Acta Neuropathologica

, Volume 109, Issue 4, pp 449–455 | Cite as

Fulminant inflammatory leukoencephalopathy associated with HAART-induced immune restoration in AIDS-related progressive multifocal leukoencephalopathy

  • Aurélie Vendrely
  • Boris Bienvenu
  • Jacques Gasnault
  • Jean Baptiste Thiebault
  • Dominique Salmon
  • Françoise Gray
Case Report

Abstract

HAART-induced immune restoration is beneficial for patients with AIDS-related progressive multifocal leukoencephalopathy (PML). However, in rare instances, an immune-reconstitution inflammatory syndrome (IRIS) may cause paradoxical clinical deterioration. We report the neuropathological study of an AIDS patient who presented with progressive cognitive deterioration; CD4+ count was 117 and the HIV viral load >104; imaging showed non-enhancing lesions consistent with PML. Following initiation of HAART, CD4+ was 300 and HIV viral load <103, but his neurological symptoms continued to deteriorate. Imaging revealed an increase in the size and number of lesions and enhancement of all the lesions. A stereotactic biopsy showed severe inflammatory and demyelinating lesions with marked infiltration by macrophages and T lymphocytes in the absence of a detectable infectious agent. Despite high doses of steroids, the patient died 3 months after admission. Autopsy showed two types of lesions: (1) active inflammatory PML changes with abundant JC virus, and intraparenchymal and perivascular infiltration by T lymphocytes, and (2) acute perivenous leukoencephalitis devoid of JC virus. Most lymphocytes were CD8+ lymphocytes; CD4+ lymphocytes were virtually absent. Two pathological reactions were associated with the paradoxical clinical deterioration related to dysregulation of the immune response characteristic of IRIS in PML: (1) an accentuation of JCV infection, and (2) a nonspecific acute perivenous leukoencephalitis. We suggest that both these types of lesions are due to an imbalance of CD8+/CD4+ T cells, with massive infiltration of the cerebral parenchyma by CD8+ cytotoxic T lymphocytes in the absence of sufficient CD4+ response. Better understanding of the mechanisms of the IRIS may enable prevention or cure of this severe, sometimes fatal complication of HAART.

Keywords

Progressive multifocal leukoencephalopathy Acquired immunodeficiency syndrome Immune-reconstitution inflammatory syndrome Acute perivenous leukoencephalitis HAART 

Notes

Acknowledgements

Supported by grants to Dr. Gray from Agence Nationale de Recherches sur le SIDA (ANRS) and Ensemble Contre le SIDA (ECS). The authors wish to thank Dr. Catherine Keohane for kindly reviewing the English, Dr. Patrice LeFloch-Progent in the Service Central d’Anatomie et Cytologie Pathologiques at Hôpital Cochin (Pr. M.C. Vacher-Lavenu) who performed the autopsy, and Marie-Annick Bretel, Patrice Castagnet, Katia Dossou, Isabelle Levesque and Claudine Poron, for histological preparations.

References

  1. 1.
    Autran B, Carcelain G, Li TS, Blanc C, Mathez D, Tubiana R, Katlama C, Debre P, Leibowitch J (1997) Positive effects of combined antiretroviral therapy on CD4+ T cells homeostasis and function in advanced HIV cases. Science 277:112–116Google Scholar
  2. 2.
    Berger JR, Levy RM, Flomenhoft D, Dobbs M (1998) Predictive factors for prolonged survival in acquired immunodeficiency syndrome-associated progressive multifocal leukoencephalopathy. Ann Neurol 44:341–349Google Scholar
  3. 3.
    Bonnet F, Morlat P, Chene G, Mercie P, Neau D, Chossat I, Decoin M, Djossou F, Beylot J, Dabis F, groupe d’Epidémiologie Clinique du SIDA en Aquitaine (GECSA) (2002) Causes of death among HIV-infected patients in the era of highly active antiretroviral therapy, Bordeaux, France, 1998–1999. HIV Med 3:195–199CrossRefPubMedGoogle Scholar
  4. 4.
    Breton G, Seilhean D, Chérin P, Herson S, Benveniste O (2002) Paradoxical intracranial cryptococcoma in a human immunodeficiency virus-infected man being treated with combination antiretroviral therapy. Am J Med 113:155–157Google Scholar
  5. 5.
    Brodt HR, Kkamps BS, Gute P, Knupp B, Staszewski S, Helm EB (1997) Changing incidence of AIDS-defining illnesses in the era of antiretroviral combination therapy. AIDS 11:1731–1738Google Scholar
  6. 6.
    Cheng VCC, Yuen K-Y, Chan W-M, Wong SSY, Ma ESK, Chan RMT (2000) Immunorestitution disease involving the innate and adaptive response. Clin Infect Dis 30:882–892Google Scholar
  7. 7.
    Clifford DB, Yiannoutsos C, Glicksman M, Simpson DM, Singer EJ, Piliero PJ, Marra CM, Francis GM, McArthur JC, Tyler KL, Tselis AC, Hyslop NE (1999) HAART improves prognosis in HIV-associated progressive multifocal leukoencephalopathy. Neurology 52:623–625Google Scholar
  8. 8.
    Collazos J, Mayo J, Martinez E, Blanco MS (1999) Contrast enhancing PML as an immune reconstitution event in AIDS patients. AIDS 13:1426–1428Google Scholar
  9. 9.
    Connick E, Lederman MM, Kotzin BL, Spritzler J, Kuritzkes DR, St Clair M, Sevin AD, Fox L, Chiozzi MH, Leonard JM, Rousseau F, D’Arc Roe J, Martinez A, Kessler H, Landay A (2000) Immune reconstitution in the first year of potent antiretroviral therapy and its relationship to virologic response. J Infect Dis 181:358–563Google Scholar
  10. 10.
    Crump JA, Tyrer MJ, Lloyd-Owen SJ, Han LY, Lipman MC, Johnson MA (1998) Miliary tuberculosis with paradoxical expansion of intracranial tuberculomas complicating immunodeficiency virus infection in a patient receiving highly active antiretroviral therapy. Clin Infect Dis 26:1008–1009Google Scholar
  11. 11.
    De Simone JA Pomerantz RJ, Babinchak TJ (2000) Inflammatory reactions in HIV-1infected persons after initiation of HAART. Ann Intern Med 133:447–454Google Scholar
  12. 12.
    Dore G, Correll PK, Ly Y, Kaldor JM, Cooper DA, Brew BJ (1999) Changes to AIDS dementia complex in the era of highly active antiretroviral therapy. AIDS 13:1249–1253Google Scholar
  13. 13.
    Du Pasquier RA, Clark KW, Smith PS, Joseph JT, Mazullo JM, De Girolami U, Letvin NL, Koralnik IJ (2001) JCV-specific cellular immune response correlates with a favorable clinical outcome in HIV-infected individuals with progressive multifocal leukoencephalopathy. J Neurovirol 7:318–322Google Scholar
  14. 14.
    Foudraine NA, Hovenkamp E, Notermans DW, Meenhorst PL, Klein MR, Lange JM, Miedema F, Reiss P (1999) Immunopathology as a result of highly active antiretroviral therapy in HIV-1-infected patients. AIDS 13:177–184Google Scholar
  15. 15.
    Gasnault J, Taoufik Y, Goujard C Kousignian P, Abbed K, Boue F, Dussaix E, Delfraissy JF (1999) Prolonged survival without neurological impairment in patients with AIDS-related progressive multifocal leukoencephalopathy on potent compbined antiretroviral therapy. J Neurovirol 5:421–429Google Scholar
  16. 16.
    Gasnault J, Kahraman M, Goer de Herve MG de, Durali D, Delfraissy JF, Taoufik Y (2003) Critical role of JC virus-specific CD4 T-cell responses in preventing progressive multifocal leukoencephalopathy. AIDS 17:1443–1449Google Scholar
  17. 17.
    Gay FW, Drye TJ, Dick GW, Esiri MM (1997) The application of multifactorial cluster analysis in the staging of plaques in early multiple sclerosis. Identification and characterisation of the primary demyelinating lesion. Brain 120:1461–1483CrossRefPubMedGoogle Scholar
  18. 18.
    Gray F, Chrétien F, Vallat-Decouvelaere AV, Scaravilli F (2003) The changing pattern of HIV neuropathology in the HAART era. J Neuropathol Exp Neurol 62:429–440Google Scholar
  19. 19.
    Hartung HP, Grossman RI (2001) ADEM: distinct disease or part of MS spectrum? Neurology 56:1257–1260PubMedGoogle Scholar
  20. 20.
    Hoffmann C, Tabrizian S, Wolf E, Eggers C, Stoehr A, Plettenberg A, Buhk T, Stellbrink HJ, Horst HA, Jager H, Rosenkranz T (2001) Survival of AIDS patients with primary central nervous system lymphoma is dramatically improved by HAART-induced immune recovery. AIDS 15:2119–2127Google Scholar
  21. 21.
    Hoffmann C, Horst HA, Albrecht H, Schlote W (2003) Progressive multifocal leukoencephalopathy with unusual inflammatory response during antiretroviral treatment. J Neurol Neurosurg Psychiatry 74:1142–1144Google Scholar
  22. 22.
    Hogg RS, O’Shaughnessy MV, Gataric N, Yip B, Craib K, Schechter MT, Montaner JS (1997) Decline in deaths from AIDS due to new antiretrovirals. Lancet 349:1294Google Scholar
  23. 23.
    Jacobson MA, Zegans M, Pavan PR, O’Donnell JJ, Sattler F, Rao N, Owens S, Pollard R (1997) Cytomegalovirus retinitis after initiation of highly active antiretroviral therapy. Lancet 349:1443–1445Google Scholar
  24. 24.
    Jellinger KA, Setinek U, Drlicek M, Böhm G, Steurer A, Lintner F (2000) Neuropathology and general autopsy findings in AIDS during the last years. Acta Neuropathol 100:213–220Google Scholar
  25. 25.
    Karavellas MP, Plummer DJ, Macdonald JC, et al (1999) Incidence of immune recovery vitritis in cytomegalovirus retinitis patients following institution of successful HAART. J Infect Dis 179:697–700CrossRefPubMedGoogle Scholar
  26. 26.
    King MD, Perlino CA, Cinnamon J, Jernigan JA (2002) Paradoxical recurrent meningitis following therapy of cryptococcal meningitis: an immune reconstitution syndrome after initiation of highly active antiretroviral therapy. Int J STD AIDS 13:724–726Google Scholar
  27. 27.
    Koralnik IJ (2004) New insight into progressive multifocal leukoencephalopathy. Curr Opin Neurol 17:365–370Google Scholar
  28. 28.
    Kotecha N, George MJ, Smith TW, Corvi F, Litofsky NS (1998) Enhancing progressive multifocal leukoencephalopathy: an indicator of improved immune status? Am J Med 105:541–543CrossRefPubMedGoogle Scholar
  29. 29.
    Langford TD, Letendre SL, Marcotte TD, Ellis RJ, McCutchan JA, Grant I, Mallory ME, Hansen LA, Archibald S, Jernigan T, Masliah E, the HNRC group (2002) Severe, demyelinating leukoencephalopathy in AIDS patients on antiretroviral therapy. AIDS 16:1019–1029Google Scholar
  30. 30.
    Masliah E, DeTeresa RM, Mallory ME, Hansen LA (2000) Changes in pathological findings at autopsy in AIDS cases for the last 15 years. AIDS 14:69–74Google Scholar
  31. 31.
    Matloubian M, Concepcion RJ, Ahmed R (1994) CD4+ T cells are required to sustain CD8+ cytotoxic T-cell responses during chronic viral infection. J Virol 68:8056–8063Google Scholar
  32. 32.
    Miller RF, Isaacson PG, Hall-Craggs M, Lucas S, Gray F, Scaravilli F, An SF (2004) Cerebral CD8+ lymphocytosis in HIV-1 infected patients with immune restoration induced by HAART. Acta Neuropathol 108:17–23Google Scholar
  33. 33.
    Miralles P, Berenguer J, Lacruz C, Cosin J, Lopez JC, Padilla B, Munoz L, Garcia-de-Viedma D (2001) Inflammatory reactions in progressive multifocal leukoencephalopathy after highly active antiretroviral therapy. AIDS 15:1900–1902Google Scholar
  34. 34.
    Morgello S, Mahboob R, Yakoushina T, Khan S, Hague K (2002) Autopsy findings in human immunodeficiency virus-infected population over 2 decades: influences of gender, ethnicity, risk factors and time. Arch Pathol Lab Med 126:182–190Google Scholar
  35. 35.
    Neumann H, Medana IM, Bauer J, Lassmann H (2002) Cytotoxic T lymphocytes in autoimmune and degenerative CNS disease. Trends Neurosci 25: 313–319CrossRefPubMedGoogle Scholar
  36. 36.
    Nicoll JAR, Wilkinson D, Holmes C, Steart P, Markham H, Weller RO (2003) Neuropathology of human Alzheimer disease after immunization with amyloid-β peptide: a case report. Nat Med 9: 448–452CrossRefPubMedGoogle Scholar
  37. 37.
    Nuttall JJC, Wilmshurst JM, Ndondo AP, Yeats J, Corcoran C, Hussey GD, Eley BS (2004) Progressive multifocal leukoencephalopathy after initiation of highly active antiretroviral therapy in a child with advanced human immunodeficiency virus infection: a case of immune reconstitutioninflammatory syndrome. Pediatr Infect Dis J 23:683–685Google Scholar
  38. 38.
    Pakker NG, Ross MTL, Leeuwen R van, Jong MD de, Koot M, Reiss P, lange JM, Miedema F, Danner SA, Schellekens PT (1997) Patterns of T-cell repopulation, virus load replication, and restoration of T-cell function on HIV-infected persons during therapy with different antiretroviral agents. J Acquir Immune Defic Syndr Hum Retrovirol 16:318–326Google Scholar
  39. 39.
    Sacktor N, Lyles RH, Skolasky R, Kleeberger C, Selnes OA, Miller EN, Becker JT, Cohen B, McArthur JC (2001) HIV associated neurologic disease incidence changes: Multicenter AIDS cohort study, 1990–1998. Neurology 56:257–260Google Scholar
  40. 40.
    Safdar A, Rubocki RJ, Horvath JA, Narayan KK, Waldron RL (2002) Fatal immune restoration disease in human immunodeficiency virus type 1-infected patients with progressive multifocal leukoencephalopathy: impact of antiretroviral therapy-associated immune reconstitution. Clin Infect Dis 35:1250–1257Google Scholar
  41. 41.
    Scaravilli F, Esiri M, Sharer L, Gray F (2004) Infections of the central nervous system. In: Gray F, DeGirolami U, Poirier J (eds) Escourolle and Poirier Manual of Basic Neuropathology, 4th edn, Chapter 5. Butterworth Heinemann, Philadelphia, pp 113–144Google Scholar
  42. 42.
    Schmidbauer M, Budka H, Shah KV (1990) Progressive multifocal leukoencephalopathy (PML) in AIDS and in the pre-AIDS era. A neuropathological comparison using immunocytochemistry and in situ DNA hybridisation for virus detection. Acta Neuropathol 80:375–380Google Scholar
  43. 43.
    Shelburne SA, Hamill RJ, Rodriguez-Barradas MC, Greenberg SB, Atmar RL, Musher DW, Gathe JC Jr, Visnegarwala F, Trautner BW(2002) Immune reconstitution inflammatory syndrome. Emergence of a unique syndrome during HAART. Medicine 81:213–227Google Scholar
  44. 44.
    Tantisiriwat W, Tebas P, Clifford DB, Powderly WG, Fichtenbaum CJ (1998) Progressive multifocal leukoencephalopathy in patients with AIDS receiving highly active antiretroviral therapy. Clin Infect Dis 28:1152–1154Google Scholar
  45. 45.
    Tassié JM, Gasnault J, Bentata M, Deloumeaux J, Boué F, Billaud E, Costagliola D, the French Hospital Database on HIV (1999) Survival improvement of AIDS-related progressive multifocal leukoencephalopathy in the era of protease inhibitors. AIDS 13:1881–1887Google Scholar
  46. 46.
    Vago L, Bonetto S, Nebuloni M, Duca P, Carsana L, Zerbi P, D’Arminio-Monforte A (2002) Pathological findings in the CNS of AIDS patients on assumed ART regimens: retrospective study of 1597 autopsies. AIDS 16:1925–1928Google Scholar
  47. 47.
    Vallat-Decouvelaere AV, Chrétien F, Lorin de la Grandmaison G, Carlier R, Force G, Gray F (2003) La pathologie du système nerveux central liée au VIH à l’ère des multithérapies. Ann Pathol 23:408–423Google Scholar
  48. 48.
    Woods ML, MacGinley R, Eisen DP, Allworth AM (1998) HIV combination therapy: partial immune restitution unmasking latent cryptococcal infection. AIDS 12:1491–1494Google Scholar

Copyright information

© Springer-Verlag 2005

Authors and Affiliations

  • Aurélie Vendrely
    • 1
  • Boris Bienvenu
    • 2
  • Jacques Gasnault
    • 3
  • Jean Baptiste Thiebault
    • 4
  • Dominique Salmon
    • 2
  • Françoise Gray
    • 1
  1. 1.Service Central d’Anatomie et de Cytologie PathologiquesAP-HP Hôpital LariboisièreParisFrance
  2. 2.Service de Médecine Interne IIAP-HP Hôpital CochinParisFrance
  3. 3.UF de Suites et de Réadaptation, Service de Médecine Interne, et des Maladies InfectieusesAP-HP Hôpital BicêtreParisFrance
  4. 4.Service de NeurochirurgieFondation Adolphe de RothschildParisFrance

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