Neuroleptic malignant syndrome (NMS) …

Joseph H Friedman MD

Movement Disorders

Updated 06.19.2024
Released 08.31.1995
Expires For CME 06.19.2027

Neuroleptic malignant syndrome

Author: Joseph H Friedman MD

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Editor: Robert Fekete MD

Neuroleptic malignant syndrome

In This Article

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Introduction

Overview

Neuroleptic malignant syndrome is an often mentioned, but not commonly seen, syndrome that occurs in a small percentage of otherwise healthy people taking antipsychotic medications, including the so-called “atypicals” or second-generation antipsychotics. It is potentially lethal and should be considered in anyone taking an antipsychotic drug who has fever or increased extrapyramidal signs, especially rigidity or decreased level of alertness, or a Parkinson disease patient who has stopped taking anti-Parkinson disease medications. It can be difficult to distinguish from the effects of a severe infection in someone taking a neuroleptic drug as well as from serotonin syndrome. In this article, the author reviews the clinical manifestations of neuroleptic malignant syndrome and reviews suggested treatment approaches. The little that is known of its pathophysiology is also reviewed.

Key points

	• Neuroleptic malignant syndrome is a life-threatening condition that should be suspected in any patient taking a dopamine receptor-blocking drug who has a high fever or decline in level of alertness.
	• A neuroleptic malignant-like syndrome may also occur in Parkinson disease patients who have sudden reductions in their anti-Parkinson disease medications.
	• The diagnosis of neuroleptic malignant syndrome is clinical and may be impossible to distinguish from coincident infection. Both may be present.
	• Although there are disagreements about treatment options, most agree that the offending drug must be stopped. Most authors recommend adding a short course of dopamine-agonist medication, but some prefer dantrolene.
	• Neuroleptic malignant syndrome has been reported with each of the atypical antipsychotics, including clozapine, the most atypical.

Historical note and terminology

First described in 1960 (21) in French and in 1968 (20) in English, the neuroleptic malignant syndrome underwent a dramatic transformation in perception with the publication of a review article by Caroff in 1980 (16). Initially perceived as a rare complication of antipsychotic drugs, it is now known to be common enough that any neurologist, psychiatrist, or internist with a significant hospital-based consultative practice will see several cases over the course of a few years. A similar syndrome called lethal catatonia, occurring in untreated psychotic patients, has been recognized since the early 19th century (54). The overlap between lethal catatonia and neuroleptic malignant syndrome has been the subject of debate, with evidence supporting the idea of some cases being related to catatonia (50; 99).

A related syndrome, called “neuroleptic malignant-like syndrome” or “parkinson hyperpyrexia syndrome,” occurs in Parkinson disease patients whose anti-Parkinson disease medications have been abruptly discontinued (36) or reduced, even, in a case, by reduced absorption due to concomitant use of enteral nutrition (13), and even as an “off” episode when Parkinson disease medications stop working (68).

Clinical manifestations

Presentation and course

	• Neuroleptic malignant syndrome is defined clinically but lacks universally accepted criteria. All criteria include fever.
	• It must be treated if suspected, along with suspected infectious causes.
	• Hyperpyrexia, rhabdomyolysis, and autonomic dysfunction must be treated aggressively to avoid irreversible damage or death.

Neuroleptic malignant syndrome is one of the most serious drug-induced movement disorders and is frequently included in reviews of tardive dyskinesia (12; 94; 93; 61; 77). Because no definition is universally accepted for the diagnosis of neuroleptic malignant syndrome (90), an expert panel convened and published a set of guidelines for evaluating the importance of various aspects of the syndrome (31). These have subsequently been validated (29). Diagnosis rests on clinical criteria, supportive laboratory tests, and the exclusion of other potential diagnoses. Despite the large number of papers written about the topic, diagnostic criteria have not changed in many years. Oftentimes, patients require treatment for two disorders simultaneously, as a clear-cut diagnosis is impossible.

Neuroleptic malignant syndrome should be considered a medical emergency (59). Kurlan and colleagues defined neuroleptic malignant syndrome as a triad of fever, "movement disorder," and altered mentation (46). Levenson suggested a definition using the sum of three major or two major and four minor criteria. The major criteria were fever (above 99.0°F), rigidity, and elevated creatine phosphokinase; and the minor criteria were tachycardia, diaphoresis, tachypnea, abnormal blood pressure, leukocytosis, and altered consciousness (51). Pope and colleagues required a temperature above 99.4°F, severe extrapyramidal signs, and autonomic dysfunction for a "definitive" diagnosis (70). Addonizio and colleagues diagnosed "definite" neuroleptic malignant syndrome if temperature was above 99.0°F, severe rigidity or tremor was present, and if three of the following seven minor criteria were present: heart rate above 100 beats per minute, diaphoresis, peripheral white count above 10,800 cells/mm3, elevated creatine phosphokinase, hypertension, confusion, and incontinence (02). Guze and Baxter required hyperthermia, rigidity, fluctuating level of consciousness, and autonomic instability (34). Research criteria for diagnosing neuroleptic malignant syndrome from the fourth edition of the Diagnostic and Statistical Manual of Mental Disorders require severe rigidity and fever accompanied by 2 of 10 minor features including diaphoresis, dysphagia, tremor, incontinence, altered mentation, mutism, tachycardia, elevated or labile blood pressure, leukocytosis, and elevated creatine phosphokinase (05). Interestingly, DSM V lists clinical signs of neuroleptic malignant syndrome, but does not provide clear criteria for the diagnosis (06). Less stringent criteria have been used for classification of "probable" neuroleptic malignant syndrome (32).

From a clinical vantage point, it is obvious that many criteria are intertwined. Fever will be accompanied by tachycardia, diaphoresis, and tachypnea in all with potential neuroleptic malignant syndrome and by mental impairment in the elderly.

It is also clear from all literature reviews that a large spectrum of clinical presentations exists. It is important to realize this when approaching any particular patient. In general, most patients thought to have had neuroleptic malignant syndrome have had fever, movement disorder, and autonomic dysfunction (46). Addonizio and colleagues found 92% of 115 patients with temperatures above 100.4°F and 91% with rigidity (03). In most cases mental changes and rigidity preceded or accompanied the fever (92). Dystonia was present in 29%, and tremor in 48%. Creatine phosphokinase was elevated in 97%, and 97% were tachycardic. Obviously, criteria for diagnosis skew the percentage of presenting features. It also appears that patients may only exhibit parts of the syndrome (101).

The 2011 expert panel, using a Delphi procedure, published their “consensus regarding the clinical features that are most valuable in making the diagnosis of neuroleptic malignant syndrome, the relative importance of these features, and the corresponding critical values” (eg, temperature greater than 100.4° F; CPK greater than 4x upper limit of normal; etc.). They did not, however, use these values to define the syndrome. They restricted the movement disorder associated with neuroleptic malignant syndrome to rigidity.

A review from 2012 reported that cases of neuroleptic malignant syndrome associated with atypical antipsychotics were indistinguishable clinically from those induced by the first generation of antipsychotics, except that clozapine-associated cases had less rigidity and tremor (90).

Some authors believe that the spectrum is so diverse and that reported cases include so many patients with other potential diagnoses that they "question the assumption of a unitary neuroleptic malignant syndrome and suggest greater attention to identification of medical contributing factors" (52); however, this is a distinctly minority opinion. Other authors question the diagnosis being unitary as well, and they point to the lack of scientific study of the individual neuroleptic malignant syndrome patients (27).

Neuroleptic malignant syndrome appears to be clinically identical in children as in adults (84; 56). The greater numbers of boys reportedly affected, most likely, represents their greater use of neuroleptics.

Lee describes a progression of symptoms, based on 14 patients followed prospectively, beginning either with catatonia preceding the use of antipsychotics, or developing in association with the introduction of antipsychotics, or without catatonia at any time (50). In this study, the five patients without catatonia all developed delirium and rigidity before fever and autonomic dysfunction.

In Parkinson disease patients with the “neuroleptic malignant-like syndrome” (parkinson hyperpyrexia syndrome), the most common sign was fever followed by altered mental state (reduced level of consciousness in particular), and then worsening of motor function (10). Interestingly, as is true of patients with psychosis, mild elevations of creatine phosphokinase compared to controls were found at baseline in Parkinson disease patients (87). Similar signs were noted in parkinsonian patients who did not have Parkinson disease.

Isolated case reports have confirmed transient brain MRI changes that reversed with resolution of the clinical syndrome (37). These have included diffuse T2 enhancement in the cerebellum, brainstem, basal ganglia, thalamus, corpus callosum, white and gray matter, and white matter hemispheric lesions.

Diagnosing neuroleptic malignant syndrome. To diagnose neuroleptic malignant syndrome, one should have a history of neuroleptic exposure and, in most cases, a tetrad of fever, confusion or diminished level of alertness, marked extrapyramidal dysfunction, and autonomic dysfunction. Neuroleptic malignant syndrome is a diagnosis of exclusion; therefore, infectious causes of fever must be evaluated because fever may cause an exacerbation of mild baseline extrapyramidal signs as well as altered mentation in mentally impaired patients. Sewell and Jeste found that 29% of suspected neuroleptic malignant syndrome patients had infections and, although there were statistical differences in various extrapyramidal signs between neuroleptic malignant syndrome and non-neuroleptic malignant syndrome febrile psychiatric patients, there were no clearly discernible differences in individual patients, nor were there differences in laboratory studies, including serum creatine phosphokinase (80). This underscores the importance of an adequate medical evaluation. Drug withdrawal syndromes, such as delirium tremens and drug interactions, must also be excluded. "Serotonin syndrome" is characterized by the Hunter serotonin toxicity criteria of clonus, hyperreflexia, agitation, diaphoresis, tremor, hypertonicity, and temperature greater than 38°C (24). Serotonin syndrome may clinically overlap with neuroleptic malignant syndrome (63; 97). Monoamine oxidase inhibitors and meperidine can interact to cause a fatal hyperpyrexic reaction; thus, toxicology screens on urine and blood, in addition to a complete history, need to be obtained. A rare syndrome called "lethal catatonia" (54; 99), characterized by a prodromal manic phase with anorexia, destructive behavior, and altered consciousness leading to catatonia, fever, and autonomic instability, may mimic neuroleptic malignant syndrome (80); however, the main differential is with pneumonia and acute generalized dystonic reaction. A relatively newly recognized disorder, NMDA receptor encephalitis, has been mistaken for neuroleptic malignant syndrome (76). Because NMDAR encephalitis typically causes psychosis, it may be impossible to distinguish whether the fever, altered mental state, and rigidity is due to an antipsychotic given to treat the psychosis, the encephalitis, or both. It may also cause involuntary movements, such as dystonia, chorea, athetosis, and opisthotonus, which are also sometimes observed in neuroleptic malignant syndrome. NMDAR encephalitis is most commonly seen in young women with ovarian teratomas but may also occur without an identifiable malignancy. It is unclear if patients with NMDAR encephalitis are more prone to adverse effects of antipsychotics or not (69). Malignant hyperthermia, although phenomenologically similar to neuroleptic malignant syndrome, occurs after anesthetic and not neuroleptic exposure and is generally more fulminant. Neuroleptic malignant syndrome patients can be paralyzed with pancuronium, whereas malignant hyperthermia patients cannot. Baclofen withdrawal, either as an oral or intra-thecal agent, may cause hyperthermia, rigidity, muscle changes, and mental and autonomic dysfunction, thus simulating neuroleptic malignant syndrome (17). “Adrenergic stimulation syndrome” from amphetamines and various sympathomimetic drugs of abuse may also mimic neuroleptic malignant syndrome (17).

Parkinsonism hyperpyrexia syndrome (PHS) is an analogous syndrome to neuroleptic malignant syndrome, with the development of fever, altered mental status, severely increased rigidity, autonomic dysfunction, and possible CPK elevations over several hours. It appears to be extremely rare and generally associated with sudden withdrawal of L-dopa in chronically treated patients. However, it has been reported with stopping amantadine, dopamine agonists, failure to recharge a battery for subthalamic nucleus deep brain stimulation in a patient taking his usual L-Dopa (18), and even a case occurring as an “off” period (68). Deep brain stimulation likely increases dopamine release (04). Most have had idiopathic Parkinson disease, but some reports concern patients with other forms of parkinsonism. None of the reported parkinsonism hyperpyrexia syndrome patients had taken concurrent dopamine receptor blocking medications. Its onset usually occurs more than 24 hours after the last dose, sometimes several days later, and has not been reported in any Parkinson disease patient entering a treatment trial or deep brain stimulation evaluation in a “practical off” state, usually off Parkinson disease medications for 12 hours or more (see Medlink chapter on Movement Disorder Emergencies).

Prognosis and complications

Once a patient has had the disorder, the risk of recurrence is significant. One report describes six of eight patients (75%) suffering repeat neuroleptic malignant syndrome when rechallenged, but whether the same or a different neuroleptic was used is not stated (83). Pearlman noted that 20 of 54 (37%) rechallenged patients suffered recurrent neuroleptic malignant syndrome, but also failed to note which drugs induced the problem (66). One case report describes three episodes of neuroleptic malignant syndrome with three different drugs (49). Rosebush and colleagues found that when rechallenge was postponed for two weeks or more, there was less chance of recurrence (71). These authors found that 13 of 15 rechallenges did not induce neuroleptic malignant syndrome. Focal brain lesions have been ascribed to neuroleptic malignant syndrome, but this is rare (53).

Mortality from neuroleptic malignant syndrome is generally due to pneumonia or renal failure secondary to myoglobinuria. The mortality figures suggest a decline over the last three decades, presumably due to earlier recognition of the syndrome. Kellam's review notes a 76% mortality before 1970, 23% between 1970 and 1980, and 14% since 1980 (41). Undoubtedly, the high early mortality is partly the result of reporting bias.

Other mortality figures generally range from 4% to 22% (82). Risk factors for death have not been identified (82). Early recognition leading to drug withdrawal and appropriate management may produce a better outcome, but no current data justify this conclusion.

Biological basis

Etiology and pathogenesis

The diagnosis of neuroleptic malignant syndrome requires exposure to a dopamine receptor-blocking drug; however, parkinsonism hyperpyrexia syndrome is similar (10), and the same syndrome has occurred with reserpine (15) and tetrabenazine (67), which are dopamine depleting drugs. This occurrence has prompted some authors to suggest renaming the syndrome the "acute dopamine depletion syndrome" (42). Complicating our understanding of neuroleptic malignant syndrome are reports of similar syndromes occurring after exposure to non-neuroleptics, including carbamazepine (64) and trimipramine (48).

In Parkinson disease patients, the most common etiology was stopping L-dopa abruptly, but reduction in any Parkinson disease medications was also believed to be causal (10). It is important to keep this in mind when Parkinson disease medications are stopped, when patients cannot take medications by mouth, as with digestive system problems (81), and after deep brain stimulation (18), where rare cases have been reported (10).

The pathophysiology of neuroleptic malignant syndrome is unknown. The few cases that have been autopsied have yielded few neurophysiological clues to the mechanism. The occurrence of the syndrome with the use of dopamine receptor blockers, dopamine depletors, and the abrupt discontinuation of dopamine stimulating drugs in Parkinson disease suggests that neuroleptic malignant syndrome represents a relatively acute dopamine deficiency state. Although many cases occur during escalation of dose of dopamine receptor blocker, some cases have been reported to have occurred shortly after abrupt discontinuation of neuroleptics (07; 47). The occurrence of neuroleptic malignant syndrome with the atypical neuroleptic clozapine (09) may imply that a specifically "parkinsonian state" may not be relevant to a drug's ability to cause neuroleptic malignant syndrome so that abrupt D2 dopamine receptor blockage may not be the major factor. No theory explains why neuroleptic malignant syndrome occurs in only about 0.5% of those exposed or why it may occur after a patient has been on stable neuroleptic doses for months to years. Specific theories on pathophysiology are highly speculative. Although one report suggests an association between neuroleptic malignant syndrome and a particular polymorphism of the dopamine D2 receptor gene (44), this is based on 32 neuroleptic malignant syndrome cases compared with 132 schizophrenic noncases and does not explain the observation that some dopamine receptor blocking drugs, but not others, cause the problem in the same patient.

One report of SPECT scans being transiently abnormal with asymmetrically increased basal ganglia metabolism (62) supports a basal ganglia role in neuroleptic malignant syndrome, but this finding also could represent a response to neuroleptic malignant syndrome, rather than its cause. A case report describes MRI abnormalities in the cerebellum and the basal ganglia in a single case, most likely representing the result of hyperthermia rather than a specific neuroleptic malignant syndrome-induced lesion (53).

One report described an increased frequency of one particular allele for a dopamine D2 receptor (86). This allele is associated with a decreased density of D2 receptors in dopamine rich regions of the brain, perhaps exacerbating a dopamine stimulation decrease.

An interesting observation has been the elevated creatinine phosphokinase levels that are frequently found in psychotic patients who are neurologically normal. These patients tend to have similar creatinine phosphokinase elevations at each admission. As in neuroleptic malignant syndrome, men are more likely to have elevations than women (55). The relevance of this to neuroleptic malignant syndrome is unknown, but provocative.

A rabbit model of neuroleptic malignant syndrome has been described involving intramuscular injections of haloperidol (1 mg/kg) with atropine in a 35°C environmental setting (88). The relevance of this model remains to be seen.

In a major review, Gurrera proposes an abnormality of the sympathetic adrenal autonomic axis to explain all of the clinical and laboratory findings that may occur in neuroleptic malignant syndrome (30). Why only certain individuals develop the problem and why rechallenge does not always induce the syndrome is explained by alpha-state dependence (that is, a propitious constellation of factors such as emotional distress, brain injury, and other unknown factors).

Epidemiology

Neuroleptic malignant syndrome typically occurs 3 to 9 days after neuroleptic administration (66) but may occur as early as the day of drug initiation (66; 03) or as late as years after initiation (66). Half the patients with neuroleptic malignant syndrome develop it within one week of a medication change (03), and only 3% develop it on stable medications after six months. It may occur at any age but has a predilection for young adults (41) and favors men over women at a ratio of 1.5:1 to 2:1 (29). Whether this reflects vulnerability or prescribing patterns is uncertain. The syndrome usually evolves over 24 to 72 hours (34), but may develop fulminantly over hours. It generally lasts 10 to 13 days once oral neuroleptics are stopped (03) and twice as long with depot neuroleptics (03); however, cases of slow resolution of neuroleptic malignant syndrome without drug discontinuation have been reported (01).

The incidence of the disorder appears to be about 0.5% per year (26; 22; 40; 91) in prospective studies, but the small number of cases at surveyed institutions may inflate small variations (39; 33). The prospective report by Lee found 14 episodes in 13 subjects out of 1257 admissions (0.4%) in a psychiatric unit, and 9 out of 893 (1%) in another psychiatric unit (50). Risk factors for neuroleptic malignant syndrome may include use of depot drug (16; 66; 40; 35), affective disorder (35), genetic predisposition (65), high potency neuroleptics (83; 35), rapidity of dose increase (83; 74), dehydration, and agitation (74). It is also probably more likely to occur in patients never before on a neuroleptic, as may be found in hospital wards, than in large surveys, which are primarily composed of patients who have been on the medications for decades. Thus, an 11-year study from Denmark involving almost 225,000 patients found only 83 cases, for an incidence of 0.04% (60). One literature review suggests that selective serotonin inhibitors may precipitate neuroleptic malignant syndrome in patients on atypical antipsychotics based on some isolated case reports and the hypothesis that SSRIs increase serotonin, which worsens the hypodopaminergic state (85). This was not found in the large Danish study, in which concomitant benzodiazepine use was associated with increased risk (60). The observed relationship between neuroleptic malignant syndrome and catatonia implies that catatonia may be a risk factor for neuroleptic malignant syndrome (50). Implicated in causing neuroleptic malignant syndrome are 128 different neuroleptics (82). Other purported risk factors include brain damage, use of multiple neuroleptics, concomitant use of lithium, and stress. Unfortunately, none of these risk factors have been proven, and all must be considered speculative. Although many experts think that neuroleptic malignant syndrome is less common with the use of atypical antipsychotic drugs, there are no data to support this contention.

Although neuroleptics are primarily prescribed for adults, they are sometimes required for children; neuroleptic malignant syndrome rarely develops in this population (43).

Parkinsonism hyperpyrexia syndrome incidence is unknown, but the fact that the first published case due to gastrointestinal surgery making patients unable to eat or drink was published in 2024 (18) and that the ICD-10 does not have a code for it suggests it is very rare.

Diagnostic workup

	• Check for toxins such as stimulants, anticholinergics, and aspirin overdose.
	• Exclude infectious causes, including meningitis and sepsis.
	• Evaluate for CPK, “routine” blood tests.
	• Monitor ECG, blood pressure, and urine output.

The major differential includes infection and serotonin syndrome; as a result, patients should have an appropriate evaluation for the more likely causes of fever even when neuroleptic malignant syndrome is highly suspect. Evaluation should include a complete blood count, chest x-ray, urinalysis, and blood and urine cultures. Imaging studies of the brain are not indicated unless focal features or risk factors for brain abscess or AIDS are present. Cerebrospinal fluid analysis is usually required to exclude encephalitis and meningitis. Evaluation for systemic lupus erythematosus, polyarteritis nodosa, or other collagen vascular disorders may be indicated. Toxicology screens of urine and blood may be helpful in proving neuroleptic exposure in patients who deny it and in excluding drug interactions.

Toxic causes for hyperpyrexia should be considered, especially in patients with major psychiatric or substance abuse disorders, including high intake of aspirin, anticholinergics, sympathomimetics, and baclofen withdrawal (17).

A trial of intravenous benztropine or diphenhydramine may be useful in distinguishing a generalized acute dystonic reaction from neuroleptic malignant syndrome.

Two pathological reports on muscle changes in neuroleptic malignant syndrome patients revealed different changes. Kubo and colleagues believe that mitochondria and muscle associated proteins are lost in significant quantities from skeletal muscle, not from cardiac muscle, and that this may be pathognomonic (45); however, Behan and colleagues reported two cases without mitochondrial loss, but "a characteristic picture…in which fiber oedema is the main feature," with endomysial edema and frequently present contraction bands and necrosis (11). A report showed muscle MRI changes in a patient whose maximum temperature reached 39.1 C (102.4 F) (38). Muscle biopsy showed noninflammatory changes, with “minimal necrotizing and regenerating processes.” Given the variable degree of muscle involvement in neuroleptic malignant syndrome, some patients having normal creatine phosphokinase values and others having elevations of several orders of magnitude, it is unlikely that a single muscle pathological change will be found.

Management

	• Discontinue offending drug.
	• Add a dopaminergic.
	• Lower temperature with an ice bath, if possible, or cold mist.
	• Monitor in an ICU setting.

While deciding how to treat, core temperature should be lowered to 40 C as soon as possible. Although an ice bath is the fastest method, this may not be available. Cold mist is thought to work faster than ice packs or cold intravenous solutions (96), as autonomic dysfunction and possible renal failure are addressed. Drug treatment of neuroleptic malignant syndrome is controversial. Several reports describe the benefit of dantrolene (28), bromocriptine (23), dantrolene and bromocriptine together (58), lisuride (79), amantadine (50), and electroconvulsive therapy (01; 100), but some doubt has been raised about these claims. Rosebush and colleagues claim that the course of neuroleptic malignant syndrome was actually significantly prolonged in patients receiving dantrolene and bromocriptine compared to those receiving only supportive care at their institutions (72); however, the results are retrospective. The treated patients had a higher incidence of unrelated medical problems, and the duration of neuroleptic malignant syndrome in their conservatively treated patients was considerably shorter than the mean in the literature. Electroconvulsive therapy reportedly ameliorates neuroleptic malignant syndrome within hours, although the full effect may take days, and this treatment involves some risk (01). The largest review of electroconvulsive therapy treatment for neuroleptic malignant syndrome at a single center describes 15 patients, all of whom had failed lorazepam as treatment for possible malignant catatonia, eight had failed bromocriptine, and five had failed dantrolene (57). Eleven had remission, but three adolescents required maintenance electroconvulsive therapy for recurrent catatonia, not neuroleptic malignant syndrome. And, the benefit of electroconvulsive therapy in these pharmacologically refractory patients took a mean of 4.2 days. Dantrolene presumably works peripherally by uncoupling contracting myofibrils, whereas the dopaminergic drugs presumably act centrally, countering the neuroleptic effect on the brain. Dopamine agonists have not caused worsened psychosis in this situation. One report describes beneficial responses to carbamazepine (89).

Whether drug therapy is helpful in neuroleptic malignant syndrome is unclear, but this author and many others believe that dopamine agonists are helpful (14). A review of recommendations in English, French, Italian, and German for treating neuroleptic malignant syndrome developed by a variety of societies focused on schizophrenia found nine with clear recommendations (78). These included benzodiazepines, dantrolene, dopamine agonists, anticholinergics, amantadine, and electroconvulsive therapy. Some recommended continuation of the offending antipsychotic if second generation. It is doubtful that a double-blind controlled trial will be launched to answer the question as to which dopamine agonists are most effective, but in view of emerging data about cardiac complications associated with the use of the ergot dopamine agonists, ropinirole, pramipexole, or rotigotine may be considered as the dopamine agonists of choice, even though bromocriptine has been recommended in the past. Apomorphine, which can be given parenterally and would act faster than oral dopamine agonists, may also be helpful (95). Rotigotine is given by patch so that swallowing is not necessary. An inhaled preparation of L-dopa has been approved in the United States and may be considered, although patients are unlikely to be able to inhale the medication properly and an increase in coughing may preclude its tolerance. One review of the literature reported a marked decline in mortality as a direct result of the drug intervention (75), whereas another did not (82); however, all reviewers report a decline in mortality and attribute it to either therapy or earlier recognition. Benzodiazepines may be helpful in treating cases accompanied by catatonia (50).

Once the diagnosis of neuroleptic malignant syndrome is considered, it is this author’s recommendation that the offending drug be discontinued. Patients with true neuroleptic malignant syndrome may develop rhabdomyolysis-induced renal failure, which may be avoided with adequate hydration. Pulmonary function is crucial so that pulmonary toilet must be scrupulous. When rigidity is so severe that adequate ventilation is impeded or rhabdomyolysis is occurring, the patient should be sedated and paralyzed. Evaluation for infections must take place in parallel with treatment of neuroleptic malignant syndrome.

In Parkinson disease patients, a Japanese consensus conference recommends that the medication reduction that caused the malignant syndrome be restored, that bromocriptine 5 to 10 mg three times daily be added, and that dantrolene 80 mg intravenously three times daily be considered as well (36). Presumably other dopamine agonists may be substituted for bromocriptine. The rationale for dantrolene is that it relaxes muscles. It was useful for malignant hyperthermia, a calcium channel disorder. Dantrolene binds to a receptor to inhibit calcium release (98). Some recommendations have included steroids.

A rating scale for neuroleptic malignant syndrome has been proposed that may be used for following patients with the disorder (73). Although it is not intended for diagnosis, it may be supportive.

No agreed-on approach to treating neuroleptic malignant syndrome exists. There are no data comparing treatments. There is no agreement that treatment, other than supportive, is of any value. The algorithms that exist are not in agreement with each other. The following algorithm represents this author’s suggestion (Table 1).

Table 1. Treatment of Neuroleptic Malignant Syndrome

• Evaluate and treat infection. • Aim to lower core body temperature to 40 C as soon as possible. • Hydrate and alkalinize urine with sodium hydrogen carbolate solution. • If muscle rigidity is causing rhabdomyolysis and fever, then paralyze and sedate. • Does patient have neuroleptic malignant syndrome or neuroleptic malignant syndrome-like disorder with Parkinson disease?
	- If Parkinson disease, then resume drug that was discontinued; continue other Parkinson disease drugs. - If neuroleptic malignant syndrome, then:
		• If signs of catatonia, use intravenous lorazepam and switch to oral lorazepam. • If no signs of catatonia, then:
			- Add 5 mg bromocriptine three times per day (or equivalent) and increase as indicated to 15 mg three times per day; or, 1 to 3 mg/kg dantrolene to start, then 10 mg/kg per day total, given orally or intravenously in divided doses.

Outcomes

Treatment, even in a timely manner, may not reverse the course of the illness. Because the diagnosis rests on clinical grounds and many patients have concomitant infections, the cause of death may not be clear. It is also unknown what the course of the illness would be if untreated.

References

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All contributors' financial relationships have been reviewed and mitigated to ensure that this and every other article is free from commercial bias.

Author

Joseph H Friedman MD

Dr. Friedman, Chief, Division of Movement Disorders, Department of Neurology, at the Warren Alpert Medical School of Brown University and Stanley Aronson Chair in Neurodegenerative Disorders at Butler Hospital received consultant fees from EPI-Q.
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Editor

Robert Fekete MD

Dr. Fekete of New York Medical College received consultation fees from Acadia Pharmaceutical, Acorda, Adamas/Supernus Pharmaceuticals, Amneal/Impax, Kyowa Kirin, Lundbeck Inc., Neurocrine Inc., and Teva Pharmaceutical, Inc.
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Former Authors

Joseph Jankovic MD

Patient Profile

Age range of presentation: 0 month to 65+ years
Sex preponderance: male>female, >2:1
Heredity: heredity may be a factor
Population groups selectively affected: none selectively affected
Occupation groups selectively affected: none selectively affected

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Neuroleptic malignant syndrome

Associated Disorders

Myoglobinuria
Renal failure

Differential Diagnosis

infectious causes of fever
drug withdrawal syndromes (eg, delirium tremens, baclofen, drug interactions)
serotonin syndrome
lethal catatonia
acute generalized dystonic reaction
- malignant hyperthermia
- parkinsonism
- toxins (cholinergic, stimulant or salicylate overdoses)

Also Relevant

Acute drug-induced movement disorders
Catatonia
Coma due to drug intoxication
Drug-induced myopathies
Levodopa
- Malignant hyperthermia
- Movement disorder emergencies
- Myoglobinuria
- Serotonin syndrome
- Tolcapone

Clinical Categories

Movement Disorders

Neuroleptic malignant syndrome (NMS) …

Neuroleptic malignant syndrome

Introduction

Overview

Key points

Historical note and terminology

Clinical manifestations

Presentation and course

Prognosis and complications

Biological basis

Etiology and pathogenesis

Epidemiology

Prevention

Diagnostic workup

Management

Table 1. Treatment of Neuroleptic Malignant Syndrome

Outcomes

Special considerations

Pregnancy

Anesthesia

References

Contributors

Author

Editor

Former Authors

Patient Profile

ICD & OMIM codes

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Also in This Category

Hemifacial spasm

Wilson disease

Neuroacanthocytosis

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Dementia in Parkinson disease

ALS-like disorders of the Western Pacific

Sleep-related leg cramps

Sleep and cerebral degenerative disorders

Neuroleptic malignant syndrome

Introduction

Overview

Key points

Historical note and terminology

Clinical manifestations

Presentation and course

Prognosis and complications

Biological basis

Etiology and pathogenesis

Epidemiology

Prevention

Diagnostic workup

Management

Table 1. Treatment of Neuroleptic Malignant Syndrome

Outcomes

Special considerations

Pregnancy

Anesthesia

References

Contributors

Author

Editor

Former Authors

Patient Profile

ICD & OMIM codes

This is an article preview. Start a Free Account to access the full version.

Questions or Comment?

Also in This Category

Hemifacial spasm

Wilson disease

Neuroacanthocytosis

Restless legs syndrome

Dementia in Parkinson disease

ALS-like disorders of the Western Pacific

Sleep-related leg cramps

Sleep and cerebral degenerative disorders

This is an article preview.
Start a Free Account
to access the full version.