Fingolimod-associated PML with mild IRIS in MS

Abstract

Objective:To clarify the clinical, neuropathologic, and virologic characteristics of progressive multifocal leukoencephalopathy (PML) and its immune reconstitution inflammatory syndrome (IRIS) in a patient with fingolimod-treated MS.Methods:A case study.Results:A 34-year-old patient with MS using fingolimod for 4 years had a gradual progression of right hemiparesis and aphasia with a new subcortical white matter lesion in the precentral gyrus by initial MRI. Blood tests were normal, except for lymphopenia (160 cells/μL). One month after the cessation of fingolimod, brain MRI depicted a diffusely exacerbated hyperintensity on fluid-attenuated inversion recovery and diffusion-weighed imaging in the white matter with punctate gadolinium enhancement, suggesting PML-IRIS. A very low level of JC virus (JCV)-DNA (15 copies/mL) was detected in the CSF as judged by quantitative PCR. Brain tissues were biopsied from the left frontal lesion, which showed some small demyelinated foci with predominant loss of myelin-associated glycoprotein with infiltrations of lymphocytes and macrophages, but clear viral inclusion was not observed with hematoxylin-eosin staining. JCV-DNA was uniquely detectable in an active inflammatory demyelinating lesion by in situ hybridization, possibly suggesting an early phase of PML. DNA extracted from the brain sample was positive for JCV-DNA (151 copies/cell). It took 3 months to normalize the blood lymphocyte count. The patient was treated with 1 g of IV methylprednisolone for 3 days and a weekly oral dose (375 mg) of mefloquine, and her symptoms gradually improved.Conclusion:Low CSF JCV-DNA and unfound viral inclusions initially made her diagnosis difficult. The clinical course of fingolimod-associated PML may be associated with mild immune reconstitution.

The Use of Antimalarial Drugs against Viral Infection

“…Seventeen case reports described the use of MQ at different doses [72][73][74][75][76][77][78][79][80][81][82][83][84][85][86][87][88]. Although in 12 cases there was no progression of the disease at follow-up [72][73][74][77][78][79][81][82][83][84]86,87], it is difficult to draw conclusions due to the challenging treatment protocols and compromised health of the patients. In many cases, MQ was combined with mirtazapine, an antidepressant that, acting on the 5-HT2A serotonin receptor, is able to inhibit JCPyV entry into glial cells, preventing the diffusion of the infection in oligodendrocytes.…”

“…Herpesviridae HCMV Artesunate [12,13,[46][47][48] Artesunate-amodiaquine [49] Arthemeter-lumefantrine [64] HHV6 Artesunate [52] Polyomaviridae JCPyV Artesunate [54,55] Mefloquine [72][73][74][75][76][77][78][79][80][81][82][83][84][85][86][87][88][122][123][124][125][126] Mefloquine and mirtazapine [86,87,127,128] Mefloquine, mirtazapine and a third drug [118,119] Mefloquine and risperidone [75] Mefloquine, risperidone and cytarabine [120] Mefloquine and cidofovir [121] Mefloquine and PML standard of care [129] Filoviridae EBOV Artesunate-amodiaquine [58,60] Nevertheless, some drugs have already been used in several clinical trials, as summarized in Table 1. Most of them regard the use of antimalarial drugs against HIV infection, but some of them failed, and...…”

Magnetic resonance imaging diagnosis of demyelinating diseases: An update

“…The most important roles of magnetic resonance imaging (MRI) in demyelinating diseases include: (i) diagnosis; [1][2][3][4][5] (ii) imaging biomarkers; [5][6][7][8][9][10][11][12][13][14][15][16][17] and (iii) monitoring of sideeffects from disease-modifying drugs. [18][19][20][21] The present review will focus on the diagnostic role of MRI in these diseases. Precise diagnosis of demyelinating diseases is crucial, because treatment strategies differ between pathologies and thus can greatly influence patient prognosis.…”

Debate on the treatment of multiple sclerosis: Experience from an intractable multiple sclerosis case with rebound syndrome after fingolimod cessation

“…In the present case, the disease activity before fingolimod treatment was high, the lymphocyte counts were well suppressed during fingolimod treatment and the recovery of lymphocyte count after drug cessation was rapid. 20 In the present case, the concern about PML was the trigger for drug discontinuation; therefore, concise risk stratification for PML in fingolimod treatment is imperative. In such high-risk patients, switching from fingolimod to DMF has been attempted, but could not prevent rebound syndrome efficiently.…”

“…Furthermore, PML has been recognized as a risk in fingolimod-treated MS patients. 20 In the present case, the concern about PML was the trigger for drug discontinuation; therefore, concise risk stratification for PML in fingolimod treatment is imperative. Taken together, the risk-benefit analysis for fingolimod treatment including rebound syndrome, as well as PML, is required to initiate the drug.…”