Background

Optic neuritis (ON) is a frequent manifestation in aquaporin-4 antibody (AQP4-IgG) seropositive neuromyelitis optica spectrum disorders (NMOSD). Due to limited samples, existing optical coherence tomography (OCT) studies are inconsistent regarding retinal changes in eyes with a history of ON (NMO-ON) and without a history of ON (NMO-NON), and their functional relevance.

Objectives

The CROCTINO (Collaborative Retrospective Study on retinal OCT in Neuromyelitis Optica) project aims to reveal correlates of retinal pathology and to generate hypotheses for prospective OCT studies in NMOSD. The objective of this study was to analyze retinal changes of AQP4-IgG seropositive NMO-ON and NMO-NON eyes in an international cross-sectional OCT dataset.

Methods

Of 656 subjects, we enrolled 283 AQP4-IgG seropositive NMOSD patients and 72 healthy controls (HC) from 22 international expert centers. OCT data was acquired with Spectralis SD-OCT, Cirrus HD-OCT and Topcon 3D OCT-1. Mean thickness for the combined ganglion cell and inner plexiform layer (GCIP) and inner nuclear layer (INL) were calculated from macular volume scans. Clinical, functional and laboratory testing were performed at discretion of each center.

Results

We compared NMO-ON eyes (N = 260), NMO-NON eyes (N = 241) and HC eyes (N = 136). GCIP was reduced in NMO-ON (57.4 ± 12.2 µm) compared with NMO-NON (75.9 ± 7.7 µm; p < 0.001) and HC (81.4 ± 5.7 µm; p < 0.001). NMO-NON had thinner GCIP (p < 0.001) compared with HC. INL was thicker in NMO-ON (40.3 ± 3.9 µm) compared with NMO-NON (38.6 ± 3.9µm; p < 0.001), but not HC (39.4 ± 2.6 µm). Microcystic macular edema were visible in 6.6 % of NMOSD eyes.

Conclusions

AQP4-IgG seropositive NMOSD is characterized by a functionally relevant loss of retinal neuroaxonal content and a - probably inflammatory - increase of INL after ON. Our study further supports the existence of attack-independent damage in the visual system of patients with AQP4-IgG seropositive NMOSD.

Background

To predict the clinical course of myelin oligodendrocyte glycoprotein (MOG)-antibody (Ab)-associated disease (MOGAD) is essential to guide treatment recommendations.

Objectives

We aimed to 1) compare clinical features and disease course, and 2) to evaluate the association of MOG-Ab dynamics and relapses, between children and adults with MOGAD.

Methods

Retrospective study evaluating clinical features of 98 children and 266 adults with MOGAD, between January 2014 and September 2019. To analyse relapses over the whole disease course, a Cox regression analysis for recurrent time-to-event data was performed, introducing treatment as time-dependent covariate. To evaluate dynamics, delta mean fluorescence intensity ratio signal (ΔMFIratio) of MOG-Ab was measured in patients with a minimum time elapsed between two samples of 4 months.

Results

Median age at onset of symptoms was 10.9 (interquartile range 5.4-14.3) years in children and 36.2 (27.7-47.6) in adults. Isolated optic neuritis was the most frequent clinical presentation both in children (40.8%) and adults (55.9%), p=0.013, and acute disseminated encephalomyelitis syndrome was more frequent in children (36.7% vs. 5.6%; p<0.001). Compared to adults, children displayed a better recovery (EDSS ≥3.0 at last follow-up reached only by 10 of 97 [10.3%] vs. 66/247 [26.7%], p<0.001).

In the multivariate analysis, adults were at higher risk of relapse than children (Hazard ratio 1.41, 95%Confidence interval [CI] 1.12-1.78; p=0.003). Among the 124 participants evaluated for MOG-Ab dynamics, 36.3% became seronegative, 60.5% decrease and 3.2% increase the ΔMFIratio. At two years, 64.2% (95%CI 40.9-86.5) of non-relapsing children became MOG-Ab negative compared to 14.1% (95%CI 4.7-38.3) of relapsing ones, log-rank p<0.001, with no differences observed between non-relapsing and relapsing adults, log-rank p=0.280.

Conclusions

MOGAD differs in its clinical presentation at onset, showing a progressive shift in the clinical features across age-groups. Compared to children, adults have a higher risk of relapses and a worse functional recovery. Finally, children with monophasic disease became MOG-Ab negative earlier than relapsing ones, but not in adults. Considering these differences, management and treatment guidelines should be considered independently in children and adults.

Background

To predict the clinical course of myelin oligodendrocyte glycoprotein (MOG)-antibody (Ab)-associated disease (MOGAD) is essential to guide treatment recommendations.

Objectives

We aimed to 1) compare clinical features and disease course, and 2) to evaluate the association of MOG-Ab dynamics and relapses, between children and adults with MOGAD.

Methods

Retrospective study evaluating clinical features of 98 children and 266 adults with MOGAD, between January 2014 and September 2019. To analyse relapses over the whole disease course, a Cox regression analysis for recurrent time-to-event data was performed, introducing treatment as time-dependent covariate. To evaluate dynamics, delta mean fluorescence intensity ratio signal (ΔMFIratio) of MOG-Ab was measured in patients with a minimum time elapsed between two samples of 4 months.

Results

Median age at onset of symptoms was 10.9 (interquartile range 5.4-14.3) years in children and 36.2 (27.7-47.6) in adults. Isolated optic neuritis was the most frequent clinical presentation both in children (40.8%) and adults (55.9%), p=0.013, and acute disseminated encephalomyelitis syndrome was more frequent in children (36.7% vs. 5.6%; p<0.001). Compared to adults, children displayed a better recovery (EDSS ≥3.0 at last follow-up reached only by 10 of 97 [10.3%] vs. 66/247 [26.7%], p<0.001).

In the multivariate analysis, adults were at higher risk of relapse than children (Hazard ratio 1.41, 95%Confidence interval [CI] 1.12-1.78; p=0.003). Among the 124 participants evaluated for MOG-Ab dynamics, 36.3% became seronegative, 60.5% decrease and 3.2% increase the ΔMFIratio. At two years, 64.2% (95%CI 40.9-86.5) of non-relapsing children became MOG-Ab negative compared to 14.1% (95%CI 4.7-38.3) of relapsing ones, log-rank p<0.001, with no differences observed between non-relapsing and relapsing adults, log-rank p=0.280.

Conclusions

MOGAD differs in its clinical presentation at onset, showing a progressive shift in the clinical features across age-groups. Compared to children, adults have a higher risk of relapses and a worse functional recovery. Finally, children with monophasic disease became MOG-Ab negative earlier than relapsing ones, but not in adults. Considering these differences, management and treatment guidelines should be considered independently in children and adults.

Background

In the present pandemic, gathering information regarding Multiple Sclerosis (MS) patients with COVID-19 is needed.

Objectives

To investigate the incidence of COVID-19 in a Barcelona cohort of MS patients, to describe the characteristics of MS patients with COVID-19, and to identify risk factors for susceptibility and severity.

Methods

Retrospective cohort study of adult MS patients included from February to May 2020. COVID-19 and non-affected cases were identified through a COVID-19 mail survey and clinical visits. Demographic, clinical, MS characteristics, and laboratory data (lymphocyte and CD19+ count, immunoglobulins, and vitamin D) were obtained. Serological SARS-CoV-2 testing was performed in all suspected cases. We examined the relationship between the previously mentioned variables with COVID-19 susceptibility and severity.

Results

Out of the 2903 surveys sent, a total of 875 were answered. 117 (13.37%) patients were excluded for not meeting inclusion criteria. 48 out of 758 were suspected COVID-19 and the remaining were classified as non-COVID-19. The estimated incidence was 6.3%. 45 additional suspected COVID-19 cases were detected in clinical visits. In the multivariate analysis, COVID-19 susceptibility was associated with being younger (OR 0.54, IC95% 0.34-0.87,p<0.01), having had contact with a confirmed case (OR 193.20, IC95% 55.34-674.43,p<0.01), living in Barcelona (OR 2.35, IC95% 1.08-5.09, p=0.03) and a longer MS disease duration (OR 1.43, IC95% 1.10-1.85,p<0.01). In patients treated with an anti-CD20 therapy, COVID-19 susceptibility increased with treatment duration (OR 3.36, IC95% 1.42-7.96, p<0.01). 19 (20.43%) of the 93 COVID-19 cases were hospitalized, 9(9.68%) presented a severe course and 2(2.15%) of them died. In the univariate analysis, older patients with comorbidities, a progressive and longer MS duration, and without disease-modifying therapies, presented a more severe disease although these results were not observed in the multivariate analysis. Out of the 79 (84.9%) with serological test, 45.6% had generated antibodies and 17.6% in patients receiving anti-CD20. No relation of lymphopenia, vitamin D, or immunoglobulins levels with COVID-19 susceptibility or severity was found.

Conclusions

MS patients present similar incidence, risk factors, and outcomes for COVID-19 than the general population. Patients treated with an anti-CD20 therapy for a longer period of time might be in a higher risk of COVID-19 and of generating lower antibody response.

Background

Oligoclonal bands (OB) are part of the 2017 McDonald criteria but their determination is rater-dependent. Kappa free light chains (KFLC) are determined quantitatively and could be an alternative to OB, but a vendor-specific index cut-off is needed.

Objectives

To compare the proportion of patients with clinically isolated syndromes (CIS) and positive OB and a KFLC index equal or greater than 6.6 (KFLC-6.6, Leurs CE Mult Scler 2020) or 10.61 (KFLC-10.61, Gaetani L J Neuroimmunol 2020). To compare the diagnostic properties of OB, KFLC-6.6 and KFLC-10.61 for 2nd attack and 2017 MRI dissemination in space (DIS) and time (DIT).

Methods

MRIs were obtained 3-5 months after the CIS, at 1 year and every 5 years. OB were determined by isoelectric focusing combined with immunoblotting. We selected 228 patients with sufficient data to assess DIS and DIT, OB determination and enough remnant frozen samples to measure KFLC by turbidimetry (Optilite, The Binding Site). We compared the proportion of patients with positive OB, KFLC-6.6 and KFLC-10.61 and the 3-year diagnostic properties for the following outcomes: 2nd attack (n=179) and MRI DIS and DIT (n=192).

Results

Of all patients, 146 (64.0%) had OB, 147 (65.5%) KFLC-6.6 and 137 (60.1%) KFLC-10.61. In total, 130 (57.0%) had OB and KFLC-6.6, 16 (7.0%) only OB, 17 (7.5%) only KFLC-6.6 and 65 (28.5%) had neither. As for OB and KFLC-10.61, 122 (53.5%) had both, 24 (10.5%) only OB, 15 (6.6%) only KFLC-10.61 and 67 (29.4%) had neither. At baseline, the criteria were fulfilled by patients with OB, KFLC-6.6 and KFLC-10.61 as follows: DIS 109/135 (80.7%), 114 (84.4%) and 106 (78.5%); DIT 70/87 (80.5%), 78 (89.7%) and 74 (85.1%); DIS plus DIT 64/78 (81.2), 71 (91.0%) and 67 (85.9); DIS plus OB 109 (100.0%), 101 (92.7%) and 94 (86.2); and McDonald 111/130 (85.4%), 113 (86.9%) and 106 (81.5%). The diagnostic properties of OB, KFLC-6.6 and KFLC-10.61 for 2nd attack were sensitivity 77.8, 85.6 and 78.0; specificity 44.9, 48.3 and 51.7; and accuracy 61.5, 67.0 and 65.4. Results for MRI DIS plus DIT were sensitivity 81.8, 87.9 and 82.6; specificity 66.7, 70.0 and 73.3; and accuracy 77.1, 82.3 and 79.7.

Conclusions

KFLC-10.61 had the greatest specificity and KFLC-6.6 the best overall diagnostic properties. The results were probably due to the higher proportion of positive KFLC patients with DIT compared to those with positive OB, suggesting KFLC-6.6 could be used as an alternative to OB in the McDonald criteria.

Background

In the constantly evolving field of MS, personalized medicine is still one of the most important unmet need that requires further attention

Objectives

We aimed to develop a dynamic risk calculator to predict the long-term prognosis of MS in the context of a large MS Centre in Catalonia

Methods

This is an observational study based on data prospectively acquired from a deeply phenotyped CIS cohort from Barcelona. We first built a natural history baseline risk score (BRS) for predicting moderate disability, integrating baseline prognostic factors: Sex, age at CIS, CIS topography, number of T2 lesions, contrast-enhancing lesions (CEL) and oligoclonal bands. This BRS was designed as follows: For untreated patients, we built a Weibull model to estimate the median time to confirmed EDSS 3.0 and with these estimates we identified risk groups based on the median of the cut-offs of 2000 survival trees. Then we obtained the BRS of the full cohort. In patients with more than ten years of follow-up, we performed an inverse probability weighting to balance patients during their follow up for the propensity of being treated or lost to follow-up. The weights were estimated via a proportional hazards (PH) Cox model considering both baseline information (CIS year, BRS) and time-dependent (diagnosis status, new T2 lesions, CEL and cumulative number of relapses). Finally, a weighted PH Cox model was built to estimate the time to confirmed EDSS 3.0 considering the BRS and time-dependent events (new T2 lesions, cumulative number of relapses and first or second-line treatment use). Sensitivity analyses using other disability outcomes and different follow-ups were conducted.

Results

Of 956 patients, 577 (60.4%) were untreated before confirmed EDSS 3.0. Two BRS were obtained: low and high-BRS. Of 400 patients followed for more than ten years, 226 (56.5%) were low-BRS and 174 (43.5%) were high-BRS. High-BRS showed a HR=2.16 95%CI (1.16,4.02). Each new T2 lesion presented HR=1.04 95%CI (1.00,1.08) and each new relapse HR=1.46 95%CI (1.23,1.74). Being on second-line treatment showed a protective effect (HR=0.23 95%CI (0.06,0.94)) but no association was found for first-line treatments (HR=1.32 95%CI (0.67,2.60). Sensitivity analyses confirmed the association between BRS, new T2 lesions and the accumulation of relapses with the prognosis. However, treatment results were inconclusive.

Conclusions

Presenting a high-BRS doubles the risk of reaching moderate disability. Each new lesion and new relapse increses the risk by 4% and 46%, respectively; and second-line treatments seem to be protective. If validated, this risk calculator could be a crucial step to personalized medicine.

Background

Counselling and managing women with active Multiple Sclerosis (MS) during pregnancy and the postpartum period is a challenge. Alemtuzumab (ALZ) might be an option for patients with severe MS who desire pregnancy. However, data on relapse activity during and after pregnancy is scarce.

Objectives

Our objective was to describe our experience with ALZ treatment prescribed in highly active MS women with a pregnancy desire.

Methods

From all ALZ treated women (n=62), patients starting treatment because of a pregnancy desire were selected. Demographic, clinical, and radiological data before and during ALZ treatment as well as during and after pregnancy were collected.

Results

From 1^st September 2019, thirteen patients were identified with a mean age at ALZ onset of 33.9 years (SD 5.5), median disease duration of 12.0 years (IQR 12.5). The median number of relapses 1 year prior to ALZ onset was 2.0 (IQR 2.0) and 6 out of 10 patients (60%) had Gd-enhancing lesions at baseline MRI (median of 4.5 lesions; IQR 8.3). Only one patient was treatment naïve prior to ALZ onset, 5 patients (38%) were receiving fingolimod, 3 patients (23.1%) injectable therapies, and 3 patients (23,1%) other monoclonal antibodies. As of 1^st June 2020, 4 patients (30%) were still not pregnant, 8 patients (61.5%) have had a full-term pregnancy, and 1 patient (7.7%) was still pregnant. All 9 pregnant patients have received two cycles of ALZ with a median time from the last ALZ dose to pregnancy of 9 months (IQR 18). After 1-2 years ALZ treatment, and prior to the pregnancy, 4 out of 9 patients (44.4%) had at least one relapse and 3 (33.3%) patients had an active brain MRI either at 12 or 24 months after ALZ onset. During pregnancy, only 1 patient had a relapse during the first trimester. During the postpartum period, 2 out of 8 (25%) patients experienced a disease reactivation with a relapse occurring with a mean time of 42 days (SD 41) after delivery and a brain MRI showing a high number of Gd-enhancing lesions.

Conclusions

Alemtuzumab treatment in women with high disease activity and a pregnancy desire might be an option. However, it is warned that some patients could present a disease reactivation short after delivery. Thus, close monitoring is needed, especially in patients with a high disease activity during the preconception period.