Neuroleptic malignant syndrome

Neuroleptic malignant syndrome (NMS) is a lethal medical emergency associated with the use of neuroleptic agents and antiemetics that is characterized by a typical clinical syndrome of hyperthermia, rigidity, mental status alteration, and dysautonomia.

Associated with dopamine receptor blocking agents – antipsychotic agents,  and may be dope misdiagnosed as serotonin syndrome.

Symptoms typically evolve over 1 to 3 days and include hyperthermia, rigidity, mental status changes, and autonomic dysregulation. 


Autonomic dysregulation: tachycardia, 88% of cases, high blood pressure,up to 77% of cases, dysrhythmias, and tachypnea are seen.


Autonomic instability, which can manifest with tachycardia, nausea, vomiting, and diaphoresis.




-Mental status change with confusion, hallucinations, coma.


Muscle rigidity


Laboratory abnormalities: elevated creatine kinase, reduced iron plasma levels, electrolyte abnormalities.


It occurs within 10 days after the start of therapy in up to 90% of cases.

A rare but life-threatening neurologic disorder most often caused by an adverse reaction to neuroleptic or anti-psychotic drugs.

NMS symptoms usually develop during the first 10 to 14 days of neuroleptic drugtherapy initiation. 


It is not a dose-dependent phenomenon, but high doses is a risk factor.


Risk factors include:  high-potency antipsychotics, rapid dose increase of antipsychotics, and using long-acting injectable neuroleptics such as fluphenazine enanthate and haloperidol decanoate.

Additional risk factors include dehydration, malnutrition, organic brain disease, and lithium usage.


Causative medications include: antipsychotics and antiemetics, mainly high-potency first-generation antipsychotic agents such as fluphenazine and haloperidol. 


Can  occur with use of low-potency antipsychotics such as chlorpromazine and second-generation antipsychotic drugs such as clozapine and olanzapine, as well as antiemetic drugs such as prochlorperazine, metoclopramide, and promethazine.


It may occur with the withdrawal of l-dopa or dopamine agonist therapy.


Drug dose reductions and a switch from one agent to another in patients treated for Parkinsonism can cause NMS.

Antipsychotic medications lead to increased calcium release from the sarcoplasmic reticulum, resulting in increased contractility, which can worsen the rigidity and hyperthermia and increase the chance of rhabdomyolysis.

Associated with fever, blood pressure variation, muscle rigidity and increased creatine kinase.

Characterized by the following symptoms: tremor, rigidity, hyperthermia, tachycardia, mental status changes.

Altered mental status occurs as delirium with confusion and possible profound encephalopathy and coma.


Muscular rigidity is mostly generalized and can be accompanied with dystonia and dyskinesias.


 Fevers with temperatures above 38C are typical.


Temperatures greater than 40C are not uncommon, seen in up to 40% of cases.

Occurs as a result of changes in dopamine signaling: proposed mechanism by which antipsychotics and antiemetics cause NMS is that of dopamine D2 receptor antagonism. 

A reduced dopamine signaling may result from sudden withdrawal of dopaminergic agents, or when the drug dosage is abruptly reduced in people taking dopaminergic drugs such as levodopa for Parkinson disease.


Suspected central D2 receptor blockade in the nigrostriatal pathways, hypothalamus, and spinal cord leads to increased tremor and muscle rigidity through the extrapyramidal pathways. 


D2 receptor blockade in the hypothalamus results in an increased temperature set point and impairment of heat-dissipating mechanisms.

Genetic studies reveal the presence of a specific allele of the dopamine D2 receptor gene that is overrepresented in persons with NMS.


The sympathetic nervous system  hyperactivity and dysregulation, leads to autonomic dysfunction manifesting as labile blood pressure, tachycardia, and tachypnea due to D2 receptor blockade.


D2 receptor blockade might cause NMS by removing tonic inhibition from the sympathetic nervous system.

Dopamine receptor blockade has a slow onset and typically evolves over several days after administration of a neuroleptic drug and responds to dopamine agonists such as bromocriptine.

It carries high morbidity and mortality.

Incidence rates for NMS range from 0.07% to 2.2% among those taking neuroleptic medications. 

Recent estimates of mortality from 10% to 20%.

It is more common in men than in women, possibly because of greater use of neuroleptics among men rather than a greater susceptibility.


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