Episodic ataxia/myokymia syndrome is associated with point mutations in the human potassium channel gene, KCNA1.

Episodic ataxia (EA) is a rare, familial disorder producing attacks of generalized ataxia, with normal or near-normal neurological function between attacks. One type of EA is characterized by brief episodes of ataxia with myokymia (rippling of muscles) evident between attacks. Linkage studies in four such families suggested localization of an EA/myokymia gene near the voltage gated K+ channel gene, KCNA1 (Kv1.1), on chromosome 12p. Mutation analysis of the KCNA1 coding region in these families identified four different missense point mutations present in the heterozygous state, indicating that EA/myokymia can result from mutations in this gene.

Gilles de la Tourette syndrome is not linked to D2-dopamine receptor.

Gilles de la Tourette syndrome has an important genetic component; the pathophysiology of this disorder may involve the dopamine system. We tested a D2-dopamine receptor (locus DRD2, recognized by probe hD2G1) for genetic linkage with Gilles de la Tourette syndrome. Using a genetic linkage map of the region of DRD2 on the long arm of chromosome 11 and restriction fragment length polymorphism data from a total of four markers (DRD2 itself, D11S84, D11S29, and PBGD), we were able to exclude linkage of this candidate gene and Gilles de la Tourette syndrome in two extended kindreds segregating for Gilles de la Tourette syndrome. This rules out causation of Gilles de la Tourette syndrome by mutation in DRD2 in the kindreds studied under the genetic assumptions we employed; use of the map and multipoint linkage analyses also allowed us to exclude a Gilles de la Tourette syndrome susceptibility locus from a larger genetic region.

Time course of tolerance to apomorphine in parkinsonism.

We sought to determine if tolerance developed to the antiparkinsonian effects of apomorphine and, if so, what temporal factors influenced its development. Seven patients with parkinsonism and motor fluctuations received short (6-hour) and long (22- to 31-hour) apomorphine infusions. Tolerance was evaluated by comparison of the responses to test doses of apomorphine that were administered before and after each infusion. The responses to the test doses that followed either infusion were reduced by 35% after the short infusion and by 68% after the long infusion, although plasma apomorphine levels were similar to or higher than levels achieved with preinfusion test doses. The duration of improvement in parkinsonism after discontinuation of the long infusion was briefer than that after the short infusion. We conclude that tolerance to apomorphine occurs in parkinsonism, and the loss of response is greater after longer periods of drug administration.

Effect of long-term therapy on the pharmacodynamics of levodopa. Relation to on-off phenomenon.

To determine how the response to levodopa is altered by long-term therapy, we examined the dose response to 2-hour infusions of levodopa in three groups of parkinsonian patients: those who were previously untreated, those who exhibited stable responses, and those who exhibited fluctuating responses to levodopa therapy, using tapping speed as an index of bradykinesia. The baseline tapping speed was greater in the patients with stable responses than in the untreated patients, probably representing a "long-duration response" to levodopa therapy. A "short-duration response," indicated by an increase in tapping speed lasting hours, was observed in most patients in all groups. The onset of the short-duration effect was more rapid and the incremental increase in tapping speed was twice as large in the patients with fluctuating responses compared with the untreated patients and patients with stable responses. The duration of the short-duration effect was greatest in the untreated group but did not differ between the groups with stable and fluctuating responses. Dyskinesia was not observed in any of the de novo patients but was observed in three of 12 patients with stable responses and eight of nine patients with fluctuating responses to levodopa therapy. Dyskinesia appeared before or with the antiparkinsonian effects in patients with stable responses, giving no indication of a higher threshold for dyskinesia in these patients compared with those with fluctuating responses. The plasma half-life clearance, volume of distribution, and maximum plasma concentrations of levodopa did not differ among groups.(ABSTRACT TRUNCATED AT 250 WORDS)

Diurnal responsiveness to apomorphine.

Many parkinsonian patients respond to L-dopa better in the morning than at other times. To explore the possibility that this phenomenon represents diurnal fluctuations in dopaminergic receptor responsiveness, we compared the effects of subcutaneously administered apomorphine during "off" periods in the mornings and afternoons in nine fluctuating patients. The duration of response and area under the time-response curve, but not the magnitude of improvement, were dose responsive. Response durations to the same dose administered in the morning and afternoon were similar, although at threshold doses three subjects responded only to the afternoon dose. These observations suggest there is no large diurnal change in striatal dopaminergic responsiveness.

Response to brief levodopa infusions in parkinsonian patients with and without motor fluctuations.

The fluctuating response to levodopa may result from progressive loss of striatal dopamine terminals and consequently increasingly impaired dopamine storage capacity. This hypothesis predicts that the acute response to levodopa would shorten with increasing disease severity. To test this, we compared the duration of improvement in tapping and walking speeds following discontinuation of 2-hour levodopa infusions in nine previously untreated (UT), seven stable (ST), and 17 fluctuating (FL) subjects. Mean Hoehn and Yahr disability in the morning prior to levodopa infusion was 2.8, 2.2, and 4.4 for UT, ST, and FL subjects. Six of nine UT, six of seven ST, and all FL subjects exhibited improvement with the infusions, which produced similar peak plasma levodopa levels in all groups. The duration of the response was similar in the ST and FL groups. The response in the UT group was heterogeneous; in three, the response was of similar length as compared with the ST and FL groups, but was longer in the other three UT subjects. The correlation between disease severity and response duration was poor. The ST and FL groups, while differing in disease severity, exhibited a similar duration of response to levodopa infusion. This does not support a reduced dopamine "storage capacity" as the sole explanation for the length of the short-duration response. Furthermore, motor fluctuations appear to be present from early in treatment, but only become noticeable when "off" disability becomes marked.

Peripheral pharmacokinetics of levodopa in untreated, stable, and fluctuating parkinsonian patients.

We compared the pharmacokinetics of oral and IV infusions of levodopa in untreated, stable, and fluctuating patients pretreated with carbidopa. After oral dosing, mean peak plasma levodopa levels, time to peak level concentration after oral levodopa, and area under the curve were similar in all groups. Absorption was proportional to dose. Plasma elimination half-lives, clearance rates, and volumes of distribution after levodopa infusions were similar in all groups. 3-O-Methyldopa levels were similar in stable and fluctuating subjects. We conclude that the peripheral pharmacokinetics of levodopa do not differ between untreated, stable, and fluctuating patients, and that altered peripheral kinetics of the drug are unlikely to explain the development of the fluctuating state.

Does an inhibitory action of levodopa contribute to motor fluctuations?

The possibility that levodopa can both acutely improve as well as worsen motor function was investigated in eight fluctuating parkinsonian patients by administering 2-hour infusions of placebo and of levodopa at suprathreshold, threshold, and subthreshold rates when the subjects had been without medication overnight. Plasma levodopa and clinical status were monitored for an hour before, during, and for 3 hours after the infusions. Placebo infusions were associated with a mild deterioration in motor status during the period of monitoring. Subthreshold infusions were associated with greater motor deterioration than were placebo infusions in five of six subjects, but this deterioration did not occur in any specific temporal relation to the infusion. Threshold infusion rates in three subjects produced a transient improvement in motor function followed by deterioration to below the scores during the hour preceding the infusion and then returned to baseline. Suprathreshold rates in seven of the eight subjects were associated with motor improvement for 1/2 to 3 1/2 hours followed by worsening to below baseline for 30 to 90 minutes and then spontaneous improvement to baseline function. These observations suggest that levodopa causes an acute deterioration in motor function following drug-induced improvement. Thus, the nadir of motor function in levodopa-treated patients may not be simply loss of dopaminergic stimulation and return to the untreated state, but may represent an inhibitory effect of levodopa.

Effect of peripheral catechol-O-methyltransferase inhibition on the pharmacokinetics and pharmacodynamics of levodopa in parkinsonian patients.

Catechol-O-methyltransferase (COMT) metabolizes a portion of administered levodopa and thus makes it unavailable for conversion to dopamine in the brain. In an open-label trail, we examined the effects of entacapone, a peripheral inhibitor of COMT, administered acutely or for 8 weeks, on the pharmacokinetics and pharmacodynamics of levodopa in 15 parkinsonian subjects with a fluctuating response to levodopa. Acutely and chronically administered entacapone similarly decreased the plasma elimination of orally and intravenously administered levodopa. Absorption of levodopa was minimally affected. During chronic entacapone treatment, daily levodopa dosages were reduced by 27% yet mean plasma levodopa concentrations were increased by 23%. Plasma 3-O-methyldopa concentrations were decreased by 60%. Entacapone increased the duration of action of single doses of levodopa by a mean of 56%. The percent of the day "on" after 8 weeks of entacapone treatment was 77%; it dropped to 44% upon withdrawal of entacapone. We conclude that inhibition of COMT by entacapone increases the plasma half-life of levodopa and augments the antiparkinsonian effects of single and repeated doses of levodopa.

Apomorphine tolerance in Parkinson's disease: lack of a dose effect.

The development of tolerance to dopaminergic drugs may be important in the long-term therapy of Parkinson's disease. In this study, we sought to determine whether tolerance developed during infusions of apomorphine and if there was evidence of any dose dependency. Eight patients with Parkinson's disease received 4- to 6-h infusions of apomorphine at low, medium, and high rates on consecutive days. Before and after each infusion, test boluses of apomorphine were administered to measure sensitivity to the drug. The duration of motor effects after the postinfusion boluses were reduced in comparison to those of the preinfusion boluses, indicating that tolerance developed during the infusions. The infusion rate did not affect the responses to the postinfusion test boluses. Our observations indicate that tolerance develops to the antiparkinsonian effect of apomorphine after several hours of its constant infusion, but is not influenced by the dose of drug administered.

Pharmacodynamics of the hypotensive effect of levodopa in parkinsonian patients.

Blood pressure effects of i.v. levodopa were examined in parkinsonian patients with stable and fluctuating responses to levodopa. The magnitude of the hypotensive effect of levodopa was concentration dependent and was fit to an Emax model in fluctuating responders. Stable responders demonstrated a small hypotensive response. Baseline blood pressures were higher in fluctuating patients; a higher baseline blood pressure correlated with greater hypotensive effects. Antiparkinsonian effects of levodopa temporally correlated with blood pressure changes. Phenylalanine, a large neutral amino acid (LNAA) competing with levodopa for transport across the blood-brain barrier, reduced the hypotensive and antiparkinsonian effects of levodopa. We conclude that levodopa has a central hypotensive action that parallels the motor effects in fluctuating patients. The hypotensive effect appears to be related to the higher baseline blood pressure we observed in fluctuating patients relative to stable patients.

Differences in the motor response to apomorphine between untreated and fluctuating patients with Parkinson's disease.

Behavioral hyposensitivity to repeated apomorphine administration has been observed in fluctuating parkinsonian patients. To investigate whether a similar phenomenon occurs in patients never treated with levodopa, we studied the response to apomorphine in 20 de novo patients with Parkinson's disease. Six patients showed no or minimal improvement after apomorphine injections (maximal dose 3.5 mg). Fourteen patients responded and were then given up to four repeated subcutaneous injections of apomorphine [minimal effective dose (MED)]. The responses of de novo patients were compared with responses in 10 patients with motor fluctuations previously studied by the same protocol. There was no significant difference in latency and duration of motor responses after repeated apomorphine injections in de novo patients. MED was similar in de novo and fluctuating patients, but duration of improvement induced by each apomorphine bolus was longer in the de novo group. These results indicate that response duration to apomorphine is longer in previously untreated patients and that behavioral tolerance associated with pulsatile dopaminergic stimulation by apomorphine occurs mainly in patients with more advanced disease under chronic levodopa therapy.

Controlled release levodopa/carbidopa 25/100 (Sinemet CR 25/100): pharmacokinetics and clinical efficacy in untreated parkinsonian patients.

The pharmacokinetics of the clinically determined optimal dose of controlled release levodopa/carbidopa 25/100 (Sinemet CR 25/100) after 12 weeks of therapy was studied in nine parkinsonian patients without prior exposure to levodopa. The pharmacokinetics of single oral doses of controlled release levodopa/carbidopa 25/100 and 50/200 were also compared. As predicted from the plasma half-life (1.7 +/- 0.3 h) and confirmed by morning trough levels, levodopa did not accumulate when controlled released levodopa/carbidopa 25/100 was administered twice daily. The absorption and bioavailability of CR 25/100 are minimally greater than CR 50/200. Controlled released levodopa/carbidopa 25/100 levodopa plasma levels peak slightly faster than controlled release levodopa/carbidopa 50/200.

Digoxin prevents MPTP-induced dopamine depletion in mouse striatum.

Inhibition of Na+/K+ ATPase by cardiac glycosides has been shown to potentiate toxic effects of excitatory amino acids and mitochondrial poisons in neurons in vitro. The present study tested the hypothesis that the systemic administration of the cardiac glycoside, digoxin, potentiates effects of the dopamine neurotoxin 1-methyl-4-phenyl-1,2,5,6-tetrahydropyridine (MPTP) in vivo. Mice were injected with digoxin (1 mg/kg) or vehicle followed by MPTP (20 mg/kg) or saline 1 h later. After 1 or 8 days, mice were euthanized and dopamine levels in the striatum were measured by high-performance liquid chromatography with electrochemical detection. MPTP caused a significant 35-45% reduction in striatal dopamine levels compared to those in control mice. However, pretreatment with digoxin completely prevented the MPTP-induced dopamine depletion. This result was unexpected and suggests that cardiac glycosides may protect against MPTP neurotoxicity.

Autosomal dominant episodic ataxia: a heterogeneous syndrome.

We describe six kindreds with autosomal dominant episodic ataxia, apparently representing three distinct syndromes. Four kindreds were characterized by episodic ataxia and response to acetazolamide, and in three, interictal nystagmus. One kindred was characterized by paroxysmal ataxia and in one member, paroxysmal choreoathetosis. The last kindred had brief attacks of ataxia and interictal neuromyotonia. The age of onset and severity of the disorder varied within each kindred. These kindreds illustrate the heterogeneity of episodic ataxia as well as the variable expressivity within each kindred.

Absorption of apomorphine by various routes in parkinsonism.

We wanted to determine the absorption and clinical effect of sublingual (SL) and transdermal apomorphine in parkinsonism. Patients received single SL apomorphine doses (N = 7) and the absorption was compared with parenteral (N = 5) and oral (N = 4) doses. One patient received a transdermal dose of apomorphine. The relative bioavailability of SL apomorphine ranged from 10 to 22% of a parenteral apomorphine dose. Oral apomorphine was less than 4% bioavailable, and the transdermal dose did not produce detectable plasma levels. Three patients with motor fluctuations responded to SL apomorphine, with a latency to effect of 20-40 min and a duration of effect of 15-100 min. One patient used SL apomorphine as an adjunct with levodopa, and during 1 month reported a large decrease in "off" periods. We conclude that apomorphine is effectively absorbed by the sublingual route.

Apomorphine infusional therapy in Parkinson's disease: clinical utility and lack of tolerance.

We assessed the clinical utility of apomorphine infusional therapy in patients with parkinsonism and motor fluctuations and sought evidence for alterations in drug response resulting from chronic treatment. Six patients with Parkinson's disease were treated for 3 months with s.c. infusions of apomorphine administered during waking hours. At the beginning and the end of the study, test doses of apomorphine (12.5-100 micrograms/kg) were administered to establish a dose-response curve. Over the study, the patients reported a significant improvement in the number of "on" hours experienced per day and substantially reduced the dose and frequency of levodopa and other antiparkinsonian medications. No average change in apomorphine dose-response relationships or pharmacokinetics was observed during the study. However, two patients lowered the infusion rate during the 3-month observation and exhibited higher drug levels and longer responses following test doses of apomorphine given at the end of the study. Although pragmatic concerns with the use of infusion pumps solutions and adverse effects limited the overall benefit afforded by the treatment, this kind of drug treatment may be useful in selected patients with severe parkinsonism and fluctuations.

Studies of renal function in animals chronically treated with apomorphine.

Based on the observation that orally administered apomorphine may induce nephrotoxicity, we studied the renal effects of a two-week subcutaneous infusion of apomorphine in rats. Drug-treated rats did not exhibit any change in renal cortical uptake of an organic cation (tetraethyl ammonium), organic anion (para-hippuric acid), creatinine clearance, or fractional excretion of sodium and potassium. Renal histology showed no change specific to drug. A small increase in urinary N-acetylglucosaminidase, a tubular enzyme, was measured but a second tubular enzyme showed no change. We conclude that parenterally administered apomorphine is not associated with renal toxicity.

Movement disorders in multiple sclerosis.

Movement disorders other than cerebellar tremor are rare clinical manifestations of multiple sclerosis (MS). Two cases of parkinsonism and a case of chorea associated with MS are reported, and the literature is reviewed.