Neuroleptic Malignant Syndrome (Nms)

Essentials

• The possibility of neuroleptic malignant syndrome should be kept in mind in patients on antipsychotic medication with
  • fever
  • extrapyramidal symptoms
  • disturbances in the function of the autonomic nervous system
  • disturbances of consciousness
  • leucocytosis or an increase in the plasma creatine kinase (CK) concentration as an additional laboratory finding.
• NMS may occur with any type of antipsychotic drug and also with metoclopramide.
• Other disorders causing clouding of consciousness, confusion and elevation of body temperature should be excluded.
• Restarting antipsychotic medication after NMS requires the opinion of a specialist.

Epidemiology

• The incidence of NMS is approximately 0.01-0.02% of persons taking antipsychotic medication. The adverse effect usually develops soon after initiation of an antipsychotic drug or after a major change in the dosage.
• NMS may also be caused by metoclopramide and newer antipsychotic drugs.

Clinical picture

• Probable NMS can be diagnosed if the patient has two of the main symptoms listed below together with either clouding of consciousness, leucocytosis or an increased plasma creatine kinase concentration.

1. Hyperthermia: body temperature over 37.5°C without an alternative explanation
2. Severe extrapyramidal symptoms; at least two of the following:
   • rigidity (often the dominant symptom in addition to fever)
   • oculogyric crisis (dystonia of the eye muscles)
   • opisthotonus
   • retrocollis
   • trismus
   • choreoathetotic movements
   • dyskinesias
   • failure to eat, inability to swallow)
   • salivation.
3. Disturbances of the autonomic nervous system:
   • elevation or changes in blood pressure
   • tachycardia
   • tachypnoea
   • profuse perspiration
   • incontinence or urinary retention.

Laboratory investigations

• Changes in laboratory parameters are not diagnostic. The most commonly seen changes are:
  • increased concentration of plasma creatine kinase (in about two thirds of cases)
  • leucocytosis
  • elevation of the haematocrit due to dehydration.
• In addition, the patients may have electrolyte or acid-base imbalance (towards respiratory or metabolic acidosis).
• Plasma creatine kinase monitoring is advisable, as normalization of the level indicates a favourable treatment response.

Differential diagnosis

• It is important to exclude other disorders featuring clouding of consciousness, confusion and elevation of body temperature.
  • Meningitis, encephalitis (cerebrospinal fluid tap, CT/MRI scan of the head)
  • Malignant hyperthermia (related to anaesthesia)
  • Lethal catatonia in a schizophrenic patient. The condition is preceded by extreme agitation and hallucinations. Muscle rigidity, abnormal postures and stupor develop later. The condition is often difficult to distinguish from NMS. Electroconvulsive therapy is beneficial.
  • Thermal paralysis in patients receiving anticholinergics. There is no sweating, rigidity or increase in plasma creatine kinase.
  • Central anticholinergic syndrome is a condition brought on by excessive use of anticholinergic drugs and some psychopharmaceuticals. Symptoms include confusion, agitation, convulsions and mild elevation of body temperature. The pupils are wide, skin dry and reddened, mouth dry. Tachycardia, urinary retention and dull bowel sounds are typical.
• Serotonin syndrome is a condition resembling NMS caused by concurrent use of antidepressants inhibiting serotonin reuptake (SSRIs)and MAO inhibitors. Symptoms include fever, tremor, confusion, restlessness, rigidity, myoclonus,and epileptic seizures. The patient may also be predisposed to the serotonin syndrome by concurrent use of tramadol or a triptan-type antimigraine drug and an SSRI. The condition is managed by stopping serotonergic drugs.

Treatment

• Mild cases can be managed in primary care if laboratory follow-up can be arranged.
  • Cessation of the antipsychotic drug
  • Administration of fluids and monitoring of renal functioning (observe for rhabdomyolysis Rhabdomyolysis and renal failure)
  • Body temperature control by giving antipyretics and by mechanical means
  • Respiratory support
  • Treatment of infections (aspiration pneumonia may be present)
  • Laboratory follow-up
  • Drug treatment with bromocriptine (or dantrolene)
    • The recommended starting dose of bromocriptine is 5 mg 3 times daily. The dose is increased by 15 mg/day monitoring the response (alleviation of muscle rigidity, fall in body temperature and plasma creatine kinase level) to a level at which the symptoms of NMS have been alleviated (up to 20 mg 3-4 times daily). After the symptoms have been relieved, the medication is continued for 10 days and thereafter tapered down.
• During the syndrome, restlessness can be treated with benzodiazepines intravenously. If catatony is suspected, eletroconvulsive therapy should be considered. Anticholinergics have not been proven effective.

Treatment after NMS

• Restarting antipsychotic medication after NMS takes place at discretion of a specialist. It is advisable to wait at least 2-4 weeks after the symptoms have subsided before the medication is restarted. The new antipsychotic drug is chosen from another chemical class than the one that caused the syndrome.

Pharmacovigilance

• NMS is a severe treatment complication that should be reported to the national drug authority. Find out about local requirements