Clinical features and outcomes in children with seronegative autoimmune encephalitis.

AIM: To characterize the presenting features and outcomes in children with seronegative autoimmune encephalitis, and to evaluate whether scores at nadir for the Modified Rankin Scale (mRS) and Clinical Assessment Scale for Autoimmune Encephalitis (CASE) or its paediatric-specific modification (ped-CASE) are predictive of outcomes. METHOD: This observational study included children younger than 18 years of age with seronegative autoimmune encephalitis. Demographics and clinical data were collected. The mRS and CASE/ped-CASE scores were used to evaluate disease severity. Descriptive statistics and logistic regression were used for data analysis and to evaluate associations between scale scores and outcomes. RESULTS: Sixty-three children were included (39 [62%] females, median age 7 years, interquartile range [IQR] 4 years 1 months-11 years 6 months), with follow-up available for 56 out of 63 patients (median follow-up 12.2 months, IQR 13.4-17.8). The most frequent presenting neurological manifestation was encephalopathy (81%). Median CASE/ped-CASE and mRS scores at nadir were 12.0 (IQR 7.0-17.0) and 1.0 (IQR 0-2.0) respectively. Thirty-three patients (59%) had persistent neurological deficits at follow-up. Both scoring systems suggested good functional recovery (mRS score ≤2, 95%; CASE/ped-CASE score <5, 91%). CASE/ped-CASE score was more likely than mRS to distinguish children with worse outcomes. INTERPRETATION: Children with seronegative autoimmune encephalitis are likely to have neurological deficits at follow-up. CASE/ped-CASE is more likely to distinguish children with worse outcomes than MRS.

Magnetization transfer saturation reveals subclinical optic nerve injury in pediatric-onset multiple sclerosis.

BACKGROUND: The presence of subclinical optic nerve (ON) injury in youth living with pediatric-onset MS has not been fully elucidated. Magnetization transfer saturation (MTsat) is an advanced magnetic resonance imaging (MRI) parameter sensitive to myelin density and microstructural integrity, which can be applied to the study of the ON. OBJECTIVE: The objective of this study was to investigate the presence of subclinical ON abnormalities in pediatric-onset MS by means of magnetization transfer saturation and evaluate their association with other structural and functional parameters of visual pathway integrity. METHODS: Eleven youth living with pediatric-onset MS (ylPOMS) and no previous history of optic neuritis and 18 controls underwent standardized brain MRI, optical coherence tomography (OCT), Magnetoencephalography (MEG)-Visual Evoked Potentials (VEPs), and visual battery. Data were analyzed with mixed effect models. RESULTS: While ON volume, OCT parameters, occipital MEG-VEPs outcomes, and visual function did not differ significantly between ylPOMS and controls, ylPOMS had lower MTsat in the supratentorial normal appearing white matter (-0.26 nU, p = 0.0023), and in both in the ON (-0.62 nU, p < 0.001) and in the normal appearing white matter of the optic radiation (-0.56 nU, p = 0.00071), with these being positively correlated (+0.57 nU, p = 0.00037). CONCLUSIONS: Subclinical microstructural injury affects the ON of ylPOMS. This may appear as MTsat changes before being detectable by other currently available testing.

Serum MOG-IgG in children meeting multiple sclerosis diagnostic criteria.

BACKGROUND: Myelin oligodendrocyte glycoprotein antibody-associated disease (MOGAD) is now recognized as distinct from multiple sclerosis (MS). OBJECTIVE: To evaluate the importance of considering myelin oligodendrocyte glycoprotein (MOG)-immunoglobulin-G (IgG) serology when applying MS diagnostic criteria in children. METHODS: Within a prospective cohort of children meeting MS criteria (median follow-up = 6 years, interquartile range (IQR) = 4-9), we measured MOG-IgG in serial archived serum obtained from presentation, and compared imaging and clinical features between seropositive and seronegative participants. RESULTS: Of 65 children meeting MS criteria (median age = 14.0 years, IQR = 10.9-15.1), 12 (18%) had MOG-IgG at disease onset. Seropositive participants were younger, had brain magnetic resonance imaging (MRI) features atypical for MS, rarely had cerebrospinal fluid (CSF) oligoclonal bands (2/8, 25%), and accumulated fewer T2 lesions over time. On serial samples, 5/12 (42%) were persistently seropositive, 5/12 (42%) became seronegative, and 2/12 (17%) had fluctuating results. All 12 children experienced a disease course different from typical MS. CONCLUSION: While children with MOG-IgG can have clinical, CSF, and MRI features conforming to MS criteria, the presence of MOG-IgG is associated with atypical features and predicts a non-MS disease course. Given MOG-IgG seropositivity can wane over time, testing at first attack is of considerable importance for the diagnosis of MOGAD.

Machine learning classification of multiple sclerosis in children using optical coherence tomography.

BACKGROUND: In children, multiple sclerosis (MS) is the ultimate diagnosis in only 1/5 to 1/3 of cases after a first episode of central nervous system (CNS) demyelination. As the visual pathway is frequently affected in MS and other CNS demyelinating disorders (DDs), structural retinal imaging such as optical coherence tomography (OCT) can be used to differentiate MS. OBJECTIVE: This study aimed to investigate the utility of machine learning (ML) based on OCT features to identify distinct structural retinal features in children with DDs. METHODS: This study included 512 eyes from 187 (neyes = 374) children with demyelinating diseases and 69 (neyes = 138) controls. Input features of the analysis comprised of 24 auto-segmented OCT features. RESULTS: Random Forest classifier with recursive feature elimination yielded the highest predictive values and identified DDs with 75% and MS with 80% accuracy, while multiclass distinction between MS and monophasic DD was performed with 64% accuracy. A set of eight retinal features were identified as the most important features in this classification. CONCLUSION: This study demonstrates that ML based on OCT features can be used to support a diagnosis of MS in children.

Rituximab in children with myelin oligodendrocyte glycoprotein antibody and relapsing neuroinflammatory disease.

The aim of this study was to evaluate tolerability of and response to rituximab in children with myelin oligodendrocyte glycoprotein (MOG) antibody-positive relapsing neuroinflammatory disease. This was an observational study of prospectively collected data on 12 consecutive children (eight females, four males; median age at onset 10y 6mo [interquartile range {IQR} 7y 2mo-12y 5mo], median follow-up 2y 1mo [IQR 1y 7mo-2y 6mo]) with central nervous system inflammation and persistent serum MOG immunoglobulin G positivity more than 12 weeks after clinical presentation. Patients received a standardized rituximab treatment protocol. MOG antibody testing was performed following standardized cell-based methods. Median clinical follow-up after rituximab induction was 2 years (IQR 1y 7mo-2y 10mo). The relapse rate in the first 12 months posttreatment was 0 (IQR 0-0). After rituximab, two patients relapsed during B-cell suppression and four showed clinical or radiological disease recurrences at B-cell reconstitution. Mild-to-moderate infusion related adverse events occurred in two patients. Leukopenia developed in seven patients and serum immunoglobulin suppression in five patients with no significant age effect on the risk of their development. None developed severe life-threatening events. Rituximab-induced B-cell suppression was associated with absence of relapses in 10 patients who were MOG-positive with recurrent disease. Rituximab was well tolerated. The most frequent adverse effects were hypogammaglobulinemia and leukopenia. We recommend monitoring of complete blood counts and immunoglobulins in this population. WHAT THIS PAPER ADDS: Rituximab appears to control disease in most anti-myelin oligodendrocyte glycoprotein-positive patients with relapsing neuroinflammatory disease. Rituximab was associated with transitory, mild-to-moderate infusion-related effects. Half of patients treated with rituximab developed leukopenia or hypogammaglobulinemia. No opportunistic infections were observed.

White matter plasticity and maturation in human cognition.

White matter plasticity likely plays a critical role in supporting cognitive development. However, few studies have used the imaging methods specific to white matter tissue structure or experimental designs sensitive to change in white matter necessary to elucidate these relations. Here we briefly review novel imaging approaches that provide more specific information regarding white matter microstructure. Furthermore, we highlight recent studies that provide greater clarity regarding the relations between changes in white matter and cognition maturation in both healthy children and adolescents and those with white matter insult. Finally, we examine the hypothesis that white matter is linked to cognitive function via its impact on neural synchronization. We test this hypothesis in a population of children and adolescents with recurrent demyelinating syndromes. Specifically, we evaluate group differences in white matter microstructure within the optic radiation; and neural phase synchrony in visual cortex during a visual task between 25 patients and 28 typically developing age-matched controls. Children and adolescents with demyelinating syndromes show evidence of myelin and axonal compromise and this compromise predicts reduced phase synchrony during a visual task compared to typically developing controls. We investigate one plausible mechanism at play in this relationship using a computational model of gamma generation in early visual cortical areas. Overall, our findings show a fundamental connection between white matter microstructure and neural synchronization that may be critical for cognitive processing. In the future, longitudinal or interventional studies can build upon our knowledge of these exciting relations between white matter, neural communication, and cognition.

Benefits of Physical Activity for Depression and Fatigue in Multiple Sclerosis: A Longitudinal Analysis.

OBJECTIVES: To examine the longitudinal relationship between physical activity and fatigue and depression among youth with demyelinating conditions. STUDY DESIGN: From September 2013 to March 2017, we performed a longitudinal study of consecutive youth diagnosed at their first visit with pediatric onset multiple sclerosis (POMS) or monophasic acquired demyelinating syndromes (mono-ADS) at a neuroinflammatory disorders clinic in a tertiary children's hospital. Fatigue was determined at each visit by the Pediatric Quality of Life Multidimensional Fatigue Scale, depressive symptoms by the Center of Epidemiologic Studies Depression Children Rating Scale, and physical activity level by the Godin Leisure Time Exercise Questionnaire. Mixed linear models were used to examine the associations of moderate-to-vigorous physical activity (MVPA) with fatigue and depression over time, adjusting for age, time from incident demyelination, sex, number of relapses, relapse within 30 days, and disability. RESULTS: In 182 patients (48 POMS, age 15 ± 1.7 years, 35 female; and 134 mono-ADS, age 12 ± 3.6 years 67 female) with 538 visits (mean follow-up 3.6 ± 2.7 years and 4.2 ± 3.3 years, respectively), a trajectory of increased fatigue over time was observed in POMS (2.28 points/year, P = .008) and mono-ADS (1.33 points/year, P = .007) patients. Youth with POMS had more depressive symptoms (estimate = 11.4 points, P < .002) than mono-ADS. Depressive symptoms increased over time in female patients with POMS (estimate = 1.4 points/year, P < .02). MVPA was associated with lower depression (-0.09, P < .001) and general fatigue (0.13, P = .02) over time in POMS. CONCLUSIONS: Youth with POMS who have higher levels of MVPA demonstrate lesser depressive symptoms and lower fatigue over time. Our results may inform future interventions to manage mood and fatigue in POMS.

Evaluation and treatment of Langerhans cell histiocytosis patients with central nervous system abnormalities: Current views and new vistas.

Central nervous system (CNS) involvement in Langerhans cell histiocytosis (LCH) can include mass lesions of the hypothalamic pituitary axis, choroid plexus, cerebrum, and cerebellum or magnetic resonance imaging (MRI) signal abnormalities of the cerebellum, pons, and basal ganglia. The term neurodegenerative (ND) CNS-LCH has been given to the MRI signal abnormalities and neurologic dysfunction, although initially patients may have no clinical symptoms. Standardized evaluations to better understand the natural history and response to therapy are needed. We propose guidelines for clinical, radiologic, and physiologic tests as a framework for developing the best methods of evaluation, which can then be tested in prospective treatment protocols.

White matter changes in paediatric multiple sclerosis and monophasic demyelinating disorders.

See Hacohen et al. (doi:10.1093/awx075) for a scientific commentary on this article. Most children who experience an acquired demyelinating syndrome of the central nervous system will have a monophasic disease course, with no further clinical or radiological symptoms. A subset will be diagnosed with multiple sclerosis, a life-long disorder. Using linear mixed effects models we examined longitudinal diffusion properties of normal-appearing white matter in 505 serial scans of 132 paediatric participants with acquired demyelinating syndromes followed for a median of 4.4 years, many from first clinical presentation, and 106 scans of 80 healthy paediatric participants. Fifty-three participants with demyelinating syndromes eventually received a diagnosis of paediatric-onset multiple sclerosis. Diffusion tensor imaging measures properties of water diffusion through tissue, which normally becomes increasingly restricted and anisotropic in the brain during childhood and adolescence, as fibre bundles develop and myelinate. In the healthy paediatric participants, our data demonstrate the expected trajectory of more restricted and anisotropic white matter diffusivity with increasing age. However, in participants with multiple sclerosis, fractional anisotropy decreased and mean diffusivity of non-lesional, normal-appearing white matter progressively increased after clinical presentation, suggesting not only a failure of age-expected white matter development but also a progressive loss of tissue integrity. Surprisingly, patients with monophasic disease failed to show age-expected changes in diffusion parameters in normal-appearing white matter, although they did not show progressive loss of integrity over time. Further analysis demonstrated that participants with monophasic disease experienced different post-onset trajectories in normal-appearing white matter depending on their presenting phenotype: those with acute disseminated encephalomyelitis demonstrated abnormal trajectories of diffusion parameters compared to healthy paediatric participants, as did patients with non-acute disseminated encephalomyelitis presentations associated with lesions in the brain at onset. Patients with monofocal syndromes such as optic neuritis, transverse myelitis, or isolated brainstem syndromes in whom multifocal brain lesions were absent, showed trajectories more closely approximating normal-appearing white matter development. Our findings also suggest the existence of sexual dimorphism in the effects of demyelinating syndromes on normal-appearing white matter development. Overall, we demonstrate failure of white matter maturational changes and progressive loss of white matter integrity in paediatric-onset multiple sclerosis, but also show that even a single demyelinating attack-when associated with white matter lesions in the brain-negatively impacts subsequent normal-appearing white matter development.

In vivo evidence of hippocampal dentate gyrus expansion in multiple sclerosis.

Using MR-based radial mapping, we assessed morphological alterations of the hippocampal dentate gyrus (DG) in patients with relapse-onset multiple sclerosis (MS). We analyzed different stages of the disease and the association of DG alterations with hippocampal-related cognitive functions. Using high-resolution morphological imaging, hippocampal radial mapping analysis was performed in 28 relapsing-remitting (RR), 34 secondary progressive, and 26 benign MS patients and 28 healthy controls (HC). Between-groups differences of DG radial distance (from surface points to the central core of the hippocampus) and correlations with clinical, neuropsychological, and radiological measures were evaluated using surface-based mesh modeling. Compared with HC, all MS clinical phenotypes revealed a larger radial distance of the DG, which was more marked on the left side. Radial distance enlargement was more pronounced in RRMS patients compared with the other disease clinical phenotypes and was inversely correlated to disease duration. Radial distance enlargement was correlated with higher T2 lesion volume and a better cognitive performance in RRMS and with a poor cognitive performance in secondary progressive and benign MS patients. Surface expansion of the DG might represent an inflammation-induced neurogenic (reactive) process of the subgranular zone of the hippocampus primarily aimed at rescuing the functional competence of hippocampal circuitry.

Brain Volumes in Opsoclonus-Myoclonus Ataxia Syndrome: A Longitudinal Study.

INTRODUCTION: Little is known about the longitudinal trajectory of brain growth in children with opsoclonus-myoclonus ataxia syndrome. We performed a longitudinal evaluation of brain volumes in pediatric opsoclonus-myoclonus ataxia syndrome patients compared with age- and sex-matched healthy children. PATIENTS AND METHODS: This longitudinal case-control study included brain magnetic resonance imaging (MRI) scans from consecutive pediatric opsoclonus-myoclonus ataxia syndrome patients (2009-2020) and age- and sex-matched healthy control children. FreeSurfer analysis provided automatic volumetry of the brain. Paired t tests were performed on the curvature of growth trajectories, with Bonferroni correction. RESULTS: A total of 14 opsoclonus-myoclonus ataxia syndrome patients (12 female) and 474 healthy control children (406 female) were included. Curvature of the growth trajectories of the cerebral white and gray matter, cerebellar white and gray matter, and brainstem differed significantly between opsoclonus-myoclonus ataxia syndrome patients and healthy control children (cerebral white matter, P = .01; cerebral gray matter, P = .01; cerebellar white matter, P < .001; cerebellar gray matter, P = .049; brainstem, P < .01). DISCUSSION/CONCLUSION: We found abnormal brain maturation in the supratentorial brain, brainstem, and cerebellum in children with opsoclonus-myoclonus ataxia syndrome.

Delayed oculomotor response associates with optic neuritis in youth with demyelinating disorders.

INTRODUCTION: Impairment in visual and cognitive functions occur in youth with demyelinating disorders such as multiple sclerosis, neuromyelitis optica spectrum disorder, and myelin oligodendrocyte glycoprotein antibody-associated disease. Quantitative behavioral assessment using eye-tracking and pupillometry can provide functional metrics for important prognostic and clinically relevant information at the bedside. METHODS: Children and adolescents diagnosed with demyelinating disorders and healthy, age-matched controls completed an interleaved pro- and anti-saccade task using video-based eye-tracking and underwent spectral-domain optical coherence tomography examination for evaluation of retinal nerve fiber layer and ganglion cell inner plexiform layer thickness. Low-contrast visual acuity and Symbol Digit Modalities Test were performed for visual and cognitive functional assessments. We assessed saccade and pupil parameters including saccade reaction time, direction error rate, pupil response latency, peak constriction time, and peak constriction and dilation velocities. Generalized Estimating Equations were used to examine the association of eye-tracking parameters with optic neuritis history, structural metrics, and visual and cognitive scores. RESULTS: The study included 36 demyelinating disorders patients, aged 8-18 yrs. (75% F; median = 15.22 yrs., SD = 2.8) and 34 age-matched controls (65% F; median = 15.26 yrs., SD = 2.3). Surprisingly, pro- and anti-saccade performance was comparable between patients and controls, whereas pupil control was altered in patients. Oculomotor latency measures were strongly associated with the number of optic neuritis episodes, including saccade reaction time, pupil response latency, and peak constriction time. Peak constriction time was associated with both retinal nerve fiber layer and ganglion cell inner plexiform layer thickness. Pupil response latency and peak constriction time were associated with visual acuity. Pupil velocity for both constriction and dilation was associated with Symbol Digit Modalities Test scores. CONCLUSION: The strong associations between oculomotor measures with history of optic neuritis, structural, visual, and cognitive assessments in these cohorts demonstrates that quantitative eye-tracking can be useful for probing demyelinating injury of the brain and optic nerve. Future studies should evaluate their utility in discriminating between demyelinating disorders and tracking disease progression.

Pandemic-associated mental health changes in youth with neuroinflammatory disorders.

BACKGROUND: Children with neuroinflammatory disorders have high rates of anxiety and depression, alongside low rates of physical activity. Given general concerns for mental and physical health in children during the COVID-19 pandemic lockdown, here we sought to understand how sleep, anxiety, depression, and physical activity changed with the lockdown in children with neuroinflammatory disorders. We hypothesized that outcomes would worsen during the lockdown, and that they would differ by underlying disorder category and age. METHODS: Patients attending a specialized neuroinflammatory clinic (n = 314) completed questionnaires (n = 821 responses; Jan 2017-Aug 2020) assessing sleep, anxiety, depression, and physical activity. Respondents had either: childhood-onset chronic or recurrent neuroinflammatory disorders (CRNI), a history of Autoimmune Encephalitis (AE) or Monophasic Acquired Demyelinating Syndromes (monoADS). We performed linear mixed models to examine the association between our outcome measures (sleep, anxiety, depression, and physical activity) and categories of disorder type, sex, age, physical activity, relapses, and time (pre- vs. post- COVID-19 lockdown). Participant ID acted as a random effect, to account for repeated measures. RESULTS: Sleep significantly increased in the first 6 months of the COVID-19 lockdown (F(1, 544)=56.85, P<0.001,). Across the whole group, anxiety and depression did not change with the pandemic, but we found differing trends by age category. Anxiety decreased in teenagers (≥13y) (Z = 3.96, P<0.001), but not for pre-teens. Depression remained higher in teenagers than preteens across both timepoints (F(1, 597)=6.30, p = 0.012). Physical activity levels did not change with the pandemic in comparison to pre-pandemic (F(1, 629)=1.92, P = 0.166). Anxiety was higher in inactive individuals regardless of timing (F(2, 547)=3.74, p = 0.024). CONCLUSION: For youth with neuroinflammatory disorders, the COVID-19 pandemic lockdown resulted in increased hours of nighttime sleep but did not result in significant overall changes in self-reported anxiety or depression. Pre-lockdown, teenagers had higher depression and anxiety scores than preteens. Post-lockdown, anxiety and depression scores decreased in teenagers compared to pre-teens. Physical activity was low both pre- and post-lockdown, and rates of anxiety were higher for inactive participants at both timepoints. Differences based on age suggest that younger children (<13 years) were more negatively affected by the pandemic than older children (≥ 13 years).

Patterns of white and gray structural abnormality associated with paediatric demyelinating disorders.

The impact of multiple sclerosis (MS) and myelin oligodendrocyte glycoprotein (MOG) - associated disorders (MOGAD) on brain structure in youth remains poorly understood. Reductions in cortical mantle thickness on structural MRI and abnormal diffusion-based white matter metrics (e.g., diffusion tensor parameters) have been well documented in MS but not in MOGAD. Characterizing structural abnormalities found in children with these disorders can help clarify the differences and similarities in their impact on neuroanatomy. Importantly, while MS and MOGAD affect the entire CNS, the visual pathway is of particular interest in both groups, as most patients have evidence for clinical or subclinical involvement of the anterior visual pathway. Thus, the visual pathway is of key interest in analyses of structural abnormalities in these disorders and may distinguish MOGAD from MS patients. In this study we collected MRI data on 18 MS patients, 14 MOGAD patients and 26 age- and sex-matched typically developing children (TDC). Full-brain group differences in fixel diffusion measures (fibre-bundle populations) and cortical thickness measures were tested using age and sex as covariates. Visual pathway analysis was performed by extracting mean diffusion measures within lesion free optic radiations, cortical thickness within the visual cortex, and retinal nerve fibre layer (RNFL) and ganglion cell layer thickness measures from optical coherence tomography (OCT). Fixel based analysis (FBA) revealed MS patients have widespread abnormal white matter within the corticospinal tract, inferior longitudinal fasciculus, and optic radiations, while within MOGAD patients, non-lesional impact on white matter was found primarily in the right optic radiation. Cortical thickness measures were reduced predominately in the temporal and parietal lobes in MS patients and in frontal, cingulate and visual cortices in MOGAD patients. Additionally, our findings of associations between reduced RNFLT and axonal density in MOGAD and TORT in MS patients in the optic radiations imply widespread axonal and myelin damage in the visual pathway, respectively. Overall, our approach of combining FBA, cortical thickness and OCT measures has helped evaluate similarities and differences in brain structure in MS and MOGAD patients in comparison to TDC.

Progressive retinal changes in pediatric multiple sclerosis.

Objectives To determine to what extent acute demyelinating episodes versus chronic degenerative phenomena drive retinal neuroaxonal damage in pediatric acquired demyelinating syndromes (ADS). Methods We acquired optical coherence tomography (OCT) data (follow-up range: 2 weeks - 5 years, at variable intervals from presentation) in pediatric participants who had multiple sclerosis (MS), monophasic ADS, or were healthy. Multivariable mixed effects models were used to assess the association of the number of demyelinating episodes (either optic neuritis [ON], or non-ON relapses) with changes in retinal nerve fiber layer (RNFL) or ganglion cell layer-inner plexiform layer (GCIPL) thickness. Results 64 OCT sans from 23 MS, and 33 scans from 12 monophasic ADS participants were compared with 68 scans from 62 healthy participants. The first ON episode had the biggest impact on RNFL or GCIPL thickness in monophasic ADS (RNFL: -7.9 µm, CI=5.5, p = 0.0056; GCIPL: -8.4 µm, CI=4.4, p = 0.0002) and MS (RNFL: -16 µm, CI = 3.7, p < 10-6; GCIPL: -15 µm, CI = 2.6, p < 10-6). Non-ON relapses were also associated with small but significant retinal thickness reductions in MS (RNFL: -2.6 µm/relapse, CI = 1.4, p = 0.0003; GCIPL: -2.8 µm/relapse, CI = 0.89, p < 10-6). MS participants showed progressive GCIPL thinning independent of acute demyelinating episodes (-2.7 µm/year, CI = 1.9, p = 0.0058). Conclusions We showed a prominent impact of early ON episodes on OCT measures of neuroaxonal structure in patients with ADS. We also demonstrated negative effects of non-ON relapses, and the presence of chronic retinal neurodegenerative changes, in youth with MS.

The White Matter Rounds experience: The importance of a multidisciplinary network to accelerate the diagnostic process for adult patients with rare white matter disorders.

Introduction: Adult genetic leukoencephalopathies are rare neurological disorders that present unique diagnostic challenges due to their clinical and radiological overlap with more common white matter diseases, notably multiple sclerosis (MS). In this context, a strong collaborative multidisciplinary network is beneficial for shortening the diagnostic odyssey of these patients and preventing misdiagnosis. The White Matter Rounds (WM Rounds) are multidisciplinary international online meetings attended by more than 30 physicians and scientists from 15 participating sites that gather every month to discuss patients with atypical white matter disorders. We aim to present the experience of the WM Rounds Network and demonstrate the value of collaborative multidisciplinary international case discussion meetings in differentiating and preventing misdiagnoses between genetic white matter diseases and atypical MS. Methods: We retrospectively reviewed the demographic, clinical and radiological data of all the subjects presented at the WM Rounds since their creation in 2013. Results: Seventy-four patients (mean age 44.3) have been referred and discussed at the WM Rounds since 2013. Twenty-five (33.8%) of these patients were referred by an MS specialist for having an atypical presentation of MS, while in most of the remaining cases, the referring physician was a geneticist (23; 31.1%). Based on the WM Rounds recommendations, a definite diagnosis was made in 36/69 (52.2%) patients for which information was available for retrospective review. Of these diagnosed patients, 20 (55.6%) had a genetic disease, 8 (22.2%) had MS, 3 (8.3%) had both MS and a genetic disorder and 5 (13.9%) had other non-genetic conditions. Interestingly, among the patients initially referred by an MS specialist, 7/25 were definitively diagnosed with MS, 5/25 had a genetic condition (e.g., X-linked adrenoleukodystrophy and hereditary small vessel diseases like Cerebral Autosomal Dominant Arteriopathy with Subcortical Infarcts and Leukoencephalopathy (CADASIL) and COL4A1-related disorder), and one had both MS and a genetic demyelinating neuropathy. Thanks to the WM Rounds collaborative efforts, the subjects who currently remain without a definite diagnosis, despite extensive investigations performed in the clinical setting, have been recruited in research studies aimed at identifying novel forms of genetic MS mimickers. Conclusions: The experience of the WM Rounds Network demonstrates the benefit of collective discussions on complex cases to increase the diagnostic rate and decrease misdiagnosis in patients with rare or atypical white matter diseases. Networks of this nature allow physicians and scientists to compare and share information on challenging cases from across the world, provide a basis for future multicenter research studies, and serve as model for other rare diseases.

MRI measurements of brainstem structures in patients with Richardson's syndrome, progressive supranuclear palsy-parkinsonism, and Parkinson's disease.

We investigated the diagnostic accuracy of brainstem MRI measurements in patients with different progressive supranuclear palsy (PSP) syndromes and Parkinson's disease (PD). Using 3D T1-weighted images, midbrain, and pons areas, as well as superior (SCP) and middle cerebellar peduncle (MCP) widths were measured in 10 patients with Richardson's syndrome (PSP-RS), 10 patients with PSP-parkinsonism (PSP-P), 25 patients with PD, and 24 healthy controls. The ratio between pons and midbrain areas (pons/midbrain), that between MCP and SCP widths (MCP/SCP), and the MR parkinsonism index ([pons/midbrain]*[MCP/SCP]) were calculated. The pons/midbrain and the MR parkinsonism index allowed to differentiate PSP-RS from PD with high sensitivity (90%, 100%), specificity (96%, 92%), and accuracy (94%, 97%). Only the pons/midbrain was found to distinguish PSP-P from PD, but with a lower diagnostic accuracy (sensitivity = 60%, specificity = 96%, accuracy = 86%). Compared to PSP-RS, PSP-P experience a relatively less severe involvement of infratentorial brain. The pons/midbrain looks as a promising measure in the differentiation of individual PSP-P from PD patients.

Impact of COVID-19 public health measures on myelin oligodendrocyte glycoprotein IgG-associated disorders in children.

BACKGROUND: Despite better characterization of the spectrum of MOG-IgG-associated disorders (MOGAD) in children, the role of infection in its pathophysiology remains unclear. The goal of this study was to evaluate if public health measures put in place to prevent the spread of SARS-CoV-2 in March 2020 in Ontario (Canada) have been associated with a change in the incidence of MOGAD and other neuroinflammatory disorders in children. METHODOLOGY: We reviewed a single-centre cohort of children referred for a suspicion of neuroinflammatory disorder between January 2015 and March 2021. Age, date, sex, diagnosis, MOG-IgG antibodies status and detected pathogens at presentation were identified. Comparative statistical analysis was performed based on diagnosis between years and seasons using Pearson's Chi-squared test or Fisher's exact test for categorical variables and using ANOVA or Kruskal-Wallis test for continuous variables, as appropriate. We compared the post-lockdown period (March 17th, 2020, to March 31st, 2021) to previous calendar years (2015 to 2019) alone and to previous calendar years and the pre-lockdown 2020 period (January 1st, 2020, to March 16th, 2020). A p-value of < 0.05 was considered significant. Post-hoc pairwise comparisons between the post-lockdown period and previous years were performed on significant results. A false discovery rate adjustment with an adjusted p-value (q-value) < 0.05 was computed. We hypothesized that the number of new MOGAD would be significantly lower in the post-lockdown period compared to previous years due to decreased regional pathogen transmission. RESULTS: Among 491 referred cases, we identified 415 new cases of neuroinflammatory disorder between January 2015 and March 2021. The number of new neuroinflammatory disorder diagnoses did not change between years. We noted significantly fewer new MOGAD diagnoses in 2020 compared to previous years, with no MOGAD patients presenting in 2020 after the spring lockdown (q=0.0009). In addition, there were significantly fewer parainfectious neuroinflammatory cases (q=0.04) and pathogen detected (q=0.04) in the post-lockdown period. The number of new multiple sclerosis (MS) and aquaporin-4 neuromyelitis optica spectrum disorders (AQP4-NMOSD) cases remained stable despite the lockdown (q=0.185 and 0.693 respectively). INTERPRETATION: Enhanced population-based infection control strategies may have a role in modulating the incidence of MOGAD and parainfectious neuroinflammatory disorders, but not MS or AQP4-NMOSD.

Memory, processing of emotional stimuli, and volume of limbic structures in pediatric-onset multiple sclerosis.

OBJECTIVE: The limbic system is involved in memory and in processing of emotional stimuli. We measured volume of the hippocampus, amygdala, and thalamus, and assessed their relative contribution to episodic memory and emotion identification in POMS. METHOD: Sixty-five POMS participants (Mage = 18.3 ± 3.9 years; 48 female (73.8%)), average disease duration = 3.8 ± 3.8 years) and 76 age- and sex-matched controls (Mage = 18.1 ± 4.6 years; 49 female (64.5%)) completed the Penn Computerized Neurocognitive Battery (PCNB); 59 of 65 POMS participants and 69 out of 76 controls underwent 3 T MRI scanning. We derived age-adjusted Z-scores on accuracy and response time (RT) measures of episodic memory and emotion identification of the PCNB. Magnetic resonance imaging (MRI) volumetrics were normalized using the scaling factor computed by SIENAx. On PCNB tests that differed between groups, we used multiple linear regression to assess relationships between regional brain volumes and either episodic memory or emotion identification outcomes controlling for age, sex, accuracy/RT, and parental education. RESULTS: POMS participants were slower and less accurate than controls on the episodic memory domain but did not differ from controls on emotion outcomes. At the subtest level, POMS participants showed reduced accuracy on Word Memory (p = .002) and slower performance on Face Memory (p = .04) subtests. POMS participants had smaller total and regional brain volumes of the hippocampus, amygdala, and thalamus (p values ≤ 0.01). Collapsing across groups, both hippocampal and thalamic volume were significant predictors of Word Memory accuracy; hippocampal volume (B = 0.24, SE = 0.10, p = .02) was more strongly associated with Word Memory performance than thalamic volume (B = 0.16, SE = 0.05, p = .003), though the estimate with was less precise. CONCLUSIONS: POMS participants showed reduced episodic memory performance compared to controls. Aspects of episodic memory performance were associated with hippocampal and thalamic volume. Emotion identification was intact, despite volume loss in the amygdala.