Pathology of immune reconstitution inflammatory syndrome in multiple sclerosis with natalizumab-associated progressive multifocal leukoencephalopathy

Abstract

Natalizumab is an approved medication for highly active multiple sclerosis (MS). Progressive multifocal leukoencephalopathy (PML) may occur as a severe side effect of this drug. Here, we describe pathological and radiological characteristics of immune reconstitution inflammatory syndrome (IRIS), which occurs in natalizumab-associated PML after the cessation of therapy, and we differentiate it from ongoing PML. Brain biopsy tissue and MRI scans from five MS patients with natalizumab-associated PML were analyzed and their histology compared with non-MS PML. Histology showed an extensive CD8-dominated T cell infiltrate and numerous macrophages within lesions, and in nondemyelinated white and grey matter, in four out of five cases. Few or no virally infected cells were found. This was indicative of IRIS as known from HIV patients with PML. Outstandingly high numbers of plasma cells were present as compared to non-MS PML and typical MS lesions. MRI was compatible with IRIS, revealing enlarging lesions with a band-like or speckled contrast enhancement either at the lesion edge or within lesions. Only the fifth patient showed typical PML pathology, with low inflammation and high numbers of virally infected cells. This patient showed a similar interval between drug withdrawal and biopsy (3.5 months) to the rest of the cohort (range 2.5–4 months). MRI could not differentiate between PML-associated IRIS and ongoing PML. We describe in detail the histopathology of IRIS in natalizumab-associated PML. PML–IRIS, ongoing PML infection, and MS exacerbation may be impossible to discern clinically alone. MRI may provide some clues for distinguishing different pathologies that can be differentiated histologically. In our individual cases, biopsy helped to clarify diagnoses in natalizumab-associated PML.

Neurological safety of fingolimod: An updated review

“…Autopsy showed massive cavitary lesions containing abundant perivascular and parenchymal CD8‐positive T‐cell infiltrates, and numerous macrophages within lesions 75, 80. Plasma cells are also prominent as compared with typical MS lesions.…”

Treatment options for patients with multiple sclerosis who have a suboptimal response to interferon‐β therapy

“…In a study of 35 patients with natalizumab-associated PML, 25 of them (71%) survived, and amongst 12 survivors who had at least 6 months' follow-up, disability levels were evenly distributed amongst mild (33%), moderate (33%) and severe (33%) ratings, based on physician-reported Karnofsky scores [68]. Presenting as a clinical decline in the patient's condition after withdrawal of natalizumab, immune reconstitution inflammatory syndrome has been observed in at least 90% of cases of PML, leading to death in 14% of cases [68][69][70].…”

Immunology of progressive multifocal leukoencephalopathy

“…PML patients show generally JCV-specific oligoclonal IgG bands in the CSF and elevated intrathecal JCV VP1-specific antibodies with further increase at onset of IRIS (Aly et al, 2011;Sindic et al, 1997;Warnke et al, 2014;Weber et al, 1997). This goes in line with the observation that plasma cells are prominent -4-among the brain immune infiltrates in PML-IRIS (Aly et al, 2011;Metz et al, 2012). The occurrence of PML during immunomodulatory treatments which affect B cells indicates the importance of B cell functions for controlling JCV.…”

“…Both studies included either HIV + donors and/or donors with lymphopenic and immunosuppressed conditions having as hallmark a global reduced number of CD4 + T cells. In addition, a recent survey of five brain biopsies from natalizumab-associated PML-IRIS patients revealed in four out of five cases brain infiltrates dominated by CD8 + T cells which appeared to be present in adjacent white and gray matter (Metz et al, 2012). In fact this might vary between patients or over time, since an in depth analysis of a brain biopsy from a PML-IRIS patient revealed abundant infiltration of JCV VP1-specific CD4 + T cells besides brain-infiltrating JCV VP1-specific CD8 + T cells (Aly et al, 2011;Yousef et al, 2012).…”