Comment on extensive white matter lesions after 2 years of fingolimod: Progressive multifocal leukoencephalopathy or MS relapse?

Cases as the one presented by de la Motte et al. represent big challenges in clinical practice. Speech disturbances as well as large extensive white matter lesions are red flags in multiple sclerosis (MS). New MS lesions are usually small, have round or oval shape, are typically T2-hyperintense, T1-hypointense and enhance with gadolinium. New lesions may be hyperintense in diffusion-weighted imaging (DWI), and it usually represents a T2 shine effect and apparent diffusion coefficient (ADC) is high; however, transient ADC decreases may occur in acute MS plaques. The large lesion depicted in the paper is far from a typical MS plaque. However, there is increasing evidence about patients with atypical extensive MS lesions during fingolimod treatment, ¹ which pose a diagnostic challenge particularly with progressive multifocal leukoencephalopathy (PML) lesions. Although most fingolimod-associated PML cases developed after natalizumab (NTZ) treatment, recent cases of fingolimod-associated PML were reported. PML initiates as a focal small lesion that continuously expands into large extensive diffuse lesion. The most frequent patterns are those of large subcortical lesion, hyperintense in T2-weighted images, hypointense in T1-weighted images and hyperintense in DWI, ² mostly due to T2 shine effect with a decrease in ADC map in the border. Frontal and parietal lobe are frequently involved and affection of the cortical grey matter was reported in up to 83% in some series. ³ Punctate T2 lesions and ⁴ U-fibre involvement are common in presymptomatic PML and are a good predictor for PML diagnosis, ⁵ although U-fibre lesions are also a hallmark of MS. Whereas contrast enhancement may be found in PML, it is the most common imaging sign suggestive of PML-immune reconstitution inflammatory syndrome (IRIS), affecting the border of the lesion. ⁶ Presence of punctate T2 lesions, cortical grey matter involvement, juxtacortical white matter involvement, ill-defined and mixed lesion borders towards both grey and white matter, lesion size of >3 cm and contrast enhancement were all depicted in PML.

In cons of MS plaque and in favour of PML, the lesion presented in this report was large, diffusely hyperintense in DWI and with decrease in ADC map. Polymerase chain reaction (PCR) for John Cunningham virus (JCV) in cerebrospinal fluid (CSF) was mandatory in order to exclude PML and prior to initiate any immunosuppressive treatment. Fortunately, PCR for JCV in CSF was negative, corticosteroids were administrated and the patient showed clinical and radiological improvement. As in this case, distinguishing MS plaques from PML lesions can be difficult. Even though PML has typical radiological characteristics, they are not invariable. High-resolution T2*-weighted imaging may help distinguishing PML from MS brain lesions by the presence or absence of a characteristic central intralesional vein which is a hallmark of MS. ⁷ Recent reports of fingolimod-associated PML emphasize the importance of PML surveillance in atypical MS plaques.