A Case of Fulminant West Nile Virus Encephalitis Presenting With Non-ST-Segment Elevation Myocardial Infarction (NSTEMI) and Diagnostic Discordance

West Nile virus (WNV) is a mosquito-borne flavivirus that typically causes mild febrile illness but can progress to neuroinvasive disease and even death, particularly in older adults with comorbidities. We describe a 77-year-old male with coronary artery disease, carotid artery disease, hypertension, and hyperlipidemia, who was notified that his recent blood donation had tested positive for WNV by nucleic acid testing (NAT) on initial screening, with confirmatory testing pending. Shortly thereafter, he developed a fever, confusion, dizziness, and worsening gait instability. On admission, he was febrile to 103.6°F, hypotensive at 97/65 mmHg, and noted to have monocytosis, elevated troponin, and electrocardiogram (ECG) abnormalities consistent with type II non-ST-segment elevation myocardial infarction (NSTEMI). He rapidly developed severe encephalopathy and acute hypoxemic respiratory failure. Lumbar puncture revealed elevated opening pressure (29 cm H₂O), neutrophil-predominant pleocytosis (265 WBC/µL), markedly elevated protein (149 mg/dL), and normal glucose. Despite findings consistent with viral encephalitis, cerebrospinal fluid (CSF) polymerase chain reaction (PCR) testing for WNV ribonucleic acid (RNA) was negative. Extensive testing for alternative bacterial, viral, and tickborne pathogens was also negative. Despite broad empiric antimicrobial and antiviral therapy, the patient deteriorated rapidly, was transitioned to comfort measures, and died within 48 hours of admission. This case highlights the diagnostic challenges of neuroinvasive WNV encephalitis, particularly in the setting of discordant or unavailable diagnostic testing. Molecular assays, such as CSF PCR for WNV RNA, have limited sensitivity and frequently yield false-negative results when performed outside the early viremic window. In contrast, serologic testing, such as CSF WNV immunoglobulin M (IgM) antibody, is more sensitive but may be limited by IgM cross-reactivity and clinical availability. In this patient, the prior positive blood donation NAT provided a rare early diagnostic clue, while the atypical NSTEMI presentation could have delayed recognition of neuroinvasive disease. Accurate diagnosis, therefore, requires synthesis of clinical presentation, epidemiologic exposure, and available diagnostic data, and clinicians should maintain a high index of suspicion for WNV encephalitis even when standard diagnostic tests are negative.