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.

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 RESULTS: We report 21 patients with SCN2A-associated EA, of which 9 are unpublished cases.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

Minor anomalies in children of mothers with epilepsy.

Minor anomalies are small, structural deviations that result from alterations in morphogenesis during gestation. Multiple minor anomalies are clinically significant, because they are associated with an increased risk of major developmental defects in the affected individuals. Children of mothers with epilepsy have an excess of minor and major anomalies as compared with the incidence in children of parents without epilepsy. Of the typical minor anomalies described in offspring of mothers with epilepsy, most features appear to be genetically linked with epilepsy. Only distal digital hypoplasia seems to be a specific marker for phenytoin teratogenicity. In most children, distal digital hypoplasia is not associated with serious developmental disorders. Genetic defects in the mechanisms of drug detoxification in the fetus and treatment of the mother with more than one antiepileptic drug during pregnancy increase the risk of severe teratogenic effects in offspring.

Psychomotor development in children of mothers with epilepsy.

The risk of psychomotor retardation and the prevalence of mental subnormality are slightly increased in offspring of mothers with epilepsy. The prevalence rates of mental deficiency observed in population-based studies have been lower than those in reports of hospital-based studies. In addition to use of antiepileptic drugs (AEDs), several other factors associated with maternal epilepsy, such as seizures during pregnancy, inherited brain disorders, and nonoptimal psychosocial environment, can affect the child's psychomotor development. None of the major AEDs carries any special risk for mental retardation. However, polytherapy and inherited deviations in AED metabolism in the fetus probably do increase the risk for mental retardation.

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.

Distal phalangeal hypoplasia in children with prenatal phenytoin exposure: results of a controlled anthropometric study.

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.

A transient retardation of early postnatal growth in drug-exposed children of epileptic mothers.

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.

Head circumference in children of epileptic mothers: contributions of drug exposure and genetic background.

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.

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.

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.

Intelligence of children of epileptic mothers.

Intellectual performance was investigated in a group of 148 children of epileptic mothers enrolled in a prospective study during pregnancy, and in 105 control children; 121 of the 148 children (82%) were examined together with the control group at the age of 5 1/2 years. The intelligence of 116 study and 104 control children was assessed by both verbal (Wechsler Preschool and Primary Scale of Intelligence) and nonverbal (Leiter International Performance Scale) methods. The prevalence of mental subnormality among the remaining 32 study children was calculated on the basis of psychologic assessments done outside our study, or school achievement, or both. Of the 148 study group children, 131 had been exposed in utero to antiepileptic drugs, most commonly phenytoin (103 exposed). The prevalence of mental deficiency in the study group (1.4%) was either the same or only slightly elevated in comparison with that in the general population. In the control group, there were no mentally deficient children. The mean intelligence quotients obtained at the 5 1/2-year examination were significantly lower in the study group than in the control group. There was no increased risk of low intelligence attributable to fetal exposure either to antiepileptic drugs below toxic levels or to brief maternal convulsions. In a few cases, there seemed to be a genetic connection between epilepsy in the mother and poor intellectual performance in the child. A high number of minor anomalies was associated with a lower mean intelligence quotient in both the study and the control groups. However, those features previously reported as typical of children of epileptic mothers, and those shown to be associated with phenytoin exposure in a previous phase of this study, did not predict low intelligence in the affected children.

Minor anomalies in offspring of epileptic mothers.

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.