Malignant syndrome in Parkinson's disease: concept and review of the literature

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Abstract

We reviewed literature on malignant syndrome occurring in patients with Parkinson's disease (PD) during the course of drug therapy. Clinical features were high fever, marked rigidity, consciousness disturbance, autonomic dysfunction, and elevation of serum creatine kinase. The clinical features were essentially similar to those of neuroleptic malignant syndrome. The immediate triggering event was, most often, discontinuation or reduction of anti-parkinsonian drugs, particularly of levodopa. But no anti-parkinsonian drug was the exception to the induction of malignant syndrome. Serious complications were severe pneumonia, disseminated intravascular coagulation, and acute renal failure. Early treatment with intravenous fluid infusion and external body cooling are essential for good recovery. Bromocriptine and dantrolene sodium were used frequently. It has been claimed that they are effective; however, randomized controlled studies are needed to explicitly prove the efficacy of these drugs in malignant syndrome associated with PD.

Introduction

Malignant syndrome occurring during the course of treatment of Parkinson's disease (PD) was first described by Toru et al. [1]. They reported a 63-year-old woman diagnosed of PD who had developed a symptom complex consisting of extrapyramidal symptoms, altered consciousness, diaphoresis, fever, and increased serum creatine kinase (CK) following the discontinuation of large doses of combined anti-parkinsonian drugs. Their patient recovered uneventfully after treatment with levodopa/carbidopa.

Then Fujitake et al. [2] reported seven patients with PD and one patient with olivopontocerebellar atrophy (OPCA) who developed acutely high fever, altered consciousness, marked rigidity, and shock in some of the patients during the course of levodopa treatment. All of them showed a marked increase in serum CK, had developed drug related psychotic symptoms prior to the onset of malignant syndrome and levodopa or amantadine HCl was reduced in six out of the eight patients. Their clinical features were essentially similar to those of neuroleptic malignant syndrome reported in the literature [3], [4], [5]. Their patients recovered after treatment with intravenous fluid infusion, levodopa, bromocriptine and, in some patients, dantrolene sodium. The authors concluded that acute reduction in both the nigrostriatal and hypothalamic cerebral dopaminergic transmission, was responsible for this syndrome.

In the same year, Sechi et al. [6] reported a patient affected with idiopathic PD and levodopa-induced dyskinesias who had developed fatal hyperpyrexia after simultaneous levodopa withdrawal and decrease in the dosage of diphenhydramine. The clinical features were essentially similar to those of neuroleptic malignant syndrome. They suggested that the rapid decrease in dopaminergic activity might have caused this syndrome.

Since then, many similar cases have been reported in the literature. Figa-Talamanca et al. [7] reported a patient who had developed hyperthermia as a complication following discontinuation of levodopa/carbidopa and bromocriptine. They suggested that impaired nigrostriatal, hypothalamic, and mesolimbic dopaminergic functions could be involved in the pathogenesis.

In the same year, Friedman et al. [8] reported three patients resembling neuroleptic malignant syndrome. Each patient had a long history of PD treated with levodopa–carbidopa. Two patients developed the syndrome when administration of the drug was temporarily discontinued. One developed the syndrome before a ‘drug holiday,’ and then died during the holiday. This patient is the second reported case to die of malignant syndrome after levodopa withdrawal.

Gibb and Griffith [9] reported a patient with PD and schizophrenia. This 60-year-old woman had been taking levodopa/carbidopa and thioridazine. Five months after thioridazine had been stopped levodopa/carbidopa was withdrawn. One week later she developed features of neuroleptic malignant syndrome accompanied by myoglobinuric renal failure. Post-mortem examination showed nigral degeneration with Lewy bodies. No additional abnormality was detected that could explain her malignant syndrome.

Di Rosa et al. [10] reported a patient who developed malignant syndrome during a drug holiday. They ascribed the hyperthermia to functional hypothalamic deficiency resulting in defective heat dispersion due to the lack of cutaneous vasodilatation.

There are many additional reports of MS in similar patients induced by levodopa withdrawal [11], [12], [13].

Section snippets

Clinical features

Clinical features of levodopa-withdrawal malignant syndrome consist of worsening parkinsonism with a marked increase in muscle tone, elevation of the body temperature, altered consciousness, marked elevation of serum CK, and autonomic dysfunction such as tachycardia, perspiration, loss of sweating, non-paralytic ileus, and fluctuation of the blood pressure (Table 1). Clinical features of levodopa withdrawal malignant syndrome are essentially very similar to those of neuroleptic malignant

Malignant syndrome in secondary parkinsonism

The malignant syndrome due to levodopa withdrawal has been reported in multiple system atrophy (MSA) after discontinuation of levodopa [26], [27], [28]. It is interesting to note that while levodopa does not effectively control the motor symptoms of MSA, nevertheless, an abrupt reduction can still cause malignant syndrome. Clinical features of malignant syndrome in MSA were essentially similar to those of malignant syndrome in PD.

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