Pathophysiology
The mechanism of the neuroleptic malignant syndrome is commonly thought to depend on decreased levels of dopamine activity due to:
It has been proposed that blockade of D2-like (D2, D3, and D4) receptors induce massive glutamate release, generating catatonia, neurotoxicity, and myotoxicity. Additionally, the blockade of diverse serotonin receptors by atypical antipsychotics and activation of 5HT1 receptors by certain of them reduces GABA release and indirectly induces glutamate release, worsening this syndrome.
The muscular symptoms are most likely caused by blockade of the dopamine receptor D2, leading to abnormal function of the basal ganglia similar to that seen in Parkinson’s disease.
However, the failure of D2 dopamine receptor antagonism, or dopamine receptor dysfunction, does not 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. This has led to the hypothesis of sympathoadrenal hyperactivity (results from removing tonic inhibition from the sympathetic nervous system) as a mechanism for NMS. The release of calcium is increased from the sarcoplasmic reticulum with antipsychotic usage. This can result in increased muscle contractility, which can play a role in the breakdown of muscle, muscle rigidity, and hyperthermia. Some antipsychotic drugs, such as typical neuroleptics, are known to block dopamine receptors; other studies have shown that when drugs supplying dopamine are withdrawn, symptoms similar to NMS present themselves.
There is also thought to be considerable overlap between malignant catatonia and NMS in their pathophysiology, the former being idiopathic and the latter being the drug-induced form of the same syndrome.
The raised white blood cell count and creatine phosphokinase (CPK) plasma concentration was seen in those with NMS is due to increased muscular activity and rhabdomyolysis (destruction of muscle tissue). The patient may suffer a hypertensive crisis and metabolic acidosis. A non-generalized slowing on an EEG is reported in around 50% of cases.
The fever seen with NMS is believed to be caused by the hypothalamic dopamine receptor blockade. The peripheral problems (the high white blood cell and CPK count) are caused by antipsychotic drugs. They cause an increased calcium release from the sarcoplasmic reticulum of muscle cells which can result in rigidity and eventual cell breakdown. No major studies have reported an explanation for the abnormal EEG, but it is likely also attributable to dopamine blockage leading to changes in neuronal pathways.
Symptoms
High fever, confusion, rigid muscles, variable blood pressure, sweating
Complications
Rhabdomyolysis, high blood potassium, kidney failure, seizures
Usual onset
Within a few weeks
Causes
Neuroleptic or antipsychotic medication
Risk factors
Dehydration, agitation, catatonia
Diagnostic method
Based on symptoms in someone who has started neuroleptics within the last month
Differential diagnosis
Heatstroke, malignant hyperthermia, serotonin syndrome, lethal catatonia
Treatment
Stopping the offending medication, rapid cooling, starting other medications
Medication
Dantrolene, bromocriptine, diazepam
Prognosis
10% risk of death
Frequency
15 per 100,000 per year (on neuroleptics)