Neuroleptic Malignant Syndrome

Synonyms: NMS, malignant neuroleptic syndrome

This is a rare but potentially life-threatening idiosyncratic reaction to neuroleptic drugs. It causes fever, muscular rigidity, altered mental status and autonomic dysfunction. Although the syndrome is usually associated with potent neuroleptics such as haloperidol and fluphenazine, other drugs or changes in drug regimen that antagonise central dopamine D2 receptors may occasionally cause it. 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. The condition shares many features with the serotonin syndrome and malignant hyperpyrexia. It presents a diagnostic challenge.

• Incidence is very low and probably falling because of decreased use of older antipsychotics, preventive measures and an increase in awareness.¹
• The exact incidence is difficult to calculate but is estimated to range from 0.02 to 2.4% with conventional antipsychotics, and a much lower incidence for atypical antipsychotics.²
• A large Chinese randomised controlled trial showed an incidence of 0.12% of patients taking neuroleptics, and an Indian study gave a similar incidence of 0.14%.³
• Incidence is higher in those under 40 years old, probably reflecting use of antipsychotics.³

Symptoms

• NMS is most common after initiation or increase in dosage of neuroleptic therapy and in 90% of cases this occurs within 10 days.¹
• The onset is usually gradual over 1 to 3 days and tends to occur within 4 weeks of starting or increasing neuroleptic medication. However, it can occur at any time in those taking neuroleptics.
• Symptoms can persist for up to 5 to10 days after discontinuation of offending drug, or longer if depot medication.
• There is always a history of taking neuroleptics or other relevant agents within the last 4 weeks.
• 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.

Signs

• There will be hyperthermia with temperature > 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 BP, excessive sweating/salivation, tremor and incontinence.

• Simple dystonic/akathisia reaction to neuroleptics (usually responds rapidly to anti-cholinergics)
• Serotonin syndrome
• Malignant hyperpyrexia
• Recreational drug toxicity, especially cocaine, amphetamines, MDMA (ecstasy)
• Phenothiazine-related heat stroke (no rigidity and absence of sweating, the cause of pyrexia in this condition)
• Lethal catatonia (rare psychiatric syndrome – catatonia with rigidity ± raised CK, usually no autonomic involvement or involuntary movement)
• Organophosphorous poisoning
• Heat stroke
• 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)

• Full blood count often shows leucocytosis.
• Urea and electrolytes may show metabolic disturbance due to acidosis or renal failure.
• Arterial blood sample to assess acid-base balance.
• Liver function tests may show elevated transaminases and lactate dehydrogenase (LDH) of muscle origin.
• Creatine kinase is usually elevated.
• Urine myoglobin should be checked.
• Coagulation studies (particularly prothrombin time, activated partial thromboplastin time and international normalised ratio or INR) should be checked (to detect coagulopathy).
• A urinary drug screen should be performed (particularly for salicylates, cocaine and amphetamines).
• If sepsis is suspected then blood and other relevant cultures should be taken.
• Imaging may be indicated:
  • CXR should be considered if sepsis suspected.
  • CT of head in order to exclude other diagnoses.
• Lumbar puncture may be required to exclude other diagnoses (particularly where there is fever and altered mental status). There are no significant CSF findings in NMS other than raised protein.

• Airway and breathing need to be protected if evidence of compromise. Severe cases may require circulatory and ventilatory support.
• Agitated patients require intravenous benzodiazepines. Physical restraint is best avoided or minimised as it can worsen the hyperthermia.
• The offending drug should be discontinued.
• Intravenous fluids should be given for dehydration.
• If there has been a recent overdose of the agent then activated charcoal may help to prevent absorption.
• Cooling devices and antipyretics are used to treat hyperthermia.
• If rhabdomyolysis and renal failure occur then acidification of urine and dialysis is often required.
• Dopaminergic drugs such as bromocriptine and amantadine, and muscle relaxants such as dantrolene sodium are frequently used in severe cases, but there is little empirical evidence for their efficacy. However, there are many anecdotal reports of their usefulness.
• ECT is sometimes used if medication fails to improve condition and there appears to be some evidence to support its use.^11,12,13

• Overall prognosis appears to be improving as a result of earlier recognition and intervention.
• The mortality is difficult to estimate because of under-reporting but is thought to be as high as 20%.³
• If renal failure occurs then mortality can be as high as 50%.¹
• The outlook is good on the whole if there is:
  • Early recognition of the condition
  • Adequate supportive care and treatment
  • No complications

• Cardiac arrest
• Rhabdomyolysis
• Renal failure
• Seizures
• Respiratory failure
• Disseminated Intravascular Coagulation
• Aspiration pneumonitis
• Deterioration in psychiatric condition due to drug withdrawal
• Infection
• Hepatic failure
• Pulmonary embolism

• Awareness of 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 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 a Medic Alert pendant.