Concurrent Serotonin Toxicity and CRMP5-associated Autoimmune Encephalitis: Diagnostic Challenges in a Complex Neurotoxic-autoimmune Overlap
Background:
Neurologists often face diagnostic uncertainty when clinical findings and ancillary tests appear discordant. Serotonin syndrome results from excess serotonergic activity leading to autonomic instability, neuromuscular hyperreactivity, and altered mental status. In contrast, CRMP5-associated autoimmune encephalitis is often a paraneoplastic process causing multifocal CNS involvement. When such pathologies coexist, distinguishing overlapping manifestations requires strong clinical judgment and coordinated multidisciplinary evaluation.
Results:
A 27-year-old Hispanic male presented with fever and acute encephalopathy. The examination revealed hyperthermia, tachycardia, diffuse flushing, lethargic state, ocular clonus, spontaneous and inducible limb clonus, and hyperreflexia, all suggestive of serotonin syndrome. He denied prescribed medications but reported taking several natural supplements, later confirmed to possess serotonergic properties. He was treated with cyproheptadine and supportive care, returning to baseline within 48 hours. However, cerebrospinal fluid showed mononuclear pleocytosis, and brain MRI revealed multifocal T2-hyperintense lesions not typical for serotonin syndrome. The patient was lost to follow-up before further workup could be conducted. Six months later, he developed focal seizures with sensory aura. MRI demonstrated resolution of prior lesions but showed new right frontal and left insular T2-hyperintensities. EEG revealed right frontal-temporal sharp waves. Concern about autoimmune/paraneoplastic encephalitis was raised, prompting a panel to be sent. CSF testing was positive for CRMP5 antibodies. Malignancy screening uncovered an anterior mediastinal lymphoma, which was resected. The patient remains functional and seizure-free two years post-treatment under neurology and hematology follow-up.
Conclusions:
This case underscores two key principles in neurologic practice. First, natural supplements can have potent pharmacologic effects and should be scrutinized as potential etiologies for toxic syndromes such as serotonin syndrome. Second, persistence of atypical findings should prompt reconsideration of the initial diagnosis and evaluation for overlapping pathologies. Co-occurrence of serotonin syndrome and CRMP5-associated encephalitis is rare and highlights the importance of maintaining diagnostic flexibility when clinical and paraclinical data diverge.
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