Efficacy and safety of corticosteroids and ACTH in epileptic syndromes beyond Infantile Epileptic Spasms Syndrome (IESS): A systematic review and meta-analysis.

We conducted a systematic review investigating the efficacy and tolerability of adrenocorticotropic hormone (ACTH) and corticosteroids in children with epilepsies other than infantile epileptic spasm syndrome (IESS) that are resistant to anti-seizure medication (ASM). We included retrospective and prospective studies reporting on more than five patients and with clear case definitions and descriptions of treatment and outcome measures. We searched multiple databases and registries, and we assessed the risk of bias in the selected studies using a questionnaire based on published templates. Results were summarized with meta-analyses that pooled logit-transformed proportions or rates. Subgroup analyses and univariable and multivariable meta-regressions were performed to examine the influence of covariates. We included 38 studies (2 controlled and 5 uncontrolled prospective; 31 retrospective) involving 1152 patients. Meta-analysis of aggregate data for the primary outcomes of seizure response and reduction of electroencephalography (EEG) spikes at the end of treatment yielded pooled proportions (PPs) of 0.60 (95% confidence interval [CI] 0.52-0.67) and 0.56 (95% CI 0.43-0.68). The relapse rate was high (PP 0.33, 95% CI 0.27-0.40). Group analyses and meta-regression showed a small benefit of ACTH and no difference between all other corticosteroids, a slightly better effect in electric status epilepticus in slow sleep (ESES) and a weaker effect in patients with cognitive impairment and "symptomatic" etiology. Obesity and Cushing's syndrome were the most common adverse effects, occurring more frequently in trials addressing continuous ACTH (PP 0.73, 95% CI 0.48-0.89) or corticosteroids (PP 0.72, 95% CI 0.54-0.85) than intermittent intravenous or oral corticosteroid administration (PP 0.05, 95% CI 0.02-0.10). The validity of these results is limited by the high risk of bias in most included studies and large heterogeneity among study results. This report was registered under International Prospective Register of Systematic Reviews (PROSPERO) number CRD42022313846. We received no financial support.

Mutations in plasticity-related-gene-1 (PRG-1) protein contribute to hippocampal seizure susceptibility and modify epileptic phenotype.

The Phospholipid Phosphatase Related 4 gene (PLPPR4,  *607813) encodes the Plasticity-Related-Gene-1 (PRG-1) protein. This cerebral synaptic transmembrane-protein modulates cortical excitatory transmission on glutamatergic neurons. In mice, homozygous Prg-1 deficiency causes juvenile epilepsy. Its epileptogenic potential in humans was unknown. Thus, we screened 18 patients with infantile epileptic spasms syndrome (IESS) and 98 patients with benign familial neonatal/infantile seizures (BFNS/BFIS) for the presence of PLPPR4 variants. A girl with IESS had inherited a PLPPR4-mutation (c.896C > G, NM_014839; p.T299S) from her father and an SCN1A-mutation from her mother (c.1622A > G, NM_006920; p.N541S). The PLPPR4-mutation was located in the third extracellular lysophosphatidic acid-interacting domain and in-utero electroporation (IUE) of the Prg-1p.T300S construct into neurons of Prg-1 knockout embryos demonstrated its inability to rescue the electrophysiological knockout phenotype. Electrophysiology on the recombinant SCN1Ap.N541S channel revealed partial loss-of-function. Another PLPPR4 variant (c.1034C > G, NM_014839; p.R345T) that was shown to result in a loss-of-function aggravated a BFNS/BFIS phenotype and also failed to suppress glutamatergic neurotransmission after IUE. The aggravating effect of Plppr4-haploinsufficiency on epileptogenesis was further verified using the kainate-model of epilepsy: double heterozygous Plppr4-/+|Scn1awt|p.R1648H mice exhibited higher seizure susceptibility than either wild-type, Plppr4-/+, or Scn1awt|p.R1648H littermates. Our study shows that a heterozygous PLPPR4 loss-of-function mutation may have a modifying effect on BFNS/BFIS and on SCN1A-related epilepsy in mice and humans.

Mutations in PMPCB Encoding the Catalytic Subunit of the Mitochondrial Presequence Protease Cause Neurodegeneration in Early Childhood.

Mitochondrial disorders causing neurodegeneration in childhood are genetically heterogeneous, and the underlying genetic etiology remains unknown in many affected individuals. We identified biallelic variants in PMPCB in individuals of four families including one family with two affected siblings with neurodegeneration and cerebellar atrophy. PMPCB encodes the catalytic subunit of the essential mitochondrial processing protease (MPP), which is required for maturation of the majority of mitochondrial precursor proteins. Mitochondria isolated from two fibroblast cell lines and induced pluripotent stem cells derived from one affected individual and differentiated neuroepithelial stem cells showed reduced PMPCB levels and accumulation of the processing intermediate of frataxin, a sensitive substrate for MPP dysfunction. Introduction of the identified PMPCB variants into the homologous S. cerevisiae Mas1 protein resulted in a severe growth and MPP processing defect leading to the accumulation of mitochondrial precursor proteins and early impairment of the biogenesis of iron-sulfur clusters, which are indispensable for a broad range of crucial cellular functions. Analysis of biopsy materials of an affected individual revealed changes and decreased activity in iron-sulfur cluster-containing respiratory chain complexes and dysfunction of mitochondrial and cytosolic Fe-S cluster-dependent enzymes. We conclude that biallelic mutations in PMPCB cause defects in MPP proteolytic activity leading to dysregulation of iron-sulfur cluster biogenesis and triggering a complex neurological phenotype of neurodegeneration in early childhood.

Developmental outcomes in children/adolescents and one adult with tuberous sclerosis complex (TSC) and refractory epilepsy treated with everolimus.

This prospective observational study focuses on developmental outcomes in the treatment of tuberous sclerosis complex (TSC) with everolimus (EVO). Fourteen children/adolescents aged 1.7-13.07 and one adult aged 31 years, all with TSC and refractory epilepsy participated. All were treated with EVO for 3-70 months (md: 37). Development/adaptive functioning were evaluated at baseline with follow-up in 11 patients; all patients were assessed during the course of treatment. Our exploratory analyses included factors contributing to developmental impairment and change from baseline to last evaluation. The majority of patients showed severe developmental impairment (86%). Patients with a higher age at inclusion, duration of epilepsy, and number of previous antiepileptic drugs (AEDs) showed lower developmental levels. Earlier onset of epilepsy and a higher number of current AEDs were associated with worse adaptive functioning. At their last examination, four patients were seizure-free (27%), and four experienced a reduction of seizures >50% (27%). With treatment, (slight) increase was seen in absolute values of developmental age (DA) regarding both development and adaptive functioning. Yet, when accounting for age, decrease was seen in both assessments. While developmental disorders were prominent, we observed an overall progression at a slower pace. Despite a positive effect on seizure occurrence, treatment with EVO did not reverse developmental problems in the observation period of this study.

Neurogeriatrics-a vision for improved care and research for geriatric patients with predominating neurological disabilities.

Geriatric medicine is a rapidly evolving field that addresses diagnostic, therapeutic and care aspects of older adults. Some disabilities and disorders affecting cognition (e.g. dementia), motor function (e.g. stroke, Parkinson's disease, neuropathies), mood (e.g. depression), behavior (e.g. delirium) and chronic pain disorders are particularly frequent in old subjects. As knowledge about these age-associated conditions and disabilities is steadily increasing, the integral implementation of neurogeriatric knowledge in geriatric medicine and specific neurogeriatric research is essential to develop the field. This article discusses how neurological know-how could be integrated in academic geriatric medicine to improve care of neurogeriatric patients, to foster neurogeriatric research and training concepts and to provide innovative care concepts for geriatric patients with predominant neurological conditions and disabilities.

A multicenter, matched case-control analysis comparing burden-of-illness in Dravet syndrome to refractory epilepsy and seizure remission in patients and caregivers in Germany.

OBJECTIVE: To compare direct and indirect costs and quality of life (QoL) of pediatric and adult patients with Dravet syndrome (DS), with drug-resistant epilepsy (DRE) and in seizure remission (SR), and their caregivers, in Germany. METHODS: Questionnaire responses from 93 DS patients and their caregivers were matched by age and gender with responses from 93 DRE and 93 SR patients collected in independent studies, and were compared across main components of QoL, direct costs (patient visits, medication use, care level, medical equipment, and ancillary treatments), and indirect costs (quitting job, reduced working hours, missed days). RESULTS: Mean total direct costs were highest for DS patients (€4864 [median €3564] vs €3049 [median €1506] for DRE [excluding outliers], P = 0.01; and €1007 [median €311], P < 0.001 for SR). Total lost productivity over 3 months was highest among caregivers of pediatric DS (€4757, median €2841), compared with those of DRE (€1541, P < 0.001; median €0) and SR patients (€891, P < 0.001; median €0). The proportions of caregivers in employment were similar across groups (62% DS, 63% DRE, and 63% SR) but DS caregivers were more likely to experience changes to their working situation, such as quitting their job (40% DS vs 16% DRE and 9% SR, P < 0.001 in both comparisons). KINDL scores were significantly lower for DS patients (62 vs 74 and 72, P < 0.001 in both comparisons), and lower than for the average German population (77). Pediatric caregiver EQ-5D scores across all cohorts were comparable with population norms, but more DS caregivers experienced moderate to severe depressive symptoms (24% vs 11% and 5%). Mean Beck Depression Inventory (BDI-II) score was significantly higher in DS caregivers than either of the other groups (P < 0.001). SIGNIFICANCE: This first comparative study of Dravet syndrome to difficult-to-treat epilepsy and to epilepsy patients in seizure remission emphasizes the excess burden of DS in components of QoL and direct costs. The caregivers of DS patients have a greater impairment of their working lives (indirect costs) and increased depression symptoms.

Variants in the ATP1A3 Gene Mutations within Severe Apnea Starting in Early Infancy: An Observational Study of Two Cases with a Possible Relation to Epileptic Activity.

Mutations in the ATP1A3 gene are known to cause alternating hemiplegia of childhood (AHC) and rapid-onset dystonia parkinsonism (RDP). Both conditions are childhood-onset neurological disorders with distinct symptoms and different times of onset. ATP1A3 has also been associated with CAPOS syndrome (cerebellar ataxia, areflexia, pes cavus, optic atrophy, and sensorineural hearing loss). Within the various ATP1A3-related neurological syndromes, a specific genotype-phenotype correlation is starting to emerge. Several mutations such as the relatively common p.E815K pathogenic variant have been shown to strongly correlate with AHC, while others may cause both AHC and RDP. A significant subset of patients with AHC and RDP are reported to have epileptic seizures. Even though detailed clinical descriptions of seizures in childhood are rare, seizures involving apneic events seem to be frequent in ATP1A3-related neurological disorders. Here, we describe two children with unexplained severe apnea beginning around the first year of life and pathogenic variants in ATP1A3. We hypothesize that the symptoms are early-onset autonomic seizures related to the underlying pathogenic ATP1A3 variants.

Burden analysis of rare microdeletions suggests a strong impact of neurodevelopmental genes in genetic generalised epilepsies.

Genetic generalised epilepsy (GGE) is the most common form of genetic epilepsy, accounting for 20% of all epilepsies. Genomic copy number variations (CNVs) constitute important genetic risk factors of common GGE syndromes. In our present genome-wide burden analysis, large (≥ 400 kb) and rare (< 1%) autosomal microdeletions with high calling confidence (≥ 200 markers) were assessed by the Affymetrix SNP 6.0 array in European case-control cohorts of 1,366 GGE patients and 5,234 ancestry-matched controls. We aimed to: 1) assess the microdeletion burden in common GGE syndromes, 2) estimate the relative contribution of recurrent microdeletions at genomic rearrangement hotspots and non-recurrent microdeletions, and 3) identify potential candidate genes for GGE. We found a significant excess of microdeletions in 7.3% of GGE patients compared to 4.0% in controls (P = 1.8 x 10-7; OR = 1.9). Recurrent microdeletions at seven known genomic hotspots accounted for 36.9% of all microdeletions identified in the GGE cohort and showed a 7.5-fold increased burden (P = 2.6 x 10-17) relative to controls. Microdeletions affecting either a gene previously implicated in neurodevelopmental disorders (P = 8.0 x 10-18, OR = 4.6) or an evolutionarily conserved brain-expressed gene related to autism spectrum disorder (P = 1.3 x 10-12, OR = 4.1) were significantly enriched in the GGE patients. Microdeletions found only in GGE patients harboured a high proportion of genes previously associated with epilepsy and neuropsychiatric disorders (NRXN1, RBFOX1, PCDH7, KCNA2, EPM2A, RORB, PLCB1). Our results demonstrate that the significantly increased burden of large and rare microdeletions in GGE patients is largely confined to recurrent hotspot microdeletions and microdeletions affecting neurodevelopmental genes, suggesting a strong impact of fundamental neurodevelopmental processes in the pathogenesis of common GGE syndromes.

Smad anchor for receptor activation contributes to seizures in temporal lobe epilepsy.

PURPOSE: Smad anchor for receptor activation (SARA) is an important regulator of transforming growth factor ß (TGF-ß) signaling by recruiting Smad2/3 to TGF-ß receptors. Although TGF-ß signaling is critically involved in epileptogenesis, whether SARA activation is sufficient to facilitate TGF-ß pathway to regulate epilepsy remains unknown. METHODS: The expression of SARA and downstream Phospho-Smad3 (p-Smad3) was examined in rats with pilocarpine induced epilepsy. Additionally, knockdown of SARA was performed via recombinant lentiviral vector in the pilocarpine-induced rats. RESULTS: Here we show that expressions of SARA and p-Smad3 are increased in the hippocampus as rats subjected to pilocarpine-induced status epilepticus (SE). Both SARA and p-Smad3 are also upregulated in the temporal cortex of epileptic rats. Furthermore, SARA mRNA levels reach peak as early as 6 hr following SE onset and remain elevated in the chronic phase. Transfection of recombinant lentiviral shRNA targeting SARA knocks down SARA expression, attenuates TGF-ß/p-Smad3 signaling in the hippocampus, and postpones the SE onset. CONCLUSION: Our results demonstrate that SARA/Smad3 pathway contributes to mechanism of seizure and SARA in TGF-ß signaling may be a potential therapeutic target for epilepsy.

Neuronal networks in epileptic encephalopathies with CSWS.

OBJECTIVE: The aim of our study was to investigate the neuronal networks underlying background oscillations of epileptic encephalopathy with continuous spikes and waves during slow sleep (CSWS). METHODS: Sleep electroencephalography (EEG) studies before and after the treatment were investigated in 15 patients with CSWS. To investigate functional and effective connectivity within the network generating the delta activity in the background sleep EEG, the methods of dynamic imaging of coherent sources (DICS) and renormalized partial directed coherence (RPDC) were applied. RESULTS: Independent of etiology and severity of epilepsy, background EEG pattern in patients with CSWS before treatment is associated with the complex network of coherent sources in medial prefrontal cortex, somatosensory association cortex/posterior cingulate cortex, medial prefrontal cortex, middle temporal gyrus/parahippocampal gyrus/insular cortex, thalamus, and cerebellum. The analysis of information flow within this network revealed that the medial parietal cortex, the precuneus, and the thalamus act as central hubs, driving the information flow to other areas, especially to the temporal and frontal cortex. The described CSWS-specific pattern was no longer observed in patients with normalized sleep EEG. In addition, frequency of spiking showed a strong linear correlations with absolute source power, source coherence strength, and source RPDC strength at both time points: (1) Spike and wave index (SWI) versus absolute source power at EEG1 (r = 0.56; p = 0.008) and at EEG2 (r = 0.45; p = 0.009); (2) SWI versus source coherence strength at EEG1 (r = 0.71; p = 0.005) and at EEG2 (r = 0.52; p = 0.006); and (3) SWI versus source RPDC strength at EEG1 (r = 0.65; p = 0.003) and at EEG2 (r = 0.47; p = 0.009). SIGNIFICANCE: The leading role of the precuneus and thalamus in the hierarchical organization of the network underlying the background EEG points toward the significance of fluctuations of vigilance in the generation of CSWS. This hierarchical network organization appears to be specific for CSWS as it is resolved after successful treatment.

CHD2 variants are a risk factor for photosensitivity in epilepsy.

Photosensitivity is a heritable abnormal cortical response to flickering light, manifesting as particular electroencephalographic changes, with or without seizures. Photosensitivity is prominent in a very rare epileptic encephalopathy due to de novo CHD2 mutations, but is also seen in epileptic encephalopathies due to other gene mutations. We determined whether CHD2 variation underlies photosensitivity in common epilepsies, specific photosensitive epilepsies and individuals with photosensitivity without seizures. We studied 580 individuals with epilepsy and either photosensitive seizures or abnormal photoparoxysmal response on electroencephalography, or both, and 55 individuals with photoparoxysmal response but no seizures. We compared CHD2 sequence data to publicly available data from 34 427 individuals, not enriched for epilepsy. We investigated the role of unique variants seen only once in the entire data set. We sought CHD2 variants in 238 exomes from familial genetic generalized epilepsies, and in other public exome data sets. We identified 11 unique variants in the 580 individuals with photosensitive epilepsies and 128 unique variants in the 34 427 controls: unique CHD2 variation is over-represented in cases overall (P = 2.17 × 10(-5)). Among epilepsy syndromes, there was over-representation of unique CHD2 variants (3/36 cases) in the archetypal photosensitive epilepsy syndrome, eyelid myoclonia with absences (P = 3.50 × 10(-4)). CHD2 variation was not over-represented in photoparoxysmal response without seizures. Zebrafish larvae with chd2 knockdown were tested for photosensitivity. Chd2 knockdown markedly enhanced mild innate zebrafish larval photosensitivity. CHD2 mutation is the first identified cause of the archetypal generalized photosensitive epilepsy syndrome, eyelid myoclonia with absences. Unique CHD2 variants are also associated with photosensitivity in common epilepsies. CHD2 does not encode an ion channel, opening new avenues for research into human cortical excitability.

Costs of epilepsy and cost-driving factors in children, adolescents, and their caregivers in Germany.

OBJECTIVE: To provide first data on the cost of epilepsy and cost-driving factors in children, adolescents, and their caregivers in Germany. METHODS: A population-based, cross-sectional sample of consecutive children and adolescents with epilepsy was evaluated in the states of Hessen and Schleswig-Holstein (total of 8.796 million inhabitants) in all health care sectors in 2011. Data on socioeconomic status, course of epilepsy, and direct and indirect costs were recorded using patient questionnaires. RESULTS: We collected data from 489 children and adolescents (mean age ± SD 10.4 ± 4.2 years, range 0.5-17.8 years; 264 [54.0%] male) who were treated by neuropediatricians (n = 253; 51.7%), at centers for social pediatrics ("Sozialpaediatrische Zentren," n = 110, 22.5%) and epilepsy centers (n = 126; 25.8%). Total direct costs summed up to €1,619 ± €4,375 per participant and 3-month period. Direct medical costs were due mainly to hospitalization (47.8%, €774 ± €3,595 per 3 months), anticonvulsants (13.2%, €213 ± €363), and ancillary treatment (9.1%, €147 ± €344). The total indirect costs amounted to €1,231 ± €2,830 in mothers and to €83 ± €593 in fathers; 17.4% (n = 85) of mothers and 0.6% (n = 3) of fathers reduced their working hours or quit work because of their child's epilepsy. Independent cost-driving factors were younger age, symptomatic cause, and polytherapy with anticonvulsants. Older age, active epilepsy, symptomatic cause, and polytherapy were independent predictors of higher antiepileptic drug (AED) costs, whereas younger age, longer epilepsy duration, symptomatic cause, disability, and parental depression were independent predictors for higher indirect costs. SIGNIFICANCE: Treatment of children and adolescents with epilepsy is associated with high direct costs due to frequent inpatient admissions and high indirect costs due to productivity losses in mothers. Direct costs are age-dependent and higher in patients with symptomatic epilepsy and polytherapy. Indirect costs are higher in the presence of a child's disability and parental depression.

Long-term seizure outcome in 211 patients with focal cortical dysplasia.

OBJECTIVE: Focal cortical dysplasia (FCD) is currently recognized as the most common cause of neocortical pharmacoresistant epilepsy. Epilepsy surgery has become an increasingly successful treatment option. Herein, the largest patient cohort reported to date is analyzed regarding long-term outcome and factors relevant for long-term seizure control. METHODS: Two hundred eleven children and adults undergoing epilepsy surgery for histologically proven FCD and a follow-up period of 2-12 years were analyzed regarding the longitudinal course of seizure control, effects of FCD type, localization, magnetic resonance imaging (MRI), timing of surgery, and postoperative antiepileptic treatment. RESULTS: After 1 year, Engel class I outcome was achieved in 65% of patients and the percentage of seizure-free patients remained stable over the following (up to 12) years. Complete resection of the assumed epileptogenic area, lower age at surgery, and unilobar localization were positive prognostic indicators of long-term seizure freedom. Seizure recurrence was 12% after the first year, whereas 8% achieved late seizure freedom either following additional introduction of antiepileptic drugs (AEDs) (4%), a reoperation (2%), or a running down phenomenon (2%). Thirty-nine percent of patients had a reduction of AED from polytherapy to monotherapy or a complete cessation of AED treatment. Late seizure relapse was seen in nine patients during reduction of AEDs (i.e., in 12% of all patients with AED tapering); in four of them seizures persisted after reestablishment of antiepileptic medication. SIGNIFICANCE: Postoperative long-term seizure outcome was favorable in patients with FCD and remained stable in 80% of patients after the first postoperative year. Several preoperative factors revealed to be predictive for the postoperative outcome and may help in the preoperative counseling of patients with FCD and in the selection of ideal candidates for epilepsy surgery.

Investigating the genetic basis of fever-associated syndromic epilepsies using copy number variation analysis.

Fever-associated syndromic epilepsies ranging from febrile seizures plus (FS+) to Dravet syndrome have a significant genetic component. However, apart from SCN1A mutations in >80% of patients with Dravet syndrome, the genetic underpinnings of these epilepsies remain largely unknown. Therefore, we performed a genome-wide screening for copy number variations (CNVs) in 36 patients with SCN1A-negative fever-associated syndromic epilepsies. Phenotypes included Dravet syndrome (n = 23; 64%), genetic epilepsy with febrile seizures plus (GEFS+) and febrile seizures plus (FS+) (n = 11; 31%) and unclassified fever-associated epilepsies (n = 2; 6%). Array comparative genomic hybridization (CGH) was performed using Agilent 4 × 180K arrays. We identified 13 rare CNVs in 8 (22%) of 36 individuals. These included known pathogenic CNVs in 4 (11%) of 36 patients: a 1q21.1 duplication in a proband with Dravet syndrome, a 14q23.3 deletion in a proband with FS+, and two deletions at 16p11.2 and 1q44 in two individuals with fever-associated epilepsy with concomitant autism and/or intellectual disability. In addition, a 3q13.11 duplication in a patient with FS+ and two de novo duplications at 7p14.2 and 18q12.2 in a patient with atypical Dravet syndrome were classified as likely pathogenic. Six CNVs were of unknown significance. The identified genomic aberrations overlap with known neurodevelopmental disorders, suggesting that fever-associated epilepsy syndromes may be a recurrent clinical presentation of known microdeletion syndromes.

The role of SLC2A1 mutations in myoclonic astatic epilepsy and absence epilepsy, and the estimated frequency of GLUT1 deficiency syndrome.

The first mutations identified in SLC2A1, encoding the glucose transporter type 1 (GLUT1) protein of the blood-brain barrier, were associated with severe epileptic encephalopathy. Recently, dominant SLC2A1 mutations were found in rare autosomal dominant families with various forms of epilepsy including early onset absence epilepsy (EOAE), myoclonic astatic epilepsy (MAE), and genetic generalized epilepsy (GGE). Our study aimed to investigate the possible role of SLC2A1 in various forms of epilepsy including MAE and absence epilepsy with early onset. We also aimed to estimate the frequency of GLUT1 deficiency syndrome in the Danish population. One hundred twenty patients with MAE, 50 patients with absence epilepsy, and 37 patients with unselected epilepsies, intellectual disability (ID), and/or various movement disorders were screened for mutations in SLC2A1. Mutations in SLC2A1 were detected in 5 (10%) of 50 patients with absence epilepsy, and in one (2.7%) of 37 patient with unselected epilepsies, ID, and/or various movement disorders. None of the 120 MAE patients harbored SLC2A1 mutations. We estimated the frequency of SLC2A1 mutations in the Danish population to be approximately 1:83,000. Our study confirmed the role of SLC2A1 mutations in absence epilepsy with early onset. However, our study failed to support the notion that SLC2A1 aberrations are a cause of MAE without associated features such as movement disorders.

Cortical Thickness Changes Associated with Photoparoxysmal Response.

Photoparoxysmal response (PPR) is an EEG trait of spike and spike-wave discharges in response to photic stimulation that is closely linked to idiopathic generalized epilepsy (IGE). In our previous studies we showed that PPR is associated with functional alterations in the occipital and frontal cortices. The aim of the present study was to determine structural changes associated with PPR. For this purpose we analysed the cortical thickness as derived from T1 MRI images in PPR-positive-subjects (n = 12; 15.5 ± 8.6 years; 4 males), PPR-positive-IGE-patients (n = 12; 14.9 ± 2.7 years; 4 males) and compared these groups with a group of PPR-negative-healthy-controls (HC, n = 17; 15.3 ± 3.6 years; 6 males). Our results revealed an increase of cortical thickness in the occipital, frontal and parietal cortices bilaterally in PPR-positive-subjects in comparison to HC. Moreover PPR-positive-subjects presented a significant decrease of cortical thickness in the temporal cortex in the same group contrast. IGE patients exhibited lower cortical thickness in the temporal lobe bilaterally and in the right paracentral region in comparison to PPR-positive-subjects. Our study demonstrates structural changes in the occipital lobe, frontoparietal regions and temporal lobe, which also show functional changes associated with PPR. Patients with epilepsy present changes in the temporal lobe and supplementary motor area.

Effectiveness and tolerability of perampanel in children and adolescents with refractory epilepsies: first experiences.

OBJECTIVE: This article aims to report the first clinical experiences concerning effectiveness and tolerability of perampanel (PER) in a pediatric population with refractory epilepsies. PATIENTS AND METHODS: This nonsponsored, observational, retrospective survey was conducted through collaboration with multiple centers in Europe. The clinical course of the first pediatric patients treated in these centers with PER was documented with the help of a questionnaire completed by the treating physicians. Effectiveness and adverse effects were evaluated. The study population consisted of 58 patients (mean age, 10.5 years; range, 2-17 years), suffering from various refractory epilepsies, classified as focal epilepsy (n = 36), unclassified generalized epilepsy (n = 12), Lennox-Gastaut syndrome (n = 5), West syndrome (n = 3), and Dravet syndrome (n = 2). RESULTS: The response rate (≥ 50% seizure reduction) after the first 3 months of therapy was 31% (18/58 patients) in total. Complete seizure control was achieved in five patients (9% overall). Aggravation of seizures occurred in five cases (9%). The most frequently occurring adverse effects were reduced vigilance or fatigue (n = 16) and behavioral changes (n = 14). DISCUSSION: PER seems to be effective also in children and adolescents with pharmaco-refractory epilepsies. Tolerability was acceptable.

Genome-wide association analysis of genetic generalized epilepsies implicates susceptibility loci at 1q43, 2p16.1, 2q22.3 and 17q21.32.

Genetic generalized epilepsies (GGEs) have a lifetime prevalence of 0.3% and account for 20-30% of all epilepsies. Despite their high heritability of 80%, the genetic factors predisposing to GGEs remain elusive. To identify susceptibility variants shared across common GGE syndromes, we carried out a two-stage genome-wide association study (GWAS) including 3020 patients with GGEs and 3954 controls of European ancestry. To dissect out syndrome-related variants, we also explored two distinct GGE subgroups comprising 1434 patients with genetic absence epilepsies (GAEs) and 1134 patients with juvenile myoclonic epilepsy (JME). Joint Stage-1 and 2 analyses revealed genome-wide significant associations for GGEs at 2p16.1 (rs13026414, P(meta) = 2.5 × 10(-9), OR[T] = 0.81) and 17q21.32 (rs72823592, P(meta) = 9.3 × 10(-9), OR[A] = 0.77). The search for syndrome-related susceptibility alleles identified significant associations for GAEs at 2q22.3 (rs10496964, P(meta) = 9.1 × 10(-9), OR[T] = 0.68) and at 1q43 for JME (rs12059546, P(meta) = 4.1 × 10(-8), OR[G] = 1.42). Suggestive evidence for an association with GGEs was found in the region 2q24.3 (rs11890028, P(meta) = 4.0 × 10(-6)) nearby the SCN1A gene, which is currently the gene with the largest number of known epilepsy-related mutations. The associated regions harbor high-ranking candidate genes: CHRM3 at 1q43, VRK2 at 2p16.1, ZEB2 at 2q22.3, SCN1A at 2q24.3 and PNPO at 17q21.32. Further replication efforts are necessary to elucidate whether these positional candidate genes contribute to the heritability of the common GGE syndromes.

Phenotypic spectrum of eleven patients and five novel MTFMT mutations identified by exome sequencing and candidate gene screening.

Defects of mitochondrial oxidative phosphorylation (OXPHOS) are associated with a wide range of clinical phenotypes and time courses. Combined OXPHOS deficiencies are mainly caused by mutations of nuclear genes that are involved in mitochondrial protein translation. Due to their genetic heterogeneity it is almost impossible to diagnose OXPHOS patients on clinical grounds alone. Hence next generation sequencing (NGS) provides a distinct advantage over candidate gene sequencing to discover the underlying genetic defect in a timely manner. One recent example is the identification of mutations in MTFMT that impair mitochondrial protein translation through decreased formylation of Met-tRNA(Met). Here we report the results of a combined exome sequencing and candidate gene screening study. We identified nine additional MTFMT patients from eight families who were affected with Leigh encephalopathy or white matter disease, microcephaly, mental retardation, ataxia, and muscular hypotonia. In four patients, the causal mutations were identified by exome sequencing followed by stringent bioinformatic filtering. In one index case, exome sequencing identified a single heterozygous mutation leading to Sanger sequencing which identified a second mutation in the non-covered first exon. High-resolution melting curve-based MTFMT screening in 350 OXPHPOS patients identified pathogenic mutations in another three index cases. Mutations in one of them were not covered by previous exome sequencing. All novel mutations predict a loss-of-function or result in a severe decrease in MTFMT protein in patients' fibroblasts accompanied by reduced steady-state levels of complex I and IV subunits. Being present in 11 out of 13 index cases the c.626C>T mutation is one of the most frequent disease alleles underlying OXPHOS disorders. We provide detailed clinical descriptions on eleven MTFMT patients and review five previously reported cases.

Transition issues for benign epilepsy with centrotemporal spikes, nonlesional focal epilepsy in otherwise normal children, childhood absence epilepsy, and juvenile myoclonic epilepsy.

This chapter covers the syndromes of benign epilepsy with centrotemporal spikes (BECTS), nonlesional focal epilepsy in otherwise normal children (NLFN), and the genetic generalized epilepsies. BECTS is an epilepsy syndrome that always enters terminal remission before the general age of a planned transition of adolescents. This is also the case for the majority (65%) of those with childhood absence epilepsy (CAE). Approximately 15% of patients with CAE who initially remit during their childhood years later develop juvenile myoclonic epilepsy (JME) as teenagers. They will have many issues for continuing medical care and transition, because their seizure disorder generally persists into adulthood. A significant minority of NLFN (~35%) and most patients with JME continue to have active epilepsy into adulthood. In addition, CAE, JME, and NLFN patients are at risk of a number of significant adverse social outcomes that require ongoing advice and counseling.