Clinical and genetic spectrum of SCN2A-associated episodic ataxia.

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 RESULTS: We report 21 patients with SCN2A-associated EA, of which 9 are unpublished cases.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%.

Mutations in the sodium channel gene SCN2A cause neonatal epilepsy with late-onset episodic ataxia.

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.

Long-term outcome in pyridoxine-responsive infantile epilepsy.

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.

Measuring spike strength in patients with continuous spikes and waves during sleep: comparison of methods for prospective use as a clinical index.

OBJECTIVE: To compare methods of estimating spike strength as a potential index in the assessment of continuous spikes and waves during sleep (CSWS). METHODS: Spikes were searched and averaged automatically from pre- and postoperative EEGs of ten patients with CSWS who underwent corpus callosotomy (eight) or resective epilepsy surgery (two). From the most prominent spike, we measured peak amplitude and root mean square (RMS) over ±150ms window around the peak. In order to compensate for spatiotemporal instability of spikes, the cumulative amplitude and RMS were computed from the highest quartile of electrodes (Ampl-Q and RMS-Q, respectively). The stability of parameters was studied by comparing two ten minute epochs during the first hour of NREM sleep, as well as by analyzing overnight variation of indices in further ten patients with CSWS. The Ampl-Q and RMS-Q were compared between pre- and postoperative recordings. RESULTS: All four measures, amplitude, RMS, Ampl-Q and RMS-Q, were correlated with each other and highly dependent on NREM/REM-sleep stage and arousals. Expectedly, Ampl-Q and RMS-Q had the greatest intra-individual stability. The amplitude had up to 71% intra-individual variation making it unhelpful for clinical use. Ampl-Q and RMS-Q were comparable in assessing change following surgical treatment. CONCLUSIONS: Computing an integrated RMS over multiple electrodes during steady NREM sleep offers a stable and reliable parameter for evaluating the strength of spikes in CSWS. SIGNIFICANCE: Analyzing spike strength with RMS-Q may offer a clinically useful, supplementary index for EEG monitoring of CSWS where spike index has been of limited value.

Semiautomatic quantification of spiking in patients with continuous spikes and waves in sleep: sensitivity to settings and correspondence to visual assessment.

OBJECTIVE: To define the optimal analysis protocol for semiautomatic quantification of spike index (SI) in continuous spikes and waves in sleep (CSWS). METHODS: Ten overnight EEGs (nine patients) with abundant spiking were used to quantify SI with a previously published semiautomatic quantification based on spike detection with BESA software. We studied (i) dependency of SI on maximal interspike interval (maxISI) defining the continuous discharge, (ii) sensitivity of SI to variations in the spike search protocol, and (iii) stability of SI over time. Finally, the semiautomatic method was compared with the quantification based on visual scoring by two neurophysiologists. RESULTS: MaxISI of 3s appeared to yield the best combination of sensitivity and stability in SI quantification. The SI of the first hour of sleep did not differ significantly from the SI of the whole night. Mean error of the semiautomatic method compared to visual scoring was only seven percentage units. CONCLUSIONS: Semiautomatic quantification of SI functions well with maxISI of 3s, and the first hour of sleep represents the whole night SI with a clinically relevant accuracy. SIGNIFICANCE: This method opens a possibility for objective quantification of near-continuous epileptiform spiking during sleep, and it supports the use of shorter epochs for quantitative assessment of CSWS.

SCN2A mutation associated with neonatal epilepsy, late-onset episodic ataxia, myoclonus, and pain.

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.

Combined use of non-invasive techniques for improved functional localization for a selected group of epilepsy surgery candidates.

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.

Normal intelligence in children with prenatal exposure to carbamazepine.

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 through 1994. 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 micro mol/L for carbamazepine and 950 mg and 300 micro mol/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.

Focal and global cortical hypometabolism in patients with newly diagnosed infantile spasms.

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.

Infantile spasms: diagnosis and assessment of treatment response by video-EEG.

The purpose of this study was to investigate early electroclinical manifestations and evaluate treatment responses by video-EEG in infants with newly diagnosed spasms. Spasms were recorded in 44 infants (27 males, 17 females) before adequate treatment. Mean ages at onset of spasms and at first video-EEG were 5.3 months (range 0.9 to 9 months) and 5.9 months (range 2.4 to 11.5 months) respectively. Thirteen infants had cryptogenic and 31 had symptomatic aetiology. First treatment was vigabatrin in 36 infants. All infants were followed until 12 months of age or death. Treatment response in the first months of therapy was assessed by repeated video-EEG studies in 23 infants. On the first video-EEG, 34 infants had typical symmetric motor spasms, three infants showed asymmetric or asynchronous behaviour, and seven infants had only subtle spasms. Interictal EEG showed hypsarrhythmia in 27 infants and multifocal spikes with normal or nearly normal background in 17 infants. Subtle spasms, asymmetric or asynchronous spasms, and asymmetric ictal or interictal EEG abnormalities were associated with symptomatic aetiology and poor cognitive and seizure outcome at 12 months. Serial video-EEG recordings showed a transition from motor to subtle spasms during the first 2 weeks of vigabatrin therapy in four infants and only subtle spasms in two therapy-resistant infants at 12 months. Cessation of spasms usually preceded disappearance of hypsarrhythmia or multifocal spikes, but persistence of multifocal spikes over several weeks was always associated with existing spasms. Transition of hypsarrhythmia into multifocal spikes was observed during vigabatrin therapy even in infants with intractable spasms. Initial diagnosis of infantile spasms requires video-EEG studies especially in infants with symptomatic aetiology who may show only subtle spasms. Video-EEG is the only reliable method for assessing treatment response as spasms and interictal EEG abnormalities are modified by treatment and may become subtle.

Proton spectroscopic imaging shows abnormalities in glial and neuronal cell pools in frontal lobe epilepsy.

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.

Transmission imaging for registration of ictal and interictal single-photon emission tomography, magnetic resonance imaging and electroencephalography.

A method developed for registration of ictal and interictal single-photon emission tomography (SPET), magnetic resonance imaging (MRI) and electroencephalography (EEG) is described. For SPET studies, technetium-99m ethyl cysteinate dimer (ECD) was injected intravenously while the patient was monitored on video-EEG to document the ictal or interictal state. Imaging was performed using a triple-head gamma camera equipped with a transmission imaging device using a gadolinium-153 source. The images (128x128 pixels, voxel size 3.7x3.7x3.6 mm3) were reconstructed using an iterative algorithm and postfiltered with a Wiener filter. The gold-plated silver electrodes on the patient's scalp were utilized as markers for registration of the ictal and interictal SPET images, as these metallic markers were clearly seen on the transmission images. Fitting of the marker sets was based on a non-iterative least squares method. The interictal SPET image was subtracted from the ictal image after scaling. The T1-weighted MPRAGE MR images with voxel size of 1.0x1.0x1.0 mm3 were obtained with a 1.5-T scanner. For registration of MR and subtraction SPET images, the external marker set of the ictal SPET study was fitted to the surface of the head segmented from MR images. The SPET registration was tested with a phantom experiment. Registration of ictal and interictal SPET in five patient studies resulted in a 2-mm RMS residual of the marker sets. The estimated RMS error of registration in the final result combining locations of the electrodes, subtraction SPET and MR images was 3-5 mm. In conclusion, transmission imaging can be utilized for an accurate and easily implemented registration procedure for ictal and interictal SPET, MRI and EEG.

Cognitive deficits after cryptogenic infantile spasms with benign seizure evolution.

Between 1989 and 1994, 18 children with cryptogenic infantile spasms-defined by normal development before onset of spasms, symmetrical hypsarrhythmia or multifocal spikes, and typical spasms on presentation, and no abnormal findings on aetiological studies including neuroradiology-were diagnosed and treated. To assess the risk of cognitive impairment later in life, 15 of these 18 children whose spasms completely resolved within the first year of life were studied. Age at onset of spasms varied between 4.4 and 9.8 months (mean 6.5 months). Children were effectively treated with adrenocorticotrophic hormone (10 children), pyridoxine (three), vigabatrin (one), or sodium valproate (one). Spasms lasted between 11 and 138 days (mean 50 days) and stopped between the age of 6.3 and 10.2 months(mean 8.1 months). EEGs normalized between the age of 7.1 and 13.2 months (mean 9.4 months). Early development was assessed on presentation and within a few months after spasms had stopped. A detailed neuropsychological assessment was performed between the age of 4.0 and 5.9 years. Twelve children had normal intelligence; specific cognitive deficits were found in five. Three children had mild learning disability. Abnormal developmental status at age 8 to 15 months after complete resolution of spasms and EEG abnormalities was associated with cognitive deficits at age 4 to 6 years.

Treatment of infantile spasms: results of a population-based study with vigabatrin as the first drug for spasms.

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.

Pons tumour behind a phenotypic Rett syndrome presentation.

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.

Oxcarbazepine in the treatment of epilepsy in children and adolescents with intellectual disability.

Oxcarbazepine is similar to carbamazepine in its mechanisms of action and antiepileptic efficacy, but has better tolerability and fewer interactions with other drugs. Very few data are available on the usefulness of oxcarbazepine in patients with intellectual disability and epilepsy. From January 1991 until October 1994, the present authors treated 40 patients with intellectual disability and epilepsy under the age of 18 years with oxcarbazepine. The mean age at onset of epilepsy was 12 months (range = 0-132 months). All patients had previously been intractable to antiepileptic drugs (including carbamazepine in 29 patients). The age at onset of oxcarbazepine therapy ranged from 0.8 to 17.1 years (mean = 6.2 years). Thirty-one patients (78%) received other antiepileptic drugs simultaneously with oxcarbazepine. The mean follow-up with oxcarbazepine treatment was 18.8 months. The mean maximum oxcarbazepine dose was 49 mg kg(-1) day(-1) (range = 21-86 mg kg(-1) day(-1). A reduction in seizures of at least 50% during oxcarbazepine treatment was observed in 14 out of 28 (50%) patients with localization-related epilepsy and in 5 out of 12 (42%) patients with generalized epilepsy. Efficacy was transient in three patients. An increase of atypical absences was observed in one child and an emergence of drop attacks in another. Side-effects were observed in 16 (40%) patients; in eight (20%), these lead to dose reduction or discontinuation. Oxcarbazepine appears to be an effective and well-tolerated drug for children and adolescents with intellectual disability and epilepsy.

Oxcarbazepine in the treatment of early childhood epilepsy.

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 treatment 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 micromol/L (range, 42-130 micromol/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.

Maternal use of antiepileptic drugs and the risk of major congenital malformations: a joint European prospective study of human teratogenesis associated with maternal epilepsy.

PURPOSE: To quantify the risks of intrauterine antiepileptic drug (AED) exposure in monotherapy and polytherapy. 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 VPA/day were at a significantly increased risk of MCA, especially neural tube defects, compared to offspring exposed < or =600 mg VPA/day (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 < or =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.