[1][7] Symptoms include high fever, confusion, rigid muscles, variable blood pressure, sweating, and fast heart rate.
[1] Complications may include muscle breakdown (rhabdomyolysis), high blood potassium, kidney failure, or seizures.
[11] Symptoms may also be mistaken for similarly presenting conditions such as malignant hyperthermia, serotonin syndrome, or withdrawal from illicit drugs such as alcohol cocaine, or MDMA.
[7] Neuroleptic malignant syndrome (NMS) usually presents with a "lead pipe rigidity" in which the muscles are stiffened and resistance is observed throughout the range of motion on testing.
[17] However, concomitant use of lithium is associated with a higher risk of NMS when a person starts on an antipsychotic drug.
[27] The mechanism 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.
[31] 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.
The introduction of atypical antipsychotic drugs, with lower affinity to the D2 dopamine receptors, was thought to have reduced the incidence of NMS.
However, recent studies suggest that the decrease in mortality may be the result of increased physician awareness and earlier initiation of treatment rather than the action of the drugs themselves.
[33] This has led to the hypothesis of sympathoadrenal hyperactivity (results from removing tonic inhibition from the sympathetic nervous system) as a mechanism for NMS.
[4] In support of the sympathoadrenal hyperactivity model, it has been hypothesized that a defect in calcium regulatory proteins within the sympathetic neurons may bring about the onset of NMS.
[citation needed] 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.
[37] The raised white blood cell count and creatine phosphokinase (CPK) plasma concentration seen in those with NMS is due to increased muscular activity and rhabdomyolysis (destruction of muscle tissue).
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.
The diagnosis is suggested on patients with a history of drug exposure to the most common inducing agents such as strong antidopaminergic medications.
[6][40] The differential diagnosis includes serotonin syndrome,[41] encephalitis, toxic encephalopathy, status epilepticus, heat stroke, catatonia and malignant hyperthermia.
[4][42][6] Features which distinguish NMS from serotonin syndrome include bradykinesia, muscle rigidity, and a high white blood cell count.
The first step is to stop the culprit medication and treat the hyperthermia aggressively, such as with cooling blankets or ice packs to the axillae and groin.
Dantrolene has been used when needed to reduce muscle rigidity, and dopamine pathway medications such as bromocriptine have shown benefit.
Highly elevated blood myoglobin levels from muscle breakdown (rhabdomyolysis) can result in kidney damage, therefore aggressive intravenous hydration with diuresis may be required.