Different MRI patterns in MS worsening after stopping fingolimod

Abstract

Objective: To analyze MRI images in patients with MS who experienced worsening of neurologic status (WNS) after stopping fingolimod (FTY).

Methods: In this retrospective study, demographic, clinical, and radiologic data of patients with MS who experienced WNS after stopping FTY were retrospectively collected. We introduced the "δExpanded Disability Status Scale (EDSS)-ratio" to identify patients who, after FTY withdrawal, showed an inflammatory flare-up exceeding the highest lifetime disease activity level. Patients with δEDSS-ratio > 1 were enrolled in the study.

Results: Eight patients were identified. The mean (SD) age of the 8 (7 female) patients was 35.3 (4.9) years. The mean FTY treatment duration was 3.1 (0.8) years. The mean FTY discontinuation-WNS interval was 4 (0.9) months. The 4 patients with δEDSS-ratio ≥ 2 developed severe monophasic WNS (EDSS score above 8.5), characterized by clinical features and MRI findings not typical of MS, which we classified as "tumefactive demyelination pattern" (TDL) and "Punctuated pattern" (PL). Conversely, patients whose δEDSS-ratio was between 1 and 2 had clinical features and brain MRI compatible with a more typical, even if aggressive, MS relapse. In patients with TDL and PL, the flare-up of inflammatory activity led to severe tissue damage resulting in T2 but also T1 lesion volume increase at 6-month follow-up.

Conclusions: Peculiar MRI features (TDL and PL), different from a typical MS flare-up, might occur in some patients who experienced WNS after stopping FTY. Further studies, also involving immunologic biomarkers, are necessary to investigate TDL or PL pathophysiology.

Figure 1. EDSS score (A), T2LV (B) and T1LV (C) courses in patients who experienced WNS after FTY withdrawal

(A) EDSS scores were reported at FTY stop, WNS and 2-year follow-up. Patients with δEDSS-ratio ≥ 2 reached very high EDSS scores at WNS and accumulated more disability at 2-year follow-up when compared to patients with >1 δEDSS-ratio >2. (B) T2LV was calculated at FTY stop, WNS and 6-month FU. At the 6-month follow-up, all patients and particularly those with δEDSS-ratio ≥ 2, had a T2LV increase compared to the pre-FTY suspension MRI, although decreased with respect to the MRI scan at WNS, likely due to the resolution of a portion of T2 hyperintensity, probably reflecting oedema. (C) T1LV was calculated at FTY stop and 6-month FU to consider chronic black holes. At 6-month follow-up all patients, and particularly those with δEDSS-ratio ≥ 2, showed a T1LV increase with respect to the MRI scan at WNS. EDSS = expanded disability status scale; FTY = fingolimod; FU = follow-up; T1LV = T1 lesion volume; T2LV = T2 lesion volume; WNS = worsening of neurologic status; δEDSS-ratio = post-FTY withdrawal δEDSS/pre-FTY withdrawal δEDSS ratio.

Figure 2. Brain MRI features of 3 representatives patients with MS who experienced WNS after FTY withdrawal

(A) Tumefactive demyelination pattern (TDL), Pt.3. (A.a) Axial T2/FLAIR images, showing large and edematous lesions, causing mass effect on adjacent structures; (A.b) Axial TSE-T1 after Gd administration images, showing multiple ring and nodular enhancing lesions; (A.c) axial DWI (on the left) and correspondent ADC maps (on the right) images, showing hyperintense lesions on DWI with correspondent hypointense signal on ADC maps (red arrows), expression of restricted diffusion. (B) Punctuated pattern (PL), Pt.1, SPMS patient. (B.a) axial TSE-T2 images, medium in size (already detectable in previous scans) and new small hyperintense lesions, with no edema and mass effect; (B.b) axial TSE-T1 after gadolinium administration images, showing innumerable millimetric enhancing lesions, both in infratentorial and supratentorial areas. (B.c) axial DWI (on the left) and correspondent ADC maps (on the right) images, showing hyperintense lesions on DWI with correspondent hypointense signal on ADC maps (red arrows), expression of restricted diffusion. (C) Classic MS pattern (CL). (Pt.6) (C.a) Axial FLAIR images, showing medium in size lesions, with no edema and mass effect; (B.b) axial TSE-T1 after gadolinium administration images, showing nodular and ring enhancing lesions. (C.c) Axial DWI (on the left) and correspondent ADC maps (on the right) images, showing hyperintense lesions on DWI with correspondent hyperintense signal on ADC maps (“T2-shine through effect”).