Harold L. Klawans

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.

United Parkinson Foundation Neurotransplantation Registry on adrenal medullary transplants Presurgical, and 1‐ and 2‐year follow‐up

Thirteen centers participated in a multicenter database with systematic evaluation of US and Canadian patients who had adrenal medullary transplantation for Parkinsons disease. This voluntary registry collected demographic, safety, and efficacy data using the same scoring measures over a 2-year follow-up period. Baseline data on 61 patients and 2-year follow-up data on 56 patients were compared. Eighteen percent died during the study period, and one-half of these deaths were related or questionably related to the surgery. Of the remaining 45 patients with data, global improvement, defined as an improved summed score of the “n” and “off” motor and activities of daily living functions from the Unified Parkinsons Disease Rating Scale, occurred in 32% of the patients at 2 years after surgery. At follow-up, significant group improvement persisted in the amount of daily “on” time and the quality of “off” function, but other measures were no better than baseline. When the global improvement calculation was based on the total sample and included deaths and patients lost to follow-up as “not improved,” only 19% were improved 2 years after surgery. Twenty-two percent of survivors had persistent psychiatric morbidity not present prior to surgery. These data document a modest group improvement in “off” function after neurotransplantation, but a serious level of mortality and morbidity.

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.

Bupropion in Parkinson's disease

Bupropion is an antidepressant, thought to be an indirect dopaminergic agonist. No significant sympathomimetic, anticholinergic, or MA0 inhibitor effects have been reported. We evaluated this drug in 20 patients with idiopathic Parkinsons disease. Parkinsonism lessened by at least 30% (Northwestern University Disability Scale or Modified New York University Parkinsons Disease Scale) in half the patients. Depression, present in 12 of 20, was alleviated in only 5. Bupropion is mildly efficacious in Parkinsons disease, although side effects were frequent and were dose-limiting in five patients.

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.

High speed memory scanning in parkinsonism.

This study tested the hypothesis that the slowing seen in parkinsonism includes cognitive as well as motoric components. The sample consisted of 20 nondemented parkinsonian patients, group matched to 16 normals by age, education, and verbal IQ. Each group was divided into young (64 and under) and old (65 and over) subsets. The Sternberg character classification paradigm was used to measure the speed and accuracy of one cognitive function, short term memory scanning. Following a logarithmic transformation of the reaction time data, scanning speed was found to be increased, but only for the elderly patients (p = .01). Scanning accuracy was normal for both patient groups. These findings suggest that at least one cognitive function, the scanning of elements held in short term memory, is slowed in parkinsonism. This mnemonic slowing, like bradykinesia, is seen primarily in elderly parkinsonian patients. It is not readily explained as a motor phenomenon, as part of a generalized mnemonic or intellectual deficit, or as an artifact secondary to periodic extreme reaction times. The term bradyphrenia, used in early descriptions of parkinsonism, may be an apt descriptor of this deficit.

Calcification of the basal ganglia Computerized tomography and clinical correlation

Duringa1-year period, 4219 consecutive computerized tomograms (CT) were reviewed for basal ganglia calcification; 14 patients with such calcification were identified. Calcifications on CT scan were bilateral in 12 of these cases and unilateral in 2. All bilateral calcifications were symmetric. The globus pallidus was the site of calcification in 13 ofthe 14 patients. Bilateral dentate nucleus calcification was seen in one patient. Skull radiograms were normal in all but one. Patients had diverse symptoms that were often explained by other findings, suggesting that calcifications may be coincidental and that basal ganglia calcification may not be a nosologic entity. Disturbances of calcium metabolism were not found in these patients, minimizing the pathophysiologic significance of altered calcium metabolism and the need for extensive endocrinologic evaluation. The finding of basal ganglia calcification alone does not justify invasive diagnostic procedures. Extrapyramidal signs may be associated with basal ganglia calcification; parkinsonism associated with basal ganglia calcification differs from idiopathic parkinsonism in being resistant to levodopa therapy.

5-Hydroxytryptophan-induced myoclonus in guinea pigs and the possible role of serotonin in infantile myoclonus.

The term “myoclonus” has been used for more than 80 years to describe a wide variety of abnormal and even normal muscle contraction s. The p he n o m e n a referred t o by this term differ i n virtually all of the parameters that can be used to describe movements. They differ in the extent o f muscular involvement; the speed and duration, degree of rhythmicity, and degree of symmetry of the contractions; the manner in which the contractions may be precipitated; and the clinical setting in which they occur . i Aigner and Mulder’ recognized these difficulties in their attempt to define myoclonus as “an involuntary repetitive, desultory instantaneous irregular contraction o f a group of muscles o r occasionally a single muscle.” These movements may be symmetrically synchronous or asymmetric, and in some patients various types of stimulation, including sudden noises, can accentuate the tnyoc10nus.2.:’ Myoclonus itself is n o t associated with a d i s t u r b a n c e o f consc iousness , a n d the movements may o r may not be accompanied by a discharge detectable on the elect r o e n c e p ha I o gr a m . L~:’ T he se move m e n t s , i n fact, may represent a manifestation of hyperexcitability of the nervous system at almost any level, and the form o f the movement abnormality may vary according to the level of nervous system dysfunction.’.:’ The various types of niovements classified as myoclonus can be seen in numerous disease states, and the pathophysiology of myoclonus 1234 Neurology / Volume 23 /November 1973 may be different in different disorders. Two sets of observations suggest that, in certain instances, a neurohumoral mechanism may play a part i n the pathophysiology of at least some types of myoclonus. The first of these mechanisms is the occur re lice o f shock I i ke in v o I u n t a r y move in en ts of muscles in children with occult tumors of neural crest origin, especially neurob l a ~ t o m a s . ~ ~ These rapid, j e rky movements of the head, trunk and limbs often a re associated with abnormal rapid eye movements. The syndrome was first described in 1962 by Kinsbourne under the term myoclonic encephalopathy.’” Dyken and Kolarj and Moe and Nellhaus’ feel that infantile polymyoclonia is a better descriptive term. This type of syndrome apparently can be observed as a benign manifestation of encephalitic, postencephalitic o r immunologic

On the role of dopamine in the pathophysiology of anorexia nervosa

Based on a review of the pathophysiology of the major symptoms of anorexia nervosa, it was suggested that increased activity of dopamine at central dopamine receptors plays a role in the pathophysiology of this disorder. Although dopamine receptor site hypersensitivity, or synthesis, of a false transmitter could account for this, a defect in negative feedback control mechanisms is more consistent with the known characteristics of anorexia nervosa. The possible role of pure dopamine antagonists in symptomatic treatment and of dopamine agonists in reversing this disorder was discussed.

THEORETICAL IMPLICATIONS OF THE USE OF L‐DOPA IN PARKINSONISM.

The production of all the major symptoms of parkinsonism is attributed chiefly to the loss of the normal dopaminergic input into the striatum. This loss of dopaminergic input is due to degeneration of the cell bodies of the substantia nigra. An analogous loss of serotonin (5‐hydroxytryptamine) may be of significance in the production of parkinsonian tremor. L‐dopa ameliorates the symptoms of parkiusonism as a result of reinstitution of dopamine inhibition of the striatal neurons. L‐dopa induced dyskinesias are felt to be related to denervation hypersensitivity of striatal neurons to dopamine produced by dopaminergic denervation. Failure to respond to L‐dopa is related to degeneration of striatal dopaminergic receptors. The efficacy of amantadine hydrochloride is felt to be related to a block of the presynaptic reuptake of dopamine and thereby a prolongation of dopamines effect at the receptor site.