Teaching Case

A 63-year-old man with a history of relapsing – remitting multiple sclerosis (RRMS), treated with fingolimod, presented to the emergency department with progressive focal motor and sensory deficits. Brain MR revealed diffuse, subcortical and coalescent juxtacortical hyperintense  lesions . Cerebrospinal fluid (CSF) tap was positive for JC virus DNA via quantitative PCR.

Brain MR showed bilateral, diffuse high signal intensity areas on T2 and FLAIR sequences located to the white matter of the frontal lobes and discrete punctate lesions (Figure 1,2). The margins of the lesions, showed a peripheral rim of restricted diffusion on DWI images indicative of active margins of inflammation and some punctuate lesions with restricted diffusion on white matter of the right parietal lobe (Figure 3). The lesions had sharp margins and did not cause mass effect on the adjacent brain structures. Small perilesional, mildly enhancing foci were recognised on the left frontal lobe and on the right parietal lobe.(Figure 4).

Progressive multifocal leukoencephalopathy (PML) is a severe demyelinating disease of the brain occurring from reactivation of the human polyomavirus, JC virus (JCV) in the setting of immunosuppression. The reactivated JCV becomes neurotropic and insults oligodendrocytes.PML occurs in the setting of HIV-induced immunodeficiency, immunosuppression for solid organ or bone marrow transplantation, chemotherapy with rituximab for hematologic malignancies, collagen vascular disease and treatment with immunosuppressive agents (eg. natalizumab) for MS or Crohn’s disease. Fingolimod is a sphingosine-1-phosphate receptor modulator approved as a disease-modifying drug for the treatment of relapsing–remitting multiple sclerosis. Fingolimod reduces circulating lymphocyte counts, preventing them from entering into the central nervous system. Its use increases the risk for developing PML due to lymphopenia and reactivation of JCV as in our case [1,2,3]. MR findings of classic PML account for hyperintense white matter lesions on T2-weighted and FLAIR images, hypointense on T1-weighted images, usually multifocal and bilateral, with predilection for frontal and parieto-occipital lobes [4]. The lesions may be focal, diffuse or coalescent, involving the subcortical, juxtacortical or deep white matter, but characteristically involving the U-fibers. Involvement of the overlying grey matter cortex, thought to be rare, but has been increasingly reported. PML lesions neither enhance nor cause mass effect [2,3,4,5,6]. On DWI, lesions of new onset show prominent restricted diffusion. Slightly older lesions show a central core with high diffusivity, surrounded by a rim of restricted diffusion, in accordance with the sharply delineated margins seen on T2 and FLAIR images in our case. Chronic lesions do not exhibit restricted diffusion. In the context of active inflammation, contrast enhancement within PML lesions, edema and mild mass effect may be seen [2,6]. Characteristic imaging finding is the “milky way sign” mostly observed in natalizumab – associated PML, an association that may possibly extend also to other iatrogenic PML cases eg. fingolimod – induced PML, as in our case. Overall survival depends on reversal of the underlying immunosuppression and immune reconstitution remains the most effective strategy for treatment of PML [2].