Hyperthermic Toxidromes: A Triad of Hyperthermia, Muscle Rigidity and Altered Mental Status

Dr. Tess Wiskel, PGY3
Department of Emergency Medicine
Brown University
Providence, RI

Hyperthermia is an elevated body temperature without a change in the hypothalamic set point.1 Xenobiotics can cause hyperthermia through various mechanisms, including dystonia, withdrawal, uncoupling of oxidative phosphorylation and impaired autonomic response. 2 The symptomatic triad of hyperthermia, muscle rigidity and altered mental status in toxicology consists of three commonly confused syndromes with distinct pathophysiology: serotonin syndrome, neuroleptic malignant syndrome and malignant hyperthermia.

Treatment for all three if these syndromes begins first with supportive care. For the hyperthermia, this is cooling, beginning with external cooling progressing to internal cooling as needed. For the muscle rigidity, the treatment is muscle relaxation, typically with benzodiazepine therapy, but can also escalate to neuromuscular blockade. Altered mental status can also be treated with benzodiazepines as needed for agitation as well as seizures. 2 Despite similar supportive care for all three syndromes, there are specific antidotes for each syndrome of varying efficacy, making recognition and diagnosis paramount for each syndrome, which first requires understanding of the pathophysiology.

Serotonin syndrome results from increased stimulation of 5HT receptors by serotonin, classically evidenced by hyperthermia and tachycardia, hyperreflexia, clonus and agitation. There are no laboratory confirmatory tests, however diagnostic criteria have been developed, with the most sensitive and specific being the Hunter Criteria, requiring exposure to a serotonergic drug and symptoms of clonus or hyperreflexia. 3 There is a broad range of serotonergic drugs implicated, including but not limited to: serotonin precursors such as tryptophan, drugs increasing serotonin release including amphetamines and cocaine, serotonin reuptake inhibitors such as SSRIs and TCAs as well as serotonin breakdown inhibitors including MAOis and linezolid and finally serotonin agonists including triptans and lithium. 2,4 Specific treatment for serotonin syndrome after supportive care is cyproheptadine, a first generation antihistamine that has proven mortality benefit in animal trials and symptomatic benefit in humans. 2

Neuroleptic malignant syndrome is a syndrome of central dopaminergic hypoactivity, specifically decrease in activity on D2 receptors in the nigrostriatal, hypothalamic and mesocortical tracts. 2,5 The presentation, although similar to serotonin syndrome, presents initially with lead pipe rigidity and bradykinesia, followed by fever and altered mental status. Common causative agents are typical antipsychotics greater than atypicals as well as antiemetics with antidopaminergic properties and withdrawal of dopamine agonists including levodopa-carbidopa. 5 Additionally, this syndrome presents with leukocytosis and elevated creatinine phosphokinase, with both the DSM criteria and expert consensus criteria for diagnosis incorporating the physical symptoms as well as these abnormal, however not specific labs 5,6. Bromocriptine, as well as other dopamine agonists, can be employed for treatment with failure of supportive care, and in increasingly severe cases dantrolene has been used, however no clear evidence supports this use. Finally, in refractory cases, electroconvulsive therapy has proven consistently effective in case reports. 7,8

Malignant hyperthermia is a genetic syndrome of skeletal muscle hypermetabolism resulting from numerous mutations, the majority affecting the ryanodine receptor. The clinical syndrome consists of uncontrolled muscle contraction, with an initial hypercarbia and jaw rigidity progressing to hyperthermia.2 Although classically a syndrome after exposure to volatile anesthetic agents and depolarizing muscle relaxants, case reports also describe susceptible individuals succumbing to malignant hyperthermia after exercise, infection or other physical stressors. This rare diagnosis is essential to make, with dantrolene being definitive treatment, inhibiting calcium release from the sarcoplasmic reticulum. A final diagnosis can be made caffeine halothane testing of muscle biopsy as the gold standard. 9

  1. Kasper D. Harrison's Principles of Internal Medicine. In: Fauci A, Hauser S, Longo D, Jameson J, Loscalzo J, eds. 19th ed. ed. New York :: McGraw-Hill Professional Publishing; 2015.
  2. Lewis Nelson NL, Mary Ann Howland, Robert Hoffman, Lewis Goldfrank, Neal Flomenbaum. Goldfrank's Toxicologic Emergencies: McGraw Hill; 2011.
  3. Dunkley EJC, Isbister GK, Sibbritt D, Dawson AH, Whyte IM. The Hunter Serotonin Toxicity Criteria: simple and accurate diagnostic decision rules for serotonin toxicity. Qjm 2003;96:635-42.
  4. Ener RA, Meglathery Sb Fau - Van Decker WA, Van Decker Wa Fau - Gallagher RM, Gallagher RM. Serotonin syndrome and other serotonergic disorders.
  5. Berman BD. Neuroleptic malignant syndrome: a review for neurohospitalists. Neurohospitalist 2011;1:41-7.
  6. Gurrera RJ, Caroff SN, Cohen A, et al. An international consensus study of neuroleptic malignant syndrome diagnostic criteria using the Delphi method. J Clin Psychiatry 2011;72:1222-8.
  7. Jeffrey Strawn PKJ, Stanley Caroff. Neuroleptic Malignant Syndrome. American Journal of Psychiatry 2007;6.
  8. Geethan Chandran JM, David Keegan. Neuroleptic malignant syndrome: case report and discussion. Canadian Medical Association Journal 2003;5.
  9. Reske-Nielsen C, Schlosser K, Pascucci RC, Feldman JA. Is It Exertional Heatstroke or Something More? A Case Report. J Emerg Med 2016;51:e1-5.

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