Transient punctuate enhancing lesions preceding natalizumab-associated progressive multifocal leukoencephalopathy.

We reported a 52-year-old woman with a relapsing–remitting MS treated by natalizumab since 3 years ago. JC virus (JCV) serostatus was positive (STRATIFY JCV test, Unilabs, Denmark). During this period no relapse occurred and her neurological state was stable (EDSS 1.5). Routine brain MRI performed at the 37th infusion of natalizumab displayed no new lesions (Fig. 1, month 37 [M37]). The day of the 41st natalizumab infusion, routine brain MRI revealed frontal, parietal and thalamic punctate gadolinium-enhancement in the absence of new lesions on FLAIR sequences in the corresponding areas (Fig. 1, M41). Natalizumab therapy was stopped. The PCR for JCV in CSF was negative (lower limit of detection of 200 copies/ml) and anti-natalizumab antibodies were absent. Six weeks later, while her clinical state was unchanged, MRI showed disappearance of the gadolinium-enhancing lesions, together with some new punctate lesions on FLAIR images matching with previously punctate enhancing lesions (Fig. 1, M42). Three weeks later, the patient presented with slurred speech and right-sided ataxia (EDSS 4.0). At this time, MRI showed additional lesions on FLAIR sequences, still in the absence of gadolinium-enhancement (Supplemental Figure 1, M43). In the second CSF analysis, PCR revealed 580 copies/ml of JCV DNA. The diagnosis of progressive multifocal leukoencephalopathy (PML) was made. Despite five plasma exchanges, administration of mirtazepine (60 mg/day) and mefloquine (250 mg/day), her neurological state worsened progressively, and she became bedridden (EDSS 9.0). At M44, MRI showed progression of the lesions on FLAIR sequences, in the absence of oedema or mass effect, associated with frontal and parietal punctuates enhancing lesions (Supplemental Figure 1, M44). Because of suspected progressive multifocal leukoencephalopathy-immune reconstitution inflammatory syndrome (PML-IRIS), intravenous methylprednisolone (1 g/day during 5 days) was started. At M45, MRI displayed diffuse extensive lesions on FLAIR sequences with disappearance of enhancing lesions seen previously (Supplemental Figure 1, M45). The patient deceased at M46. Panels A, B, and C are axial FLAIR sequences, and panels D, E, and F are axial gadolinium T1-weighted images. Panels A and D correspond to imaging at M (months after natalizumab starting) 37, B and E to imaging at M41, and C and F to imaging at M42. Lesion load on FLAIR sequences was stable at M37 (A) and M41 (B). New punctuate lesions on FLAIR sequences appeared in the right internal capsule and in the left thalamus (arrows) at M42 (C). Punctuate gadolinium-enhancing lesions involving the right internal capsule and the left thalamus, absent at M37 (D), appeared at M41 (arrows, E) leading to natalizumab withdrawal. These lesions disappeared at M42 (F).