In immunocompetent patients, Herpes simplex virus encephalitis (HSV-1) affects medial temporal, orbitofrontal, insular regions, with necrotizing hemorrhagic inflammation with CD8⁺ T-cells, microglial nodules, viral inclusions, and B-cell infiltrates aiding viral clearance. In antibody-deficient hosts, the infection can be diffuse and prolonged with sparse B cells, dominant CD8⁺/macrophage inflammation, abundant viral inclusions, and persistent viral activity. Parainfectious encephalitis is a post-infectious, immune-mediated process requiring recognition for immunotherapy rather than antiviral treatment. 

After no clinical improvement with acyclovir treatment, further work up revealed pan-hypogammaglobulinemia and he was started on IVIG. PET scan was negative. Repeat MRI showed worsening of diffuse lentiform meningeal enhancement. Brain biopsy showed a T-cell–predominant inflammatory infiltrate, microglial activation, negative CD19, negative HSV and SV40 immunostains. Given the concern for para-infectious encephalitis, the patient received IVMP followed by high dose oral steroid taper. Patient improved radiographically and clinically, and was discharged without additional immunosuppressive medications.

Immunocompromised patients with HSV-1 encephalitis often show more widespread brain involvement due to impaired viral control. In our patient, lack of clinical improvement despite antiviral therapy, worsening MRI findings, CSF pleocytosis with elevated protein, and severe hypogammaglobulinemia suggested an autoimmune or T-cell–mediated encephalitis. The patient did improve after immunotherapy with IVIG and corticosteroids. Brain biopsy showed T-cell–predominant meningoencephalitis, negative for HSV without B-cell infiltrates—consistent with a T-cell–driven autoimmune process in the setting of CVID. This rare case emphasizes early recognition of post-infectious, T-cell–mediated encephalitis to guide timely immunotherapy and recovery.