Paradoxial response to dopaminergic agents in parkinsonism.

A patient with the classical stigmata of parkinsonism was treated on three separate occasions with levodopa, a combination of levodopa and carbidopa, and lergotrile mesylate, a direct-acting dopamine-receptor agonist. All three treatment regimens resulted in dose-related increases in parkinsonian features. To our knowledge, this response has not been previously described. Lergotrile did not alter CSF homovanillic acid concentration. It is suggested that this rare paradoxical motor response to dopaminergic agents may be associated with dysfunction of the postsynaptic dopamine receptor site.

Dystonic foot response of Parkinsonism.

One third of a patient population with idiopathic parkinsonism was found to suffer from debilitating, painful dystonic movements of the lower extremities. The prevalence of this involuntary movement disorder was found to be positively correlated with the duration of dopaminergic treatment, but it also occurred occasionally in untreated persons. We suggest that the "dystonic foot response of parkinsonism" is a distinct clinical entity that has no localizing value in frontal lobe disorders and is associated with extrapyramidal disease. This disorder, though exacerbated by dopaminergic therapy, also differs from well-accepted dopaminergic side-effects and does not predictably respond to manipulation of antiparkinsonian medications. Although the precise pathophysiology of this movement disorder is unknown, its response to baclofen therapy suggests that neurotransmitter systems other than cholinergic or dopaminergic ones may be implicated.

Long-term suppression of central serotonergic activity by corticosteroids: a possible model of steroid-responsive myoclonic disorders.

Chronic administration of cortisol succinate (12.5 mg per kilogram per day) to guinea pigs suppressed jumping behavior induced by 1-5 hydroxytryptophan and abolished diurnal threshold variations of this behavior. Chronic corticosteroid administration did not alter threshold or diurnal variations of apomorphine-induced stereotypy. These observations suggest that the efficacy of corticosteroids in some human myoclonic movement disorders may be related to central serotonergic inhibition.

Methylphenidate-induced chorea: case report and pharmacologic implications.

In a child with minimal brain dysfunction, we found that chorea was related to the major central effect of methylphenidate and probably to the effect of the drug on central catecholaminergic systems. Also, after 3 weeks of treatment with methylphenidate, guinea pigs showed a hypersensitive response to apomorphine, suggesting that chronic administration of methylphenidate leads to hypersensitivity of receptor sites. Chorea beginning shortly after initiation of methylphenidate therapy probably is related to the central dopaminergic effect of the drug; when choreic movements appear after chronic methylphenidate administration, altered responsiveness of striatal dopamine receptor sites may be responsible.

The effect of levodopa, lergotrile, and bromocriptine on brain iron, manganese, and copper.

Chronic administration of a levodopa-carbidopa combination, bromocriptine, or lergotrile produced alterations of essential metal concentrations in the guinea pig caudate nucleus, frontal cortex, and cerebellar hemisphere. All long-term treatment regimens resulted in significantly increased concentrations of manganese in all brain areas, and these same regimens resulted in almost universally decreased copper concentrations. Since the long-term administration of these dopamine agonists in man results in extrapyramidal dysfunction, these observations suggest that alterations of trace metal concentrations in the brain may be related to the chronic toxicity of these dopamine agonists.

Weekly drug holiday in Parkinson disease.

Patients with Parkinson disease and drug-related side effects entered an open-trial study in which they stopped all dopaminergic medications for 2 consecutive days each week. Nine of 17 patients could tolerate the cessation of dopaminergic medication, and all of them showed improvement of side effects during the drug holiday and often throughout the week. Patients who could not tolerate withdrawal of medication were identified within 3 weeks by increased tremor or bradykinesia. This at-home drug holiday offers a potential therapy applicable to large numbers of parkinsonian outpatients who suffer progressive drug-related side effects.

Meige syndrome (blepharospasm-oromandibular dystonia) after long-term neuroleptic therapy.

Two patients developed either blepharospasm or blepharospasm-oromandibular dystonia following chronic therapy with chlorpromazine, haloperidol, or thioridazine. In one patient, appearance of the movement disorder was associated with neuroleptic withdrawal, and in the other patient, the movement disorder began while neuroleptic therapy continued. Because of the age of one patient and the severe intermittent psychosis in the other, these Meige-like symptoms were attributed to chronic neuroleptic use rather than to spontaneously occurring Meige syndrome. The symptoms occurring as part of a tardive dyskinesia suggest that dopaminergic mechanisms play a role in idiopathic Meige syndrome.

Dopaminergic antagonism of L-5-hydroxytryptophan-induced myoclonic jumping behavior.

We studied the effect of dopamine agonists (levodopa, apomorphine, lergotrile, and M-7 [2(dimethylamino)5,6-dihydroxytetralin] on myoclonic jumping behavior in young male guniea pigs. All these agents had a significant antagonistic effect on the frequency of this serotonin-mediated behavior. The duration of the antagonism corresponded in all cases to the duration of stereotyped chewing behavior induced by these agents alone. The dopamine antagonist haloperidol potentiated jumping behavior. Therefore myoclonic jumping behavior is influenced by dopaminergic mechanisms, and this behavior may be the result of interaction between dopaminergic and serotonergic activity. The role of dopaminergic mechanisms in human myoclonic disorders needs further clarification.

Sydenham chorea: an update.

To document possible changing characteristics of Sydenham chorea, we reviewed records of 240 patients with this diagnosis who were seen between 1951 and 1976. A dramatic progressive decline in the number of cases was observed. The syndrome occurred mainly in childhood. Female predominance was apparent only after the 10. There was a high femilial incidence for both chorea and rheumatic fever. Most patients had generalized chorea, and fewer than 20% had hemichorea. Dysarthria, probably of extrapyramidal origin, was frequent but neurologic abnormalities other than diffuse encephalopathy were rare. One-third of the patients had coexisting heart disease. Repeat attacks of Sydenham chorea occurred, but the recurrence rate was much less than noted in previous studies.

Drug holiday and management of Parkinson disease.

Chronic treatment of parkinsonism with levodopa or levodopa/carbidopa is associated with problems that include dyskinesia, on-off phenomena, hallucinosis, and possible loss of therapeutic efficacy. We studied the effects of a period of transient drug withdrawal (drug holiday) in 16 patients who manifested these complications of chronic levodopa therapy. Patients were evaluated daily before, during, and after the period of drug withdrawal. Eleven of the 16 patients exhibited enhanced motor responsiveness after the holiday and required only half of the initial daily dose for improved motor performance. Most levodopa-induced side effects decreased after the holiday. Hallucinosis was ameliorated in all cases. The frequency of on-off phenomena and myoclonus also diminished. Sensitivity to levodopa-induced dyskinesia was not affected by the drug holiday. Because most patients required lower dosage after the holiday, dyskinesias were no longer present. These observations suggest that parkinsonian patients who suffer complications of chronic levodopa therapy may benefit from a period of drug withdrawal.

Bromocriptine-induced behavioral hypersensitivity: implications for the therapy of parkinsonism.

Bromocriptine (CB-154) is a direct-acting dopamine agonist of proven clinical efficacy in parkinsonism. The capacity of bromocriptine to induce receptor site hypersensitivity was investigated utilizing a behavioral model in guinea pigs. Following 4 weeks of bromocriptine treatment, animals demonstrated a subsequent long-lasting hypersensitivity to amphetamine and apomorphine. The data suggest that chronic use of bromocriptine can induce receptor site hypersensitivity. These results may be an indication that, because of a similar propensity to side effects during chronic therapy, direct-acting dopamine agonists will offer no long-term advantage over current antiparkinsonian drugs. The observed phenomena suggest that chronic dopaminergic agonism may not be an ideal therapy for parkinsonism.

Lergotrile in the treatment of parkinsonism.

Lergotrile mesylate, a direct-acting dopamine agonist, was administered for up to 10 months to 25 patients with Parkinson disease. Of six patients not receiving levodopa concurrently, five showed definite improvement in parkinsonian signs and symptoms. These results are the first clear indication that lergotrile is efficacious, independently of any interaction with levodopa, in the treatment of Parkinson disease. The drug was also effective in relieving some complications of long-term levodopa therapy. Lergotrile was more effective in alleviating on-off problems than in reversing loss of levodopa efficacy. Side effects of lergotrile included exacerbation of hallucinations, dyskinesias, hypotension, and alterations in liver function tests.

Amphetamine-induced hypersensitivity in guinea pigs.

Chronic administration of d-amphetamine to young guinea pigs results in an increased behavioral response to this drug. After 6 months of daily amphetamine exposure, animals demonstrated behavioral hypersensitivity and developed full amphetamine-induced stereotyped behavior with decreased latency. The data suggest that chronic agonism with amphetamine can produce dopaminergic hypersensitivity, a behavior that contrasts with the development of drug tolerance to other pharmacologic agents. The mechanism of this induced hypersensitivity was studied by comparing brain amphetamine levels after acute and chronic amphetamine treatment. The two groups of guinea pigs showed no significant difference in amphetamine levels or drug distribution. These results suggest that altered amphetamine metabolism cannot account for the hypersensitivity seen after amphetamine exposure. Guinea pigs chronically pretreated with d-amphetamine were hypersensitive to another dopaminergic agonist whose metabolic pathway is distinct from that of amphetamine. These results have therapeutic implications in the management of clinical conditions related to chronic agonist-induced hypersensitivity.

Chorea induced by oral contraceptives.

A rare complication of oral contraceptive therapy is the induction of chorea. We here describe five cases of chorea in patients receiving low- or high-dose estrogen-containing contraceptives. All patients were nulliparous, young (average age 19 years), and became symptomatic shortly (average of 5 weeks) after initiation of contraceptive therapy. Two patients previously suffered an episode of Syndenham chorea; one experienced chorea in the course of Henoch-Schönlein purpura; and two had a history of congenital cyanotic heart disease without chorea. Dyskinesia resolved in all patients upon discontinuing the medication. Patients with preexisting striatal abnormalities appear more susceptible to oral contraceptive-induced chorea which is reversible on drug discontinuation. The mechanism of oral contraceptive-induced chorea is unknown, but clinical and experimental data suggest that it involves altered central dopaminergic activity.

PIP: It is known that chorea is a rarely-occurring complication of oral contrceptive therapy. 5 case histories of chorea in patients receiving either low- or high-dose estrogen-containing contraceptives are reviewed. All the patients were young and nulliparous. They developed the symptoms within an average of 5 weeks after therapy initiation. Dyskinesia ceased upon cessation of the oral contraceptive therapy. A summary of 17 previously-reported cases of oral contraceptive-associated chorea is also presented in tabular form. These cases plus the 5 reviewed in this paper suggest that chorea arises in women with abnormalities of the basal ganglia of various etiologies and will probably not occur in normal individuals. Studies with animals have indicated that female sex hormones may enhance central dopaminergic sensitivity, bringing on chorea in oral contraceptive patients. In the 3 of 5 patients here described who had previously experienced an episode of chorea, the contraceptive-induced disorders, i.e., asymmetries, orofacial involvement, and personality changes, were similar to the original movement disorders. The other 2 cases studied here had not experienced a chorea episode but did have a history of neonatal cyanosis.

Drug-induced asterixis in Parkinson disease.

Asterixis was observed in five parkinsonian patients who were taking levodopa. A prospective study revealed that 4 of 55 consecutive patients had asterixis. Liver and metabolic functions were normal in all patients. Asterixis always occurred as part of a toxic confusional state superimposed on a parkinsonian state associated with some dementia. Insomnia, hallucinosis, and myoclonus were also prominent in the affected patients. Because of this association with other signs of chronic drug toxicity and its reversal with drug withdrawal, the asterixis seemed to be drug-related.

Pemoline-induced chorea.

Acute chorea in a child followed ingestion of pemoline mesylate. In guinea pigs, in an experimental model of chorea, chronic administration of pemoline induced behavioral supersensitivity to other dopaminergic agonists. Pemoline is similar to both d-amphetamine and methylphenidate in altering central dopaminergic sensitivity, and may cause chorea by similar mechanisms. Chronic pemoline therapy may offer no significant advantage over therapy with other indirect dopamine agonists.

Gilles de la Tourette syndrome after long-term chlorpromazine therapy.

Following 6 years of continuous chlorpromazine therapy for schizophrenia, a young woman developed multifocal tics and vocalizations characteristic of Tourette syndrome. The symptoms first appeared when chlorpromazine was withdrawn. They were permanent, although partially ameliorated by chronic haloperidol therapy. Because of her age and past history, these symptoms were attributed to chronic neuroleptic therapy analogous to neuroleptic-induced tardive dyskinesia, rather than to Tourette syndrome per se. These symptoms suggest that chronic receptor-site blockade can result in hypersensitivity of dopamine receptor sites, and that this may play a role in the pathophysiology of Gilles de la Tourette syndrome. This is the first evidence that hypersensitivity of dopamine receptors is involved in the pathophysiology of Tourette syndrome.

Chronic dopaminergic sensitivity after Sydenham's chorea.

We studied psychometric performance on the Minnesota Multiphasic Personality Inventory (MMPI) mini-mult and drug-induced choreic reactions in a group of patients with a history of Syndenham's chorea. Action tremor, motor signs, and residual chorea were common. One-half of the patients reported adverse choreic reactions to one or more agents. Patients with adverse reactions to central stimulants and anorectics had statistically significant elevations in the psychotic tetrad of the MMPI. Sydenham's chorea in childhood seems to confer persistent sensitivity to agents that augment central dopaminergic activity, which may be expressed as acute chorea. Central dopaminergic sensitivity may explain earlier reports of psychologic difficulties in survivors of rheumatic chorea.

PIP: 32 patients with Sydenham's chorea were studied at the La Rabida Institute for psychometric performance on the Minnesota Multiphasic Personality Inventory (MMPI). Questionnaires used included a definition of chorea and a description of choreic movements which the patients and members of their households were asked to read. Results were: 1) the only medical condition frequently reported was arthritis; 20/32 patients reported medical consultation for this complaint; 2) 19 patients including 2 with chorea gravidium, reported motor or psychiatric side effects from 1 or more agents; 3) in patients with multiple drug exposures a history of adverse motor reactions to decongestants was always associated with adverse reactions to anorectics or amphetamine in patients with exposure to all agents, and a similar pattern was noted with thyroid hormone and oral contraceptives (OCs); 4) 1 patient with chorea gravidium reported dyskinesias after administration of decongestants or amphetamine but tolerated OCs; and 5) MMPI scores from patients reporting adverse responses to amphetamines were statistically elevated in the psychotic tetrad. This study provides support for the belief that Sydenham's chorea is not a benign self-limited disease of childhood. In addition to mild residual neurologic abnormalities, the disorder appears to confer long-standing sensitivity to a variety of dopaminergically active agents.

Complications of chronic levodopa therapy: long-term efficacy of drug holiday.

Chronic use of levodopa may be complicated by dyskinesias, on-off effect, or hallucinosis. Transient levodopa withdrawal (drug holiday) may increase motor responsiveness and decrease levodopa-induced side effects, and the improved state may persist for as long as 9 months. After 1 year, parkinsonian signs approached pre-holiday levels, and two of the patients required a second drug holiday; side effects began to reappear 9 to 12 months after the holiday. Four of six patients with psychiatric complications remained free of hallucinations for the entire year.

Modification of central serotonergic and dopaminergic behaviors in the course of chronic corticosteroid administration.

The effect of chronic cortisol administration (12.5 mg/kg per day p.o.) was studied in guinea pigs using two behavioral models; apomorphine-induced stereotypy (SB) and 1-5-HTP-induced myoclonus (MJB). Diurnal variations in behavioral sensitivity were evaluated by behavioral testing at five time points over a 24 h period at bi-weekly intervals. Cortisol succinate administration suppresses 1-5-HTP myoclonus in all animals and abolishes diurnal fluctuations in sensitivity during the first two weeks of therapy. At four weeks, a subgroup is observed which is behaviorally hypersensitive to 1-5-HTP. These changes occur in association with a reduction in the behavioral response to apomorphine but in the absence of major disruption in diurnal behavioral threshold variation to apomorphine. Chronic cortisol administration appears to induce major alterations in central serotonin-mediated behaviors. This observation may explain the therapeutic effect of corticosteroids in certain forms of myoclonus and the role of cortisol rhythm disturbances in the context of a variety of psychiatric disorders.