Prenatal and family risks of children born to mothers with epilepsy: effects on cognitive development

The offspring of mothers with epilepsy are considered to be at developmental risk during pregnancy from: (1) generalized maternal seizures (hypoxia); (2) teratogenicity of antiepileptic drugs (AEDs); and (3) adverse socio-familial conditions associated with having a chronically sick mother. Sixty-seven children of mothers with epilepsy and 49 children from non-affected mothers, matched for control variables, were followed from birth to adolescence (53 males, 63 females; mean age 14y 2mo, range 10-20y). Prediction of intellectual performance of these children during adolescence was calculated from the following variables: maternal generalized seizures, prenatal exposure to AEDs, and quality of family stimulation (HOME Inventory) assessed in children at 2 years of age. Children who were prenatally exposed to AEDs achieved lower IQs than control children at adolescence. This effect was moderately significant for children who had been exposed to monotherapy (6 IQ points lower), but was considerable in those exposed to polytherapy (12 IQ points lower). Generalized seizures during pregnancy, observed in half the mothers, did not exacerbate this effect. Relative to prenatal risk status, the quality of the family environment had varied effects on intellectual development. Children with prenatal risks appeared to be more vulnerable to environmental disadvantage than control children, but they also showed longer-lasting effects of environmental support.     

Intellectual and language functions in children of mothers with epilepsy

PURPOSE: To compare the intellectual and language functions of children of mothers with epilepsy (CME) with that of controls matched for age and socioeconomic status. METHODS: Cases were CME, aged six years or more (n = 71), drawn from a prospective cohort in the Kerala Registry of Epilepsy and Pregnancy. Controls were 201 children of parents without epilepsy, matched for age and socioeconomic status. The outcome measures included Indian adaptation of Wechsler Intelligence Scale for children and MLT-a locally developed proficiency test for regional language. All relevant data were abstracted from the registry records. RESULTS: The Full Scale IQ and MLT scores were significantly lower for the cases (87.7 +/- 22.6 and 73.4 +/- 17.3) compared to controls (93.0 +/- 14.4 and 83.2 +/- 11.8). Compared to controls, CME scored poor on all subtests of MLT but their impairment was confined to only some of the subtests of IQ. Maternal education and maternal IQ significantly correlated with low IQ and MLT scores for CME whereas type of epilepsy, seizures during pregnancy or low birth weight did not have any significant association with these outcome measures. Polytherapy and higher dosage of antiepileptic drugs (AEDs) were associated with significant impairment in outcome measures. Infants with low developmental quotient at one year of age continued to have low scores on outcome measures at six years. CONCLUSIONS: Low maternal IQ, maternal education, and antenatal AED exposure were associated with significant impairment of intellectual and language functions for CME at six years.     

Neuropsychological outcomes in children of mothers with epilepsy.

The study investigated the nature of the effects of maternal epilepsy on cognitive performance of the offspring. One hundred fifty-four children of mothers with epilepsy aged 5 to 11 years (study group), along with 130 control children, comparable with respect to IQ, socio-economic status, age, and gender underwent a neuropsychological assessment using subtests from the NEPSY: A Developmental Neuropsychological Assessment, tapping attentional, auditory-verbal, visuomotor, fine motor, and memory abilities. The study group scored significantly lower than the controls on measures of attention, memory, and fine-motor function. Deficits were more marked in but not limited to the subset of the study group exposed to maternal medication in utero. Group differences on auditory attention were found only in younger children. Valproate-exposed children obtained lower scores on sentence repetition, as well as on the more demanding part of a test of auditory attention, than other children in the study group, suggesting weaknesses in working memory in the former subgroup. Confounding by maternal epilepsy type and polytherapy complicate interpretation of this finding. Differences between subsets of children not exposed to anti-epileptic drugs in utero and controls suggest that both drug exposure and genetic factors may contribute to cognitive deficits associated with maternal epilepsy.     

Mental and behavioural outcome of infantile epilepsy treated by vigabatrin in tuberous sclerosis patients

Vigabatrin (VGB) has demonstrated high efficacy in infantile spasms (IS) due to tuberous sclerosis. Our first objective was to evaluate the cognitive long term effect outcome of children whose refractory spasms definitely disappeared when VGB was given as an add on drug. Our second objective was to determine the response of generalized epilepsy (infantile spasms) compared to partial epilepsy on cognitive impairment. A non selected series of 13 children underwent psychometric and behavioural evaluation before VGB initiation at a mean of 3 years on VGB treatment. Eight of them could perform detailed neuropsychological tests at follow-up. Seven had infantile spasms (Group I), they all were spasm free before 2 years of age and five remained with rare partial seizures (mean age, 5.5 years). Six others had partial epilepsy without spasms (Group II) and five remained with rare seizures (mean age, 7.5 years). Patients of Group I experienced dramatic changes. Developmental quotient (DQ) significantly rose in six out of seven by ten to more than 45 points (P = 0.03) and autistic behaviour disappeared in five out of the six who presented with. The four tested children had normal verbal level after 5 years and could integrate at school but they remained with marked visuospatial disabilities. By contrast, patients of Group II remained with an unchanged DQ of about 60 so that both groups had similar DQ levels on follow-up. The cessation of spasms with VGB is therefore associated with significant improvement of cognition and behaviour in children with tuberous sclerosis. Controlling secondary generalization induced by infantile spasms seems to be a key factor for mental development.     

Psychomotor development and minor anomalies in children exposed to antiepileptic drugs in utero: a prospective population-based study

The aim of this study was to assess psychomotor development, using Griffiths' test, and the incidence of minor anomalies at birth in children who had been exposed to antiepileptic drugs (AEDs) in utero. The study sample comprised 100 children of mothers who were treated with AEDs during pregnancy and 100 matched control children. Women with epilepsy were recruited from a pregnant urban population (450 000 inhabitants). The lowest possible dose of the fewest AEDs to maintain seizure control was used. Drug levels were controlled on a monthly basis. The children were assessed at 9 months of age. The study children had a significant increase in the number of minor anomalies (31 compared with 18 control children; odds ratio 2.4, CI 1.15 to 5.02, P=0.02 McNemars test), and an increased number of facial anomalies after carbamazepine exposure (11 compared with six control children). Drug exposure did not influence the Griffiths' score at 9 months of age. Even a meticulous AED treatment strategy during pregnancy increases the number of minor anomalies. However, treatment with AEDs does not necessarily influence short-term psychomotor development.     

Fetal antiepileptic drug exposure: motor, adaptive, and emotional/behavioral functioning at age 3 years

The Neurodevelopmental Effects of Antiepileptic Drugs (NEAD) Study is an ongoing prospective observational multicenter study in the United States and United Kingdom that enrolled pregnant women with epilepsy on antiepileptic drug (AED) monotherapy from 1999 to 2004. The study seeks to determine if differential long-term neurodevelopmental effects exist across four commonly used AEDs (carbamazepine, lamotrigine, phenytoin, valproate). In this article, we examine fetal AED exposure effects on motor, adaptive, and emotional/behavioral functioning in 229 children who completed at least one of these tests at 3 years of age. Adjusted mean scores for the four AED groups were in the low average to average range for motor functioning, parental ratings of adaptive functioning, and parental ratings of emotional/behavioral functioning. A significant dose-related performance decline in motor functioning was seen for both valproate and carbamazepine. A significant dose-related performance decline in parental ratings of adaptive functioning was also seen for valproate, with a marginal performance decline evident for carbamazepine. Further, parents endorsed a significant decline in social skills for valproate that was dose related. Finally, on the basis of parent ratings of attention span and hyperactivity, children of mothers who took valproate during their pregnancy appear to be at a significantly greater risk for a future diagnosis of attention-deficit/hyperactivity disorder. Additional research is needed to confirm these findings, examine risks of other AEDs, define the risks in the neonate associated with AEDs for treatment of seizures, and determine the underlying mechanisms of adverse AED effects on the immature brain.     

Benign childhood epilepsy with centro-temporal spikes (BCECTS): early onset of seizures is associated with poorer response to initial treatment.

AIM: Benign childhood epilepsy with centro-temporal spikes (BCECTS) is the most common idiopathic partial epilepsy in children. Treatment attitudes remain a controversial issue. We examine features that could suggest refractoriness at onset. METHODS: We retrospectively reviewed the medical records of 144 children with BCECTS diagnosed at the Division of Pediatric Neurology, Asan Medical Center, from March 1, 1995, to April 30, 2002 and treated with AEDs. The patients were subdivided into two groups according to the number of antiepileptic drugs used for effective seizure control. RESULTS: Of the 144 patients, 75 were male and 69 were female, with a mean age at seizure-onset of 7.2 +/- 2.3 years (range, 2.1-14.3 years); 119 children were taking one antiepileptic drug (AED) (Group A), and 25 were taking more than one (Group B). There were no significant group differences in female-to-male ratio, prescribed AEDs, number of seizures before the start of treatment, interval between seizure-onset and start of treatment, presence of secondarily generalized seizures, or presence of bilateral EEG abnormalities. The groups differed however, in mean age at seizure onset (7.6 +/- 2.2 years versus 5.1 +/- 1.9 years, p < 0.05) and percentage of patients with seizure-onset before 3 years (p < 0.05). CONCLUSIONS: When treated with AEDs, children with BCECTS usually respond well. However, an earlier onset of seizures is associated with more frequent seizures and initial refractoriness to medical treatment.     

Epilepsy in children: the evidence for new antiepileptic drugs

Childhood epilepsy remains a challenge to treat. Despite the availability of antiepileptic drugs (AEDs), >25% of children with childhood epilepsy continue to have seizures. Conventional AEDs have been the mainstay of therapy for many years but are often poorly tolerated and have a tendency to interact with other drugs. Current American Academy of Neurology guidelines support the use of four of the newer AEDs (gabapentin, lamotrigine, topiramate, and oxcarbazepine) as adjunctive treatment of refractory partial seizures in children, based on class I evidence. This paper includes a summary of the results from a recent randomized, double-blind, placebo-controlled study, which shows that levetiracetam is also effective and well tolerated in this pediatric population, and provides evidence supporting its use in refractory partial seizures in children.     

Antiepileptic Drugs in Pediatric Practice

Summary: Several factors characterize the current medical treatment of epilepsy during childhood. Children do not present the same types of seizures or epilepsies as adults, and certain epilepsy syndromes are seen only during childhood. Accordingly, the choice of antiepileptic drugs (AEDs) may differ in children. In addition, certain medical therapies, such as ACTH or pyridoxine, are used only in children. It is also common practice to prescribe AEDs in children for indications that are "off-label," such as the treatment of partial-onset seizures with car-bamazepine before the age of 6 years. The natural history of epilepsy and the risk for seizure recurrence may be different in the pediatric age range, and this may influence the decision to institute chronic prophylactic therapy in children. Similar considerations may apply to the decision to discontinue AED therapy. The pharmacokinetics of several AEDs are age-dependent, and dosages are more variable among patients. The adverse effects of AEDs may be age-dependent, and the pattern of exacerbation of certain seizures by AEDs may be different in children. In addition, several new AEDs are now available, or are about to be released, and the preferential sequence of AEDs of choice in children with epilepsy will need to be reassessed as experience grows and as the results of comparative studies become available.     

Neurodevelopmental effects of antiepileptic drugs

Although the vast majority of children born to women with epilepsy are normal, these children are at increased risk for both anatomic and cognitive impairments. Current evidence suggests that the defects are the result of in utero antiepileptic drug (AED) exposure combined with a genetic predispositon. However, the exact mechanisms underlying these effects remain to be delineated. AED polytherapy increases the risk, but it remains uncertain if specific AEDs pose an overall greater threat. Most women with epilepsy cannot avoid AEDs during pregnancy because of the greater risks posed by seizures to the mother and fetus. Therefore, current recommendations emphasize definitive diagnosis and the use of AED monotherapy at the lowest effective dose if treatment is indicated. Prenatal folate and multivitamins should also be given routinely to women of childbearing age who require AED therapy.     

Postoperative development of children after hemispherotomy

We studied the postoperative development of 14 children with cortical dysgenesis who underwent modified functional hemispherectomy (hemispherotomy) at the age of 6 years or younger. At follow-up of 24-72 months (median of 47 months), six (43%) were seizure-free, six achieved>90% reduction, one achieved 50-90% reduction, and one achieved 0-50% reduction in seizure frequency. At the preoperative and final postoperative examinations, mean scores of developmental quotient (DQ) were as follows: 25.5 and 31.9 in total DQ, 26.0 and 33.7 in intellectual DQ, and 27.4 and 22.9 in motor DQ. Children scoring >50 points in preoperative intellectual DQ score obtained near-normal intellectual DQ postoperatively, while, those scoring <10 DQ preoperatively remained at a low developmental level. Among children with DQ scores in the range from 10 to 50, two children who obtained seizure-free outcome and were operated upon in the first 3 years of life achieved marked developmental progress. The present study indicated that high preoperative intellectual DQ and cessation of seizures seem to be associated with better postoperative intellectual development. However, long-term observation of postoperative development and an accumulation of more cases will be needed before we can reach a firm conclusion.     

Active seizures are associated with reduced adaptive functioning in children with epilepsy

Children with epilepsy are at risk of suboptimal adaptive functioning. Research has not yet established how specific seizure and treatment variables may affect adaptive functioning, which would allow clinicians to better identify at-risk children. This study sought to determine the seizure and treatment variables predictive of adaptive functioning. Forty-six children with epilepsy participated in this study. Using multiple regression, active seizures (one or more seizures in the prior year) significantly predicted scores on the General Adaptive Composite of the Adaptive Behavior Assessment System-II. The active seizures variable uniquely explained 19% of the variance in adaptive functioning, with children with active seizures demonstrating significantly poorer adaptive functioning. The number of current AEDs, past AEDs, seizure types, age at seizure onset, and temporal lobectomy were not significant predictors. Post hoc analyses that divided the active seizures group according to seizure frequency in the prior month did not find significant differences in adaptive functioning. The results of this study suggest that children with seizures that are not fully controlled are at greater risk of suboptimal adaptive functioning.     

Intractable childhood epilepsy and maternal fatigue

BACKGROUND: Mothers of children with intractable epilepsy are generally stressed and experience more emotional problems. Fatigue may affect their productivity, social interactions, and their ability to adequately take care of their children. The objectives were to examine the relationship between intractable childhood epilepsy and maternal fatigue, and explore possible contributing factors. METHODS: Sixty-four consecutive mothers of children with intractable epilepsy were identified prospectively. Exclusion criteria included degenerative/metabolic disorders or life threatening illness, such as brain tumors. Fatigue was measured using a standardized 11-item questionnaire, which has been revalidated in an Arabic speaking population. RESULTS: Mothers' ages were 24-45 years (mean 34) and ages of their epileptic children were 1-15 years (mean 6.7). Most children (64%) had epilepsy for >2 years, were on >1 antiepileptic drug (AED) (72%), and had daily seizures (47%). Thirty-four (54%) of the children had motor deficits and 83% had mental retardation (severe in 41%). Twenty-eight (44%) mothers were fatigued. Factors associated with increased maternal fatigue included child's age <2 years (p=0.01), cryptogenic epilepsy (p=0.03), and severe motor deficits (p=0.04). Factors associated with lowered fatigue included performing regular exercise (p=0.006), lack of mental retardation (p=0.01), seizure control (p=0.05), using one AED (p=0.002), infrequent ER visits (p=0.005), and lack of recent hospitalization (p=0.005). CONCLUSIONS: Mothers of children with intractable epilepsy are increasingly fatigued. Several correlating factors were identified, mostly related to seizure control, mental and physical handicap. Strategies to manage the problem include proper education, seizure control, participation in regular exercise, social support, and psychological counseling.     

Diagnosis of pyridoxine-dependent epilepsy in an adult presenting with recurrent status epilepticus

Pyridoxine-dependent epilepsy (PDE) is a genetic metabolic disease caused by inborn errors affecting vitamin B6 metabolism, which typically presents with neonatal seizures resistant to antiepileptic drugs (AEDs). Treatment with pyridoxine terminates seizures and prevents neurological decline. We describe a case in which the diagnosis was established at the age of 22 years. Birth and development were normal, but there was a history of three isolated tonic-clonic seizures during childhood and adolescence. At the age of 18 years, she developed frequent focal motor seizures, many evolving into tonic-clonic seizures. Electroencephalography identified a focus in the posterior right hemisphere, but magnetic resonance imaging of the brain was normal. Over the next 3 years, she was hospitalized with uncontrolled seizures on six occasions and spent a total of 121 days in intensive care. The seizures proved resistant to 12 different AEDs. Exome sequencing revealed two pathogenic mutations in ALDH7A1. Since starting on pyridoxine 50 mg once daily, she has been seizure-free, all AEDs have been withdrawn, and cognition has improved to premorbid levels. This case illustrates the importance of considering PDE in drug-resistant epilepsy in adults.     

Antiepileptic drugs in pregnancy: late effects on the children's cognitive abilities. Preliminary data.

The authors report preliminary data on cognitive development of 57 children, perspectively followed, who were exposed to antiepileptic drugs in utero for maternal epilepsy. Cognitive impairments are associated with other risk factors in 5 cases, so that a direct AEDs responsibility is not easy to prove.     

The longer term outcome of children born to mothers with epilepsy

OBJECTIVES: To determine the prevalence of cognitive delay and possible associated dysmorphic features in children exposed to antiepileptic drugs (AEDs) in utero. DESIGN: Retrospective study of children born to mothers with epilepsy. SETTING: Regional epilepsy clinics in Liverpool and Manchester, UK. PARTICIPANTS: Children aged between 6 months and 16 years born to mothers with epilepsy. MAIN OUTCOME MEASURES: Structured interviews, hospital records, clinical examination, and psychometric tests (Wechsler) were used to assess exposure and intelligence quotient (IQ). Blinded assessment of photographs was used to score children with characteristic dysmorphic features. RESULTS: A total of 249 children aged 6 and over were studied: 41 were exposed to sodium valproate, 52 to carbamazepine, 21 to phenytoin, 49 to polytherapy, and 80 were unexposed. Mean verbal IQ was significantly lower in the valproate group compared to unexposed and other monotherapy groups. Multiple regression analysis showed that both valproate exposure and frequent tonic-clonic seizures in pregnancy were significantly associated with a lower verbal IQ despite adjusting for other confounding factors. There was a significant negative correlation between dysmorphic features and verbal IQ in children exposed to valproate. CONCLUSIONS: This study identifies valproate as a drug carrying potential risks for developmental delay and cognitive impairment and is the first to suggest that frequent tonic-clonic seizures have a similar effect. Our results need to be interpreted with caution given their retrospective nature. Women with epilepsy need careful counselling about individual risk benefit of AED treatment before pregnancy.     

School performance of Nigerian adolescents with epilepsy

PURPOSE: The study assessed the school performance of Nigerian adolescents with epilepsy compared with healthy controls and examined the variables correlating with their academic difficulties. METHODS: The school grades of adolescents with epilepsy aged 12 to 18 years (n = 73) over the past academic year were compared with the grades of their classmates of the same age and gender. Risk factors possibly associated with school performance, such as adolescent variables (age, gender, perceived stigma, attitude toward epilepsy, and psychopathology), seizure variables (age at onset of illness, years of illness, types of seizures, and frequency of seizures per month), drug variables [types of antiepileptic drugs (AEDs), number of AEDs and side effects of AEDs], and family variables (family's socioeconomic status, family functioning, caretakers' psychopathology, and caretakers' perceived stigma) were assessed. RESULTS: The mean school grades of adolescents with epilepsy are significantly lower than are those of their healthy controls (p < 0.001) in all the subjects. The variables that significantly predict poor school performance in adolescents with epilepsy include psychopathology in the caretaker (p < 0.001), adolescents' perceived poor family functioning (p = 0.002), adolescents' attitude toward the illness (p = 0.001), adolescents' felt stigma (p = 0.002), externalizing symptoms in the adolescents (p = 0.004), and duration of illness (p = 0.024). CONCLUSIONS: The determinants of poor school performance in adolescents with epilepsy in Nigeria are multivariate, with psychosocial factors most important. These should be noted for early identification and screening of those children at greatest risk for academic failure and the greatest need for appropriate educational remediation services.     

No deterioration in epilepsy and motor function in children with medically intractable epilepsy ineligible for surgery

The aim of this study was to examine whether severity of epilepsy, motor functioning, and epilepsy-related restrictions change in children with medically intractable epilepsy who are ineligible for epilepsy surgery. The study was a prospective, longitudinal, 2-year follow-up of 28 children (14 females, 14 males). Their median age was 6 years 1 month (range 7mo-15y 4mo). Seizure types were: complex partial seizures (n=16), secondary generalized seizures (n=7), simple partial seizures (n=2), and mixed seizures (n=3). Severity of seizures, motor impairments, motor development, activities of daily life, and epilepsy-related restrictions were rated at baseline and 6, 12, and 24 months thereafter. Seizure severity did not change significantly, nor did muscle strength, range of motion, or muscle tone. Motor retardation was ubiquitous but did not increase in 20 children without spasticity. Motor function of eight children with spasticity improved (Gross Motor Function Measure: baseline 70.5 [SD 35.5]; 24 months later 81.6 [SD 29.6], p < 0.05) but remained below reference values in four children. In the entire group, functional skills increased and caregiver assistance lessened. Restrictions did not change significantly. We conclude that during a 2-year follow-up period, in children with medically intractable epilepsy who do not have surgical intervention, seizure severity does not deteriorate, motor impairments do not increase, motor development does not deflect negatively, and activities of daily living and restrictions do not worsen.     

Epilepsy in hemiplegic cerebral palsy due to perinatal arterial ischaemic stroke

Aim The aim of this study was to describe the frequency, risk factors, manifestations, and outcome of epilepsy in children with hemiplegic cerebral palsy (CP) due to perinatal arterial ischaemic stroke (AIS). Method The study group comprised 63 participants (41 males, 22 females) from a population‐based CP register whose brain imaging showed perinatal AIS. Information collected included occurrence of neonatal seizures, family history of epilepsy, motor function and epilepsy onset, treatment, and outcome. Electroclinical findings were classified according to seizure semiology, seizure type, and epilepsy syndrome. Results Mean age of participants at the time of study was 10 years 6 months (SD 4y 7mo, range 4–20y). Gross Motor Function Classification System levels I and II were reported in 96% of participants, and Manual Ability Classification System levels I and II were reported in 79% of children. Thirty‐four children (54%) developed epilepsy. Term delivery and more severe motor impairment were associated with epilepsy, but neonatal seizures and family history of epilepsy were not. Initial seizures were epileptic spasms, focal seizures, or myoclonic seizures. Focal seizure semiology suggested Rolandic or occipital seizure origin in the majority of children. Focal epileptic discharges in children with focal seizures had features of idiopathic partial epilepsy. Only 15% of children had active epilepsy 10 years after onset. Interpretation Despite a high incidence of epilepsy in children with hemiplegic CP due to AIS, the prognosis for seizure remission is good. Many children have clinical features, electroencephalography findings, and remission typical of idiopathic partial epilepsy.     

结节性硬化致癫痫发作的临床特点及治疗观察

目的　分析结节性硬化 (TS)所致癫痫的临床特点及治疗效果。方法　对 2 0例TS所致癫痫患者的临床发作特点 ,电生理、影像学资料及抗癫痫药物 (AEDs)的治疗效果进行分析。结果　本组癫痫发作均出现在 1 0岁之前 ,其中 2岁之前发病 1 5例 (75 .0 % ) ,主要发作类型为部分性发作 1 0例 (50 .0 % )。 5例患者在疾病发展过程中 ,从部分发作转化为全身强直 阵挛发作。 2例结节位于皮质且直径 >1 0mm ,其位置与脑电图 (EEG)主要放电的部位相符。 1 1例 (61 .1 1 % )AEDs治疗有效。 1 0例随诊 1年以上 ,其中 3例恶化。结论TS所致癫痫患者发病年龄低 ,主要发作类型为部分性发作 ,在疾病的发展过程中 ,发作形式可发生转变。皮质结节的大小与致痫灶有关。AEDs治疗有效 ,但随年龄增长 ,疗效下降