Department 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.
Neurol Neuroimmunol Neuroinflamm. 2019 Apr 10;6(3):e559. doi: 10.1212/NXI.0000000000000559. eCollection 2019 May.
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.
Case series and literature review.
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).
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.
报告 3 例近期日本和欧洲的芬戈莫德相关进行性多灶性白质脑病（PML）病例，并分析其在日本的风险因素和发病率增高。
病例系列和文献复习。
芬戈莫德相关 PML 可引起幕上和幕下病变，并导致明显残疾。由于 PML 病变（尤其是幕下病变）最初可能误诊为广泛 MS 病变，因此诊断具有挑战性。免疫重建炎症综合征（IRIS）在停用芬戈莫德后数周发生，通常较轻。年龄因素和治疗时间似乎是相关的，因为大多数报告的患者年龄超过 45 岁，且接受芬戈莫德治疗超过 3 年。1 例患者存在 IgG/IgM 联合缺乏，被认为是可能的进一步易患因素。另一位患者在发生 PML 前，因细胞免疫反应普遍受损，出现内源性真菌性皮肤感染。报告的 3 例患者中没有 1 例的淋巴细胞计数低于 200/μl。报告的 3 例中有 2 例和登记的 21 例（19%）中有 4 例（估计风险为每 1000 例 0.652 例，全球为每 1000 例 0.083 例）发生在日本。
在芬戈莫德治疗下 PML 的风险较低，但没有可靠的预测指标。尽管 IRIS 期较轻，但它会导致严重残疾。年龄超过 45 岁的患者，尤其是已知合并免疫缺陷或出现其他机会性感染的患者，应更密切监测。日本急需增加监测并确定进一步的风险因素。
