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Different neuroimaging techniques (fMRI, spectroscopy, PET) are being used to evaluate candidate drugs in pharmacological development. In patients with epilepsy fast propagation of the epileptiform activity between different brain areas occurs. Electric Source Imaging (ESI), in contrast to the aforementioned techniques, has a millisecond time resolution, allowing visualization of this fast propagation. The purpose of the current project was to use ESI to investigate whether introduction of an antiepileptic drug (levetiracetam, LEV) would change the propagation patterns of the interictal epileptiform activity. Thirty patients with epilepsy were subject to an EEG recording before (pre-LEV) and after (in-LEV) introduction of LEV. Interictal spikes with similar topographic distribution were averaged within each subject, and a distributed source model was used to localize the EEG sources of the epileptiform activity. The temporal development of the activity within 20 regions of interest (ROIs) was determined, and source propagation between different regions was compared between the pre-LEV and in-LEV recordings. Patients with epileptic seizures showed propagation in 22/24 identified spike types in the pre-LEV recordings. In the in-LEV recordings only 7/15 spike types showed propagation, and six of these seven propagating spikes were recorded in patients with poor effect of treatment. Also in patients without seizures LEV tended to suppress propagation. We conclude that the observed suppression of source propagation can be considered as an indicator of effective antiepileptic treatment. ESI might thus become a useful tool in the early clinical evaluation of new candidate drugs in pharmacological development

Sarcopenia corresponds to the degenerative loss of skeletal muscle mass, quality, and strength associated with ageing and leads to a progressive impairment of mobility and quality of life. However, the cellular and molecular mechanisms involved in this process are not completely understood. A hallmark of cellular and tissular ageing is the accumulation of oxidatively modified (carbonylated) proteins, leading to a decreased quality of the cellular proteome that could directly impact on normal cellular functions. Although increased oxidative stress has been reported during skeletal muscle ageing, the oxidized protein targets, also referred as to the 'oxi-proteome' or 'carbonylome', have not been characterized yet. To better understand the mechanisms by which these damaged proteins build up and potentially affect muscle function, proteins targeted by these modifications have been identified in human rectus abdominis muscle obtained from young and old healthy donors using a bi-dimensional gel electrophoresis-based proteomic approach coupled with immunodetection of carbonylated proteins. Among evidenced protein spots, 17 were found as increased carbonylated in biopsies from old donors comparing to young counterparts. These proteins are involved in key cellular functions such as cellular morphology and transport, muscle contraction and energy metabolism. Importantly, impairment of these pathways has been described in skeletal muscle during ageing. Functional decline of these proteins due to irreversible oxidation may therefore impact directly on the above-mentioned pathways, hence contributing to the generation of the sarcopenic phenotype.

Background: From a population based study of epilepsy in Swedish children a subgroup designated well-functioning with an epilepsy diagnosis in 1997 was worked up from a medical point of view 10 years later. Aim: To describe the psychological and social outcome in this subgroup. Methods: Thirty-one patients aged 11-22 years and their parents/partners responded to a questionnaire according to Achenbach System of Empirically Based Assessment (ASEBA) to evaluate behavioural and emotional problems, and social competence. Results: Active epilepsy, diagnosed in 32%, was related to attention problems, somatic complaints, and school problems. Polytherapy, used in 16%, was related to attention problems and aggressive behaviour. School problems were found in six of seven children younger than 18 years. Internalizing, externalizing, and 'other' syndromes were found in 29% of the individuals, but a grouping of these syndromes in the clinical range only in two (6.5%), a girl with generalized tonic clonic seizures alone, and a boy with structural focal epilepsy. Both had active epilepsy and were treated with polytherapy. All ten individuals with Rolandic epilepsy were classified as normal. The answers to the ASEBA questionnaire of individuals and parents/partners were inconsistent, and parents generally stated more problems than the individuals. Summary.: This 10-year follow-up study of psychological and social outcome in well-functioning children and adolescents with childhood onset epilepsy shows some emotional, behavioural, and social problems. Thus, early information to increase knowledge about epilepsy and associated psychological co-morbidities in order to decrease risk of low self-esteem, social anxiety, and depression later in life is of importance.

We report comparison and assessment of the clinical utility of different automated methods for the estimation of the alpha frequency in electroencephalograph (EEG) and compare them with visual evaluation. A total of 56 consecutive patients, aged 17 to 78 years, who had a routine EEG recording, were included, and they were grouped as patients with epilepsy (Ep) and without epilepsy (nEp). Five different methods were used for alpha frequency estimation: visually guided manual counting and visually guided Fourier transform, and 3 methods were fully automated: time domain estimation of alpha (automatic assessment of alpha waves in time domain [ATD]) and 2 fast Fourier transform (FFT)-based methods, a segmented (automatic assessment of EEG segments by FFT) and one full FFT (automatic assessment of whole EEG by one FFT of the full recording [AWF]). The AWF discriminated significantly between Ep and nEp. Visually guided manual counting showed an almost significant difference independently in the 2 occipital electrodes. The ATD underestimated high frequencies and returned a too low mean frequency. This study shows that AWF is the best suited method for automatic assessment of the alpha frequency.

OBJECTIVE: Rare copy number variants (CNVs)-deletions and duplications-have recently been established as important risk factors for both generalized and focal epilepsies. A systematic assessment of the role of CNVs in epileptic encephalopathies, the most devastating and often etiologically obscure group of epilepsies, has not been performed. METHODS: We evaluated 315 patients with epileptic encephalopathies characterized by epilepsy and progressive cognitive impairment for rare CNVs using a high-density, exon-focused, whole-genome oligonucleotide array. RESULTS: We found that 25 of 315 (7.9%) of our patients carried rare CNVs that may contribute to their phenotype, with at least one-half being clearly or likely pathogenic. We identified 2 patients with overlapping deletions at 7q21 and 2 patients with identical duplications of 16p11.2. In our cohort, large deletions were enriched in affected individuals compared to controls, and 4 patients harbored 2 rare CNVs. We screened 2 novel candidate genes found within the rare CNVs in our cohort but found no mutations in our patients with epileptic encephalopathies. We highlight several additional novel candidate genes located in CNV regions. INTERPRETATION: Our data highlight the significance of rare CNVs in the epileptic encephalopathies, and we suggest that CNV analysis should be considered in the genetic evaluation of these patients. Our findings also highlight novel candidate genes for further study.

BACKGROUND A population based study of epilepsy in children from a Swedish county including all children aged 1 month to 16 years was reported in 2006. AIM To describe the medical outcome, seizure types, epilepsy syndromes, treatment, individual and family history in children from this study who were well-functioning in January 1997 and the outcome after 10 years. METHODS Forty-five individuals, 11-21 years, 19 females, and their parents responded to a questionnaire and the hospital records were reviewed. RESULTS At the end of the 10-year period 75.6% of the patients were in remission. Focal seizures and focal seizures with secondary generalization were found in 57.8%. Rolandic epilepsy had been diagnosed in 33.3%, other idiopathic focal epilepsies in 11.0%, cryptogenic and symptomatic focal epilepsies in 22.2%, childhood absence epilepsy in 8.9%, juvenile absence epilepsy and Jeavons syndrome in each 2.2%, West syndrome in 4.4%, and other "generalized" epilepsies in 15.5%. The patients had a history of simple febrile seizures in 15.6% and of primary headache in 24.4%. Monotherapy with antiepileptic drugs was used by 64.4%, and valproate was the most common first drug of choice. A family history of epilepsy was found in 44.4%, febrile seizures in 17.7%, and primary headache in 57.8%. A coincidence of focal and generalized epilepsy phenotypes was found in some families. CONCLUSIONS Longitudinal studies are of importance in epilepsy epidemiology. Our results reflect the selection of only well-functioning individuals with epilepsy from the population based original study.

BACKGROUND: Symptoms of attention deficit hyperactivity disorder (ADHD) are more common in children with epilepsy than in the general paediatric population. Epileptiform discharges in EEG may be seen in children with ADHD also in those without seizure disorders. Sleep enhances these discharges which may be suppressed by levetiracetam. AIM: To assess the effect of levetiracetam on focal epileptiform discharges during sleep in children with ADHD. METHOD: In this retrospective study a new semi-automatic quantitative method based on the calculation of spike index in 24-h ambulatory EEG recordings was applied. Thirty-five ADHD children, 17 with focal epilepsy, one with generalised epilepsy, and 17 with no seizure disorder were evaluated. Follow-up 24-h EEG recordings were performed after a median time of four months. RESULTS: Mean spike index was 50 prior to levetiracetam treatment and 21 during treatment. Seventeen children had no focal interictal epileptiform discharges in EEG at follow-up. Five children had a more than 50% reduction in spike index. Thus, a more than 50% reduction in spike index was found in 22/35 children (63%). Out of these an improved behaviour was noticed in 13 children (59%). CONCLUSION: This study shows that treatment with levetiracetam reduces interictal epileptiform discharges in children with ADHD. There is a complex relationship between epilepsy, ADHD and epileptiform activity, why it is a need for prospective studies in larger sample sizes, also to ascertain clinical benefits.

Quantification of epileptiform activity in EEG has been applied for decades. This has mainly been done by visual inspection of the recorded EEG. There have been many attempts using computers to quantify the activity, usually with moderate success. In a row of contexts, including Landau-Kleffner syndrome and the syndrome of epilepsy with continuous spike wave during slow sleep, the spike index (SI) has been applied to quantify [Symbol: see text]interictal nocturnal focal epileptiform activity', which is suggested as a general term for the epileptiform activity enhanced by sleep. However, the SI has been implemented differently by different authors and has usually not been well described and never properly defined. This study suggests a definition of SI that gives a semiautomatic and relatively robust algorithm for assessment. The method employs spike detection by means of template matching of the current source density estimate. The percentage of time within an epoch with interspike interval (ISI) below a given limit, usually 3 s, is returned as the SI. This is calculated during daytime and in non-REM sleep. The standard epoch length is 10 min. The parameter selection is discussed in the context of the influence of spikes and bursts on cognition. The described method gives reproducible results in routine use, gives clinical valuable information, and is easily implemented in a clinical setting. There is only a minor added workload for the electroencephalographer.

OBJECTIVE: To explore the involvement of M-type potassium channels KCNQ2, Q3, and Q5 in the pathogenesis of common idiopathic epilepsies. METHODS: Sequence analysis of the KCNQ2, Q3, and Q5 coding regions was performed in a screening sample consisting of 58 nuclear families with rolandic epilepsy. Subsequently, an association study was conducted for all discovered variants in a case-control sample comprising 459 German patients with idiopathic generalized epilepsy (IGE) and 462 population controls. RESULTS: An in-frame deletion of codon 116 in KCNQ2 (p.Lys116del) and a missense mutation in KCNQ3 (p.Glu299Lys) were detected in two index cases exhibiting rolandic epilepsy and benign neonatal convulsions. Both mutations resulted in reduced potassium current amplitude in Xenopus oocytes. Mutation analysis of families with rolandic epilepsy without neonatal seizures discovered three novel missense variations (KCNQ2 p.Ile592Met, KCNQ3 p.Ala381Val, KCNQ3 p.Pro574Ser). The KCNQ2 p.Ile592Met variant displayed a significant reduction of potassium current amplitude in Xenopus oocytes and was present only once in 552 controls. Both missense variants identified in KCNQ3 (p.Ala381Val and p.Pro574Ser) were present in all affected family members and did not occur in controls, but did not show obvious functional abnormalities. The KCNQ3 missense variant p.Pro574Ser was also detected in 8 of 455 IGE patients but not in 454 controls (p = 0.008). In KCNQ2, a silent single nucleotide polymorphism (rs1801545) was found overrepresented in both epilepsy samples (IGE, p = 0.004). CONCLUSION: Sequence variations of the KCNQ2 and KCNQ3 genes may contribute to the etiology of common idiopathic epilepsy syndromes.

Familial hyperCKemia is a rare condition, and a combination with Duchenne muscular dystrophy (DMD) is extremely rare. A boy showed muscle weakness from the age of 10 months and presented typical signs of DMD at the age of 18 months. The diagnosis was supported by markedly elevated serum creatine kinase (CK) value as well as by neurophysiological and muscle biopsy findings at the age of 23 months. The diagnosis was confirmed by identification of a stop codon in exon 43 (p.2095Arg>X) of the dystrophin gene. Interestingly, the father and his near relatives had increased serum CK values without any clinical symptoms or signs, nor a defect in caveolin-3 gene. We suggest that the occurrence of familial hyperCKemia may have triggered the early onset of symptoms in our patient.

Återkommande huvudvärk är ett av de vanligaste hälsoproblemen bland skolbarn och rapporteras av cirka en fjärdedel. Den är särskilt vanlig bland flickor i tonåren. Vanligast är huvudvärk av spänningstyp och/eller migrän. Hos skolbarn medför återkommande huvudvärk sänkt livskvalitet, högre grad av emotionella och sociala problem samt andra somatiska symtom. Prognosen för sådan huvudvärk är också osäker. Det är av stor vikt att lärare och skolsköterskor/läkare tidigt uppmärksammar återkommande huvudvärk hos barn och ungdom så att den blir diagnostiserad och behandlad i enlighet med bästa tillgängliga kunskap. Ett sådant omhändertagande omfattar både aktiv psykologisk och farmakologisk behandling, vilket påtagligt kan minska besvären och deras psykosociala konsekvenser.

Childhood absence epilepsy (CAE) is an idiopathic generalised epilepsy characterised by absence seizures manifested by transitory loss of awareness with 2.5-4 Hz spike-wave complexes on ictal EEG. A genetic component to aetiology is established but the mechanism of inheritance and the genes involved are not fully defined. Available evidence suggests that genes encoding brain expressed voltage-gated calcium channels, including CACNG3 on chromosome 16p12-p13.1, may represent susceptibility loci for CAE. The aim of this work was to further evaluate CACNG3 as a susceptibility locus by linkage and association analysis. Assuming locus heterogeneity, a significant HLOD score (HLOD = 3.54, alpha = 0.62) was obtained for markers encompassing CACNG3 in 65 nuclear families with a proband with CAE. The maximum non-parametric linkage score was 2.87 (P < 0.002). Re-sequencing of the coding exons in 59 patients did not identify any putative causal variants. A linkage disequilibrium (LD) map of CACNG3 was constructed using 23 single nucleotide polymorphisms (SNPs). Transmission disequilibrium was sought using individual SNPs and SNP-based haplotypes with the pedigree disequilibrium test in 217 CAE trios and the 65 nuclear pedigrees. Evidence for transmission disequilibrium (P < or = 0.01) was found for SNPs within a approximately 35 kb region of high LD encompassing the 5'UTR, exon 1 and part of intron 1 of CACNG3. Re-sequencing of this interval was undertaken in 24 affected individuals. Seventy-two variants were identified: 45 upstream; two 5'UTR; and 25 intronic SNPs. No coding sequence variants were identified, although four variants are predicted to affect exonic splicing. This evidence supports CACNG3 as a susceptibility locus in a subset of CAE patients.

OBJECTIVE: To describe the clinical phenotype of paroxysmal extreme pain disorder (previously called familial rectal pain syndrome), an autosomal dominant condition recently shown to be a sodium channelopathy involving SCN9A. METHODS: An international consortium of clinicians, scientists, and affected families was formed. Clinical details of all accessible families worldwide were collected, including age at onset, features of attacks, problems between attacks, investigational results, treatments tried, and evolution over time. A validated pain questionnaire was completed by 14 affected individuals. RESULTS: Seventy-seven individuals from 15 families were identified. The onset of the disorder is in the neonatal period or infancy and persists throughout life. Autonomic manifestations predominate initially, with skin flushing in all and harlequin color change and tonic attacks in most. Dramatic syncopes with bradycardia and sometimes asystole are common. Later, the disorder is characterized by attacks of excruciating deep burning pain often in the rectal, ocular, or jaw areas, but also diffuse. Attacks are triggered by factors such as defecation, cold wind, eating, and emotion. Carbamazepine is effective in almost all who try it, but the response is often incomplete. CONCLUSIONS: Paroxysmal extreme pain disorder is a highly distinctive sodium channelopathy with incompletely carbamazepine-sensitive bouts of pain and sympathetic nervous system dysfunction. It is most likely to be misdiagnosed as epilepsy and, particularly in infancy, as hyperekplexia and reflex anoxic seizures.

Information is sparse concerning the incidence and prognosis of headache in children from the general population, especially of tension-type headache. In this study, headache diagnoses and symptoms were reassessed in 122 out of 130 schoolchildren after 3 years. Nearly 80% of those with headache at first evaluation still reported headache at follow-up. Although the likelihood of experiencing the same headache diagnosis and symptoms was high, about one-fifth of children with tension-type headache developed migraine and vice versa. Female gender predicted migraine and frequent headache episodes predicted overall headache at follow-up. The estimated average annual incidence was 81 and 65 per 1000 children, for tension-type headache and migraine, respectively. We conclude that there is a considerable risk of developing and maintaining headache during childhood. Headache diagnoses should be reassessed regularly and treatment adjusted. Girls and children with frequent headache have a poorer prognosis and therefore intervention is particularly important in these groups.

Background: Epidemiological studies of childhood epilepsy are of importance to compare incidence and prevalence rates, age distribution, inheritance, seizure types, epilepsy syndromes and treatment strategies. Aim: To perform an epidemiological study on children with epilepsy in a Swedish county using current ILAE classifications and a recent proposal. Methods: A population-based study was performed using the hospital data register to select children aged 1 month to 16 years with the diagnosis 'convulsions' or 'epilepsy' recognized between January 1996 and December 2000. Only patients with active epilepsy were included. Results: Two hundred and five children met the study criteria on the prevalence day 31st December, 2000. The total prevalence rate was 3.4/1000 with a peak prevalence in the age group 8-11 years. The incidence year 2000 was 40/100,000. Additional neuroimpairments were registered in 47.3%. A majority of the patients, 54.0%, had focal or focal plus secondarily generalized seizures. A named syndrome could be diagnosed in 49.4%. The most common. syndrome was rolandic epilepsy occurring in 17.0%. Childhood absence epilepsy occurred in 5.9%. Different disorders associated with epilepsy were found in 31.7%. The most common associated phenomenon was malformation of cortical development. Antiepileptic drug treatment was used in 81.0%, the most common first choice being valproate. Conclusions: The prevalence and incidence rates in this strictly delineated study are lower than those found in other epidemiological studies. Together with many divergences between reported studies concerning frequencies of different items, the results apparently depend on design, e.g. differences in age groups included, inclusion criteria used, and general methodology.

Twelve children, all boys, aged 4 to 7 years, with a diagnosis of autistic disorder and low concentrations of spinal 6R-l-erythro-5,6,7,8-tetrahydrobiopterin (tetrahydrobiopterin) were selected to participate in a double-blind, randomized, placebo-controlled, crossover study. The children received a daily dose of 3 mg tetrahydrobiopterin per kilogram during 6 months alternating with placebo. Treatment-induced effects were assessed with the Childhood Autism Rating Scale every third month. The results showed small nonsignificant changes in the total scores of Childhood Autism Rating Scale after 3- and 6-month treatment. Post hoc analysis looking at the 3 core symptoms of autism, that is, social interaction, communication, and stereotyped behaviors, revealed a significant improvement of the social interaction score after 6 months of active treatment. In addition, a high positive correlation was found between response of the social interaction score and IQ. The results indicate a possible effect of tetrahydrobiopterin treatment.