Managing an Effective Treatment for Neuroleptic Malignant Syndrome
Introduction: Neuroleptic malignant syndrome (NMS) is a rare, but sometimes fatal, adverse reaction to neuroleptics characterized principally by fever and rigor. The aim of this study was to prove the efficacy of different NMS treatment strategies, focusing on the efficacy of dantrolene.
Methods: Altogether, 271 case reports were included. These cases were categorized into four treatment groups and compared to each other according to effectiveness of therapy within 24 hours, mortality, complete time of remission in days, effectiveness due to increase of dosage, relapse on the basis of decrease of dosage, and improvement of symptoms.
Results: Between the four treatment groups, the complete time of remission was significantly different (analysis of variance, F = 4.02; degrees of freedom = 3; p = 0.008). In a logistic regression with adjustment for age, gender, and severity code, no significant predictor of the treatment for the complete time of remission (dichotomized by median) could be found. However, if the premedication was a monotherapy with neuroleptics, the complete time of remission was significantly shorter with dantrolene monotherapy (t = -2.97; p = 0.004).
Conclusion: The treatment of NMS with drugs that are combined with dantrolene is associated with a prolongation of clinical recovery. Furthermore, treatment of NMS with dantrolene as monotherapy seems to be associated with a higher overall mortality. Therefore, dantrolene does not seem to be the evidence-based treatment of choice in cases of NMS but might be useful if premedication consisted of a neuroleptic monotherapy.

Neuroleptic malignant syndrome (NMS) is a rare, but sometimes fatal, adverse reaction to neuroleptics. It is characterized principally by fever and muscle rigidity. Furthermore, signs such as altered consciousness, autonomic instability, and laboratory findings such as elevated creatine phosphokinase (CPK), leukocytosis, raised liver enzymes, and low serum iron or potassium levels are also found (serum iron and potassium levels differ in the sets of diagnostic criteria according to several authors). NMS is observed mainly in patients treated with neuroleptics, especially with high-potency neuroleptics, atypical neuroleptics, low-potency D2-receptor antagonists such as metoclopramide and tricyclic antidepressants, or after withdrawal of antiparkinsonians. Because clinical NMS studies have been conducted mainly in psychiatric units, it has been suggested that special attention to cancer patients undergoing psychopharmacologic treatment is necessary even in oncologic practice.

Although the origin of NMS remains unknown, a reduction in dopaminergic activity in the brain, probably by dopamine D2-receptor blockade in the striatum and hypothalamus, is generally assumed as its cause. Nevertheless, other theories about its pathophysiology have been raised, including a disturbance of glutamate or serotonin receptors, central hyponatremia, overreaction of the sympathetic nerve system, as well as a kind of acute-phase reaction. However, these theories are able to explain neither the symptoms mentioned above nor the low incidence rate between less than 0.1% and 2.5% of all patients treated with neuroleptic medication.

Therefore, a therapeutic approach inevitably seems to be through trial rather than evidence-based. It is generally agreed that it is of highest importance to identify the syndrome, suddenly withdraw the offending agent, and entertain supportive therapy as rehydration and restoring electrolyte balance. Because anticholinergics anticipate diaphoresis, they should be avoided. In regard to special treatment, several therapeutic options have been established. In addition to bromocriptine and other dopamine D2-receptor agonists, dantrolene sodium has been recommended predominantly in the past. Dantrolene is a peripheral muscle relaxant, which inhibits the intracellular calcium release from the sarcoplasmatic reticulum. It was originally applied to treat cases of malignant hyperthermia. It was first mentioned in 1981 as a treatment of NMS and since then has been employed with more or less success. Nevertheless, dantrolene therapy is still considered the treatment of first choice in current pharmacologic and psychiatric textbooks as well as in recent publications. Some authors have suggested a positive central effect of dantrolene in cases of NMS. Since the mid-1980s, the benefit of specific treatment with dantrolene has been controversial. No significant benefit or even a shortened course of recovery from NMS through single dantrolene therapy, compared to supportive therapy alone, could be observed. In fact, failures of dantrolene therapy have been documented in several case reports. as well as in relatively large samples.

Taking into account the low incidence rate of NMS, a randomized, controlled, and double-blinded prospective study did not seem to be feasible. Therefore, the aim of this study was to prove the efficacy of dantrolene therapy by a review of published cases and a complete review of the literature.