A systematic review of the epidemiology of pediatric autoimmune encephalitis: disease burden and clinical decision-making.

Background: Autoimmune encephalitis (AIE) comprises a group of rare, immune system-mediated conditions. Clinical manifestations among children are not well-characterized, and there are challenges in testing and diagnosis. This can result in treatment delays, which has been found to correlate with poorer long-term outcomes. This challenge is exacerbated by the scarcity of epidemiological reporting of AIE. The objective of this systematic literature review (SLR) was to identify studies reporting epidemiological data on AIE in children. Methods: MEDLINE, Embase, the Cochrane Library, and the University of York Centre for Reviews and Dissemination (CRD) were searched in May 2023 for studies reporting on the epidemiology of AIE in children. These were supplemented with additional searches of conference proceedings, gray literature, and the reference lists of identified SLRs. Quality of studies was assessed using a modified version of the Joanna Briggs Institute (JBI) Checklist for Prevalence Studies. Results: Forty-three publications reporting on 41 unique studies were included. Nine studies reported incidence estimates of different subtypes of AIE, with only one reporting the incidence of overall AIE in children ≤ 18 years, estimated at 1.54 per million children per year in the Netherlands. Three studies reported the incidence of pediatric N-methyl-D-aspartate receptor (NMDAR)-AIE [in United Kingdom (UK), Hong Kong, and Denmark]. The other studies reported incidence data for selected populations. Conclusion: This SLR highlights a paucity of epidemiology data for AIE in children, which is likely reflective of difficulties in testing and diagnosis. There is a clear need for further research and awareness of these challenges in clinical practice to avoid treatment delays and improve patient outcomes. A deeper understanding of the epidemiology of AIE will help determine the worldwide burden of disease and inform research, health policies and clinical decision-making.

Study of seasonality of attacks in MOG antibody-associated disease.

BACKGROUND: Seasonal variation in attacks of acute disseminated encephalomyelitis (ADEM1) is reported in some studies. Myelin oligodendrocyte glycoprotein (MOG) antibodies are found in up to 50 % of ADEM cases. Despite this, there has been no adequately powered study of seasonality in MOG antibody-associated disease (MOGAD). We sought to determine whether there was an effect of season on incidence of total attacks and onset attacks of MOGAD. METHODS: We searched the large national Oxford-based NMO Service database to identify attacks of MOGAD occurring between 2010 and 2021. Month of each attack was extracted and Edwards' test of seasonal variation was applied to determine whether there was a seasonal effect on total attacks and onset attacks. RESULTS: Neither incidence of total attacks nor incidence of onset attacks varied significantly by month. CONCLUSION: There is no evidence of seasonal fluctuations in the incidence of MOGAD attacks in the UK.

A study of referral bias in NMOSD and MOGAD cohorts.

BACKGROUND: Neuromyelitis optica spectrum disorder (NMOSD) and myelin oligodendrocyte glycoprotein antibody-associated disease (MOGAD) are rare disorders often seen in highly specialized services or tertiary centres. We aimed to assess if cohort characteristics depend on the origin of the referral catchment areas serviced by our centre (i.e. local, regional or national). METHODS: Retrospective cohort study using a national referral service database including local (Oxfordshire), regional (Oxfordshire and neighbouring counties), and national patients. We included patients with the diagnosis of NMOSD, seronegative NMOSD or MOGAD, followed at the Oxford Neuromyelitis Optica Service. RESULTS: We included 720 patients (331 with MOGAD, 333 with aquaporin-4 antibody (AQP4)-NMOSD, and 56 with seronegative NMOSD. The distribution of diagnoses was similar across referral cohorts. There were no significant differences in the proportion of pediatric onset patients, sex, or onset phenotype; more White AQP4-NMOSD patients were present in the local than in the national cohort (81 % vs 52 %). Despite no differences in follow-up time, more relapsing MOGAD disease was present in the national than in the local cohort (42.9 % vs. 24 %, p = 0.029). CONCLUSION: This is the first study assessing the impact of potential referral bias in cohorts of NMOSD or MOGAD. The racial difference in the AQP4-NMOSD cohorts likely reflects the variation in the population demographics rather than a referral bias. The over representation of relapsing MOGAD patients in the national cohort probably is a true referral bias and highlights the need to analyze incident cohorts when describing disease course and prognosis. It seems reasonable therefore to compare MOGAD and NMOSD patients seen withing specialised centres to general neurology services, provided both use similar antibody assays.

Radiologic Lag and Brain MRI Lesion Dynamics During Attacks in MOG Antibody-Associated Disease.

BACKGROUND AND OBJECTIVES: Knowledge of the evolution of CNS demyelinating lesions within attacks could assist diagnosis. We evaluated intra-attack lesion dynamics in patients with myelin oligodendrocyte glycoprotein antibody-associated disease (MOGAD) vs multiple sclerosis (MS) and aquaporin-4 antibody seropositive neuromyelitis optica spectrum disorder (AQP4+NMOSD). METHODS: This retrospective observational multicenter study included consecutive patients from Mayo Clinic (USA) and Great Ormond Street Hospital for Children (UK). Inclusion criteria were as follows: (1) MOGAD, MS, or AQP4+NMOSD diagnosis; (2) availability of ≥2 brain MRIs (within 30 days of attack onset); and (3) brain involvement (i.e., ≥1 T2 lesion) on ≥1 brain MRI. The initial and subsequent brain MRIs within a single attack were evaluated for the following: new T2 lesions(s); resolved T2 lesion(s); both; or no change. This was compared between MOGAD, MS, and AQP4+NMOSD attacks. We used the Mann-Whitney U test and χ2/Fisher exact test for statistical analysis. RESULTS: Our cohort included 55 patients with MOGAD (median age, 14 years; interquartile range [IQR] 5-34; female sex, 29 [53%]) for a total of 58 attacks. The comparison groups included 38 patients with MS, and 19 with AQP4+NMOSD. In MOGAD, the initial brain MRI (median of 5 days from onset [IQR 3-9]) was normal in 6/58 (10%) attacks despite cerebral symptoms (i.e., radiologic lag). The commonest reason for repeat MRI was clinical worsening or no improvement (33/56 [59%] attacks with details available). When compared with the first MRI, the second intra-attack MRI (median of 8 days from initial scan [IQR 5-13]) showed the following: new T2 lesion(s) 27/58 (47%); stability 24/58 (41%); resolution of T2 lesion(s) 4/58 (7%); or both new and resolved T2 lesions 3/58 (5%). Findings were similar between children and adults. Steroid treatment was associated with resolution of ≥1 T2 lesion (6/28 [21%] vs 1/30 [3%], p = 0.048) and reduced the likelihood of new T2 lesions (9/28 vs 18/30, p = 0.03). Intra-attack MRI changes favored MOGAD (34/58 [59%]) over MS (10/38 [26%], p = 0.002) and AQP4+NMOSD (4/19 [21%], p = 0.007). Resolution of ≥1 T2 lesions was exclusive to MOGAD (7/58 [12%]). DISCUSSION: Radiologic lag is common within MOGAD attacks. Dynamic imaging with frequent appearance and occasional disappearance of lesions within a single attack suggest MOGAD diagnosis over MS and AQP4+NMOSD. These findings have implications for clinical practice, clinical trial attack adjudication, and understanding of MOGAD pathogenesis.

Validation of the 2023 International Diagnostic Criteria for MOGAD in a Selected Cohort of Adults and Children.

BACKGROUND AND OBJECTIVES: To test the performance of the 2023 myelin oligodendrocyte glycoprotein antibody-associated disease (MOGAD) criteria in adults and children with inflammatory demyelinating conditions who were tested for MOG antibodies (Abs). METHODS: This was a retrospective study of patients tested for MOG-Abs from 2018 to 2022 in 2 specialist hospitals. The inclusion criteria comprised ≥1 attendance in an adult or pediatric demyelinating disease clinic and complete clinical and MRI records. The final clinical diagnosis of MOGAD, made by the treating neurologist, was taken as the benchmark against which the new criteria were tested. The international MOGAD diagnostic criteria were applied retrospectively; they stipulate at least 1 clinical or MRI supporting feature for MOGAD diagnosis in positive fixed MOG cell-based assay without a titer. The performance MOG-Ab testing alone for MOGAD diagnosis was also assessed and compared with that of MOGAD criteria using the McNemar test. RESULTS: Of the 1,879 patients tested for MOG-Abs, 539 (135 pediatric and 404 adults) met the inclusion criteria. A clinical diagnosis of MOGAD was made in 86/539 (16%) patients (37 adults, 49 children), with a median follow-up of 3.6 years. The MOGAD diagnostic criteria had sensitivity of 96.5% (adults 91.9%, children 100%), specificity of 98.9% (adults 98.8%, children 98.9%), positive predictive value of 94.3% (adults 89.4%, children 98%), negative predictive value of 99.3% (adults 99.2%, children 100%), and accuracy of 98.5% (adults 98.3%, children 99.2%). When compared with MOG-Ab testing alone, a difference was seen only in adults: a significantly higher specificity (98.9% vs 95.6%, p = 0.0005) and nonstatistically significant lower sensitivity (91.9% vs 100%, p = 0.08). DISCUSSION: The international MOGAD diagnostic criteria exhibit high performance in selected patients with inflammatory demyelinating diseases (who had a high pretest probability of having MOGAD) compared with best clinical judgment; their performance was better in children than in adults. In adults, the MOGAD criteria led to an improvement in specificity and positive predictive value when compared with MOG-Ab testing alone, suggesting that the requirement of at least 1 clinical or MRI supporting feature is important. Future work should address the generalizability of the diagnostic criteria to cohorts of greater clinical diversity seen within neurologic settings.

Long term outcome in non-multiple sclerosis paediatric acquired demyelinating syndromes.

OBJECTIVES: We aimed to study the risks of relapse and long term disability in children with non-MS acquired demyelinating syndromes (ADS). METHODS: In this prospective, multi-centre study, from the 14 UK pediatric neurology centres, children (<16 years) experiencing a first episode of ADS were recruited from 2010 to 2014. Case report forms were collected prospectively. RESULTS: A total of 269 children were recruited and followed up for a median of 7.2 years. Median age at onset was 9y (IQR 9.5-14.5, 126 females). At last follow-up, 46 (18 %) had MS, 4 AQP4-Ab NMOSD and 206 (80 %) had other ADS, of which 27 (13 %) relapsed. Relapsing MOGAD was the diagnosis in 12/27, 6 were seronegative and 9 did not have antibodies tested. Frequency of relapse differed according to first presentation in non-MS ADS, being least likely in transverse myelitis (p = 0.025). In the non-MS group, MOG-Ab was predictive of relapse (HR = 8.42; p < 0.001) occurring 8 times as often decreasing over time. Long-term difficulties did not differ between children with monophasic vs relapsing diseases. CONCLUSION: The risk of relapse in non-MS ADS depends on initial diagnosis, and MOG-Ab positivity. Long-term difficulties are observed regardless of relapses and are determined by presenting phenotype.