Studies on viral encephalitis with emphasis on herpes simplex encephalitis

In this thesis studies of two types of viral CNS-infections are presented; influenza related encephalitis and herpes simplex encephalitis (HSE). Influenza related encephalitis/encephalopathy has been reported to increase both in incidence and severity in the Japanese population the last decade. We wanted to assess the incidence of the disease in Sweden and evaluate the clinical picture of the disease. The cases were identified through the Swedish National Inpatient Register, and the patient records were evaluated. Between the years 1987 and 1998 the incidence of influenza related encephalitis was 0.21 cases per million population and year. All 8 cases whose records could be evaluated recovered without sequelae. There were no pandemic influenza outbreaks during the study period and all but one of the evaluated cases occurred during A(H3N2)-dominated seasonal outbreaks. We conclude that, in Sweden during seasonal influenza outbreaks, influenza related encephalitis is a very rare complication, which resolves without sequelae.

HSE is the most common of the sporadically occurring forms of viral encephalitis. We have investigated the incidence, morbidity, case fatality rate, and virological diagnoses of HSE in Sweden during a 12-year period. The incidence was 2.2 cases per million population and year. No diseases predisposing to HSE could be found. The post-HSE morbidity was considerable with elevated risk for epilepsy, neuropsychiatric disability, infections, diabetes and venous thromboembolism. The one-year mortality rate was 14%.

In a material from a clinical trial of acyclovir vs.vidarabine on HSE, we studied if antibody levels and viral load correlates with outcome. Viral load dropped rapidly in the acyclovir treated patient, but there was no difference between outcome groups. In the patients treated with vidarabine, high IgG-antibodies to herpes simplex virus (HSV) in the cerebrospinal fluid (CSF) at admission was protective, indicating that anti-HSV-IgG in CSF has some ability to control the infection.

Acute or subacute neurological deterioration after HSE has been described as relapsing HSE. In a prospective cohort of 32 HSE-patients there were 4 patients with relapse. At relapse none of the patients had positive HSV PCR in the CSF, suggesting that the pathogenesis is not mediated by direct viral cytotoxicity. An immunological imbalance with low antiinflammatory activity and elevated proinflammatory activity indicates that the pathogenesis in relapsing cases can be immunologically mediated.

This thesis gives baseline epidemiological data on influenza related encephalitis that can be useful when influenza epidemiology changes. A nation wide study establishes that HSE still is a serious disease with high morbidity, despite access to current antiviral therapy. Our studies support the hypothesis that the immunological response to herpes simplex virus can aggravate the brain damage in HSE. Immunomodulating therapy regimens should be studied.

List of scientific papers

I. Hjalmarsson A, Blomqvist P, Brytting M, Linde A, Sköldenberg B (2009). Encephalitis after influenza in Sweden 1987-1998: a rare complication of a common infection. Eur Neurol. 61(5): 289-94. Epub 2009 Mar 17
https://pubmed.ncbi.nlm.nih.gov/19295216

II. Hjalmarsson A, Blomqvist P, Sköldenberg B (2007). Herpes simplex encephalitis in Sweden, 1990-2001: incidence, morbidity, and mortality. Clin Infect Dis. 45(7): 875-80. Epub 2007 Aug 24
https://pubmed.ncbi.nlm.nih.gov/17806053

III. Hjalmarsson A, Granath F, Forsgren M, Brytting M, Blomqvist P, Sköldenberg B (2009). Prognostic value of intrathecal antibody production and DNA viral load in cerebrospinal fluid of patients with herpes simplex encephalitis. J Neurol. 256(8): 1243-51. Epub 2009 Apr 8
https://pubmed.ncbi.nlm.nih.gov/19353228

IV. Sköldenberg B, Aurelius E, Hjalmarsson A, Sabri F, Forsgren M, Andersson B, Linde A, Strannegård O, Studahl M, Hagberg L, Rosengren L (2006). Incidence and pathogenesis of clinical relapse after herpes simplex encephalitis in adults. J Neurol. 253(2): 163-70. Epub 2005 Oct 17
https://pubmed.ncbi.nlm.nih.gov/16222428

V. Hjalmarsson A, Aurelius E, Glimåker M, Tüll Nyman A, Hart J, Sköldenberg B (2009). Subacute contralateral relapse in herpes simplex encephalitis. neuropsychological follow-up, magnetic resonance volumetry and markers of inflammation. [Manuscript]