Chronic granulomatous herpes simplex encephalitis (CGHSE) is a rare complication following infantile and pediatric herpes simplex virus encephalitis (HSVE). Clinically, it follows a biphasic course, with acute HSVE later followed by drug-resistant seizures and progressive neurologic deterioration. Convincing evidence is lacking for whether CGHSE occurs due to virus reactivation versus post-infectious inflammatory sequelae.

The neuropathologic findings of two patients who underwent epilepsy surgery following remote infectious encephalitis are herein discussed. The first case is previously unreported and confirmed to be associated with HSV-I, and the second case, newly re-examined, is previously reported and of presumed HSV-I encephalitis.

The histological findings in the current cases were consistent with chronic, ongoing inflammation, both of which harboured parenchymal HSV-I DNA by PCR. There were no HSV antigens detected via immunohistochemistry nor viral inclusions seen on the H&E sections. A novel finding, shared by both cases, is the identification of cytoplasmic phosphorylated tau-immunopositive components: neurofibrillary tangles, pretangles and neuropil threads. These were demonstrated within regions of inflammation as well as seemingly uninvolved areas. 

Tau hyperphosphorylation has been reported following other infections, such as post-measles subacute sclerosing panencephalitis and HIV-associated neurocognitive disorders. HSV-I infection has been postulated to promote tau protein hyperphosphorylation. HSV-I primary infection and reactivation have been associated with phosphorylated tau accumulation in murine models. HSV-I in vitro infection models exposed to acyclovir treatment demonstrate dose-dependent reductions in phosphorylated tau accumulation. While in vitro murine, monkey and human experimental data have demonstrated hyperphosphorylated tau accumulates following HSV-I infection, to our knowledge, this may represent the first patient report of abnormal phosphorylated tau accumulation associated with neuropathologic chronic granulomatous HSVE. Further investigation into the possibility that tau accumulation contributes to long-term neurologic sequelae among HSVE survivors may be warranted.