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Three cases of non-carryover fingolimod-PML: Is the risk in Japan increased?
Jin Nakahara1, Laura Tomaske1, Kodai Kume1
1Department of Neurology (J.N., K. Kufukihara), Keio University School of Medicine, Tokyo; Department of Neurology (L.T., R.S., R.G., I.A.), St. Josef Hospital, Ruhr University Bochum, Bochum, Germany; Department of Gastroenterology and Neurology (K. Kume, T.T., M.K., K.D.), Kagawa University Faculty of Medicine, Japan; and Department of Neurology (I.A.), Sechenov First Moscow State Medical University, Moscow, Russia.
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.
Insights
Fingolimod-associated progressive multifocal leukoencephalopathy (PML) can cause severe disability. Risk factors include age over 45 and longer treatment duration, with higher incidence noted in Japan.
Area of Science:
- Neurology
- Immunology
- Pharmacology
Background:
- Fingolimod is a sphingosine-1-phosphate receptor modulator used for multiple sclerosis.
- Progressive multifocal leukoencephalopathy (PML) is a rare but serious opportunistic infection of the brain.
- Fingolimod-associated PML presents unique challenges in diagnosis and management.
Observation:
- Three recent cases of fingolimod-associated PML in Japan and Europe were analyzed.
- PML lesions can mimic multiple sclerosis (MS) lesions, complicating diagnosis.
- Immune reconstitution inflammatory syndrome (IRIS) following fingolimod discontinuation was generally mild.
- Risk factors may include age over 45, prolonged fingolimod therapy (>3 years), and comorbid immunodeficiencies.
- An increased incidence of fingolimod-PML was noted in Japan compared to global estimates.
Findings:
- Fingolimod-associated PML can lead to significant neurological disability.
- No reliable predictors for fingolimod-PML were identified.
- Lymphocyte counts below 200/μl were not observed in the reported cases.
- The estimated risk of PML in Japan appears higher than the worldwide average.
Implications:
- Close monitoring of patients over 45, particularly those with comorbidities or opportunistic infections, is recommended.
- Enhanced surveillance and further research into risk factors for fingolimod-PML are necessary, especially in Japan.
- Early diagnosis and management are critical to mitigate the profound disability associated with fingolimod-PML.
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