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Neuroleptic Malignant Syndrome
Updated: Dec 9, 2008
Introduction
Background
Neuroleptic malignant syndrome (NMS), first described in 1963 by Delay et al in the French psychiatric literature, is a rare but potentially lethal complication of treatment with potent neuroleptics.
Neuroleptic drugs (ie, antipsychotic drugs, antischizophrenic drugs) are primarily used to treat schizophrenia and other psychotic states. Traditional drugs have action through inhibition of dopaminergic receptors, whereas the newer agents work by causing blockade of serotonin receptors.
Neuroleptic malignant syndrome often occurs as treatment begins, when physicians progressively increase doses of neuroleptics. No clear relationship has been established between neuroleptic dosage and risk of developing neuroleptic malignant syndrome. A drug's potential for inducing neuroleptic malignant syndrome seems to parallel its antidopaminergic activity.
Pathophysiology
Neuroleptic malignant syndrome pathophysiology is largely speculative. Neuroleptic drugs block dopaminergic receptors, creating a functional dopamine-deficiency state. Dopaminergic receptor blockade in the substantia nigra causes muscle rigidity and alters thermoregulation in the hypothalamus. Increased heat production from muscle rigidity causes fever, impaired heat dissipation (by reducing cutaneous vasodilatation or by sweating), and possibly a higher core temperature set point in the hypothalamus.
MM isoenzyme of creatine kinase increases. Muscle biopsy demonstrates morphologic and histoenzymologic abnormalities in muscle fibers.
Frequency
International
Incidence varies because of differing diagnostic criteria, patient characteristics, and available information. Reported incidence of neuroleptic malignant syndrome in neuroleptic-treated patients ranges from 0.1-5.5%.
Neuroleptic malignant syndrome onset ranges from 1-44 days following administration of neuroleptic drug; mean onset is 10 days. Lazarus et al reported neuroleptic malignant syndrome occurring in 67% of patients within 1 week and 96% of patients within 30 days following administration of neuroleptics.1
Mortality/Morbidity
Once reported to be 20-30%, the mortality rate is now estimated at 5-11.6%. Mortality is caused by one or more complications (eg, respiratory failure, cardiovascular collapse, renal failure, arrhythmias, thromboembolism). Renal failure is associated with a 50% mortality rate.
No consistent long-term physical, neurological, cognitive, or laboratory sequelae have been attributed to neuroleptic malignant syndrome alone, although sequelae may result from such secondary complications as prolonged hypoxia or ischemic encephalopathy. Researchers have noted sporadic cases of prolonged rigidity and long-term neuropsychological deficits.
Sex
The male-to-female ratio is 2:1.
Age
Neuroleptic malignant syndrome occurs in people of all age groups, with a reported mean age of 40 years.
Clinical
History
Symptoms of neuroleptic malignant syndrome include the following:
- Neuroleptics either recently started or dosage recently increased
- Neuroleptic malignant syndrome usually evolves over 24-72 hours.
- Hyperthermia (temperature >38°C)
- Altered mental status
- Rigidity and other extrapyramidal syndrome (EPS) symptoms
- Autonomic dysfunction (eg, urinary incontinence, diaphoresis, sialorrhea)
- Dyspnea, dysphagia
Physical
- General examination findings
- Hyperthermia
- Tachycardia
- Tachypnea, respiratory distress (31% of cases)
- Hypotension or hypertension
- Hypoxemia (low pulse oximeter reading)
- Dehydration (secondary to hyperpyrexia and inadequate oral intake)
- Neuromuscular examination findings
- Altered mental status (status ranging from drowsiness and confusion to coma)
- Muscular rigidity (usually lead-pipe type)
- Autonomic dysfunction (eg, dysrhythmias, urinary incontinence, diaphoresis, sialorrhea, tachycardia, hypotension, hypertension)
- Other EPS
Causes
- Most common agents
- Butyrophenones
- Haloperidol
- Phenothiazines
- Thioxanthenes
- Long-acting neuroleptics (benzamines)
- Several other agents that reportedly have caused neuroleptic malignant syndrome - Tricyclic antidepressants, monoamine oxidase inhibitors (MAOIs), anticonvulsants, lithium, and dopamine antagonists (eg, metoclopramide, sulpiride)
- Agent risk factors
- Rapid initiation of antipsychotic therapy
- Use of high-potency drugs (drug's potential for inducing neuroleptic malignant syndrome seems to parallel its antidopaminergic activity)
- Depot preparations
- Host risk factors
- Age - People of all age groups affected (reported mean age is 40 y)
- Sex - More common in men (2:1 ratio)
- Concomitant illnesses
- Organic brain disease or alcoholism
- Dehydration, nutritional deficits
- Affective disorder
- Severe patient agitation or catatonia
- History of neuroleptic malignant syndrome
- Simultaneous use of predisposing drugs (eg, lithium, anticholinergic agents)
- Environmental risk factors: Environmental risk factors may include seasonality. Some investigators report higher incidence of neuroleptic malignant syndrome in summer in connection with heat stroke; other investigators have reported no seasonal clustering.
- Caveats
- Higher incidence of neuroleptic malignant syndrome with parenteral administration of neuroleptics was noted in one study.
- Coadministration of anti-Parkinson drugs and neuroleptics effectively prevents neuroleptic malignant syndrome, according to one investigator; however, another investigator found no such benefit. Withdrawal of parkinsonian medication is reported to be one etiological factor for neuroleptic malignant syndrome.
- Not all patients have recurrent neuroleptic malignant syndrome, even if the same neuroleptic is administered in the same dose after recovery from neuroleptic malignant syndrome.
More on Neuroleptic Malignant Syndrome |
Overview: Neuroleptic Malignant Syndrome |
| Differential Diagnoses & Workup: Neuroleptic Malignant Syndrome |
| Treatment & Medication: Neuroleptic Malignant Syndrome |
| Follow-up: Neuroleptic Malignant Syndrome |
| References |
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References
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Further Reading
Keywords
neuroleptic malignant syndrome, NMS, neuroleptics, antidopaminergic activity, serotonin, schizophrenia, respiratory failure, cardiovascular collapse, renal failure, arrhythmias, thromboembolism, hypoxia, ischemic encephalopathy, urinary incontinence, diaphoresis, sialorrhea, hypertension, respiratory distress, dehydration, hypotension, butyrophenones, haloperidol, phenothiazines, thioxanthenes, long-acting neuroleptics, benzamines, tricyclic antidepressants, monoamine oxidase inhibitors, MAOIs, anticonvulsants, lithium, domatine antagonists
Overview: Neuroleptic Malignant Syndrome