Search

Summary Objective Navigated transcranial magnetic stimulation (nTMS) is becoming increasingly popular in noninvasive preoperative language mapping, as its results correlate well enough with those obtained by direct cortical stimulation (DCS) during awake surgery in adult patients with tumor. Reports in the context of epilepsy surgery or extraoperative DCS in adults are, however, sparse, and validation of nTMS with DCS in children is lacking. Furthermore, little is known about the risk of inducing epileptic seizures with nTMS in pediatric epilepsy patients. We provide the largest validation study to date in an epilepsy surgery population. Methods We compared language mapping with nTMS and extraoperative DCS in 20 epilepsy surgery patients (age range 9‐32 years; 14 children and adolescents). Results In comparison with DCS, sensitivity of nTMS was 68 specificity 76 positive predictive value 27 and negative predictive value 95 Age, location of ictal‐onset zone near or within DCS‐mapped language areas or severity of cognitive deficits had no significant effect on these values. None of our patients had seizures during nTMS. Significance Our study suggests that nTMS language mapping is clinically useful and safe in epilepsy surgery patients, including school‐aged children and patients with extensive cognitive dysfunction. Similar to in tumor surgery, mapping results in the frontal region are most reliable. False negative findings may be slightly more likely in epilepsy than in tumor surgery patients. Mapping results should always be verified by other methods in individual patients.

Introduction: Prenatal exposure to antiepileptic drugs (AEDs) is associated with developmental compromises in verbal intelligence and social skills in childhood. Our aim was to evaluate whether a multifeature Mismatch Negativity (MMN) paradigm assessing semantic and emotional components of linguistic and emotional processing would be useful to detect possible alterations in early auditory processing of newborns with prenatal AED exposure. Material and methods: Data on AED exposure. pregnancy outcome, neuropsychological evaluation of the mothers, information on maternal epilepsy type, and a structured neurological examination of the newborn were collected prospectively. Blinded to AED exposure, we compared a cohort of 36 AED-exposed with 46 control newborns at the age of two weeks by measuring MMN with a multifeature paradigm with six linguistically relevant deviant sounds and three emotionally uttered sounds. Results: Frontal responses for the emotionally uttered stimulus Happy differed significantly in the exposed newborns compared with the control newborns. In addition, responses to sounds with or without emotional component differed in newborns exposed to multiple AEDs compared with control newborns or to newborns exposed to only one AED. Conclusions: These preliminary findings suggest that prenatal AED exposure may alter early processing of emotionally and linguistically relevant sound information. (C) 2019 Elsevier Inc. All rights reserved.

Background: Pathogenic variants in SCN2A are associated with various neurological disorders including epilepsy, autism spectrum disorder and intellectual disability. Few reports have recently described SCN2A-associated episodic ataxia (EA). Our study identifies its broader clinical and genetic spectrum, and describes pharmacological approaches. Results: We report 21 patients with SCN2A-associated EA, of which 9 are unpublished cases. The large majority of patients present with epileptic seizures (18/21, 86%), often starting within the first three months of life (12/18, 67%). In contrast, onset of episodic ataxia ranged from 10 months to 14 years of age. The frequency of EA episodes ranged from brief, daily events up to 1-2 episodes per year each lasting several weeks. Potential triggers include minor head traumas and sleep deprivation. Cognitive outcome is favorable in most patients with normal or mildly impaired cognitive development in 17/21 patients (81%). No clear genotype-phenotype correlations were identified in this cohort. However, two mutational hotspots were identified, i.e. 7/21 patients (33%) harbor the identical pathogenic variant p.A263V, whereas 5/21 (24%) carry pathogenic variants that affect the S4 segment and its cytoplasmic loop within the domain IV. In addition, we identified six novel pathogenic variants in SCN2A. While acetazolamide was previously reported as beneficial in SCN2A-associated EA in one case, our data show a conflicting response in 8 additional patients treated with acetazolamide: three of them profited from acetazolamide treatment, while 5/8 did not. Conclusions: Our study describes the heterogeneous clinical spectrum of SCN2A-associated EA, identifies two mutational hotspots and shows positive effects of acetazolamide in about 50%. (C) 2019 European Paediatric Neurology Society. Published by Elsevier Ltd. All rights reserved.

Background Dose regimens of pyridoxine (vitamin B6) for treatment of infantile spasms have varied from 200 mg/d to 300 mg/kg/d. Only two long-term outcome studies of the treated patients are available. Methods We asked all pediatric neurologists treating pediatric epilepsy in Finland if they had seen patients with pyridoxine-responsive infantile epilepsy. Five children with infantile spasms and hypsarrhythmia and one with focal epilepsy were reported as pyridoxine responders. Data on clinical presentation and outcome were collected from patient charts. Results All B6 responders had un-known aetiology. Two patients were studied for pyridoxal 5′-phosphate oxidase (PNPO) deficiency and showed negative results. Ages at seizure onset ranged from 4 to 7 months. The maintenance dose of oral pyridoxine was 150 mg/day. Response occurred within 1-to 14 days (mean 5 days). Two patients were treated with concomitant antiepileptic drugs. Duration of pyridoxine therapy varied from 6 weeks to 4 years (mean 26 months). Four patients had later seizure recurrence: one at 15 months with motor seizures (stopped by valproate), another two in adolescence with focal epilepsy and one at 20 years with unclassified epilepsy. Intelligence was normal in five patients and one had a mild mental deficiency. Follow-up ranged from 8.5 to 24 years. Conclusions Rare patients with infantile epilepsy but not pyridoxine dependency may respond to smaller doses of pyridoxine than reported before. Long-term cognitive outcome appears to be good but late seizure recurrence (in adolescence or in adulthood) occur. So far it is unknown if the response was determined by genetic traits or disease-related factors.

This document provides guidance on the use of valproate in girls and women of childbearing age from a joint Task Force of the Commission on European Affairs of the International League Against Epilepsy (CEA-ILAE) and the European Academy of Neurology (EAN), following strengthened warnings from the Coordination Group for Mutual Recognition and Decentralised Procedures-Human (CMDh) of the European Medicines Agency (EMA), which highlight the risk of malformations and developmental problems in infants who are exposed to valproate in the womb. To produce these recommendations, the Task Force has considered teratogenic risks associated with use of valproate and treatment alternatives, the importance of seizure control and of patient and fetal risks with seizures, and the effectiveness of valproate and treatment alternatives in the treatment of different epilepsies. The Task Force's recommendations include the following: (1) Where possible, valproate should be avoided in women of childbearing potential. (2) The choice of treatment for girls and women of childbearing potential should be based on a shared decision between clinician and patient, and where appropriate, the patient's representatives. Discussions should include a careful risk-benefit assessment of reasonable treatment options for the patient's seizure or epilepsy type. (3) For seizure (or epilepsy) types where valproate is the most effective treatment, the risks and benefits of valproate and other treatment alternatives should be discussed. (4) Valproate should not be prescribed as a first-line treatment for focal epilepsy. (5) Valproate may be offered as a first-line treatment for epilepsy syndromes where it is the most effective treatment, including idiopathic (genetic) generalized syndromes associated with tonic-clonic seizures. (6) Valproate may be offered as a first-line treatment in situations where pregnancy is highly unlikely (e.g., significant intellectual or physical disability). (7) Women and girls taking valproate require regular follow-up for ongoing consideration of the most appropriate treatment regimen.

Summary Purpose Dravet syndrome is an autosomal dominant epileptic encephalopathy of childhood, which is caused mainly by SCN1A and PCHD19 mutations. Although Dravet syndrome is well recognized, the causes of acute encephalopathy are still elusive, and reported data on ictal electroencephalography (EEG) and structural brain abnormalities are scarce. Methods We studied 30 children who fulfilled the clinical criteria for Dravet syndrome. All patients were screened for SCN1A mutations and 25 for POLG mutations with bidirectional sequencing. Clinical data, including etiologic studies done as part of the clinical workup, were collected from hospital charts. Ictal video-EEG recordings and magnetic resonance (MR) images were reanalyzed by the authors. Key Findings SCN1A mutations were found in 25 patients (83%). Two SCN1A mutation–negative patients had chromosomal translocations involving chromosomes 9 and X, and one had a mutation in PCDH19. Prolonged seizures were associated with acute encephalopathy in three SCN1A mutation–positive patients. One showed evidence of a significant hypoxic–ischemic event during status epilepticus. The other two demonstrated new persistent neurologic deficits postictally; they both carried heterozygous POLG variants (p.Trp748Ser or p.Gly517Val). Hippocampal sclerosis or loss of gray–white matter definition in the temporal lobe was observed in 7 of 18 patients who had MRI after age 3 years (39%). Motor seizures were recorded on video-EEG for 15 patients, of whom 12 were younger than 6 years at recording; 11 patients (73%) showed posterior onsets. Significance Our data imply that a heterozygous X;9 translocation and rare POLG variants may modify the clinical features of Dravet syndrome. The latter may increase susceptibility for acute encephalopathy. Temporal lobe abnormalities are common in patients imaged after 3 years of age. Focal seizures seem to localize predominantly in the posterior regions in young children with Dravet syndrome.

SummaryObjective Population-based studies on infantile epilepsy syndromes are scarce. Our aim was to provide syndrome-specific data on the incidence and outcome of epilepsy in a population-based cohort of infants with epilepsy onset in the first year. Methods Included were all infants born in 1997 through 2006 whose epileptic seizures started before 12 months of age and who were residents of the Helsinki University Hospital district at the time of seizure onset. Patients were ascertained from hospital statistics, and all patient charts were reviewed. A reevaluation of the epilepsy syndromes, age at onset, etiology, and outcome at 24 months of age was based on data abstracted from the patient files. Results Inclusion criteria were fulfilled by 158 infants, of whom 92% were followed until age 24 months or death. The incidence of epilepsy in the first year was 124 of 100,000. An epilepsy syndrome recognized by the revised organization of epilepsies by ILAE was identified in 58% of the patients. The most common syndromes were West syndrome (41/100,000) and benign familial or nonfamilial infantile epilepsy (22/100,000). Etiology was structural-metabolic in 35%, genetic in 17%, and unknown in 48%. Early age at onset was associated with structural-metabolic etiology. Seven infants (4.4%) died before age 2 years. One infant with an SCN2A mutation died of sudden unexplained death in epilepsy (SUDEP). At 24 months, 58% of all children included in the cohort were seizure-free, and 46% had both seizure freedom and age-appropriate cognitive development. Age at onset was not associated with outcome when etiology was controlled for. Significance Benign familial and nonfamilial infantile epilepsy appears to be more common than previously suggested, second only to West syndrome. Early age at onset is not an independent risk factor for poor outcome.

Introduction: Prenatal antiepileptic drug (AED) exposure is associated with an increased risk of cognitive impairment and autism spectrum disorders detected mainly at the age of two to six years. We examined whether the developitiental aberrations associated with prenatal AED exposure-could be-detected already in infancy and whether effects on visual attention can be observed at this early age. Material and methods: We compared a prospective cohort of infants with in utero exposure to AED (n = 56) with infants without drug exposures (n = 62). The assessments performed at the age of seven months included standardized neurodevelopmental scores (Griffiths Mental Developmental Scale and Hammersmith Infant Neurological Examination) as well as a novel eye-tracking-based test for visual attention and orienting to faces. Background information included prospective collection of AED exposure data, pregnancy outcome, neuropsychological evaluation of the mothers, and information on maternal epilepsy type. Results: Carbamazepine, oxcarbazepine, and valproate, but not lamotrigine or levetiracetam, were associated with impaired early language abilities at the age of seven months. The general speed of visuospatial orienting or attentional bias for faces measured by eye-tracker-based tests did not differ between AED-exposed and control infants. Discussion: Our findings support the idea that prenatal AED exposure may impair verbal abilities, and this effect may be detected already in infancy. In contrast, the early development of attention to faces was spared after in utero AED exposure. (C) 2016 Elsevier Inc. All rights reserved.

BACKGROUND: Sanger sequencing, still the standard technique for genetic testing in most diagnostic laboratories and until recently widely used in research, is gradually being complemented by next-generation sequencing (NGS). No single mutation detection technique is however perfect in identifying all mutations. Therefore, we wondered to what extent inconsistencies between Sanger sequencing and NGS affect the molecular diagnosis of patients. Since mutations in SCN1A, the major gene implicated in epilepsy, are found in the majority of Dravet syndrome (DS) patients, we focused on missed SCN1A mutations.METHODS: We sent out a survey to 16 genetic centers performing SCN1A testing.RESULTS: We collected data on 28 mutations initially missed using Sanger sequencing. All patients were falsely reported as SCN1A mutation-negative, both due to technical limitations and human errors.CONCLUSION: We illustrate the pitfalls of Sanger sequencing and most importantly provide evidence that SCN1A mutations are an even more frequent cause of DS than already anticipated.

SUMMARY Purpose: Ictal video‐electroencephalography (EEG) is commonly used to establish ictal onset-zone location. Recently software development has enabled systematic studies of ictal magnetoencephalography (MEG). In this article, we evaluate the ability of ictal MEG signals tolocalize the seizure-onset zone. Methods: Twenty-six patients underwent ictal MEG and epilepsy surgery. Prediction of seizure-onset zone by ictal and interictal MEG was retrospectively compared with ictal-onset area found by intracranial EEG in 12 patients. The specificity and sensitivity of the prediction were calculated at hemisphere-lobe (HL) and at hemisphere-lobesurface (HLS) levels. Key Findings: The sensitivity of ictal MEG source localization was 0.958 on HL and 0.706 on HLS levels, and its specificity was 0.900 on HL and 0.731 on HLS levels. The interictal MEG dipole cluster, defined as >10 dipoles on one lobar surface, had sensitivity of 0.400 and specificity of 0.769. Ictal MEG was equally sensitive and specific on dorsolateral and nondorsolateral neocortical surfaces up to a depth of 4 cm from the scalp. Significance: Sources of ictal-onset MEG signals and interictal dipole clusters are essentially equally specific in estimation of the ictal-onset zone on lobar surface resolution, but ictal MEG is more sensitive. On the lobe resolution, ictal MEG estimates ictal-onset zone with high sensitivity

Mutations in the cyclin-dependent kinase-like 5 gene (CDKL5) have been identified in female patients with early onset epileptic encephalopathy and severe mental retardation with a Rett-like phenotype. Subsequently CDKL5 mutations were shown to be associated with more diverse phenotypes including mild epilepsy and autism without epilepsy. Furthermore, CDKL5 mutations were found in patients with Angelman-like phenotype. The severity of epilepsy associated with CDKL5 mutations was recently shown to correlate with the type of CDKL5 mutations and epilepsy was identified to involve three distinct sequential stages. Here, we describe the phenotype of a severe form of neurodevelopmental disease in a female patient with a de novo nonsense mutation of the CDKL5 gene c.175C > T (p.R59X) affecting the catalytic domain of CDKL5 protein. Mutations in the CDKL5 gene are less common in males and can be associated with a genomic deletion as found in our male patient with a deletion of 0.3 Mb at Xp22.13 including the CDKL5 gene. We review phenotypes associated with CDKL5 mutations and examine putative relationships between the clinical epilepsy phenotype and the type of the mutation in the CDKL5 gene.

Summary Purpose: We analyzed clinical and electroencephalography (EEG) outcomes of 13 patients with pharmacoresistant encephalopathy with electrical status epilepticus during sleep (ESES) following epilepsy surgery. Methods: All patients had symptomatic etiology of ESES and preoperative neuropsychological deterioration. Ten patients had daily atypical absences. Clinical outcome was assessed at 6 months and at 2 years after surgery. Clinical and EEG data were reviewed retrospectively. The spike propagation pattern and area and source strength in source montage were analyzed from preoperative and postoperative EEG studies. Key Findings: Preoperative sleep EEG showed electrical status epilepticus during sleep (SES) with one-way interhemispheric propagation in nine patients and with two-way interhemispheric propagation in four. The age of the patients at the time of surgery ranged from 3.6–9.9 years. Focal resection (two patients) or hemispherotomy (one patient with postoperative EEG) either terminated SES or restricted the discharge to one region. Either reduced SES propagation area or source strength was found in four of eight callosotomy patients with postoperative EEG. Of patients who had seizures preoperatively, Engel class I–II seizure outcome was observed in two of three children after focal resection or hemispherotomy and in two of eight children after callosotomy. None of these patients with Engel class I–II outcome had SES with two-way interhemispheric propagation on preoperative EEG. Cognitive deterioration was halted postoperatively in all except one patient. Cognitive catch-up of more than 10 IQ points was seen in three patients, all of whom had shown a first measured IQ of >75. Significance: Patients with pharmacoresistant ESES based on symptomatic etiology may benefit from resective surgery or corpus callosotomy regarding both seizure outcome and cognitive prognosis.

Summary Purpose: CO2 has been long recognized for its anticonvulsant properties. We aimed to determine whether inhaling 5% CO2 can be used to suppress seizures in epilepsy patients. The effect of CO2 on cortical epileptic activity accompanying behavioral seizures was studied in rats and nonhuman primates, and based on these data, preliminary tests were carried out in humans. Methods: In freely moving rats, cortical afterdischarges paralleled by myoclonic convulsions were evoked by sensorimotor cortex stimulation. Five percent CO2 was applied for 5 min, 3 min before stimulation. In macaque monkeys, hypercarbia was induced by hypoventilation while seizure activity was electrically or chemically evoked in the sensorimotor cortex. Seven patients with drug-resistant partial epilepsy were examined with video-EEG (electroencephalography) and received 5% CO2 in medical carbogen shortly after electrographic seizure onset. Results: In rats, 5% CO2 strongly suppressed cortical afterdischarges, by approximately 75%, whereas responses to single-pulse stimulation were reduced by about 15% only. In macaques, increasing pCO2 from 37 to 44–45 mm Hg (corresponding to inhalation of 5% CO2 or less) suppressed stimulation-induced cortical afterdischarges by about 70% and single, bicuculline-induced epileptiform spikes by approximately 25%. In a pilot trial carried out in seven patients, a rapid termination of electrographic seizures was seen despite the fact that the application of 5% CO2 was started after seizure generalization. Conclusions: Five percent CO2 has a fast and potent anticonvulsant action. The present data suggest that medical carbogen with 5% CO2 can be used for acute treatment to suppress seizures in epilepsy patients.

SUMMARY Purpose: To prospectively evaluate the efficacy of drug treatment and long-term cognitive outcome in children with encephalopathy with status epilepticus during sleep (ESESS). Methods: Thirty-two children were diagnosed and prospectively followed up for at least 3 years at our unit between 1991 and 2007. Twenty-seven children were included in the prospective treatment study with valproate (VPA) and 17 with VPA combined with ethosuximide (ESM). Treatment response of disappearance of electrical status epilepticus during sleep (SES) was documented with overnight EEG recordings. Neuropsychological follow up for at least 5 years was available in 18 patients. Results: Six children had atypical rolandic (AR) epilepsy, nine Landau-Kleffner syndrome (LKS), and 17 symptomatic epilepsy. Before ESESS, 20 children were cognitively normal. Prospective treatment with VPA and ESM was effective in 3 of the 17 children (18%) treated. Abolition of SES with drug treatment was observed in 16 patients. In all, 10 children (31%), 4 with AR (67%), 3 with LKS (33%), and 3 with symptomatic etiology (19%), including 9 with treatment response regained the pre-ESESS cognitive level. Unfavorable cognitive outcome was predicted by younger age at ESESS diagnosis, lower IQ at the time of the diagnosis, and no response to drug treatment when compared with those with favorable cognitive outcome. Eight of the 16 nonresponders underwent epilepsy surgery. Discussion: Treatment response with VPA combined with ESM was observed more often than with other drug combinations. Most children with ESESS experienced permanent cognitive impairment. Cognitive outcome depends on treatment response on electroencephalography (EEG) and seizures, and on underlying etiology.

Summary Purpose: The use of vigabatrin (VGB) as an antiepileptic drug (AED) has been limited by evidence showing that it causes vigabatrin-attributed visual field loss (VAVFL) in at least 20–40% of patients exposed at school age or later. VGB is an effective drug for infantile spasms, but there are no reports on later visual field testing after such treatment. Our aim was to investigate the risk of VAVFL in school-age children who had received VGB in infancy. Methods: Visual fields of 16 children treated with VGB for infantile spasms were examined by Goldmann kinetic perimetry at age 6–12 years. Normal fields were defined as the temporal meridian extending to more than 70°, and mild VAVFL between 50 and 70°. Abnormal findings were always confirmed by repeating the test. Exposure data were collected from hospital charts. Results: Vigabatrin was started at a mean age of 7.6 (range, 3.2–20.3) months. The mean duration of therapy was 21.0 (9.3–29.8) months and cumulative dose 655 g (209–1,109 g). Eight children were never treated with other AEDs, five received only adrenocorticotropic hormone (ACTH) in addition to VGB, and three children had been treated with other AEDs. Fifteen children had normal visual fields. Mild VAVFL was observed in one child (6%) who had been treated with VGB for 19 months and who received a cumulative dose of 572 g. Conclusions: The risk of VAVFL may be lower in children who are treated with VGB in infancy compared to patients who receive VGB at a later age.

The majority of children of mothers with epilepsy are normal, but they are at increased risk for developmental delay. Antiepileptic drugs (AEDs) appear to play a role. Our current knowledge is reviewed, including research design issues and recommendations for future research. In animals, exposure of the immature brain to some AEDs can produce widespread neuronal apoptosis and behavioral deficits. The risks of AEDs in humans are less clear, but recent studies raise concerns, especially for valproate. There is a critical need for well-designed systematic research to improve our understanding of AED effects on the fetal brain.

SummaryObjective Prenatal exposure to antiepileptic drugs (AEDs) is associated with an increased risk of cognitive dysfunction at early school age. Our aim was to investigate whether signs of adverse drug effects on brain function could be detected already during the first 2 weeks of life. Methods We studied prospectively 56 full-term newborns with prenatal exposure to AEDs and 67 unexposed newborns for the following characteristics: Background information, AED exposure data, pregnancy outcome, neuropsychological evaluation of the mothers, clinical neurologic status with Hammersmith Neonatal Neurological Examination and early cortical activity using electroencephalography (EEG). For EEG assessment, we developed and provide automated quantitation algorithms of several earlier described features: oscillatory bouts at theta and alpha frequencies, frequency spectra, interhemispheric synchrony, and interburst intervals (IBIs). Results The AED-exposed newborns had lower limb and axial tone and were less irritable than the unexposed newborns. EEG assessment disclosed significant differences in alpha bouts, in the frequency spectra, as well as in the spatial distributions of interhemispheric synchrony and IBIs. Significance The results indicate that fetal AED exposure may affect early neonatal neurologic status and several features of early cortical activity. The findings suggest that interference of activity-dependent network development may be a possible mechanism to explain the link from fetal AED exposure to later neurocognitive sequelae.

Mutations in SCN2A cause epilepsy syndromes of variable severity including neonatal-infantile seizures. In one case, we previously described additional childhood-onset episodic ataxia. Here, we corroborate and detail the latter phenotype in three further cases. We describe the clinical characteristics, identify the causative SCN2A mutations and determine their functional consequences using whole-cell patch-clamping in mammalian cells. In total, four probands presented with neonatal-onset seizures remitting after five to 13 months. In early childhood, they started to experience repeated episodes of ataxia, accompanied in part by headache or back pain lasting minutes to several hours. In two of the new cases, we detected the novel mutation p.Arg1882Gly. While this mutation occurred de novo in both patients, one of them carries an additional known variant on the same SCN2A allele, inherited from the unaffected father (p.Gly1522Ala). Whereas p.Arg1882Gly alone shifted the activation curve by -4 mV, the combination of both variants did not affect activation, but caused a depolarizing shift of voltage-dependent inactivation, and a significant increase in Na+ current density and protein production. p.Gly1522Ala alone did not change channel gating. The third new proband carries the same de novo SCN2A gain-of-function mutation as our first published case (p.Ala263Val). Our findings broaden the clinical spectrum observed with SCN2A gain-of-function mutations, showing that fairly different biophysical mechanisms can cause a convergent clinical phenotype of neonatal seizures and later onset episodic ataxia.

Objectives The purpose of the study was to evaluate the etiology and long-term outcomes of late-onset epileptic spasms (LOS). Methods This is a retrospective analysis of all consecutive patients seen at our center with onset of clusters of epileptic spasms between 1 and 3 years of age in 1995 through 2005. Results Overall, 17 children with LOS were identified. Overall, 14 children (82%) had structural etiology. Six patients received resective surgical treatment. Five had focal cortical dysplasia type 1 (FCD1) histology (29% of all the patients). Overall, 16 children were followed for 2 to 18 years. At the latest follow-up, seizure freedom was observed in 67% of the operated and in 50% of the nonoperated patients. Normal cognition or only mild mental deficiency was observed in nine patients (56%), of whom eight were seizure-free. All patients with intractable spasms had a severe mental deficiency. Conclusion The overall cognitive outcome of LOS was more favorable than in the previous reports and was associated with seizure freedom. FCD1 is a frequent etiology for LOS and the cognitive outcome of patients with FCD1 seemed to be favorable.

Research findings concerning cognitive effects of pediatric epilepsy surgery form an important basis for decisions about surgery. However, most follow-up studies have been of limited duration. In this study, a 2-year follow-up of intelligence was undertaken. Risk factors were analyzed. Included were 38 patients aged 3 to 17 years. Surgery was left in 19 patients and right in 19 patients. Types of surgery included temporal lobe resection (n = 23), extratemporal or multilobar resection (n = 8), and hemispherectomy (n = 7). The Wechsler Scales of Intelligence were administered presurgically, 6 months postsurgically, and 2 years postsurgically. No significant change in verbal or performance intelligence quotient (IQ) was demonstrated on a group level. Lateralization, type of surgery, age at surgery, sex, and presurgical IQ did not affect outcome. Across assessments, IQ scores of left-hemisphere patients were lower than those of right-hemisphere patients. Scores of patients in the hemispherectomy group were lower than those of the extratemporal or multilobar resection group, which were lower than the temporal lobe resection group. Scores improved significantly in six patients and deteriorated in seven. In conclusion, epilepsy surgery in children and adolescents does not, in general, have a significant impact on cognitive development in a 2-year perspective. In individual patients, poor seizure control and extensive surgery for Rasmussen's encephalitis were related to a deterioration of IQ.

To assess proton magnetic resonance (MR) spectroscopy in differentiating between low-grade gliomas and focal cortical developmental malformations (FCDMs).Eighteen patients with seizures and a cortical brain lesion on MR images were studied with proton MR spectroscopy. A metabolite ratio analysis was performed, and the metabolite signals in the lesion core were compared with those in the contralateral centrum semiovale and in the corresponding brain sites in 18 control subjects to separately obtain the changes in N-acetylaspartate (NAA), choline-containing compounds (Cho), and creatine-phosphocreatine (Cr). Ten patients had a low-grade glioma (three, oligodendrogliomas; three, oligoastrocytomas; three, astrocytomas; and one, pilocytic astrocytoma), and eight had FCDM (five, focal cortical dysplasias and three, dysembryoplastic neuroepithelial tumors). Linear discriminant analysis and Student t test were used for statistical comparisons.Loss of NAA and increase of Cho were more pronounced in low-grade gliomas than in FCDMs (NAA, -72% +/- 15 [+/- SD] vs -29% +/- 22, P.001; Cho, 117% +/- 56 vs 21% +/- 66, P.01). Changes in NAA and Cho helped differentiate low-grade gliomas from FCDMs, and changes in Cho and Cr helped differentiate astrocytomas from oligodendrogliomas and oligoastrocytomas. Metabolite NAA/Cho and NAA/Cr ratios helped differentiate low-grade gliomas from FCDMs but did not differentiate glioma subtypes.MR spectroscopy allows distinction between low-grade gliomas and FCDMs and between low-grade glioma subtypes. Metabolite changes are more informative than are metabolite ratios.

Objective: To investigate the effect of antiepileptic drugs, especially carbamazepine and valproate, on intelligence in prenatally exposed children of mothers with epilepsy. Methods: Intelligence of 182 children of mothers with epilepsy (study group) and 141 control children was tested in a blinded setting at preschool or school age using Wechsler Preschool and Primary Scale of Intelligence–Revised or Wechsler Intelligence Scale for Children–Revised. Data on maternal antiepileptic treatment and seizures during pregnancy were gathered prospectively. The study group represented approximately 50% of the children born to mothers with epilepsy in Uusimaa province during 1989 through1994. One hundred seven children were exposed to antiepileptic monotherapy: 86 to carbamazepine and 13 to valproate. Thirty children were exposed to polytherapy: 23 combinations included carbamazepine, and 17 included valproate. The median maternal doses and blood levels during the second half of pregnancy were 600 mg and 26 μmol/L for carbamazepine and 950 mg and 300 μmol/L for valproate. Results: The mean verbal and nonverbal IQ scores in the children exposed in utero to carbamazepine monotherapy were 96 (95% CI, 93–100) and 103 (95% CI, 100–106). They did not differ from control subjects, whose mean verbal and nonverbal IQ scores were 95 (95% CI, 92–97) and 102 (95% CI, CI, 100–105). Significantly reduced verbal IQ scores were found in children exposed to valproate (mean, 82; 95% CI, 78–87) and to polytherapy (mean, 85; 95% CI, 80–90) compared with the other study group children and control subjects. Conclusions: Carbamazepine monotherapy with maternal serum levels within the reference range does not impair intelligence in prenatally exposed offspring. Exposures to polytherapy and to valproate during pregnancy were associated with significantly reduced verbal intelligence. The independent effects of valproate remain unconfirmed because the results were confounded by low maternal education and polytherapy.

Summary: Purpose: Proton magnetic resonance spectroscopic imaging (1H MRSI) can lateralize the epileptogenic frontal lobe by detecting metabolic ratio abnormalities in frontal lobe epilepsy (FLE). We used 1H MRS to lateralize and localize the epileptogenic focus, and we also sought to characterize further the metabolic abnormality in FLE. Methods: We measured signals from N-acetyl aspartate (NAA), choline-containing compounds (Cho), and creatine + phosphocreatine (Cr) in the supraventricular brain of 14 patients with frontal or frontoparietal epilepsy and their matched controls. The supratentorial brain also was segmented into gray matter, white matter, and cerebrospinal fluid classes. Regional metabolite alterations were compared with localizing and lateralizing results from other examination modalities and with histology from three patients. Results: Spectroscopy lateralized the epileptogenic focus in 10 patients in agreement with video-EEG and functional imaging. In four patients, spectroscopy showed bilateral, focal metabolic abnormality, whereas video-EEG suggested unilateral or midline abnormality. In the epileptogenic focus, Cho and Cr were increased by 23% and 14%, respectively, and NAA was decreased by 11%, suggesting metabolic disturbances both in the glial and in the neuronal cell pools. Two Taylor dysplasia lesions confirmed by histology and one with radiologic diagnosis showed high Cho and low or normal NAA, whereas two dysembryoplastic neurogenic tumors had normal Cho and low NAA. Contralateral hemisphere NAA/(Cho + Cr) was decreased in FLE, indicating diffusely altered brain metabolism. Segmentation of brain tissue did not reveal atrophic changes in FLE. Conclusions: Spectroscopy is useful in lateralizing frontoparietal epilepsy and shows promise as a “noninvasive biopsy” in epileptogenic lesions.

Recent studies reported mutations in the gene encoding the proline-rich transmembrane protein 2 (PRRT2) to be causative for paroxysmal kinesigenic dyskinesia (PKD), PKD combined with infantile seizures (ICCA), and benign familial infantile seizures (BFIS). PRRT2 is a presynaptic protein which seems to play an important role in exocytosis and neurotransmitter release. PKD is the most common form of paroxysmal movement disorder characterized by recurrent brief involuntary hyperkinesias triggered by sudden movements. Here, we sequenced PRRT2 in 14 sporadic and 8 familial PKD and ICCA cases of Caucasian origin and identified three novel mutations (c.919C>T/p.Gln307*, c.388delG/p.Ala130Profs*46, c.884G>A/p.Arg295Gln) predicting two truncated proteins and one probably damaging point mutation. A review of all published cases is also included. PRRT2 mutations occur more frequently in familial forms of PRRT2-related syndromes (80–100 %) than in sporadic cases (33-46 %) suggesting further heterogeneity in the latter. PRRT2 mutations were rarely described in other forms of paroxysmal dyskinesias deviating from classical PKD, as we report here in one ICCA family without kinesigenic triggers. Mutations are exclusively found in two exons of the PRRT2 gene at a high rate across all syndromes and with one major mutation (c.649dupC) in a mutational hotspot of nine cytosines, which is responsible for 57 % of all cases in all phenotypes. We therefore propose that genetic analysis rapidly performed in early stages of the disease is highly cost-effective and can help to avoid further unnecessary diagnostic and therapeutic interventions.

Infantile spasms syndrome (IS) (also known as West syndrome) is an epileptic encephalopathy with a heterogeneous etiology. One of the most common specific causes is tuberous sclerosis, diagnosed in almost 10% of the affected infants. Adrenocorticotropic hormone or steroids have been the preferred treatments for IS for several decades. Clinical studies have shown that vigabatrin is superior to placebo in decreasing the frequency of infantile spasms. In tuberous sclerosis, vigabatrin may be considered the first-line treatment for IS. The mode of action is increasing concentrations of the inhibitory neurotransmitter GABA in the brain. The use of vigabatrin is limited by a serious adverse effect, permanent visual field constriction, which may affect 6-7% of exposed infants. Treatment choices are based on balancing the potential adverse effects against the risk of catastrophic cognitive and behavioral outcomes caused by uncontrolled spasms.

BACKGROUND: Inherited and de novo mutations in sodium channel genes underlie a variety of channelopathies. Mutations in SCN2A, encoding the brain sodium channel Na(V)1.2, have previously been reported to be associated with benign familial neonatal infantile seizures, febrile seizures plus, and intractable epilepsy of infancy. METHODS: We evaluated the clinical characteristics in a patient with a neonatal-onset complex episodic neurologic phenotype. We screened SCN2A for mutations and carried out in vitro electrophysiologic analyses to study the consequences of the identified mutation. We studied the developmental expression of Na(V)1.2 in cerebellum by immunohistochemical analysis. RESULTS: The patient presented with neonatal-onset seizures and variable episodes of ataxia, myoclonia, headache, and back pain after 18 months of age. The patient carries a de novo missense mutation (p.Ala263Val) in SCN2A, which leads to a pronounced gain-of-function, in particular an increased persistent Na(+) current. Immunohistochemical studies suggest a developmentally increasing expression of Na(V)1.2 in granule cell axons projecting to Purkinje neurons. CONCLUSIONS: These results can explain a neuronal hyperexcitability resulting in seizures and other episodic symptoms extending the spectrum of SCN2A-associated phenotypes. The developmentally increasing expression of Na(V)1.2 in cerebellum may be responsible for the later onset of episodic ataxia.

Invasive cortical mapping is conventionally required for preoperative identification of epileptogenic and eloquent cortical regions before epilepsy surgery. The decision on the extent and exact location of the resection is always demanding and multimodal approach is desired for added certainty. The present study describes two non-invasive preoperative protocols, used in addition to the normal preoperative work-up for localization of the epileptogenic and sensorimotor cortical regions, in two young patients with epilepsy. Magnetoencephalography (MEG) was used to determine the primary somatosensory cortex (S1) and the ictal onset zones. Navigated transcranial magnetic stimulation (nTMS) was used to determine the location and the extent of the primary motor representation areas. The localization results from these non-invasive methods were used for guiding the subdural grid deployment and later compared with the results from electrical cortical stimulation (ECS) via subdural grids, and validated by surgery outcome. The results from MEG and nTMS localizations were consistent with the ECS results and provided improved spatial precision. Consistent results of our study suggest that these non-invasive methods can be added to the standard preoperative work-up and may even hold a potential to replace the ECS in a subgroup of patients with epilepsy who have the suspected epileptogenic zone near the sensorimotor cortex and seizures frequent enough for ictal MEG.

Phalangeal and metacarpal bone length was measured from hand radiographs in 111 children of epileptic mothers and 96 control children of nonepileptic mothers. Seventy-six children of the study group had been exposed to phenytoin in the first 20 weeks of pregnancy, 21 had been exposed to other anti-epileptic drugs excluding phenytoin, and 14 had not been exposed. Distal phalangeal lengths were significantly reduced in phenytoin-exposed children. The second and fifth digits were most affected. Phenytoin exposure was associated with a significantly elevated prevalence (11%) of radiologically defined distal phalangeal hypoplasia. The subgroup of children exposed to phenytoin levels over 40 mumol/l showed more prominent effects than did the subgroup exposed to lower or unknown concentrations. These results confirm that early fetal exposure to phenytoin decreases distal phalangeal size, as suggested by several previous studies relying on clinical examination only. Distal phalangeal hypoplasia was not accompanied by other serious abnormalities.

Objective To assess long-term outcome of infantile epilepsy responsive to pyridoxine (vitamin B6). Methods We inquired all pediatric neurologists treating pediatric epilepsy in Finland if they had seen pyridoxine responsive patients with infantile epilepsy. Five children with infantile spasms and hypsarrhythmia and one with focal epilepsy were reported as pyridoxine responders. Data on clinical presentation was collected from patient charts. Results All B6 responders had unknown etiology. Ages at seizure onset ranged from 4 to 7 months. The patients had been treated with p.o. pyridoxine 150 mg/day or i.v. 50 mg pyridoxal phosphate and responded within 1 to 14 days (mean 6 days). Two patients were treated with concomitant antiepileptic drugs. Duration of pyridoxine therapy varied from 6 weeks to 4 years (mean 26 months). Four patients had later seizure relapses: one at 15 months with motor seizures (stopped By valproate), another two in adolencence with focal epilepsy and one at 20 years with unclassified epilepsy. Intelligence was normal in five patients and one had a mild mental deficiency. Follow-up ranged from 8.5 to 24 years. Conclusion This study showed that long-term cognitive outcome is good for the rare patients with infantile epilepsy who respond to B6 therapy but later seizure recurrence occur. So far it is unknown, if the response is determined by genetic traits or disease-related factors.

Very little data are available on the usefulness of oxcarbazepine in young children with epilepsy. From January 1991 through October 1994, we treated 53 children under age 7 years with oxcarbazepine. The mean follow-up with oxcarbazepine treat ment was 13 months. Etiology was symptomatic in 39, cryptogenic in 12, and idiopathic in 2 children. Forty-three children had previously been intractable to one or more antiepileptic drugs (including carbamazepine in 30 patients) and two had carbamazepine hypersensitivity. The age at onset of oxcarbazepine therapy ranged from 0.6 to 6.9 years (mean, 3.9 yr). The mean maximum oxcarbazepine dose was 50 mg/kg/day (range, 21-86 mg/kg/day). Of the children with localization-related epilepsy, 12 of 44 (27%) became seizure free and an additional 16 of 44 (36%) had an at least 50% reduction of seizures. Five of nine children with generalized epilepsy also had some benefit but none became seizure free. In the 33 children with at least 50% seizure reduction, the mean effective dose and trough serum level of the active metabolite monohydroxycarbazepine were 47 mg/kg/day (range, 21-75 mg/kg/day) and 91 μmol/L (range, 42-130 μmol/L), respectively. Efficacy was transient in 4 children; side effects were observed in 17 children (32%); in 9 (17%) of whom, they led to dose reduction or discontinuation. Oxcarbazepine appears to be an effective and well-tolerated drug for localization-related early childhood epilepsy. Young children need a higher dose per body weight than adults. (J Child Neurol 1997;12:496-498).

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.

It is not yet established which antiepileptic drugs (AEDs) are most likely to allow an uncomplicated pregnancy and delivery of a baby who develops normally. Two recent studies of the risk of major malformations, a national birth registry1 and a prospective single experience,2 consisted mainly of carbamazepine (CBZ) or valproate (VPA) exposed pregnancies. Both suggested that first semester exposure to VPA monotherapy carried a higher risk of fetal malformation than exposure to CBZ monotherapy. There is an increased risk3 for abnormalities in infants exposed in utero to phenobarbital, a drug that not long ago was the recommended drug for pregnant women with epilepsy (WWE). In this and a future issue of Neurology , three birth registries are reported. Cunnington et al.4 report results from the lamotrigine (LTG) registry and Wyszynski et al.5 report results from VPA-exposed pregnancies. Both reports track major birth defects evident by ultrasound or inspection within the first few days of life. Artama et al.6 report on the rate of malformations in offspring of WWE after exposure to several AEDs in monotherapy and polytherapy compared to offspring of untreated WWE. Cunnington et al.4 report a 2.9% incidence of major defects in the infants of 414 WWE treated with LTG monotherapy. When LTG was used in polytherapy, there was a 12.5% incidence if it was used with VPA (88 exposures) and a 2.5% incidence with other AEDs (182 exposures). This multinational registry (12 years of observations) enrolled patients voluntarily by physician report, with postpartum physician information. Wyszynski et al.5 report results …

Objective: To evaluate the occurrence and prognostic importance of focal defects in cerebral cortical glucose metabolism in infants with newly diagnosed symptomatic and cryptogenic infantile spasms. Patients and Methods: Ten children with symptomatic and seven with cryptogenic infantile spasms underwent MRI, video-EEG, and PET using fluorodeoxyglucose as a tracer within 2 weeks of diagnosis. PET was repeated at 1 year of age in 12 patients. Results: Cortical hypometabolic foci were found in 13 children (77%) with newly diagnosed spasms (six cryptogenic and seven symptomatic). The hypometabolic foci disappeared in seven of nine reexamined at age 1. The occipital foci disappeared in all (n = 6). Focal findings on PET correlated well with focal findings on video-EEG. There was no difference in quantitative cortical or subcortical glucose metabolic rate at the onset of infantile spasms between children with cryptogenic and symptomatic etiology of spasms. The glucose metabolic rate at the onset of spasms or focal lesions in glucose metabolism did not have prognostic value for seizure outcome. Conclusions: Infantile spasms are often associated with transient cortical, especially occipital, hypometabolic foci that are not necessarily associated with structural lesions and do not indicate a poor prognosis.

Summary: Purpose: The efficacy of a protocol consisting of vigabatrin (VGB) as the first and adrenocorticotropic hormone (ACTH) or valproate (VPA) as the second drug was studied in the treatment of newly diagnosed infantile spasms (IS) during 1994 to 1997 in a population-based design. Methods: Only total disappearance of the spasms with a minimal duration of 1 month was accepted as a response. The treatment response was confirmed by video-EEG study. All infants were studied by magnetic resonance imaging (MRI) or computed tomography (CT) for etiology. Results: Altogether 42 infants, 10 with cryptogenic and 32 with symptomatic etiology, were treated. Eleven (26%) responded to VGB, five (50%) with cryptogenic, and six (19%) with symptomatic etiology; 91% of infants responded to a dose of 50–100 mg/kg/day, and 82% of them within 1 week. ACTH was offered in combination with VGB to 22 and VPA to four infants for whom VGB failed. Eleven responded to ACTH and one to VPA. In total, 26 (62%) infants responded to the treatment protocol; all (100%) with cryptogenic etiology and 16 (50%) with symptomatic etiology. ACTH treatment was associated with more severe side effects than VGB or VPA. Only one infant relapsed after a spasm-free period with VGB of >4 months, but none after ACTH was combined with VGB. Conclusions: We suggest VGB as a first drug to all infants with IS. After a treatment trial of 10–14 days with increasing dose from 50 to 150 mg/kg, ACTH should be considered.

We describe a girl with a brain-stem tumour and symptoms very similar to those of Rett syndrome (RS). Her early history was uneventful and development was normal (except for hypotonia). At the age of 6 months her development slowed. Subsequently, deterioration occurred and the features characteristic of RS were seen: loss of purposeful hand use, stereotypic hand movements, impaired social contact, decelerated head growth, and ataxia. Cerebral CT at the age of 3 years and 4 months revealed a tumour in the region of the pons and hydrocephalus. We suggest that a pons/midbrain tumour appearing at an early age may affect the developing CNS and cause symptoms similar to those of RS. A possible causal connection between midbrain pathology and RS is supported by this case.

Summary: Purpose: To quantify the risks of intrauterine antiepileptic drug (AED) exposure in monotherapy and poly-therapy. Methods: Data from five prospective European studies totaling 1,379 children were pooled and reanalyzed. Data were available for 1,221 children exposed to AED during pregnancy and for 158 children of unexposed control pregnancies. Results: Overall, when comparing a subgroup of 192 children exposed to AED with 158 children of matched nonepileptic controls, there was an increased risk of major congenital malformations (MCA) in children exposed to AED during gestation [relative risk (RR) 2.3; 95% confidence interval (CI): 1.2–4.7]. A significant increase in risk was found for children exposed to valproate (VPA) (RR 4.9; 95% CI: 1.6–15.0) or carbamazepine (CBZ) (RR 4.9; 95% CI: 1.3–18.0) in monotherapy. When comparing different AED regimens during all 1,221 pregnancies, risks of MCA were significantly increased for the combination of phenobarbital (PB) and ethosuximide (RR 9.8; 95% CI: 1.4–67.3) and the combination of phenytoin, PB, CBZ, and VPA (RR 11.0; 95% CI: 2.1–57.6). Offspring of mothers using > 1,000 mg VPNday were at a significantly increased risk of MCA, especially neural tube defects, compared to offspring exposed ≥600 mg VPNday (RR 6.8; 95% CI: 1.4–32.7). No difference in risk of MCA was found between the offspring exposed to 601–1,000 mg/day and ≥600 mg/day. Conclusions: This reanalysis shows that VPA is consistently associated with an increased risk of MCA in babies born to mothers with epilepsy. Significant associations were also observed with CBZ. Larger prospective population-based studies are needed to evaluate the risks of many other less frequently prescribed treatment regimens, including newly marketed AEDs.

Head circumference after the first year of life was investigated in 144 children of epileptic mothers ('study group'). Fifty-two children had been exposed to phenytoin monotherapy, 19 to carbamazepine monotherapy, 27 to drug combinations including barbiturates, 29 to other drug combinations, and 17 children had not been exposed to antiepileptic drugs (AEDs) during pregnancy. The prevalence of microcephaly (2.1%) was no higher than that in the general population. Head circumference was measured at 5.5 years in 121 of the study group children, in 105 control children, and in the majority of their parents (118 mothers and 89 fathers in the study group, and 103 mothers and 65 fathers in the control group). The sex-adjusted head circumferences of the children showed a significant variation according to exposure subgroup, with the barbiturate and carbamazepine monotherapy exposed children having the lowest mean values. This result is similar to our previous findings in the same children at birth and at 18 months of age. Paternal head circumference was also below average in the same subgroups. After further adjustment for parental head circumference, the significant variation between the subgroups of children disappeared, even though the barbiturate exposed children continued to have the lowest mean value. Genetic causes may thus contribute to the relatively small head circumference in some AED exposed children of epileptic mothers. However, a mild drug effect in the barbiturate and carbamazepine exposed children cannot be excluded.

Increase of length and weight during the first 6 months of life, and height at 1 and 5.5 years of age were investigated in 132 children of epileptic mothers (the study group) and 103 control children born after 37 completed gestational weeks. One hundred and seventeen children had been exposed to antiepileptic drugs in utero: 48 to phenytoin monotherapy, 16 to carbamazepine monotherapy, 24 to barbiturates (23 in combination with other drugs), 27 to drug combinations including phenytoin and/or carbamazepine but not barbiturates, and 2 to other drugs. There was no evidence of intrauterine drug exposure causing prenatal growth retardation. The mean length increment in the first postnatal month was significantly smaller in the drug-exposed children than in the non-exposed study children or controls. The drug-exposed children also gained significantly less weight during the first postnatal month than non-exposed study group children. A normal growth rate was already resumed in the drug-exposed group in the second postnatal month. Sedative drug effects on the neonate probably partly explain the transient weight lag, especially in the barbiturate-exposed subgroup. The marked delay in length gain suggests that a hormonal mechanism, perhaps a reversible suppression of thyroid function, might also be involved. The transient growth retardation was not associated with an excess of minor anomalies or impaired intelligence at 5.5 years of age. As only 1 drug-exposed child had persistent postnatal growth deficiency combined with other signs suggesting a prenatal disorder, the risk of teratogenic growth deficiency caused by antiepileptic drug exposure seems to be very low.

In a prospective study, 121 children of mothers with epilepsy (study group) and 105 control children were examined in a blinded fashion at age 5 1/2 years for 80 minor physical anomalies, including nine typical features previously reported characteristic of fetal hydantoin syndrome. Of the study group, 106 children had been exposed to antiepileptic drugs (82 to phenytoin) during pregnancy; 44 (36%) mothers had had generalized convulsions during pregnancy. One hundred fourteen mothers and 87 fathers of study group children and 101 mothers and 58 fathers of control children were also examined. A significant excess of minor anomalies considered characteristic of hydantoin syndrome was observed in children of epileptic mothers and in epileptic mothers, compared with the control group. There was no excess of other minor anomalies studied. Several minor anomalies previously regarded as typical of fetal hydantoin syndrome were shown to be genetically linked to epilepsy. Only hypertelorism and digital hypoplasia were associated with phenytoin exposure. The current concept of the syndrome seems to be incorrect; most of the "typical" characteristics are not caused by phenytoin. None of the phenytoin-exposed children had all of the main characteristics of hydantoin syndrome (typical acrofacial features, intellectual deficiency, growth retardation, and microcephaly). The risk of developmental disturbance associated with intrauterine phenytoin exposure seems to be much lower than the 7% to 11% risk of fetal hydantoin syndrome reported earlier.