Severe early natalizumab-associated PML in MS: Effective control of PML-IRIS with maraviroc

Case report. A 55-year-old Caucasian HIV-negative man diagnosed with relapsing-remitting MS in 2013 and an Expanded Disability Status Scale (EDSS) score of 2.0 had received 20 infusions of natalizumab over 21 months without a history of prior immunotherapy. John Cunningham–virus (JCV) antibodies were positive at the initiation of treatment (index: 0.4). Natalizumab was then discontinued because of an increase of anti-JCV antibody index (2.6) and switched to fingolimod following a 2-month washout period. Brain MRI performed 2 months before the initiation of fingolimod showed no signs of MS disease activity or progressive multifocal leukoencephalopathy (PML). The patient was first admitted to our hospital 10 days after fingolimod initiation with progressive left-sided hemiparesis and an extensive T2 MRI lesion in the right central region without gadolinium (Gd)-enhancement suspicious for PML (figure, A and B). JCV DNA was detectable in the CSF (50 copies/ mL) by PCR analysis. The patient was diagnosed with natalizumabassociated PML, fingolimod was discontinued, and 4 cycles of plasmapheresis were conducted. Clinically, the patient rapidly deteriorated to complete left-sided paralysis and developed focal seizures and a severe organic psychosyndrome, resulting in a 30% Karnofsky Index (KI). Correspondingly, MRI after plasmapheresis showed a markedly increased PML lesion size on T2 sequences but again no intraparenchymal Gd-enhancement (figure, C and D). Oral maraviroc (300 mg twice daily) was initiated 6 days after admission. No glucocorticoids or any other immunomodulating therapy was given throughout the course of PML. Eight days after maraviroc initiation, MRI follow-up revealed stable PML lesion size with Gd-enhancement consistent with localized moderate immune reconstitution inflammatory syndrome (IRIS) (figure, E and F). Over the following weeks, the patient continuously improved. PML lesion size regressed without Gd-enhancement (figure, G and H). After 25 weeks of maraviroc treatment, JCV DNA was no longer detectable in the CSF. Maraviroc was continued and well tolerated at a stable dose. The patient survived both PML and IRIS with considerable persisting sequelae; after 10 months of treatment with maraviroc, the EDSS score was 3.0 without cognitive or psychiatric deficits. He was able to perform nearly all activities of daily living without support (KI 70%). Since there was neither clinical nor radiologic MS disease activity detectable during the follow-up period of 10 months, due to the lack of any recommendations (and even larger individual physicians’ experience) on the use of a diseasemodifying therapy (DMT) after survival of PML, and published reports of PML associated with other DMTs (such as fingolimod or dimethylfumarate), we have chosen not to start a new DMT yet.