Brain pathology in fatal serotonin syndrome: Presentation of two cases

Abstract

Serotonin syndrome is a potentially life-threatening reaction that occurs in patients using drugs that elevate the serotonin level in the body. Excess serotonergic activity in the CNS and peripheral serotonin receptors results in neuromuscular hyperactivity, mental changes and autonomic symptoms. Hyperthermia is a characteristic feature of the syndrome. We describe neuropathological findings from two cases of lethal serotonin syndrome, both patients presenting with hyperthermia and neuromuscular symptoms. One of the patients had been taking amitriptylin and mirtazapin and the other had used amitriptylin and citalopram. They died, respectively, 10 days and 2½ months after the onset of serotonin syndrome symptoms. Post-mortem examination of the brains showed subtotal loss of cerebellar Purkinje cells in both cases. In the case with shorter survival time, areas with partial loss of cerebellar granule cells were observed, whereas in the case with longer survival time general and extensive loss of granule cells was found. Cells in other areas of the brain known to be sensitive to hypoxic injury were not affected. Selective loss of Purkinje cells has previously been described in neuroleptic malignant syndrome and heatstroke, conditions that are characterized by hyperthermia. This suggests that hyperthermia may be a causative factor of brain damage in serotonin syndrome. This is the first report describing neuropathological findings in serotonin syndrome.

Neuroleptic Malignant Syndrome

“…This finding was postulated by several investigators to reflect the effects of hyperthermia rather than any underlying pathophysiology of NMS [73,75]. Slettedal et al demonstrated similar findings in two patients with the serotonin syndrome [76]. Similar cerebellar changes have been demonstrated on autopsy in patients with severe hyperthermia from other causes [75].…”

Two cases of mild serotonin toxicity via 5-hydroxytryptamine 1A receptor stimulation

“…Studies in experimental animals have indicated that a slight elevation of serotonin levels decreases body temperature through neural transmission involving the 5-HT1A receptors, whereas the considerable elevation of serotonin levels induces high body temperature through 5-HT2A neural transmission 14,15. Therefore, it could be hypothesized that while a slight excess of serotonin causes side effects by activating the 5-HT1A receptor, a significant increase in serotonin levels can induce lethal side effects with hyperthermia, which can cause severe brain damage16 through the activation of the 5-HT2A receptor. The early observation17 that the affinity of endogenous serotonin for the 5-HT1A receptors (K i =5.1 nM) is much higher than its affinity for 5-HT2A receptors (K i =420 nM) supports this hypothesis.…”

(Extracorporeal membrane oxygenation in a patient with yew and escitalopram intoxication)

“…Serotoninový syndrom také může vést k mozkové smrti, snad mechanismem hypertermie. 34 Závěr VA-ECMO je velmi efektivní modalita u mnoha různých intoxikací. 19 Otrava tisem se zdá být vhodnou indikací.…”