Cerebrospinal fluid JC virus antibody index for diagnosis of natalizumab‐associated progressive multifocal leukoencephalopathy

Abstract

Objective Progressive multifocal leukoencephalopathy (PML), caused by JC virus (JCV), can occur in patients receiving natalizumab for multiple sclerosis (MS). JCV detection by quantitative polymerase chain reaction (qPCR) in cerebrospinal fluid (CSF), or brain biopsy, is required for probable or definite diagnosis of PML. However, in some patients only low levels of JCV DNA (<100 copies/ml) are present in CSF, making the diagnosis challenging. Our objective was to assess the complementary value of a CSF JCV antibody index (AIJCV) in the diagnosis of natalizumab-associated PML. Methods AIJCV was assessed in 37 cases of natalizumab-associated PML and 89 MS-patients treated with natalizumab without PML. Sera and CSF were tested in a capture enzyme-linked immunosorbent assay, using JCV-VP1 fused to glutathione S-transferase as antigen. Albumin levels and total immunoglobulin G concentration were determined by immunonephelometry, and the AIJCV was calculated as published. Results Twenty-six of 37 (70%) patients with natalizumab-associated PML exhibited an AIJCV > 1.5, whereas this was seen in none of the controls (p < 0.0001). At time of the first positive qPCR for JCV DNA, 11 of 20 (55%) patients with natalizumab-associated PML had an AIJCV > 1.5. JCV DNA levels of <100 copies/ml were seen in 14 (70%) of these 20 patients, of whom 8 (57%) demonstrated an AIJCV > 1.5. Interpretation Determination of the AIJCV could be an added tool in the diagnostic workup for PML and should be included in the case definition of natalizumab-associated PML.

Estimation of intrathecal IgG synthesis: simulation of the risk of underestimation

“…The IgG CSF/serum ratio increased after PLEX in most cases (anti‐Yo and anti‐Hu). In natalizumab‐treated MS patients treated by PLEX in relation with a progressive multifocal encephalopathy (PML), IgG index increased34 and the activity index (AI) against JCV increased 4‐fold 35. Although a rebound of local IgG synthesis induced by PML‐immune reconstitution inflammatory syndrome (IRIS) could not be excluded, these results are in line with the predicted outcome of ITS after PLEX.…”

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

“…38 Indeed, an adequate and frequent clinical monitoring, including serological tests and radiological evaluation, are of extreme importance in the follow-up of these patients in order to prevent and enable early detection of PML lesions. [39][40][41] At our center there is only 1 patient diagnosed with PML in the context of MS treatment with natalizumab. Considering this, we believe that any results obtained evaluating non-HIV PML patients would lack significance and we decided to focus our work only on patients with HIV-associated PML.…”

High-frequency MRI monitoring should be performed in natalizumab-treated MS patients with higher risk of PML – Commentary

“…Indeed, standardized protocols may help to move the field forward, allowing for more reliable interpretation of MRI in the context of suspicion of PML in the future, and the search for added diagnostic tools to earlier facilitate the diagnosis of PML. 10 Technical solutions such as a web-based MRI second opinion reporting platform providing easy access to a world-wide expert opinions may be developed, and help physicians reading and interpreting MRI scans (http://www.ixico. com/digital-health), possibly in the future even outside of diagnosing natalizumab-associated PML.…”