Familial History of Autoimmune Disorders Among Patients With Pediatric Multiple Sclerosis.

BACKGROUND AND OBJECTIVE: The objective of this study was to determine whether family members of patients with pediatric multiple sclerosis (MS) have an increased prevalence of autoimmune conditions compared with controls. METHODS: Data collected during a pediatric MS case-control study of risk factors included information about various autoimmune diseases in family members. The frequency of these disorders was compared between cases and controls. RESULTS: There was an increased rate of autoimmune diseases among family members of pediatric MS cases compared with controls with first-degree history of MS excluded (OR = 2.27, 95% CI 1.71-3.01, p < 0.001). There was an increased rate of MS among second-degree relatives of pediatric MS cases compared with controls (OR = 3.47, 95% CI 1.36-8.86, p = 0.009). The OR for MS was 2.64 when restricted to maternal relatives and 6.37 when restricted to paternal relatives. DISCUSSION: The increased rates of autoimmune disorders, including thyroid disorders and MS among families of patients with pediatric MS, suggest shared genetic factors among families with children diagnosed with pediatric MS.

Pediatric N-Methyl-d-Aspartate (NMDA) Receptor Encephalitis, With and Without Herpes Encephalitis.

OBJECTIVE: To compare clinical, diagnostic, management, and outcome factors in children with anti-N-methyl-d-aspartate receptor (NMDAR) encephalitis and a history of herpes simplex encephalitis (HSE) to children with NMDAR encephalitis without a history of HSE. METHODS: All patients with anti-NMDAR antibodies in cerebrospinal fluid treated at our institution between 2012 and 2019 were identified and divided into those with a history of HSE (HSE+NMDAR group) and those without a history of HSE (NMDAR-only group). Demographic data, clinical characteristics, immunotherapy, and outcome data were collected on all patients and compared between the 2 groups. RESULTS: Seventeen patients were identified with anti-NMDAR antibodies in cerebrospinal fluid, 6 of whom had a history of HSE. Mean age in the HSE+NMDAR cohort was significantly younger in the HSE+NMDAR cohort, as 5 of the 6 patients were infants. Of HSE+NMDAR patients, 50% had behavioral symptoms, 67% had movement disorders, and 100% had seizures at disease nadir. In the NMDAR-only group, 100% had behavioral symptoms, 73% had movement disorders, and 73% had seizures at nadir. HSE+NMDAR patients received a median of 1 immunotherapy, compared to a median of 4.5 immunotherapies in the NMDAR-only group. CONCLUSION: Behavioral symptoms were more common in NMDAR-only patients, whereas seizures were more common in HSE+NMDAR patients. Both groups had significant disability at disease nadir, with more improvement in disability over time in the NMDAR-only group. HSE+NMDAR patients received fewer immunotherapies than NMDAR-only patients. Outcomes of infants with HSE appear to primarily reflect sequelae from HSE.

Cognitive processing speed in pediatric-onset multiple sclerosis: Baseline characteristics of impairment and prediction of decline.

BACKGROUND: Cognitive impairment occurs in approximately one-third of pediatric-onset multiple sclerosis (POMS) patients. The Symbol Digit Modalities Test (SDMT), a widely used cognitive screen in adults, has yet to be incorporated early into the standard care of POMS. OBJECTIVE: To screen for cognitive impairment early in the course of POMS and analyze predictive factors. METHODS: Of the 955 POMS or clinically isolated syndrome (CIS) patients prospectively assessed from March 2014 to July 2018, 500 POMS and 116 CIS patients met inclusion criteria (disease onset before the age of 18, one or more SDMTs, and 8 years or older at the time of testing). Those with relapse were analyzed separately from those who were relapse-free. RESULTS: At initial assessment, the mean (interquartile range (IQR)) age at symptom onset was 13.5 years (12.0, 15.9) and the mean (±SD) disease duration was 3.0 ± 2.9 years. Impaired processing speed occurred in 23.4% of POMS and in 16.4% of CIS. On serial testing (n = 383, mean follow-up: 1.8 years), 14.1% had clinically meaningful decline predicted by older age of multiple sclerosis (MS) onset and male gender. Disease relapse or steroid use led to transient worsening on the SDMT. CONCLUSION: Early in the disease, some POMS and CIS patients are at risk for cognitive impairment and subsequent decline.

Pediatric multiple sclerosis: current perspectives on health behaviors.

PURPOSE: Pediatric-onset multiple sclerosis (POMS) accounts for ~5% of all multiple sclerosis cases, and has a prevalence of ~10,000 children in the USA. POMS is associated with a higher relapse rate, and results in irreversible disability on average 10 years earlier than adult-onset multiple sclerosis. Other manifestations of POMS include mental and physical fatigue, cognitive impairment, and depression. We believe that the health behaviors of physical activity, diet, and sleep may have potential benefits in POMS, and present a scoping review of the existing literature. METHODS: We identified papers by searching three electronic databases (PubMed, GoogleScholar, and CINAHL). Search terms included: pediatric multiple sclerosis OR pediatric onset multiple sclerosis OR POMS AND health behavior OR physical activity OR sleep OR diet OR nutrition OR obesity. Papers were included in this review if they were published in English, referenced nutrition, diet, obesity, sleep, exercise, or physical activity, and included pediatric-onset multiple sclerosis as a primary population. RESULTS: Twenty papers were identified via the literature search that addressed health-promoting behaviors in POMS, and 11, 8, and 3 papers focused on diet, activity, and sleep, respectively. Health-promoting behaviors were associated with markers of disease burden in POMS. Physical activity participation was associated with reduced relapse rate, disease burden, and sleep/rest fatigue symptoms. Nutritional factors, particularly vitamin D intake, may be associated with relapse rate. Obesity has been associated with increased risk of developing POMS. POMS is associated with better sleep hygiene, and this may benefit fatigue and quality of life. DISCUSSION: Participation in health behaviors, particularly physical activity, diet, and sleep, may have benefits for POMS. Nevertheless, there are currently no interventions targeting promotion of these behaviors and examining the benefits of managing the primary and secondary manifestations of POMS.

Dietary factors and pediatric multiple sclerosis: A case-control study.

BACKGROUND: The role of diet in multiple sclerosis (MS) is largely uncharacterized, particularly as it pertains to pediatric-onset disease. OBJECTIVE: To determine the association between dietary factors and MS in children. METHODS: Pediatric MS patients and controls were recruited from 16 US centers (MS or clinically isolated syndrome onset before age 18, <4 years from symptom onset and at least 2 silent lesions on magnetic resonance imaging). The validated Block Kids Food Screener questionnaire was administered 2011-2016. Chi-squared test compared categorical variables, Kruskal-Wallis test compared continuous variables, and multivariable logistic regression analysis was performed. RESULTS: In total, 312 cases and 456 controls were included (mean ages 15.1 and 14.4 years). In unadjusted analyses, there was no difference in intake of fats, proteins, carbohydrates, sugars, fruits, or vegetables. Dietary iron was lower in cases ( p = 0.04), and cases were more likely to consume below recommended guidelines of iron (77.2% of cases vs 62.9% of controls, p < 0.001). In multivariable analysis, iron consumption below recommended guidelines was associated with MS (odds ratio = 1.80, p < 0.01). CONCLUSION: Pediatric MS cases may be less likely to consume sufficient iron compared to controls, and this warrants broader study to characterize a temporal relationship. No other significant difference in intake of most dietary factors was found.

T cell cytokine signatures: Biomarkers in pediatric multiple sclerosis.

Although multiple sclerosis is predominantly regarded as a disease of young adulthood, up to 5% of MS patients are diagnosed prior to age eighteen. The predominant form of MS is relapsing-remitting characterized by exacerbations of symptoms followed by periods of remission. The majority of disease modifying drugs target T cell proliferation or block migration into the central nervous system. Although these treatments reduce relapses, disease progression still occurs, warranting therapeutic strategies that protect the CNS. Biomarkers to indicate relapses would facilitate a personalized approach for add-on therapies that protect the CNS. A multiplex cytokine bead array was performed to detect T cell associated cytokines in sera from patients 6-20years of age with pediatric onset MS clinically diagnosed in relapse or remission compared to healthy control patients. Of the 25 cytokines evaluated, 17 were increased in patients clinically diagnosed in relapse compared to sera from control patients in contrast to only 9 cytokines in the clinically diagnosed remission group. Furthermore, a linear regression analysis of cytokine levels in the remission population showed 12 cytokines to be statistically elevated as a function of disease duration, with no effect observed in the relapse population. To further explore this concept, we used a multivariable stepwise discriminate analysis and found that the following four cytokines (IL-10, IL-21, IL-23, and IL-27) are not only a significant predictor for MS, but have important predictive value in determining a relapse. Since IL-10 and IL-27 are considered anti-inflammatory and IL-21 and IL-23 are pro-inflammatory, ratios of these cytokines were evaluated using a Duncan's multiple range test. Of the six possible combinations, increased ratios of IL-10:IL-21, IL-10:IL-23, and IL-10:IL-27 were significant suggesting levels of IL-10 to be a driving force in predicting a relapse.

BAFF/APRIL system in pediatric OMS: relation to severity, neuroinflammation, and immunotherapy.

BACKGROUND: B-cell dysregulation has been implicated but not fully characterized in pediatric opsoclonus-myoclonus syndrome (OMS), a neuroblastoma-associated neuroinflammatory disorder. OBJECTIVE: To assess the role of B-cell activating factor (BAFF) and a proliferation-inducing ligand (APRIL), two critical B cell-modulating cytokines, as potential biomarkers of disease activity and treatment biomarkers in OMS. METHODS: Soluble BAFF and APRIL were measured in cerebrospinal fluid (CSF) and serum by ELISA in 433 children (296 OMS, 109 controls, 28 other inflammatory neurological disorders (OIND)). BAFF-R receptors on circulating CD19+ B cells were measured by flow cytometry. A blinded scorer rated motor severity on the OMS Evaluation Scale. Immunotherapies were evaluated cross-sectionally and longitudinally. RESULTS: The mean CSF BAFF concentration, which was elevated in untreated OMS and OIND, correlated with OMS severity category (P = 0.006), and reduction by adrenocorticotropic hormone or corticotropin (ACTH) (-61%) or corticosteroids (-38%) was seen at each level of severity. In contrast, CSF APRIL was normal in OMS and OIND and unaffected by immunotherapy. When the entire OMS dataset was dichotomized into 'high' versus 'normal' CSF BAFF concentration, the phenotype of the high group included greater motor severity and number of CSF oligoclonal bands, and a higher concentration of inflammatory chemokines CXCL13 and CXCL10 in CSF and CXCL9 and CCL21 in serum. Serum APRIL was 6.7-fold higher in the intravenous immunoglobulins (IVIg) group, whereas serum BAFF was 2.6-fold higher in the rituximab group. The frequency of B cell BAFF-R expression was similar in untreated and treated OMS. Longitudinal studies of CSF BAFF revealed a significant decline in ACTH-treated patients (with or without rituximab) (P < 0.0001). Longitudinal studies of serum APRIL showed a 2.9-fold increase after 1 to 2 g/kg IVIg monotherapy (P = 0.0003). CONCLUSIONS: Striking distinctions in BAFF/APRIL signaling were found. OMS displayed heterogeneity in CSF BAFF expression, which met many but not all criteria as a potential biomarker of disease activity. We speculate that CSF BAFF may have more utility in a biomarker panel than as a stand-alone biomarker, and that the selective upregulation of both serum APRIL by IVIg and BAFF by rituximab, as well as downregulation of CSF BAFF by ACTH/steroids, may have utility as treatment biomarkers.

Key role of CXCL13/CXCR5 axis for cerebrospinal fluid B cell recruitment in pediatric OMS.

To study aberrant B cell trafficking into the CSF in opsoclonus-myoclonus syndrome (OMS), chemoattractants CXCL13 and CXCL12, and B cell frequency and CXCR5 expression, were evaluated. CSF CXCL13 concentration and the CSF/serum ratio were higher in untreated OMS than controls, related directly to OMS severity and inversely to OMS duration, and correlated with CSF B cell frequency and oligoclonal bands. CXCL12 showed the opposite pattern. Selective accumulation of CXCR5+ memory B cells in CSF was found. In ACTH-treated OMS, CXCL13, but not CXCL12, was lower. These data implicate the chemokine/chemoreceptor pair CXCL13/CXR5 in B cell recruitment to the CNS in OMS. CXCL13 and CXCL12 may serve as reciprocal biomarkers of disease activity, but CXCL13 also had utility as a treatment biomarker.

Age-dependent B cell autoimmunity to a myelin surface antigen in pediatric multiple sclerosis.

Multiple sclerosis (MS) typically manifests in early to mid adulthood, but there is increasing recognition of pediatric-onset MS, aided by improvements in imaging techniques. The immunological mechanisms of disease are largely unexplored in pediatric-onset MS, in part because studies have historically focused on adult-onset disease. We investigated autoantibodies to myelin surface Ags in a large cohort of pediatric MS cases by flow cytometric labeling of transfectants that expressed different myelin proteins. Although Abs to native myelin oligodendrocyte glycoprotein (MOG) were uncommon among adult-onset patients, a subset of pediatric patients had serum Abs that brightly labeled the MOG transfectant. Abs to two other myelin surface Ags were largely absent. Affinity purification of MOG Abs as well as competition of binding with soluble MOG documented their binding specificity. Such affinity purified Abs labeled myelin and glial cells in human CNS white matter as well as myelinated axons in gray matter. The prevalence of such autoantibodies was highest among patients with a very early onset of MS: 38.7% of patients less than 10 years of age at disease onset had MOG Abs, compared with 14.7% of patients in the 10- to 18-year age group. B cell autoimmunity to this myelin surface Ag is therefore most common in patients with a very early onset of MS.

Intravenous thrombolysis followed by intra-arterial thrombolysis and mechanical thrombectomy for the treatment of pediatric ischemic stroke.

Experience with systemic or selective local administration of thrombolytic agents in pediatric ischemic stroke is limited to sporadic case reports, since patients of age less than 18 years were systematically excluded from randomised controlled trials. We report a case of childhood IS attributable to the terminal internal carotid artery occlusion that was treated successfully with mechanical thrombectomy which followed unsuccessful attempts to recanalize the artery with intravenous and intra-arterial thrombolytics. Combined systemic and intra-arterial thrombolysis followed by mechanical thrombectomy can be feasible and may be considered as means of achieving reperfusion in pediatric ischemic stroke patients with persisting arterial occlusion.

Adult T-cell leukemia/lymphoma in an adolescent presenting with skin lesions.

Adult T-cell leukemia/lymphoma is a T-cell malignancy caused by the human T-cell lymphotropic virus-I. Adult T-cell leukemia/lymphoma is primarily a disease of adults due to the long latency period between initial infection and development of leukemia. We present a case of acute adult T-cell leukemia/lymphoma in an adolescent. Skin lesions had appeared 3 years earlier and were the initial sign of human T-cell lymphotropic virus-I infection and T-cell malignancy. Her disease failed to respond to both intensive chemotherapy and antiviral therapy. Cutaneous lesions are sometimes the initial sign of adult T-cell leukemia/lymphoma and early recognition is imperative.

Differential activation of c-fos and caspase-3 in hippocampal neuron subpopulations following neonatal hypoxia-ischemia.

Neonatal hypoxia-ischemia (HI) induces immediate early gene (IEG) c-fos expression as well as neuron death. The precise role of IEGs in neonatal HI is unclear. We investigated the temporal and spatial patterns of c-Fos expression in postnatal day 7 mice after unilateral carotid ligation and exposure to 8% oxygen. mRNA levels of c-fos quantitated by real-time polymerase chain reaction (PCR) increased nearly 40-fold (log 1.2 +/- 0.4) in the ipsilateral hippocampus 3 hr following neonatal HI, then returned to basal levels within 12 hr, although no change was observed in c-jun mRNA. Frozen coronal brain sections were stained with cresyl violet or used for immunohistochemical detection of c-Fos, cleaved caspase-3, glial fibrillary acidic protein (GFAP), and the mature neuron marker NeuN. c-Fos immunoreactivity increased throughout the injured hippocampus 3 hr after HI but became restricted to the CA2-3 subregion and the dentate gyrus (DG) at 6-12 hr and declined by 24 hr. In contrast, cleaved (activated) caspase-3 immunoreactivity was most abundant in the ipsilateral CA1 region at 3-6 hr after neonatal HI, then became more prominent in CA2-3 and DG. Double-labeling experiments showed c-Fos and cleaved caspase-3 immunoreactivity localized in spatially distinct neuron subpopulations. Prominent c-Fos immunoreactivity was observed in surviving CA2-3 and external granular DG neurons, and robust cleaved caspase-3 immunoreactivity was observed in pyknotic CA1, CA2-3, and subgranular DG neurons. The differential expression of c-Fos in HI-resistant hippocampal subpopulations vs. cleaved caspase-3 in dying neurons suggests a neuroprotective role for c-Fos expression in neonatal HI.

Selective involvement of BH3-only Bcl-2 family members Bim and Bad in neonatal hypoxia-ischemia.

Perinatal hypoxic-ischemic injury is a common cause of neurologic disability mediated in part by Bcl-2 family-regulated neuronal apoptosis. The Bcl-2 protein family consists of both pro- (e.g. Bax, Bad, Bid, Bim) and anti-apoptotic (e.g. Bcl-2, Bcl-X(L)) proteins that regulate mitochondrial outer membrane integrity, cytochrome c release and caspase activation. Previous studies have implicated Bax as an important mediator of neuronal death in several models of brain injury, including neonatal hypoxia-ischemia (HI). In this study, we assessed the roles of several members of the pro-apoptotic BH3 domain-only Bcl-2 sub-family in an in vivo mouse model of neonatal HI. Seven-day old control and gene-disrupted mice underwent unilateral left carotid ligation followed by 45 min exposure to 8% oxygen and the extent of brain injury was assessed 2 days later. Following HI, mice deficient in Bad or Bim exhibited reduced activated caspase-3 and glial fibrillary acidic protein immunostaining in their brains compared to similarly treated control animals. Measurement of hippocampal area showed decreased parenchymal loss in both Bad- and Bim-deficient mice versus control animals. In contrast, loss of Bid, another BH3-only protein, provided no protection from neonatal HI brain injury. These results indicate that Bad and Bim are selectively involved in neuron death following neonatal HI and may be targets for therapeutic intervention.

Bcl-2 family regulation of neuronal development and neurodegeneration.

Neuronal cell death is a key feature of both normal nervous system development and neuropathological conditions. The Bcl-2 family, via its regulation of both caspase-dependent and caspase-independent cell death pathways, is uniquely positioned to critically control neuronal cell survival. Targeted gene disruptions of specific bcl-2 family members and the generation of transgenic mice overexpressing anti- or pro-apoptotic Bcl-2 family members have confirmed the importance of the Bcl-2 family in the nervous system. Data from studies of human brain tissue and experimental animal models of neuropathological conditions support the hypothesis that the Bcl-2 family regulates cell death in the mature nervous system and suggest that pharmacological manipulation of Bcl-2 family action could prove beneficial in the treatment of human neurological conditions such as stroke and neurodegenerative diseases.

Combined tyramide signal amplification and quantum dots for sensitive and photostable immunofluorescence detection.

Conventional immunofluorescence detection of biologically relevant proteins and antigens in tissue sections is often limited by relatively weak signals that fade rapidly on illumination. We have developed an immunohistochemical protocol that combines the sensitivity of tyramide signal amplification with the photostability of quantum dots to overcome these limitations. This simple method provides a sensitive and stable fluorescence immunohistochemical alternative to standard chromogen detection.