Three cases of non-carryover fingolimod-PML
Is the risk in Japan increased?

A 47-year-old male Japanese patient was diagnosed with MS in 2002. There was no evidence of previous immunodeficiency or immunosuppression, except for a single cyclophosphamide infusion in 2009. He was treated with interferon-β for 11 years and in 2013 switched to FTY. At this time point, he had no relapses and reached an Expanded Disability Status Scale (EDSS) score of 6.0 so that transition to secondary progressive MS must be assumed. The ALC maintained over 200/μl. Biannual MRI (November 2016) revealed a new T2 lesion in the cerebellar peduncle and an enlarging T2 lesion in the cerebral white matter near the angular gyrus, without a contrast enhancement (CE) (figure 1). He remained clinically stable and continued FTY (44 months) until late December 2016 when he exhibited word-finding difficulties with cognitive impairment akin to Gerstmann syndrome, followed by right-sided progressive hemiparesis, focal seizures, and ataxia. PML was confirmed by positive JCV-PCR in CSF (25 copies/mL), and mirtazapine and levetiracetam have been started. Follow-up MRI 4 weeks later revealed punctate CE, compatible with immune reconstitution inflammatory syndrome (IRIS). Despite IV methylprednisolone (IVMP) with oral tapering, subsequent biweekly MRI controls revealed 2 further IRIS episodes (8 and 20 weeks after onset, treated with IVMP each time by an EDSS score of 8.5) (figure 1). On the last visit in June 2017, JCV-PCR was negative, and the patient stabilized with an EDSS score 7.5 and moderate cognitive impairment.

The medical history of this 63-year-old Japanese woman with RRMS (since 2012) included no autoimmune, oncologic, or chronic infectious disease. She had low IgG and IgM levels (IgG: 593 mg/dL, IgM: 26 mg/dL, and IgA: 121 mg/dL), yet no other evidence of immunodeficiency or previous immunosuppression. Despite a stable disease course (EDSS score 1.0, no relapses), interferon β-1a has been replaced with FTY in 2013 because of depression. Her ALC ranged all the time between 400 and 600 cells/μL. In February 2016, she developed subacute progressive aphasia with severe cognitive impairments and reached an EDSS score of 5.0. MRI revealed multiple T2 lesions in the left hemisphere, involving subcortical U-fibers, without CE (figures 2, A and B). The CSF JCV load was 197 copies/mL. Despite mefloquine and mirtazapine, follow-up MRI in 4 weeks revealed massive progression of the lesions, now in both hemispheres (figure 2C). Because no contrast agent had been injected, IRIS development cannot be assessed. She achieved partial remission spontaneously 2 months later. The JCV in CSF was not detected, and cerebral lesions were slightly diminished. At the last visit in February 2018, the patient significantly improved and now lives independently despite difficulties of word recall and mild cognitive impairments (EDSS score 2.5).

A 48-year-old Caucasian woman with RRMS (since 2001) had been switched in 2010 from glatiramer acetate to fingolimod because of ongoing disease activity with 1–2 relapses per year. Afterward, she was stable during the next 7 years (EDSS score 3.0). Neither other autoimmune, oncologic, or chronic infectious diseases nor evidence of immunodeficiency or previous immunosuppressive treatment was available. The lowest ALC was 360 cells/μL. In July 2017, she was diagnosed with pityriasis versicolor, an endogenous fungal infection of the skin, possibly indicating an insufficient T-cell–mediated immune response. In August 2017, she developed subacute progressive dysarthria, moderate cognitive dysfunction, and left hemiparesis with impaired walking (EDSS score 6.0). MRI revealed PML-suspected bihemispheric T2 lesions, involving subcortical U-fibers (figure 2D), and JCV-PCR in CSF was positive (990 copies/mL). Fingolimod has been discontinued, and the patient was treated with mefloquine and mirtazapine. Follow-up MRI 4 weeks later showed moderate progression in the left hemisphere (figure 2E) and discrete scattered punctate CE in the lesion margins consistent with a milder IRIS (figure 2F). Because of minimal IRIS expression and clinical stability, only the CCR5 receptor antagonist maraviroc has been administered. Her next MRI 3 months later demonstrated unchanged punctate CE, and IVMP has been started. In April 2018, her EDSS score improved to 6.0, and frontoparietal lesions were slightly diminished. Because of a new active but clinically silent MS lesion, glatiramer acetate has been started. In June 2018, JCV-PCR in CSF was negative.