YI02.01 - Optic Neuritis-Independent Retinal Atrophy In Neuromyelitis Optica Spectrum Disorders
Prior studies have suggested that retinal neuro-axonal loss may occur in aquaporin-4 (AQP4)-IgG seropositive neuromyelitis optica spectrum disorder (NMOSD) in the absence of optic neuritis (ON), but data are conflicting.
To examine whether patients with AQP4-IgG seropositive NMOSD exhibit progressive retinal neuro-axonal loss, independently of optic neuritis (ON) attacks.
In this single-center, longitudinal study, 32 AQP4-IgG+ NMOSD patients and 48 healthy controls (HC) were followed with serial spectral-domain optical coherence tomography (OCT). NMOSD patients with ON less than 6 months prior to baseline were excluded, while data from patients with ON during follow-up were censored at the last visit prior to ON. Rates of peri-papillary retinal nerve fiber layer (pRNFL) and macular ganglion cell+inner plexiform layer (GCIPL) thinning were compared between groups utilizing mixed-effects linear regression models adjusted for age, race and sex.
Median follow-up duration was 4.3 years (IQR: 2.6 -7.5) for the NMOSD cohort and 4.0 years (IQR: 1.8 – 7.5) for the HC. We observed faster pRNFL (β=-0.25µm/year, 95%CI: -0.45 to -0.05, p=0.014) and GCIPL thinning (β=-0.09µm/year, 95%CI: -0.17 to 0, p=0.05) in NMOSD compared to HC eyes. This difference appeared to be driven by faster pRNFL and GCIPL thinning in NMOSD eyes without a history of ON compared to HC (GCIPL: β=-0.15µm/year, 95%CI: -0.25 to -0.05, p=0.005; pRNFL: β=-0.43µm/year, 95%CI: -0.67 to -0.19, p<0.001), while rates of pRNFL (β=-0.07µm/year , 95%CI: -0.31 to 0.16, p=0.53) and GCIPL (β=-0.01µm/year, 95%CI: -0.11 to 0.10, p=0.90) thinning did not differ between NMOSD-ON and HC eyes .
Furthermore, we explored the effects of non-ON relapses during follow-up on rates of pRNFL and GCIPL thinning. Ten patients had relapses during follow-up (9 transverse myelitis, 1 area postrema syndrome). Patients with relapses did not exhibit differences in rates of GCIPL (β=0.05µm/year, 95%CI:-0.10 to 0.20, p=0.51) or pRNFL thinning (pRNFL: β=0.08µm/year, 95%CI: -0.28 to 0.43, p=0.67), compared to those who were clinically stable.
In this longitudinal study, we observed progressive pRNFL and GCIPL atrophy in AQP4-IgG+ NMOSD eyes unaffected by ON. These results support that subclinical involvement of the anterior visual pathway may occur in AQP4-IgG+ NMOSD.
YI02.02 - Assessing No Evidence of Disease Activity in Pediatric Onset Multiple Sclerosis
Pediatric onset multiple sclerosis (POMS) account for 5-10% of all MS cases. The optimal treatment target in POMS is not known. No Evidence of Disease Activity (NEDA), defined as the lack of clinical and radiologic evidence of MS activity, has been proposed as a possible outcome measure and treatment target in MS.
We aim to determine POMS NEDA rate, compare NEDA and evidence of disease activity (EDA) patient characteristics, and determine NEDA predictors.
Retrospective analyses of POMS cases from the Multiple Sclerosis and other Demyelinating Diseases Database (PedMSDD) were conducted. Multiple imputation was employed to reduce bias relative to complete-case methods. NEDA proportions at 12, 18, and 24 months post-diagnosis were calculated. Demographic and clinical disease characteristics between NEDA and EDA were compared. The odds of achieving NEDA at each time interval were modeled using separate univariable logistic regressions, and significant predictors were included in final multivariable models.
Demographics and clinical characteristics were similar between NEDA and EDA. In patients with at least six months of follow-up (N=913), an estimated 56%, 64%, and 69% of patients achieve NEDA at months 12, 18, and 24, respectively. A significant proportion (>70%) of patients were not on disease modifying therapy (DMT) in the first 6 months. Among those on DMT, intravenous (IV) DMT was more common among the NEDA group compared to EDA. Recent DMT use was more important than initial DMT use in its ability to explain NEDA status at 18 and 24 months. Those on IV DMT had increased odds of achieving NEDA compared to those on no DMT or other DMTs.
A majority of POMS patients achieved NEDA at some point within 2 years of MS diagnosis, despite being treatment-naïve initially. In those on DMT, recent intravenous DMT use was associated with higher likelihood of NEDA.
YI02.03 - Identifying distinct cognitive phenotypes in multiple sclerosis
Cognitive impairment is one of the most disabling symptoms of multiple sclerosis (MS), affecting about 50% of patients.
We sought to define homogeneous cognitive phenotypes in a large cohort of MS patients by using a data-driven approach, and to assess their distinctive clinical and MRI features.
A cohort of 1212 MS patients and 196 healthy controls (HC) from 8 Italian MS centers underwent cognitive evaluation with Rao’s Brief Repeatable Battery and Stroop Color Word Test. A subgroup (172 MS patients and 50 HC) also underwent a 3T MRI examination, including 3D T1-weighted and dual-echo sequences. Latent-profile analysis was used on cognitive tests’ z-scores for identifying cognitive phenotypes. Linear regression and mixed effects models were used to define the clinical and MRI features of each phenotype.
Five cognitive phenotypes were identified, characterized by “preserved-cognition” (19%), “mild verbal memory/semantic fluency” impairment (30%), “mild-multi-domain” impairment (19%), “severe-attention/executive” impairment with mild impairment of other domains (14%), and “severe-multi-domain” impairment (18%). “Preserved-cognition” patients had shorter disease duration and lower Expanded Disability Status Scale (EDSS) score than all other groups, and mildly impaired phenotypes included patients with shorter disease duration and less likely progressive disease compared to severely impaired groups. However, the “preserved-cognition” group also included patients with progressive disease and high EDSS scores, and severely impaired phenotypes were also represented in early MS stages. Comparing each phenotype to “preserved-cognition” group, distinctive MRI features emerged: “mild verbal memory/semantic fluency” patients had reduced hippocampal volume (p=0.02), “mild-multi-domain” reduced cortical gray matter volume (p=0.04), “severe-attention/executive” higher lesion volume (p=0.04) and severe-multi-domain” extensive brain damage (p<0.01 for lesion, brain, gray matter and thalamic volumes).
We identified five cognitive phenotypes of MS patients, with distinctive MRI substrates. By defining homogenous and clinically meaningful groups, this characterization may be useful for future research on cognitive impairment in MS, and for defining personalized management approaches and rehabilitative strategies in clinical practice.
YI02.04 - Comparison of clinical characterization, risk of relapses and antibody dynamics between children and adults with MOGAD
- A. Cobo Calvo
- A. Ruiz
- F. Rollot
- G. Arrambide
- R. Deschamps
- E. Maillart
- C. Papeix
- B. Audoin
- A. Lépine
- H. Maurey
- H. Zephir
- D. Biotti
- J. Ciron
- F. Durand-Dubief
- N. Collongues
- X. Ayrignac
- P. Labauge
- P. Meyer
- E. Thouvenot
- B. Bourre
- A. Montcuquet
- M. Cohen
- P. Horellou
- M. Tintore
- J. De Seze
- S. Vukusic
- K. Deiva
- R. Marignier
To predict the clinical course of myelin oligodendrocyte glycoprotein (MOG)-antibody (Ab)-associated disease (MOGAD) is essential to guide treatment recommendations.
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.
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.
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.
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.
YI02.05 - Cognition and socio-professional attainment in paediatric onset multiple sclerosis: a reappraisal after 10 years
- A. Bellinvia
- R. Fratangelo
- E. Portaccio
- M. Fonderico
- L. Tudisco
- L. Razzolini
- L. Pastò
- B. Goretti
- C. Niccolai
- A. Ghezzi
- M. Zaffaroni
- L. Pippolo
- L. Moiola
- M. Falautano
- C. Celico
- R. Viterbo
- F. Patti
- C. Chisari
- P. Gallo
- A. Riccardi
- M. Borghi
- M. Simone
- A. Bertolotto
- C. Pozzilli
- V. Bianchi
- M. Roscio
- V. Martinelli
- G. Comi
- M. Filippi
- M. Trojano
- M. Amato
Cognitive impairment (CI) affects nearly 30% of paediatric patients with Multiple Sclerosis (MS) and has a negative impact on school performance and participation in social activities. This study is a re-appraisal of cognitive functioning and socio-professional attainment in adulthood in an Italian cohort of paediatric MS patients after 10 years from baseline neuropsychological assessment.
To re-assess cognitive performance and its impact on socio-professional attainment in our cohort of paediatric MS patients after 10 years from baseline evaluation and to determine predictors of the individual outcomes.
Sixty-three paediatric patients were assessed at baseline and 48 followed-up after five years. To date, 31 out of these 48 patients (17 females, mean age 27.9±2.5 years, mean EDSS 1.7±1.6) were reassessed on an extensive neuropsychological battery and compared with a matched group of 31 healthy controls. CI was defined as the failure of > 2 tests. Socio-professional attainment was evaluated on the Work and Social Assessment Scale (WSAS). Predictors of CI and WSAS score were assessed through multivariable logistic and linear models.
After a mean follow-up of 12.5±2.3 years, 15 (54%) subjects were classified as cognitively impaired. Patients with CI compared with those cognitively preserved at follow-up had higher Expanded Disability Status Scale (EDSS) score (1.9±1.4 vs 1.0±0.7; p = 0.046), lower baseline intelligence quotient (IQ) (86.2±23.8 vs 103.6±14.7; p = 0.025) and were less frequently treated with disease modifying therapy (DMT) at baseline [6 (35.3%) vs 11 (78.6%); p = 0.016]. In the regression model, CI after 10 years was related to lower IQ (OR 0.93, 95% CI 0.87-0.99, p = 0. 027) and absence of DMT at baseline assessment (OR 17.78 95%; 1.72-183.65, p = 0.017).
Baseline predictors of worse socio-professional attainment on the WSAS in adulthood were CI (B=6.3, p=0.016), higher EDSS (B=2.2, p=0.023) and higher age at onset (B=0.6, p=0.041). As for 10-year correlates, only CI was associated to poor functional outcome (B=5.2, p=0.006).
Complete data collection is ongoing; available findings to date show that in paediatric onset subjects CI remains significant in adulthood, is related to lower cognitive reserve, higher levels of neurological impairment and delay in DMT initiation. Moreover, CI plays a key role in predicting the subject social performance and professional outcome. Early treatment and promotion of strategies aimed at enhancing cognitive reserve are recommended in paediatric patients with MS.
YI02.06 - Central nervous system infections in adolescence and MS risk after age 20 years
Infectious agents in MS etiology have been previously investigated. Theories of pathogenic mechanisms include molecular mimicry or activation of macrophages and natural killer cells with subsequent infiltration of the blood brain barrier. Epstein-Barr virus (EBV) infection often signaled by infectious mononucleosis (IM) is a notable MS risk factors, but other infections including Chlamydia pneumoniae, among others, are also associated with MS. Adolescence is a potentially critical period for susceptibility MS and associations with exposures in adolescence such as concussion, pneumonia, BMI, and EBV/IM have been found. No studies to our knowledge have examined CNS infection as a risk factor for MS.
To determine if CNS infection in childhood (age 0-11 years) or adolescence (age 11-20) is associated with MS risk after age 20 years.
A cohort born in Sweden between 1970-1994 followed until 31 December 2014, was identified using the Total Population Register, excluding those diagnosed with MS before age 20 years (y) (N=2,422,969). ICD codes from the National Patient Register identified diagnoses of MS after age 20y (n=4,022) (two or more diagnoses), and CNS infection (bacterial and viral) before age 20y. Diagnoses of IM, pneumonia, and other bacterial or viral infections were identified. Infections were classified as present/absent at 0-10y or 11-20y. Cox regression was used to determine associations of CNS infection with MS, with follow-up from age 20y to first MS diagnosis, adjusting for gastrointestinal, genitourinary, respiratory, skin, other infections, sex and parental socioeconomic position.
CNS infection before age 11y was not associated with MS. CNS infection in adolescence was statistically significantly associated with increased MS risk producing an adjusted hazard ratio of 2.80 (95%CI 1.90-4.12). Excluding encephalomyelitis (as this includes acute disseminated encephalitis, often a precursor of MS) the estimate was 1.85 (95%CI 1.11-3.07): an accurate estimate of risk lies between these two hazard ratios. Further adjustment for other infections did not alter the estimates notably.
This novel finding of CNS infection in adolescence associated with MS risk suggests such infections may cause cellular damage in the CNS triggering autoimmune processes pertinent to multiple sclerosis pathogenesis. It also adds to the evidence of a critical susceptibility period in adolescence for MS initiation.