Behavior problems in children at time of first recognized seizure and changes over the following 3 years.

OBJECTIVES: The purposes of this 36-month study of children with first recognized seizures were: (1) to describe baseline differences in behavior problems between children with and without prior unrecognized seizures; (2) to identify differences over time in behavior problems between children with seizures and their healthy siblings; (3) to identify the proportions of children with seizures and healthy siblings who were consistently at risk for behavior problems for 36 months; and (4) to identify risk factors for behavior problems 36 months following the first recognized seizure. Risk factors explored included demographic (child age and gender, caregiver education), neuropsychological (IQ, processing speed), seizure (epileptic syndrome, use of antiepileptic drug, seizure recurrence), and family (family mastery, satisfaction with family relationships, parent response) variables. METHODS: Participants were 300 children aged 6 through 14 years with a first recognized seizure and 196 healthy siblings. Data were collected from medical records, structured interviews, self-report questionnaires, and neuropsychological testing. Behavior problems were measured using the Child Behavior Checklist and the Teacher's Report Form. Data analyses included descriptive statistics and linear mixed models. RESULTS: Children with prior unrecognized seizures were at higher risk for behavior problems at baseline. As a group, children with seizures showed a steady reduction in behavior problems over time. Children with seizures were found to have significantly more behavior problems than their siblings over time, and significantly more children with seizures (11.3%) than siblings (4.6%) had consistent behavior problems over time. Key risk factors for child behavior problems based on both caregivers and teachers were: less caregiver education, slower initial processing speed, slowing of processing speed over the first 36 months, and a number of family variables including lower levels of family mastery or child satisfaction with family relationships, lower parent support of the child's autonomy, and lower parent confidence in their ability to discipline their child. CONCLUSIONS: Children with new-onset seizures who are otherwise developing normally have higher rates of behavior problems than their healthy siblings; however, behavior problems are not consistently in the at-risk range in most children during the first 3 years after seizure onset. When children show behavior problems, family variables that might be targeted include family mastery, parent support of child autonomy, and parents' confidence in their ability to handle their children's behavior.

Academic problems in children with seizures: relationships with neuropsychological functioning and family variables during the 3 years after onset.

OBJECTIVES: Children with long-standing epilepsy have a significantly increased risk of academic underachievement compared with healthy controls. We prospectively followed children from seizure onset to assess the relationship between change in neuropsychological functioning and change in academic achievement and to explore the risk and protective moderating effects of demographic, seizure, and family variables. METHODS: As part of a larger study, neuropsychological and academic data were collected at both baseline and 36 months for 219 children 6-14 years of age with seizures. Prior factor analysis of results from a battery of well-standardized neuropsychological tests yielded four factors: language, processing speed, attention/executive/construction, and verbal memory/learning. Academic achievement was measured with the Woodcock-Johnson Revised Achievement Test Battery. Correlation coefficients and linear mixed models were used for analysis. RESULTS: The reading and math scores of children with seizures and siblings did not differ at baseline, but children with seizures had lower scores than siblings at 36 months. Writing scores were significantly lower for affected children than siblings at both times. Among children with seizures, there were positive correlations between neuropsychological functioning and academic achievement at baseline and 36 months. Changes in language and in verbal memory/learning were positively correlated with change in reading achievement (r = 0.25 and r = 0.17, respectively). Age at onset moderated the association between change in neuropsychological functioning and change in reading and writing achievement (P ≤ 0.006), with stronger relationships among younger children (ß = 0.25-0.44). The association between change in language and change in writing achievement was moderated by caregiver anxiety (P = 0.04; stronger for more anxious parents, ß = 0.40), and the association between change in processing speed and change in math achievement was moderated by etiology (P = 0.02; stronger for symptomatic/cryptogenic vs idiopathic, ß = 0.29). Gender and other family variables did not have significant moderating effects. CONCLUSIONS: Changes in neuropsychological function were associated with changes in academic achievement following onset of seizures, with risk factors being younger age at onset, lower caregiver education, high parental anxiety, and symptomatic/cryptogenic etiology. Academic performance should be closely monitored in children with early-onset seizures.

Characterization of chronic daily headaches in children in a multidisciplinary headache center.

BACKGROUND: Chronic daily headaches (CDH) occur in >4% of the adult population. The criteria for CDH, however, are controversial. In children, the characterization of frequent headaches and CDH is limited. METHODS: A Headache Center to characterize headaches in children (3 to 18 years old) was established. Over 34 months, 577 children have been evaluated. With use of a definition of > or =15 headaches per month, 200 (34.6%) children had CDH. RESULTS: The average age at the first headache in these children was 9.3 +/- 3.6 years, whereas the average age at presentation to the Headache Center was 12.5 +/- 3.1 years. Sixty-eight percent were girls, 88% were Caucasian, and 11% were African American. Ninety-two percent clinically had migraine headaches, whereas 60.5% met the International Headache Society migraine criteria. The pain was pulsatile in 79%, 63.5% had nausea with or without vomiting, and 59.5% had photophobia and phonophobia. Three subcategories emerged, with 37% having frequent headaches but not daily, 43.5% having episodic daily headaches, and 19.5% having a continuous headache. CONCLUSION: The features of CDH in children most closely match those of migraine. A clear division of these children using frequency identifies three groups: frequent headaches (15 to 29), daily intermittent, and daily continuous. The daily continuous group is the most unique; however, the nature of these headaches continues to remain migrainous.

Seizure frequency and characteristics in children with Down syndrome.

Seizures have not historically been considered a major component of Down syndrome. We examined the prevalence of epileptic seizures in 350 children and adolescents with Down syndrome evaluated at a regional center between 1985 and 1997. Results showed that 28 patients (8%) had epileptic seizures: 13 (47%) partial seizures; 9 (32%) infantile spasms, and 6 (21%) generalized tonic-clonic seizures. In the infantile spasm group, there was no relationship between the initial electroencephalogram (EEG) pattern and response to treatment or long-term seizure control, or between type of pharmacologic treatment (valproic acid, adrenocorticotropic hormone or both) and clinical remission, EEG normalization or long-term seizure control. Neurodevelopmental outcome was poor despite good seizure control in the infantile spasm group. This regional study reinforces the relative association of seizures and Down syndrome. A prospective study including a national/international registry with emphasis on developmental assessment and long-term follow up is warranted.

Strokes, cutis marmorata telangiectatica congenita, and factor V Leiden.

Cutis marmorata telangiectatica congenita is an uncommon, congenital cutaneous condition typified by persistent cutis marmorata and other associated abnormalities. Progressive neurologic complications are generally not a feature of the disorder. A case is reported of cutis marmorata telangiectatica congenita associated with diffuse cerebrovascular infarcts at 7 months of age. Moyamoya-like vascular abnormalities were demonstrated in addition to the factor V Leiden mutation, a congenital hypercoagulable disorder. This novel case illustrates the importance of evaluating children with strokes for congenital thrombophilic disorders.

Neuropsychological status at seizure onset in children: risk factors for early cognitive deficits.

OBJECTIVE: This large, prospective, community-based study characterized neuropsychological functioning and academic achievement at the time of the first recognized seizure and identified risk factors for cognitive deficits. METHODS: We compared 282 children (ages 6-14 years, IQ > or =70) with a first recognized seizure to 147 healthy siblings on a battery of well-standardized and widely used neuropsychological and academic achievement tests and examined relationships with demographic and clinical variables. RESULTS: In this intellectually normal cohort, 27% with just one seizure and up to 40% of those with risk factors exhibited neuropsychological deficits at or near onset. Risk factors associated with neuropsychological deficits included multiple seizures (i.e., second unprovoked seizure; odds ratio [OR] = 1.96), use of antiepileptic drugs (OR = 2.27), symptomatic/cryptogenic etiology (OR = 2.15), and epileptiform activity on the initial EEG (OR = 1.90); a child with all 4 risks is 3.00 times more likely than healthy siblings to experience neuropsychological deficits by the first clinic visit. Absence epilepsy carried increased odds for neuropsychological impairment (OR = 2.00). CONCLUSIONS: A subgroup of intellectually normal children with seizures showed neuropsychological deficits at onset. Academic achievement was unaffected, suggesting that there is a window early in the disorder for intervention to ameliorate the impact on school performance. Therefore, the risk factors identified here (especially if multiple risks are present) warrant swift referral for neuropsychological evaluation early in the course of the condition.

Lectins are markers of neuronal migration and differentiation in rat brain.

The binding of the lectins concanavalin A (Con A), peanut lectin (PNL), Ricinus communis agglutinin I (RCA I), Ulex europaeus agglutinin I (UEA I) and wheat germ agglutinin (WGA) to rat brains at several fetal and neonatal stages of development was evaluated. Cytochemical staining was performed using biotinylated lectins with an avidin-biotin complex with and without neuraminidase digestion. Differential binding to ventricular and intermediate layers, cortical plate and blood capillaries was demonstrated at different stages of development. WGA bound to blood capillaries at all ages, RCA I and PNL + N (PNL after neuraminidase digestion) from gestational day 22 on. During migration RCA I bound to cell fibers, PNL and UEA I to migrating cell bodies. Con A and UEA I stained perikaryonal structures of cortical neurons increasingly during neonatal development. It appears that cytochemical methods utilizing lectins can be used for the investigation of developmental processes of the central nervous system.

Diagnosis of migraine in children attending a pediatric headache clinic.

The International Headache Society (IHS) criteria for migraine are not sufficient to diagnose migraine in children. Specifically, the duration and localization of the headache are different in children and adults with migraine. This study compared the formal IHS criteria with pediatric-amended IHS criteria and IHS criteria with the duration factor removed in children younger than 18 years. In addition, the older criteria by Vahlquist and by Prensky and Sommer were also compared. Finally, clinical diagnosis of migraine was compared with IHS criteria with the duration factor removed. The study showed that many children with a shorter duration headache have migraine and also that a number of children with a very long duration of headaches still fit the diagnosis of migraine. Unilateral headache is quite uncommon. The majority of children with migraine complained of bilateral headaches. It is concluded that the IHS criteria for pediatric migraine should be revised. We suggest making the duration factor a minor criteria for migraine in children or to exclude headaches lasting longer than 72 hours only in children younger than 15 years.

Effectiveness of amitriptyline in the prophylactic management of childhood headaches.

OBJECTIVE: To study the effectiveness of a standardized dose of amitriptyline, 1 mg/kg, for childhood headaches. BACKGROUND: Amitriptyline has been shown to be effective for the prophylaxis of migraine in adults. Studies in children, however, have been quite limited. In adults, the suggested effective dose range is 10 to 150 mg. In children, a standardized dosage is often not used, resulting in a dosage range in clinical practice that often varies from a very low dose to a dose equivalent to that used in adults. METHODS: Children with more than three headaches per month were treated with amitriptyline, slowly increasing the dose to 1 mg/kg per day. The frequency, severity, and duration of their headaches were initially evaluated and subsequently measured at each follow-up evaluation. Two hundred seventy-nine children had headaches occurring frequently enough to indicate prophylactic treatment. Of these children, 192 (68.8%) were treated with amitriptyline. The average age at presentation was 12.0 (+/- 3.0) years. The ratio of boys to girls was 1:1.74. The average frequency of headaches was 17.1 (+/- 10.1) days per month. The average severity was 6.84 (+/- 1.67) on a 10-point pain scale. The average duration was 11.5 (+/- 15.0) hours. The most frequent diagnoses using International Headache Society criteria were migraine (60.6%), migraine with aura (7.9%), and tension-type headache (10.4%). Of these children, 146 have been seen for at least one follow-up examination, occurring on average 67.3 (+/- 32.3) days after beginning prophylactic treatment. RESULTS: A total of 84.2% of the children reported an overall perception of being better, while 11.6% reported being the same. The frequency of headaches improved to 9.2 (+/- 10.0) days per month. The average severity was reduced to 5.1 (+/- 2.1), and the average duration was reduced to 6.3 (+/- 11.1) hours. If daily or continuous headaches were excluded, the improvements were more marked. Minimal side effects were reported from these children and their families. Long-term evaluation (156 to 415 days) showed continued sustained improvement. CONCLUSIONS: Amitriptyline is an effective prophylactic medication for children with frequent headaches. A standardized dosing regimen results in a significant number of children responding with minimal side effects. The children are able to tolerate this dosing scheme and demonstrate good adherence to a dosing schedule of once a day.

Congenital creatine transporter deficiency.

BACKGROUND: Two inborn errors of metabolism of creatine synthesis as well as the X-linked creatine transporter (SLC6A8) deficiency have been recognized. This report describes the features of five identified male patients and their female relatives who are carriers of the X-linked creatine transporter deficiency syndrome. METHODS: Proton MR spectroscopy was used to recognize creatine deficiency in the patients. Molecular analysis of the SLC6A8 gene was performed, confirming the diagnosis of homozygous males and heterozygous females. RESULTS: We describe four families from a metropolitan area in the U. S. with X-linked creatine transporter deficiency. All affected males present with developmental delay and severe developmental language impairment. Proton MR spectroscopy shows significantly depressed to essentially absent creatine and phosphocreatine in the male patients. Nonsense mutations and amino acid deletions were found in the SLC6A8 gene in the affected families. CONCLUSION: Creatine transporter deficiency may be a more common X-linked genetic disorder than originally presumed. The affected males exhibit mental retardation with severe expressive language impairment.

Irreversible brain creatine deficiency with elevated serum and urine creatine: a creatine transporter defect?

Recent reports highlight the utility of in vivo magnetic resonance spectroscopy (MRS) techniques to recognize creatine deficiency syndromes affecting the central nervous system (CNS). Reported cases demonstrate partial reversibility of neurologic symptoms upon restoration of CNS creatine levels with the administration of oral creatine. We describe a patient with a brain creatine deficiency syndrome detected by proton MRS that differs from published reports. Metabolic screening revealed elevated creatine in the serum and urine, with normal levels of guanidino acetic acid. Unlike the case with other reported creatine deficiency syndromes, treatment with oral creatine monohydrate demonstrated no observable increase in brain creatine with proton MRS and no improvement in clinical symptoms. In this study, we report a novel brain creatine deficiency syndrome most likely representing a creatine transporter defect.

X-linked creatine transporter defect: an overview.

In 2001 we identified a new inborn error of metabolism caused by a defect in the X-linked creatine transporter SLC6A8 gene mapped at Xq28 (SLC6A8 deficiency, McKusick 300352). An X-linked creatine transporter defect was presumed because of (1) the absence of creatine in the brain as indicated by proton magnetic resonance spectroscopy (MRS); (2) the elevated creatine levels in urine and normal guanidinoacetate levels in plasma, ruling out a creatine biosynthesis defect; (3) the absence of an improvement on creatine supplementation; and (4) the fact that the pedigree suggested an X-linked disease. Our hypothesis was proved by the presence of a hemizygous nonsense mutation in the male index patient and by the impaired creatine uptake by cultured fibroblasts. Currently, at least 7 unrelated families (13 male patients and 13 carriers) with a SLC6A8 deficiency have been identified. Four families come from one metropolitan area. This suggests that SLC6A8 deficiency may have a relatively high incidence. The hallmarks of the disorder are X-linked mental retardation, expressive speech and language delay, epilepsy, developmental delay and autistic behaviour. In approximately 50% of the female carriers, learning disabilities of varying degrees have been noted.

X-linked creatine-transporter gene (SLC6A8) defect: a new creatine-deficiency syndrome.

We report the first X-linked creatine-deficiency syndrome caused by a defective creatine transporter. The male index patient presented with developmental delay and hypotonia. Proton magnetic-resonance spectroscopy of his brain revealed absence of the creatine signal. However, creatine in urine and plasma was increased, and guanidinoacetate levels were normal. In three female relatives of the index patient, mild biochemical abnormalities and learning disabilities were present, to various extents. Fibroblasts from the index patient contained a hemizygous nonsense mutation in the gene SLC6A8 and were defective in creatine uptake. The three female relatives were heterozygous for this mutation in SLC6A8, which has been mapped to Xq28.