Paul A. Nausieda

Sleep disruption in the course of chronic levodopa therapy: an early feature of the levodopa psychosis.

Sleep disruption is a common complaint in levodopa-treated parkinsonian patients. A survey of 100 parkinsonian patients revealed prominent sleep complaints in 74%. Sleep complaints were unrelated to patient age and the duration of disease but increased in prevalence with longer periods of levodopa therapy. Sleep abnormalities tended to increase in severity with continued treatment and insomnia tended to be followed by daytime somnolence, altered dream events, and episodic nocturnal vocalization and myoclonus. While dyskinetic side effects and on-off syndrome were encountered in patients with and without sleep complaints, 98% of patients experiencing psychiatric side effects also reported sleep disruption. It is suggested that sleep-related symptoms constitute an early stage of levodopa-induced dopaminergic psychiatric toxicity in the parkinsonian population. Clinical and experimental observations suggest that serotonergic mechanisms are important in this symptom complex.

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 lowor 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 Sydenham chorea; one experienced chorea in the course of Henoch-Schonlein 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.

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. These symptoms first appeared when chlorpromazine was withdrawn.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.

Modification of postsynaptic dopaminergic sensitivity by female sex hormones

Abstract Stereotyped behavior in response to d-amphetamine or apomorphine was significantly reduced in female guinea pigs following cophorectamy. Responsiveness to either dopamine agonist was significantly increased by the subsequent chronic administration of either estradiol valerate or progesterone. Modification of postsynatpic dopaminergic sensitivity by female sex hormones may underly the clinical association of hyperkinetic movement disorders, psychosis or depression seen with alterations in female sex hormones in man.

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 age 10. There was a high familial 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.

Respiratory Dyskinesias: Extrapyramidal Dysfunction and Dyspnea

Four patients had acute dyspnea and chest pain due to primary neurologic disease, not to cardiac or pulmonary disorders. They suffered from severe, involuntary respiratory dyskinesias, which resulted in an irregular respiratory rate, shortness of breath, and chest discomfort. These respiratory dyskinesias occurred as one aspect of more generalized choreiform movement disorders. Three patients had neuroleptic-induced tardive dyskinesias, and one had levodopa-induced dyskinesias. As a result of their ages and the nature of their complaints, some of these patients were originally thought to have cardiac and pulmonary disorders. Respiratory dyskinesias should be considered as a possible cause of respiratory distress in patients with extrapyramidal dysfunction.

Treatment and prognosis of hemiballismus.

Acute hemiballismus due to a cerebrovascular lesion may have a grave prognosis. In the past nine years, we have treated 11 patients who had an acute onset of hemiballismus believed to be the result of an acute vascular lesion with neuroleptic drugs (most frequently haloperidol). None of the 11 died, and the movement disorders were greatly reduced or eliminated. In eight patients the drugs were withdrawn within six months, without recurrence of the movement disorders. Spinal-fluid homovanillic acid levels were increased in three patients, suggesting that altered dopaminergic feedback mechanisms may be involved in the pathophysiology of hemiballismus. Our observations suggest that the prognosis of hemiballismus is not necessarily as grave as has been believed, and that neuroleptic therapy may alter the outcome of this disorder.

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.

Influence of female sex hormones on neuroleptic-induced behavioral supersensitivity

Abstract The influence of various states of female sex hormones were investigated on the development of neuroleptic-induced behavioral supersensitivity to a dopamine agonist. The chronic administration of haloperidol induced behavioral hypersensitivity in male guinea-pigs. This effect has often been reported with male animals. In female guinea-pigs, haloperidol failed to induce any behavioral changes. Oophorectomy of female guinea-pigs significantly reduced the behavioral response to apomorphine when compared to normal female animals. This behavioral hyposensitivity increased as a function of time after oophorectomy. Chronic haloperidol treatment in oophorectomized animals produced behavioral hypersensitivity. Chronic treatment of either estradiol or progesterone in oophorectomized animals caused a significant enhancement of the behavioral response. In oophorectomized animals treated chronically with estradiol plus haloperidol or progesterone plus haloperidol no greater behavioral response was observed than with treatment with estradiol or progesterone alone. These results suggest that female sex hormones are able to modify dopamine receptor sensitivity and alter the development of behavioral supersensitivity induced by neuroleptics.

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.