Effects of valproic acid on organic acid metabolism in children: a metabolic profiling study.

Young children are at increased risk for valproic acid (VPA) hepatotoxicity. Urinary organic acid profiles, as a surrogate of mitochondrial function, were obtained in children 1.9 to 17.3 years of age (n = 52) who were undergoing treatment with VPA for seizure disorders. Age-matched patients receiving treatment with carbamazepine (CBZ; n = 50) and healthy children not undergoing treatment (n = 22) served as controls. Age-related changes in organic acid profiles were observed in all three groups. Although the untreated and CBZ control groups were indistinguishable from each other with respect to the principal-component analysis (PCA) score plots of the subjects, a distinct boundary was apparent between the VPA and each of the control groups. Interindividual variability was observed in the VPA-induced alterations in endogenous pathways corresponding to branched-chain amino acid metabolism and oxidative stress. The data suggest that more detailed metabolomic analysis may provide novel insights into biological mechanisms and predictive biomarkers for children at highest risk for serious toxicity.

Infant botulism in the age of botulism immune globulin.

Infant botulism causes acute bulbar dysfunction, weakness, and respiratory failure in infants living in endemic regions of the United States. Until Food and Drug Administration approval of botulism immune globulin (BIG) in October 2003, management of infant botulism had changed little since the 1970s. Currently, IV therapy with BIG is advised to shorten the duration and diminish the potential complications of the disorder. This review describes two decades of experience with infant botulism and provides a contemporary perspective on the role and benefit of BIG.

Specialty care by child neurologists: a workforce analysis.

OBJECTIVE: To provide a current profile of the practice of child neurology, report the attitudes of child neurologists toward practice, and analyze the supply of child neurologists. METHODS: In March 2002, a questionnaire was sent to all active members of the Child Neurology Society (n = 1,051) and to nonmember physicians under age 70 who listed child neurology as a primary or secondary specialty on the American Medical Association Masterfile (n = 433). The response rate was 65%. Eligibility criteria were then applied to arrive at the sample of main specialty in child neurology working at least 20 hours per week in patient care. The final population was 604. Differences in practice characteristics were tested by practice type, and the number of full-time patient care child neurologists was projected by extrapolating to nonrespondents. RESULTS: There are 904 full-time patient care child neurologists in the United States and 1.27 per 100,000 children. Career satisfaction is 90%, yet no growth in the supply is projected over the next 20 years. Wait times for an appointment average 53 and 44 days for a new and return visit, with longer wait times in university settings. Average annual income is 151,000 dollars. CONCLUSION: The practice characteristics of child neurologists suggest that the specialty will be challenged to meet patient demands.

Human cytomegalovirus a sequence and UL144 variability in strains from infected children.

Human cytomegalovirus (HCMV) displays genetic polymorphisms. This variability may contribute to strain-specific tissue tropism and disease expression in HCMV-infected humans. To determine strain variability in a sequence and UL144 gene regions, 51 low-passage isolates from 44 HCMV-infected children were studied. Isolates were obtained from 28 healthy children attending child care centers in Iowa and from 16 congenitally infected infants born in Texas. Isolates demonstrated substantial nucleotide variation in each gene region. Phylogenetic analysis of a sequence variability allowed 39 isolates to be grouped into six clades. The largest clade contained 16 isolates with > or = 95% nucleotide homology. Forty-eight of the 49 HCMV isolates yielding UL144 amplicons was grouped according to the clades described a few years ago [Lurain et al. (1999) Journal of Virology 73:10040-10050]. No linkage was observed among a sequence, UL144, and glycoprotein B (gB; UL55) polymorphisms. Four Texas and 11 Iowa isolates displayed > or = 95% sequence homology for a sequence and UL144 regions and possessed identical gB genotypes. No relationship between UL144 polymorphisms and outcome of congenital HCMV infection was observed. These data indicate that HCMV strains circulating among young children have UL144 polymorphisms similar to those of HCMV strains excreted by immunocompromised adults. Identification of conserved nucleotide sequences among Iowa and Texas children suggests genetic stability and biologic importance of these gene regions.

Characterization of human cytomegalovirus strains by analysis of short tandem repeat polymorphisms.

Human cytomegalovirus (HCMV) strains display genetic polymorphisms, and these polymorphisms can be analyzed to study viral transmission and pathogenesis. Recently, short tandem repeat (STR) length polymorphisms have been identified in the HCMV genome. We assessed the utility of STRs in characterizing HCMV strains and found that a multiplexed PCR assay using primers based upon these STRs accurately maps HCMV strains. Using primers for 10 microsatellite regions, the STR profiles of 44 wild-type and 2 laboratory strains of HCMV were characterized. The results of STR analysis were compared with those for strain characterization using nucleotide sequencing and restriction fragment length polymorphism analysis. In each instance, STR analysis accurately and specifically identified strains that were indistinguishable or distinct by conventional molecular analysis. Analysis of short tandem repeats also detected polymorphisms that supported simultaneous excretion of two HCMV strains. These results indicate that STR analysis allows rapid, precise molecular characterization of HCMV strains.

Early predictors of neurodevelopmental outcome in symptomatic congenital cytomegalovirus infection.

OBJECTIVE: To determine the ability of neonatal clinical, audiologic, and computed tomography (CT) findings to predict long-term neurodevelopmental outcome in children with symptomatic congenital cytomegalovirus (CMV) infection. METHODS: Longitudinal cohort study of children (n = 41) with symptomatic congenital CMV infection evaluated at birth and followed up with serial age-appropriate neurodevelopmental testing. The performance of birth characteristics as predictors of long-term outcome were determined, and clinical and CT scoring systems were developed and correlated with intellectual outcome. RESULTS: Microcephaly was the most specific predictor of mental retardation (100%; 95% CI 84.5-100) and major motor disability (92.3%; 95% CI 74.8-99). An abnormality detected by CT was the most sensitive predictor for mental retardation (100%; 95% CI 82.3-100) and motor disability (100%; 95% CI 78.2-100). A highly significant (P <.001) positive correlation was found between head size at birth and the intelligence/developmental quotient (IQ/DQ). Approximately 29% of children had an IQ/DQ >90. There was no association between sensorineural hearing loss at birth and cognitive outcome. However, children with sensorineural hearing loss on follow-up (congenital and late-onset) had a lower IQ/DQ (P =.006) than those with normal hearing. CONCLUSIONS: The presence of microcephaly at birth was the most specific predictor of poor cognitive outcome in children with symptomatic congenital CMV infection, whereas children with normal findings on head CT and head circumference proportional to weight exhibited a good cognitive outcome.

Cysticercosis.

Cysticercosis, the consequence of ingesting viable eggs of the porcine tapeworm Taenia solium, currently remains one of the most common human parasitic conditions worldwide. Although preventable by the proper disposal of human wastes, cysticercosis of the central nervous system (neurocysticercosis) accounts for a substantial proportion of cases of epilepsy and hydrocephalus among children and adults in many developing countries. Cases also occur in nonendemic regions, reflecting patterns of immigration from highly endemic countries, especially Mexico and other areas of Latin America. Antiparasitic treatment during active infections, using albendazole or praziquantel, can eradicate the parasite, may lower the risk of late complications, and potentially reduces the morbidity of acute disease. Considerable controversy persists regarding the role of antiparasitic therapy in neurocysticercosis, however. Persons with active parenchymal or extraparenchymal disease, defined by the neuroradiographic appearance of lesions, can be treated with albendazole, 15 mg/kg/d divided into two daily doses for 8 days. Patients with parenchymal disease who do not respond to albendazole can receive a second course of albendazole or praziquantel, 50 mg/kg/d divided into three daily doses for 15 days. Concurrent administration of dexamethasone in standard doses is usually required during the first several days of antiparasitic therapy to minimize the inflammation and cerebral edema associated with death of the parasites. Patients with intraventricular cysts and hydrocephalus require shunting and surgical removal of cysticerci. By contrast, persons with inactive lesions and seizures as a consequence of remote infections typically require only symptomatic therapy with standard anticonvulsants.

Intrauterine cytomegalovirus infection and glycoprotein B genotypes.

Cytomegalovirus (CMV) strains display polymorphisms for the gene encoding glycoprotein B (gB; gpUL55). Recent data suggest that the gB genotype may influence the outcome of acquired CMV infections. To determine whether the gB genotype also contributes to the outcome of intrauterine infection, CMV strains were studied from 56 infants with culture-confirmed intrauterine CMV infections who were born in Iowa or Texas. CMV gB genotypes were compared with the neonatal clinical features and neurodevelopmental outcomes. Fifty-three strains (95%) could be assigned a gB genotype. The overall distribution of genotypes was as follows: type 1, 50%; type 2, 18%; type 3, 23%; and type 4, 4%. Strains with the gB 3 genotype were more common among the Iowa infants (P=.082). The gB 3 genotype was more common among infants with asymptomatic infections (P=.004), but geographic location and ascertainment biases may have accounted for these differences. The gB genotypes did not correlate with the neurodevelopmental outcome of intrauterine infection.

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 theta = 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.

Bilateral hippocampal encephalitis caused by enteroviral infection.

Nonpolio enteroviral encephalitis usually presents as a diffuse, generalized encephalitis. Focal cerebral involvement by nonpolioviruses is uncommon, and neuroradiologic studies in these cases are usually normal. The authors present a case of a 5-year-old male with an acute encephalitic illness and bilateral lesions of the hippocampi on magnetic resonance imaging. Enteroviral nucleic acids were detected in the cerebrospinal fluid by the reverse transcription polymerase chain reaction. The findings suggest that enteroviral infection should be considered in the differential diagnosis of acute bilateral hippocampal encephalitis in patients in whom polymerase chain reaction fails to demonstrate the presence of herpes simplex virus.

Effect of long-term valproic acid administration on the efficiency of carnitine reabsorption in humans.

To elucidate the etiology of valproic acid-induced carnitine deficiency, we tested the hypothesis that long-term valproic acid administration decreases the rate of carnitine reabsorption. Thirteen healthy men participated in a 34-day protocol in which carnitine clearance was measured before and after 28 days of valproic acid administration. During valproic acid administration (days 6 to 33), plasma free and total carnitine concentrations decreased (18% and 12%, respectively, P<.05) by 16 days, but returned to pretreatment concentrations by 28 days. From day 14 to day 30, the rate of free carnitine excretion was 50% lower than at baseline (day 4, P<.05). Free and total carnitine clearance, indexed to the glomerular filtration rate, was lower after valproic acid administration (P<.01). Contrary to our hypothesis, after 28 days of valproic acid administration, the rate of carnitine reabsorption was enhanced independent of the glomerular filtration rate and filtered load. Changes in the plasma concentration, rate of excretion, and clearance were specific for carnitine and were not generalized in magnitude or direction to the other amino acids. We conclude that the kidney adapts to conserve carnitine during valproic acid administration and therefore does not cause valproic acid-induced carnitine depletion in adults.

Cytomegalovirus transmission in child care homes.

BACKGROUND: Children attending child care centers have high rates of cytomegalovirus (CMV) excretion. Women exposed to such children have an increased risk of acquiring CMV infection, and primary infection places the offspring of such women at risk of congenital CMV infection. We studied family child care homes to determine if this child care alternative might represent a safe haven from CMV. METHODS: One hundred thirty-two women providing care in their homes were studied using a latex agglutination method to determine the rate of CMV seropositivity at baseline. Women who were seronegative for CMV were then sampled prospectively at 6-month intervals between March 1991 and August 1994 to determine the annual rate of CMV acquisition. A point prevalence of CMV excretion in family homes was determined by sampling 106 children from 25 randomly selected homes. Cytomegalovirus isolates were compared by molecular analysis using polymerase chain reaction-based methods to identify transmission. RESULTS: At baseline, 57.6% of the 132 providers were seropositive for CMV. Seropositive providers were more likely to be caring for toddlers (aged 1-2 years) (67% vs 46%; P=.02) and had worked in child care somewhat longer (median of 28.5 vs 21.5 months; P=.11). Using stepwise logistic regression, the strongest predictors of seropositivity at baseline were caring for children aged 1 to 2 years (odds ratio [OR] =2.37; P=.02) and number of months as a child care provider (OR= 1.17 for an increase of 24 months as provider; P=.08). Six or more years as a provider was highly associated with seropositivity (OR=3.27; P=.02). During follow-up, 5 of 51 seronegative providers seroconverted, yielding an annual infection rate of 6.8%. The point prevalence survey of children from the 25 homes (14 had seropositive providers) identified 8 CMV-excreting children. Three children in 1 home had indistinguishable isolates by polymerase chain reaction mapping. The provider seroconverted and excreted an isolate with a molecular profile indistinguishable from that of the children. CONCLUSIONS: The prevalence of CMV excretion is low among children attending child care homes (8% vs 15% in prior studies of child care centers; P=.07), and only 1 (20%) in 5 of the homes had CMV-excreting children. However, the overall CMV seroconversion rate of home child care providers was comparable to the rate observed among providers in child care centers. Families who use family home child care as an alternative to large child care centers are exposed to a low and unpredictable risk of CMV infection.

Human herpesviruses and neurological disorders of childhood.

The human herpesviruses, a group of DNA viruses that includes herpes simplex viruses types 1 and 2, varicella zoster virus, cytomegalovirus, Epstein-Barr virus, and human herpes viruses types 6, 7, and 8, cause substantial neurological morbidity among infants and children. This review describes the biology of these viruses and summarizes the clinical manifestations and therapy of the diseases that result from childhood infection with these important pathogens.

Hemophilia morbidity, cognitive functioning, and academic achievement.

Data from the Hemophilia Growth and Development Study (HGDS) were used to evaluate the association between hemophilia morbidity, measured by abnormalities in coordination and gait (CG), and intellectual ability and academic achievement. The CG abnormalities observed in the HGDS participants (n = 333) were primarily due to hemophilia-related morbidity. Although HGDS participants performed within the average range for age on measures of intellectual ability, there were meaningful differences between CG outcomes at baseline and throughout the 4 years of study. Participants without CG abnormalities consistently achieved higher scores than those with CG abnormalities on Reading, Spelling, and Arithmetic subtests of the Wide Range Achievement Test-Revised. Our findings suggest that lowered achievement is related to the functional severity of hemophilia.

Epidemiology of congenital cytomegalovirus infection: maternal risk factors and molecular analysis of cytomegalovirus strains.

To determine factors that influence the occurrence of congenital cytomegalovirus (CMV) infection, the authors surveyed prospectively 8,254 infants born in eastern Iowa between October 1989 and June 1994. The authors conducted a case-control study to identify maternal risk factors, matching each CMV-infected infant with three uninfected infants according to hospital and date of birth. CMV strains were compared by using the polymerase chain reaction (PCR) to identify common sources of infection. Of the 7,229 infants cultured successfully for CMV, 35 (0.48%) were congenitally infected. Mothers of CMV-infected infants were more likely to be single (odds ratio (OR) = 3.05, p = 0.016), to work in sales (OR = 4.93, p = 0.008), or to be students (OR = 5.01, p = 0.017). Conversely, women who worked in health-care professions were less likely to have a congenitally infected infant (OR = 0.14, p = 0.049). PCR analysis indicated 27 distinct strains of CMV, but two groups of infants (two infants per group) excreted strains with indistinguishable molecular patterns. One of these pairs of infants had older siblings who attended the same child-care center during their mothers' pregnancies. The authors concluded that demographic and occupational factors influenced the risk of giving birth to an infant with congenital CMV infection. Many distinct CMV strains were identified, suggesting that major point source outbreaks had not occurred. Nonetheless, point source acquisition of CMV from child-care environments did account for some cases of congenital CMV infection in eastern Iowa.

Hemophilia growth and development study: relationships between neuropsychological, neurological, and MRI findings at baseline.

OBJECTIVE: To determine the effects of human immunodeficiency virus (HIV) infection on children's development by identifying neurological and environmental variables associated with neuropsychological measures of cognitive development in HIV-seronegative (HIV-) and HIV-seropositive (HIV+)children and adolescents with hemophilia. METHODS: Participants (N = 298; 60% HIV+) were males ages 7-19 years enrolled in the Hemophilia Growth and Development Study (HGDS). Least squares modeling was used to determine whether there was a difference at baseline in mean neuropsychological test scores by HIV status, age, and neurological baseline findings, adjusting for selected environmental and medical history variables. RESULTS: The participants were within age expectations for general intelligence. Variables associated with lowered neuropsychological performance included academic problems, coordination and/or gait abnormalities, parents' education, and previous head trauma. CONCLUSIONS: Hemophilia-related morbidity has a subtle adverse influence on cognitive performance. HIV infection was not associated with neuropsychological dysfunction in this group even when MRI abnormalities were present.

Infections of the central nervous system in the newborn.

Safe, effective vaccines and potent antimicrobial agents have diminished substantially the morbidity and mortality associated with neonatal infections of the central nervous system (CNS), and new molecular methods, such as the polymerase chain reaction, enable clinicians to detect micro-organisms rapidly. Despite these advances, CNS infections remain an important cause of death and neurodevelopmental sequelae. This article summarizes current concepts regarding infections of the developing CNS.

Longitudinal neurological follow-up of a group of HIV-seropositive and HIV-seronegative hemophiliacs: results from the hemophilia growth and development study.

BACKGROUND: Boys and young men with hemophilia treated with factor infusions before 1985 had a substantial risk of acquiring the human immunodeficiency virus (HIV) and the acquired immunodeficiency syndrome. This study was designed to assess the effects of HIV and hemophilia per se on neurological function in a large cohort of subjects with hemophilia, and to investigate the relationships between neurological disease and death during follow-up. METHODS: Three hundred thirty-three boys and young men (207 HIV seropositive and 126 HIV seronegative) were evaluated longitudinally in a multicenter, multidisciplinary study. Neurological history and examination were conducted at baseline and annually for 4 years. The relationship between neurological variables, HIV serostatus, CD4+ cell counts, and vital status at the conclusion of the study was examined using logistic regression models. RESULTS: The risks of nonhemophilia-associated muscle atrophy, behavior change, and gait disturbance increased with time in immune compromised HIV-seropositive subjects compared with HIV seronegative or immunologically stable HIV-seropositive subjects. The risk of behavior change in immune compromised HIV-seropositive hemophiliacs, for example, rose to 60% by year 4 versus 10% to 17% for the other study groups. Forty-five subjects (13.5%), all of whom were HIV seropositive, died by year 4. Subjects who died had had increased risks of hyperreflexia, nonhemophilia-associated muscle atrophy, and behavior change. CONCLUSIONS: These results indicate that immune compromised, HIV-seropositive hemophiliacs have high rates of neurological abnormalities over time and that neurological abnormalities were common among subjects who later died. By contrast, immunologically stable HIV-seropositive subjects did not differ from the HIV-seronegative participants. Hemophilia per se was associated with progressive abnormalities of gait, coordination, and motor function.

Congenital lymphocytic choriomeningitis virus syndrome: a disease that mimics congenital toxoplasmosis or Cytomegalovirus infection.

OBJECTIVE: To describe the clinical characteristics of intrauterine infection with lymphocytic choriomeningitis (LCM) virus, an uncommonly recognized cause of congenital viral infection. PATIENTS: Three infants born in the midwestern United States in 1994 and 1995 with clinical features and serologic studies consistent with congenital LCM virus infection and cases of congenital infection identified by review of the medical literature between 1955 and 1996. RESULTS: Twenty-six infants with serologically confirmed congenital LCM virus infection were identified. Twenty-two infants were products of term gestations, and birth weights ranged from 2384 to 4400 g (median, 3520 g). Ocular abnormalities, macrocephaly, or microcephaly were the most commonly identified neonatal features. Twenty-one infants (88%) had chorioretinopathy, 10 (43%) had macrocephaly (head circumference >90th percentile) at birth, and 3 (13%) were microcephalic (head circumference <10th percentile). Macrocephaly and hydrocephalus developed postnatally in one of the latter infants. Hydrocephalus or intracranial calcifications were documented in five infants by computed tomography or magnetic resonance imaging. Nine infants (35%) died, and 10 (63%) of the 16 reported survivors had severe neurologic sequelae, consisting of spastic quadriparesis, seizures, visual loss, or mental retardation. One-half of the mothers reported illnesses compatible with LCM virus infection, and 25% reported exposures to rodents during their pregnancies. CONCLUSIONS: These cases suggest that congenital LCM virus infection could be an underrecognized cause of congenital infection among infants born in the United States. Because of the clinical similarities of these congenital infections, cases of congenital LCM virus infection can be confused with infections with cytomegalovirus or Toxoplasma gondii.