Fleur du Mal: IRIS in AIDS-Related PML

Abstract & Commentary

By John J. Caronna, MD, Vice-Chairman, Department of Neurology, Cornell University Medical Center, Professor of Clinical Neurology, New York Hospital. Dr. Caronna reports no consultant, stockholder, speaker’s bureau, research, or other relationships related to this field of study.

Synopsis: Better understanding of the mechanisms of the IRIS may enable prevention or cure of this severe, sometimes fatal complication of HAART.

Source: Vendrely A, et al. Fulminant Inflammatory Leukoencephalopathy Associated With HAART-Induced Immune Restoration in AIDS-Related Progressive Multifocal Leukoencephalopathy. Acta Neuropathol. 2005;109:449-455.

The clinical introduction of combination anti-retroviral treatment, also called highly active anti-retroviral therapy (HAART), has dramatically reduced morbidity and mortality in human immune virus (HIV) infected patients. HAART-induced immune restoration has improved survival in AIDS patients with progressive multifocal leukoencephalopathy (PML),1 and has become standard therapy for AIDS-related PML. Nevertheless, PML can develop in AIDS patients while on HAART.2 In some PML patients with prolonged survival, neurological and radiological signs may not improve or may even worsen despite good virological and immunological response to HAART.2,3 In rare instances, immune reconstitution inflammatory syndrome (IRIS) causes acute deterioration of both clinical and radiologic features. A recent case of IRIS in a patient with AIDS-related PML led us to review the case report by Vendrely and colleagues.

A 52-year-old man, HIV positive for 16 years, began HAART (lopinavir boosted by ritonavir, lamivudine and zidovudine, then didanosine) 4 weeks after hospital admission for confusion, aggressiveness, and aphasia. Initial MRI showed nonenhancing T1 hypointense and FLAIR hyperintense lesions in the left hemisphere consistent with PML. CSF tests were negative for pathogens, including PCR for JC virus.

One month later, in the setting of a reduced viral load and a strong immunological response to treatment, his neurological condition worsened. A second brain MRI showed an increase in the size and number of lesions, and enhancement of all lesions. Stereotactic biopsy of a lesion showed severe inflammation and demyelination. He was treated with high doses of corticosteroids without improvement and died 3 months later of sepsis.

At postmortem examination, multiple demyelinating lesions were found in the subcortical areas of the cerebral and cerebellar hemispheres. Most were small and discrete but some were large, confluent, and necrotic. Microscopic examination showed lesions characteristic of PML, with an intense inflammatory reaction and abundant swollen oligodendrocytes containing JC virus. No other infectious agent could be identified. The intense perivascular inflammation correlated topographically with the areas of contrast enhancement noted antemortem on MRI. In addition to the inflammatory PML changes, there were other white matter lesions that did not contain JC virus and were typical of acute disseminated encephalomyelitis (ADEM), a nonspecific immune complication of many causative factors.

Commentary

IRIS is an acute, symptomatic, or paradoxical deterioration of a preexisting infection that is temporally related to the recovery of the immune system. There are 4 diagnostic criteria:

1. Patient with AIDS
2. HAART-induced decrease in HIV viral load and increase in CD4 + T lymphocytes
3. Symptoms consistent with inflammation who appeared on HAART
4. No other infectious or toxic explanation for symptoms

IRIS results from the response of a newly reconstituted immune system to infectious antigens already present before antiretroviral therapy was started. In the case of PML reported by Vendrely et al, paradoxical clinical and radiological deterioration was associated with accentuated JC virus infection and acute leukoencephalitis. They hypothesized that the neuropathological changes they observed may have been due to an imbalance of the CD8+ to CD4+ T cell ratio, with massive infiltration of the brain by CD8+ cytotoxic cells in the absence of sufficient CD4+ cells.

IRIS has been described in a wide variety of infections, including mycobacterial, herpes zoster, hepatitis C and B, CMV retinitis, cryptococcal meningitis, pneumocystis carinii pneumonia, and others,4 and is likely to become more common as improved retroviral therapy prolongs the survival of AIDS patients.

Neurologists who are involved in the care of AIDS patients should be aware of this often fatal complication of antiretroviral treatment for which no prevention or cure exists.

References

1. Clifford DB, et al. HAART Improves Prognosis in HIV-Associated Progressive Multifocal Leukoencephalopathy. Neurology. 1999;52:623-625.

2. Tantisiriwat W, et al. Progressive Multifocal Leukoencephalopathy in Patients With AIDS Receiving Highly Active Antiretroviral Therapy. Clin Infec Dis. 1999; 28:1152-1154.

3. Gasnault J, et al. Prolonged Survival Without Neurological Improvement in Patients With AIDS-Related Progressive Multifocal Leukoencephalopathy on Potent Combined Antiretroviral Therapy. J Neurovirol. 1999;5:421-429.

4. Schmidbauer M, et al. Progressive Multifocal Leukoencephalopathy (PML) in AIDS and in the Pre-AIDS Era. A Neurological Comparison Using Immunocytochemistry and In Situ DNA Hybridization for Virus Detection. Acta Neuropathol. 1990;80:375-380.