CASE REPORT Aure´ lie Vendrely Æ Boris Bienvenu Æ Jacques Gasnault Jean Baptiste Thiebault Æ Dominique Salmon Franc¸ oise Gray Fulminant inflammatory leukoencephalopathy associated with HAART-induced immune restoration in AIDS-related progressive multifocal leukoencephalopathy Received: 10 November 2004 / Revised: 22 December 2004 / Accepted: 22 December 2004 / Published online: 1 March 2005 Ó Springer-Verlag 2005 Abstract HAART-induced immune restoration is bene- ficial for patients with AIDS-related progressive multi- focal leukoencephalopathy (PML). However, in rare instances, an immune-reconstitution inflammatory syn- drome (IRIS) may cause paradoxical clinical deteriora- tion. We report the neuropathological study of an AIDS patient who presented with progressive cognitive dete- rioration; CD4 + count was 117 and the HIV viral load >10 4 ; imaging showed non-enhancing lesions consistent with PML. Following initiation of HAART, CD4 + was 300 and HIV viral load <10 3 , 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 lym- phocytes 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 accen- tuation 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 under- standing of the mechanisms of the IRIS may enable prevention or cure of this severe, sometimes fatal complication of HAART. Keywords Progressive multifocal leukoencephalopathy Æ Acquired immunodeficiency syndrome Æ Immune-reconstitution inflammatory syndrome Æ Acute perivenous leukoencephalitis Æ HAART Introduction Introduction of combination anti-retroviral treatment, also called highly active anti-retroviral therapy (HAART), has dramatically reduced morbidity and mortality in HIV infected patients [22], as well as improving their quality of life. These benefits are mainly due to decreased human immunodeficiency virus (HIV) viral load (VL) and restored immune function with increased CD4 + lymphocytes [1, 38]. The spectrum of acquired immune deficiency syn- drome (AIDS)-related diseases has changed [3, 5]. With regard to the central nervous system (CNS), epidemiological studies show that most opportunistic A. Vendrely Æ F. Gray (&) Service Central d’Anatomie et de Cytologie Pathologiques, AP-HP Hoˆpital Lariboisie`re, 2 rue Ambroise Pare´, 75475 Paris, France E-mail: francoise.gray@lrb.ap-hop-paris.fr Tel.: +33-1-4995-8421 Fax: +33-1-4995-8536 B. Bienvenu Æ D. Salmon Service de Me´decine Interne II, AP-HP Hoˆpital Cochin, Paris, France J. Gasnault UF de Suites et de Re´adaptation, Service de Me´decine Interne, et des Maladies Infectieuses, AP-HP Hoˆpital Biceˆtre, Paris, France J. B. Thiebault Service de Neurochirurgie, Fondation Adolphe de Rothschild, Paris, France Acta Neuropathol (2005) 109: 449–455 DOI 10.1007/s00401-005-0983-y