PT  - JOURNAL ARTICLE
AU  - Jin Nakahara
AU  - Laura Tomaske
AU  - Kodai Kume
AU  - Tadayuki Takata
AU  - Masaki Kamada
AU  - Kazushi Deguchi
AU  - Kenji Kufukihara
AU  - Ruth Schneider
AU  - Ralf Gold
AU  - Ilya Ayzenberg
TI  - Three cases of non-carryover fingolimod-PML
AID  - 10.1212/NXI.0000000000000559
DP  - 2019 May 01
TA  - Neurology - Neuroimmunology Neuroinflammation
PG  - e559
VI  - 6
IP  - 3
4099  - http://nn.neurology.org/content/6/3/e559.short
4100  - http://nn.neurology.org/content/6/3/e559.full
SO  - Neurol Neuroimmunol Neuroinflamm2019 May 01; 6
AB  - Objective To report the course of 3 recent Japanese and European cases of fingolimod-associated progressive multifocal leukoencephalopathy (PML) and to analyze its risk factors and increased incidence in Japan.Methods Case series and literature review.Results Fingolimod-associated PML may cause both supratentorial and infratentorial lesions and a pronounced disability. Diagnosis can be challenging because PML lesions (especially infratentorial) can be initially misdiagnosed as extensive MS lesions. Immune reconstitution inflammatory syndrome (IRIS) develops a few weeks after fingolimod discontinuation and is usually mild. Age factor and therapy duration seem to be relevant because most reported patients were older than 45 years and were treated with fingolimod for more than 3 years. Combined IgG/IgM deficiency has been identified as a possible further predisposing condition in 1 case. Another patient developed an endogenous fungal skin infection, as a sign of generally compromised cellular immune response, shortly before PML. None of the reported patients had lymphocyte counts below 200/μl. Two of the 3 reported and 4 of the 21 (19%) registered fingolimod-PML cases occurred in Japan (estimated risk of 0.652 per 1,000 compared with 0.083 per 1.000 worldwide).Conclusions The risk of PML under fingolimod is low, but there are no reliable predictors. Despite a mild IRIS phase, it causes profound disability. Patients older than 45 years, especially with known comorbid immunodeficiencies or manifestation of other opportunistic infections, should be monitored more closely. Increased surveillance and identification of further risk factors are urgently needed in Japan.ALC=absolute lymphocyte count; CE=contrast enhancement; EDSS=Expanded Disability Status Scale; IRIS=immune reconstitution inflammatory syndrome; IVMP=IV methylprednisolone; JCV=JC virus; PML=progressive multifocal leukoencephalopathy; RRMS=relapsing-remitting MS