A New Therapy for Neuroleptic Malignant Syndrome

Abstract & Commentary

Source: Sato Y, et al. Efficacy of methylprednisolone pulse therapy on neuroleptic malignant syndrome in Parkinson’s disease. J Neurol Neurosurg Psychiatry. 2003;74:574-576.

Neuroleptic malignant syndrome (NMS) presents several unique challenges for the treating physician. Although the disorder classically follows exposure to typical neuroleptics (often in young men given high-dose depot preparations of antipsychotics), any agent that blocks the D2 family of dopamine receptors, including metoclopramide or prochlorperazine, may trigger the disorder. It also occurs in patients with Parkinson’s disease (PD) who decrease or discontinue their dopaminergic therapy. Symptoms of NMS include fever, rigidity, alteration of consciousness, autonomic dysfunction, and elevations in creatine kinase. However, a patient may present with NMS without florid signs of autonomic instability or high fever, and the diagnosis should be considered in any patient who presents with lethargy, fever, and elevation in creatine kinase.

In this paper, Sato and colleagues conducted a double-blind, placebo-controlled study of the effect of 3 days of treatment with steroid pulse therapy in NMS. Forty PD patients were enrolled in this trial and randomly assigned to receive either 1000 mg of methylprednisolone IV per day for 3 days or placebo. In all patients, NMS was triggered by discontinuation of dopaminergic agents, either because of hallucinations, dyskinesias, or on-off phenomena. For the duration of the trial, all patients were treated with oral levodopa (300 mg/d), bromocriptine (7.5 mg/d), and dantrolene (75 mg/d).

Symptoms and signs of NMS lasted 7 days in the steroid-treated group vs 18 days in the placebo group. Disseminated intravascular coagulation occurred in 3 patients in the placebo group (with 1 death); there were no deaths in the steroid group. Systolic and diastolic blood pressure normalized in 18 patients in the steroid group during or immediately after steroids were given, while blood pressure took at least 10 days to normalize in the placebo group. Ten days after enrollment, creatine kinase levels were normal in all patients in the steroid group but normal in only 6 patients in the placebo group.


Despite the small sample size, this study demonstrates that the addition of 3 days of high-dose IV methylprednisolone substantially reduced morbidity and mortality in NMS. Most impressive, markers of NMS including creatine kinase, autonomic instability, and time to resolution of symptoms were all affected by the treatment. Based on this study, IV methylprednisolone should be administered to any patient suspected of suffering from NMS as soon as the diagnosis is considered.

Although this is an important study, Neurology Alert readers should be aware of several issues. In the 1980s, several PD patients were reported to develop fatal episodes of NMS after discontinuation of levodopa. This was observed following the practice of admitting patients to the hospital to withdraw their PD medications for a "levodopa holiday." After these reports, neurologists abandoned the practice of completely withdrawing dopaminergic stimulation in PD patients. Even in the setting of psychosis, severe dyskinesias, or motor fluctuations, most PD patients can be managed with a reduction in levodopa dose or the addition of other agents (such as atypical neuroleptics or amantadine). In practice, my colleagues and I never completely withdraw levodopa, particularly in advanced PD patients. More concerning, Sato et al gave each patient the same low dose of levodopa, bromocriptine, and dantrolene. In fact, the dose of levodopa and agonist required by a patient with NMS should be determined by their dopaminergic regimen prior to the development of NMS (ie, giving a patient 300 mg of levodopa when their usual daily dose is 1200 mg is insufficient and might be considered below an acceptable standard of care).

Although this trial yielded important results, readers should be aware that the treatment paradigm in this study is not appropriate for routine clinical care of PD patients who develop this devastating neurologic emergency. — Steven Frucht, MD. Dr. Frucht, Assistant Professor of Neurology, Movement Disorders Division, Columbia-Presbyterian Medical Center, is Assistant Editor of Neurology Alert.

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