In a patient with new‑onset seizures and MRI showing bilateral frontal‑lobe T2/FLAIR hyperintensities with possible diffusion restriction and meningeal enhancement, what infectious etiologies should be considered and what empiric antimicrobial therapy is recommended?

Infectious Causes of Seizures with Bilateral Frontal Lobe Hyperintensities

Immediate Empiric Antimicrobial Therapy

Start intravenous acyclovir 10 mg/kg every 8 hours immediately (20 mg/kg every 8 hours in children) without waiting for diagnostic confirmation, as HSV encephalitis remains the most treatable cause of viral encephalitis and delays in treatment significantly increase mortality and morbidity. 1, 2

Primary Infectious Etiologies to Consider

Herpes Simplex Virus (HSV) Encephalitis

• HSV-1 accounts for 25-40% of all sporadic encephalitis cases worldwide and is the most common identified infectious cause 2
• Classic presentation includes fever, new-onset seizures, and altered mental status 1, 2
• While HSV typically affects temporal lobes bilaterally in >90% of cases, extratemporal involvement including frontal lobes is not uncommon 1, 2
• CSF HSV PCR has 95-98% sensitivity and should be obtained between days 2-10 of illness 2
• MRI shows T2/FLAIR hyperintensities with possible diffusion restriction 1

Bacterial Meningitis with Encephalitic Component

• Bacterial meningitis can progress to involve brain parenchyma, causing meningoencephalitis 1
• Look for high fever, nuchal rigidity, and rapid clinical deterioration 1
• CSF typically shows elevated protein, low glucose, and polymorphonuclear pleocytosis 1
• Add empiric bacterial coverage with vancomycin plus third-generation cephalosporin (ceftriaxone or cefotaxime) if bacterial meningitis cannot be excluded 1

Neurosyphilis

• Can present as acute limbic encephalitis with bilateral temporal and frontal lobe involvement 3
• May cause sudden onset behavioral changes, seizures, and altered consciousness 3
• Requires serum and CSF syphilis testing (RPR, VDRL, FTA-ABS) 1
• Treatment is penicillin G if confirmed 1, 3

Autoimmune/Antibody-Mediated Encephalitis

• NMDA-receptor antibody and VGKC-complex antibody encephalitis should be considered, as 20% of encephalitis cases in children have autoantibody etiology 1
• Presents with seizures, behavioral changes, and psychiatric symptoms 1, 4
• MRI may show bilateral but asymmetric hyperintense lesions on T2/FLAIR involving subcortical and periventricular white matter 1
• CSF often shows lymphocytosis and elevated protein 1
• High-dose intravenous corticosteroids are first-line treatment for antibody-mediated encephalitis 1, 4

Other Viral Encephalitides

• Varicella-zoster virus (VZV) causes ischemic or hemorrhagic infarcts with intracranial arterial abnormalities 2
• Enterovirus may cause generalized parenchymal destruction or brainstem predominant disease 2
• Japanese encephalitis typically involves thalamus and basal ganglia, not frontal lobes 2

Parasitic Infections

• Neurocysticercosis (Taenia solium) presents with seizures as most common manifestation 1
• CT or MRI reveals cystic lesions, some with calcifications; ring enhancement suggests cyst degeneration 1
• Treatment with albendazole or praziquantel should be individualized; corticosteroids often needed 1

Critical Diagnostic Workup

Immediate Neuroimaging

• MRI brain with and without contrast is the imaging modality of choice, with 90% sensitivity within 48 hours compared to only 25% for CT 1, 2
• Obtain T1, T2, FLAIR, diffusion-weighted imaging (DWI), and post-contrast sequences 1
• Look for meningeal enhancement, diffusion restriction, and pattern of involvement 1

Lumbar Puncture (if no contraindication)

• Perform after neuroimaging if no evidence of increased intracranial pressure 1, 2
• Send CSF for: cell count with differential, protein, glucose, Gram stain, bacterial culture 2
• HSV PCR (sensitivity 96-98%), VZV PCR, enterovirus PCR 1, 2
• CSF antibody testing for autoimmune encephalitis (NMDA-receptor, VGKC-complex) 1
• Syphilis serology (VDRL) 1
• Consider CSF oligoclonal bands if demyelinating process suspected 1

Additional Testing

• EEG should be performed to detect periodic lateralizing epileptiform discharges (seen in ~80% of HSV encephalitis) and to identify non-convulsive status epilepticus 2
• Serum autoantibody panel (NMDA-receptor, VGKC-complex antibodies) 1
• Serum syphilis testing (RPR, FTA-ABS) 1
• Blood cultures if bacterial infection suspected 1

Key Differentiating Features

Acute Disseminated Encephalomyelitis (ADEM)

• More common in children, typically follows viral illness or vaccination by several days 1
• MRI shows multifocal, bilateral but asymmetric large hyperintense lesions on T2/FLAIR involving mainly subcortical and periventricular white matter 1
• Generally absence of fever at presentation distinguishes from acute infectious encephalitis 1
• Treatment is corticosteroids, not antimicrobials 1

Seizure-Related MRI Changes

• Prolonged seizure activity alone can cause T2/FLAIR hyperintensities 5, 6
• These changes are typically unilateral (75.9% of cases) and affect anterior circulation territories 5
• Corresponding decreased signal on DWI with normal ADC helps distinguish seizure-related changes from infectious/inflammatory processes 5
• EEG abnormalities localize to areas of MR signal change 5

Common Pitfalls to Avoid

• Never delay acyclovir while awaiting HSV PCR results or definitive imaging, as mortality increases significantly with treatment delays 1, 2
• Do not rely on CT alone to rule out encephalitis due to its poor sensitivity (25%) 1, 2
• Do not discontinue acyclovir if initial CSF PCR is negative but clinical suspicion remains high, as false negatives occur especially early in disease 2
• Do not assume bilateral frontal involvement excludes HSV—extratemporal involvement occurs and should not delay treatment 1, 2
• Do not miss autoimmune encephalitis by focusing solely on infectious causes—obtain autoantibody testing in all cases 1, 4
• Behavioral changes can be mistaken for primary psychiatric illness, delaying appropriate treatment 4

Treatment Duration and Monitoring

• Continue IV acyclovir for minimum 14-21 days in adults with confirmed HSV encephalitis 2
• Adjust acyclovir dose for renal impairment 1
• Repeat lumbar puncture at end of treatment to document clearance of HSV DNA from CSF may be considered in severe cases 1
• All patients require comprehensive rehabilitation assessment before discharge, as neurological sequelae may not be immediately apparent 7, 4
• Arrange outpatient follow-up with neurology and infectious diseases 7, 4