Central Nervous System–Immune Reconstitution Inflammatory Syndrome

Introduction

Central nervous system–immune reconstitution inflammatory syndrome (CNS-IRIS) represents a diverse group of disorders, all of which are characterized by an exaggerated inflammatory response to either a dead or dying opportunistic infection, viable pathogen from a persistent infection, or a self-antigen. First described in 1992 and most commonly seen in patients with HIV immunosuppression, CNS-IRIS has also been reported in patients following discontinuation of corticosteroids, anti-TNF-α therapy, or immunosuppression, as well as during the recovery of cell counts following cytotoxic chemotherapy, following engraftment of stem cell transplantation, and following plasma exchange or immunoabsorption in natalizumab-treated patients with multiple sclerosis diagnosed with progressive multifocal leukoencephalopathy (PML).

CNS-IRIS is due to an abnormally regulated CD8+/CD4+ ratio resulting in excessive tissue inflammation. Histopathology demonstrates CD8+ lymphocytosis with CD8+ cells in both perivascular and parenchymal distributions. No universally accepted diagnostic criteria for CNS-IRIS have been developed. Rather, the diagnosis is suggested when the patient's clinical status worsens despite immune reconstitution and without evidence of drug toxicity, opportunistic infection, medical noncompliance, or allergic reaction. Patients with life-threatening IRIS may need to have their antiretroviral therapy (ART) discontinued with initiation of treatment of their underlying infection and corticosteroids. Prophylactic antiepileptic therapy may also be considered.

CNS-IRIS remains a significant public health issue affecting the morbidity of the world's HIV-positive population. The incidence, severity, and mortality of CNS-IRIS varies with respect to patient population, type of AIDS-defining illness, and geography. In one meta-analysis, out of 13,103 patients started on ART from 54 cohort studies, 12.97% developed IRIS. More specifically, IRIS developed in 37.7% of patients with cytomegalovirus (CMV) retinitis, 19.5% with cryptococcal meningitis (CM), 16.7% with PML, 15.7% with tuberculosis (TB), 12.2% with herpes zoster, and 6.4% with Kaposi sarcoma. Risk factors in patients with HIV immunosuppression include ART naivety, severe immunosuppression at ART initiation (CD4+ < 50), rapid fall in HIV-1 RNA levels within 90 days of ART initiation, rising CD4+ count with ART initiation, opportunistic infection at ART initiation, ART resumption after an interruption, young age, and male gender.