CNS–Immune Reconstitution Inflammatory Syndrome in the Setting of HIV Infection, Part 1: Overview and Discussion of Progressive Multifocal Leukoencephalopathy–Immune Reconstitution Inflammatory Syndrome and Cryptococcal–Immune Reconstitution Inflammatory Syndrome

Abstract

SUMMARY:While uncommon, CNS-IRIS developing after the initiation of HAART in the setting of HIV-related severe immunosuppression is characterized by an intense inflammatory reaction to dead or latent organisms or to self-antigens due to a heightened but dysregulated immune response. While this reaction can range from mild to fulminating, encompassing a very wide clinical spectrum, it is important to recognize because changes in medical management may be necessary to prevent neurologic decline and even death. Once contained, however, this inflammatory response can be associated with improved patient outcome as immune function is restored. Among the infectious organisms that are most commonly associated with CNS-IRIS are the JC virus and Cryptococcus organisms, which will be the subject of this review. CD8 cell infiltration in the leptomeninges, perivascular spaces, blood vessels, and even parenchyma seems to be the pathologic hallmark of CNS-IRIS. While recognition of CNS-IRIS may be difficult, the onset of new or progressive clinical symptoms, despite medical therapy and despite improved laboratory data, and the appearance on neuroimaging studies of contrast enhancement, interstitial edema, mass effect, and restricted diffusion in infections not typically characterized by these findings in the untreated HIV-infected patient should raise the strong suspicion for CNS-IRIS. While CNS-IRIS is a diagnosis of exclusion, the neuroradiologist can play a critical role in alerting the clinician to the possibility of this syndrome. ABBREVIATIONS:ART ϭ antiretroviral therapy; CM ϭ cryptococcal meningitis; HAART ϭ highly active antiretroviral therapy; IRIS ϭ immune reconstitution

Clinical and Radiological Characterization of Progressive Multifocal Leukoencephalopathy in HIV-Infected Patients: A Retrospective Analysis and Review of the Literature

“…CNS-immune reconstitution syndrome (IRIS) defines a paradoxical deterioration of clinical response, mostly encountered in HIV-infected patients who have received HAART, 60 although it may also be developed in patients with immunological deficits related to other conditions. It represents a diagnostic challenge, with limited treatment options and variable prognosis.…”

HIV-associated progressive multifocal leukoencephalopathy: current perspectives

“…Immune reconstitution inflammatory syndrome (IRIS) represents an exuberant inflammatory response to a dead, dying, or viable pathogen from a persistent infection. 60,63,64 PML-IRIS manifests as a neurologic deterioration with evidences of CNS JCV infection after cART initiation. 63 PML-IRIS lesions are pathologically different from classical PML, being characterized by lymphocyte perivascular infiltrates, BBB damage with brain edema, and consequent mass effect, which are lacking in classical PML lesions.…”

“…65 Neuroimaging of PML-IRIS lesions is characterized by contrast enhancement as well as mass effect and interstitial edema. 60 Considering the lack of an effective anti-JCV treatment, PML-IRIS therapy is essentially based on corticosteroids administration, with the aim of reducing brain inflammation. However, a case series of 54 patients with AIDS-associated PML-IRIS treated with corticosteroids showed contrasting results.…”

“…58 PML lesions are histopathologically characterized by demyelination, astrocyte modifications, and oligodendroglial nuclei changes, while edema, lymphocyte infiltration, and blood -brain barrier (BBB) damage are usually absent. 59,60 In AIDS-presenter therapy-naïve HIV-infected subjects with PML, the only therapeutic intervention is cART initiation, with the aim of controlling HIV replication and consequently improving the host immune system. 61 If PML occurs in a cART-treated patient, who is experiencing either virological or immunological failure, a therapeutic optimization (switch or intensification) should be considered in order to better control HIV replication and improve CD4 cell count.…”

Update and New Directions in Therapeutics for Neurological Complications of HIV Infections

“…Common opportunistic infections associated with IRIS are Cryptococcus, Mycobacterium tuberculosis (MTB), and JC virus [41]. IRIS is rare in the setting of cerebral toxoplasmosis and primary CNS lymphoma [32].…”