Epilepsies with onset during the first year of life: A prospective study on syndromes, etiologies, and outcomes.

OBJECTIVE: Infantile seizures cause great concern for both doctors and parents. In addition to modern neuroimaging and genetics, clinical tools helpful in predicting the course of the disease are needed. We prospectively studied the incidence, electroclinical characteristics and etiologies of epilepsy syndromes with onset before the age of 12 months and looked for prognostic determinants of outcome by age 24 months. METHODS: From February 2017 through May 2019, we recruited all eligible infants diagnosed with epilepsy at our unit. Data on electroclinical studies, genetic investigations and drug response were gathered prospectively. The infants were given a structured neurological examination (Hammersmith Infantile Neurological examination [HINE] and Griffiths scales) at predetermined intervals until age 24 months at which age neurocognitive evaluation with Bayley scales was performed. RESULTS: Included were 60 infants (27 female). The mean onset age of epilepsy was 5.3 (±2.5 standard deviation) months. The incidence of epilepsy in the population-based cohort was 131 (95% confidence interval 99-172)/100 000. Epilepsy syndrome was identified in 80% and etiology in 58% of infants. Self-limited infantile epilepsy was the second most common syndrome (incidence 18/100 000) after infantile epileptic spasms syndrome. PRRT2 was the most common monogenic cause. At age 24 months, 37% of the infants had drug-resistant epilepsy (DRE) and half had a global developmental delay (GDD). Abnormal first HINE was the strongest predictor of GDD, followed by DRE and identified etiology. DRE was associated with structural etiology and GDD. Those with normal first HINE and good response to treatment had favorable outcomes, irrespective of the identified etiology. SIGNIFICANCE: Our results support a high incidence of self-limited epilepsy in infancy and PRRT2 as the genetic cause in the first year of life. Notwithstanding the advances in etiological discovery, we want to highlight the importance of clinical evaluation as standardized neurological examination with HINE proved a valuable tool in prognostication. PLAIN LANGUAGE SUMMARY: One in every 700-800 babies develop epilepsy within the first year after birth. Our study identified an epilepsy syndrome in 80% and the cause of epilepsy in 60% of the participants. By age 2 years, over one-third of the children still experienced seizures, and almost half faced significant developmental delay. Structural brain abnormalities increased the likelihood of difficult epilepsy and developmental challenges. Babies whose epilepsy was caused by a gene defect varied widely in development and response to medications. Babies with normal neurological examination at first visit, especially if their seizures stopped quickly, had favorable development.

Clinical and electrophysiological features of SCN8A variants causing episodic or chronic ataxia.

BACKGROUND: Variants in SCN8A are associated with a spectrum of epilepsies and neurodevelopmental disorders. Ataxia as a predominant symptom of SCN8A variation has not been well studied. We set out to investigate disease mechanisms and genotype-phenotype correlations of SCN8A-related ataxia. METHODS: We collected genetic and electro-clinical data of ten individuals from nine unrelated families carrying novel SCN8A variants associated with chronic progressive or episodic ataxia. Electrophysiological characterizations of these variants were performed in ND7/23 cells and cultured neurons. FINDINGS: Variants associated with chronic progressive ataxia either decreased Na+ current densities and shifted activation curves towards more depolarized potentials (p.Asn995Asp, p.Lys1498Glu and p.Trp1266Cys) or resulted in a premature stop codon (p.Trp937Ter). Three variants (p.Arg847Gln and biallelic p.Arg191Trp/p.Asp1525Tyr) were associated with episodic ataxia causing loss-of-function by decreasing Na+ current densities or a hyperpolarizing shift of the inactivation curve. Two additional episodic ataxia-associated variants caused mixed gain- and loss-of function effects in ND7/23 cells and were further examined in primary murine hippocampal neuronal cultures. Neuronal firing in excitatory neurons was increased by p.Arg1629His, but decreased by p.Glu1201Lys. Neuronal firing in inhibitory neurons was decreased for both variants. No functional effect was observed for p.Arg1913Trp. In four individuals, treatment with sodium channel blockers exacerbated symptoms. INTERPRETATION: We identified episodic or chronic ataxia as predominant phenotypes caused by variants in SCN8A. Genotype-phenotype correlations revealed a more pronounced loss-of-function effect for variants causing chronic ataxia. Sodium channel blockers should be avoided under these conditions. FUNDING: BMBF, DFG, the Italian Ministry of Health, University of Tuebingen.

Visual field defects after vigabatrin treatment during infancy: retrospective population-based study.

AIM: To investigate the prevalence of vigabatrin-attributed visual field defect (VAVFD) in infantile spasms and the utility of optical coherence tomography (OCT) in detecting vigabatrin-related damage. METHOD: We examined visual fields by Goldmann or Octopus perimetry and the thickness of peripapillary retinal nerve fiber layer (RNFL) with spectral-domain OCT at school age or adolescence. RESULTS: Out of 88 patients (38 females, mean age at study 15y, SD 4y 3mo, range 6y 4mo-23y 3mo [n=65] or deceased [n=21] or moved abroad [n=2]) exposed to vigabatrin in infancy, 28 were able to perform formal visual field testing. Two had visual field defect from structural causes. We found mild VAVFD in four patients and severe VAVFD in one patient. Median vigabatrin treatment duration for those with normal visual field was 11 months compared to 19 months for those with VAVFD (p=0.04). OCT showed concomitant attenuated RNFL in three children with VAVFD, and was normal in one. The temporal half of the peripapillary RNFL was significantly thinner in the VAVFD group compared to the normal visual field group. INTERPRETATION: The overall prevalence of VAVFD is lower after exposure in infancy compared to 52% which has been reported after exposure in adulthood. The risk increases with longer treatment duration. Further studies should identify infants particularly susceptible to VAVFD and clarify the role of OCT.

Interictal magnetoencephalography in parietal lobe epilepsy - Comparison of equivalent current dipole and beamformer (SAMepi) analysis.

OBJECTIVE: To evaluate a novel analysis method (SAMepi) in the localization of interictal epileptiform magnetoencephalographic (MEG) activity in parietal lobe epilepsy (PLE) patients in comparison with equivalent current dipole (ECD) analysis. METHODS: We analyzed the preoperative interictal MEG of 17 operated PLE patients utilizing visual analysis and: (1) ECD with a spherical conductor model; (2) ECD with a boundary element method (BEM) conductor model; and (3) SAMepi - a kurtosis beamformer method. Localization results were compared between the three methods, to the location of the resection and to the clinical outcome. RESULTS: Fourteen patients had an epileptiform finding in the visual analysis; SAMepi detected spikes in 11 of them. A unifocal finding in both the ECD and in the SAMepi analysis was associated with a better chance of seizure-freedom (p = 0.02). There was no significant difference in the distances from the unifocal MEG localizations to the nearest border of the resection between the different analysis methods. CONCLUSIONS: Localizations of unifocal interictal spikes detected by SAMepi did not significantly differ from the conventional ECD localizations. SIGNIFICANCE: SAMepi - a novel semiautomatic analysis method - is useful in localizing interictal epileptiform MEG activity in the presurgical evaluation of parietal lobe epilepsy patients.

Trends in pediatric epilepsy surgery in Europe between 2008 and 2015: Country-, center-, and age-specific variation.

OBJECTIVE: To profile European trends in pediatric epilepsy surgery (<16 years of age) between 2008 and 2015. METHODS: We collected information on volumes and types of surgery, pathology, and seizure outcome from 20 recognized epilepsy surgery reference centers in 10 European countries. RESULTS: We analyzed retrospective aggregate data on 1859 operations. The proportion of surgeries significantly increased over time (P < .0001). Engel class I outcome was achieved in 69.3% of children, with no significant improvement between 2008 and 2015. The proportion of histopathological findings consistent with glial scars significantly increased between the ages of 7 and 16 years (P for trend = .0033), whereas that of the remaining pathologies did not vary across ages. A significant increase in unilobar extratemporal surgeries (P for trend = .0047) and a significant decrease in unilobar temporal surgeries (P for trend = .0030) were observed between 2008 and 2015. Conversely, the proportion of multilobar surgeries and unrevealing magnetic resonance imaging cases remained unchanged. Invasive investigations significantly increased, especially stereo-electroencephalography. We found different trends comparing centers starting their activity in the 1990s to those whose programs were developed in the past decade. Multivariate analysis revealed a significant variability of the proportion of the different pathologies and surgical approaches across countries, centers, and age groups between 2008 and 2015. SIGNIFICANCE: Between 2008 and 2015, we observed a significant increase in the volume of pediatric epilepsy surgeries, stability in the proportion of Engel class I outcomes, and a modest increment in complexity of the procedures.

Prenatal exposure to antiepileptic drugs and early processing of emotionally relevant sounds.

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.

Language mapping with navigated transcranial magnetic stimulation in pediatric and adult patients undergoing epilepsy surgery: Comparison with extraoperative direct cortical stimulation.

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.

Evidence for spared attention to faces in 7-month-old infants after prenatal exposure to antiepileptic drugs.

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 developmental 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.

Incidence and outcome of epilepsy syndromes with onset in the first year of life: A retrospective population-based study.

OBJECTIVE: 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.

Pitfalls in genetic testing: the story of missed SCN1A mutations.

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.

Effects of prenatal antiepileptic drug exposure on newborn brain activity.

OBJECTIVE: 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.

Etiology and Long-Term Outcomes of Late-Onset Infantile Spasms.

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.

Valproate in the treatment of epilepsy in girls and women of childbearing potential.

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.

Dravet syndrome: new potential genetic modifiers, imaging abnormalities, and ictal findings.

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.

[EEG under the surface]. / EEG pintaa syvemmältä.

Epilepsy work-up is based on history and scalp EEG. Drug resistant epilepsy should be evaluated in a dedicated epilepsy surgery unit. Sometimes non-invasive studies fail to localize the epileptogenic area in focal epilepsy and then the work up can be complemented with intracranial EEG. Intracranial electrodes are implanted either in the subdural space or intraparenchymally. This is followed by one to two weeks of EEG monitoring in a specialized videotelemetry unit. Intracranial EEG helps to define the borders of the epileptogenic area for resection. The ultimate objective is to render the patient seizure free. The outcome of resective epilepsy surgery depends on the etiology of epilepsy, localization of the epileptogenic area and MR image yield.

Interictal MEG reveals focal cortical dysplasias: special focus on patients with no visible MRI lesions.

PURPOSE: To investigate the value of interictal magnetoencephalography (MEG) in localizing epileptogenic cortex in epilepsy surgery patients with focal cortical dysplasias (FCD), particularly in patients having no visible MRI lesions. METHODS: Thirty-four patients with FCD and preoperative MEG were retrospectively evaluated. Interictal MEG spike source localizations in respect to the resected area were studied using postoperative MR imaging. The possible predictive value of MEG-findings in respect to the clinical outcome was evaluated. Results from intracranial recordings were also compared with the MEG localizations. RESULTS: Interictal MEG spikes were observed in all but one patient. 17 of the 34 (50%) patients became seizure free (Engel class I). In patients with MEG dipole clusters (n=20) and Engel class I or II (n=15) 49% of the source clusters were removed on the average; the corresponding value in patients with Engel class III or IV (n=5) was 5.5% (p=0.02). Seven (54%) of the 13 patients with an MRI-negative lesion achieved Engel class I; the outcomes did not differ from patients having a visible MRI lesion (n=21; p=0.82). The concordance between MEG localizations and the invasive studies was good in nine of the 13 patients with no visible MRI lesions CONCLUSION: MEG is particularly useful in finding small FCDs not visible on MRI. A more complete removal of MEG source cluster area is associated with better clinical outcome These features make it a valuable tool in pre-surgical evaluation of patients with intractable focal-type epilepsy and normal MRI.

PRRT2-related disorders: further PKD and ICCA cases and review of the literature.

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.

Functional plasticity of the motor cortical structures demonstrated by navigated TMS in two patients with epilepsy.

BACKGROUND: Recently, navigated transcranial magnetic stimulation (nTMS) has been suggested to be useful in preoperative functional localization of motor cortex in patients having tumors close to the somatomotor cortex. Resection of tumors in anatomically predicted eloquent areas without adverse effects have emphasized functional plasticity elicited by intracranial pathology. OBJECTIVE: To describe functional plasticity of motor cortex indicated by nTMS in two patients with epilepsy. METHODS: nTMS, functional MRI (fMRI), diffusion-tensor (DT)-tractography and magnetoencephalography (MEG) were utilized to preoperatively localize motor cortical areas in the workup for epilepsy surgery. The localizations were compared with each other, with the cortical anatomical landmarks, and in one patient with invasive electrical cortical stimulation (ECS). RESULTS: In two out of 19 studied patients, nTMS identified motor cortical sites that differed from those indicated by anatomical landmarks. In one patient, nTMS activated preferentially premotor cortex rather than pathways originating from the precentral gyrus. MEG and fMRI localizations conformed with nTMS whereas ECS localized finger motor function into the precentral gyrus. Resection of the area producing motor responses in biphasic nTMS did not produce a motor deficit. In the other patient, nTMS indicated abnormal ipsilateral hand motor cortex localization and confirmed the functionality of aberrant motor cortical representations of the left foot also indicated by fMRI and DT-tractography. CONCLUSION: nTMS may reveal the functional plasticity and shifts of motor cortical function. Epileptic foci may modify cortical inhibition and the nTMS results. Therefore, in some patients with epilepsy, the nTMS results need to be interpreted with caution with regard to surgical planning.

Sensitivity and specificity of seizure-onset zone estimation by ictal magnetoencephalography.

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 to localize 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-lobe-surface (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 and specificity.

Vigabatrin monotherapy for infantile spasms.

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.