Daniel Tarsy

Behavioural supersensitivity to apomorphine following chronic treatment with drugs which interfere with the synaptic function of catecholamines

Stereotyped gnawing behaviour in the rat induced by apomorphine was studied from 1 to 4 weeks after withdrawal of drugs given daily for 3 weeks. Significant shifts in the dose-response relationship toward increased sensitivity to the agonist were observed following α-methyl-p-tyrosine (α-MPT), reserpine, chlorpromazine or haloperidol, while promethazine, phenobarbital and diazepam were ineffective. The addition of atropine did not alter the enhanced sensitivity following chlorpromazine. The enhanced response following chlorpromazine and haloperidol persisted for at least 4 weeks. It was not significant after only 11 days of chronic pretreatment with chlorpromazine, reserpine or α-MPT. The effective drug treatments did not lead to changes in spontaneous locomotor activity at the time of testing stereotyped responses. The appearance of increased behavioural sensitivity to apomorphine, a putative direct agonist of dopamine receptors in the corpus striatum and limbic system, when non-specific withdrawal effects and changes in the metabolism of catecholamines or of the agonist were unlikely, suggest that the phenomenon of receptor supersensitivity following pharmacologically-induced “denervation” may be involved.

Effects of newer antipsychotics on extrapyramidal function.

AbstractFollowing acceptance of clozapine as a superior antipsychotic agent with low risk of adverse extrapyramidal syndromes (EPS), such as dystonia, parkinsonism, akathisia or tardive dyskinesia, several novel antipsychotic drugs have been developed with properties modelled on those of clozapine. Though generally considered ‘atypical’ in their relatively low risk of inducing EPS, these agents vary considerably in their pharmacology and impact on neurological functioning.Although few comparative data are available, the atypical antipsychotics can be tentatively ranked by EPS risk (excluding akathisia and neuroleptic malignant syndrome) in the following order: clozapine < quetiapine < olanzapine = ziprasidone. At higher doses, risperidone is ranked with a higher EPS risk than olanzapine and ziprasidone, but its risk of EPS is lower with lower doses. In general, this ranking is inversely related to antidopaminergic (D2 receptor) potency. The high antiserotonergic (5-HT2A receptor) potency of risperidone, clozapine, ziprasidone and olanzapine, but not quetiapine, as well as the anti-muscarinic activity of olanzapine and clozapine may also limit EPS.For the treatment of psychotic reactions to dopamine agonist therapy in Parkinson’s disease, clozapine is both effective and relatively well tolerated; quetiapine may be tolerated, olanzapine is not well tolerated, risperidone is poorly tolerated, and amisulpride and ziprasidone have not been well evaluated. Clozapine, perhaps because of its anticholinergic activity, can reduce parkinsonian tremor. It is useful for ongoing psychosis with tardive dyskinesia, especially for dystonic features. No atypical antipsychotic is clearly effective for motor abnormalities in Huntington’s disease or Tourette’s syndrome, and the effect of these drugs on other neurological disorders have been well evaluated in only small numbers of patients. In summary, with the exception of clozapine, and perhaps quetiapine, atypical antipsychotics have brought only relative avoidance of EPS, strongly encouraging continued searches for novel antipsychotic agents.

Botulinum toxin type B: A double-blind, placebo-controlled, safety and efficacy study in cervical dystonia

We enrolled and treated 122 patients with idiopathic cervical dystonia in a double-blind, placebo-controlled safety and efficacy study of botulinum toxin type B (BotB). Both A-responsive and A-resistant patients were enrolled. Patients received intramuscular injections of either BotB (2,500 U, 5,000 U, or 10,000 U) or placebo. The primary outcome measure of efficacy was the Toronto Western Spasmodic Torticollis Rating Scale (TWSTRS)-Total score at 4 weeks following study drug administration. Secondary measures of efficacy were TWSTRS-Severity, -Disability, and -Pain subscale scores, and Analog Pain Assessment, Investigator Global Assessment, Patient Global Assessment, and Sickness Impact Profile scores. Duration of effect was estimated with an intent-to-treat analysis of responders. Safety measures included clinical parameters, laboratory tests, and adverse events. The primary and most of the secondary analyses indicated a statistically significant treatment effect and a dose response. BotB is safe, well tolerated, and efficacious in the treatment of cervical dystonia at the doses tested.

Abnormalities of spatial and temporal sensory discrimination in writer's cramp.

Clinical observations of patients with writers cramp suggest that abnormalities of the sensory system may be a frequent finding in this disorder. Neurophysiological data from an animal model of focal dystonia have revealed cells in somatosensory cortex with enlarged and overlapping tactile receptive fields. However, psychophysical studies so far have been unable to document a clinical correlate supporting a similar enlargement of receptive fields in humans. We compared the fingertip discrimination of the orientation of fine spatial gratings between writers cramp and control subjects and found a significant decrease in grating sensitivity in the patients, consistent with the possibility of enlarged tactile receptive fields. In addition, we duplicated previous experiments showing an abnormality of tactile temporal discrimination. The results provide psychophysical measures which may relate to the development of sensory cortical reorganization in patients with writers cramp. Mov. Disord. 16:94–99, 2001.

Epidemiology of tardive dyskinesia: Is risk declining with modern antipsychotics?

Second‐generation antipsychotic drugs (APDs), including aripiprazole, clozapine, olanzapine, risperidone, quetiapine, and ziprasidone dominate outpatient and inpatient clinical practice, having largely displaced the older neuroleptics. Modern APDs have relatively low risk for acute extrapyramidal syndromes characteristic of older neuroleptics, particularly acute dystonia and Parkinsonism, with variable risks of akathisia and the rare neuroleptic malignant syndrome. Anticipated reduction in risk of tardive dyskinesia (TD) is less well documented. Nearly 50 years after initial reports on TD, it is appropriate to reexamine the epidemiology of this potentially severe late adverse effect of long‐term APD treatment in light of current research and practice. We compared recent estimates of incidence and prevalence of TD identified with some modern APDs to the epidemiology of TD in the earlier neuroleptic era. Such comparisons are confounded by complex modern APD regimens, uncommon exposure limited to a single modern APD, effects of previous exposure to typical neuroleptics, and neurological assessments that are rarely prospective or systematic. Available evidence suggests that the risk of TD may be declining, but longitudinal studies of patients never treated with traditional neuroleptics and exposed to only a single modern APD are required to quantify TD risks with specific drugs. Long‐term use of APDs should continue to be based on research‐supported indications, with regular specific examination for emerging TD.

Botulinum toxin a in the treatment of spasticity: Functional implications and patient selection☆

OBJECTIVE To explore the range of functional indications and benefit of botulinum toxin A (BTA) in spastic patients. DESIGN Case report of a series of patients selected for BTA treatment. Clinical information was collected in a prospective fashion on each patient. SETTING Freestanding acute rehabilitation hospital. PATIENTS 39 consecutive patients with 40 limbs with acquired spasticity. INTERVENTION All 39 patients received BTA injections into muscles targeted for treatment based on functional indications. MAIN OUTCOME MEASURES Objective evaluation of outcome was measured by Ashworth Scale, goniometry, ambulation score, and brace wear scale. Subjective measures included patient self report of improvement and pain relief. RESULTS Mean BTA dose per limb was 180 units, mean number of muscles injected per limb was 2. Twenty-nine patients had subjective and/or objective improvement with treatment. Mean Ashworth Scale improvement was one point. Mean gain in active range of motion (AROM) was 17.0 degrees, and in passive range of motion (PROM) 18.4 degrees. Brace tolerance improved in 14 of 22 patients and pain relief occurred in 10 of 13 patients. There were no adverse effects, and there was no difference in duration of effect compared to dystonia patients. CONCLUSION BTA is a useful intervention in the treatment of spasticity, with the majority of patients demonstrating improvement on objective measures of tone and function, and reporting improvement on subjective measures. Careful patient selection will maximize functional benefit.

A Web-Based System for Home Monitoring of Patients With Parkinson's Disease Using Wearable Sensors

This letter introduces MercuryLive, a platform to enable home monitoring of patients with Parkinsons disease (PD) using wearable sensors. MercuryLive contains three tiers: a resource-aware data collection engine that relies upon wearable sensors, web services for live streaming and storage of sensor data, and a web-based graphical user interface client with video conferencing capability. Besides, the platform has the capability of analyzing sensor (i.e., accelerometer) data to reliably estimate clinical scores capturing the severity of tremor, bradykinesia, and dyskinesia. Testing results showed an average data latency of less than 400 ms and video latency of about 200 ms with video frame rate of about 13 frames/s when 800 kb/s of bandwidth were available and we used a 40% video compression, and data feature upload requiring 1 min of extra time following a 10 min interactive session. These results indicate that the proposed platform is suitable to monitor patients with PD to facilitate the titration of medications in the late stages of the disease.

Rotational behavior induced in rats by intranigral picrotoxin.

There is considerable anatomic, biochemical, and physiologic evidence for a descending pathway in mammalian brain between the caudate nucleus-putamen (neostriatum) and substantia nigra (SN) which is mediated by y-aminobutyric acid (GABA) and exerts an inhibitory effect on neurons of the substantia nigra. GABA and its synthesizing enzyme, glutamic acid decarboxytase (GAD) are both found in high concentration in the SN 7,11 and mechanisms of uptake and release have been demonstrated for GABA in brain slice preparations of SN 13,25, Striatal ablation or transection of striatonigral pathways both produce a reduction in the concentration of GABA and GAD in the SN of several animal species 13,1a,20,2a, together with degeneration of a specific group of nigral terminal boutons 1~ which, on the basis of autoradiographic evidence, are believed to be GABA terminals 5. Intracellular recordings of SN neurons following electrical stimulation of the caudate nucleus in ether-anesthetized cats have disclosed short latency EPSPs followed by IPSPs 14. Electrical stimulation of the caudate nucleus in barbiturateanesthetized cats, however, has produced longer latency IPSPs in nigral neurons which are believed to be mediated by monosynaptic transmission3L This inhibition of SN neurons is mimicked by microiontophoretic application of GABA onto nigral neurons 10,12 and blocked by intravenous 27 or microiontophoretic 1° picrotoxin, a drug believed to block the postsynaptic inhibitory action of GABA in the mammalian central nervous systemlS,24, 27. Since the SN gives rise to an ascending dopaminergic projection to the neostriatum 30, this GABA-mediated inhibitory striatonigral projection would be expected to influence activity in the nigrostriatal dopaminergic system. Recent biochemical studies indicate that GABA, in fact, does mediate an inhibitory effect on dopamine synthesis in the nigrostriatal tract 1,3,17. This study provides behavioral evidence for GABA-mediated inhibition of the dopaminergic nigrostriatal system. In rodents, a relative increase in activity of one nigrostriatal system is known to produce rotational behavior towards the contra-

Double‐blind, randomized, controlled trial of rasagiline as monotherapy in early Parkinson's disease patients

Rasagiline (N‐propargyl‐1(R)‐aminoindan) mesylate is a potent, selective, and irreversible monoamine oxidase‐B inhibitor. This study was designed to evaluate the safety, tolerability, and preliminary efficacy of rasagiline monotherapy in early Parkinsons disease (PD) patients not receiving levodopa. The study was performed as a multicenter, parallel‐group, double‐blind, randomized, placebo‐controlled, 10‐week study. Fifty‐six PD patients were randomly assigned to rasagiline mesylate 1, 2, or 4 mg once daily, or placebo. A 3‐week dose‐escalation period was followed by a 7‐week maintenance phase. At week 10, the mean (±SE) changes from baseline in total Unified Parkinsons Disease Rating Scale (UPDRS) score were −1.8 (±1.3), −3.6 (±1.7), −3.6 (±1.2), and −0.5 (±0.8) in the rasagiline 1, 2, and 4 mg/day and placebo groups, respectively. Analysis of responders showed that 28% of patients (12 of 43) receiving rasagiline had an improvement in total UPDRS score of greater than 30%, compared with none of the patients receiving placebo (P < 0.05, Fishers exact test). The frequency and types of adverse events reported by rasagiline‐treated and placebo‐treated patients were similar. These results suggest that rasagiline monotherapy is well tolerated and efficacious in early PD.

Novel THAP1 sequence variants in primary dystonia

Background: THAP1 encodes a transcription factor (THAP1) that harbors an atypical zinc finger domain and regulates cell proliferation. An exon 2 insertion/deletion frameshift mutation in THAP1 is responsible for DYT6 dystonia in Amish-Mennonites. Subsequent screening efforts in familial, mainly early-onset, primary dystonia identified additional THAP1 sequence variants in non-Amish subjects. Objective: To examine a large cohort of subjects with mainly adult-onset primary dystonia for sequence variants in THAP1. Methods: With high-resolution melting, all 3 THAP1 exons were screened for sequence variants in 1,114 subjects with mainly adult-onset primary dystonia, 96 with unclassified dystonia, and 600 controls (400 neurologically normal and 200 with Parkinson disease). In addition, all 3 THAP1 exons were sequenced in 200 subjects with dystonia and 200 neurologically normal controls. Results: Nine unique melting curves were found in 19 subjects from 16 families with primary dystonia and 1 control. Age at dystonia onset ranged from 8 to 69 years (mean 48 years). Sequencing identified 6 novel missense mutations in conserved regions of THAP1 (G9C [cervical, masticatory, arm], D17G [cervical], F132S [laryngeal], I149T [cervical and generalized], A166T [laryngeal], and Q187K [cervical]). One subject with blepharospasm and another with laryngeal dystonia harbored a c.-42C>T variant. A c.57C>T silent variant was found in 1 subject with segmental craniocervical dystonia. An intron 1 variant (c.71+9C>A) was present in 7 subjects with dystonia (7/1,210) but only 1 control (1/600). Conclusions: A heterogeneous collection of THAP1 sequence variants is associated with varied anatomical distributions and onset ages of both familial and sporadic primary dystonia.