title: Incidence and pathogenesis of clinical relapse after herpes simplex encephalitis in adults.
abstract: OBJECTIVE
  To study the occurrence of relapse of herpes simplex encephalitis (HSE) and to find out whether soluble activity markers in cerebrospinal fluid (CSF) indicate direct viral or immune- mediated events.
  
  
  METHODS
  A consecutive series of 32 adult survivors of HSE were followed to determine the incidence of clinical relapse of HSE. Four patients had neurological deterioration interpreted as relapsing HSE. Four non-relapsing HSE cases were selected as matched controls. Fifty nine batched, paired CSF and serum samples from the eight HSE patients were analysed for soluble activity markers, predominantly cytokines and mediators (interferon-gamma, soluble CD8, tumour necrosis factor-alpha, and interleukin-10), amount of HSV-DNA and markers of glial and neuronal destruction (neurofilament protein, glial fibrillary acidic protein, S-100-beta, and neuron specific enolase).
  
  
  RESULTS
  Relapse of HSE was diagnosed in 3 of 26 (12 %) acyclovir-treated patients (5 episodes during 6.1 years of followup) and in 1 of 6 vidarabine-recipients. All relapses occurred from 1 to 4 months after acute HSE, except for a second relapse after 3.3 years in one patient. Computer tomography at relapses revealed few abnormalities apart from those found during the primary disease. Intravenous acyclovir and corticosteroids were given for 7-21 days in all the relapse patients. All relapse patients seemed to recover to the pre-relapse condition. HSV-DNA was demonstrated in CSF in all patients during the acute stage but not in any of 13 CSF samples taken during relapse phases. The HSV viral load during the acute stage of HSE was not higher or of longer duration in the relapsing patients than in the non-relapsing HSE controls. The levels of sCD8 were increased in nearly all CSF samples tested with peaks of sCD8 at one month of acute HSE. In all episodes of relapse, sCD8 peaks were detected during the first week at high levels. CSF levels of neuron-specific enolase, S-100 and glial fibrillary acidic protein were markedly lower at relapse than at the acute stage of HSV-1 encephalitis.
  
  
  CONCLUSIONS
  The lack of demonstrable HSV DNA in CSF, the lack of acute CSF signs and the lack of signs of neural and glia cells destruction indicate that a direct viral cytotoxicity is not the major pathogenic mechanism in relapse. Instead, the pronounced CSF proinflammatory immunological response and the relative lack of CSF anti-inflammatory cytokine IL-10 response suggest immunologically-mediated pathogenicity.
authors.affiliation: Karolinska Institutet, Division of Infectious Diseases, Department of Medicine, Karolinska University Hospital, Stockholm, Sweden. birgit.skoldenberg@medks.ki.se
authors.forename: B
authors.initials: B
authors.lastname: Sköldenberg
authors.forename: E
authors.initials: E
authors.lastname: Aurelius
authors.forename: A
authors.initials: A
authors.lastname: Hjalmarsson
authors.forename: F
authors.initials: F
authors.lastname: Sabri
authors.forename: M
authors.initials: M
authors.lastname: Forsgren
authors.forename: B
authors.initials: B
authors.lastname: Andersson
authors.forename: A
authors.initials: A
authors.lastname: Linde
authors.forename: O
authors.initials: O
authors.lastname: Strannegård
authors.forename: M
authors.initials: M
authors.lastname: Studahl
authors.forename: L
authors.initials: L
authors.lastname: Hagberg
authors.forename: L
authors.initials: L
authors.lastname: Rosengren
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D016022:Case-Control Studies; D016207:Cytokines / Q000134:cerebrospinal fluid; D020803:Encephalitis, Herpes Simplex / Q000134:cerebrospinal fluid* / Q000453:epidemiology / Q000473:pathology* / Q000503:physiopathology; D004797:Enzyme-Linked Immunosorbent Assay / Q000379:methods; D005260:Female; D005500:Follow-Up Studies; D005904:Glial Fibrillary Acidic Protein / Q000134:cerebrospinal fluid; D006561:Herpes Simplex / Q000134:cerebrospinal fluid* / Q000235:genetics; D006801:Humans; D015994:Incidence; D008297:Male; D008875:Middle Aged; D010751:Phosphopyruvate Hydratase / Q000134:cerebrospinal fluid; D011446:Prospective Studies; D012333:RNA, Messenger / Q000096:biosynthesis; D012008:Recurrence; D012189:Retrospective Studies; D020133:Reverse Transcriptase Polymerase Chain Reaction / Q000379:methods; D013997:Time Factors
chemical_list: D016207:Cytokines; D005904:Glial Fibrillary Acidic Protein; D012333:RNA, Messenger; D010751:Phosphopyruvate Hydratase