Neuroimaging of neuronal circuits involved in tic generation in patients with Tourette syndrome.

OBJECTIVE: To identify brain regions generating tics in patients with Tourette syndrome using sleep as a baseline. METHODS: We used [15O]H2O PET to study nine patients with Tourette syndrome and nine matched control subjects. For patients, conditions included tic release states and sleep stage 2; and for control subjects, rest states and sleep stage 2. RESULTS: Our study showed robust activation of cerebellum, insula, thalamus, and putamen during tic release. CONCLUSION: The network of structures involved in tics includes the activated regions and motor cortex. The prominent involvement of cerebellum and insula suggest their involvement in tic initiation and execution.

Translating A2A antagonist KW6002 from animal models to parkinsonian patients.

Improving the translation of novel findings from basic laboratory research to better therapies for neurologic disease constitutes a major challenge for the neurosciences. This brief review of aspects of the development of an adenosine A2A antagonist for use in the management of Parkinson's disease (PD) illustrates approaches to some of the relevant issues. Adenosine A2A receptors, highly expressed on striatal medium spiny neurons, signal via kinases whose aberrant activation has been linked to the appearance of parkinsonian signs after dopaminergic denervation and to the motor response complications produced by dopaminomimetic therapy. To assess the ability of A2A receptor blockade to normalize certain of these kinases and thus benefit motor dysfunction, the palliative and prophylactic effects of the selective antagonist KW6002 were first evaluated in rodent and primate models. In hemiparkinsonian rats, KW6002 reversed the intermittent L-dopa treatment-induced, protein kinase A-mediated hyperphosphorylation of striatal alpha-amino-3-hydroxy-5-methyl-4-isoxazole proprionic acid receptor GluR1 S845 residues and the concomitant shortening in motor response duration. In 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-lesioned monkeys, coadministration of KW6002 with daily apomorphine injections acted prophylactically to prevent dyskinesia onset. These and related preclinical observations guided the design of a limited, randomized, controlled, proof-of-concept study of the A2A antagonist in patients with moderately advanced PD. Although KW6002 alone or in combination with a steady-state IV infusion of optimal-dose L-dopa had no effect on parkinsonian severity, the drug potentiated the antiparkinsonian response to low-dose L-dopa with fewer dyskinesias than produced by optimal-dose L-dopa alone. KW6002 also safely prolonged the efficacy half-time of L-dopa. The results suggest that drugs capable of selectively blocking adenosine A2A receptors could confer therapeutic benefit to L-dopa-treated parkinsonian patients and warrant further evaluation in phase II studies. They also illustrate a strategy for successfully bridging a novel approach to PD therapy from an evolving research concept to pivotal clinical trials.

Adenosine A(2A) receptor antagonist treatment of Parkinson's disease.

BACKGROUND: Observations in animal models suggest that A(2A) antagonists confer benefit by modulating dopaminergic effects on the striatal dysfunction associated with motor disability. This double-blind, placebo-controlled, proof-of-principle study evaluated the pathogenic contribution and therapeutic potential of adenosine A(2A) receptor-mediated mechanisms in Parkinson disease (PD) and levodopa-induced motor complications. METHODS: Fifteen patients with moderate to advanced PD consented to participate. All were randomized to either the selective A(2A) antagonist KW-6002 or matching placebo capsules in a 6-week dose-rising design (40 and 80 mg/day). Motor function was rated on the Unified PD Rating Scale. RESULTS: KW-6002 alone or in combination with a steady-state IV infusion of each patient's optimal levodopa dose had no effect on parkinsonian severity. At a low dose of levodopa, however, KW-6002 (80 mg) potentiated the antiparkinsonian response by 36% (p < 0.02), but with 45% less dyskinesia compared with that induced by optimal dose levodopa alone (p < 0.05). All cardinal parkinsonian signs improved, especially resting tremor. In addition, KW-6002 prolonged the efficacy half-time of levodopa by an average of 47 minutes (76%; p < 0.05). No medically important drug toxicity occurred. CONCLUSIONS: The results support the hypothesis that A(2A) receptor mechanisms contribute to symptom production in PD and that drugs able to selectively block these receptors may help palliate symptoms in levodopa-treated patients with this disorder.

Continuous transdermal dopaminergic stimulation in advanced Parkinson's disease.

The objective of the study was to determine the safety and efficacy of increasing doses of Rotigotine CDS in patients with advanced Parkinson's disease. The development of motor complications in Parkinson's disease has been linked to intermittent stimulation of dopamine receptors. Continuous, noninvasive, dopaminergic stimulation has not been available to date. Rotigotine CDS is a lipid-soluble D2 dopamine agonist in a transdermal delivery system that could fill this void. This inpatient study consisted of a 2-week dose escalation phase followed by a 2-week dose maintenance phase at the highest dose (80 cm2). Each individual's L-Dopa dose was back-titrated as feasible. The primary outcome measure was L-Dopa dose, and secondary outcome measures included early morning "off"-L-Dopa Unified Parkinson's Disease Rating Scale motor scores by a blinded evaluator and motor fluctuation data obtained from patient diaries ("on" without dyskinesia, "on" with dyskinesia, and "off"). Seven of 10 subjects provided data that could be evaluated. There were two administrative dropouts, and one individual was eliminated from the study because of recrudescence of hallucinations. The median daily L-Dopa dose decreased from 1,400 to 400 mg (p = 0.018, Wilcoxon test). Unified Parkinson's Disease Rating Scale motor scores were unchanged. Although diary variables improved in most individuals, only the reduction in "off" time attained statistical significance. Adverse effects were mild and consisted mainly of dopaminergic side effects and local skin reactions. The data suggest that Rotigotine CDS is an effective treatment for advanced Parkinson's disease and permits patients to substantially lower L-Dopa doses without loss of antiparkinsonian efficacy. Full-scale controlled clinical trials are warranted. In addition to potential therapeutic benefits, this drug can be used to test the hypothesis that continuous dopaminergic stimulation from the initiation of Parkinson's disease therapy will limit the development of motor complications.

Periodic limb movements in sleep: state-dependent excitability of the spinal flexor reflex.

OBJECTIVE: To test the hypothesis that periodic limb movements (PLMs) are related to spinal flexor reflexes (FRs), the authors compared the state-dependent changes in FR excitability in 10 patients with restless legs syndrome (RLS) and PLMs with those from matched controls. BACKGROUND: PLM is a disorder of motor control during sleep, frequently occurring in RLS. Clinically, PLMs resemble spinal FRs. METHODS: FRs were obtained by electrically stimulating the medial plantar nerve and recording from antagonist leg and thigh muscles bilaterally. RESULTS: Compared with controls, patients had significantly increased spinal cord excitability, as indicated by lower threshold and greater spatial spread of the FR, which was more prominent during sleep. Multiple late responses were seen during sleep in all patients and in some controls at higher threshold. The most prominent of these responses had a very long duration and a latency range of 250 to 800 msec, and because of its close temporal relationship to the FR stimulus, the authors considered it was a late, high-threshold component of the FR (FR3). The authors also found a similarity between the pattern of muscle recruitment and spatial spread of late components of the FR and those of spontaneous PLMs. CONCLUSIONS: The results support the hypothesis that PLMs in RLS and FRs share common spinal mechanisms and suggest that PLMs may result from enhanced spinal cord excitability in RLS patients. Because dopaminergic mechanisms are involved in spinal FR control, the results are consistent with the current view that RLS is a disorder of dopaminergic function.

Sensory discrimination capabilities in patients with focal hand dystonia.

To explore the concept that dystonia may result from dysfunction of the sensory system, 14 patients with focal hand dystonia were tested during two somatosensory discrimination tasks. Compared with controls, patients had a higher threshold in a task involving discrimination of two electric stimuli closely related temporally, an abnormality that correlated with the degree of severity of dystonia. There was no significant difference in a single-touch, gross localization task. The possible relevance of these findings to the pathogenesis of dystonia is discussed.

Spatial discrimination is abnormal in focal hand dystonia.

BACKGROUND: In patients with focal hand dystonia, abnormal digit representations in the primary somatosensory cortex (S1) could be the result of enlarged and overlapping receptor fields, as suggested by an animal model of dystonia. A possible clinical correlate of this S1 abnormality is a disturbed spatial discrimination capability. OBJECTIVE: To test the hypothesis that somatosensory spatial discrimination is abnormal in focal hand dystonia. METHODS: Seventeen patients with focal hand dystonia underwent a quantitative evaluation of somatosensory spatial frequency (gap detection, JVP domes, applied to the distal phalanx of the index finger) and single-touch localization (Von Frey monofilaments, applied to the middle phalanx of the index finger). RESULTS: Compared with control subjects, patients had a decreased performance in both the gap detection (p = 0.004) and the localization (p = 0.013) tasks. The extent of spatial frequency abnormality correlated with age in both groups. CONCLUSIONS: These findings, together with a previously shown temporal discrimination deficit, support a role for sensory dysfunction in the pathophysiology of dystonia.

An open trial of clozapine for dystonia.

Pharmacologic treatment of severe dystonia is often unsatisfactory. The atypical antipsychotic medication clozapine appears to improve tardive dystonia associated with conventional neuroleptic use. We studied the efficacy of clozapine for severe dystonia in five patients in an open trial. The patient cohort included four with generalized dystonia and one with Meige syndrome. All patients were evaluated at baseline and at least weekly while on medication with subjective assessment of response by the patient and physician rating using the Burke-Fahn-Marsden Evaluation Scale for Dystonia. All five subjects had significant improvement detected by the Burke-Fahn-Marsden Evaluation Scale as well as subjective improvement while on clozapine. Side effects, such as sedation and orthostatic hypotension, developed in all patients but was only treatment-limiting in one subject who developed persistent symptomatic orthostatic hypotension and tachycardia. Two of the four remaining patients continued clozapine after completion of the study; an additional patient was uncertain if the benefit outweighed the side effects. One patient discontinued treatment because of difficulty obtaining the FDA-required weekly white blood cell counts for patients on clozapine. We conclude that clozapine appears to be effective for generalized and refractory focal dystonia although its use may be limited by the side effects and need for hematologic monitoring.

Effect of muscle activity immediately after botulinum toxin injection for writer's cramp.

Animal and human studies have shown that nerve stimulation enhances some effects of botulinum toxin (btx A) injection. Voluntary muscle activity might work similarly and would focus the effect of an injection into the active muscles. We studied the effects of exercise immediately after btx A injection in eight patients with writer's cramp with established response to btx A over two injection cycles with a single-blinded, randomized, crossover design. Immediately after the first study injection, they were randomly assigned to write continuously for 30 min or have their hand and forearm immobilized for 30 min. Following the second injection, they were assigned the alternate condition. Patients were assessed just before each injection, and at 2 weeks, 6 weeks, and 3 months post-injection. Assessment included objective strength testing, self-reported rating of benefit and weakness, and blinded evaluation of videotapes and writing samples of the patients writing a standard passage. Strength testing showed that the maximum weakness occurred at 2 weeks post-injection, but the benefit was maximum at 6 weeks post-injection. The "write" condition resulted in greater reduction in strength than the "rest" condition. Btx A treatment led to improvement in self-reported ratings, writer's cramp rating scale scores by blinded raters, and reduction in writing time, but the differences between the "write" and "rest" conditions were not significant. We conclude that voluntary muscle activity immediately after btx A injection leads to greater reduction in muscle strength. Our findings raise the possibility that voluntary muscle activation may allow reduction of btx A doses and favorably alter the balance of benefit and side effects of btx A injections.

Parkinsonism after a wasp sting.

A 49-year-old man had mild parkinsonism after being stung by a wasp, a member of the Hymenoptera order. His clinical course was stable for 6 months after which his condition rapidly progressed to a severe akinetic-rigid syndrome with evidence, on a magnetic resonance imaging brain scan, of marked destruction of the basal ganglia. The symptoms did not respond to standard antiparkinsonian medications. Repeated courses of plasmapheresis followed by monthly intravenous infusions of immunoglobulin and long-term administration of azathioprine halted and appeared to partially reverse his deterioration. The literature on the neurologic, particularly the extrapyramidal, manifestations of stings by insects of the Hymenoptera order is reviewed and the possible pathophysiological mechanisms of injury are discussed. Hymenoptera stings should be included in the differential diagnosis of acute and chronic extrapyramidal syndromes.

Abnormal somatosensory homunculus in dystonia of the hand.

Abnormalities of the sensory system have been proposed as causative factors for dystonia By mapping the human cortical hand somatosensory area of 6 patients with focal dystonia of the hand, we found an abnormality of the normal homuncular organization of the finger representations in the primary somatosensory cortex (S1). Although a remote antecedent event or even a developmental anomaly cannot entirely be ruled out, our findings may support the concept that abnormal plasticity is involved in the development of dystonia.