To describe a rare case of herpes simplex virus type 1 (HSV-1) meningoencephalitis presenting with nonclassical neuroimaging, atypical cerebrospinal fluid (CSF) findings, and resistance to standard antiviral therapy, highlighting diagnostic and therapeutic challenges in acute encephalitis with rapid neurological decline.

HSV-1 meningoencephalitis is the most common cause of sporadic viral encephalitis in adults. Early recognition and initiation of acyclovir are critical for survival; however, atypical clinical, CSF, and imaging presentations can delay diagnosis. Although MRI typically demonstrates frontotemporal involvement, cases with nonclassical features—particularly cortical ribboning without temporal lesions—are exceedingly uncommon and may mimic autoimmune, metabolic, or vascular etiologies.

A 35-year-old previously healthy man presented with subacute fever, headache, and altered mental status following travel to Southeast Asia. Initial CSF analysis revealed elevated protein and red blood cells without significant pleocytosis; early HSV PCR was negative. Repeat lumbar puncture demonstrated elevated opening pressure and positive HSV-1 PCR. MRI showed cortical ribboning on DWI/FLAIR without frontotemporal involvement. Despite high-dose acyclovir, steroids, IVIG, and plasma exchange for suspected autoimmune overlap, the patient’s condition deteriorated, requiring intubation, lumbar drainage, and hypertonic therapy for rising intracranial pressure. Extensive infectious and autoimmune workups were negative. He ultimately progressed to multiorgan failure and was transitioned to comfort care.

This case underscores the need for persistent diagnostic vigilance when evaluating suspected HSV-1 encephalitis. Nonclassical MRI findings and atypical CSF parameters can obscure diagnosis, emphasizing the importance of repeat testing and integration of serial imaging. HSV-1 encephalitis should remain high in the differential even when initial PCR and imaging are inconclusive. Early empiric antiviral therapy, timely reconsideration of autoimmune overlap, and proactive management of intracranial hypertension are essential to improving outcomes in atypical, treatment-refractory cases of viral meningoencephalitis.