Risk of central nervous system demyelinating attack or optic neuritis recurrence after pediatric optic neuritis in Korea.

PURPOSE: To investigate the rate of development of symptomatic central nervous system (CNS) demyelinating attacks or recurrent optic neuritis (ON) after the first episode of ON and its risk factors for Korean pediatric patients. METHODS: This multicenter retrospective cohort study included the patients under 18 years of age (n=132) diagnosed with ON without previous or simultaneous CNS demyelinating diseases. We obtained the clinical data including the results of neuro-ophthalmological examinations, magnetic resonance images (MRIs), antibody assays, and laboratory tests. We investigated the chronological course of demyelinating disease with respect to the occurrence of neurological symptoms and/or signs, and calculated the 5-year cumulative probability of CNS demyelinating disease or ON recurrence.  RESULTS: During the follow-up period (63.1±46.7 months), 18 patients had experienced other CNS demyelinating attacks, and the 5-year cumulative probability was 14.0±3.6%. Involvement of the extraorbital optic nerve or optic chiasm and asymptomatic lesions on the brain or spinal MRI at initial presentation were significant predictors for CNS demyelinating attack after the first ON. The 5-year cumulative probability of CNS demyelinating attack was 44.4 ± 24.8% in the AQP4-IgG group, 26.2±11.4% in the MOG-IgG group, and 8.7±5.9% in the double-negative group (P=0.416). Thirty-two patients had experienced a recurrence of ON, and the 5-year cumulative probability was 24.6±4.0%. In the AQP4-IgG group, the 5-year cumulative probability was 83.3±15.2%, which was significantly higher than in the other groups (P<0.001). CONCLUSIONS: A careful and multidisciplinary approach including brain/spinal imaging and antibody assay can help predict further demyelinating attacks in pediatric ON patients.

Impact of COVID-19 vaccination or infection on disease activity in a radiologically isolated syndrome cohort: The VaxiRIS study.

BACKGROUND: Vaccination in patients with multiple sclerosis (MS) treated with immunosuppressive drugs is highly recommended. Regarding COVID-19 vaccination, no specific concern has been raised. OBJECTIVES: We aimed to evaluate if COVID-19 vaccination or infection increased the risk of disease activity, either radiological or clinical, with conversion to MS in a cohort of people with a radiologically isolated syndrome (RIS). METHODS: This multicentric observational study analyzed patients in the RIS Consortium cohort during the pandemic between January 2020 and December 2022. We compared the occurrence of disease activity in patients according to their vaccination status. The same analysis was conducted by comparing patients' history of COVID-19 infection. RESULTS: No difference was found concerning clinical conversion to MS in the vaccinated versus unvaccinated group (6.7% vs 8.5%, p > 0.9). The rate of disease activity was not statistically different (13.6% and 7.4%, respectively, p = 0.54). The clinical conversion rate to MS was not significantly different in patients with a documented COVID-19 infection versus non-infected patients. CONCLUSION: Our study suggests that COVID-19 infection or immunization in RIS individuals does not increase the risk of disease activity. Our results support that COVID-19 vaccination can be safely proposed and repeated for these subjects.

Association between vaccination and the risk of central demyelination: results from a case-referent study.

BACKGROUND: Few studies documented the potential association between vaccination and the risk of central demyelination (CD). Specifically, anti-hepatitis B and anti-human papillomavirus (HPV) vaccines have been the subject of distrust with regard to their implication to trigger CD. METHODS: From a systematic national registry, patients with first signs of CD (cases) were identified and documented for their exposure to vaccination up to 24 months before the first signs occurred. This exposure was compared to that of a representative sample of general practice patients without a history of CD, randomly selected from a national registry (referents). CD cases were 2:1 matched on age, sex, index date (ID), and region of residence. Vaccines against influenza, HPV, hepatitis B and diphtheria-tetanus-pertussis-poliomyelitis-haemophilus (DTPPHae) were considered. Associations between vaccination and CD were assessed using multivariate conditional logistic regressions, controlled for confounding factors. FINDINGS: 564 CD cases were matched to 1,128 randomly selected referents (age range: 2-79 years old). Overall, 123 (22%) CD cases and 320 (28%) referents had received at least one vaccine within 24 months before ID. Adjusted odds ratios (ORs) for any vaccination were 0.69, 95% confidence interval (CI) [0.54-0.88] with respect to any CD first signs, 0.68 [0.51-0.90] for myelitis and 0.70 [0.42-1.17] for optic neuritis. Adjusted ORs for any CD first signs were 1.02 [0.71-1.47] for influenza vaccine (administered in 9.6% of cases and 10.4% of referents) and 0.72 [0.53-0.99] for DTPPHae vaccine (administered in 10.8% of cases and 14.5% of referents). Vaccines against hepatitis B and HPV were only administered in 1.1% and 1.2% of cases and in 2.9% and 3.2% of referents respectively, which statistically explained the point estimates < 1 (ORs of 0.39 [0.16-0.94] and of 0.32 [0.13-0.80]). INTERPRETATION: No increased risk of CD incidence was observed amongst vaccinated patients. Lower rates of vaccination against hepatitis B and HPV observed in patients with CD compared to referents may be due to the reluctance of physicians to vaccinate patients considered at risk of CD.

Incidental demyelination in magnetic resonance imaging and 10-year risk of multiple sclerosis: A data lake cohort study.

BACKGROUND AND PURPOSE: There is an absence of data from large population-based cohort studies on the incidence of radiologically isolated syndrome (RIS). The incidence of RIS and the subsequent risk for multiple sclerosis (MS) were investigated. METHODS: A population-based, retrospective cohort study was conducted using a data-lake-based analysis of digitalized radiology reports. All brain and spinal cord magnetic resonance imaging (MRI) in people aged 16-70 during the years 2005-2010 (n = 102,224) were screened using optimized search terms to detect cases with RIS. The subjects with RIS were followed up until January 2022. RESULTS: The cumulative incidence of RIS was 0.03% when all MRI modalities were included and 0.06% when only brain MRI was included according to MAGNIMS 2018 recommendation criteria. With the Okuda 2009 criteria, the respective figures were 0.03% and 0.05% (86% concordance). The overall risk for MS after RIS was similar, 32% by using the MAGNIMS and 32% by using the Okuda definition of RIS. Individuals aged <35.5 years exhibited the most significant predisposition to MS (80%), whilst those >35.5 years had less than 10% risk of MS. MS diagnosed after RIS constituted 0.8% of the incident MS cases in the population during 2005-2010. CONCLUSIONS: A population-wide context was provided for the incidence of RIS and its relationship to MS. MAGNIMS recommendations were only slightly more sensitive to detect RIS compared to the Okuda criteria. RIS has a subtle effect on the overall incidence of MS, yet the risk for MS in individuals under the age of 35.5 years is substantial.

Silent findings: Examination of asymptomatic demyelination in a pediatric US cohort.

BACKGROUND AND OBJECTIVES: Limited data is available on children with evidence of silent central nervous system demyelination on MRI. We sought to characterize the population in a US cohort and identify predictors of clinical and radiologic outcomes. METHODS: We identified 56 patients such patients who presented with incidental MRI findings suspect for demyelination, enrolled through our US Network of Pediatric Multiple Sclerosis Centers, and conducted a retrospective review of 38 patients with MR images, and examined risk factors for development of first clinical event or new MRI activity. MRI were rated based on published MS and radiologically isolated syndrome (RIS) imaging diagnostic criteria. RESULTS: One-third had a clinical attack and ¾ developed new MRI activity over a mean follow-up time of 3.7 years. Individuals in our cohort shared similar demographics to those with clinically definite pediatric-onset MS. We show that sex, presence of infratentorial lesions, T1 hypointense lesions, juxtacortical lesion count, and callosal lesions were predictors of disease progression. Interestingly, the presence of T1 hypointense and infratentorial lesions typically associated with worse outcomes were instead predictive of delayed disease progression on imaging in subgroup analysis. Additionally, currently utilized diagnostic criteria (both McDonald 2017 and RIS criteria) did not provide statistically significant benefit in risk stratification. CONCLUSION: Our findings underscore the need for further study to determine if criteria currently used for pediatric patients with purely radiographic evidence of demyelination are sufficient.

Higher consumption of ultra-processed foods and increased likelihood of central nervous system demyelination in a case-control study of Australian adults.

BACKGROUND: Consumption of ultra-processed foods (UPFs) has been linked to risk of chronic diseases, with scant evidence in relation to multiple sclerosis (MS). METHODS: We tested associations between UPF consumption and likelihood of a first clinical diagnosis of central nervous system demyelination (FCD) (267 cases, 508 controls), a common precursor to MS. We used data from the 2003-2006 Ausimmune Study and logistic regression with full propensity score matching for age, sex, region of residence, education, smoking history, body mass index, physical activity, history of infectious mononucleosis, dietary misreporting, and total energy intake. RESULTS: Higher UPF consumption was statistically significantly associated with an increased likelihood of FCD (adjusted odds ratio = 1.08; 95% confidence interval = 1.0,1.15; p = 0.039), representing an 8% increase in likelihood of FCD per one energy-adjusted serving/day of UPFs. CONCLUSION: Higher intakes of UPF were associated with increased likelihood of FCD in this Australian cohort. Nutrition education and awareness of healthy eating patterns may benefit those at high risk of FCD.

ABCB1 gene variants as risk factors and modulators of age of onset of demyelinating disease in Mexican patients.

INTRODUCTION: The C1236T, G2677T/A, and C3435T variants of the ABCB1 gene alter the functioning of P-glycoprotein and the transport of endogenous and exogenous substances across the blood-brain barrier, and act as risk factors for some neurodegenerative diseases. This study aimed to determine the association between demyelinating disease and the C1236T, G2677T/A, and C3435T variants of ABCB1 and its haplotypes and combinations of genotypes. METHODS: Polymerase chain reaction with restriction fragment length polymorphism analysis (PCR-RFLP) and Sanger sequencing were used to genotype 199 patients with demyelinating disease and 200 controls, all Mexicans of mixed race; frequencies of alleles, genotypes, haplotypes, and genotype combinations were compared between patients and controls. We conducted a logistic regression analysis and calculated chi-square values and 95% confidence intervals (CI); odds ratios (OR) were calculated to evaluate the association with demyelinating disease. RESULTS: The TTT and CGC haplotypes were most frequent in both patients and controls. The G2677 allele was associated with demyelinating disease (OR: 1.79; 95% CI, 1.12-2.86; P =  .015), as were the genotypes GG2677 (OR: 2.72; 95% CI, 1.11-6.68; P =  .025) and CC3435 (OR: 1.82; 95% CI, 1.15-2.90; P =  .010), the combination GG2677/CC3435 (OR: 2.02; 95% CI, 1.17-3.48; P =  .010), and the CAT haplotype (OR: 0.21; 95% CI, 0.05-0.66; P =  .001). TTTTTT carriers presented the earliest age of onset (23.0 ±â€¯7.7 years, vs 31.6 ±â€¯10.7; P =  .0001). CONCLUSIONS: The GG2677/CC3435 genotype combination is associated with demyelinating disease in this sample, particularly among men, who may present toxic accumulation of P-glycoprotein substrates. In our study, the G2677 allele of ABCB1 may differentially modulate age of onset of demyelinating disease in men and women.

Factors Related to the Progression of Clinically Isolated Syndrome to Multiple Sclerosis: A Retrospective Study in Lithuania.

Background and Objectives: Multiple sclerosis (MS) is a demyelinating disease which usually manifests as clinically isolated syndrome (CIS). Approximately 70% of patients with CIS progress to MS. Therefore, there is a pressing need to identify the most accurate predictive factors of CIS developing into MS, some of which could be a clear clinical phenotype of early MS as well as lesions in magnetic resonance imaging (MRI), pathological findings in cerebrospinal fluid (CSF) and evoked potentials (EP) tests. The problem is of outstanding importance since early MS diagnosis and treatment prevents long-term disability. The aim of our study is to analyze the factors that could influence the progression of CIS to MS. Materials and Methods: This study is a retrospective data analysis which included patients with their primary CIS diagnosis between 1st January 2015 and 1st January 2020. The prevalence and predictive value of clinical symptoms, MRI lesions, pathological CSF and EP findings were evaluated in accordance with the final diagnosis and compared between the sexes and age groups. Results: Out of 138 CIS patients, 49 (35.5%) patients progressed to MS. MS patients were more likely to have a diminished sense of vibration and proprioception (χ2 = 9.033, p = 0.003) as well as spinal cord MRI lesions (χ2 = 7.209, p = 0.007) in comparison with the non-MS group. Positive oligoclonal bands (OCBs) in CSF (χ2 = 34.859, p ≤ 0.001) and pathological brainstem auditory evoked potential (BAEP) test findings (χ2 = 10.924, p ≤ 0.001) were more prevalent in the MS group. Diminished sense of vibration and proprioception increased the risk for developing MS by 13 times (p = 0.028), whereas positive OCBs in CSF increased the risk by 100 times (p < 0.001). MS patients that were older than 50 years were more likely to exhibit positive Babinski's reflex (χ2 = 6.993, p = 0.03), decreased muscle strength (χ2 = 13.481, p = 0.001), ataxia (χ2 = 8.135, p = 0.017), and diminished sense of vibration and proprioception (χ2 = 7.918, p = 0.019) in comparison with both younger age groups. Conclusions: Diminished sense of vibration and proprioception, spinal cord MRI lesions, positive OCBs and pathological BAEP test findings were more common among patients that developed MS. Diminished sense of vibration and proprioception along with positive CSF OCBs are predictors of CIS progressing to MS. Older patients that develop MS have more symptoms in general, such as positive Babinski's reflex, decreased muscle strength, ataxia, and diminished sense of vibration and proprioception.

Incidence and risk factors of overcorrection in patients presenting with severe hyponatremia to the emergency department.

BACKGROUND: Hyponatremia is one of the most common electrolyte abnormalities. Overcorrection of severe hyponatremia can result in serious neurological complications such as osmotic demyelination syndrome, but the incidence and risk factors of overcorrection and osmotic demyelination have not been thoroughly investigated. METHODS: This is a single-center retrospective cohort study of 50 patients admitted through the emergency department with initial serum sodium (serum Na) < 125 mEq/L between January 2015 and December 2017. Incidence and risk factors of overcorrection and osmotic demyelination were examined. Overcorrection was defined as an increase in serum sodium concentration > 10 mEq/L at 24 h and/or > 18 mEq/L at 48 h, respectively. RESULTS: Six patients (12%) and one patient (2%) had overcorrection at 24 h and 48 h, respectively. A total of 5 (10%) patients had a brain MRI completed after overcorrection, and no patient showed radiologic evidence of osmotic demyelination. Symptomatic hyponatremia at presentation and 3% saline use were associated with the risk of overcorrection in univariable analysis (p < 0.001; p = 0.006, respectively). CONCLUSIONS: Among patients admitted with severe hyponatremia, overcorrection occurred in 14%. Symptomatic hyponatremia at presentation and 3% saline use were associated with the risk of overcorrection.

Is there a link between neuropathic pain and constipation in NMOSD and MOGAD? Results from an online patient survey and possible clinical implications.

BACKGROUND: Neuropathic pain (NP) and constipation are common among people with neuromyelitis optica spectrum disorder (NMOSD) and myelin oligodendrocyte glycoprotein antibody disease (MOGAD) and have a negative impact on quality-of-life measures. The possible association between the two symptoms has not been explored. METHODS: Patients with NMOSD and MOGAD, who were members of a closed international Facebook group, were recruited to complete an anonymous survey on REDCap. Participants were queried regarding demographic and disease-related characteristics, the presence and severity of NP and constipation, and whether they believe there is a relationship between the two symptoms. RESULTS: Of the 317 participants who completed the survey, 213 (67.2%) reported a diagnosis of aquaporin-4 (AQP-4) positive NMOSD, 93 (29.4%) - MOGAD, and 11 (3.4%) - double-seronegative NMOSD. The mean age was 43.9 ± 16.4 years; 259 were female (81.7%). 206 participants (65%) reported NP, of whom 133 (64.6%) were being treated for it with one or more medications. 167 participants (52.7%) reported constipation, of whom 67 (40.2%) received one or more medications. 137 of 206 participants with NP (66%) also had constipation. Both symptoms were significantly more common among patients with a history of myelitis. Among patients with NP and constipation, 47 participants (34.3%) thought there was a relationship between the two conditions, with the majority reporting increased severity of NP when constipation severity was increased and, conversely, alleviation of NP when constipation lessened. CONCLUSIONS: NP and constipation were seen in the majority of NMOSD and MOGAD patients with a history of myelitis. Interestingly, one-third of patients with both symptoms reported a link between them, with the majority reporting that NP severity was increased with worse constipation. The possible association opens a possibility of a new approach to managing NP, which tends to be poorly responsive to symptomatic therapies and is associated with worse quality of life in NMOSD and MOGAD. Further studies are warranted to confirm our results.

Osmotic Demyelination Syndrome in Hospitalized Patients With Cirrhosis: Analysis of the National Inpatient Sample (NIS).

GOAL: Characterize prevalence of osmotic demyelination syndrome (ODS) in hospitalized patients with cirrhosis. BACKGROUND: ODS is a serious complication of rapid serum sodium correction. Patients with cirrhosis experience labile sodium levels related to portal hypertension and diuretic use, often with rapid correction-intentional or unintentional-during hospitalizations. STUDY: We used validated International Classification of Diseases, Ninth Revision (ICD-9) codes to identify inpatients 18 years and older with cirrhosis from the 2009-2013 National Inpatient Sample, excluding those with liver transplantation during hospitalization. The primary outcome was ODS (ICD-9 341.8). Baveno IV defined decompensated cirrhosis (stages 3 and 4); Charlson Comorbidity Index identified severe comorbid illness (score >3). Logistic regression modeled factors associated with ODS. RESULTS: Of 547,544 adult inpatients with cirrhosis, 94 (0.02%) had ODS. Inpatients with versus without ODS were younger (54 vs. 57 y, P=0.0001), and more likely to have alcohol-related cirrhosis (58% vs. 33%, P<0.0001). ODS did not associate with decompensated cirrhosis (33% vs. 37%, P=0.43), specific complications (ascites 33% vs. 33%, P=0.97; hepatic encephalopathy 24% vs. 17%, P=0.06), or severe comorbid illness (12% vs. 16%, P=0.24). In both univariable and multivariable analysis, age [adjusted odds ratio (ORadj): 0.97, 95% confidence interval (CI): 0.95-0.99], female gender (ORadj: 1.53, 95% CI: 1.01-2.30), Hispanic race (ORadj: 0.41, 95% CI: 0.19-0.89), alcohol-related cirrhosis (ORadj: 2.65, 95% CI: 1.71-4.09), and congestive heart failure (ORadj: 0.37, 95% CI: 0.15-0.95) significantly associated with ODS. CONCLUSION: In hospitalized patients with cirrhosis, ODS is extremely rare, and associated with alcohol-related cirrhosis, younger age, and female gender. ODS is not associated with liver disease severity, specific complications including ascites, or comorbid disease.

Acute Demyelinating Syndromes: A report of child neurology department of Sfax University Hospital.

INTRODUCTION: The yearly incidence of Acute Demyelinating Syndromes (ADS) in a multiethnic cohort of children published by Langer-Gould and al in 2011 was estimated at about 1.66 per 100,000. Nevertheless, the real incidence for these disorders is still underestimated as the iterative revision for diagnosis criteria have failed to classify a significant number of children with ADS. PURPOSE: This work was aimed to describe clinical and paraclinical characteristics of ADS in a pediatric population. MATERIAL AND METHODS: Demographic, clinical and paraclinical data of 42 children (24 females; 18 male; SR = 1.33), were collected from the medical records of patients admitted to the child neurology department of Sfax University Hospital between 2008 and 2021 for clinical events with presumed inflammatory origin. Next, patients were categorized as per M. N. Nouri and al. up dated classification for ADS. Finally, characteristics of different ADS categories were compared. RESULTS: The mean age onset was 6 years (± 3.5 years). For a mean follow-up period of 28 months, 69% of patients had a monophasic course. ADS in our pediatric population were Acute disseminated encephalomyelitis (ADEM) (36%), Clinically isolated syndrome (CIS) (24%), Multiple sclerosis (MS) (19%), Neuromyelitis optica spectrum disorder (NMOSD) (7%), Myelin oligodendrocyte glycoprotein antibodies-associated diseases (MOGAD) (2%) and Recurrent demyelinating disease not otherwise specified (RD-NOS) (10%). At presentation, patients showed different clinical picture according to ADS-subtype with more patients with epileptic seizure in ADEM-group (53.3%), optic neuritis in CIS-group (70%), motor deficit in MS-group (62.5%), area postrema syndrome in NMOSD-group (33.3%) and vesico-sphincter dysfunction in RD-NOS-group (75%). Among patients presenting with visual impairment (21.4%), Visual evoked potential (VEP) guided the diagnosis of NMOSD in 22.2% by objectifying axonal optic nerve damage. Different ADS subtypes were identified according to MRI results in 100% of ADEM-patients and 75% of MS-patients and on antibody testing in three patients. The ADS-subtype was recognized based on antibody testing in three patients. Two patients from CIS-group: the first with isolated optic neuritis (ON) was positive for antiaquaporin 4 antibodies (anti-AQP4) and the other with clinically polyfocal ADS was positive for antinuclear antibodies (ANA) type anti-RNP. The remaining patients who presented with ADEM-phenotype was positive for anti-myelin oligodendrocyte glycoprotein (anti-MOG). SIGNIFICANCE: Recognizing distinctive features of each ADS category may improve diagnosis accuracy as well as the indication of suitable treatment.

Radiologically isolated syndrome: A single-center, retrospective cohort study.

BACKGROUND: Radiologically Isolated Syndrome (RIS) likely represents the earliest detectable form of multiple sclerosis (MS). There are recognized risk factors for conversion of RIS to clinically definite central nervous system (CNS) demyelinating disease. We aim to characterize a new clinical cohort with RIS and to analyze previously established risk factors for conversion to clinically definite disease. METHODS: A medical records search was performed for patients who were diagnosed with RIS by their treating neurologist at our institution in Boston, USA, from January 2005 to April 2020. Demographic data, clinical outcomes, and treatment courses were analyzed. The time to first clinical event representing a demyelinating disease attack or last follow up without clinically definite disease was calculated for each person. Hazard ratios (HRs) for known risk factors for the conversion of RIS to clinically definite disease were calculated using Cox proportional hazards models. RESULTS: Of 89 patients, the median age at RIS diagnosis was 41.0 years (76% female, 8% with a family history of MS and 16% of any autoimmune disorder, 66% never smokers, 40% BMI >30 kg/m2, 45% with spinal cord MRI lesions). Clinically definite disease was observed in 16 patients (18%) during follow-up (median time to first event 3.4 years; median follow-up duration of full cohort 3.8 years). Median EDSS for those who developed clinically definite disease was 1.25 (range: 0-4) at most recent follow up. Of 84 patients with longitudinal brain imaging, 42 (50%) had new demyelinating lesions. Gadolinium-enhancing lesions were seen in 36 patients (43%) at either baseline (n=24) or follow-up (n=12). Most patients had at least one T1-hypointense lesion (n=70, 83%). Five patients underwent ultra-high field MRI (7 Tesla); all were positive for central vein sign, two demonstrated leptomeningeal enhancement, and one was found to have cortical lesions. Out of 30 patients with susceptibility-weighted imaging acquired during routine clinical care, 8 had at least one paramagnetic rim positive lesion. Previously reported risk factors for conversion to MS were not significant: age ≤37 years HR 1.3 (95% confidence interval (CI), 0.47-3.5), male sex 1.5 (95% CI, 0.41-5.2), and spinal cord lesions 1.3 (0.47-3.4). Nearly one-third of RIS patients (n=26) took a disease modifying therapy (DMT) for MS (median total treatment duration on any DMT=2.7 years). The sub-cohort treated with a DMT had a statistically significantly greater number of recognized risk factors for conversion to clinically definite disease compared with the untreated group (p=0.028). Most patients took a DMT for MRI changes demonstrating new demyelinating disease activity (n=16). Dimethyl fumarate (n=9) and glatiramer acetate (n=7) were the most frequently prescribed DMTs. A second-line DMT was started in 10 patients. CONCLUSION: We characterize a new cohort of RIS patients, demonstrating time to clinically evident demyelinating disease from RIS diagnosis of approximately 3.4 years. Our data suggest that early use of a DMT in RIS may mitigate the impact of recognized risk factors on the occurrence of clinically evident disease and reduce the likelihood of conversion to clinically definite CNS demyelinating disease in high-risk individuals.

Conus medullaris involvement in demyelinating disorders of the CNS: A comparative study.

BACKGROUND: Differentiation of the demyelinating disorders of the CNS seems challenging in practice. Conus medullaris, the cone-shaped end of the spinal cord, is more involved in anti-MOG patients based on preliminary studies, a possibly helpful detail in its differentiation. Nevertheless, the evidence is still limited and the underlying cause is unclear and undiscussed in previous studies. OBJECTIVE: To contribute to preliminary studies by comparing conus involvement among patients with MS, anti-AQP4, and anti-MOG diseases using larger sample size. METHODS: More than a thousand MS, anti-AQP4, and anti-MOG patients were followed up for a maximum of five years, scanned for conus medullaris involvement. Data regarding each cohort were then analyzed and compared using statistical methods. RESULTS: The rate of conus medullaris involvement was significantly higher in anti-MOG patietns (OR = 27.109, P < 0.001), followed by anti-AQP4 (OR = 4.944, P = 0.004), and MS patients (OR = reference). Survival analysis showed higher pace and cumulative incidence of conus attacks in anti-MOG patients. Conus-involved patients, showed no significant difference regarding age, sex, concurrent brain lesions, and their partial recovery. Predictive values show that the probability of being diagnosed with anti-MOG is roughly 13 times higher in conus-involved patients (25.93% vs. 1.97%), although this probability was still higher for MS, as it has a much higher incidence. CONCLUSION: Despite minor differences, the results were in line with previous studies, confirming the higher rate of conus medullaris involvement among anti-MOG patients. Potential underlying causes are proposed and remain to be investigated in future studies.

Long-term trajectory of acquired demyelinating syndrome and multiple sclerosis in children.

AIM: We assessed the frequency, characteristics, and future trajectory of monophasic acquired demyelinating syndromes (ADS) associated with conversion to paediatric multiple sclerosis. METHOD: This was a retrospective observational study of Sardinian children (<18y of age) with onset of ADS between 2001 and 2018. RESULTS: We identified 44 children with ADS (21 males, 23 females; median age at onset 16y, range 4mo-18y), 21 of whom were already presenting with criteria for paediatric multiple sclerosis. The mean crude prevalence of ADS in Sardinian children was 59.2 per 100 000, while incidence was 3.1 per 100 000 per year (1.3 in children aged ≤10y and 11.9 in those aged 10-17y). After a mean (SD) follow-up of 8 years 5 months (5y 4mo), the most common (n=32) trajectory was conversion to paediatric multiple sclerosis. At onset, the total prevalence and mean annual incidence of paediatric multiple sclerosis were 35.6 per 100 000 and 2.3 per 100 000 respectively (0.5 in individuals aged ≤10y, 10.0 in the older group). INTERPRETATION: Sardinia is a very high risk area for ADS in children. Nearly half of this population can already be diagnosed with paediatric multiple sclerosis at onset. Overall, 72% of those with ADS will have paediatric multiple sclerosis after a mean of 8 years. What this paper adds Sardinia is a very high risk area for paediatric acquired demyelinating syndromes (ADS). A high proportion of those with paediatric multiple sclerosis are diagnosed at onset of ADS. After an average 8 years from onset of paediatric ADS, three-quarters of patients are diagnosed with paediatric multiple sclerosis.

Prevalence of radiologically isolated syndrome in a pediatric population-based cohort: A longitudinal description of a rare diagnosis.

BACKGROUND: Radiologically isolated syndrome (RIS) is typified by multiple sclerosis (MS)-like lesions on imaging, without clinical MS symptoms. The prevalence of pediatric RIS is largely unknown. OBJECTIVE: The objective of the study is to provide an estimated RIS prevalence in a population-based cohort of children. METHODS: We used data from the Generation R study to identify the childhood RIS prevalence. RESULTS: In 5238 participants, only one RIS case was identified (prevalence: 0.02%; 95% confidence interval (CI): 0.00-0.11). During a 62-month follow-up, imaging examinations showed accrual of new focal demyelinating lesions; however, no clinical MS symptoms occurred. CONCLUSIONS: This study shows that the occurrence of RIS in children from the general population is rare.

Association of Pregnancy With the Onset of Clinically Isolated Syndrome.

Importance: Multiple sclerosis (MS) is usually diagnosed in women during their childbearing years. Currently, no consensus exists on whether pregnancy can delay the first episode of demyelination or clinically isolated syndrome (CIS). Objective: To investigate the association of pregnancy with time to CIS onset. Design, Setting, and Participants: This multicenter cohort study collected reproductive history (duration of each pregnancy, date of delivery, length of breastfeeding) on all participants between September 1, 2016, and June 25, 2019. Adult women being treated at the MS outpatient clinics of 4 tertiary hospitals in 2 countries (Charles University and General University Hospital in Prague, Czech Republic; Royal Melbourne Hospital in Melbourne, Australia; Alfred Hospital in Melbourne, Australia; and John Hunter Hospital in Newcastle, Australia) were recruited to participate in the study. Preexisting data (date of CIS onset, date of birth, sex, date of clinical onset, and Expanded Disability Status Scale result) were collected from MSBase, an international registry of long-term prospectively collected data on patients with MS. Data analyses were performed from June 1, 2019, to February 3, 2020. Exposures: Gravida (defined as any pregnancy, including pregnancy that ended in miscarriage and induced abortion) and parity (defined as childbirth after gestational age of more than 20 weeks, including livebirth and stillbirth) before CIS onset. Main Outcomes and Measures: Time to CIS onset. The following were assessed: (1) whether women with previous pregnancies and childbirths had a delayed onset of CIS compared with those who had never been pregnant and those who had never given birth, and (2) whether a dose response existed, whereby a higher number of gravidity and parity was associated with a later onset of CIS. Results: Of the 2557 women included in the study, the mean (SD) age at CIS onset was 31.5 (9.7) years. Of these women, before CIS onset, 1188 (46%) had at least 1 pregnancy and 1100 (43%) had at least 1 childbirth. The mean (SD) age at first pregnancy was 23.3 (4.5) years and at first childbirth was 23.8 (4.5) years. Women with previous pregnancies and childbirths had a later onset of CIS compared with those who had never been pregnant (HR, 0.68; 95% CI, 0.62-0.75; P < .001), with a median delay of 3.3 (95% CI, 2.5-4.1) years. Women who had given birth also had a later CIS onset compared with women who had never given birth (HR 0.68; 95% CI, 0.61-0.75; P < .001), with a similar median delay of 3.4 (95% CI, 1.6-5.2) years. A higher gravidity and parity number was not associated with delay in CIS onset. Conclusions and Relevance: This study suggests an association between previous pregnancies and childbirths and timing of CIS onset, but having more pregnancies or childbirths did not appear to be associated with a later CIS onset. Further studies are needed to help explain the mechanisms behind the associations between pregnancy and onset of multiple sclerosis.

Estimating the relative frequency of leukodystrophies and recommendations for carrier screening in the era of next-generation sequencing.

Leukodystrophies are a heterogeneous group of heritable disorders characterized by abnormal brain white matter signal on magnetic resonance imaging (MRI) and primary involvement of the cellular components of myelin. Previous estimates suggest the incidence of leukodystrophies as a whole to be 1 in 7,000 individuals, however the frequency of specific diagnoses relative to others has not been described. Next generation sequencing approaches offer the opportunity to redefine our understanding of the relative frequency of different leukodystrophies. We assessed the relative frequency of all 30 leukodystrophies (associated with 55 genes) in more than 49,000 exomes. We identified a relatively high frequency of disorders previously thought of as very rare, including Aicardi Goutières Syndrome, TUBB4A-related leukodystrophy, Peroxisomal biogenesis disorders, POLR3-related Leukodystrophy, Vanishing White Matter, and Pelizaeus-Merzbacher Disease. Despite the relative frequency of these conditions, carrier-screening laboratories regularly test only 20 of the 55 leukodystrophy-related genes, and do not test at all, or test only one or a few, genes for some of the higher frequency disorders. Relative frequency of leukodystrophies previously considered very rare suggests these disorders may benefit from expanded carrier screening.

Risk factors for academic difficulties in children with myelin oligodendrocyte glycoprotein antibody-associated acute demyelinating syndromes.

AIM: To describe cognitive abilities through the evaluation of academic difficulties in children with acute demyelinating syndromes (ADS) and myelin oligodendrocyte glycoprotein (MOG) antibodies. METHOD: This was an observational, retrospective study of a French paediatric cohort that included children aged 18 years and younger. Clinical, biological, and imaging data were collected and academic outcome was measured. RESULTS: Seventy-six children were included in the study with a mean (SD) follow-up of 4 years 7 months (6y 4mo). Median age at disease onset was 9 years 1 months (interquartile range=4y 7mo-13y 11mo; 36 females, 40 males). Thirty-six children relapsed and 20 had academic difficulties at the last follow-up. Academic difficulties, as well as deep grey matter and putaminal lesions (p=0.047 and p=0.006 respectively), were significantly more prevalent in children aged 10 years and younger (p=0.02). Using univariate binary regression analysis, we found that age at disease onset of 10 years and younger (odds ratio [OR] 3.72 [95% confidence interval {CI} 1.19-11.64]; p=0.024), acute disseminated encephalomyelitis at disease onset (OR 52.5 [95% CI 5.97-461.4]; p<0.001), and deep grey matter lesions (OR 17.33 [95% CI 3.87-77.72]; p<0.001) were associated with academic difficulties. INTERPRETATION: MOG antibody-associated ADS have distinct clinical and radiological patterns that are age-dependent. Indirect cognitive evaluation through academic difficulties was prevalent in younger children and is associated with specific clinical and magnetic resonance imaging factors that need to be considered earlier on when assessing this patient population.