Idiopathic Focal Epilepsy Research Articles

Partial deletion of DEPDC5 in a child with focal epilepsy.

SummaryWe report on a child, aged 47/12 years, with borderline intelligence quotient, normal brain magnetic resonance imaging, and focal epilepsy. The polysomnographic electroencephalogram recording revealed asynchronous central spikes at both brain hemispheres resembling the features observed in focal idiopathic epileptic syndromes. Array comparative genomic hybridization analysis revealed a 32‐kb partial deletion of the DEP domain‐containing protein 5 (DEPDC5) gene, involved in a wide spectrum of inherited focal epileptic syndromes. The parental origin of the deletion could not be fully ascertained because the pregnancy had been achieved through anonymous egg donation and insemination by intracytoplasmic sperm injection. However, we demonstrate that the deletion, shared by all alternatively spliced isoforms of DEPDC5, produces a transcript presumably generating a DEPDC5 protein missing the entire DEP domain. Our findings suggest that partial deletion of DEPDC5 may be sufficient to cause the focal epilepsy in our patient, highlighting the importance of the DEP domain in DEPDC5 function. This study expands the phenotypic spectrum of DEPDC5 to sporadic forms of focal idiopathic epilepsy and underscores the fact that partial deletions, albeit probably very rare, are part of the genetic spectrum of DEPDC5 mutations.

Treatment of Classic Syndromes in Idiopathic Focal Epilepsies in Childhood

Of the classic syndromes of idiopathic (benign) focal epilepsies in childhood, more than half of children with Rolandic epilepsy and Panayiotopoulos syndrome do not need antiepileptic drug (AED) treatment. Monotherapy with carbamazepine, levetiracetam, sodium valproate, or clobazam is usually recommended for those with seizures that are unusually frequent (more than three), lengthy, distressing, or otherwise significantly interfering with the child's life. Other factors in favor of treatment include a short interval between the first three seizures, a younger age of onset (less than 4 years), or a presence of recurrent tonic–clonic seizures and diurnal seizures. In contrast to Rolandic epilepsy and Panayiotopoulos syndrome that may not need treatment, idiopathic childhood occipital epilepsy of Gastaut should be treated because seizures are frequent and secondarily generalized convulsions are probably unavoidable without medication. It is likely that all AEDs licensed as monotherapy for focal seizures and mainly carbamazepine and levetiracetam are suitable.The electroencephalogram does not predict prognosis or AED treatment needs, though there are views supporting that interictal spikes have an adverse effect on cognition.Strategies of withdrawing medication in idiopathic focal epilepsies in childhood differ among experts, although all agree that there is no need to continue medication 1 to 3 years after the last seizure, and certainly not after the age of 14 years, when most benign childhood focal seizures remit, or age 16, when they are practically nonexistent.In the acute stage of status epilepticus, control of the seizures is of paramount importance. Convulsive status epilepticus is a life threatening condition and should be terminated as soon as possible. Autonomic status epilepticus needs thorough evaluation for proper diagnosis and management. Benzodiazepines, intravenously, in rectal or buccal preparations are commonly used to terminate long lasting seizures and status epilepticus. Early parental treatment is more effective than late emergency treatment. Buccal midazolam is probably the first choice medication for out-of-hospital termination of status epilepticus.Parental education and psychological support are the cornerstone of the optimal management because despite excellent prognosis, idiopathic focal epilepsies in childhood usually have a dramatic impact to parents.

Physiopathology of Atypical Evolutions of Idiopathic Focal Epilepsies in Childhood

This article aims to discuss if the underlying etiology is an important determinant of atypical evolution of idiopathic focal epilepsy (IFE) in childhood and if there might be biomarkers that would predict atypical evolution. It appears that the determinants of atypical evolution remain largely unknown but that both genetic and epigenetic factors are likely to be involved. The analysis of scalp electroencephalography remains the best biomarker of atypical evolution. However, functional neuroimaging methods of investigation are helpful to better understand how epileptic activity affects brain functioning at rest and during goal-directed tasks and to delineate the extent of brain networks that are impaired by epileptic activity. Moreover, neuroimaging bring new arguments favoring the idea that typical and atypical IFE should not be viewed as distinct entities but as a unique syndrome with various degrees of severity that should be treated using tailored strategies and robust biomarkers of efficacy.

Genetics Studies in Idiopathic Focal Epilepsies in Childhood

Numerous “epilepsy genes” have been identified in the recent years, thanks to the recent progress in massive parallel sequencing and genome analysis. Among the formerly called “idiopathic” childhood focal epilepsies, a first and major gene responsible for focal epilepsies and epileptic encephalopathies with speech and language dysfunction (the epilepsy–aphasia spectrum, EAS), GRIN2A, has been identified. GRIN2A encodes the GluN2A subunit of N-methyl-D-aspartate receptors, which are gated by the excitatory neurotransmitter glutamate. More than 60 mutations of various types and with various functional consequences in vitro have been reported. Several rare genetic variants that may influence EAS have been reported in a few other genes. The identification of GRIN2A as a first cause of EAS represents a first key point that will help in deciphering the underlying pathophysiology and in understanding the clinical heterogeneity and variability seen in the patients and families.

Treatment of Atypical Evolutions of Idiopathic Focal Epilepsies in Childhood

The relationship between continuous spike-and-wave discharges during slow sleep (CSWSS) and neuropsychological impairment (cognitive functions, memory consolidation, and language and behavior disturbances) has been clearly demonstrated. These phenomena occur not only in symptomatic cases of CSWSS or electrical status epilepticus in sleep (ESES) syndrome, but also in the different conditions that constitute the spectrum of atypical evolutions of idiopathic focal epilepsies of childhood (IFEC). In spite of continuous advances in treatment, management is still difficult and challenging. Treatment options of atypical evolutions of IFEC include benzodiazepines, sulthiame, levetiracetam, valproic acid, and ethosuximide. Other drugs such as lacosamide and acetazolamide have been proposed. Usual antiepileptic drugs such as carbamazepine, phenobarbital, phenytoin, oxcarbazepine, lamotrigine, and topiramate were proven to be capable of inducing ESES. Steroids and intravenous immunoglobulins were recommended in refractory cases. Surgery, ketogenic diet, and vagal nerve stimulation were also used in some cases. Our interest regarding a scheme of treatment in atypical evolutions of IFEC is centered on two questions: (1) Is it possible to prevent the evolution of IFEC into atypical focal epilepsies of childhood, status epilepticus of IFEC, Landau–Kleffner's syndrome, or ESES syndrome? (2) Which is the treatment of choice once one of these conditions is installed?

Atypical Evolutions of Idiopathic Focal Epilepsies in Childhood

Clinical and electroencephalographic (EEG) features of the three well-defined idiopathic focal epilepsies in childhood (IFEC)—benign childhood epilepsy with centrotemporal spikes (BCECTS), Panayiotopoulos syndrome, and the Gastaut type of idiopathic occipital epilepsy of childhood (IOEC-G)—have been clearly described and reported. It is also known that a significant percentage of children with IFEC present what were named atypical features in seizures and EEG abnormalities. We are studying here the small number of patients with IFEC who not only present atypical features, but also evolve into the spectrum of epileptic encephalopathies related with continuous spike-and-wave during sleep (CSWSS) or electrical status epilepticus during sleep (ESES), which includes atypical benign focal epilepsy of childhood, status of BCECTS, Landau-Kleffner syndrome, and CSWSS or ESES syndrome. We also emphasize that some patients with these encephalopathic course of IFEC present a mix or a sequence in time of the four mentioned subsyndromes.

Clinical and EEG Features of Idiopathic Focal Epilepsies in Childhood

The International League Against Epilepsy (ILAE) report lists three well-defined syndromes of idiopathic focal epilepsies in childhood: benign childhood epilepsy with centrotemporal spikes (BCECTS), Panayiotopoulos syndrome (PS), and idiopathic childhood occipital epilepsy of Gastaut (ICOE-G). The concept of idiopathic and benign focal epilepsies in childhood is relevant as the term implies absence of structural brain lesions and genetic predisposition in the presence of age-dependent seizures. BCECTS is the most frequent of the benign focal epilepsies in childhood accounting for 15 to 25% of epilepsy syndromes in children below 15 years of age. It is also the most frequent epilepsy syndrome occurring at school age. The prevalence of PS was around 13% in children aged 3 to 6 years with one or more nonfebrile seizures, and 6% in the age group of 1 to 15 years. These figures may be higher if children who are currently considered to have an atypical clinical presentation are included in the syndrome. PS is the most common specific cause of nonfebrile status epilepticus in childhood. ICOE “Gastaut type” is a rare manifestation of a focal idiopathic epilepsy that has an age-related onset and is often age limited. The seizures of ICOE Gastaut type are always of occipital-lobe onset and primarily manifest with visual seizures, which are the most typical and usually the first ictal symptom, but other types of seizures may be associated. ICOE “Gastaut type” is a rare condition with a probable prevalence of 0.2 to 0.9% of all epilepsies, and accounting for 2 to 7% of benign childhood focal seizures.The recognition of these age-dependent epileptic syndromes is crucial for the adequate management of the children and their family.

Atypical Evolutions of Idiopathic Focal Epilepsies in Childhood

Atypical Evolutions of Idiopathic Focal Epilepsies in Childhood

Averaged EEG spike dipole analysis may predict atypical outcome in Benign Childhood Epilepsy with Centrotemporal Spikes (BCECTS)

PurposeBenign Childhood Epilepsy with Centrotemporal Spikes (BCECTS) is the most common childhood idiopathic focal epilepsy with a good outcome. However, an increasing number of reports suggest a ‘not so benign’ outcome showing atypical evolution. MethodsWe analyzed the electroencephalographic (EEG) spike source dipoles of BCECTS patients to compare patients with confirmed typical and atypical outcome showing intractable epilepsy and cognitive decline. Thirty-seven patients that were diagnosed for BCECTS and whose clinical information was sufficient enough to confirm long-term outcome were included in the study. Eight patients (22%, 7 patients for poor seizure control and 1 patient for cognitive decline) were classified as showing atypical outcome. Forty-seven averaged spike dipole sources were analyzed using the single equivalent current dipole (ECD) method. The inverse problem was solved using the 4 shells ellipsoidal model. ResultsThe coordinate value of yori differed significantly between the two groups (mean±standard deviation, 0.32±0.33 for the typical group and −0.33±0.77 for the atypical group, P<0.001). These findings suggest that the averaged spike source dipoles were oriented anteriorly in patients with typical outcome and posteriorly in patients with atypical outcome. Spike source dipoles seemed to be located higher in patients with atypical presentation but this finding was insignificant. ConclusionWe can conclude that there are significant differences in spike source dipole in patients with BCECTS that shows atypical outcome, and we can use this finding as a marker for predicting an outcome at the time of diagnosis.

Epilepsy diagnostic and treatment needs identified with a collaborative database involving tertiary centers in France.

To obtain perspective on epilepsy in patients referred to tertiary centers in France, and describe etiology, epilepsy syndromes, and identify factors of drug resistance and comorbidities. We performed a cross-sectional analysis of the characteristics of 5,794 pediatric and adult patients with epilepsy included in a collaborative database in France between 2007 and 2013. Comparisons between groups used Student's t-test or Fisher's exact test for binary or categorical variables. Factors associated with drug resistance and intellectual disability were evaluated in multi-adjusted logistic regression models. Mean age at inclusion was 17.9 years; children accounted for 67%. Epilepsy was unclassified in 20% of patients, and etiology was unknown in 65%, including those with idiopathic epilepsies. Etiologies differed significantly in adult- when compared to pediatric-onset epilepsy; however, among focal structural epilepsies, mesial temporal lobe epilepsy with hippocampal sclerosis began as often in the pediatric as in adult age range. Drug resistance concerned 53% of 4,210 patients evaluable for seizure control and was highest in progressive myoclonic epilepsy (89%), metabolic diseases (84%), focal cortical dysplasia (70%), other cortical malformations (69%), and mesial temporal lobe epilepsy with hippocampal sclerosis (67%). Fifty-nine percent of patients with focal structural epilepsy and 69% with epileptic encephalopathies were drug resistant; however, 40-50% of patients with West syndrome and epileptic encephalopathy with continuous spike-and-waves during sleep were seizure-free. Ages at onset in infancy and in young adults shared the highest risk of drug resistance. Epilepsy onset in infancy comprised the highest risk of intellectual disability, whereas specific cognitive impairment affected 36% of children with idiopathic focal epilepsy. Our study provides a snapshot on epilepsy in patients referred to tertiary centers and discloses needs for diagnosis and treatment. Large databases help identify patients with rare conditions that could benefit from specific prospective studies.

Atypical benign partial epilepsy of childhood with acquired neurocognitive, lexical semantic, and autistic spectrum disorder.

Atypical benign partial epilepsy (ABPE) of childhood or pseudo-Lennox syndrome is a form of idiopathic focal epilepsy characterized by multiple seizure types, focal and/or generalized epileptiform discharges, continuous spike–wave during sleep (CSWS), and sometimes reversible neurocognitive deficits. There are few reported cases of ABPE describing detailed correlative longitudinal follow-up of the various associated neurocognitive, language, social communicative, or motor deficits, in parallel with the epilepsy. Furthermore, the molecular inheritance pattern for ABPE and the wider spectrum of epilepsy aphasia disorders have yet to be fully elucidated. We describe the phenotype–genotype study of a boy with ABPE with follow-up from ages 5 to 13 years showing acquired oromotor and, later, a specific lexical semantic and pervasive developmental disorder. Exome sequencing identified variants in SCN9A, CPA6, and SCNM1. A direct role of the epilepsy in the pathogenesis of the oromotor and neurocognitive deficits is apparent.

CLINICAL AND ELECTROENCEPHALOGRAPHIC CHARACTERISTICS OF IDIOPATHIC CHILDHOOD FOCAL EPILEPSY WITH CENTROTEMPORAL SPIKES

Idiopathic childhood focal epilepsy with centrotemporal spikes, which is more known as rolandic epilepsy (RE), is age- and localization-related epilepsy with childhood onset, which is characterized mainly by short-lasting hemifacial and oropharyngeal seizures generally occurring when awakening or falling asleep, by the normal neurological status of patients, by specific electroencephalographic changes and complete arrest of seizures during therapy or when achieving puberty. RE is the most common epilepsy in childhood. Its prevalence is 21 per 100,000 healthy children. It is characterized by an onset that is clearly related to age. In 85 % of cases, RE occurs at 4–10 years of age with its peak at about 9 years. The clinical manifestations of this form of epilepsy are several types of seizures, such as oropharyngolaryngeal, hemifacial, faciobrachial, secondarily generalized convulsive, unilateral seizures with the possible development of short duration Todd’s paresis. Other types of seizures (absence, atonic, and myoclonic ones) are uncharacteristic of RE. They may occur occasionally on aggravation resulting from the use of carbamazepine or oxcarbazepine or permanently on transformation into pseudo-Lennox syndrome. According to the definition, focal neurological symptoms and behavioral and intellectual disorders are absent in patients with RE. However, there have been recent observations suggesting that speech, cognitive, and behavioral disorders may occur (at the same time rarely) in children with RE. Magnetic resonance imaging (MRI) fails to reveal the abnormality in the vast majority of cases. The described MRI changes in nearly 10 % of the patients with RE are an incidental finding and irrelevant to the course of the disease. Valproate in small doses is a first-choice drug; if it is inefficient, levetiracetam, topiramate, or a combination of valproate and ethosuximide are administered. Sulthiame (ospolot) as monotherapy is used in Germany. Based on their findings and the data available in the literature, the authors consider the etiology, pathogenesis, clinical manifestations of RE and its diagnosis, treatment principles, and prognosis. The specific features of the electroencephalographic pattern in this disease are detailed.

Altered Structural and Functional Feature of Striato-Cortical Circuit in Benign Epilepsy with Centrotemporal Spikes.

Benign epilepsy with centrotemporal spikes (BECT) is the most common form of childhood idiopathic focal epilepsy syndrome. We investigated quantitative evidence regarding brain morphology and functional connectivity features to provide insight into the neuroanatomical foundation of this disorder, using high resolution T1-weighted magnetic resonance imaging (MRI) and resting state functional MRI in 21 patients with BECT and in 20 healthy children. The functional connectivity analysis, seeded at the regions with altered gray-matter (GM) volume in voxel-based morphometry (VBM) analysis, was further performed. Then, the observed structural and functional alteration were investigated for their association with the clinical and behavior manifestations. The increased GM volume in the striatum and fronto-temporo-parietal cortex (striato-cortical circuit) was observed in BECT. The decreased connections were found among the motor network and frontostriatal loop, and between the default mode network (DMN) and language regions. Additionally, the GM of striatum was negatively correlated with age at epilepsy onset. The current observations may contribute to the understanding of the altered structural and functional feature of striato-cortical circuit in patients with BECT. The findings also implied alterations of the motor network and DMN, which were associated with the epileptic activity in patients with BECT. This further suggested that the onset of BECT might have enduring structural and functional effects on brain maturation.

Investigation of GRIN2A in common epilepsy phenotypes

Recently, mutations and deletions in the GRIN2A gene have been identified to predispose to benign and severe idiopathic focal epilepsies (IFE), revealing a higher incidence of GRIN2A alterations among the more severe phenotypes. This study aimed to explore the phenotypic boundaries of GRIN2A mutations by investigating patients with the two most common epilepsy syndromes: (i) idiopathic generalized epilepsy (IGE) and (ii) temporal lobe epilepsy (TLE). Whole exome sequencing data of 238 patients with IGE as well as Sanger sequencing of 84 patients with TLE were evaluated for GRIN2A sequence alterations. Two additional independent cohorts comprising 1469 IGE and 330 TLE patients were screened for structural deletions (>40kb) involving GRIN2A. Apart from a presumably benign, non-segregating variant in a patient with juvenile absence epilepsy, neither mutations nor deletions were detected in either cohort. These findings suggest that mutations in GRIN2A preferentially are involved in genetic variance of pediatric IFE and do not contribute significantly to either adult focal epilepsies as TLE or generalized epilepsies.

PECULIARITIES OF TREATMENT OF EPILEPSY AT GIRLS AND WOMEN

The epilepsy treatment is to be based on existing general principles and standards of therapy with differential approach to each patient. Besides peculiarities of treatment of different types of seizures and forms of epilepsy there are also differential approaches to special groups of patients. To one of such groups are referred to women of reproductive age. These patients are referred to special group of risk due to the development of certain side effects of antiepileptic drugs (АED). This article focuses in details on peculiarities of treatment of women of reproductive age with epilepsy with accent made on tolerability and safety of the antiepileptic therapy. It is necessary to take into consideration, that at women neuroendocrinal disorders can be caused both by the disease itself – epilepsy (in such case disorders depend on the starting age, form of epilepsy, focal localization, duration of disorder and other factors, referred to the disease), as well as by the undertaken therapy. The article hereunder considers only issues, referred to the treatment, i. e. AED side effects and its input in the decrease of life quality of women with epilepsy. As women’s reproductive function starts forming long ago before childbearing age, it is necessary for this category to comprise not only women and adolescents, but girls as well. Notwithstanding the fact that so called benign forms of epilepsy pass before the pubescence period (idiopathic focal epilepsies, several forms of idiopathic generalized epilepsy), in many cases the epilepsy, which has started in childhood, continues in the adult age as well. In the same time there can be possible remote negative consequences of the antiepileptic therapy, which can show at a woman of a reproductive age. The data, given in the article, witnesses the need of the right AED selection at women of reproductive age, suffering from epilepsy. The AED should be selected not only depending on the form of the epilepsy and on the kind of seizures, but also provided its influence on the neuroen docrinal status of a woman, as well as on its influence on the reproductive system. With that it should be kept in mind that the reproductive function is very important not only from the point of view of woman’s health, but also from the point of view of her family and social status. If possible, women and men of reproductive age (including adolescents) should avoid AED with strong induction of the fermentative system of the liver (all barbiturates, hydantoins, carbamazepine), women should also avoid AED, containing valproic acid. In such cases the priority can be given to new AED, not affecting neuroendocrinal functions and the reproductive system.

Gastaut type idiopathic occipital epilepsy

Idiopathic occipital epilepsy is a rare epileptic syndrome. Its incidence in a Novosibirsk cohort of patients with idiopathic focal epilepsy is 0.9%. Objective : to present a clinical description of new cases of Gastaut syndrome, the types of its course, and treatment options in these patients. Patients and methods. The study covers 17 cases of Gastaut type idiopathic occipital epilepsy in 13 women and 4 men aged 11–53 years. Results . Among 17 cases we present 4 family cases with the disease. Three generations in 2 families were observed to have epilepsy, including Gastaut syndrome concurrent with childhood absence epilepsy. The adolescent onset of the disease was seen in most cases. Its main symptoms were focal visual seizures (100%), focal sensory seizures (58.9%), cephalalgia (47.1%), speech disorders (41.2%), and secondarily generalized convulsive seizures (35.3%). According to the frequency of seizures, the investigators identified 5 types of the course: single focal seizures, rare focal seizures with or without convulsions, frequent focal seizures with or without convulsions. The identity of the course of epilepsy was found in familial cases. 76.5% of the patients had a good quality of life: 41.2% of them were untreated while 35.3% were treated; no seizures were noted.

Impaired sleep-related consolidation of declarative memories in idiopathic focal epilepsies of childhood

ObjectiveDeclarative memory is consolidated during sleep in healthy children. We tested the hypothesis that consolidation processes are impaired in idiopathic focal epilepsies (IFE) of childhood in association with frequent interictal epileptiform discharges (IEDs) during sleep. MethodsA verbal (word-pair association) and a nonverbal (2D object location) declarative memory task were administrated to 15 children with IFEs and 8 control children 6–12years of age. Patients had either centrotemporal (11 patients) or occipital (4 patients) IEDs. All but 3 patients had a history of unprovoked seizures, and 6 of them were treated with valproate (VPA). The learning procedure (location of object pairs presented on a grid; association of word pairs) was executed in the evening. Retrieval was tested immediately after learning and on the next morning after a night of sleep. Participants were tested twice, once in natural home conditions and one month later in the unfamiliar conditions of the sleep unit under EEG monitoring. ResultsOvernight recall performance was lower in children with IFE than in control children on both tasks (ps<0.05). Performance in home conditions was similar to that in hospital conditions. Higher spike–wave index (SWI) during nonrapid eye movement (NREM) sleep was associated with poorer performance in the nonverbal task (p<0.05). Valproate treatment was not associated with overnight recall performance for both tasks (ps>0.05). ConclusionMemory consolidation is impaired in IFE of childhood. The association between higher SWI during NREM sleep and poorer nonverbal declarative memory consolidation supports the hypothesis that interictal epileptic activity could disrupt sleep memory consolidation.

The Clinical and Neurophysiological Features of Epileptic Syndromes Associated with Benign Focal Epileptiform Discharges of Childhood

Benign focal epileptiform discharge of childhood (BFEDC) is an age-dependent pattern determined in electroencephalograms (EEGs), which is associated with idiopathic benign focal epilepsy (BFE). Studies of BFE revealed symptomatic phenocopies in patients with cerebral struc- tural abnormalities in such conditions as infantile cerebral palsy and malformations. Some arguments against the «benign» nature of BFEDC are presented, since BFEDC may impair various cognitive functions and behavior (e.g., cause epileptic encephalophathies). Objective. To determine the clinical and neurophysiological features of epileptic syndromes associated with prolonged epileptiform activity during sleep in children and adolescents, as well as approaches to rational therapy. Patients and Methods . A total of 1862 children aged 2–18 admitted to the specialized Department of Psychoneurology of the Voronezh Regional Children Clinical Hospital No 1 in 2004–2007, who had epileptic seizures and non-epileptic neurological disorders, were exam- ined. The children underwent assessment of the neurological status, neuropsychological assessment, and video-EEG monitoring. The spike- wave index (SWI) was calculated and magnetic resonance imaging (MRI) of the brain was performed to register the epileptiform activity during sleep. Results and Discussion. It was demonstrated that when ISW of BFEDC patterns is >30%, evolution into epileptic encephalopathy was observed in 66% of patients (including epilepsy with electrical status epilepticus in sleep in 49% of patients and cognitive epileptiform disinte- gration in 17% of patients). The results prove the justification of prescribing antiepileptic drugs to patients with SWI ≥30% even if they have no epileptic seizures. Duo-therapy with valproate and ethosuximide or levetiracetam is most the effective therapy. Further prospective studies for children with BFEDC will give new insight into this area.

16p11.2 600 kb Duplications confer risk for typical and atypical Rolandic epilepsy.

Rolandic epilepsy (RE) is the most common idiopathic focal childhood epilepsy. Its molecular basis is largely unknown and a complex genetic etiology is assumed in the majority of affected individuals. The present study tested whether six large recurrent copy number variants at 1q21, 15q11.2, 15q13.3, 16p11.2, 16p13.11 and 22q11.2 previously associated with neurodevelopmental disorders also increase risk of RE. Our association analyses revealed a significant excess of the 600 kb genomic duplication at the 16p11.2 locus (chr16: 29.5-30.1 Mb) in 393 unrelated patients with typical (n = 339) and atypical (ARE; n = 54) RE compared with the prevalence in 65,046 European population controls (5/393 cases versus 32/65,046 controls; Fisher's exact test P = 2.83 × 10(-6), odds ratio = 26.2, 95% confidence interval: 7.9-68.2). In contrast, the 16p11.2 duplication was not detected in 1738 European epilepsy patients with either temporal lobe epilepsy (n = 330) and genetic generalized epilepsies (n = 1408), suggesting a selective enrichment of the 16p11.2 duplication in idiopathic focal childhood epilepsies (Fisher's exact test P = 2.1 × 10(-4)). In a subsequent screen among children carrying the 16p11.2 600 kb rearrangement we identified three patients with RE-spectrum epilepsies in 117 duplication carriers (2.6%) but none in 202 carriers of the reciprocal deletion. Our results suggest that the 16p11.2 duplication represents a significant genetic risk factor for typical and atypical RE.

CEREBRAL GLUCOSE UTILIZATION MEASURED WITH HIGH RESOLUTION POSITRON EMISSION TOMOGRAPHY IN EPILEPTIC FINNISH SPITZ DOGS AND HEALTHY DOGS

In human epileptic patients, changes in cerebral glucose utilization can be detected 2-deoxy-2-[(18) F] fluoro-D-glucose positron emission tomography (FDG-PET). The purpose of this prospective study was to determine whether epileptic dogs might show similar findings. Eleven Finnish Spitz dogs with focal idiopathic epilepsy and six healthy dogs were included. Dogs were examined using electroencephalography (EEG) and FDG-PET, with epileptic dogs being evaluated during the interictal period. Visual and semi-quantitative assessment methods of FDG-PET were compared and contrasted with EEG findings. Three independent observers, unaware of dog clinical status, detected FDG-PET uptake abnormalities in 9/11 epileptic (82%), and 4/8 healthy dogs (50%). Occipital cortex findings were significantly associated with epileptic status (P = 0.013). Epileptic dogs had significantly lower standardized uptake values (SUVs) in numerous cortical regions, the cerebellum, and the hippocampus compared to the control dogs. The lowest SUVs were found in the occipital lobe. White matter normalized and left-right asymmetry index values for all pairs of homologous regions did not differ between groups. Visual evaluation of the EEGs was less sensitive (36%) than FDG-PET. Both diagnostic tests were consensual and specific (100%) for occipital findings, but EEG had a lower sensitivity for detecting lateralized foci than FDG-PET. Findings supported the use of FDG-PET as a diagnostic test for dogs with suspected idiopathic epilepsy. Visual and semiquantitative analyses of FDG-PET scans provided complementary information. Findings also supported the theory that epileptogenesis may occur in multiple brain regions in Finnish Spitz dogs with idiopathic epilepsy.