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.

Magnetoencephalography in presurgical evaluation of children with the Landau-Kleffner syndrome.

PURPOSE: Our aim was (a) to localize the primary epileptogenic cortex for possible multiple subpial transsection in four children with the Landau-Kleffner syndrome (LKS), and (b) to evaluate the impact of magnetoencephalography (MEG) in the localizing process. METHODS: We used EEG to detect the overall epileptiform activity and MEG for selective recording of fissural spikes. The cortical generators of MEG spikes were modeled with dipoles, and their activation order was determined. The voltage distribution, consistent with the earliest MEG sources, was then identified during the course of the patient's EEG spikes to determine the relative timing between stereotypic EEG and MEG spikes and to distinguish the earliest (primary) source area among the secondary ones. RESULTS: In all patients, the earliest spike activity originated in the intrasylvian cortex, spreading in one subject to the contralateral sylvian cortex within 20 ms. Secondary spikes occurred within 10-60 ms in ipsilateral perisylvian, temporooccipital, and parietooccipital areas. A single intrasylvian pacemaker initiated all epileptic activity in two patients, whereas the other two had independent left- and right-hemisphere circuits or focal spikes. MEG source dynamics predicted the results of the methohexital suppression test in two patients and was confirmed by surgery outcome in one patient, in whom all epileptic activity ceased after a small transsection of the sylvian pacemaker. CONCLUSIONS: (a) The intrasylvian cortex is a likely pacemaker of epileptic discharges in LKS, and (b) MEG provides useful presurgical information of the cortical spike dynamics in LKS patients.

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.

Neuropsychological characteristics of five children with the Landau-Kleffner syndrome: dissociation of auditory and phonological discrimination.

The Landau-Kleffner Syndrome (LKS) is characterized by acquired receptive aphasia and EEG abnormality with onset between the ages of 3 and 8 years. This study presents neuropsychological assessments in 5 children with LKS. The aims were (1) to specify the neuropsychological deficits characteristic of these children; and (2) to clarify the nature of the receptive aphasia by comparing nonverbal and verbal auditory discrimination. Receptive aphasia was present in all children. Retardation, poor motor coordination, hyperkinesia, and conduct problems were frequent but variable. All children exhibited a dissociation between the discrimination of environmental sounds and phonological auditory discrimination, the latter being more impaired than the former. This suggests that the primary deficit of the receptive aphasia is an impairment of auditory phonological discrimination rather than a generalized auditory agnosia.

Apparent asynchrony between interictal electric and magnetic spikes.

We recorded simultaneous multichannel electroencephalogram (EEG) and magnetoencephalogram (MEG) in four children with partial epilepsy. Sources of averaged spikes were modelled with current dipoles. Of 10 spike averages obtained, three peaked simultaneously in MEG and EEG, and in seven averages, the MEG peak preceded the main EEG peak by 9-40 ms. A small positive early EEG signal coincided with the MEG peak in six asynchronous spikes. The simultaneous MEG and EEG spikes originated within 5-23 mm, while sources of asynchronous peaks were 12-67 mm apart. We conclude that non-identical neurone currents underlie the MEG and EEG signals, and emphasize the importance of modelling early phases of EEG spikes when localizing interictal epileptic zones.

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.

Cognitive impairments at two years of age after prenatal alcohol exposure or perinatal asphyxia.

The purpose of this follow-up study was to assess and describe early cognitive impairments in two-year-old children exposed to alcohol (1) until the second trimester (n = 20), (2) until the third trimester (n = 20), (3) throughout pregnancy (n = 20), (4) children to mothers with preeclampsia (n = 37), (5) children surviving acute birth asphyxia (n = 14), and (6) a normal control group (n = 48). Alcohol exposure throughout pregnancy was found to be associated with impairments in language (mean SD score = -1.3) and visuo-motor development (mean SD score = -2.0). Preeclampsia was related to impairment in visuo-motor development (mean SD score = -1.2) and attention (mean SD score = -0.7). Alcohol exposure until the third trimester was associated with attention deficit alone (mean SD score = -0.9). Alcohol exposure until the second trimester and acute birth asphyxia were not associated with an increased risk of cognitive impairment. The study also showed that neuropsychological test profiles of language, visuo-motor functions and attention may be obtained with the aid of an adapted version of the Bayley Mental Scale and an evaluation of attention.

Parietal epileptic mirror focus detected with a whole-head neuromagnetometer.

Whole-head magnetoencephalographic recordings revealed two parietal epileptic foci in homotopic areas of the hemispheres. The discharges occurred 17-20 ms later on the left than on the right hemisphere, implying the existence of a left-sided mirror focus. The foci were about 1 cm posterior to the hand primary somatosensory area, identified by evoked response measurements, and thus suggested epileptic activity at the parietal association cortex, in agreement with the observed callosal conduction time.

Temporal lobe epilepsy in early childhood.

To explore the electroclinical features of temporal lobe epilepsy (TLE) in early childhood, we studied results of video-EEG and other tests of 14 children aged 16 months to 12 years selected by seizure-free outcome after temporal lobectomy. Four children had mesiotemporal sclerosis, 1 had cortical dysplasia, and 9 had low-grade temporal neoplasms. The children had complex partial seizures (CPS) with symptomatology similar to that of adults with TLE, including decreased responsiveness and automatisms. Automatisms tended to be simpler in the younger children, typically limited to lip smacking and fumbling hand gestures. Scalp/sphenoidal EEG showed anterior/inferior temporal interictal sharp waves and unilateral temporal seizure onset in the 4 children with mesiotemporal sclerosis and in the child with cortical dysplasia, but EEG findings in 9 children with low-grade temporal tumors were complex, including multifocal interictal sharp waves or poorly localized or falsely lateralized EEG seizure onset. In children without tumors, video-EEG was critical to localization of the epileptogenic zone for resection, but in patients with tumors video-EEG was less localizing and its main value was to confirm that the reported behaviors were epileptic seizures with semiology typical of temporal lobe onset.

Dysmorphic features in offspring of alcoholic mothers.

The frequencies of 60 minor physical anomalies and various craniofacial measurements in 52 children with alcohol exposure of various durations in utero were determined and compared with 48 non-exposed healthy children at a mean age of 27 months. Compared with non-exposed children a significantly higher total minor physical anomaly count was observed in those children exposed prenatally to alcohol throughout pregnancy. Binge drinking was not associated with an increased minor physical anomaly count. During the first year of life facial features were judged according to subjective impression: 10 children had typical facial features of fetal alcohol syndrome (FAS) and 19 children were judged to have possible fetal alcohol effects on their face. Only six of them fulfilled the strict craniofacial criteria for diagnosis of FAS at the age of 27 months. Our results stress the importance of recognising also the subtle dysmorphic facial features associated with prenatal alcohol exposure: 22 of 29 (76%) of exposed children judged to have typical or possible features of FAS during the first year showed signs of central nervous system dysfunction at the age of 27 months.