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1.
Mult Scler Relat Disord ; 87: 105647, 2024 Jul.
Article in English | MEDLINE | ID: mdl-38838422

ABSTRACT

BACKGROUND: Observational studies looking at clinical a++nd MRI outcomes of treatments in pediatric MS, could assess current treatment algorithms, and provide insights for designing future clinical trials. OBJECTIVE: To describe baseline characteristics and clinical and MRI outcomes in MS patients initiating ocrelizumab and fingolimod under 18 years of age. METHODS: MS patients seen at 12 centers of US Network of Pediatric MS were included in this study if they had clinical and MRI follow-up and started treatment with either ocrelizumab or fingolimod prior to the age of 18. RESULTS: Eighty-seven patients initiating fingolimod and 52 initiating ocrelizumab met the inclusion criteria. Before starting fingolimod, mean annualized relapse rate was 0.43 (95 % CI: 0.29 - 0.65) and 78 % developed new T2 lesions while during treatment it was 0.12 (95 % CI: 0.08 - 1.9) and 47 % developed new T2 lesions. In the ocrelizumab group, the mean annualized relapse rate prior to initiation of treatment was 0.64 (95 % CI: 0.38-1.09) and a total of 83 % of patients developed new T2 lesions while during treatment it was 0.09 (95 % CI: 0.04-0.21) and none developed new T2 lesions. CONCLUSION: This study highlights the importance of evaluating current treatment methods and provides insights about the agents in the ongoing phase III trial comparing fingolimod and ocrelizumab.


Subject(s)
Antibodies, Monoclonal, Humanized , Fingolimod Hydrochloride , Magnetic Resonance Imaging , Humans , Fingolimod Hydrochloride/adverse effects , Fingolimod Hydrochloride/therapeutic use , Fingolimod Hydrochloride/administration & dosage , Female , Male , Adolescent , Antibodies, Monoclonal, Humanized/adverse effects , Antibodies, Monoclonal, Humanized/administration & dosage , Child , Immunologic Factors/adverse effects , Immunologic Factors/administration & dosage , Immunosuppressive Agents/adverse effects , Immunosuppressive Agents/administration & dosage , Multiple Sclerosis/drug therapy , Multiple Sclerosis/diagnostic imaging , Treatment Outcome , Brain/diagnostic imaging , Brain/drug effects , Brain/pathology
3.
Mult Scler Relat Disord ; 82: 105351, 2024 Feb.
Article in English | MEDLINE | ID: mdl-38141560

ABSTRACT

BACKGROUND: Our previous study identified a significant association between lower time spent outdoors, as a proxy of sun exposure, and a higher risk of pediatric-onset multiple sclerosis (POMS). UV radiation modulates the expression of several genes, but it is unknown whether these genes modify the effect of sun exposure on POMS risk. METHODS: In an age- and sex-matched case-control study, we evaluated the additive and multiplicative interactions between time spent outdoors and genetic non-HLA risk variants for developing POMS within the metabolic pathways of UV radiation, including CD28(rs6435203), CD86(rs9282641), and NFkB1(rs7665090) and the top two HLA risk factors (presence of DRB1×15 and absence of A*02). RESULTS: In an adjusted model (332 POMS cases, 534 healthy controls), greater time compared to <30 min/day spent outdoors during the prior summer and higher UV radiation dose were associated with decreased odds of POMS (OR 0.66, 95% CI 0.56-0.78, p < 0.001; OR 0.78, 95 % CI 0.62-0.98, p = 0.04, respectively). No significant additive or multiplicative interactions were found between risk factors. CONCLUSIONS: The exploration of gene-environment interactions in the risk of developing MS can unravel the underlying mechanisms involved. Although we do not have evidence that our candidate genes contribute to interactions, other genes may.


Subject(s)
Gene-Environment Interaction , Multiple Sclerosis , Child , Humans , Multiple Sclerosis/etiology , Multiple Sclerosis/genetics , Case-Control Studies , Ultraviolet Rays/adverse effects , Risk Factors
4.
Genetica ; 151(4-5): 293-310, 2023 Oct.
Article in English | MEDLINE | ID: mdl-37624443

ABSTRACT

Ionotropic glutamate receptors are ligand-gated nonselective cation channels that mediate neurotransmission in the central nervous system of animals. Plants possess homologous proteins called glutamate receptor-like channels (GLRs) which are involved in vital physiological processes including seed germination, long-distance signaling, chemotaxis, Ca2+ signaling etc. Till now, a comprehensive genome-wide analysis of the GLR gene family members in different economically important species of Brassica is missing. Considering the origin of allotetraploid Brassica napus from the hybridization between the diploid Brassica oleracea and Brassica rapa, we have identified 11, 27 and 65 GLR genes in B. oleracea, B. rapa and B. napus, respectively showing an expansion of this gene family in B. napus. Chromosomal locations revealed several tandemly duplicated GLR genes in all the three species. Moreover, the gene family expanded in B. napus after allopolyploidization. The phylogenetic analysis showed that the 103 GLRs are classified into three main groups. The exon-intron structures of these genes are not very conserved and showed wide variation in intron numbers. However, protein sequences are much conserved as shown by the presence of ten short amino acid sequence motifs. Predicted cis-acting elements in 1 kb promoters of GLR genes are mainly involved in light, stress and hormone responses. RNA-seq analysis showed that in B. oleracea and B. rapa, some GLRs are more tissue specific than others. In B. napus, some GLRs are downregulated under cold stress, while others are upregulated. In summary, this bioinformatic study of the GLR gene family of the three Brassica species provides evidence for the expansion of this gene family in B. napus and also provided useful information for in-depth studies of their biological functions in Brassica.


Subject(s)
Brassica napus , Brassica napus/genetics , Brassica napus/metabolism , Diploidy , Phylogeny , Regulatory Sequences, Nucleic Acid , Receptors, Glutamate/genetics , Receptors, Glutamate/metabolism , Gene Expression Regulation, Plant , Genome, Plant , Plant Proteins/metabolism
5.
Pediatr Neurol ; 147: 36-43, 2023 10.
Article in English | MEDLINE | ID: mdl-37544084

ABSTRACT

BACKGROUND: We describe a cohort of children with severe myelin oligodendrocyte glycoprotein (MOG)-IgG-associated cerebral cortical encephalitis (CCE), manifesting with bilateral cortical cytotoxic edema and critical neurological illness. METHODS: We retrospectively reviewed our pediatric MOG antibody-associated disease (MOGAD) database and identified patients with specific radiographic pattern of bilateral, multifocal cortical cytotoxic lesions. We collected demographic, clinical, and outcomes data from these patients and compared select variables with radiographically distinct cerebral MOGAD syndromes (case-control analysis). We assessed the correlation of quantitative clinical variables with severity/outcomes measures using simple linear regression. RESULTS: Sixty-five of 88 total MOGAD cases had cerebral disease, and six of 88 met inclusion criteria for fulminant CCE (f-CCE). Age range was 2 to 7 years; five of six were male. Six of six were critically ill with severe encephalopathy and seizures, two of six required barbiturate coma, and two of six required invasive intracranial pressure monitoring. Six of six required treatment escalation beyond steroids. Four of six had favorable outcome; two of six had moderate-severe disability. Compared with other cerebral MOGAD cases (n = 59), children with f-CCE were more likely to have critical illness and poor neurological outcomes scores. Neurofilament light chain and treatment latency positively correlated with intensive care unit length of stay and outcomes scores; cerebrospinal fluid (CSF) white blood cell count and neutrophil-to-lymphocyte ratio did not. CONCLUSIONS: Pediatric CCE with bilateral cytotoxicity is associated with more fulminant disease and worse outcomes than other cerebral MOGAD syndromes.


Subject(s)
Brain Diseases , Encephalitis , Male , Humans , Female , Myelin-Oligodendrocyte Glycoprotein , Retrospective Studies , Syndrome , Encephalitis/diagnostic imaging , Phenotype , Oligodendroglia , Autoantibodies
6.
Pediatr Neurol ; 145: 125-131, 2023 Aug.
Article in English | MEDLINE | ID: mdl-37348193

ABSTRACT

BACKGROUND: Treatment of pediatric-onset multiple sclerosis (POMS) is challenging given the lack of safety and efficacy data in the pediatric population for many of the disease-modifying treatments (DMTs) approved for use in adults with MS. Our objective was to describe the demographic features and clinical and radiologic course of patients with POMS treated with the commonly used newer DMTs within the US Network of Pediatric MS Centers (NPMSC). METHODS: This is an analysis of prospectively collected data from patients who initiated treatment before age 18 with the DMTs listed below at the 12 regional pediatric MS referral centers participating in the NPMSC. RESULTS: One hundred sixty-eight patients on dimethyl fumarate, 96 on fingolimod, 151 on natalizumab, 166 on rituximab, and 37 on ocrelizumab met criteria for analysis. Mean age at DMT initiation ranged from 15.2 to 16.5 years. Disease duration at the time of initiation of index DMT ranged from 1.1 to 1.6 years with treatment duration of 0.9-2.0 years. Mean annualized relapse rate (ARR) in the year prior to initiating index DMT ranged from 0.4 to 1.0. Mean ARR while on index DMT ranged from 0.05 to 0.20. New T2 and enhancing lesions occurred in 75%-88% and 55%-73% of the patients, respectively, during the year prior to initiating index DMT. After initiating index DMT, new T2 and enhancing lesions occurred in 0%-46% and 11%-34% patients, respectively. Rates of NEDA-2 (no evidence of disease activity) ranged from 76% to 91% at 6 months of treatment with index DMTs and 66% to 84% at 12 months of treatment with index DMTs. CONCLUSIONS: Though limited by relatively short treatment duration with the index DMTs, our data suggest clinical and MRI benefit, as well as high rates of NEDA-2, in a large number of POMS patients, which can be used to guide future studies in this population.


Subject(s)
Immunosuppressive Agents , Multiple Sclerosis , Adult , Humans , Child , Adolescent , Immunosuppressive Agents/therapeutic use , Multiple Sclerosis/diagnostic imaging , Multiple Sclerosis/drug therapy , Multiple Sclerosis/epidemiology , Fingolimod Hydrochloride/therapeutic use , Recurrence , Disease Progression , Demography
7.
Mult Scler ; 29(4-5): 576-584, 2023 04.
Article in English | MEDLINE | ID: mdl-36960480

ABSTRACT

BACKGROUND: Pediatric patients with multiple sclerosis (POMS) and related disorders, clinically isolated syndrome (CIS), myelin oligodendrocyte glycoprotein antibody disorder (MOGAD), and neuromyelitis optica spectrum disorder (NMOSD), are commonly treated with immunosuppressants. Understanding the impact of SARS-CoV-2 infection in patients may inform treatment decisions. OBJECTIVE: Characterize SARS-CoV-2 infection prevalence and severity among a cohort of patients with POMS and related disorders, as well as the impact of disease-modifying therapies (DMTs). METHODS: POMS and related disorders patients enrolled in a large, prospective registry were screened for COVID-19 during standard-of-care neurology visits. If confirmed positive of having infection, further analysis was undertaken. RESULTS: Six hundred and sixty-nine patients were surveyed between March 2020 and August 2021. There were 73 confirmed COVID-19 infections. Eight of nine hospitalized patients (89%), and all patients admitted to the ICU were treated with B cell depleting therapy. The unadjusted odds ratio of hospitalization among those who tested positive of having had COVID-19 was 15.27 among those on B-cell-depleting therapy (p = 0.016). CONCLUSIONS: B-cell-depleting treatment was associated with a higher risk of COVID-19, higher rates of hospitalization, and ICU admission, suggesting this therapy carries a higher risk of severe infection in POMS and related disorders.


Subject(s)
COVID-19 , Multiple Sclerosis , Neuromyelitis Optica , Humans , SARS-CoV-2 , COVID-19/epidemiology , Multiple Sclerosis/epidemiology , B-Lymphocytes , Myelin-Oligodendrocyte Glycoprotein , Autoantibodies , Aquaporin 4
8.
Mult Scler Relat Disord ; 71: 104573, 2023 Mar.
Article in English | MEDLINE | ID: mdl-36871372

ABSTRACT

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.


Subject(s)
Autoimmune Diseases of the Nervous System , Demyelinating Diseases , Multiple Sclerosis , Humans , Child , Multiple Sclerosis/diagnostic imaging , Multiple Sclerosis/epidemiology , Demyelinating Diseases/diagnostic imaging , Demyelinating Diseases/epidemiology , Disease Progression , Magnetic Resonance Imaging , Retrospective Studies
9.
Neurology ; 100(9): e985-e994, 2023 02 28.
Article in English | MEDLINE | ID: mdl-36460473

ABSTRACT

BACKGROUND AND OBJECTIVE: Neuromyelitis optica spectrum disorder (NMOSD) is a rare autoimmune condition, which can lead to significant disability, and up to 3%-5% of the cases have a pediatric onset. There are limited studies to guide physicians in disease-modifying treatment (DMT) choices for children with NMOSD. METHODS: This retrospective cohort study evaluated children with NMOSD cases followed at 12 clinics in the US Network of Pediatric MS Centers. Cases were classified as aquaporin-4 antibody positive (AQP4+) and double seronegative (DS) when negative for AQP4+ and for myelin oligodendrocyte glycoprotein (MOG) antibody. The effect of initial DMTs including rituximab, mycophenolate, azathioprine, and IV immunoglobulin (IVIg) on the annualized relapse rate (ARR) was assessed by negative binomial regression. Time to disability progression (EDSS score increase ≥1.0 point) was modeled with a Cox proportional-hazards model. RESULTS: A total of 91 children with NMOSD were identified: 77 AQP4+ and 14 DS (85.7% females; 43.2% White and 46.6% African American). Eighty-one patients were started on a DMT, and 10 were treatment naive at the time of the analysis. The ARR calculated in all serogroups was 0.25 (95% CI 0.13-0.49) for rituximab, 0.33 (95% CI 0.19-0.58) for mycophenolate, 0.40 (95% CI 0.13-1.24) for azathioprine, and 0.54 (95% CI 0.28-1.04) for IVIg. The ARR in the AQP4+ subgroup was 0.28 (95% CI 0.14-0.55) for rituximab, 0.39 (95% CI 0.21-0.70) for mycophenolate, 0.41 (95% CI 0.13-1.29) for azathioprine, and 0.54 (95% CI 0.23-1.26) for IVIg. The ARR in the treatment-naive group was 0.97 (95% CI 0.58-1.60) in all serogroups and 0.91 (95% CI 0.53-1.56) in the AQP4+ subgroup. None of the initial DMT had a statistically significant effect on EDSS progression. DISCUSSION: The use of DMTs, particularly rituximab, is associated with a lowered annualized relapse rate in children with NMOSD AQP4+. CLASSIFICATION OF EVIDENCE: This study provides Class IV evidence that use of disease-modifying treatments is associated with a lowered annualized relapse rate in children with NMOSD AQP4+.


Subject(s)
Neuromyelitis Optica , Female , Male , Humans , Aquaporin 4 , Rituximab/therapeutic use , Azathioprine/therapeutic use , Retrospective Studies , Immunoglobulins, Intravenous/therapeutic use , Immunoglobulin G , Autoantibodies , Immunosuppressive Agents/therapeutic use , Enzyme Inhibitors/therapeutic use , Recurrence , Myelin-Oligodendrocyte Glycoprotein
10.
Child Neurol Open ; 9: 2329048X221079093, 2022.
Article in English | MEDLINE | ID: mdl-35237705

ABSTRACT

Background: MOG antibody associated demyelinating disease (MOGAD) is a newly described autoimmune disorder that presents with monophasic or multiphasic demyelination in children. Case: We report a case of MOGAD that was refractory to current treatment algorithms and required rapid escalation of immunotherapy to achieve disease control. Conclusion: This case helps to further expand the phenotype of MOGAD and emphasizes the need to consider MOGAD in patients presenting with focal neurologic deficits, altered mental status, and/or seizures.

11.
Neurol Clin ; 39(3): 811-828, 2021 08.
Article in English | MEDLINE | ID: mdl-34215388

ABSTRACT

Pediatric neuroinflammatory conditions are a complex group of disorders with a wide range of clinical presentations. Patients can present with a combination of focal neurologic deficits, encephalopathy, seizures, movement disorders, or psychiatric manifestations. There are several ways that pediatric neuroinflammatory conditions can be classified, including clinical presentation, pathophysiologic mechanism, and imaging and laboratory findings. In this article, we group these conditions into acquired demyelinating diseases, immune-mediated epilepsies/encephalopathies, primary rheumatologic conditions with central nervous system (CNS) manifestations, CNS vasculitis, and neurodegenerative/genetic conditions with immune-mediated pathophysiology and discuss epidemiology, pathophysiology, clinical presentation, treatment, and prognosis of each disorder.


Subject(s)
Brain Diseases , Central Nervous System Diseases , Epilepsy , Neurodegenerative Diseases , Vasculitis, Central Nervous System , Central Nervous System , Central Nervous System Diseases/diagnosis , Central Nervous System Diseases/epidemiology , Central Nervous System Diseases/therapy , Child , Humans , Inflammation
12.
Ann Clin Transl Neurol ; 7(12): 2467-2474, 2020 12.
Article in English | MEDLINE | ID: mdl-33506622

ABSTRACT

Febrile-infection related epilepsy syndrome (FIRES) is a devastating neurological condition characterized by a febrile illness preceding new onset refractory status epilepticus (NORSE). Increasing evidence suggests innate immune dysfunction as a potential pathological mechanism. We report an international retrospective cohort of 25 children treated with anakinra, a recombinant interleukin-1 receptor antagonist, as an immunomodulator for FIRES. Anakinra was potentially safe with only one child discontinuing therapy due to infection. Earlier anakinra initiation was associated with shorter duration of mechanical ventilation, ICU and hospital length of stay. Our retrospective data lay the groundwork for prospective consensus-driven cohort studies of anakinra in FIRES.


Subject(s)
Epileptic Syndromes/therapy , Infections/therapy , Interleukin 1 Receptor Antagonist Protein/therapeutic use , Seizures, Febrile/therapy , Child , Child, Preschool , Cohort Studies , Humans , Infectious Encephalitis , Retrospective Studies
13.
Semin Pediatr Neurol ; 26: 101-103, 2018 07.
Article in English | MEDLINE | ID: mdl-29961495

ABSTRACT

In this case report, we discuss a 15-year-old previously healthy boy who presented with acute onset encephalopathy with refractory status epilepticus requiring pentobarbital-induced burst suppression for seizure control. We review the differential diagnosis and important diagnostic considerations for pediatric patients presenting with acute encephalopathy. We then review Hashimoto encephalopathy (SREAT) and discuss presentation, diagnosis, and treatment.


Subject(s)
Encephalitis/diagnosis , Hashimoto Disease/diagnosis , Status Epilepticus/diagnosis , Adolescent , Diagnosis, Differential , Encephalitis/therapy , Hashimoto Disease/therapy , Humans , Male , Status Epilepticus/therapy
14.
Mol Cell Biochem ; 393(1-2): 89-98, 2014 Aug.
Article in English | MEDLINE | ID: mdl-24737391

ABSTRACT

The studies into the pathophysiology of viral miRNAs are still in infancy; the interspecies regulation at the miRNA level fuels the spark of the investigation into the repertoire of virus-host interactions. Reports pertaining to the viral miRNAs role in modulating/evading the host immune response are surging up; we initiated this in silico study to speculate the role of human cytomegalovirus (HCMV)-encoded miRNAs on human antiviral mechanisms such as apoptosis and autophagy. The results indicate that both the above mechanisms were targeted by the HCMV miRNAs, located in the unique long region of the HCMV genome. The proapoptotic genes MOAP1, PHAP, and ERN1 are identified to be the potential targets for the miR-UL70-3p and UL148D, respectively. The ERN1 gene plays a role in the initiation of Endoplasmic reticulum stress-induced apoptosis as well as autophagosome formation. This study shows that HCMV employs its miRNA repertoire for countering the cellular apoptosis and autophagy, particularly the mitochondrial-dependent intrinsic pathway of apoptosis. In addition, the homology studies reveal no HCMV miRNA bears sequence homology with human miRNAs.


Subject(s)
Cytomegalovirus/genetics , DNA Replication/genetics , Host-Pathogen Interactions/genetics , MicroRNAs/genetics , Apoptosis/genetics , Cytomegalovirus/pathogenicity , Genome, Viral , Humans , Immunity, Cellular/genetics , MicroRNAs/immunology , Sequence Homology , Virus Replication
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