Flow chart of treatment options in patients with neuroleptic malignant syndrome (NMS). PO=per os, NG=nasogastric tube, bd=bis in die (twice per day), qds=quaque die (four times per day), IV=intravenously.
The use of dopamine agonists has been positively correlated with faster recovery and halved mortality (56). However, the correct diagnosis of NMS is critical, as bromocriptine, for example, can cause worsening of serotonin syndrome (71). While bromocriptine has historically been used most often and is considered the drug of choice (75), other dopaminergic agents are equally effective. Some suggest the use of amantadine as it may also reverse parkinsonism in these patients (56); however, so should dopamine agonists.
In parkinsonism-hyperpyrexia syndrome L-dopa or dopamine agonist therapy should be restarted as soon as possible (76). CK levels are usually lower and hospitalization days are shorter compared to patients with NMS (76).
Dantrolene inhibits calcium release from the sarcoplasmic reticulum, decreasing available calcium for ongoing muscle contracture. This muscle relaxant, alone or in combination with benzodiazepines and dopamine agonists, can be beneficial for patients with extreme hyperthermia and hypermetabolism (56). Coadministration with calcium channel blockers should be avoided because of cardiovascular collapse (56). While the use of dantrolene is considered a treatment of first choice in many current pharmacologic and psychiatric textbooks, it is important to acknowledge that its use is largely based on small case series and a robust evidence base is lacking. In particular, a retrospective review of 271 case reports found that dantrolene is associated with a prolongation of clinical recovery when used in combination therapy, and was associated with a higher overall mortality when used as monotherapy in NMS (77).
In patients with severe NMS, with fever above 40.0°C, severe rigidity, catatonia or coma, and a heart rate above 120 beats per minute, and who are pharmacoresistent, case reports have suggested that six to ten treatments with electroconvulsive therapy (ECT) may be useful (56, 78). However, there are no prospective, randomized, controlled data supporting its efficacy. In a retrospective review of ECT, Trollor and colleagues concluded it is the preferred treatment in severe NMS, cases where the underlying psychiatric diagnosis is psychotic depression or catatonia, and in cases where lethal catatonia cannot be ruled out. However, they note that ECT has been associated with cardiovascular complications, which occurred in 4 of 55 patients, including two patients with ventricular fibrillation and cardiac arrest with permanent anoxic brain injury (78).
Most patients require continuation of neuroleptic treatment and no accepted guidelines have been published for further treatment. Rechallenge with neuroleptics of the same milligram potency as the original stimulus in six patients resulted in recurrent NMS in five of the six patients, with two deaths. Rechallenge with less potent antipsychotics, such as thioridazine, was safe in nine of 10 cases (44). Generally, it is recommended to wait for 2 weeks after symptoms have resolved and then, if possible, to switch to a low dose of a low potency neuroleptic such as chlorpromazine or thioridazine (65), or a second-generation antipsychotic.
Prognosis
The mortality rate was 76% in the 1960s but has dropped significantly over recent years and estimates now vary between 10% and 20% (54). Earlier recognition and treatment of NMS is the most likely factor contributing to the decline in mortality. Causes of death in NMS include cardiorespiratory arrest, acute renal failure, and disseminated intravascular coagulation. Most cases nowadays recover within two weeks (54). Patients receiving depot neuroleptic preparations generally have a prolonged duration of illness, and have a worse prognosis. Poor prognostic outcome has also been reported in patients with organic brain disease and those with extreme fever peaks and longer duration of hyperthermia (56). One study of 208 cases of NMS found that mortality was considerably lower for those with second-generation antipsychotic NMS (3.0%) compared with NMS following first-generation antipsychotic use (16.3%), and the former were more likely to have received supportive treatment (36). Persistent neurological complications described in NMS survivors include parkinsonism, dementia, dyskinesia (41), and cerebellar syndrome (79), as a result of parenchymal damage due to hyperpyrexia.
Conclusions
While NMS is a relatively rare disorder, the frequent use of neuroleptic medications in medicine and psychiatry behooves clinicians to be aware of this potentially fatal syndrome. Hopefully, NMS will become less common due to the increasing use of second-generation antipsychotics, more conservative antipsychotic prescribing patterns, increased awareness of risk factors, and the earlier recognition of NMS. Prevention, early recognition, and prompt treatment remain of paramount importance.
References
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