Ian M Whyte MBBS(Hons), FRACP, FRCPE, Gregory L. Carter, MBBS, FRANZCP, Cert Train Child Psych

Neuroleptic malignant syndrome (NMS) is an uncommon syndrome of adverse effects (fever, autonomic dysfunction and extrapyramidal movement disorder) classically described as being secondary to exposure to neuroleptic drugs. It has also been reported to occur in relation to exposure to other centrally acting dopamine blocking drugs or on withdrawal of dopamine agonist drugs and possibly on exposure to some other medications. Knowledge about this syndrome continues to accumulate in the medical literature although some controversies still remain. Because it is relatively uncommon and because the mild forms of the syndrome or early symptoms of the syndrome may fluctuate, its detection in the clinical setting can be difficult. There are no laboratory tests or scans, which are diagnostic. It remains a diagnosis based on clinical examination of the individual patient.

The first description of the syndrome is in the French literature as “syndrom malin” occurring as a side effect of haloperidol(1) with the first English paper being published in 1968(2). There are, however, descriptions of patients with lethal catatonia, which may present with an almost identical clinical picture, from well before the availability of neuroleptic agents. There continues to be some debate as to the delineation of the NMS from lethal catatonia on clinical and pathophysiological grounds. There has also been debate in the literature concerning the delineation of malignant hyperthermia from NMS, though this is now clearer with some of the receptor physiology of malignant hyperthermia having been resolved.(3)

NMS is due to a relative lack of dopamine at central post-synaptic receptors.(4) This may result from dopamine blockade or from inadequate dopamine production. Supporting evidence for this concept includes the occurrence of NMS on exposure to neuroleptic drugs whose prime mechanism of action is dopamine blockade.(4) NMS can also occur on therapy with other drugs with dopamine blocking action (e.g. metoclopramide(5)) and on sudden withdrawal of dopamine therapy in Parkinsonian patients.(4) When present, NMS usually responds to dopamine agonists.(6)

High affinity for dopamine D2 receptors in the striatum is characteristic of dopamine blocking drugs with a high risk of NMS. Atypical antipsychotics (e.g. clozapine) with lower affinities for dopamine D2 are less likely to cause NMS but may still do so.(7;8)
Serotonin can be an inhibitory neurotransmitter on presynaptic dopaminergic neurons with resultant decrease in dopamine release with increasing serotonin concentrations.(9;10) It is this mechanism that most likely underlies the observed episodes of NMS on therapy with SSRIs and some tricyclic antidepressants.

NMS is a drug-induced disorder. Incidence in patients on neuroleptic therapy is variously estimated as between 0.02% and 3.23%.(4) It predominantly occurs in the setting of administration of drugs that block dopamine receptors in the central nervous system but may also occur after sudden cessation or reduction of dopamine agonists in patients with idiopathic Parkinsonism. It is more likely to occur with exposure to high-potency neuroleptic drugs (e.g. haloperidol) but has been reported in low-potency neuroleptics (e.g. chlorpromazine) and the atypical neuroleptics (e.g. clozapine, risperidone, olanzapine(7;8)). Other drug groups with dopamine blocking activity such as antiemetics (e.g. metoclopramide) are also a potential cause. Most cyclic antidepressants (e.g. amitriptyline(11)) and drugs with serotonin reuptake activity (e.g. fluoxetine, venlafaxine(4)) have also had cases reported.

There are several factors associated with a higher risk of the development of NMS.(12;13) It is more common in young males with greater degrees of psychomotor agitation (particularly with affective disorders), especially if they have become dehydrated. Factors related to the neuroleptic include a neuroleptic dose in the first 24h of treatment and a maximum dose in any 24h equivalent to > 600 mg of chlorpromazine and depot neuroleptic administration. Patients requiring restraint or seclusion are at greater risk and there is an association with past ECT. Concurrent therapy with lithium and antidepressants increases risk and it is more common in patients with pre-existing brain damage.

NMS may occur from a single dose of a dopamine blocking drug but in these cases there does not seem to be a dose response present and NMS is extremely rare as a presenting feature of acute neuroleptic drug overdose.

The Diagnostic and Statistical Manual of Mental Disorders Edition IV (DSM-IV) outlines the diagnostic and research criteria for Neuroleptic Malignant Syndrome.(14)

The important elements are:

Criterion A
The development of severe muscle rigidity and elevated temperature associated with the use of neuroleptic medication.

Criterion B
Two (or more) of the following:
1. Diaphoresis
2. Dysphagia
3. Tremor
4. Incontinence
5. Changes in level of consciousness ranging from confusion to coma
6. Mutism
7. Tachycardia
8. Elevated or labile blood pressure

9. Leucocytosis
10. Laboratory evidence of muscle injury. (e.g., elevated CPK)
Criterion C
If the symptoms in criteria A & B are not due to another substance (e.g. phencyclidine) or a neurological or other general medical condition (e.g., viral encephalitis).

Criterion D
The symptoms in criteria A & B are not better accounted for by a mental disorder. (e.g., mood disorder with catatonic features).
A more useful operational definition requires some essential criteria and then makes the diagnosis based on the presence of major criteria with supporting evidence from some minor features.

Essential criteria
1. recent or current therapy with dopamine blocking drug (a neuroleptic or other drug eg metoclopramide) OR
2. recently stopped a dopamine agonist (eg L-dopa)

Major criteria (need all three to be present within a 24h period to make the diagnosis)
1. fever > 37.5oC (see below)
2. autonomic dysfunction (see below)
3. extrapyramidal features (see below)
Delirium is almost always present at some stage, is usually a hypoactive delirium, but is not essential to make the diagnosis. Fever is a major criterion, although cases of normal temperature and hypothermic variants have been reported. The presence of sepsis to account for fever should be considered, however the presence of sepsis does not exclude NMS as they can co-occur. It is possible that an episode of infection may precipitate an episode of NMS.

Autonomic dysfunction is present if there are 2 or more of the following:
1. hypertension or labile BP
1.1. systolic > 30 mmHg above baseline OR
1.2. diastolic > 20 mmHg above baseline OR
1.3. variability of > 30 mmHg systolic or >20 mmHg diastolic between readings
2. tachycardia (pulse > 30 bpm above baseline)
3. diaphoresis (intense - may be episodic)
4. incontinence
5. tachypnoea (> 25 breaths/min)

Extrapyramidal features are present if there are 2 or more of the following:
1. bradykinesia
2. lead-pipe or cogwheel rigidity
3. resting tremor
4. sialorrhoea
5. dysphagia
6. dysarthria/mutism

Additional features (which support but are not required to make the diagnosis) include:
1. rise in creatinine kinase
2. altered sensorium/delirium
3. leucocytosis > 15,000×109/L
4. low serum iron(15)

The diagnosis is also supported by a therapeutic response to a dopamine agonist (see management).

Perhaps the most common differential diagnostic situation is a neuroleptic induced extra-pyramidal syndrome (EPS) in a patient with concurrent sepsis eg. urinary tract infection exhibiting fever, tachycardia and other autonomic signs in addition to leucocytosis and sometimes delirium. Moreover the presence of a cause for sepsis does not exclude the possibility of NMS being present and having been precipitated by the infection.

The condition may be confused with serotonin toxicity. While both conditions have some clinical features in common, fever, autonomic hyperactivity, muscle rigidity, and delirium, they are, in fact, two very different conditions that have very different aetiologies (serotonin excess versus dopamine blockade) and are usually distinguished by history of medication exposure, physical examination and treatment response. Serotonin excess (serotonin toxicity) has a relatively rapid onset after a serotonergic drug and responds to serotonin blockade with drugs such as cyproheptadine and chlorpromazine. Dopamine blockade (Neuroleptic Malignant Syndrome) has a relatively slow onset after a neuroleptic drug and responds to dopamine agonists such as bromocriptine. Clinical features that distinguish between the two conditions are shown in Table 2 in the chapter on Serotonin Toxicity.

The differential diagnosis of NMS also includes causes of fever, leukocytosis, and rigidity. In a patient with fever, stiff neck, and altered mentation (all seen in NMS), meningitis must be ruled out. Other aetiologies to consider are primary central nervous system disorders including infections (viral encephalitis, AIDS, post-infectious encephalomyelitis), tumours, cerebrovascular accidents, trauma, seizures and major psychoses (lethal catatonia). Also important to consider are systemic disorders including infections, metabolic conditions, endocrinopathies (thyroid storm, pheochromocytoma), autoimmune disease (systemic lupus erythematosus), heat stroke and some toxins (carbon monoxide, tetanus, strychnine).

High risk patients (see above) should have blood pressure and pulse and any episodes of diaphoresis recorded regularly. On suspicion of NMS, assess for other illnesses and organize a complete blood count, biochemical analysis including creatine kinase and serum iron. On suspecting the diagnosis, all dopamine-blocking drugs must be withdrawn (or previously withdrawn dopaminergic therapy restarted).

Supportive care is important and the maintenance of adequate hydration is essential. If hyperpyrexia is extreme or ambient temperatures very high, cooling strategies can be used. Dysphagia may require appropriate feeding techniques. Pneumonic aspirations should be prevented where possible or treated promptly if they occur. Rhabdomyolysis with secondary renal failure may occur in severe cases as can cardiac arrhythmias, and intra-vascular coagulation syndromes. Non-pharmacological management of delirium should be employed for the delirious patient. (see chapter on Delirium)

Bromocriptine, a dopamine agonist, is very effective if the patient can take oral therapy.(6;16;17) It can be given by nasogastric tube if necessary. The dose is 2.5 mg every 8 hours up to 5 mg every 4 hours. Titration of dosage to clinical response is important for the individual patient. Dosages of 50 mg per day are occasionally needed. Clinical response should be rapid, with resolution of the fever and autonomic instability within 24 hours and clear improvement in the extrapyramidal features within 48 hours. Resolution of the delirium may take several days longer than the resolution of the autonomic and extrapyramidal symptoms. Bromocriptine should be continued for 7-10 days after resolution of NMS with tapering over a further week or two (even longer therapy is required when the causal agent is a depot neuroleptic preparation).

In the patient with extreme rigidity, very high fever (> 40oC), or unable to tolerate oral treatment, dantrolene in a dose of 2-3 mg/kg should be used until oral bromocriptine can be started.(18) If these pharmacological measures fail, the diagnosis should be reassessed and if NMS or lethal catatonia is still likely the ECT has been used successfully in treatment. (19;20).

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IMW & GC 31/1/04 This article has been used (with permission of MediTox Pty Ltd) as the basis of a chapter on neuroleptic malignant syndrome in the third edition of Medical Toxicology published by Lippincott Williams Wilkins, 2004.