Child Neurology: Intractable Epilepsy and Transient Deficits in a Patient With a History of Herpes Simplex Virus Encephalitis

Discussion

HSV is the most common cause of viral encephalitis in developed countries.² The annual incidence of HSV-1 encephalitis in the United States is estimated to be 4,000 cases, with one-third of these cases affecting children.² As per Infectious Diseases Society of America guidelines, adequate treatment of HSE requires a 3-week course of acyclovir.² Although recurrence after completed therapy is thought to be uncommon, it has been reported in the literature. HSE recurrence occurs in approximately 5% of pediatric cases, commonly within weeks to months following initial infection.² In contrast, patients with HSV-related chronic granulomatous inflammation may have intractable epilepsy and viral reactivation years from initial disease.^4,–,6 Of note, the published cases of this unusual form of slow smoldering herpes encephalitis were first described after our patient's biopsy was performed. Detection of CSF HSV DNA by PCR is the gold standard for diagnosis of both initial and recurrent infection. This test may be falsely negative when tested too early in the disease course,² if a sample has insufficient cells, or if a less-sensitive, qualitative assay is used. Our patient's intractable epilepsy is likely the sequelae of a remote episode of HSE complicated by chronic granulomatous inflammation. This is supported by her clinical course, histopathologic evidence, and positive HSV PCR during her most recent clinical event.

Several genetic mutations are associated with increased susceptibility to HSE and its recurrence. Most mutations involve the interferon-α/β and γ signaling pathways, as well as the toll-like receptor (TLR) pathway, specifically TLR3.^2,5,6 These mutations are thought to disrupt cell-autonomous immunity in neurons and oligodendrocytes. Whole exome sequencing was performed for our patient. Interestingly, it did not detect any mutations or deficiencies known to confer an increased risk of HSE recurrence.

In addition to a recurrent infectious process, HSV reactivation may also cause a recurrent aseptic meningitis, termed Mollaret meningitis. In Mollaret meningitis, recurrent meningeal symptoms last for 2 to 5 days, then spontaneously resolve.⁷ This condition may also variably manifest with seizures, hallucinations, and altered mentation.⁷ Patients typically experience 3 to 10 lifetime events.⁷ CSF analysis reveals lymphocytic pleocytosis and HSV DNA by PCR is almost always positive, more commonly HSV-2. Although Mollaret meningitis is by definition a benign, self-resolving condition, IV acyclovir is administered for suspected cases.⁷

More recently, postinfectious inflammatory syndromes secondary to HSV have been recognized. Among these is a post-HSV autoimmune encephalitis mediated by NMDAR autoantibody.^8,–,10 Anti-NMDA encephalitis is critical to identify because early immunotherapy can improve neurologic outcomes. Anti-NMDAR antibody was not tested during our patient's remote episodes. We have since tested our patient for NMDAR autoantibody and it is negative.

Although HSV is widely recognized as a devastating cause of acute encephalitis, it is important to acknowledge its potential long-term sequelae. We recommend that providers have a low threshold to obtain CSF for immunologic and viral testing when patients with a history of HSV develop recurrent neurologic symptoms. Symptom recurrence in this population may be due to either immune-mediated or virally mediated processes, each requiring targeted therapy. In our patient's case, identification of HSV-1 by PCR prompted a complete course of antiviral therapy with acyclovir, ultimately leading to clinical recovery.