How can I distinguish serotonin syndrome from neuroleptic malignant syndrome in my patient with fever and mental status changes?

Although there is often an overlap between the clinical presentation of serotonin syndrome (SS) and neuromuscular malignant syndrome (NMS), start out with the physical exam. The presence of hyperreflexia, tremors, clonus, hyperactive bowel sounds, and dilated pupils should make you think of SS, whereas hyporeflexia, “lead-pipe” rigidity in all muscle groups, normal pupils, and normal or decreased bowels sounds suggest NMS in the proper context.1-3 The most sensitive and specific sign of SS is clonus.1

Aside from physical exam findings, symptom onset in relation to the implicated drug may also be important. Onset of symptoms within 12-24 h of the initiation or change of an implicated drug suggests SS, whereas a more delayed onset (often 1-3 days) is more supportive of NMS.1-3  SS also tends to resolve within a few days after discontinuation of the offending agent, while NMS usually takes 9-14 days to resolve. 1-3 Although both SS and NMS can be associated with leukocytosis, elevated CK and low serum iron levels are more common in NMS.2

SS is caused by excess serotonin due to a variety of mechanisms—therefore medications— including inhibition of serotonin uptake ( eg, serotonin reuptake inhibitors, serotonin-norepinephrine reuptake inhibitors, tricyclic antidepressants, metoclopramide, ondansetron), inhibition of serotonin metabolism (seen with monoamine oxidase inhibitors , including linezolid, methylene blue), increased serotonin release (eg stimulants, including amphetamines, cocaine), and activation of serotonin receptors (eg, lithium), among others. 2

As for medications that can cause NMS, look for neuroleptic agents (eg, haloperidol, olanzapine, quetiapine, risperidone), as well as antiemeics, such as metoclopramide and promethazine.2

 

Bonus Pearl: Did you know that several supplements/herbal products have been associated with serotonin syndrome, including L-tryptophan, St. John’s wort and ginseng?1

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References

  1. Bienvenu OJ, Neufeld K, Needham DM. Treatment of four psychiatric emergencies in the intensive care unit. Crit Care Med 2012;40: 2662-70. https://insights.ovid.com/crossref?an=00003246-201209000-00017
  2. Turner AAH, Kim JJ, McCarron RM, et al. Differentiating serotonin syndrome and neuroleptic malignant syndrome. Current Psychiatry 2019;18: 36. https://www.mdedge.com/psychiatry/article/193418/schizophrenia-other-psychotic-disorders/differentiating-serotonin-syndrome
  3. Dosi R, Ambaliya A, Joshi H, et al. Serotonin syndrome versus neuroleptic malignant syndrome: a challenging clinical quandary. BMJ Case Rep 2014. Doi:10.1136/bcr-2014-204154. https://casereports.bmj.com/content/2014/bcr-2014-204154

 

How can I distinguish serotonin syndrome from neuroleptic malignant syndrome in my patient with fever and mental status changes?

What is the connection between methemoglobinemia and hemolytic anemia?

Methemoglobinemia coupled with hemolytic anemia (HA) has been reported under different clinical scenarios and may have therapeutic implications for treatment of methemoglobinemia in the setting of G6PD deficiency.

Increased methemoglobin levels have been observed during the hemolytic crisis of patients with favism due to G6PD deficiency. This finding has been attributed to excessive oxidative stress generated by divicine, an oxidizing constituent of fava beans, and the inability to reduce its stress because of an insufficient G6PD-dependent hexose monophosphate shunt. 1Hemolytic anemia may also follow drug-induced methemoglobinemia, especially with exposure to dapsone, sulfasalazine, or phenacetin, and may be a feature of hemoglobin MSaskatoon and MHyde Park , abnormal hemoglobin variants associated with genetic methemoglobinemia. 2The concurrence of hemolysis due to G6PD deficiency and methemoglobinemia is not just an academic curiosity and may in fact pose a therapeutic quandary. This is because methylene blue, the treatment of choice for methemoglobinemia, is also an oxidant and works only after it is reduced to leukomethylene blue by (you guessed it!) nicotinamide adenine nucleotide phosphate (NADPH), a G6PD-dependent process. 2,3 With plenty of methylene blue on hand and little leukomethylene around in G6PD-deficiency, treatment may be ineffective or even cause worsening of methemoglobinemia. It’s never simple!

Final fun fact: Did you know that methylene blue is the first synthetic drug (>100 years ago) and has been used in the prevention of UTIs in the elderly, and treatment of pediatric malaria and Alzheimer’s disease? 4References

  1. Schuurman M, van Waardenburg D, Da Costa J, et al. Severe hemolysis and methemoglobinemia following fava beans ingestion in glucose-6-phosphate dehydrogenase: Case report and literature review. Eur J Ped 2009;168:779-782. https://link.springer.com/article/10.1007/s00431-009-0952-x
  2. Rehman HU. Methemoglobinemia. West J Med 2001;175:193-96. https://www.researchgate.net/publication/11817876_Methemoglobinemia
  3. Hassan KS, Al-Riyami AZ, Al-Huneini M, et al. Methemoglobinemia in an elderly patient with glucose-6-phosphate dehydrogenase deficiency: A case report. Oman Med J 2014;29:135-37. https://squ.pure.elsevier.com/en/publications/methemoglobinemia-in-an-elderly-patient-with-glucose-6-phosphate-
  4. Schirmer RH, Adler H, Pickhardt M, et al. “Lest we forget you—Methylene blue…” Neurobiology of Aging 2011; 32:2325. https://www.ncbi.nlm.nih.gov/pubmed/21316815
What is the connection between methemoglobinemia and hemolytic anemia?