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John is a 29-year-old man who’s had chronic paranoid schizophrenia since he was 24. He presents to the emergency room in an agitated state; he hadn’t been taking his medication for the previous month and was living on the street for the last two weeks. He’s experiencing terrifying auditory hallucinations of persecutory voices and was disorganized in his behaviour and speech. A drug screen is negative. He received two intramuscular injections of haloperidol over the course of 9 hours to quell his agitation.
The next morning John is found to be confused; he’s disoriented and doesn’t know where he is. He’s rigid and his arms and legs are shaking. He’s sweaty and breathing rapidly.
- pulse: 148 beats per minute
- blood pressure: 150/95 mmHg
- rectal temperature: 40.1°C degrees
- white count: elevated at 15,000 cells/ml with excess neutrophils
- creatine kinase: 42,000 IU
- serum transaminases: elevated
- BUN: normal
- electrolytes: normal
- creatinine: all normal
- chest x-ray: normal
- lumbar puncture: negative
- blood: normal
- urine cultures: normal
- CT of the head: negative.
Diagnosis
Neuroleptic malignant syndrome (NMS) is an unpredictable and possibly fatal reaction to antipsychotic drugs, particularly “typical” antipsychotics such as haloperidol.
Key features
- acute change of mental status
- severe muscle rigidity beyond common parkinsonian reactions to these drugs
- autonomic arousal after the recent administration of an antipsychotic drug
- fever
History
- physical exhaustion and dehydration preceding the development of NMS are common
- changes in mental status and neurological symptoms precede the systemic signs of fever and muscle rigidity in 80% of cases
- 16% of cases develop within 24 hours of initiation of antipsychotic treatment
- 66% develop within the first week
- NMS always develops within the first month
Differential diagnosis
NMS is a diagnosis of exclusion.
- infections and agitated delirium (from drugs such as cocaine and amphetamine, including Ecstasy) can cause similar symptoms
- benign extrapyramidal reactions can look like NMS
- heatstroke can be very hard to distinguish from NMS, although the history of heat exposure may help as well as muscle flaccidity rather than rigidity
- Serotonin syndrome, which can be caused by selective serotonin and dopamine re-uptake inhibitors, older antidepressants — tricyclics and monoamine oxidase inhibitors — as well as triptans used to treat migraines. This usually presents as an agitated delirium but severe cases can be hard to distinguish from NMS.
Risk factors
Conventional, high-potency antipsychotics carry the greatest risk. The danger increases with total dose as well as intramuscular administration. Rare cases of NMS have been reported with some atypical antipsychotics, including clozapine, olanzapine and risperidone; clear cases with quetiapine are rare.
Management
The pathophysiology is not known.
- Treatment is to stop the antipsychotic and to restore fluids.
- There is no consensus on the use of medication to treat less extreme cases of NMS. Lorazepam is sometimes used, as are dopamine agonists such as amantadine. Dantrolene, a muscle relaxant useful in malignant hyperthermia, is used in more severe cases.
- Electroconvulsive therapy can be helpful in severe cases that don’t respond to support.
Case update
John was treated with fluids and dantrolene, and slowly recovered. He was then eased onto an atypical antipsychotic and is being carefully monitored for recurrence.
Barry L. Gilbert, MD, CCFP, FRCPC is a psychiatrist, psychoanalyst and Assistant Professor of Psychiatry at the University of Toronto.
