Mark P. Nespeca

Acute disseminated encephalomyelitis in childhood: epidemiologic, clinical and laboratory features.

Background: Acute disseminated encephalomyelitis (ADEM) is a central nervous system demyelinating disease that usually follows an apparently benign infection in otherwise healthy young persons. The epidemiology, infectious antecedents and pathogenesis of ADEM are poorly characterized, and some ADEM patients are subsequently diagnosed with multiple sclerosis (MS). Methods: We retrospectively (1991–1998) and prospectively (1998–2000) studied all persons aged < 20 years diagnosed with ADEM from the 3 principal pediatric hospitals in San Diego County, CA, during 1991–2000. Acute neurologic abnormalities and imaging evidence of demyelination were required for study inclusion. Epidemiologic variables, risk factors, clinical course, laboratory and radiographic findings, neuropathology and treatment data were analyzed. Interleukin (IL)-12, interferon-γ(IFN-γ) and IL-10 were assayed in blinded manner on cerebrospinal fluid (CSF) obtained prospectively from a subset of ADEM cases and compared with CSF from patients with enteroviral (EV) meningoencephalitis confirmed by polymerase chain reaction (PCR) and controls without pleocytosis. Results: Data were analyzed on 42 children and adolescents diagnosed with ADEM during 1991–2000, and CSF IL-12, IFN-γ and IL-10 levels were compared among ADEM (n = 14), EV meningoencephalitis (n = 14) and controls without pleocytosis (n = 28). Overall incidence of ADEM was 0.4/100,000/year; incidence quadrupled during 1998–2000 compared with earlier years. No gender, age stratum, ethnic group or geographic area was disproportionately affected. A total of 4 (9.5%) patients initially diagnosed with ADEM were subsequently diagnosed with MS after multiple episodes of demyelination. Although most children eventually recovered, 2 died, including 1 of the 3 ultimately diagnosed with MS. Magnetic resonance imaging was required for diagnosis among 74% of patients; computerized tomography findings were usually normal. Patients with EV had significantly higher mean CSF IFN-γ (P = 0.005) and IL-10 (P = 0.05) than patients with ADEM and controls without CSF pleocytosis. CSF from ADEM patients had CSF cytokine values statistically similar to those of 3 patients subsequently diagnosed with MS. Conclusions: ADEM is a potentially severe demyelinating disorder likely to be increasingly diagnosed as more magnetic resonance imaging studies are performed on patients with acute encephalopathy. Further characterization of the central nervous system inflammatory response will be needed to understand ADEM pathogenesis, to improve diagnostic and treatment strategies and to distinguish ADEM from MS.

Efficacy and Tolerability of the New Antiepileptic Drugs, II: Treatment of Refractory Epilepsy. Report of the TTA and QSS Subcommittees of the American Academy of Neurology and the American Epilepsy Society

Summary:  Purpose: To assess the evidence demonstrating efficacy, tolerability, and safety of seven new antiepileptic drugs [AEDs; gabapentin (GBP), lamotrigine (LTG), topiramate (TPM), tiagabine (TGB), oxcarbazepine (OXC), levetiracetam (LEV), and zonisamide (ZNS), reviewed in the order in which these agents received approval by the U.S. Food and Drug Administration] in the treatment of children and adults with newly diagnosed partial and generalized epilepsies.

Paroxysmal kinesigenic dyskinesia and infantile convulsions: Clinical and linkage studies

Objective: To clinically characterize affected individuals in families with paroxysmal kinesigenic dyskinesia (PKD), examine the association with infantile convulsions, and confirm linkage to a pericentromeric chromosome 16 locus. Background: PKD is characterized by frequent, recurrent attacks of involuntary movement or posturing in response to sudden movement, stress, or excitement. Recently, an autosomal dominant PKD locus on chromosome 16 was identified. Methods: The authors studied 11 previously unreported families of diverse ethnic background with PKD with or without infantile convulsions and performed linkage analysis with markers spanning the chromosome 16 locus. Detailed clinical questionnaires and interviews were conducted with affected and unaffected family members. Results: Clinical characterization and sampling of 95 individuals in 11 families revealed 44 individuals with paroxysmal dyskinesia, infantile convulsions, or both. Infantile convulsions were surprisingly common, occurring in 9 of 11 families. In only two individuals did generalized seizures occur in later childhood or adulthood. The authors defined a 26-cM region using linkage data in 11 families (maximum lod score 6.63 at θ = 0). Affected individuals in one family showed no evidence for a shared haplotype in this region, implying locus heterogeneity. Conclusions: Identification and characterization of the PKD/infantile convulsions gene will provide new insight into the pathophysiology of this disorder, which spans the phenotypic spectrum between epilepsy and movement disorder.

Epilepsy in Angelman syndrome: A questionnaire-based assessment of the natural history and current treatment options

Purpose:  Angelman syndrome (AS) commonly presents with epilepsy (>80%). The goal of this study was to examine the natural history and various treatments of epilepsy in AS in a large population.

Angelman Syndrome: Mutations Influence Features in Early Childhood

Angelman syndrome (AS) is a neurodevelopmental disorder caused by a lack of expression of the maternal copy of UBE3A. Although the “classic” features of AS are well described, few large‐scale studies have delineated the clinical features in AS. We present baseline data from 92 children with a molecular diagnosis of AS between 5 and 60 months old who are enrolled in the National Institutes of Health Rare Diseases Clinical Research Network Angelman Syndrome Natural History Study from January 2006 to March 2008. Seventy‐four percent of participants had deletions, 14% had either uniparental disomy (UPD) or imprinting defects, and 12% had UBE3A mutations. Participants with UPD/imprinting defects were heavier (P = 0.0002), while those with deletions were lighter, than the general population (P < 0.0001). Twenty out of 92 participants were underweight, all of whom had deletions or UBE3A mutations. Eight out of 92 participants (6/13 (46%) with UPD/imprinting defects and 2/11 (18%) with UBE3A mutations) were obese. Seventy‐four out of 92 participants (80%) had absolute or relative microcephaly. No participant was macrocephalic. The most common behavioral findings were mouthing behavior (95%), short attention span (92%), ataxic or broad‐based gait (88%), history of sleep difficulties (80%), and fascination with water (75%). Frequent, easily provoked laughter was observed in 60%. Clinical seizures were reported in 65% of participants but all electroencephalograms (EEGs) were abnormal. We conclude that the most characteristic feature of AS is the neurobehavioral phenotype, but specific EEG findings are highly sensitive for AS. Obesity is common among those with UPD/imprinting defects.

Analysis of EEG patterns and genotypes in patients with Angelman syndrome

We prospectively analyzed EEGs from participants in the ongoing NIH Rare Diseases Clinical Research Network Angelman Syndrome Natural History Study. Of the one-hundred-sixty enrolled patients (2006-2010), 115 had complete data (58 boys, median age 3.6 years). Distinct EEG findings were intermittent rhythmic delta waves (83.5%), interictal epileptiform discharges (74.2%), intermittent rhythmic theta waves (43.5%), and posterior rhythm slowing (43.5%). Centro-occipital and centro-temporal delta waves decreased with age (p=0.01, p=0.03). There were no specific correlations between EEG patterns and genotypes. A classification tree allowed the prediction of deletions class-1 (5.9 Mb) in patients with intermittent theta waves in <50% of EEG and interictal epileptiform abnormalities; UPD, UBE3A mutation or imprinting defects in patients with intermittent theta in <50% of EEG without interictal epileptiform abnormalities; deletions class-2 (5.0 Mb) in patients with >50% theta and normal posterior rhythm; atypical deletions in patients with >50% theta but abnormal posterior rhythm. EEG patterns are important biomarkers in Angelman syndrome and may suggest the underlying genetic etiology.

Double-blind therapeutic trial in Angelman syndrome using betaine and folic acid.

Angelman syndrome (AS) is caused by reduced or absent expression of the maternally inherited ubiquitin protein ligase 3A gene (UBE3A), which maps to chromosome 15q11–q13. UBE3A is subject to genomic imprinting in neurons in most regions of the brain. Expression of UBE3A from the maternal chromosome is essential to prevent AS, because the paternally inherited gene is not expressed, probably mediated by antisense UBE3A RNA. We hypothesized that increasing methylation might reduce expression of the antisense UBE3A RNA, thereby increasing UBE3A expression from the paternal gene and ameliorating the clinical phenotype. We conducted a trial using two dietary supplements, betaine and folic acid to promote global levels of methylation and attempt to activate the paternally inherited UBE3A gene. We performed a number of investigations at regular intervals including general clinical and developmental evaluations, biochemical determinations on blood and urine, and electroencephalographic studies. We report herein the data on 48 children with AS who were enrolled in a double‐blind placebo‐controlled protocol using betaine and folic acid for 1 year. There were no statistically significant changes between treated and untreated children; however, in a small subset of patients we observed some positive trends.

Pediatric Acute Hemorrhagic Leukoencephalitis: Report of a Surviving Patient and Review

Acute hemorrhagic leukoencephalitis (AHLE) is a rare, fulminant CNS demyelinating condition usually diagnosed at autopsy. We report the clinical, laboratory, radiographic, and pathologic features of the first nonfatal case of pediatric AHLE confirmed by brain biopsy. Pathologic diagnosis of this condition may be critical to exclude more-common processes and to expedite the decision to administer high-dose corticosteroid therapy, which is potentially lifesaving.

A Therapeutic Trial of Pro-methylation Dietary Supplements in Angelman Syndrome

Angelman syndrome (AS) is due to deficient ubiquitin protein ligase 3a, the gene for which (UBE3A) maps to chromosome 15q11–q13 and is imprinted such that only the maternally inherited gene is expressed. The paternally inherited UBE3A gene is silenced, a process mediated by an antisense transcript. We conducted a trial using methylation‐promoting dietary supplements (betaine, metafolin, creatine, and vitamin B12) in an attempt to reduce antisense transcript production, increase UBE3A expression, and ameliorate the symptoms of AS. Neuropsychological evaluations, biochemical testing, and assessment of DNA methylation were performed at the beginning and at the end of 1 year of supplementation. The primary outcome measures were changes in the level of developmental function (cognitive, motor, and language) as measured using standardized instruments. The secondary outcomes measures were changes in biochemical parameters and global DNA methylation. These data were compared to those of a control group from a previous randomized double‐blind trial using folic acid and betaine. There were no statistically significant changes in the developmental performance of children treated with supplements. There were no unexpected changes in biochemical parameters and no change in site‐specific DNA methylation when comparing samples from before and after treatment. There were 10 adverse events that resulted in study withdrawal of 7 participants (worsening of seizures, onset, or worsening of sleep problems, constipation, and anorexia). Supplementation with betaine, metafolin, creatine, and vitamin B12 appears safe but ineffective in decreasing the severity of AS.

Prediction of neurologic sequelae in childhood tuberculous meningitis: A review of 20 cases and proposal of a novel scoring system

Background: Despite effective antituberculous medications, the mortality and morbidity remain high in children with tuberculous meningitis (TBM). The traditional clinical staging for TBM developed by Lincoln et al in 1960 has been widely used to predict long term neurologic sequelae (NS). In the current era of critical care medicine and corticosteroid therapy, a new scoring system is needed to predict NS more accurately in children with TBM. Methods: We reviewed all available cases of TBM in San Diego, CA, during 1991–2001 retrospectively, and we developed a novel scoring system to predict NS in children with TBM. We assessed a tuberculous meningitis acute neurologic (TBAN) score at day 0 and on day 3 of hospitalization, to compare children who subsequently developed severe NS with those who did not. Results: Among 20 children with TBM, 7 children developed severe NS and 1 child died during hospitalization. The TBAN score was higher on day 0 in those with severe NS (5.5 versus 2.0, P = 0.09), and the difference became statistically significant by day 3 of hospitalization (5.5 versus 0.0, P = 0.02). Sensitivity and specificity of the TBAN score (≥4) on day 0 (75 and 92%) and day 3 (88 and 100%) to predict severe NS were superior to the traditional clinical staging system on day 0 (63 and 58%). Conclusions: The TBAN score is an objective marker for predicting severe NS in children with TBM.