Journal of Neurology

, Volume 253, Issue 2, pp 163–170 | Cite as

Incidence and pathogenesis of clinical relapse after herpes simplex encephalitis in adults

  • B. Sköldenberg
  • E. Aurelius
  • A. Hjalmarsson
  • F. Sabri
  • M. Forsgren
  • B. Andersson
  • A. Linde
  • Ö. Strannegård
  • M. Studahl
  • L. Hagberg
  • L. Rosengren
ORIGINAL COMMUNICATION

Abstract

Objectives

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. Fiftynine batched, paired CSF and serum samples from the eight HSE patients were analysed for soluble activity markers, predominantly cytokines and mediators (interferon– γ, soluble CD8, tumour necrosis factor–α, and interleukin–10), amount of HSV–DNA and markers of glial and neuronal destruction (neurofilament protein, glial fibrillary acidic protein, S–100–β, 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.

Conclusion

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.

Key words

relapse of herpes simplex encephalitis cerebrospinal fluid HSV–DNA soluble CD8 and interleukin–10 neurofilament protein 

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References

  1. 1.
    Sköldenberg B, Forsgren M, Alestig K, Bergström T, et al. (1984) Acyclovir versus vidarabine in herpes simplex encephalitis. Randomised multicentre study in consecutive Swedish patients. Lancet ii:707–711Google Scholar
  2. 2.
    Whitley RJ, Soong SJ, Hirsch MS, et al. (1981) Herpes simplex encephalitis. N Engl J Med 304:313–318PubMedGoogle Scholar
  3. 3.
    Koenig H, Rabinowitz SG, Day E, Miller V (1979) Post–infectious encephalomyelitis after successful treatment of herpes simplex encephalitis with adenine arabinoside. Ultrastructural observations. N Engl J Med 300:1089–1093PubMedGoogle Scholar
  4. 4.
    Davis LE, McLaren LC (1983) Relapsing herpes simplex encephalitis following antiviral therapy. Ann Neurol 13:192–195CrossRefPubMedGoogle Scholar
  5. 5.
    Dix RD, Baringer JR, Panitch HS, Rosenberg SH, et al. (1983) Recurrent herpes simplex encephalitis: Recovery of virus after ara–A treatment. Ann Neurol 13:196–200CrossRefPubMedGoogle Scholar
  6. 6.
    Yamada S, Kameyama T, Nagaya S, Hashizume Y, Yoshida M (2003) Relapsing herpes simplex encephalitis: pathological confirmation of viral reactivation. J Neurol Neurosurg Psychiatry 74:262–264PubMedGoogle Scholar
  7. 7.
    Abramson JS, Roach SE, Levy HB (1984) Post–infectious encephalopathy after treatment of herpes simplex encephalitis with acyclovir. Ped Infect Dis 3:146–147Google Scholar
  8. 8.
    Wang HS, Kuo MF, Huang SC, Chou ML (1994) Choreoathetosis as an initial sign of relapsing of herpes simplex encephalitis. Pediatric Neurol 11:341–344Google Scholar
  9. 9.
    Barthez–Carpentier MA, Rozenberg F, Dussaix E, et al. (1995) Relapse of herpes simplex encephalitis. J Child Neurol 10:363–368PubMedGoogle Scholar
  10. 10.
    De Tiège XM, Rozenberg F, Des Portes V, Lobut JB, Lebon P, Ponsot G, Héron B (2003) Herpes simplex encephalitis relapses in children. Differentiation of two neurologic entities. Neurology 61:241–243PubMedGoogle Scholar
  11. 11.
    Aurelius A, Andersson A, Forsgren M, Sköldenberg B, Strannegård Ö (1994) Cytokine and other markers of intrathecal immune response in patients with herpes simplex encephalitis. J Inf Dis 170:678–681Google Scholar
  12. 12.
    Aurelius A, Forsgren M, Sköldenberg B, Strannegård Ö (1993) Persistent intrathecal immune activation in patients with herpes simplex encephalitis. J Inf Dis 168:1248–1252Google Scholar
  13. 13.
    Glimåker M, Kragsbjerg P, Forsgren M, Olcén P (1993) TNF–α in cerebrospinal fluid from patients with meningitis of different etiology. J Infect Dis 167:882–889PubMedGoogle Scholar
  14. 14.
    Günther G, Haglund M, Lindquist L, Forsgren M, Sköldenberg B (1996) Intrathecal production of neopterin and β–2 microglobulin in Tick–borne encephalitis (TBE) compared to meningo–encephalitis of other etiology. Scand J Inf Dis 28:131–138Google Scholar
  15. 15.
    Rosengren LE, Karlsson J–E, Karlsson J–O, Persson LI, Wikkelso C (1996) Patients with amyotrophic lateral sclerosis and other neurodegenerative diseases have increased levels of neurofilament protein in CSF. J Neurochem 67:2013–2018PubMedGoogle Scholar
  16. 16.
    Mokuno K, Kato K, Kawai K, Matsuoka Y, Yanagi T, Sobue I (1983) Neuronspecific enolase and S–100 protein levels in cerebrospinal fluid of patients with various neurological diseases. J Neurol Sci 60:443–451CrossRefPubMedGoogle Scholar
  17. 17.
    Hay E, Royds JA, Davies–Jones GA, Lewtas NA, Timperley WR, Taylor CB (1984) Cerebrospinal fluid enolase in stroke. J Neurol Neurosurg Psychiatry 47:724–729PubMedGoogle Scholar
  18. 18.
    Li Y, Wang X, Yang Z (1995) Neuronspecific enolase in patients with acute ischemic stroke and related dementia. Chin Med J (Engl) 108:221–223PubMedGoogle Scholar
  19. 19.
    Aurell A, Rosengren LE, Karlsson B, Haglid KG (1991) Determination of S–100 and glial fibrillary acidic protein concentrations in cerebrospinal fluid after brain infarction. Stroke 22:1254–1258PubMedGoogle Scholar
  20. 20.
    Studahl M, Rosengren L, Gunther G, Hagberg L (2000) Difference in pathogenesis between herpes simplex virus type 1 encephalitis and tick–borne encephalitis demonstrated by means of cerebrospinal fluid markers of glial and neuronal destruction. J Neurol 247:636–642CrossRefPubMedGoogle Scholar
  21. 21.
    Aurelius E, Johansson B, Sköldenberg B, Staland Å, Forsgren M (1991) Rapid diagnosis of herpes simplex encephalitis by nested polymerase chain reaction assay of cerebrospinal fluid. Lancet 337:189–192CrossRefPubMedGoogle Scholar
  22. 22.
    Aurelius E, Forsgren M, Skoog E, Sköldenberg B (1989) Serodiagnosis of herpes simplex encephalitis by antibody capture enzyme–linked immunosorbent assay. Serodiagn Immunother Infect Dis 3:249–258Google Scholar
  23. 23.
    Schloss L, van Loon AM, Cinque P, et al. (2003) An international external quality assessment of nucleic acid amplification of herpes simplex virus. J Clin Virol 28:175–185CrossRefPubMedGoogle Scholar
  24. 24.
    Hjalmarsson A, Aurelius E, Glimåker M, Hart J, Kraut M, Sköldenberg B (2005) Contralateral, subacute relapse of herpes simplex encephalitis with severe sequels. In manuscriptGoogle Scholar
  25. 25.
    Ito Y, Kimura H, Yabuta Y, Ando Y, Murakami T, Shiomi M, Morishima T (2000) Exacerbation of herpes simplex encephalitis after successful treatment with acyclovir. Clin Infect Dis 30:185–187CrossRefPubMedGoogle Scholar
  26. 26.
    Barthez–Carpentier MA, Rozenberg F, Dussaix E, et al. (1995) Relapse of herpes simplex encephalitis. J Child Neurol 10:363–368PubMedGoogle Scholar
  27. 27.
    Hargrave DR, Webb DW (1998) Movement disorder in association with herpes simplex encephalitis in children: a review. Dev Med Child Neurol 40:640–642PubMedGoogle Scholar
  28. 28.
    Yamada S, Kameyama T, Nagaya S, Hashizume Y, Yoshida M (2003) Relapsing herpes simplex encephalitis: pathological confirmation of viral reactivation. J Neurol Neurosurg Psychiatry 7:262–264Google Scholar
  29. 29.
    Billiau A (1996) Interferon–γ. Biology and role in pathogenesis. Adv Immunology 62:61–129Google Scholar
  30. 30.
    Lebon P, Boutin B, Dulac O, Ponsot G, Arthuis M (1988) Interferon–γ in acute and subacute encephalitis. BMJ 296: 9–11PubMedGoogle Scholar
  31. 31.
    Frei K, Leist TP, Meager A, et al. (1988) Production of B–cell stimulatory factor and interferon γ in the central nervous system during viral meningitis and encephalitis. Evaluation in a murine model infection and in patients. J Exp Med 168:449–453CrossRefPubMedGoogle Scholar
  32. 32.
    Fiorentino DF, Zlotnik A, Mosmann TR, O'Garra A (1991) IL–10 inhibits cytokine production by activated macrophages. J Immunol 147:3815–3822PubMedGoogle Scholar
  33. 33.
    Abbott RJ, Bolderson I, Gruer PJK (1987) Immunoreactive IFN–γ in CSF in neurological disorders. J Neurol Neurosurg Psychiatry 50:882–885PubMedGoogle Scholar
  34. 34.
    Griffin DE, Ward BJ, Jauregui E, Johnson RT, Vaisberg A (1990) Immune activation during measles: Interferon–γ and neopterin in plasma and cerebrospinal fluid in complicated and uncomplicated disease. J Inf Dis 161:449–453Google Scholar
  35. 35.
    Fong TA, Mosmann TR (1990) Alloreactive murine CD8+ T cell clones secrete the Th1 pattern of cytokines. J Immunol 144:1744–1752PubMedGoogle Scholar
  36. 36.
    McCarron RM, Wang L, Racke MK, McFarlin DE, Spatz M (1993) Cytokine– regulated adhesion between encephalitogenic T lymphocytes and cerebrovascular endothelial cells. J Neuroimmunol 43:23–30CrossRefPubMedGoogle Scholar
  37. 37.
    Florquin S, Amraoui Z, Abramowicz D, Goldman M (1994) Systemic release and protective role of IL–10 in staphylococcal enterotoxin B–induced shock in mice. J Immunol 153:2618–2623PubMedGoogle Scholar
  38. 38.
    Chomarat P, Rissoan MC, Banchereau J, Miossec P (1993) Interferon gamma inhibits interleukin 10 production by monocytes. J Exp Med 177:523–527CrossRefPubMedGoogle Scholar
  39. 39.
    Sabri F, De Milito A, Pirskanen R, Elovaara I, Hagberg L, Cinque P, Price R, Chiodi F (2001) Elevated levels of soluble Fas and Fas ligand in cerebrospinal fluid of patients with AIDS dementia complex. J Neuroimmunol 114:197–206CrossRefPubMedGoogle Scholar
  40. 40.
    Ohsako S, Hara M, Harigai M, Fukasawa C, Kashiwazaki S (1994) Expression and function of Fas antigen and bcl–2 in human systemic lupus erythematosus lymphocytes. Clin Immunol Immunopathol 73:109–114CrossRefPubMedGoogle Scholar
  41. 41.
    Ciusani E, Frigerio S, Gelati M, Corsini E, Dufour A, Nespolo A, La Mantia L, Milanese C, Massa G, Salmaggi A (1998) Soluble Fas (Apo–1) levels in cerebrospinal fluid of multiple sclerosis patients. J Neuroimmunol 82:5–12CrossRefPubMedGoogle Scholar

Copyright information

© Steinkopff-Verlag 2005

Authors and Affiliations

  • B. Sköldenberg
    • 1
  • E. Aurelius
    • 1
  • A. Hjalmarsson
    • 1
  • F. Sabri
    • 1
  • M. Forsgren
    • 2
  • B. Andersson
    • 3
  • A. Linde
    • 4
  • Ö. Strannegård
    • 5
  • M. Studahl
    • 6
  • L. Hagberg
    • 6
  • L. Rosengren
    • 7
  1. 1.Karolinska Institutet, Division of Infectious DiseasesDepartment of Medicine, Karolinska University HospitalStockholmSweden
  2. 2.Department of Clinical VirologyKarolinska Institute, Huddinge University HospitalStockholmSweden
  3. 3.Nova Medical CALABSt Göran HospitalStockholmSweden
  4. 4.Department of VirologySwedish Institute for Infectious Diseases, ControlStockholmSweden
  5. 5.Department of Clinical MicrobiologySahlgrens University HospitalGothenburgSweden
  6. 6.Department of Infectious DiseasesSahlgrens/Östra University HospitalGothenburgSweden
  7. 7.Department of Clinical NeuroscienceUnit of Neurochemistry, Sahlgrens University HospitalGothenburgSweden

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