32-year-old woman with RRMS and no new neurologic symptoms developed MR findings on FLAIR images (a) without enhancement (b) consistent with PML (arrows) after having been on natilizumab for approximately 4.5 years. The drug was discontinued and she received PLEX and steroids. Follow-up imaging was obtained at (c-d) one month, (e-f) three months, and (g-h) four months later demonstrating progressive PML lesions, which corresponded to progressive clinical neurological decline. FLAIR (c) and postcontrast (d) images obtained at one month demonstrate disease progression without enhancement. Images obtained at three months show progressive disease (e-f) without enhancement to suggest active MS or IRIS. Like other aggressive infiltrating white matter lesions PML can cross the corpus callosum (arrows). Note also that there is now involvement of the left caudate (dotted arrow). The final images obtained four months after presentation (g-h) demonstrate swelling and compression of the gyri. There is now marked involvement of the deep gray matter structures (dotted arrows) which occurs in up to one-third of cases. However, note that despite involvement of almost the entire hemisphere, the lateral ventricle remains only mildly compressed and there is no midline shift, as would be expected with other lesions of this size, and no enhancement has developed.