Neuroleptic malignant syndrome (NMS) is a life-threatening neurological disorder most often caused by an adverse reaction to neuroleptic or antipsychotic drugs. It generally presents with muscle rigidity, fever, autonomic instability and cognitive changes such as delirium, and is proven on a raised creatine phosphokinase (CPK). Treatment is generally supportive.
NMS is caused almost exclusively by the blocking dopamine receptors with antipsychotic medications, including all types of neuroleptics (typical and atypical antipsychotic drugs). The higher the dosage of the antipsychotic, the more common the occurrence. Rapid and large increases in dosage can also trigger the development of NMS. Other drugs, environmental or psychological factors, hereditary conditions, and specific demographics may cause greater risk, but to date no conclusive evidence has been found to support this. The disorder typically develops within two weeks of the initial treatment with the drug, but may develop at any time the drug is being taken. NMS may also occur in people taking a class of drugs known as dopaminergics when the dosage is reduced (i.e. Levodopa).
The mechanism is thought to depend on decreased levels of dopamine due to:
However, the failure of D2 dopamine receptor antagonism or dopamine receptor dysfunction to fully explain the presenting symptoms and signs of NMS, as well as the occurrence of NMS with atypical antipsychotic drugs with lower D2 dopamine activity, has led to the hypothesis of sympathoadrenal hyperactivity as an etiological mechanism for NMS. There is also thought to be considerable overlap between malignant catatonia and NMS in their pathophysiology, the former being idiopathic and the latter being drug-induced form of the same syndrome.
 Signs and symptoms
The first symptom to develop is usually muscular rigidity, followed by high fever, symptoms of instability of the autonomic nervous system such as unstable blood pressure, and changes in cognition, including agitation, delirium and coma. Other symptoms may include muscle tremors and pharyngitis. Once symptoms do appear, they rapidly progress and can reach peak intensity in as little as three days. These symptoms can last anywhere from eight hours to forty days.
A raised creatine phosphokinase (CPK) plasma concentration will be reported due to increased muscular activity. The patient may be hypertensive and suffering from a metabolic acidosis. A non-generalised slowing on an EEG is reported in around 50% of cases.
Unfortunately, symptoms are sometimes misinterpreted by doctors as symptoms of mental illness, delaying treatment. NMS should be ruled out in cases of acute and significant behaviour change or deterioration in a person who has otherwise been stable for a period of time on antipsychotics, especially in situations where the dose has not been changed and the person hasn't deteriorated because of noncompliance or consumption of psychoactive substances known to worsen psychosis.
A mnemonic used to remember the features of NMS is FEVER.
- F - [[Fever]
- E - [[Encephalopathy]]
- V - Vitals unstable
- E - Elevated enzymes (elevated CPK)
- R - Rigidity of muscles
As with most illnesses, the prognosis is best when identified early and treated aggressively. In these cases NMS is usually not fatal, although there is currently no agreement on the exact mortality rate for the disorder. Studies have given the disorder a mortality rate as low as 5% and as high as 76%, although most studies agree that the correct percentage is in the lower spectrum, perhaps 1015%. Re-introduction to the drug that originally caused NMS to develop may also trigger a recurrence, although in most cases it does not.
Although treatment is not always necessary, it will help to cure the disease and prevent fatal developments from occurring. The first step in treatment is generally to remove the patient from any neuroleptic or antipsychotic drugs being taken and to treat fever aggressively. Many cases require intensive care, or some kind of supportive care at the minimum. Depending on the severity of the case, patients may require other treatments to contend with specific effects of the disorder. These include circulatory and ventilatory support, the drugs dantrolene sodium, bromocriptine, apomorphine and electroconvulsive therapy (ECT) if medication fails. Benzodiazepines may also be of great benefit.
 NMS and serotonergic syndrome
The clinical features of NMS and serotonergic syndrome are very similar. This can make differentiating them very difficult.
Features, classically present in NMS, that are useful for differentiating the two syndromes are:
- Muscle rigidity
- Laboratory Values (WBC & CK)
NMS was known about as early as 1956, shortly after the introduction of the first phenothiazines, and is derived from the French syndrome malin des neuroleptiques.
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