Neuroleptic malignant syndrome

Synonym: malignant neuroleptic syndrome

What is neuroleptic malignant syndrome?¹

Neuroleptic malignant syndrome (NMS) is a rare but potentially life-threatening idiosyncratic reaction to antipsychotic drugs. It causes fever, muscular rigidity, altered mental status and autonomic dysfunction. The syndrome is usually associated with potent neuroleptics such as haloperidol and fluphenazine.

The underlying pathological abnormality is thought to be central D2 receptor blockade or dopamine depletion in the hypothalamus and nigrostriatal/spinal pathways. This leads to an elevated temperature set-point, impairment of normal thermal homeostasis and extrapyramidally induced muscle rigidity. However, this does not explain why it sometimes occurs with low-potency neuroleptic drugs or other medication without known antidopaminergic activity.

It is thought that other mechanisms such as changes in skeletal muscle calcium metabolism or sympathoadrenal hyperactivity may be involved. The condition shares many features with the serotonin syndrome and malignant hyperpyrexia. It presents a diagnostic challenge.

How common is neuroleptic malignant syndrome? (Epidemiology)²

• Incidence ranges from 0.01% to 3.2% of patients taking neuroleptic medications - the incidence has fallen over the years because newer agents are less likely to cause NMS.

• Incidence is higher in those aged under 40 years and in males, probably reflecting the usual age of first use of antipsychotics. However, it can occur at any age in patients receiving precipitating medication.

Risk factors for developing neuroleptic malignant syndrome²³⁴

The main risk factor is that neuroleptic medication has been initiated, or the dose increased. High doses or depot preparations carry a higher risk than lower doses and oral preparations. Risk is increased by the following factors:

• Use of neuroleptic drugs and genetic/metabolic susceptibility.

• Rapid withdrawal of anti-Parkinsonian medication, or switching from one anti-Parkinsonian medication to another - this can cause NMS in the absence of antipsychotic use.

• High ambient temperature and dehydration appear to increase risk of the syndrome.

• Excessive exercise.

• Agitation.

A previous episode of neuroleptic malignant syndrome significantly increases the risk of a future similar reaction; 15-20% of patients who have NMS have had a prior episode.⁵

Less commonly, use of other agents with central D2 receptor antagonist activity may cause the syndrome:

• Prochlorperazine.

• Promethazine.

• Atypical antipsychotics such as clozapine, risperidone.

• Anticholinergic drugs.

• Metoclopramide.

• Amoxapine (tricyclic now discontinued).

• Lithium.

Symptoms of neuroleptic malignant syndrome

²

• Patients may report dyspnoea (due to hypoventilation caused by muscle rigidity), dysphagia or difficulty walking with the development of a shuffling gait.

• There may be increasing tremor or involuntary movements.

• Rarely, there may be oculogyric crises, opisthotonos, seizures or chorea.

• The onset is usually gradual over 1 to 3 days and tends to occur within four weeks of starting or increasing neuroleptic medication, with 90% of cases occurring within 10 days. However, it can occur at any time in those taking neuroleptics. There is always a history of taking neuroleptics or other relevant agents within the preceding four weeks.

• Symptoms can persist for up to 5 to 10 days after discontinuation of the offending drug, or longer if depot medication has been used.

Signs

• There will be hyperthermia with temperature above 38°C.

• Muscular rigidity (lead-pipe type) will always be present.

• There is likely to be an alteration in mental status with confusion or agitation and altered consciousness.

• Autonomic instability may manifest as pallor, tachycardia, fluctuating blood pressure, excessive sweating/salivation, tremor and incontinence.

Diagnostic features of neuroleptic malignant syndrome

Major criteria (all must be present).

• Neuroleptics within 1 to 4 weeks.

• Hyperthermia (above 38°).

• Muscle rigidity.

Minor criteria (at least two needed).

• Changed mental status.

• Tachycardia.

• Hypotension or hypertension.

• Tremor.

• Incontinence.

• Diaphoresis (excessive sweating) or sialorrhoea.

• Increased creatine phosphokinase (CPK) or urinary myoglobin.

• Elevated white cell count.

• Dysphagia.

• Mutism.

Differential diagnosis

• Simple dystonic/akathisia reaction to neuroleptics (usually responds rapidly to anticholinergics).

• Serotonin syndrome.

• Malignant hyperpyrexia.

• Recreational drug toxicity, especially cocaine, amphetamines, 3,4-methylenedioxy-N-methylamphetamine (MDMA) - also known as 'ecstasy'.

• Phenothiazine-related heatstroke (no rigidity and absence of sweating, the cause of pyrexia in this condition).

• Lethal catatonia (rare psychiatric syndrome - catatonia with rigidity ± raised creatine kinase (CK), usually no autonomic involvement or involuntary movement).

• Organophosphate poisoning.

• Heatstroke.

• Encephalitis (including herpes simplex encephalitis and rabies).

• Hyperthermic reaction to monoamine-oxidase inhibitors.

• Polymyositis.

• Rhabdomyolysis.

• Other forms of poisoning (for example, strychnine).

• Other drug toxicity (anticholinergics, selective serotonin reuptake inhibitors).

Diagnosis of neuroleptic malignant syndrome (investigations)^{3 2}

• Neuroleptic malignant syndrome is best considered as a medical emergency; any suspicion of NMS should prompt secondary care referral.

• Investigations may show raised white cell count, CK and liver transaminases, metabolic acidosis, hypokalaemia, raised CK, urine myoglobin and a coagulopathy.

• Other tests such as a CT scan, lumbar puncture and chest x-ray are mainly aimed at excluding other differentials.

Treatment of neuroleptic malignant syndrome^{6 2}

⁷

• Management is always in secondary care. Airway and breathing need to be protected if there is evidence of compromise. Severe cases may require circulatory and ventilatory support.

• Intravenous fluids and benzodiazepines might be used and the patient may be cooled to reduce the hyperthermia.

• If there has been a recent overdose of the agent then activated charcoal may help to prevent absorption.

• Agitated patients require intravenous (IV) benzodiazepines. Physical restraint is best avoided or minimised, as it can worsen the hyperthermia.

• The offending drug should be discontinued.

• IV fluids should be given for dehydration.

• Electroconvulsive therapy (ECT) is sometimes used if medication fails to improve the condition and there appears to be some evidence to support its use.

Prognosis³

Mortality has reduced from 20-30% and is now reported as less than 10%. Death is usually caused by cardiovascular collapse, respiratory failure, myoglobinuric acute kidney injury, arrhythmias or diffuse intravascular coagulation. Morbidity results from respiratory failure, acute kidney injury, seizures and arrhythmia.

Respiratory changes, severity of hyperthermia, and older age have been found to be associated with a higher mortality.¹

If acute kidney injury develops during an episode of neuroleptic malignant syndrome this increases mortality up to 50%.

Once oral neuroleptics are stopped, the condition can last for 2-14 days; for depot neuroleptics, the period may be up to 21 days.

The outlook is good on the whole if there:

• Is early recognition of the condition.

• Is adequate supportive care and treatment.

• Are no complications.

Complications of neuroleptic malignant syndrome^{3 8}

• Cardiac arrest.

• Rhabdomyolysis.

• Acute kidney injury.

• Seizures.

• Respiratory failure.

• Disseminated intravascular coagulation.

• Aspiration pneumonitis.

• Deterioration in psychiatric condition due to drug withdrawal.

• Infection.

• Hepatic failure.

• Pulmonary embolism.

Prevention of neuroleptic malignant syndrome

• Awareness of the condition and consideration of the diagnosis in those with relevant symptoms, on neuroleptics, is central to early diagnosis.

• Monitoring for features of the syndrome after changes in neuroleptic medication can assist early diagnosis.

• Early diagnosis and withdrawal of any offending drug will arrest development of worsening symptoms.

• It is important to give a warning of the risk of recurrence. Patients should be actively encouraged to inform healthcare providers of their susceptibility and given good written information to assist in this process. There is a very good case for use of medical emergency identification jewellery or similar.