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Reported rates of Epstein-Barr virus (EBV) seropositivity in children meeting multiple sclerosis (MS) diagnostic criteria are considerably lower than those reported in adult-onset MS, putting in question a requisite role for EBV in MS development. As prior work preceded recognition of myelin oligodendrocyte glycoprotein-associated disease (MOGAD), we assessed viral serologies in 251 children with incident demyelination and prospectively ascertained diagnoses. When MOGAD was serologically accounted for, the prevalence of EBV infection among MS children exceeded 90%, whereas remote EBV infection was not associated with MOGAD risk. Together, these findings substantiate EBV's role across the MS spectrum, and support distinct pathobiological mechanisms in MS versus MOGAD. ANN NEUROL 2024;95:700-705.
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Infecções por Vírus Epstein-Barr , Esclerose Múltipla , Adulto , Criança , Humanos , Autoanticorpos , Infecções por Vírus Epstein-Barr/complicações , Herpesvirus Humano 4 , Glicoproteína Mielina-OligodendrócitoRESUMO
Leptomeningeal and perivenular infiltrates are important contributors to cortical grey matter damage and disease progression in multiple sclerosis (MS). Whereas perivenular inflammation induces vasculocentric lesions, leptomeningeal involvement follows a subpial "surface-in" gradient. To determine whether similar gradient of damage occurs in deep grey matter nuclei, we examined the dorsomedial thalamic nuclei and cerebrospinal fluid (CSF) samples from 41 postmortem secondary progressive MS cases compared with 5 non-neurological controls and 12 controls with other neurological diseases. CSF/ependyma-oriented gradient of reduction in NeuN+ neuron density was present in MS thalamic lesions compared to controls, greatest (26%) in subventricular locations at the ependyma/CSF boundary and least with increasing distance (12% at 10 mm). Concomitant graded reduction in SMI31+ axon density was observed, greatest (38%) at 2 mm from the ependyma/CSF boundary and least at 10 mm (13%). Conversely, gradient of major histocompatibility complex (MHC)-II+ microglia density increased by over 50% at 2 mm at the ependyma/CSF boundary and only by 15% at 10 mm and this gradient inversely correlated with the neuronal (R = -0.91, p < 0.0001) and axonal (R = -0.79, p < 0.0001) thalamic changes. Observed gradients were also detected in normal-appearing thalamus and were associated with rapid/severe disease progression; presence of leptomeningeal tertiary lymphoid-like structures; large subependymal infiltrates, enriched in CD20+ B cells and occasionally containing CXCL13+ CD35+ follicular dendritic cells; and high CSF protein expression of a complex pattern of soluble inflammatory/neurodegeneration factors, including chitinase-3-like-1, TNFR1, parvalbumin, neurofilament-light-chains and TNF. Substantial "ependymal-in" gradient of pathological cell alterations, accompanied by presence of intrathecal inflammation, compartmentalized either in subependymal lymphoid perivascular infiltrates or in CSF, may play a key role in MS progression. SUMMARY FOR SOCIAL MEDIA: Imaging and neuropathological evidences demonstrated the unique feature of "surface-in" gradient of damage in multiple sclerosis (MS) since early pediatric stages, often associated with more severe brain atrophy and disease progression. In particular, increased inflammation in the cerebral meninges has been shown to be strictly associated with an MS-specific gradient of neuronal, astrocyte, and oligodendrocyte loss accompanied by microglial activation in subpial cortical layers, which is not directly related to demyelination. To determine whether a similar gradient of damage occurs in deep grey matter nuclei, we examined the potential neuronal and microglia alterations in the dorsomedial thalamic nuclei from postmortem secondary progressive MS cases in combination with detailed neuropathological characterization of the inflammatory features and protein profiling of paired CSF samples. We observed a substantial "subependymal-in" gradient of neuro-axonal loss and microglia activation in active thalamic lesions of progressive MS cases, in particular in the presence of increased leptomeningeal and cerebrospinal fluid (CSF) inflammation. This altered graded pathology was found associated with more severe and rapid progressive MS and increased inflammatory degree either in large perivascular subependymal infiltrates, enriched in B cells, or within the paired CSF, in particular with elevated levels of a complex pattern of soluble inflammatory and neurodegeneration factors, including chitinase 3-like-1, TNFR1, parvalbumin, neurofilament light-chains and TNF. These data support a key role for chronic, intrathecally compartmentalized inflammation in specific disease endophenotypes. CSF biomarkers, together with advance imaging tools, may therefore help to improve not only the disease diagnosis but also the early identification of specific MS subgroups that would benefit of more personalized treatments. ANN NEUROL 2022;92:670-685.
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Quitinases , Esclerose Múltipla Crônica Progressiva , Esclerose Múltipla , Córtex Cerebral/metabolismo , Progressão da Doença , Epêndima , Humanos , Inflamação/complicações , Esclerose Múltipla/patologia , Esclerose Múltipla Crônica Progressiva/complicações , Parvalbuminas/metabolismo , Receptores Tipo I de Fatores de Necrose Tumoral/metabolismo , Tálamo/patologiaRESUMO
Anti-myelin oligodendrocyte glycoprotein immunoglobulin G (MOG-IgG) antibodies are associated clinically with either a monophasic or relapsing disease course. We investigated the frequency and clinical importance of acquired asymptomatic brain magnetic resonance imaging (MRI) lesions in a prospective incident cohort of 74 MOG-IgG positive children with serial MRI scans over a median of 5 years from presentation. Silent new lesions were detected in 14% of MOG-IgG positive participants, most commonly within the first months post-onset, with a positive predictive value for clinically relapsing disease of only 20%. Detection of asymptomatic lesions alone need not prompt initiation of chronic immunotherapy. ANN NEUROL 2021;89:408-413.
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Doenças Assintomáticas , Autoanticorpos/imunologia , Encéfalo/diagnóstico por imagem , Doenças Autoimunes Desmielinizantes do Sistema Nervoso Central/diagnóstico por imagem , Encefalomielite Aguda Disseminada/diagnóstico por imagem , Esclerose Múltipla/diagnóstico por imagem , Glicoproteína Mielina-Oligodendrócito/imunologia , Adolescente , Encéfalo/fisiopatologia , Criança , Doenças Autoimunes Desmielinizantes do Sistema Nervoso Central/imunologia , Doenças Autoimunes Desmielinizantes do Sistema Nervoso Central/fisiopatologia , Doenças Autoimunes Desmielinizantes do Sistema Nervoso Central/terapia , Encefalomielite Aguda Disseminada/imunologia , Encefalomielite Aguda Disseminada/fisiopatologia , Encefalomielite Aguda Disseminada/terapia , Feminino , Glucocorticoides/uso terapêutico , Humanos , Imunoglobulina G , Imunoglobulinas Intravenosas/uso terapêutico , Fatores Imunológicos/uso terapêutico , Imunoterapia , Imageamento por Ressonância Magnética , Masculino , Esclerose Múltipla/imunologia , Esclerose Múltipla/fisiopatologia , Esclerose Múltipla/terapia , Bandas Oligoclonais/líquido cefalorraquidiano , Troca Plasmática , RecidivaRESUMO
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.
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Esclerose Múltipla , Aquaporina 4 , Autoanticorpos , Humanos , Imunoglobulina G , Esclerose Múltipla/diagnóstico por imagem , Glicoproteína Mielina-Oligodendrócito , Estudos ProspectivosRESUMO
BACKGROUND: Being obese is associated with both increased risk of developing multiple sclerosis (MS) and greater MS disease activity. OBJECTIVES: The objective of this study is to investigate levels and potential pathophysiologic contribution of serum adipose-hormones (adipokines) in pediatric-onset MS. METHODS: Following a Luminex adipokine screen, adiponectin (APN) and its isoforms were quantified by enzyme-linked immunosorbent assay (ELISA) in 169 children with incident acquired demyelinating syndromes (ADS), prospectively ascertained as having either MS or other forms of inflammatory central nervous system (CNS) demyelination. The effect of recombinant APN and APN-containing sera was assessed on functional responses of normal human peripheral blood myeloid and T cells and on human CNS-derived microglia. RESULTS: Compared to other cohorts, children with MS harbored higher serum APN levels, principally driven by higher levels of the low-molecular-weight isoform. Recombinant APN and pediatric MS serum-induced APN-dependent pro-inflammatory activation of CD14+ monocytes and of activated CD4+ and CD8+ T cells (both directly and indirectly through myeloid cells). APN induced human microglia activation while inhibiting their expression of molecules associated with quiescence. CONCLUSIONS: Elevated APN levels in children with MS may contribute to enhanced pro-inflammatory states of innate and adaptive peripheral immune responses and breach CNS-resident microglia quiescence, providing a plausible and potentially targetable mechanism by which APN contributes to MS disease activity.
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Adiponectina , Esclerose Múltipla , Adipocinas , Linfócitos T CD8-Positivos , Criança , Humanos , MicrogliaRESUMO
In conventional non-quantitative magnetic resonance imaging, image contrast is consistent within images, but absolute intensity can vary arbitrarily between scans. For quantitative analysis of intensity data, images are typically normalized to a consistent reference. The most convenient reference is a tissue that is always present in the image, and is unlikely to be affected by pathological processes. In multiple sclerosis neuroimaging, both the white and gray matter are affected, so normalization techniques that depend on brain tissue may introduce bias or remove biological changes of interest. We introduce a complementary procedure, image "calibration," the goal of which is to remove technical intensity artifacts while preserving biological differences. We demonstrate a deep learning approach to segmenting fat from within the orbit of the eyes on T1-weighted images at 1.5 and 3 âT to use as a reference tissue, and use it to calibrate 1018 scans from 256 participants in a study of pediatric-onset multiple sclerosis. The machine segmentations agreed with the adjudicating expert (DF) segmentations better than did those of other expert humans, and calibration resulted in better agreement with semi-quantitative magnetization transfer ratio imaging than did normalization with the WhiteStripe1 algorithm. We suggest that our method addresses two key priorities in the field: (1) it provides a robust option for serial calibration of conventional scans, allowing comparison of disease change in persons imaged at multiple time points in their disease; and (ii) the technique is fast, as the deep learning segmentation takes only 0.5 âs/scan, which is feasible for both large and small datasets.
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Tecido Adiposo/diagnóstico por imagem , Encéfalo/diagnóstico por imagem , Aprendizado Profundo , Doenças Autoimunes Desmielinizantes do Sistema Nervoso Central/diagnóstico por imagem , Processamento de Imagem Assistida por Computador/métodos , Imageamento por Ressonância Magnética/métodos , Neuroimagem/métodos , Órbita/diagnóstico por imagem , Adolescente , Calibragem , Criança , Feminino , Humanos , Processamento de Imagem Assistida por Computador/normas , Estudos Longitudinais , Imageamento por Ressonância Magnética/normas , Masculino , Esclerose Múltipla/diagnóstico por imagem , Neuroimagem/normasRESUMO
OBJECTIVE: Central nervous system pathology in multiple sclerosis includes both focal inflammatory perivascular injury and injury to superficial structures, including the subpial region of the cortex, which reportedly exhibits a gradient of damage from the surface inward. We assessed how early in the multiple sclerosis course a "surface-in" process of injury suggesting progressive biology may begin. METHODS: We focused on the thalamus, which notably has both a cerebrospinal fluid (CSF) interface and a white matter interface. Thalamic volume trajectories were assessed in a prospectively followed cohort of children from initial presentation with either multiple sclerosis or monophasic acquired demyelination, and healthy controls. Voxelwise volume changes were calculated using deformation-based morphometry, and analyzed in relation to distance from the CSF interface by mixed effects modeling and semiparametric smoothing methods. RESULTS: Twenty-seven children with multiple sclerosis and 73 children with monophasic demyelination were prospectively followed with yearly brain scans (mean follow-up = 4.6 years, standard deviation = 1.9). A total of 282 healthy children with serial scans were included as controls. Relative to healthy controls, children with multiple sclerosis and children with monophasic demyelination demonstrated volume loss in thalamic regions adjacent to the white matter. However, only children with multiple sclerosis exhibited an additional surface-in gradient of thalamic injury on the ventricular side, which was already notable in the first year of clinical disease (asymptote estimate = 3.01, 95% confidence interval [CI] = 1.44-4.58, p = 0.0002) and worsened over time (asymptote:time estimate = 0.33, 95% CI = 0.12-0.54, p = 0.0021). INTERPRETATION: Our results suggest that a multiple sclerosis disease-specific surface-in process of damage can manifest at the earliest stages of the disease. ANN NEUROL 2019;85:340-351.
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Esclerose Múltipla/diagnóstico por imagem , Tálamo/diagnóstico por imagem , Adolescente , Estudos de Casos e Controles , Criança , Pré-Escolar , Doenças Autoimunes Desmielinizantes do Sistema Nervoso Central/diagnóstico por imagem , Doenças Autoimunes Desmielinizantes do Sistema Nervoso Central/patologia , Progressão da Doença , Seguimentos , Humanos , Imageamento por Ressonância Magnética , Esclerose Múltipla/patologia , Tamanho do Órgão , Tálamo/patologiaRESUMO
The physiological and pathological roles of nascent amyloid beta (Aß) monomers are still debated in the literature. Their involvement in the pathological route of Alzheimer's Disease (AD) is currently considered to be the most relevant, triggered by their aggregation into structured oligomers, a toxic species. Recently, it has been suggested that nascent Aß, out of the amyloidogenic pathway, plays a physiological and protective role, especially in the brain. In this emerging perspective, the study presented in this paper investigated whether the organization of model membranes is affected by contact with Aß in the nascent state, as monomers. The outcome is that, notably, the rules of engagement and the resulting structural outcome are dictated by the composition and properties of the membrane, rather than by the Aß variant. Interestingly, Aß monomers are observed to favor the tightening of adjacent complex membranes, thereby affecting a basic structural event for cell-cell adhesion and cell motility.
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Peptídeos beta-Amiloides/metabolismo , Precursor de Proteína beta-Amiloide/metabolismo , Membranas/metabolismo , Doença de Alzheimer/metabolismo , Peptídeos beta-Amiloides/fisiologia , Precursor de Proteína beta-Amiloide/fisiologia , Humanos , Membranas/fisiologia , Modelos Biológicos , Fragmentos de Peptídeos/metabolismo , Ligação ProteicaRESUMO
The self-assembly behavior of the yeast-derived bolaamphiphile sophorolipid (SL) is generally studied under acidic/neutral pH conditions, at which micellar and fibrillar aggregates are commonly found, according to the (un)saturation of the aliphatic chain: the cis form, which corresponds to the oleic acid form of SL, spontaneously forms micelles, whereas the saturated form, which corresponds to the stearic acid form of SL, preferentially forms chiral fibers. By using small-angle light and X-ray scattering (SLS, SAXS) combined with high-sensitivity transmission electron microscopy imaging under cryogenic conditions (cryo-TEM), the nature of the self-assembled structures formed by these two compounds above pHâ 10, which is the pH at which they are negatively charged due to the presence of a carboxylate group, has been explored. Under these conditions, these compounds self-assemble into nanoscale platelets, despite the different molecular structures. This work shows that the electrostatic repulsion forces generated by COO(-) mainly drive the self-assembly process at basic pH, in contrast with that found at pH below neutrality, at which self-assembly is driven by van der Waals forces and hydrogen bonding, and thus, is in agreement with previous findings on carbohydrate-based gemini surfactants.
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Plaquetas/química , Lipídeos/química , Tensoativos/química , Ligação de Hidrogênio , Concentração de Íons de Hidrogênio , Micelas , Estrutura Molecular , Nanoestruturas , Difração de Raios XRESUMO
In the present paper, we show that the saturated form of acidic sophorolipids, a family of industrially scaled bolaform microbial glycolipids, unexpectedly forms chiral nanofibers only at pH below 7.5. In particular, we illustrate that this phenomenon derives from a subtle cooperative effect of molecular chirality, hydrogen bonding, van der Waals forces and steric hindrance. The pH-responsive behaviour was shown by Dynamic Light Scattering (DLS), pH-titration and Field Emission Scanning Electron Microscopy (FE-SEM) while the nanoscale chirality was evidenced by Circular Dichroism (CD) and cryo Transmission Electron Microscopy (cryo-TEM). The packing of sophorolipids within the ribbons was studied using Small Angle Neutron Scattering (SANS), Wide Angle X-ray Scattering (WAXS) and 2D (1)H-(1)H through-space correlations via Nuclear Magnetic Resonance under very fast (67 kHz) Magic Angle Spinning (MAS-NMR).
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Glicolipídeos/química , Nanotubos de Carbono/química , Saccharomyces cerevisiae/metabolismo , Dicroísmo Circular , Glicolipídeos/metabolismo , Ligação de Hidrogênio , Concentração de Íons de Hidrogênio , Interações Hidrofóbicas e Hidrofílicas , Conformação Molecular , Nanofibras/química , Nanotubos de Carbono/ultraestrutura , Eletricidade Estática , Estereoisomerismo , Tensoativos/química , Tensoativos/metabolismoRESUMO
Background/Objectives: Hand hygiene (HH) is pivotal in mitigating infectious disease transmission and enhancing public health outcomes. This study focuses on detailing the national surveillance system for alcohol-based hand rub (ABHR) consumption in healthcare facilities across Italy, presenting results from a comprehensive three-year evaluation period, from 2020 to 2022. It aims to delineate this surveillance system and report on ABHR consumption trends in various Regions/Autonomous Provinces (Rs/APs). Methods: ABHR consumption data, collected through the ABHR Italian national surveillance system, coordinated by the Istituto Superiore di Sanità (ISS), were analyzed. Statistical methods, e.g., the Mann-Whitney test, were used to assess trends in ABHR consumption, expressed in liters per 1000 patient days (L/1000PD). Results: The results show significant variation in ABHR consumption across Rs/APs and over the years studied. National median ABHR consumption decreased from 2020 to 2022, with a significant reduction from a median of 24.5 L/1000PD in 2020 to 20.4 L/1000PD in 2021 and 15.6 L/1000PD in 2022. Conclusions: The decline in ABHR consumption raises concerns about the ongoing adherence to HH practices in Italian healthcare settings. This underscores the essential role that systematic ABHR monitoring and improved surveillance play in enhancing HH compliance, suggesting that sustained and strategic efforts are fundamental to uphold high standards of hygiene and to effectively respond to fluctuating ABHR usage trends over time. Further research is needed to explore barriers to effective ABHR use and to develop targeted strategies to improve HH practices.
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It is estimated that between 58% and 82% of children and young people who present to paediatric emergency department (PEDs) have a non-urgent condition. This systematic review of the literature explores why parents of children with non-urgent conditions present to the PED rather than to community healthcare services. Five databases were searched for studies on children and young people's presentations to the PED for the treatment of a non-urgent condition, as identified by a low priority triage code. This article describes and discusses the findings of the 18 included studies.
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Serviço Hospitalar de Emergência , Pais , Criança , Humanos , Adolescente , TriagemRESUMO
In Italy, despite the documented positive effects of rotavirus (RV) vaccination on reducing the burden of RV disease, an updated national assessment of its impact on clinical outcomes is still lacking. This study aims to analyze the implementation of RV vaccination in Italy, evaluating its impact on discharges for acute pediatric gastroenteritis (AGE). A retrospective analysis, including hospital discharge records and data on vaccination coverage for children aged 0-71 months from 2009 to 2019, was conducted. We examined trends in hospital discharge standardized incidence before and after vaccine introduction using a negative binomial mixture model with fixed effects to evaluate the impact of universal vaccination. The percentage of vaccination coverage increased over the years, from <5% between 2009 and 2013 to 26% in 2017, reaching 70% in 2019. The standardized incidence of discharges decreased over the period from 16.6/100,000 inhabitants in 2009-2013 to 9.9/100,000 inhabitants in 2018-2019. In this phase, about 15% of the estimated hospital discharges were avoided compared with those estimated in the first phase. The implementation of RV vaccination reduced AGE incidence discharges in children aged 0-71 months. Further efforts are needed to continue monitoring the vaccination effect over time and to increase vaccination coverage.
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BACKGROUND AND OBJECTIVES: Pediatric-acquired demyelination of the CNS associated with antibodies directed against myelin oligodendrocyte glycoprotein (MOG; MOG antibody-associated disease [MOGAD]) occurs as a monophasic or relapsing disease and with variable but often extensive T2 lesions in the brain. The impact of MOGAD on brain growth during maturation is unknown. We quantified the effect of pediatric MOGAD on brain growth trajectories and compared this with the growth trajectories of age-matched and sex-matched healthy children and children with multiple sclerosis (MS, a chronic relapsing disease known to lead to failure of normal brain growth and to loss of brain volume) and monophasic seronegative demyelination. METHODS: We included children enrolled at incident attack in the prospective longitudinal Canadian Pediatric Demyelinating Disease Study who were recruited at the 3 largest enrollment sites, underwent research brain MRI scans, and were tested for serum MOG-IgG. Children seropositive for MOG-IgG were diagnosed with MOGAD. MS was diagnosed per the 2017 McDonald criteria. Monophasic seronegative demyelination was confirmed in children with no clinical or MRI evidence of recurrent demyelination and negative results for MOG-IgG and aquaporin-4-IgG. Whole and regional brain volumes were computed through symmetric nonlinear registration to templates. We computed age-normalized and sex-normalized z scores for brain volume using a normative dataset of 813 brain MRI scans obtained from typically developing children and used mixed-effect models to assess potential deviation from brain growth trajectories. RESULTS: We assessed brain volumes of 46 children with MOGAD, 26 with MS, and 51 with monophasic seronegative demyelinating syndrome. Children with MOGAD exhibited delayed (p < 0.001) age-expected and sex-expected growth of thalamus, caudate, and globus pallidus, normalized for the whole brain volume. Divergence from expected growth was particularly pronounced in the first year postonset and was detected even in children with monophasic MOGAD. Thalamic volume abnormalities were less pronounced in children with MOGAD compared with those in children with MS. DISCUSSION: The onset of MOGAD during childhood adversely affects the expected trajectory of growth of deep gray matter structures, with accelerated changes in the months after an acute attack. Further studies are required to better determine the relative impact of monophasic vs relapsing MOGAD and whether relapsing MOGAD with attacks isolated to the optic nerves or spinal cord affects brain volume over time.
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Esclerose Múltipla , Neuromielite Óptica , Humanos , Estudos Prospectivos , Substância Cinzenta/patologia , Canadá , Esclerose Múltipla/patologia , Glicoproteína Mielina-Oligodendrócito , Encéfalo/patologia , Aquaporina 4 , Doença Crônica , Imunoglobulina G , Autoanticorpos , Neuromielite Óptica/patologiaRESUMO
BACKGROUND: Myelin oligodendrocyte glycoprotein antibody-associated disease (MOGAD) is a recently described neuroinflammatory demyelinating disease. OBJECTIVE: To better understand the clinical spectrum, risk factors and outcomes in MOGAD. METHODS: Retrospective cohort study including all subjects harboring anti-MOG antibodies identified in major academic hospitals across the province of Quebec. RESULTS: We identified 45 MOGAD cases. The minimal estimated point-prevalence was 0.52/100 000 in Quebec. Median age at presentation was 32 years (range 1-71) with equal sex ratio. Most frequent ethnic groups were Caucasians and Asians. The most frequent clinical manifestations at onset were optic neuritis (ON), affecting 56% of adults, and acute disseminated encephalomyelitis (ADEM), affecting 33% of children. First MRI was abnormal in 84% of cases. Most CSF samples showed pleocytosis without oligoclonal bands. Two brain biopsies revealed lipid-laden macrophages and reactive astrocytes. Despite steroids, only 38% had fully recovered at 4 weeks after onset. Half of pediatric and two thirds of adult-onset MOGAD subjects experienced relapses. At last follow-up, 69% showed residual deficits, which were moderate to severe in 17% of adults. CONCLUSION: MOGAD has heterogeneous disease course, and it is not a benign disease for a substantial proportion of adults. Best disease-modifying therapies remain to be determined.
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Encefalomielite Aguda Disseminada , Neurite Óptica , Humanos , Glicoproteína Mielina-Oligodendrócito , Estudos Retrospectivos , Encefalomielite Aguda Disseminada/diagnóstico por imagem , Progressão da Doença , AutoanticorposRESUMO
Inflammatory myelopathies can manifest with a combination of motor, sensory and autonomic dysfunction of variable severity. Depending on the underlying etiology, the episodes of myelitis can recur, often leading to irreversible spinal cord damage and major long-term disability. Three main demyelinating disorders of the central nervous system, namely multiple sclerosis (MS), aquaporin-4-IgG-positive neuromyelitis optica spectrum disorders (AQP4+NMOSD) and myelin oligodendrocyte glycoprotein-IgG associated disease (MOGAD), can induce spinal cord inflammation through different pathogenic mechanisms, resulting in a more or less profound disruption of spinal cord integrity. This ultimately translates into distinctive clinical-MRI features, as well as distinct patterns of disability accrual, with a step-wise worsening of neurological function in MOGAD and AQP4+NMOSD, and progressive disability accrual in MS. Early recognition of the specific etiologies of demyelinating myelitis and initiation of the appropriate treatment is crucial to improve outcome. In this review article we summarize and compare the clinical and imaging features of spinal cord involvement in these three demyelinating disorders, both during the acute phase and over time, and outline the current knowledge on the expected patterns of disability accrual and outcomes. We also discuss the potential implications of these observations for patient management and counseling.
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Myelin oligodendrocyte glycoprotein (MOG) antibody-associated disease (MOGAD) is the most recently defined inflammatory demyelinating disease of the central nervous system (CNS). Over the last decade, several studies have helped delineate the characteristic clinical-MRI phenotypes of the disease, allowing distinction from aquaporin-4 (AQP4)-IgG-positive neuromyelitis optica spectrum disorder (AQP4-IgG+NMOSD) and multiple sclerosis (MS). The clinical manifestations of MOGAD are heterogeneous, ranging from isolated optic neuritis or myelitis to multifocal CNS demyelination often in the form of acute disseminated encephalomyelitis (ADEM), or cortical encephalitis. A relapsing course is observed in approximately 50% of patients. Characteristic MRI features have been described that increase the diagnostic suspicion (e.g., perineural optic nerve enhancement, spinal cord H-sign, T2-lesion resolution over time) and help discriminate from MS and AQP4+NMOSD, despite some overlap. The detection of MOG-IgG in the serum (and sometimes CSF) confirms the diagnosis in patients with compatible clinical-MRI phenotypes, but false positive results are occasionally encountered, especially with indiscriminate testing of large unselected populations. The type of cell-based assay used to evaluate for MOG-IgG (fixed vs. live) and antibody end-titer (low vs. high) can influence the likelihood of MOGAD diagnosis. International consensus diagnostic criteria for MOGAD are currently being compiled and will assist in clinical diagnosis and be useful for enrolment in clinical trials. Although randomized controlled trials are lacking, MOGAD acute attacks appear to be very responsive to high dose steroids and plasma exchange may be considered in refractory cases. Attack-prevention treatments also lack class-I data and empiric maintenance treatment is generally reserved for relapsing cases or patients with severe residual disability after the presenting attack. A variety of empiric steroid-sparing immunosuppressants can be considered and may be efficacious based on retrospective or prospective observational studies but prospective randomized placebo-controlled trials are needed to better guide treatment. In summary, this article will review our rapidly evolving understanding of MOGAD diagnosis and management.
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INTRODUCTION: Myelin oligodendrocyte glycoprotein antibodies are identified in approximately 30-50% of youth with pediatric-onset acquired demyelinating syndromes. Little is known about the cognitive sequelae of relapsing myelin oligodendrocyte glycoprotein antibody-associated disease (MOGAD) with onset in childhood or adolescence.Overall, adults had 41% more risk than children to relapse over the whole disease course Overall, adults had 41% more risk than children to relapse over the whole disease course OBJECTIVE: To compare cognitive performance in participants with pediatric-onset relapsing MOGAD, pediatric-onset multiple sclerosis (POMS), and age-matched healthy controls. METHODS: The Penn Computerized Neurocognitive Battery (PCNB) was administered to 12 individuals with relapsing MOGAD (age = 16.3 ± 4.8 years; 75% female; disease duration = 8.1 ± 2.7 years), 68 individuals with POMS (age = 18.3 ± 4.0 years; 72% female; disease duration = 3.8 ± 3.9 years), and 108 healthy controls (age = 17.0 ± 4.9 years; 68.5% female). Accuracy was assessed on four domains: Executive Function, Episodic Memory, Complex Cognition, Social Cognition; and overall response time (RT) and RT across three factors (i.e., Time Constrained, Open-Window, Memory). Global performance was determined by a composite score. Multiple linear regression was used to examine group differences on PCNB domain and factor z-scores, controlling for age and sex. We also covaried disease duration for relapsing MOGAD vs. POMS analyses. RESULTS: Relative to healthy controls, relapsing MOGAD participants were less accurate on the Complex Cognition domain (B=-0.28, SE=0.11, p=.02), and had slower overall response time (B=-0.16, SE=0.07, p=.02). Relative to POMS, relapsing MOGAD participants were more accurate on the Executive Function domain (B = 0.70, SE=0.30, p=.02) and on the battery overall (B = 0.41, SE=0.18, p=.02). Relative to controls, overall PCNB score was significantly lower in the POMS group (B=-0.28, SE=0.06, p<.001) whereas the relapsing MOGAD participants did not differ from controls (p=.06) on the overall PCNB score. CONCLUSIONS: The relapsing MOGAD group demonstrated reduced reasoning skills and slower overall response time, relative to controls. A broad pattern of deficits was observed among POMS participants relative to controls. Overall, cognitive difficulties in the MOGAD group were milder relative to the POMS group.
Assuntos
Cognição , Doenças Autoimunes Desmielinizantes do Sistema Nervoso Central , Adolescente , Autoanticorpos , Criança , Doenças Autoimunes Desmielinizantes do Sistema Nervoso Central/fisiopatologia , Feminino , Humanos , Masculino , Memória Episódica , Esclerose Múltipla , Glicoproteína Mielina-Oligodendrócito , Recidiva , Adulto JovemRESUMO
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.
RESUMO
The field of acquired CNS neuroimmune demyelination in children is transforming. Progress in assay development, refinement of diagnostic criteria, increased biological insights provided by advanced neuroimaging techniques, and high-level evidence for the therapeutic efficacy of biological agents are redefining diagnosis and care. Three distinct neuroimmune conditions-multiple sclerosis, myelin-oligodendrocyte glycoprotein antibody-associated disease (MOGAD), and aquaporin-4 antibody-associated neuromyelitis optica spectrum disorder (AQP4-NMOSD)-can now be distinguished, with evidence from humans and animal models supporting distinct pathobiological disease mechanisms. The development of highly effective therapies for adult-onset multiple sclerosis and AQP4-NMOSD that suppress relapse rate by more than 90% has motivated advocacy for trials in children. However, doing clinical trials is challenging because of the rarity of these conditions in the paediatric age group, necessitating new approaches to trial design, including age-based trajectory modelling based on phase 3 studies in adults. Despite these limitations, the future for children and adolescents living with multiple sclerosis, MOGAD, or AQP4-NMOSD is far brighter than in years past, and will be brighter still if successful therapies to promote remyelination, enhance neuroprotection, and remediate cognitive deficits can be further accelerated.