14. Neuroleptic malignant syndrome (NMS)

It is an idiosyncratic reaction (not related to dose or duration) to certain medications, mostly neuroleptics within 7 days (4 weeks with depot preparations).

Mechanisms

Pathophysiology most likely includes on acute alterations and reduction of central dopaminergic activity via antagonism of dopamine receptors (D2) or lower synaptic dopamine concentrations.

NMS has been observed in Parkinson’s patients when dopamine agonists such as levodopa are suddenly withdrawn

May occur as a result of a rapid increase in dose of neuroleptics, especially the long-acting ones (Oruch  et al., 2017).

May be caused by central acting antiemetics

Dopamine blockade in hypothalamus alters central thermoregulation

Dopamine blockade in the basal ganglia results in muscle hyperrigidity probably due to excessive calcium release from the sarcoplasmic reticulum of skeletal myocytes.

Dopamine blockade at spinal cord may be responsible for autonomic instability

Hyperthermia results from heat generated by excessive muscle hyperrigidity which may be augmented by altered central thermoregulation.

Dopamine blockade in central mesolimbic regions is associated with altered mental status

Clinical Manifestation

Muscle rigidity

Hyperthermia greater than 38 C

Autonomic instability: tachycardia, hypotension

Altered mental status

Tachypnea and hypoxia

Diaphoresis

Tremor

Elevated CPK or myoglobinuria

Metabolic acidosis

Elevations in serum transaminases and ESR.

Elevated serum creatine phosphokinase and white blood cell count.

Treatment

Discontinue offending drug- fevers usually resolve within 72 hours (Cunha and Cunha, 2017)

Monitoring ABC’s and basic supportive care

Respiratory support

Cold intravenous fluids (Oruch et al., 2017)

In severe cases-temperatures above 40° C supportive care (external cooling, volume resuscitation attempt aggressive cooling such as ice bath and pharmacologic therapy such as:

Benzodiazepines (Asztalos et al.,2014)

Bromocriptine – increases central dopamine activity

Dantrolene or neuromuscular blockers to directly relax muscle. Dantrolene is the most effective evidence-based drug treatment (Perry et al., 2010).

Amantadine-antiviral and antidyskinetic drug

Buprobion-antidepressant that acts as an norepinephrine-dopamine reuptake inhibitor (NDRI) (Foguet-Boreu  et. al., 2018)

Electroconvulsive therapy (Foguet-Boreu  et. al., 2018; Asztalos et al., 2014)

References

Foguet-Boreu Q, Coll-Negre M, Serra-Millàs M and  Cavalleria-Verdaguer M  (2018). Neuroleptic malignant syndrome: a case responding to electroconvulsive therapy plus bupropion. Clin Pract. 8(1):1044. doi: 10.4081/cp.2018.1044.

Cunha CB and Cunha BA (2017).  Fever of Unknown Origin. Infectious Diseases (Fourth Edition), Infectious Diseases (Fourth Edition). Volume 1. Pages 611–624.

Oruch R, Pryme IF, Engelsen BA, Lund A (2017). Neuroleptic malignant syndrome: an easily overlooked neurologic emergency.

Asztalos Z, Egervári L, Andrássy G, Faludi G and  Frecska E (2014). Catatonia and neuroleptic malignant syndrome in view of a psychopathological and pathophysiological overlap: a brief review. Neuropsychopharmacol Hung. 16(1):19-28.

Musselman ME and  Saely S. (2013) Diagnosis and treatment of drug-induced hyperthermia. Am J Health Syst Pharm. 70(1):34-42. doi: 10.2146/ajhp110543.

Perry PJ and Wilborn CA (2012).Serotonin syndrome vs neuroleptic malignant syndrome: a contrast of causes, diagnoses, and management. Ann Clin Psychiatry. 24(2):155-62

Steele D, Keltner NL and  McGuiness TM (2011). Are neuroleptic malignant syndrome and serotonin syndrome the same syndrome?. Perspect Psychiatr Care. 2011 Jan;47(1):58-62. doi: 10.1111/j.1744-6163.2010.00292.x.

Margetić B and Aukst-Margetić B (2010). Neuroleptic malignant syndrome and its controversies. Pharmacoepidemiol Drug Saf. 19(5):429-35. doi: 10.1002/pds.1937.

Kaufman KR, Levitt MJ, Schiltz JF and Sunderram J (2006).Neuroleptic malignant syndrome and serotonin syndrome in the critical care setting: case analysis. Ann Clin Psychiatry. 18(3):201-4.

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