Pathologic Findings of Chronic PML-IRIS in a Patient with Prolonged PML Survival Following Natalizumab Treatment

Abstract

Immune reconstitution inflammatory syndrome (IRIS) is a common complication during treatment for natalizumab-associated progressive multifocal leukoencephalopathy (PML). Although severe IRIS can result in acute worsening of disability and is associated with poor prognosis, effective immune reconstitution may account for the high survival rate of this cohort of PML patients. We present pathological evidence of chronic IRIS 3.5 years after diagnosis with natalizumab-associated PML. Our case showed that the IRIS initially developed after plasma exchange therapy and resolved clinically and radiologically following a combination treatment with corticosteroids, maraviroc, and cidofovir. Autopsy 3.5 years later revealed evidence of grey-white matter junction demyelinating lesions characteristic of PML and perivascular leukocyte infiltrates predominated by CD8+ T-lymphocytes, and polymerase chain reaction analysis demonstrated the presence of JC viral DNA in this tissue, indicative of persistent PML-IRIS. While clinical symptoms of PML-IRIS typically stabilize within 6 months, our case report suggests that prolonged low-grade inflammation may persist in some patients. Better assays are needed to determine the prevalence of prolonged low-grade IRIS among PML survivors.

Progressive multifocal leukoencephalopathy and the spectrum of JC virus-related disease

“…In follow-up studies of people who survived PML, persistence of JCV in the CSF has been detected for as long as 3 years 65,188,189 . Similarly, post-mortem studies have revealed persistence of JCV DNA in the brains of longterm survivors of HIV-related PML and natalizumabrelated PML 66,190,191 . This evidence suggests that, despite immune reconstitution and clinical stabilization, JCV is not always cleared from the CNS but can instead return to a state of latency or persistent infection.…”

“…Given that survival has increased with successful immune reconstitution, a fourth stage can be proposed, in which the host-virus equilibrium is re-established and, in some patients, persistent infection with a rearranged pathogenic virus ensues. Indeed, viral persistence with low copy detection in the CSF for years after clinical stabilization has been observed in some people who have survived PML 65,66 . The risk that PML will recur in these patients is unknown but is not negligible 67 ( fig.…”

Inflammatory Cerebellar PML with a CD4/CD8 Ratio of 2.9 Showed a Favorable Prognosis in a Patient with Rheumatoid Arthritis

“…Thus, the definition of IRIS, “a paradoxical clinical deterioration, typically occurring in the face of immunologic recovery”, is a clinical concept for which the pathology and immunology have not fully been elucidated. In the post-mortem brain, fatal PML-IRIS is characterized by excessive CD8 + T-cell infiltration without CD4 + T-cells, even with the clearance of JCV antigen (5-7). In contrast, in biopsied cases, pathological examinations revealed T-cell infiltration with a well-balanced CD4/CD8 ratio in the presence of plasma cells (8).…”

Progressive multifocal leukoencephalopathy in dimethyl fumarate-treated multiple sclerosis patients

“…Although case 9 did not have MRI visible lesions at the time with viremia and high CSF viral load, there could be diffuse pathological tissue-level changes as we showed in our previous case report. 74 JCV was also found on autopsy in immunocompetent individuals 75 without clinical evidence of PML.…”