VH2+ Antigen-Experienced B Cells in the Cerebrospinal Fluid Are Expanded and Enriched in Pediatric Anti-NMDA Receptor Encephalitis.

Pediatric and adult autoimmune encephalitis (AE) are often associated with Abs to the NR1 subunit of the N-methyl-d-aspartate (NMDA) receptor (NMDAR). Very little is known regarding the cerebrospinal fluid humoral immune profile and Ab genetics associated with pediatric anti-NMDAR-AE. Using a combination of cellular, molecular, and immunogenetics tools, we collected cerebrospinal fluid from pediatric subjects and generated 1) flow cytometry data to calculate the frequency of B cell subtypes in the cerebrospinal fluid of pediatric subjects with anti-NMDAR-AE and controls, 2) a panel of recombinant human Abs from a pediatric case of anti-NMDAR-AE that was refractory to treatment, and 3) a detailed analysis of the Ab genes that bound the NR1 subunit of the NMDAR. Ag-experienced B cells including memory cells, plasmablasts, and Ab-secreting cells were expanded in the pediatric anti-NMDAR-AE cohort, but not in the controls. These Ag-experienced B cells in the cerebrospinal fluid of a pediatric case of NMDAR-AE that was refractory to treatment had expanded use of variable H chain family 2 (VH2) genes with high somatic hypermutation that all bound to the NR1 subunit of the NMDAR. A CDR3 motif was identified in this refractory case that likely drove early stage activation and expansion of naive B cells to Ab-secreting cells, facilitating autoimmunity associated with pediatric anti-NMDAR-AE through the production of Abs that bind NR1. These features of humoral immune responses in the cerebrospinal fluid of pediatric anti-NMDAR-AE patients may be relevant for clinical diagnosis and treatment.

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.

Acute flaccid myelitis: long-term outcomes recorded in the CAPTURE study compared with paediatric transverse myelitis.

BACKGROUND: Since 2014, the USA has documented three outbreaks of acute flaccid myelitis (AFM). Unique features and treatment responses of this myelitis variant have not been prospectively studied. This study prospectively measured outcomes in paediatric myelitis patients relative to treatments. METHODS: This was a prospective, multicentre, non-randomised, observational cohort study. The study duration was 5 years and the length of follow-up was 1 year. This study collected data from children and families in North America. Patients were enrolled at academic centres with expertise in myelitis or online via a web portal. Paediatric patients diagnosed with myelitis were eligible for enrolment in the study within 6 months of onset of symptoms. Patients were characterised as transverse myelitis (TM) or the AFM variant based on clinical and radiographic findings. RESULTS: The cohort of 90 patients included patients with AFM and TM. Of the 51 patients with AFM there was evidence of two clinically relevant patterns. This included a grey matter restricted form of AFM and a cohort with concomitant white matter that could explain lower extremity motor deficits in patients with lesions restricted to the cervical spine. The improvement in deficits with the use of corticosteroids was similar to what was observed in the TM cohort (p=0.97). CONCLUSIONS: Clinicians should consider on a case by case basis the approach to therapy for AFM patients. Prospective controlled studies of long-term outcomes would be useful in this growing patient population.

Increased prevalence of potential right-to-left shunting in children with sickle cell anaemia and stroke.

'Paradoxical' embolization via intracardiac or intrapulmonary right-to-left shunts (RLS) is an established cause of stroke. Hypercoagulable states and increased right heart pressure, which both occur in sickle cell anaemia (SCA), predispose to paradoxical embolization. We hypothesized that children with SCA and overt stroke (SCA + stroke) have an increased prevalence of potential RLS. We performed contrasted transthoracic echocardiograms on 147 children (aged 2-19 years) with SCA + stroke) mean age 12·7 ± 4·8 years, 54·4% male) and a control group without SCA or stroke (n = 123; mean age 12·1 ± 4·9 years, 53·3% male). RLS was defined as any potential RLS detected by any method, including intrapulmonary shunting. Echocardiograms were masked and adjudicated centrally. The prevalence of potential RLS was significantly higher in the SCA+stroke group than controls (45·6% vs. 23·6%, P < 0·001). The odds ratio for potential RLS in the SCA + stroke group was 2·7 (95% confidence interval: 1·6-4·6) vs controls. In post hoc analyses, the SCA + stroke group had a higher prevalence of intrapulmonary (23·8% vs. 5·7%, P < 0·001) but not intracardiac shunting (21·8% vs. 18·7%, P = 0·533). SCA patients with potential RLS were more likely to report headache at stroke onset than those without. Intrapulmonary and intracardiac shunting may be an overlooked, independent and potentially modifiable risk factor for stroke in SCA.

Out-of-pocket costs for childhood stroke: the impact of chronic illness on parents' pocketbooks.

OBJECTIVE: Direct costs for children who had stroke are similar to those for adults. There is no information regarding the out-of-pocket costs families encounter. We described the out-of-pocket costs families encountered in the first year after a child's ischemic stroke. METHODS: Twenty-two subjects were prospectively recruited at four centers in the United States and Canada in 2008 and 2009 as part of the "Validation of the Pediatric NIH Stroke Scale" study; families' indirect costs were tracked for 1 year. Every 3 months, parents reported hours they did not work, nonreimbursed costs for medical visits or other health care, and mileage. They provided estimates of annual income. We calculated total out-of-pocket costs in US dollars and reported costs as a proportion of annual income. RESULTS: Total median out-of-pocket cost for the year after an ischemic stroke was $4354 (range, $0-$28,666; interquartile range, $1008-$8245). Out-of-pocket costs were greatest in the first 3 months after the incident stroke, with the largest proportion because of lost wages, followed by transportation, and nonreimbursed health care. For the entire year, median costs represented 6.8% (range, 0%-81.9%; interquartile range, 2.7%-17.2%) of annual income. CONCLUSIONS: Out-of-pocket expenses are significant after a child's ischemic stroke. The median costs are noteworthy provided that the median American household had cash savings of $3650 at the time of the study. These results with previous reports of direct costs provide a more complete view of the overall costs to families and society. Childhood stroke creates an under-recognized cost to society because of decreased parental productivity.

Brainstem strokes in children: an 11-year series from a tertiary pediatric center.

METHODS: Potential clinical barriers to making a timely diagnosis of pediatric brainstem stroke and pitfalls of noninvasive vascular imaging are presented. METHODS: An institutional review board-approved institutional database query from 2001-2012 yielded 15 patients with brainstem strokes. Medical records were reviewed for symptoms, stroke severity using the Pediatric National Institutes of Health Stroke Scale, and outcomes using the Pediatric Stroke Outcome Measure. Magnetic resonance angiography was compared with digital subtraction angiography. RESULTS: There were 10 boys and five girls; 9 months to 17 years of age (mean 7.83 years). Symptoms were headaches (eight); visual problems (eight), seizure-like activity (seven), motor deficits (six), and decreased level of consciousness in four. Time since last seen well was 12 hours to 5 days. Pediatric National Institutes of Health Stroke Scale was 1-34; <10 in eight; 3 in 1, 10-20 in two, and >20 in four. Strokes were pontine in 13/15 and involved >50% of the pons in six and <50% in seven; 2/15 had medullary strokes. Magnetic resonance angiography showed basilar artery occlusion in 8/13 patients and vertebral artery dissection in two. Digital subtraction angiography done within 9-36 hours of magnetic resonance angiography in 10/15 patients confirmed the basilar artery occlusion seen by magnetic resonance angiography and showed vertebral artery dissection in four patients. Patients were systemically anticoagulated without hemorrhagic complications. One patient died. Pediatric Stroke Outcome Measures at 2-36 months is 0-5.0/10 (mean 1.25). CONCLUSIONS: Vague symptoms contributed to delays in diagnosis. Magnetic resonance angiography was equivalent to digital subtraction angiography for basilar artery occlusion but not for vertebral artery dissection. Even with basilar artery occlusion and high stroke scales, outcome was good when systemic anticoagulation was started promptly.

Acute silent cerebral ischemia and infarction during acute anemia in children with and without sickle cell disease.

We hypothesized that the silent cerebral infarcts (SCI), which affect up to 40% of children with sickle cell disease (SCD), could occur in the setting of acute anemic events. In a prospective observational study of children with and without SCD hospitalized for an illness associated with acute anemia, we identified acute silent cerebral ischemic events (ASCIE) in 4 (18.2%) of 22 with SCD and in 2 (6.7%) of 30 without SCD, using diffusion-weighted magnetic resonance imaging. Children with ASCIE had lower hemoglobin concentration than those without (median 3.1 vs 4.4 g/dL, P = .003). The unique temporal features of stroke on diffusion-weighted magnetic resonance imaging permit estimation of incidence rates for ASCIE of 421 (95% confidence interval, 155-920) per 100 patient-years during acute anemic events for all patients. For children with SCD, the estimated incidence was 663 (95% confidence interval, 182-1707) which is much higher than previously reported. Acute anemic events are common in children with SCD and prevalence could partially account for the high SCI. Some ASCIE (1 of 4 in our study) may be reversible. Alterations in management may be warranted for children with severe anemia to identify unrecognized ischemic brain injury that may have permanent neurocognitive sequelae.

Prolonged direct catheter thrombolysis of cerebral venous sinus thrombosis in children: a case series.

Cerebral venous sinus thrombosis is a rare condition with potentially devastating neurologic outcome--death and severe disability are common in advanced cases. In adults, protocols for mechanical clot disruption and direct thrombolysis are established; no guidance exists for children. We present our experience of 6 children with cerebral venous sinus thrombosis and ominous clinical progression. We found that effective thrombolysis required substantially longer infusion, more rounds of mechanical disruption, and higher doses of thrombolytics than are commonly practiced. Despite pervasive thrombosis, prethrombolysis hemorrhage, coma, and other predictors of death and disability, our patients survived and 4 of 6 had no functional deficits. One patient had moderate, and one had severe deficits. We report these cases to illustrate that hemorrhage may not be a contraindication to thrombolysis for cerebral venous sinus thrombosis, that prolonged infusion may be required to restore perfusion, and that good neurologic outcomes can be achieved despite dire clinical presentations and extensive sinus thrombosis.