An incident case-control study of first unprovoked afebrile seizures in children: a population-based study of pre- and perinatal risk factors.

PURPOSE: The aim of this prospective incident community-based study was to assess the influence of pre- and perinatal risk factors in children in whom an unprovoked afebrile epileptic seizure later developed. METHODS: From November 1, 1985, until June 30, 1987, 75 children aged 0-15 years with a first unprovoked afebrile seizure were identified. After exclusion of cases with neonatal seizures (n = 14), two controls per case were selected from the same province in northern Sweden matched by age and sex. Files from maternity wards and pediatric clinics could be traced for 58 cases and 109 controls. These formed the study group. RESULTS: In the univariate analysis, the risk for an unprovoked afebrile seizure was significantly elevated for birth order (OR = 9.3; CI, 2.2-39), vaginal bleeding (OR = 17; 95% CI, 3.5-85), onset of hypertension during pregnancy (OR = 4.8; CI, 1.3-17), cesarean section (OR = 18; 95% CI, 3.7-88), short or long gestational age (OR = 6.7; 95% CI, 2.0-22), and an Apgar score < or =6 at any time (OR = 3.8; 95% CI, 1.2-12). None of these six factors was present in 48.3% of the cases and 89% in the controls. A combination of two or more risk factors found to be significant in the univariate analysis showed a pronounced increased risk for seizures (OR = 19; 95% CI, 5.6-65). In the multivariate analysis, the following characteristics remained statistically significant: vaginal bleeding, gestational age, and Cesarean section. Furthermore, smoking also was identified as a risk factor in the multivariate analysis (OR = 3.4; 95% CI, 1.1-10). CONCLUSIONS: Both pre- and perinatal factors may be associated with later development of epileptic seizures in children. However, in many of the cases, no such factors were identified.

Antiepileptic drug-related cognitive complaints in seizure-free children with epilepsy before and after drug discontinuation.

The cognitive complaints reported by children and their parents, as subjectively associated with antiepileptic drug (AED) treatment, were evaluated in seizure-free children before and after drug discontinuation. The aim of the design was to isolate the cognitive side effects of AEDs from other factors, such as the effect of seizures. Our inventory explored the following areas: "alertness," "concentration," "activation/ tiredness," "memory," "drowsiness," "depression," "aggressiveness," and "hyperactivity," using a 5-point Likert scaling procedure. One hundred two eligible patients were selected, each matched with a healthy control and assessed when still on antiepileptic medication. All children were seizure free for at least 1 year. The medication was then discontinued gradually over a 3-month period. Four months after the children were completely medication free, a second assessment was carried out, but only in the 83 children who remained seizure free and in their matched controls. The results of the reports made by the children themselves did not show differences with the matched controls, and only showed improvement after drug discontinuation for complaints about "tiredness." Parents of the children with epilepsy reported significant improvement in all areas related to "alertness and activation" after discontinuation of the drugs. The finding that only a limited number of children have cognitive complaints, both when still on AEDs and after discontinuation, may be in line with the reports that the major factor contributing to quality of life is whether patients are seizure free or still have seizures. All patients in this study were seizure free for a period >1 year, which may have caused the favorable pattern of response in our patient group.

A follow-up of an incident case-referent study of febrile convulsions seven years after the onset.

A cohort of 92 children with an initial febrile convulsion (FC), prospectively identified in a community-based study 1985-1987, was compared with a cohort of 185 age- and sex-matched referents from the same study area. The median time of follow-up was 6.7 years (range: 5.7-7.7) and the median age at follow-up was 8.3 years (range 6.5-14). The cases had their first FC at a median age of 18 months (range 5-67 months), their second FC at 24 months (11-108 months) and their third FC at 26 months (13-92 months). FC recurred in 42% of the FC cohort, and 3.8% of the children in the referent cohort experienced FC. Single or recurrent afebrile seizures occurred in 4.3% and epilepsy in 3.3% of the FC cohort, while no afebrile seizures occurred in the referent cohort. The risk of having a sibling with FC was three times (95% confidence interval 1.3-6.2) higher in the FC cohort, while there was no difference between the cohorts in the risk of siblings developing afebrile seizures. There was no difference between the cohorts in the utilization of health services during the follow-up period. Two children in the FC cohort went to a school for the mentally retarded. There was no aetiological relationship between the FC and the mental retardation in these cases. All other children attended normal schools and none needed remedial instruction.

Muscle morphology and mitochondrial investigations of a family with autosomal dominant cerebellar ataxia and retinal degeneration mapped to chromosome 3p12-p21.1.

The autosomal dominant cerebellar ataxias (ADCA) are a group of neurodegenerative disorders with ataxia and dysarthria as early and dominant signs. In ADCA type II, retinal degeneration causes severe visual impairment. ADCA type II has recently been mapped to chromosome 3p by three independent groups. In the family with ADCA type II studied here, the disease has been mapped to chromosome 3p12-p21.1. Histochemical examination of muscle biopsies in 5 cases showed slight neurogenic atrophy and irregular lobulated appearance or focal decreases of enzyme activity when staining for NADH dehydrogenase, succinic dehydrogenase and cytochrome oxidase. Ragged-red fibres were scarce. Electron microscopic examination showed uneven distribution of mitochondria with large fibre areas devoid of mitochondria and/or large subsarcolemmal accumulations of small rounded mitochondria, and frequent autophagic vacuoles. These vacuoles contained remnants of multiple small rounded organelles, possibly mitochondria, and had a remarkably consistent ultrastructural appearance. Biochemical investigation of mitochondrial function showed reduced activity of complex IV and slightly reduced activity of complex I in the respiratory chain in a severely affected child while no abnormalities were found in his affected uncle.

Prevalence and characteristics of epilepsy in children in northern Sweden.

Active epilepsy was assessed in all children aged 0-16 years in an area of northern Sweden with about 250,000 inhabitants and around 50,000 children in the age group. One hundred and fifty-five children fulfilled the criteria of active epilepsy giving a prevalence rate of 4.2/1000. The proportion of boys to girls was 1:1.1. This dominance of girls had also been seen in a prospective study of incidence of epilepsy in the same area. Partial seizures were more common than generalized. Among the syndromes benign childhood epilepsy with centrotemporal spikes occurred in 17.4%, absence epilepsy in 6.5% and Lennox-Gastaut syndrome in 5.8%. Children with neurodeficit (ND) more often had generalized epileptic syndromes while the non-ND groups more often had localisation related syndromes. The aetiology was regarded to be remote symptomatic in 42%, idiopathic in 28% and cryptogenic in 30% of the children. Almost all children were on antiepileptic treatment, three quarters of them on monotherapy. Neurodeficit was noted in 42%. The prevalence of epilepsy and mental retardation was 1.7/1000. Relatively few children with neurodeficit had been seizure free during the last year, 43% had more than one seizures per month compared to 19% in the non-ND group.

Localization of autosomal dominant cerebellar ataxia associated with retinal degeneration and anticipation to chromosome 3p12-p21.1.

We present linkage analysis on a large Swedish five-generation family of 15 affected individuals with autosomal dominant cerebellar ataxia (ADCA) associated with retinal degeneration and anticipation. Common clinical signs in this family include ataxia, dysarthria and severely impaired vision with the phenotype ADCA type II. Different subtypes of ADCA have proven difficult to classify clinically due to extensive phenotypic variability within and between families. Genetic analysis of a number of ADCA type I families shows that heterogeneity exists also genetically. During the last few years several types of ADCA type I have been localized and to date six genetically distinct forms have been identified including SCA1 (6p), SCA2 (12q), SCA3 and Machado-Joseph disease (MJD) (14q), SCA4 (16q), and finally SCA5 (11). We performed a genome-wide search of the Swedish ADCA type II family using a total of 270 microsatellite markers. Positive lod scores were obtained with a number of microsatellite markers located on chromosome 3p12-p21.1. Three markers gave lod scores over 3 with a maximum lod score of 4.53 achieved with the marker D3S1600. The ADCA type II gene could be restricted to a region of 32 cM by the markers D3S1547 and D3S1274.

Withdrawal of antiepileptic medication in children. Correlation of cognitive function and plasma concentration--the multicentre 'Holmfrid' study.

Eighty-three patients with epilepsy and 83 matched controls completed 12 computerized cognitive tests while on antiepileptic drugs and six months later when they had been medication-free for three to four months. All patients had been seizure-free for more than one year and were on monotherapy with carbamazepine (CBZ, n = 56), valproate (VPA, n = 17), or phenytoin (PHT, n = 10). The tests and plasma concentration collection were done at noon. The mean peak plasma concentrations in the CBZ patients were as follows: 31% below 30 mumol/l, 48% between 30 and 42 mumol/l and 21% above 42 mumol/l. No difference in performance could be detected between the groups. One significant correlation between plasma concentration and test results was found. The mean VPA concentration was 625 mumol/l (S.D. 189). A tendency towards a weak negative correlation between test results and plasma concentration was present. The PHT patients' therapeutic range had a mean concentration of 32.0 mumol/l (S.D. 18.5). One significant correlation between a memory test and plasma concentration could be detected. Overall, the patients in the different antiepileptic groups performed less good than the control group and in a few cases the differences were statistically significant when compared either before or after withdrawal. A comparison of the changes after withdrawal showed improvement in the majority of tests, but these changes were also present in the matched control group.

A community-based prospective incidence study of epileptic seizures in children.

During a 20-month period, an attempt was made to find all children with unprovoked non-febrile seizures. The first attendance and incidence rates were 95 and 89/100,000, respectively, in the age group 0-15 years. These figures are lower than those found 10 years earlier in the same area. The highest incidence was during the first year of life and there was a higher proportion of girls (male:female ratio 1:1.4). Generalized seizures dominated in the first year of life. The incidence of benign childhood epilepsy with centro-temporal spikes was 10.7/100,000 and was the most common epilepsy syndrome found. The incidence of partial seizures increased with age up to the age of 10 years. One in 10 children had a history of febrile convulsions.

Withdrawal of antiepileptic medication in children--effects on cognitive function: The Multicenter Holmfrid Study.

We present 100 children diagnosed with epilepsy who were seizure-free for more than 1 year and still on monotherapy of antiepileptic drugs (AEDs). We matched each child with a healthy classmate and performed neuropsychological testing and EEG before and after complete withdrawal of the AEDs. The withdrawal phase lasted 3 months, but the dose decrease was individualized for each patient. Three to 4 months after complete withdrawal of the drug all patients were reassessed. Patients with seizure relapse are excluded from the study. Seventeen patients are regarded as dropout, 11 because of seizure relapse and six because of protocol violation. The remaining 83 patients were treated with carbamazepine (n = 56), valproic acid (n = 17), or phenytoin (n = 10). Serum concentrations of the AEDs were measured using peak plasma levels that were taken immediately before or after psychological testing. We used neuropsychological tests to assess psychomotor function and "central" cognitive processing such as information processing or memory function. We found significant improvement attributable to drug withdrawal on only one of the cognitive tests, namely, psychomotor speed, suggesting that the impact of AED treatment on higher-order cognitive function is rather limited. In addition, we found group differences between the epilepsy group and the control group at baseline that persisted after drug withdrawal. Subsequent analysis showed some factors that may have contributed to these group differences. First, patients with a former diagnosis of absence seizures show lower scores both at baseline and after drug withdrawal. We may assume that the seizure propensity has not disappeared completely in these patients. Some evidence is found that phenytoin may have a different cognitive profile than carbamazepine, with more impairment on tests that measure motor and mental speed. Again, this impairment persists after drug withdrawal.

Attitudes of rural people in central Ethiopia towards leprosy and a brief comparison with observations on epilepsy.

To find out public attitudes toward leprosy a door-to-door survey was carried out in 1546 sampled households in the rural farming community of Meskan and Mareko in central Ethiopia, where the prevalence of leprosy is estimated to be 1:1000. Attitudes toward leprosy were compared with attitudes to epilepsy, studied in a previously performed survey in the same community. Eighty-seven per cent of the respondents were above the age of 25, and 59.5% were females. There were slightly more Muslims (54%) than Christians. The majority of the interviewees (87%) were farmers, with an illiteracy rate of 84%. Ninety-five per cent and 83%, respectively, were not willing to employ or work with a person having the disease. Seventy-five per cent would not allow their children to associate with a playmate suffering from leprosy. Comparative analysis of attitudes in the same community showed that negative attitudes toward leprosy were stronger than those toward epilepsy, particularly with regard to matrimonial associations, sharing of accommodation, and physical contact with an affected person. The reasons for these differences appear to be the community's deeply entrenched belief that leprosy is both hereditary and contagious, expressed respectively by 48% and 53% of the respondents. In order to minimize the perpetuation of negative attitudes, there is a need to educate and impress on the population that leprosy is a treatable infectious disease which is not congenitally acquired, and that it is even curable if detected early. The study reinforces previously proposed suggestions that, in developing countries such as Ethiopia, leprosy care should be integrated into the general health services.

Pre- and perinatal factors in febrile convulsions.

In a community based study, 110 children with febrile convulsions (FC) were identified prospectively. Pre- and perinatal risk factors were compared with 213 age and sex matched controls sampled from the community. During pregnancy, proteinuria and preeclampsia/eclampsia occurred more often in mothers of cases. Premature birth and bilirubinemia greater than 200 mumol/l were also more common in cases. There were no differences between cases and controls in occurrence of chronic illnesses in mothers, parents age at birth, birth order, and factors occurring during delivery such as type of anesthesia, occurrence of acute or elective cesarean section, use of vacuum extraction, mode of presentation, signs of fetal distress in amnion fluid, umbilical problems, abnormalities of fetal heart rate or duration of delivery. Perinatal asphyxia was uncommon and there was no difference between cases and referents. Occurrence of complications during the first neonatal week did not differ between groups.

Attitudes of rural people in central Ethiopia towards epilepsy.

In the farming community of the sub-district of Meskan and Mareko in central Ethiopia, where the prevalence of epilepsy is known to be 5.2/1000, a door-to-door survey was undertaken in 1546 sampled households to find out public attitudes to epilepsy. Nearly 64% of the respondents were in the age group of 14-50 years, and 58.6% were women. The majority (86%) were illiterate, and 94% had incomes of a subsistence level; 89% had heard or witnessed seizures. Traditional views on the association of evil spirits and superstition was prevalent. By 45% of the interviewees, the disease was believed to be contagious through physical contacts during an attack. Although there was sympathetic concern in the community for the person suffering from epilepsy, negative attitudes were strong on matrimonial associations, sharing of accommodation and physical contacts with affected persons, particularly when there were obvious signs and frequent attacks by seizures. The study demonstrates that the rural community has very poor knowledge of the causes and nature of epilepsy, and this has resulted in social deprivations and at times, rejection of the sufferers.

Clinical and electroencephalographic characteristics of epilepsy in rural Ethiopia: a community-based study.

A community-based epidemiological study of neurological disorders was performed in a rural area in Ethiopia. The most prevalent neurological disorder identified was epilepsy, found in 316 persons. The prevalence of epilepsy was 5.2/1000 inhabitants at risk, 5.8 for males, 4.6 for females. The highest age-specific prevalence was found for ages 10-19 years. Generalized tonic-clonic seizures were the most common seizure type and occurred in 81%. On clinical grounds, partial seizures occurred in 20% and in 29% of these secondary generalization followed. During seizures, 8.5% had been injured by burns and 5.7% by trauma. Eighty-four percent had seizures at least monthly. Seizures occurred in 4.8% of siblings. Traditional treatment with local herbs, holy water and amulets was the most common. Only 1.6% had been treated with recognized antiepileptic drugs. Mental retardation was the most common associated disorder, found in 7.9% of the persons with epilepsy. During a period of 2 years, 8 persons died of status epilepticus and 1 from severe burns as a result of falling into a domestic fire during a seizure. EEG was recorded in 73%. Epileptiform activity occurred in 18%.

An incident case-referent study of febrile convulsions in children: genetical and social aspects.

In a prospective community-based study of 103 children with febrile convulsions (FC), social and genetical factors were compared with 193 age and sex matched referents sampled from the community. FC were found more often among parents of cases than referents (odds ratio 21.0; p less than 0.001). A history of FC in any type of relative was found in 39.8% of cases and 10.4% of referents (odds ratio 5.8; p less than 0.001). The familial occurrence of FC is best described by a multifactorial (polygenic) model. No difference was found between groups in the occurrence of other diseases than FC affecting the central nervous system and only one case was mentally retarded. No difference was found between cases and referents in the age of independent walking and ability to speak at age 18 months. Children with FC more often had infectious diseases than referents (odds ratio 2.84; p = 0.002). Children with FC more often lived in apartments and spent their time in day by day care institutions (odds ratio 2.91; p = 0.02). Parents' occupation did not differ between groups. Mothers of children with FC more often had compulsory education only compared with mothers of referents.

Epilepsy in a population of mentally retarded children and adults.

All mentally retarded (MR) subjects in a northern Swedish county were assessed for the occurrence of active epilepsy on a prevalence day. Active epilepsy was found in 299 subjects (20.2% of those with MR) corresponding to a crude prevalence rate of 1.2/1000 inhabitants. The age-specific prevalence for 0-9 years was higher for females than for males, while in other age groups it was slightly higher for males or showed no difference between the sexes. Epilepsy and MR were the only disorders in 129 subjects (43.1%). Cerebral palsy was the most common associated disorder and occurred in 100 (33.4%). A presumable etiology for epilepsy and MR was identified in 73.2% and 71.9%, respectively. The presumable etiological factors which caused MR occurred prenatally in 35%, perinatally in 10% and postnatally in 9%. The pathogenetic period was unknown in 31%. In 15%, the etiological events occurred during more than one of the above periods. The presumable causes were responsible for both epilepsy and MR in all except 7 cases. MR individuals with epilepsy were significantly more retarded than those without epilepsy. The first seizure occurred during the neonatal period in 11.6% and before 1 year of age in 27.7%. Generalized tonic-clonic seizures were the most common type and occurred in 204 subjects (68.2%). Seventy-one of these also had partial seizure manifestations. Daily to weekly seizures occurred in 26.8% and 32.0% had been seizure-free for the past year.

Community-based study of neurological disorders in Ethiopia: development of a screening instrument.

This paper describes the development of a screening instrument for a community-based neuroepidemiological survey in a rural community in Ethiopia. A pilot study in 1984 to pre-test the questionnaires developed revealed that epilepsy, poliomyelitis, mental retardation and speech disturbances were the most common neurological disorders among the 3,000 rural inhabitants surveyed. The study suggested that a base-population of about 50,000 was required for a future major epidemiological survey to identify rare neurological disorders.

A prospective incidence study of febrile convulsions.

A prospective epidemiological study of febrile convulsions (FC) was performed during a 20-month period. 128 children with FCs were identified. The annual first attendance rate and annual incidence rate were 500/100,000 and 460/100,000 respectively, in the age group 0-4 years. The cumulative incidence was 4.1%. FCs were more common among boys, with a male to female ratio of 1.72 to 1. The median and mean age for first FC was for boys 16 and 19.9 months respectively, and for girls 18 and 19.7 months respectively. During an average follow-up period of 20 months, 18% had another FC and 10% had two or more FCs. 8.6% had an initial complicated FC. Four children had FCs within two weeks after being vaccinated by combined vaccine against morbilli, rubella and parotitis. Three of these had earlier had an FC.

Discontinuation of antiepileptic drugs in children who have outgrown epilepsy: effects on cognitive function.

Cognitive function is frequently impaired in children with epilepsy, compared with age-matched controls. It can be hard to evaluate the significance of various contributory factors. The effects of antiepileptic drugs may be studied in children who have outgrown their epilepsy but are still being treated. A multicenter study to assess various aspects of cognitive function in children with different forms of epilepsy, both during and after treatment with antiepileptic drugs, is currently under way. Definitive results are not yet available; interim analysis of the findings suggests that short-term memory is decreased in all subgroups of children being treated for epilepsy, compared to controls.

Community-based study of neurological disorders in rural central Ethiopia.

Between 1986 and 1988 a door-to-door survey was conducted on a stable rural population of 60,820 in central Ethiopia. Trained lay health workers made a complete census and identified cases with symptoms and signs of neurological disorders, using specially designed questionnaires which, in a previous pilot study, were found to have a sensitivity of 91% and specificity of 85%. Neurological disorders in the rural population were epilepsy, postpoliomyelitis paralysis, mental retardation, peripheral neuropathy (mainly due to leprosy), and deaf-mutism with prevalence rates (cases/100,000 population) of 520, 240, 170, 150 and 130, respectively. The prevalence rates of the other less common neurological disorders were 62 for hemiparesis (15 of which were for cerebrovascular accidents), 20 for cerebral palsy, 16 for optic atrophy, 12 for perceptive deafness, 10 for tropical spastic paraparesis, 7 for Parkinson's disease and 5 for motor neuron disease, ataxia and chorea/athetosis. Among related non-neurological conditions, blindness, locomotor disability and deafness were predominant. The significance and role of such a neuroepidemiological study in laying the strategies for the prevention of neurological disorders and rehabilitation of patients are discussed in the context of a developing country.

Folate treatment of diphenylhydantoin-induced gingival hyperplasia.

It has recently been reported that folic acid supplementation reduced DPH-induced gingival hyperplasia in cat and in a pilot study also in man. The present study was performed to further evaluate this therapy in man. Twenty-three children with DPH-treatment for more than 1 yr, and eight children with short-time DPH-treatment were randomly assigned to groups with and without daily supplementation of folic acid (5 mg Folacin) for 1 yr. Although the DPH-levels were in many cases below the lower reference value, the seizure control of the children was good before and during the year of study. The plasma and red cell folate levels were within or above the given reference values in all but one child. There were no significant changes in the size of the gingival hyperplasias after 1 yr of folate supplementation. Nine severely mentally retarded DPH-treated adults were also given supplementation with folic acid. Their serum DPH-levels were above the higher reference values both at the start and during the study. Their plasma and red cell folic acid levels were below the reference value at the start of the study, but as a consequence of the Folacin supplementation these values rose. The size of the gingival hyperplasias was significantly reduced. Seizure control was unchanged. Folate levels should be checked and supplementation with folic acid considered in patients on long-term anticonvulsive multipharmacy therapy.