Inflammatory reactions in progressive multifocal leukoencephalopathy after highly active antiretroviral therapy

Three patients with progressive multifocal leukoencephalopathy (PML) treated with highly active antiretroviral therapy (HAART) worsened clinically and radiologically. At the time of deterioration all three had reduced HIV viraemia and increased CD4 cell counts. Brain biopsy in all three disclosed PML and marked perivascular lymphoplasmacytic infiltration. We reviewed the slides of 28 brain biopsies diagnostic of PML. Inflammatory changes were observed in four out of nine patients on HAART and in one out of 19 patients not on HAART. Inflammatory reactions against several opportunistic pathogens after highly active antiretroviral therapy (HAART) have been described in individuals infected with HIV, and have been associated with pronounced reductions in plasma HIV viral load and increases in CD4 cell counts [1–3]. In this report, we describe the clinical and pathological findings that suggest the existence of an inflammatory reaction in patients with AIDS-associated progressive multifocal leukoencephalopathy (PML) related to immune recovery after HAART. In the past 6 years, 66 HIV-infected patients were diagnosed as having PML in our institution according to the following criteria: brain biopsy (n = 30), detection of JC virus DNA in the cerebrospinal fluid by polymerase chain reaction (n = 22), and clinical and neuroimaging manifestations compatible with PML and the exclusion of other aetiologies (n = 14). A total of 28 HIV-infected patients with PML have been treated with HAART. For this study, we reviewed the clinical records and neuroimaging studies of these 28 patients. We also reviewed 28 of the 30 brain biopsies diagnostic of PML performed in our institution. Two biopsies performed before 1995 were not reviewed because they were lost during a transfer of the pathology laboratory to another hospital facility. All the slides were reviewed by the same neuropathologist, who was blind to patient clinical information. The diagnosis of PML was established by the finding of foci of demyelination with scattered lipid-laden macrophages, enlarged oligodendrocytic nuclei with glassy amphophilic viral inclusions and characteristic bizarre giant astrocytes. Since the introduction of HAART in our institution, we found three patients with PML, who worsened clinically and radiologically shortly after the initiation of HAART (Table 1). At the time of deterioration all three had reduced HIV viral loads and increased CD4 cell counts. Brain biopsy in all three patients disclosed typical changes of PML, as well as a marked perivascular infiltration with lymphoplasmacytic cells. We reviewed 28 of the 30 brain biopsies diagnostic of PML performed in our institution. The diagnosis of PML was confirmed in all cases. However, in five patients a striking inflammatory reaction was observed and characterized by predominantly perivascular lymphomonocytic infiltrates. Immunohistochemical studies showed that most of the lymphoid cells were CD8 suppressor T cells and some were CD20 B cells. No CD4 helper T cells were observed. Infectious aetiologies other than JC virus were ruled out by appropriate stains and cultures of brain tissue. The absence of inflammation was observed in the biopsies from 23 patients. Four of the five patients with inflammation were receiving HAART, the fifth was receiving two nucleosides. In three of the four patients receiving HAART, the biopsy was performed to confirm the diagnosis of PML and to rule out other conditions because of serious clinical and radiological worsening (the three mentioned above). The fourth patient with a baseline CD4 cell count of 123/μl and an HIV viral load of 5.62 log copies/ml was biopsied 2 weeks after the initiation of HAART. He remains neurologically stable and medically well 2 years after the biopsy. In the 23 patients without inflammation, 11 were receiving monotherapy with a nucleoside, five were receiving HAART, and seven were not receiving antiretroviral agents. Inflammatory changes were observed in four out of nine patients receiving HAART and in one out of 19 patients not receiving HAART (difference 38.7%; 95% confidence interval 8.4–69%;P = 0.048).Table 1: Characteristics of patients with paradoxical worsening of AIDS-associated progressive multifocal leukoencephalopathy caused by an inflammatory reaction after the initiation of highly active antiretroviral therapy. In PML there is usually an absence of inflammation, although in rare instances lesions may exhibit a faint, peripheral, contrast enhancement on magnetic resonance imaging [4]. Little is known about inflammatory reactions after the addition of HAART in PML. In a recent case report [5], a patient with this disorder worsened clinically and the brain lesions enlarged and enhanced with contrast after HAART; brain biopsy showed demyelination and lymphoplasmacytic inflammation that was more prominent in the tissue from the contrast-enhancing region. In another report [6], lesions of PML were found in four patients after antiretroviral therapy using peripheral gadolinium enhancement. We found inflammatory changes in approximately half of the brain biopsies from patients with PML treated with HAART. We also found clinical and radiological deterioration of PML attributable to inflammatory reactions after HAART in three out of 28 patients (10.7%). Corticosteroid therapy was administered to two of the three patients; one died and the other, treated concurrently with cidofovir, survived and her neurological function improved. From a practical perspective, there is little doubt that HAART has had a major impact on the survival and probably of the clinical outcome of PML [7–10]. However, approximately one third of these patients follow a progressively deteriorating course and die despite HAART [11]. Clinicians caring for patients with AIDS-associated PML must be aware of this immune recovery syndrome, and consider the use of therapeutic measures that modulate the immune response, such as corticosteroids, when clinically appropriate, in order to prevent irreversible inflammatory damage to the brain. Acknowledgements The authors sincerely appreciate the help of Thomas O'Boyle in the preparation of the manuscript. Pilar Mirallesa Juan Berenguera Cesar Lacruzb Jaime Cosína Juan Carlos López Belén Padillaa Lucía Muñozc Darío García-de-Viedmaa