 patients undergoing a pallidotomy. Doses of APO (2.5-8 mg) were sufficient to produce an ON state, but not intended to induce dyskinetic movements. Following baseline recordings from a single neuron, APO was administered and the activity of the neuron followed for an average of 15 min. The spontaneous discharge of neurons encountered before (n = 309), during (n = 146, 10-60 min), and after the effect of APO had waned (n = 127, >60 min) was also sampled, and the response to passive joint movements was noted. In both nuclei, APO increased the overall proportion of spikes in burst discharges (as detected with Poisson "surprise" analysis), and a greater proportion of cells with an irregular discharge pattern was observed. APO significantly decreased the overall firing rates of GPi neurons (P < 0.01), but there was no change in the overall firing rate of neurons in the STN (P = 0.68). However, the mean firing rates of STN neurons during APO-induced movements (choreic or dystonic dyskinesias) that occurred in four patients were significantly lower than OFF-period baseline values (P < 0.05). Concurrent with a reduction in limb tremor, the percentage of cells with tremor-related activity (TCs) was found to be significantly reduced from 19 to 6% in the STN and 14 to 0% in the GPi following APO administration. APO also decreased the firing rate of STN TCs (P < 0.05). During the OFF state, more than 15% of neurons tested (STN = 93, GPi = 63) responded to passive movement of two or more joints. After APO, this proportion decreased significantly to 7% of STN cells and 4% of GPi cells (STN = 28, GPi = 26). These findings suggest that the APO-induced amelioration of parkinsonian symptoms is not solely due to a decrease in overall activity in the GPi or STN as predicted by the current model of basal ganglia function in PD.

Botulinum toxin for simple motor tics: a randomized, double-blind, controlled clinical trial.

OBJECTIVE: To determine the effect of injections of botulinum toxin on simple motor tics. BACKGROUND: Case series with unblinded assessments have reported improvement in tic frequency and associated urge with botulinum toxin. METHODS: Patients with suitable simple motor tics were randomized to receive botulinum toxin and placebo in a double blind, crossover design. All outcomes compared week 2 to baseline measurements. The primary outcome measure was the number of treated tics per minute on a videotape segment. Secondary outcome measures were number of untreated tics per minute, the Shapiro Tourette Syndrome Severity Scale score, a numerical assessment of the urge to perform the treated tic (0 to 4), the premonitory sensation associated with the treated tic (0 to 4), and the patient's global impression of change. RESULTS: Eighteen patients completed the study. The median relative change in treated tics per minute with botulinum toxin was -0.39 (or a 39% reduction) versus 0.058 (or a 5.8% increase) with placebo (net effect -0.37, p = 0.0007). The average change in urge scores (score range 0 to 4) was -0.46 in the treatment phase and +0.49 in the placebo phase (net effect 0.94, p = 0.02). Other secondary outcome measures were not significantly different between the two groups. CONCLUSION: Botulinum toxin reduced treated tic frequency and the urge associated with the treated tic. Despite these changes, patients did not report an overall benefit from the treatment. Careful consideration of the contribution of the target tic to the patient's disability is needed before making treatment decisions.

Comparative effects of unilateral and bilateral subthalamic nucleus deep brain stimulation.

OBJECTIVE: To compare the effects of unilateral subthalamic nucleus (STN) deep brain stimulation (DBS) with bilateral STN DBS in advanced PD. METHODS: Our initial 10 consecutive patients with medication-refractory motor fluctuations and levodopa-induced dyskinesias undergoing chronic bilateral STN DBS underwent a standardized evaluation of unilateral and bilateral STN DBS in the medication-off state 6 to 18 months after electrode implantation. RESULTS: Bilateral STN DBS improved the mean total Unified Parkinson's Disease Rating Scale motor score by 54%, whereas unilateral stimulation improved motor scores only 23%. Unilateral STN DBS improved postural stability and gait 14%, other axial motor features 19%, and overall parkinsonism in limbs contralateral to stimulation by 46%, including an 86% improvement in contralateral tremor. However, bilateral STN DBS resulted in greater improvement in each of these domains, including limb function, i.e., the reduction in scores from the limbs on one side was greater with bilateral than with unilateral stimulation of the contralateral STN. CONCLUSIONS: Bilateral STN DBS improves parkinsonism considerably more than unilateral STN DBS; bilateral simultaneous electrode implantation may be the most appropriate surgical option for patients with significant bilateral disability. Unilateral STN DBS results in moderate improvement in all aspects of off-period parkinsonism and improves tremor as much as is typically reported with DBS of the ventral intermedius nucleus of the thalamus (Vim). For this reason, STN DBS may be a more appropriate choice than Vim DBS or thalamotomy for parkinsonian tremor. Some patients with highly asymmetric tremor-dominant PD might be appropriately treated with unilateral instead of bilateral STN DBS.

Double-blind evaluation of subthalamic nucleus deep brain stimulation in advanced Parkinson's disease.

OBJECTIVE: To examine objectively the clinical effects of subthalamic nucleus (STN) deep brain stimulation (DBS) in advanced PD. METHODS: Our initial seven consecutive patients with medication-refractory motor fluctuations and levodopa-induced dyskinesias undergoing chronic STN DBS underwent a standardized preoperative evaluation followed by a 2-day double-blind evaluation of efficacy 6 to 12 months after electrode implantation. Diaries documenting motor fluctuations and dyskinesias were also completed preoperatively and postoperatively. RESULTS: In the medication-off state, turning the stimulators on resulted in improvement in mean total Unified Parkinson's Disease Rating Scale (UPDRS) motor score by 58% including the following improvements in composite scores: akinesia 57%, rigidity 52%, tremor 82%, and gait and postural stability 49%. Additionally, the medication-off state improved 17% without stimulation, possibly as a result of electrode insertion alone or carry-over of chronic stimulation. In the medication-on, stimulation-on state, all major features of parkinsonism improved and total UPDRS motor score improved 41% compared with before surgery. Activities of daily living were improved while off medication 30%, and levodopa-induced dyskinesias were reduced 83% while total drug dosage was decreased 40%. With chronic stimulation, patients reported that the percentage of time spent in the "on" state (without dyskinesias) increased from 26% to 52% and "off" time decreased from 30% to 6%. Operative complications including cognitive worsening were not uncommon. CONCLUSIONS: STN DBS is a promising new surgical option for the treatment of advanced PD. The marked clinical benefits obtained in these severely disabled patients outweighed the adverse effects.

High-frequency unilateral thalamic stimulation in the treatment of essential and parkinsonian tremor.

Pharmacologic treatment for essential tremor and the tremor of Parkinson's disease is often inadequate. Stereotaxic surgery, such as thalamotomy, can effectively reduce tremors. We performed a multicenter trial of unilateral high-frequency stimulation of the ventral intermedius nucleus of the thalamus in 29 patients with essential tremor and 24 patients with Parkinson's disease, using a blinded assessment at 3 months after surgery to compare clinical rating of tremor with stimulation ON with stimulation OFF and baseline and a 1-year follow-up. Six patients were not implanted because of lack of intraoperative tremor suppression (2 patients), hemorrhage (2 patients), withdrawal of consent (1 patient), and persistent microthalamotomy effect (1 patient). A significant reduction in both essential and parkinsonian tremor occurred contralaterally with stimulation. Patients reported a significant reduction in disability. Measures of function were significantly improved in patients with essential tremor. Complications related to surgery in implanted patients were few. Stimulation was commonly associated with transient paresthesias. Other adverse effects were mild and well tolerated. Efficacy was not reduced at 1 year. Chronic high-frequency stimulation is safe and highly effective in ameliorating essential and parkinsonian tremor.

Surgical interventions in the treatment of Parkinson's disease (PD) and essential tremor (ET): medial pallidotomy in PD and chronic deep brain stimulation (DBS) in PD and ET.

Surgical treatments for PD and ET are promising. Medial Pallidotomy, the surgical lesioning of the pallidum, often improves symptoms of long-standing PD. We enrolled twenty-seven late stage PD patients for unilateral medial pallidotomy who were then assessed by the Core Assessment Program for Intracranial Transplantation (CAPIT) protocol. One year after surgery persistent improvement was seen contralateral to the lesion in the following features: drug-induced dyskinesias (92%), akinesia (38%), rigidity (51%), and tremor (42%). Complications included transient dysarthria (7 patients), facial weakness (9 patients), limb weakness (1 patient), swallowing problems (4 patients) and intracerebral haemorrhage (1 patient). Thalamic DBS may improve tremor in PD and ET patients. Therefore, we enrolled fifteen patients (9 PD and 6 ET patients) with disabling tremor, unresponsive to medication. They were assessed by the United Parkinson's Disease Rating Scale (UPDRS) and the Tremor Rating Scale (for PD and ET patients, respectively). Three months after surgery, limb tremor contralateral to stimulation improved by 71% in PD patients and 76% in ET patients. Complications included transient paresthesias (all), confusional state (1 patient) and intracerebral bleed (1 patient). Unilateral medial pallidotomy safely improves some Parkinsonian symptoms contralateral to the lesion. Thalamic DBS may effectively and safely improve contralateral limb tremor in PD and ET.