Background

In multiple sclerosis (MS), perilesional chronic inflammation appears on in vivo 3T susceptibility-based magnetic resonance imaging (MRI) as non-gadolinium-enhancing paramagnetic rim lesions (PRL). A higher PRL burden has been recently associated with a more aggressive disease course. The visual detection of PRL by experts is time-consuming and can be subjective.

Objectives

To develop a multimodal convolutional neural network (CNN) capable of automatically detecting PRL on 3D-T2*w-EPI unwrapped phase and 3D-T2w-FLAIR images.

Methods

124 MS cases (87 relapsing remitting MS, 16 primary progressive MS and 21 secondary progressive MS) underwent 3T MRI (MAGNETOM Prisma and MAGNETOM Skyra, Siemens Healthcare, Erlangen, Germany). Two neurologists visually inspected FLAIR magnitude and EPI phase images and annotated 462 PRL. 4857 lesions detected by an automatic segmentation (La Rosa et al. 2019) without overlap with PRL were considered non-PRL. The prototype RimNet was built upon two single CNNs, each fed with 3D patches centered on candidate lesions in phase and FLAIR images, respectively. A two-step feature-map fusion, initially after the first convolutional block and then before the fully connected layers, enhances the extraction of low and high-level multimodal features. For comparison, two unimodal CNNs were trained with phase and FLAIR images. The areas under the ROC curve (AUC) were used for evaluation (DeLong et al. 1988). The operating point was set at a lesion-wise specificity of 0.95. The patient-wise assessment was conducted by using a clinically relevant threshold of four rim+ lesions per patient (Absinta et al. 2019).

Results

RimNet (AUC=0.943) outperformed the phase and FLAIR image unimodal networks (AUC=0.913 and 0.855, respectively, P’s <0.0001). At the operating point, RimNet showed higher lesion-wise sensitivity (70.6%) than the unimodal phase network (62.1%), but lower than the experts (77.7%). At the patient level, RimNet performed with sensitivity of 86.8% and specificity of 90.7%. Individual expert ratings yielded averaged sensitivity and specificity values of 76.3% and 99.4%, respectively.

Conclusions

The excellent performance of RimNet supports its further development as an assessment tool to automatically detect PRL in MS. Interestingly, the unimodal FLAIR network performed reasonably well despite the absence of a paramagnetic rim, suggesting that morphometric features such as volume or shape might be a distinguishable feature of PRL.

Background

Discontinuing fingolimod (FTY) in older patient is a growing concern with little evidence supporting the decision to pursue treatment and reasonable doubt for disease reactivation after withdrawal.

Objectives

We investigate the incidence of RDA and rebound in MS patients who discontinued fingolimod for any reason, and looked for risk factors influencing this risk. Of particular interest was the subgroup of older patients who discontinued FTY for other reasons than disease progression. Our hypothesis was that these patients, older at treatment discontinuation, previously stable on treatment, would have a statistically lower risk of recurrence of activity given their age.

Methods

Retrospective analysis of 288 MS patients on FTY. Recurrence of disease activity (RDA) was defined as the occurrence of either clinical and/or MRI activity in the 6 months after FTY withdrawal; among these patients with RDA, we considered rebound when the levels of disease activity surpassed pretreatment activity. We defined a subgroup of patients older than ≥ 50 years at FTY discontinuation and with NEDA-3 status during FTY treatment.

Results

128 patients discontinued FTY from 2011 to 2019 mainly for estimated high PML risk (3.6%), inefficacy (26.6%) or pregnancy planning (18%). RDA occurred in 45 patients (35.2 %) within 3.4 months (SD 2). Younger age at disease onset (p=0.008), highly active disease at baseline (p=0.037) and previous treatment with natalizumab (p=0.050) increased the risk of RDA at FTY discontinuation. Sixteen patients (12.5%) experienced rebound with a mean of 9 Gd enhancing lesions. Baseline MRI activity (p=0.008) and longer wash-out period (p=0.001) correlated with rebound. Twenty-two patients were older than 50 years at FTY withdrawal and discontinued FTY for other reasons than disease progression. The incidence of RDA was lower, yet not statistically significant, from younger patients (18.2 % RDA, p=0.068).

Conclusions

RDA occurred in 35.2% of our patients including 12.5% with rebound. Older age at FTY discontinuation may be associated with a lower risk of disease reactivation, although the incidence of RDA remains high, as 1/5 of the older patients, previously stable on treatment, experienced RDA.

Background

Randomized controled trials, post-hoc analysis and real-world post-marketing studies have confirmed fingolimod (FTY) efficacy over placebo as second-line therapy in case of persistent disease activity and in treatment-naive patients with rapidly evolving highly active RR-MS. In countries where fingolimod is available as first-line therapy without restrictions, we have an opportunity to observe long-term efficacy profile of this drug in treatment-naive patients according to their initial disease activity.

Objectives

To evaluate and compare the incidence of NEDA-3 status at last follow up according to the baseline MS disease activity.

Methods

Retrospective analysis of clinical and radiological data of 54 RR-MS patients treated with FTY. The patients were divided into highly active patients (HΑ) if ≥ 2 relapses in the year before treatment initiation and ≥1 Gd-enhancing T1 lesion or “not highly active” (NHA). NEDA-3 status at endpoint was defined as no relapses, no EDSS progression and no new T2 or Gd-enhancing lesions during the follow-up.

Results

Mean follow-up duration was 48.2, SD 18.4 months. FTY efficiently reduced relapses (NHA 90.3% reduction, p<0.001, HA 84.9%, p<0.001), and new Gd enhancing lesions (NHA 85.4% reduction, p=0.019, HA 92.3%, p=0.043). 53.7% reached NEDA-3 status at endpoint, although the distribution was different in the two subgroups with 62.2%, (n=23/37) of the NHA patients reaching NEDA 3 status compared to 35.3% (n=6/17) of the HA. The proportion of patients reaching NEDA-3 status decreased over time (first line : 80% at 2 years and 66% at 4 years, HA : 58% at 2 years and 38% at 4 years, p=0.042). 63% of patients were still on FTY at last follow-up (n=34/54). Main reason for discontinuation was lack of efficacy (75%, n=15/20).

Conclusions

Chances of reaching NEDA-3 status reduce over time with the highest relative benefit from FTY treatment observed when prescribed as a first line disease-modifying drug in treatment-naïve MS patients, which may favour its indication in that context rather than for HA patients only.

Background

In multiple sclerosis (MS), a subset of chronic active white matter lesions are identifiable on MRI by their paramagnetic rims, and increasing evidence supports their association with clinical disease severity.

Objectives

To assess the prevalence and MS-specificity of paramagnetic rim lesions (PRL) on 3-tesla susceptibility-based MR brain images in MS vs non-MS cases in a multicenter sample drawn from 5 academic research hospitals at sites in Europe (Brussels, Lausanne, Milan) and the United States (NIH and JHU).

Methods

On submillimetric 3D T2*-segmented EPI brain MRI, the presence of PRL and central vein sign (CVS) were evaluated in the supratentorial brain of adults with MS (n=329) and non-MS neurological conditions (n=83). Non-MS cases were grouped as follows: (1) other-inflammatory neurological diseases (n=41); (2) HTLV-associated myelopathy/tropical spastic paraparesis (HAM/TSP; n=10); (3) HIV-infected (n=10); (4) non-inflammatory neurological diseases (n=22).

ROC curve analysis, with diagnosis as dependent variable (MS vs non-MS), was applied to examine the diagnostic accuracy for each biomarker (PRL and CVS). Youden’s index method was used to obtain the optimal cutoff value for each biomarker.

Results

PRL were detected in 172/329 (52%) of MS cases vs. 6/83 non-MS cases (7%).

In MS, 58% of progressive cases had at least one PRL, compared to 50% of relapsing cases. MS cases with more than 4 PRL were more likely to have higher disability scores (EDSS, MSSS and ARMSS), but not significantly longer disease duration or older age.

In non-MS cases, PRL were seen exclusively in only a few inflammatory/infectious neurological conditions, including Susac syndrome (3 cases), neuromyelitis optica spectrum disorder (1 case), Sjögren disease (1 case) and HAM/TSP (1 case). Unlike in MS, PRL in non-MS cases were not associated with a high frequency of CVS+ lesions.

The identification of at least one PRL (optimal cutoff) was associated with high diagnostic specificity (93%), but relatively low sensitivity (52%) and accuracy (area under ROC curve=0.77), whereas CVS detection alone (optimal cutoff 35.5-38%) could better discriminate MS from non-MS cases with high specificity (96%), sensitivity (99%), and accuracy (area under ROC curve=0.99). The combination of the two biomarkers further improved the specificity (99%), but sensitivity remained low (59%).

Conclusions

PRL yielded high specificity for MS lesions. Future prospective multicenter studies should further validate its role as a diagnostic biomarker.