OVERVIEW: What every practitioner needs to know

Are you sure your patient has neuroleptic malignant syndrome? What are the typical findings for this syndrome?

Neuroleptic Malignant Syndrome (NMS), a life-threatening adverse reaction to anti-dopaminergic (D2 antagonist) drugs, is characterized by fever, rigidity, and mental status changes. Although this syndrome has been characterized as an idiosyncratic drug reaction, there is some evidence to suggest that it is caused by a pharmacologically explained decrease in central dopaminergic activity. The most common etiologic agents for this syndrome are the classic antipsychotic medications such as haloperidol and chlorpromazine; however, many dopamine antagonists have been indicated, including atypical antipsychotic medications such as olanzapine, as well as metoclopramide, promethazine, and similar agents.

Rapid recognition, accurate diagnosis, and initiation of therapy are essential to prevent morbidity and mortality from NMS. Immediate treatment includes withdrawal of any possible etiologic agent, supportive measures such as cooling and hydration, and expert consultation regarding the use of dopaminergic agents such as bromocriptine. A critical care environment should be considered for ongoing care for the patient with NMS. Even with appropriate therapy, up to 10% of patients with NMS may not survive.

The most common findings in patients diagnosed with NMS include muscle rigidity, mental status alteration, and fever (often >40°C). Other findings which may be present are tremor, hypermetabolism (tachypnea and tachycardia), and dysautonomia (including but not limited to blood pressure lability and abnormal thermoregulatory mechanisms). If the patient has advanced disease with rhabdomyolysis, hematuria/myoglobinuria may also be present at diagnosis.

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What other disease/condition shares some of these symptoms?

NMS is a diagnosis of exclusion, in that several other life-threatening/malignant syndromes must be confidently ruled out. NMS is most commonly confused with Malignant Hyperthermia (MH), an anesthetic-related emergency which is also characterized by fever, rigidity, and hypermetabolism. Differentiating these two conditions is essential, because MH has a very high mortality if not diagnosed and treated rapidly; even with appropriate treatment with dantrolene, mortality from MH may be up to 20%.

Distinguishing these two disorders may be most often accomplished by a careful history; patients with MH will almost universally have a history of recent (within hours) exposure to a so-called “MH triggering agent”, including the potent inhalational anesthetic medications (sevoflurane, isoflurane, etc) or the depolarizing neuromuscular blocking agent succinylcholine. Importantly, non-depolarizing agents (vecuronium, rocuronium, and other curare derivatives) do not trigger MH reaction. On the other hand, patients with NMS generally have a history of recent (within days to weeks) initiation or dosage-increase of an anti-dopaminergic agent such as the antipsychotic medication haloperidol.

While similar, the signs and symptoms of NMS and MH are not identical. The fever in MH represents severe hypermetabolism which leads to extreme hyperthermia (>42°C) associated with rhabdomyolysis and death within hours if not treated. Also, because an episode of MH is characterized by a muscle abnormality with tonic contraction, neuromuscular blocking agents will not alleviate rigidity because they act at the neuromuscular junction. In contrast, data are unclear regarding the etiology of the fever in NMS; in any case, the fever is generally not as high nor as rapidly progressive as that of MH. The rigidity associated with NMS is universally abolished by chemical neuromuscular blockade, although the use of these agents in NMS is generally not indicated.

Other important conditions on the differential diagnosis of NMS include: meningitis/meningoencephalitis, which may present with fever, alteration of mental status, and rigidity in the neck; sepsis, which may present with high fever and altered mental status generally not associated with rigidity; non-convulsive (or convulsive) status epilepticus, which is generally more abrupt in onset and only rarely associated with fever; tetanus, which causes rigidity in the absence of fever or mental status changes; and heatstroke, a condition associated with environmental exposure to dehydration and high temperatures and characterized by hyperthermia, altered mental status, and flaccidity rather than rigidity.

What caused this disease to develop at this time?

The most commonly cited etiology of NMS is recent exposure to a central dopamine (D2) receptor antagonist. In many cases a new medication may have been started within the 24-48 hours prior to onset of symptoms. In nearly all cases of NMS, a new or higher dose of medication was initiated within the preceding 30 days. NMS has also been reported after withdrawal of dopaminergic agents such as levodopa, and rarely as a consequence of severe other systemic disease such as end-stage malignancy (presumably due to secretion of an unidentified antidopaminergic substance).

Risk is increased with high total dosage or rapid escalation of antipsychotic therapy. Environmental factors such as exposure-related hyperthermia and/or dehydration may play a role in triggering symptoms of NMS in susceptible patients. Although the majority of NMS cases occur in males, this does not necessarily represent an increased incidence because there is a parallel increase in the usage of antipsychotic medications in males.

What laboratory studies should you request to help confirm the diagnosis? How should you interpret the results?

There is no specific laboratory test for NMS that is able to confirm the diagnosis. Helpful blood testing which supports a diagnosis of NMS includes elevation of creatinine phosphokinase and free serum myoglobin caused by muscle injury, thrombocytosis, leukocytosis, and relative polycythemia due to dehydration, elevation of creatinine caused by dehydration and possibly rhabdomyolysis-related renal failure, and low serum iron which is likely related to the acute phase response. Note that many of these may also be elevated in MH reactions.

Urine testing may show the presence of hemoglobin in the absence or red blood cells. Urine testing for myoglobin may also be helpful. Cerebrospinal fluid analysis should be considered to rule out evidence of central nervous system infection.

Would imaging studies be helpful? If so, which ones?

There are no imaging studies helpful in the diagnosis of NMS; however, to aid in the elimination of other disorders from the differential diagnosis, it is reasonable to consider chest radiography to evaluate for a primary cause of tachypnea and fever, brain imaging to rule out occult trauma or a central nervous system malignancy, and electroencephalography to rule out convulsive or nonconvulsive status epilepticus.

If you are able to confirm that the patient has neuroleptic malignant syndrome, what treatment should be initiated?

On the diagnosis of NMS, treatment should be initiated without delay and expert consultation should be obtained. First, any possible etiologic agent should be discontinued immediately. Supportive measures should be initiated, including aggressive hydration and active cooling. In many cases, transfer of the patient to a critical care environment for ongoing monitoring and care will be beneficial.

There is considerable debate about the use of pharmacologic therapy in NMS; expert consultation (see above) will aid in a discussion of the risks and benefits for any individual patient. Agents which may be considered include dopaminergic agents such as bromocriptine, benzodiazepines such as lorazepam, and the muscle relaxant dantrolene.

Following the initial treatment and consultation, ongoing care issues include neurologic monitoring, ongoing evaluation for an alternative diagnosis, and serial urine and serum testing for evidence of rhabdomyolysis, which may develop despite appropriate therapy. Maintenance of adequate hydration is essential, and some experts have advised alkalinization of the urine with sodium bicarbonate for enhanced renal excretion of myoglobin, although this practice is now controversial and may not be beneficial.

Long term issues to remember include the need for ongoing psychiatric evaluation and medication management, and expert guidance regarding the risks and benefits of a rechallenge with antipsychotic medications for patients who require them. If performed, this rechallenge should be preceded by thorough informed consent of the patient and family, as well as adequate education about the symptoms and signs of recurrence of NMS.

What are the adverse effects associated with each treatment option?

Bromocriptine is an ergot alkaloid-derived D2 receptor agonist which also activates serotonin (5-HT2A) receptors. Mild side effects include worsened hyperthermia, central nausea, headaches, and orthostatic hypotension. Severe side effects may include coronary vasospasm, hepatic dysfunction, pulmonary fibrosis, and psychosis.

Benzodiazepine medications act as GABA-receptor agonists, and may be associated with sedation or respiratory depression, as well as paradoxical excitation reactions (particularly in patients with psychiatric comorbidities). Intravenous formulations of diazepam and lorazepam contain propylene glycol which in large doses may cause renal insufficiency; their use in patients with rhabdomyolysis-induced renal failure should be judicious.

Dantrolene is a muscle relaxant chemically derived from phenytoin (but lacking antiepileptic activity) which may cause severe weakness, respiratory failure, and hepatotoxicity. Its use is contraindicated in patients taking calcium channel blockers, as the combination may result in cardiovascular collapse.

What are the possible outcomes of neuroleptic malignant syndrome?

As implied by its name, NMS is malignant: untreated, the mortality from an episode is approximately 30%. With supportive therapy and withdrawal of causative agents, mortality is reduced to less than 10% and appears to be lower with each passing decade; most patients experience full recovery within 14 days with discontinuation of offending agent and supportive care. The most significant long-term sequelae of disease among survivors are rhabdomyolysis-induced renal failure and permanent neurocognitive dysfunction. Other complications include ICU-acquired infections (sepsis and pneumonia) and immobilization-related venous thromboembolism. The family should be advised about the expected prognosis as well as the possible long term sequelae (including death) and updated at regular intervals regarding progression of disease.

What causes this disease and how frequent is it?

NMS is caused by exposure to antidopaminergic medications in susceptible patients. The precise incidence is unknown but has decreased due to the diminishing use of potent (“typical”) antipsychotic medications. Previous reports indicated an incidence of up to 3% among patients treated with antipsychotic medications. More recent estimates based on large studies appear to reflect a much lower incidence, approximately 0.02% of patients, resulting in an estimated 2000 cases of NMS annually in the United States.

Why certain patients appear to be susceptible while others are not is poorly understood. Furthermore, some patients will develop symptoms of NMS after a dosage change to a longstanding medication or even in the absence of any recent dosage change. Experts have speculated that perhaps there is abnormal dopaminergic activity at baseline in the brains of certain patients with psychotic disorders, and that this may contribute to the appearance of NMS, but few data exist to support this hypothesis yet.

Genetic studies of NMS have been inconclusive thus far despite reports of familial patterns in the literature.

How do these exposures cause this disease?

The exact pathogenesis of symptoms in NMS is unknown. The leading hypothesis regarding the causative mechanism of antidopaminergic medications in NMS is central dopamine deficiency due to dopamine receptor blockade in the central nervous system. This hypothesis is based on the known pharmacologic effects of the antipsychotic medications, as well as the pharmacologic link between these medications and others which have also caused NMS. Additionally, reports of clinical improvement with bromocriptine (a dopamine agonist) support this hypothesis, although reports have been inconsistent.

This pharmacologic hypothesis has led some authors to refute the concept that NMS is an idiosyncratic syndrome; by definition, idiosyncratic reactions do not have a pharmacologic basis of effects.

What complications might you expect from this disease or its treatment?

In addition to the complications noted above, one of the major complicating factors for this disease stems from the nature of the affected patient population.Psychotic patients may become hazardous to themselves or others in the absence of therapy. Patients must be monitored carefully for signs of worsening psychiatric diseases and care should be managed by an appropriate psychiatric specialist.

Additionally, drug reactions to bromocriptine, benzodiazepines, or dantrolene may occur as noted above. Lasting effects of NMS may include rhabdomyolysis-induced renal failure and irreversible neurocognitive deficits. The remainder of the clinical findings generally resolve with therapy.

Are additional laboratory studies available; even some that are not widely available?

There is no specific laboratory testing for NMS. Genetic studies have been inconclusive thus far.

How can neuroleptic malignant syndrome be prevented?

NMS cannot be prevented in all patients without a better understanding of the mechanisms of the disease. However, the incidence has decreased with declining use of the potent antipsychotic medications. When possible, avoidance of these medications and substitution of “atypical” antipsychotic medications may result in a decreased risk. Although causative relationships have not been elucidated, it may be prudent for patients on antidopaminergic agents to avoid excessive environmental heat as well as dehydration (when feasible), which have been associated with NMS in some patients.

In patients with a known history of NMS, recurrence can be prevented by avoidance of antidopaminergic medications. For patients with psychosis in whom therapy is essential, reintroduction of medical therapy should be at least 2 weeks after recovery from NMS, and only with the informed consent of patient and family. Generally a small test dose of medication is administered, followed by very slow dose escalation with careful observation for symptoms of NMS. This process should generally be guided by a psychiatric professional.

What is the evidence?

Selected bibliography for further reading:

Croarkin, PE, Emslie, GJ, Mayes, TL. “Neuroleptic malignant syndrome associated with atypical antipsychotics in pediatric patients: a review of published cases”. J Clin Psychiatry. vol. 69. 2008. pp. 1157-65. (A review of NMS and its association with atypical antipsychotic medications; although overall lower risk than typical antipsychotics, the atypical medications are responsible for a larger number of cases due to increased prescribing practices.)

Tse, L, Barr, AM, Scarapicchia, V, Vila-Rodriguez, F. “Neuroleptic malignant syndrome: a review from a clinically oriented perspective”. Curr Neuropharmacol. vol. 13. 2015. pp. 395-406. (A recent review of NMS, including discussion of an expanded list of causative agents, mechanistic theories, management and complications, and outcomes.)

Margetic, B, Margetic, BA. “Neuroleptic malignant syndrome and its controversies”. Pharmacoepidemiol Drug Saf. vol. 19. 2010. pp. 429-35. (A review of past and present controversies in NMS.)

Strawn, JR, Keck, PE, Caroff, SN. “Neuroleptic malignant syndrome”. Am J Psychiatry. vol. 164. 2007. pp. 870-6. (A well-written review article containing more in-depth explanations of many of the concepts introduced in this section.)

Modi, S, Dharaiya, D, Schultz, L, Varelas, P. “Neuroleptic malignant syndrome: complications, outcomes, and mortality”. Neurocrit Care. vol. 24. 2016. pp. 97-103. (A recent update of falling mortality and improving outcomes in adults with NMS.)

Ongoing controversies regarding etiology, diagnosis, treatment

Ongoing controversies in NMS include a discussion of whether or not NMS is an idiosyncratic reaction (see above), the diagnostic criteria for NMS, and the optimal therapy for NMS.

Many diagnostic criteria have been proposed and used in the clinical and research settings. Even the relatively objective criterion of the temperature elevation necessary for the diagnosis of fever varies greatly between diagnostic guidelines. Other criteria are far more subjective and have considerable variation in relative importance among the various published guidelines, making meta-analyses and comparative therapeutic studies difficult.

Optimal therapy may or may not include a dopaminergic agent, a benzodiazepine, and/or dantrolene. Studies of these agents have all shown variable outcomes, possibly related to the inconsistent diagnostic criteria as noted above. Bromocriptine has secondary effects as a serotonin 5-HT2A agonist, an effect which theoretically may worsen hyperthermia. A newer agent, Apomorphine, has dopamine agonist activity paired with 5-HT2A antagonism, and may prove more consistently effective. This agent is presently being evaluated for clinical use.

Electroconvulsive therapy (ECT) has been advocated by some authors for the treatment of NMS. Although its use is controversial and may be dangerous, there are limited data suggesting a potential benefit particularly in cases of NMS associated with catatonia. Further study in this area is needed before recommendations can be made for or against the use of ECT for NMS.