What is the most likely diagnosis in a 77-year-old woman presenting days after an upper respiratory infection with a new tonic‑clonic seizure, fever, ill appearance, cerebrospinal fluid showing isolated elevated protein, and MRI demonstrating temporal lobe hyperintensities?

Diagnosis: Viral Encephalitis (HSV-1)

The diagnosis is viral encephalitis, most likely HSV-1 encephalitis, based on the classic triad of fever, new-onset seizures, and temporal lobe involvement on MRI following a prodromal illness. 1

Clinical Reasoning

This 77-year-old woman presents with the pathognomonic features of HSV-1 encephalitis:

• Temporal lobe hyperintensities on MRI are nearly pathognomonic for HSV-1 encephalitis, with bilateral temporal lobe involvement being the characteristic finding in >90% of proven cases 1, 2, 3

• Fever, seizures, and altered mental status represent the classic triad, with HSV-1 being one of the most common causes of identified sporadic encephalitis worldwide (25-40% of all cases) 1

• Prodromal upper respiratory infection is consistent with the typical presentation, as patients often have a preceding febrile or influenza-like illness 1

• Elevated CSF protein alone can occur in HSV encephalitis, particularly early in the disease course, and does not exclude the diagnosis 4

Why Not the Other Options

Multiple Sclerosis (MS) is excluded because:

• MS does not present acutely with high fever and seizures 1
• MS does not cause isolated temporal lobe hyperintensities bilaterally 2
• The acute presentation following URI with systemic illness is inconsistent with MS 1

Temporal lobe epilepsy is excluded because:

• Primary epilepsy does not cause fever or acute illness 1
• Epilepsy does not produce temporal lobe hyperintensities on MRI (structural lesions would be chronic) 2
• The acute presentation with systemic symptoms indicates an infectious/inflammatory process 1, 5

Immediate Management Required

Empiric IV acyclovir must be started immediately without waiting for CSF PCR confirmation:

• Dosing: 10 mg/kg IV every 8 hours for adults (adjust for renal function) 2
• Duration: Minimum 14-21 days 1
• Delaying treatment while awaiting confirmatory testing dramatically increases mortality and morbidity 2, 6

Diagnostic Confirmation

CSF HSV PCR is the diagnostic test of choice (sensitivity 95%, specificity 99%) 1, but critical caveats include:

• False negatives can occur in the first 72 hours of illness, with subsequent testing becoming positive 3, 4
• A single negative PCR does not exclude HSV encephalitis if clinical suspicion remains high 2, 7
• Treatment should not be discontinued based on initial negative results if the clinical picture is consistent 2, 7

MRI findings support the diagnosis with:

• High signal intensity on T2-weighted and FLAIR images in temporal lobes 1, 2
• Diffusion-weighted imaging shows higher sensitivity for early changes 2
• MRI has approximately 90% sensitivity when performed within 48 hours 2

Common Pitfalls to Avoid

• Do not wait for CSF PCR results before starting acyclovir - empiric treatment is essential 2, 6
• Do not rely on normal initial CSF findings to exclude HSE - isolated protein elevation or even completely normal CSF can occur early 4
• Do not stop acyclovir prematurely if initial tests are negative but clinical suspicion remains high 2, 7
• Consider autoimmune encephalitis if the patient fails to respond to acyclovir, as this can be triggered by HSV 7