Multiorgan manifestations of COL4A1 and COL4A2 variants and proposal for a clinical management protocol.

COL4A1/2 variants are associated with highly variable multiorgan manifestations. Depicting the whole clinical spectrum of COL4A1/2-related manifestations is challenging, and there is no consensus on management and preventative strategies. Based on a systematic review of current evidence on COL4A1/2-related disease, we developed a clinical questionnaire that we administered to 43 individuals from 23 distinct families carrying pathogenic variants. In this cohort, we extended ophthalmological and cardiological examinations to asymptomatic individuals and those with only limited or mild, often nonspecific, clinical signs commonly occurring in the general population (i.e., oligosymptomatic). The most frequent clinical findings emerging from both the literature review and the questionnaire included stroke (203/685, 29.6%), seizures or epilepsy (199/685, 29.0%), intellectual disability or developmental delay (168/685, 24.5%), porencephaly/schizencephaly (168/685, 24.5%), motor impairment (162/685, 23.6%), cataract (124/685, 18.1%), hematuria (63/685, 9.2%), and retinal arterial tortuosity (58/685, 8.5%). In oligosymptomatic and asymptomatic carriers, ophthalmological investigations detected retinal vascular tortuosity (5/13, 38.5%), dysgenesis of the anterior segment (4/13, 30.8%), and cataract (2/13, 15.4%), while cardiological investigations were unremarkable except for mild ascending aortic ectasia in 1/8 (12.5%). Our multimodal approach confirms highly variable penetrance and expressivity in COL4A1/2-related conditions, even at the intrafamilial level with neurological involvement being the most frequent and severe finding in both children and adults. We propose a protocol for prevention and management based on individualized risk estimation and periodic multiorgan evaluations.

Expanding the genetic and phenotypic spectrum of CHD2-related disease: From early neurodevelopmental disorders to adult-onset epilepsy.

CHD2 encodes the chromodomain helicase DNA-binding protein 2, an ATP-dependent enzyme that acts as a chromatin remodeler. CHD2 pathogenic variants have been associated with various early onset phenotypes including developmental and epileptic encephalopathy, self-limiting or pharmacoresponsive epilepsies and neurodevelopmental disorders without epilepsy. We reviewed 84 previously reported patients carrying 76 different CHD2 pathogenic or likely pathogenic variants and describe 18 unreported patients carrying 12 novel pathogenic or likely pathogenic variants, two recurrent likely pathogenic variants (in two patients each), three previously reported pathogenic variants, one gross deletion. We also describe a novel phenotype of adult-onset pharmacoresistant epilepsy, associated with a novel CHD2 missense likely pathogenic variant, located in an interdomain region. A combined review of previously published and our own observations indicates that although most patients (72.5%) carry truncating CHD2 pathogenic variants, CHD2-related phenotypes encompass a wide spectrum of conditions with developmental delay/intellectual disability (ID), including prominent language impairment, attention deficit hyperactivity disorder and autistic spectrum disorder. Epilepsy is present in 92% of patients with a median age at seizure onset of 2 years and 6 months. Generalized epilepsy types are prevalent and account for 75.5% of all epilepsies, with photosensitivity being a common feature and adult-onset nonsyndromic epilepsy a rare presentation. No clear genotype-phenotype correlation has emerged.

Surgical outcome of temporal plus epilepsy is improved by multilobar resection.

OBJECTIVE: Temporal plus epilepsy (TPE) represents a rare type of epilepsy characterized by a complex epileptogenic zone including the temporal lobe and the close neighboring structures. We investigated whether the complete resection of temporal plus epileptogenic zone as defined through stereoelectroencephalography (SEEG) might improve seizure outcome in 38 patients with TPE. METHODS: Inclusion criteria were as follows: epilepsy surgery performed between January 1990 and December 2001, SEEG defining a temporal plus epileptogenic zone, unilobar temporal operations ("temporal lobe epilepsy [TLE] surgery") or multilobar interventions including the temporal lobe ("TPE surgery"), magnetic resonance imaging either normal or showing signs of hippocampal sclerosis, and postoperative follow-up of at least 12 months. For each assessment of postoperative seizure outcome, at 1, 2, 5, and 10 years, we carried out descriptive analysis and classical tests of hypothesis, namely, Pearson χ2 test or Fisher exact test of independence on tables of frequency for each categorical variable of interest and Student t-test for each continuous variable of interest, when appropriate. RESULTS: Twenty-one patients underwent TPE surgery and 17 underwent TLE surgery with a follow-up of 12.4 ± 8.16 years. In the multivariate models, there was a significant effect of the time from surgery on Engel Class IA versus IB-IV outcome, with a steadily worsening trend from 5-year follow-up onward. TPE surgery was associated with better results than TLE surgery. SIGNIFICANCE: This study suggests that surgical outcome in patients with TPE can be improved by a tailored, multilobar resection and confirms that SEEG is mandatory when a TPE is suspected.

Temporal lobe epilepsy surgery in children and adults: A multicenter study.

OBJECTIVE: To assess seizure and cognitive outcomes and their predictors in children (<16 years at surgery) and adults undergoing temporal lobe epilepsy (TLE) surgery in eight Italian centers. METHODS: This is a retrospective multicenter study. We performed a descriptive analysis and subsequently carried out multivariable mixed-effect models corrected for multiple comparisons. RESULTS: We analyzed data from 511 patients (114 children) and observed significant differences in several clinical features between adults and children. The possibility of achieving Engel class IA outcome and discontinuing antiepileptic drugs (AEDs) at last follow-up (FU) was significantly higher in children (P = .006 and < .0001). However, percentages of children and adults in Engel class I at last FU (mean ± SD, 45.9 ± 17 months in children; 45.9 ± 20.6 months in adults) did not differ significantly. We identified different predictors of seizure outcome in children vs adults and at short- vs long-term FU. The only variables consistently associated with class I outcome over time were postoperative electroencephalography (EEG) in adults (abnormal, improved,odds ratio [OR] = 0.414, P = .023, Q = 0.046 vs normal, at 2-year FU and abnormal, improved, OR = 0.301, P = .001, Q = 0.002 vs normal, at last FU) and the completeness of resection of temporal magnetic resonance (MR) abnormalities other than hippocampal sclerosis in children (OR = 7.93, P = .001, Q = 0.003, at 2-year FU and OR = 45.03, P < .0001, Q < 0.0001, at last FU). Cognitive outcome was best predicted by preoperative performances in either age group. SIGNIFICANCE: Clinical differences between adult and pediatric patients undergoing TLE surgery are reflected in differences in long-term outcomes and predictors of failures. Children are more likely to achieve sustained seizure freedom and withdraw AEDs after TLE surgery. Earlier referral should be encouraged as it can improve surgical outcome.

Customized multigene panels in epilepsy: the best things come in small packages.

Over the past 10 years, the increasingly important role played by next-generation sequencing panels in the genetic diagnosis of epilepsy has led to a growing list of gene variants and a plethora of new scientific data. To date, however, there is still no consensus on what constitutes the "ideal panel design," or on the most rational criteria for selecting the best candidates for gene-panel analysis, even though both might optimize the cost-benefit ratio and the diagnostic efficiency of customized gene panels. Even though more and more laboratories are adopting whole-exome sequencing as a first-tier diagnostic approach, interpreting, "in silico," a set of epilepsy-related genes remains difficult. In the light of these considerations, we performed a systematic review of the targeted gene panels for epilepsy already reported in the available scientific literature, with a view to identifying the best criteria for selecting patients for gene-panel analysis, and the best way to design an "ideal," gold-standard panel that includes all genes with an established role in epilepsy pathogenesis, as well as those that might help to guide decisions regarding specific medical interventions and treatments. Our analyses suggest that the usefulness and diagnostic power of customized gene panels for epilepsy may be greatest when these panels are confined to rationally selected, relatively small, pools of genes, and applied in more carefully selected epilepsy patients (those with complex forms of epilepsy). A panel containing 64 genes, which includes the 45 genes harboring a significant number of pathogenic variants identified in previous literature, the 32 clinically actionable genes, and the 21 ILAE (International League Against Epilepsy) recommended genes, may represent an "ideal" core set likely able to provide the highest diagnostic efficiency and cost-effectiveness and facilitate gene prioritization when testing patients with whole-exome/whole-genome sequencing.

Clinical and electroencephalographic correlates of psychiatric features in children with frontal lobe epilepsy.

BACKGROUND AND OBJECTIVE: Frontal lobe epilepsy (FLE) is often associated with psychiatric features, although the factors predisposing to the concurrence of these conditions have yet to be determined, especially in younger children. We aimed at defining possible clinical and electroencephalography (EEG) features that may enhance the psychiatric risk in pediatric FLE. METHOD: We performed a structured psychiatric assessment of 59 children with FLE, using both categorical and dimensional approaches, correlated psychopathology with epilepsy data, and cognitive development. RESULTS: About 1/3 of patients with FLE displayed intellectual disability (ID), and more than 2/3 displayed psychiatric disorders, including depression, disruptive behaviors, anxiety, and bipolar/psychotic disorders. Psychiatric dimensions such as impulse control problems, attentional deficits, social problems, and aggressive behaviors were frequent features of FLE. Intellectual disability was associated with an earlier onset of psychiatric disorders and more frequent disruptive behavior disorders and aggressiveness. Long-standing epilepsy and bilateral or anterior frontal EEG abnormalities also increased the risk of psychopathology. Finally, right-hemisphere lesions were associated with disruptive behavior disorders, fast EEG rhythms with attention/memory problems, and phases of seizure remission with impulse control problems. CONCLUSIONS: Clinical and EEG markers of increased psychopathological risk may help in defining consistent at-risk subgroups within FLE and improving early diagnosis, prognosis, and treatment. Categorical and dimensional approaches to psychiatric diagnosis may generate new research hypotheses and support the investigation of the complex pathophysiological bases shared by different neurodevelopmental disturbances.

Internalizing and externalizing symptoms in preschool and school-aged children with epilepsy: Focus on clinical and EEG features.

INTRODUCTION: Psychiatric and behavioral problems are frequent comorbidities of epilepsy, although their clinical and electroencephalographic (EEG) correlates remain uncertain. In this study, we have assessed the frequency of psychopathological problems in a cohort of children with epilepsy, and established their main clinical and EEG-associated features. METHODS: One hundred fifty-nine young patients with epilepsy were recruited and assessed through the Child Behavior Checklist for preschool-aged children (CBCL 1 1/2-5) or for school-aged children (CBCL 6-18). Child Behavior Checklist (CBCL) results were then correlated to the main clinical and EEG data. RESULTS: We found emotional and behavioral problems in about half of the children in our sample. Internalizing, social, and attention problems were more common than externalizing features. Moderate intellectual disability, a nonidiopathic etiology of epilepsy, a poor control of seizures, and antiepileptic polytherapies, as well as an early age at seizure-onset and a longer duration of the disorder, were all associated with specific behavioral and emotional problems. A temporal site of interictal EEG abnormalities also enhanced the risk for psychiatric comorbidities, especially in the externalizing domain. CONCLUSIONS: Several clinical and EEG features are associated with an increased risk for emotional and behavioral comorbidities in children with epilepsy. Their identification may foster an early diagnosis and appropriate care, limiting the worsening of psychiatric symptoms and their impact on quality of life and health status. A better understanding of the underlying clinical and molecular mechanisms is needed to further improve prevention and treatment interventions.

Increasing volume and complexity of pediatric epilepsy surgery with stable seizure outcome between 2008 and 2014: A nationwide multicenter study.

OBJECTIVE: The objective of the study was to assess common practice in pediatric epilepsy surgery in Italy between 2008 and 2014. METHODS: A survey was conducted among nine Italian epilepsy surgery centers to collect information on presurgical and postsurgical evaluation protocols, volumes and types of surgical interventions, and etiologies and seizure outcomes in pediatric epilepsy surgery between 2008 and 2014. RESULTS: Retrospective data on 527 surgical procedures were collected. The most frequent surgical approaches were temporal lobe resections and disconnections (133, 25.2%) and extratemporal lesionectomies (128, 24.3%); the most frequent etiologies were FCD II (107, 20.3%) and glioneuronal tumors (105, 19.9%). Volumes of surgeries increased over time independently from the age at surgery and the epilepsy surgery center. Engel class I was achieved in 73.6% of patients (range: 54.8 to 91.7%), with no significant changes between 2008 and 2014. Univariate analyses showed a decrease in the proportion of temporal resections and tumors and an increase in the proportion of FCDII, while multivariate analyses revealed an increase in the proportion of extratemporal surgeries over time. A higher proportion of temporal surgeries and tumors and a lower proportion of extratemporal and multilobar surgeries and of FCD were observed in low (<50surgeries/year) versus high-volume centers. There was a high variability across centers concerning pre- and postsurgical evaluation protocols, depending on local expertise and facilities. SIGNIFICANCE: This survey reveals an increase in volume and complexity of pediatric epilepsy surgery in Italy between 2008 and 2014, associated with a stable seizure outcome.

Morphometric network-based abnormalities correlate with psychiatric comorbidities and gene expression in PCDH19-related developmental and epileptic encephalopathy.

Protocadherin-19 (PCDH19) developmental and epileptic encephalopathy causes an early-onset epilepsy syndrome with limbic seizures, typically occurring in clusters and variably associated with intellectual disability and a range of psychiatric disorders including hyperactive, obsessive-compulsive and autistic features. Previous quantitative neuroimaging studies revealed abnormal cortical areas in the limbic formation (parahippocampal and fusiform gyri) and underlying white-matter fibers. In this study, we adopted morphometric, network-based and multivariate statistical methods to examine the cortex and substructure of the hippocampus and amygdala in a cohort of 20 PCDH19-mutated patients and evaluated the relation between structural patterns and clinical variables at individual level. We also correlated morphometric alterations with known patterns of PCDH19 expression levels. We found patients to exhibit high-significant reductions of cortical surface area at a whole-brain level (left/right pvalue = 0.045/0.084), and particularly in the regions of the limbic network (left/right parahippocampal gyri pvalue = 0.230/0.016; left/right entorhinal gyri pvalue = 0.002/0.327), and bilateral atrophy of several subunits of the amygdala and hippocampus, particularly in the CA regions (head of the left CA3 pvalue = 0.002; body of the right CA3 pvalue = 0.004), and differences in the shape of hippocampal structures. More severe psychiatric comorbidities correlated with more significant altered patterns, with the entorhinal gyrus (pvalue = 0.013) and body of hippocampus (pvalue = 0.048) being more severely affected. Morphometric alterations correlated significantly with the known expression patterns of PCDH19 (rvalue = -0.26, pspin = 0.092). PCDH19 encephalopathy represents a model of genetically determined neural network based neuropsychiatric disease in which quantitative MRI-based findings correlate with the severity of clinical manifestations and had have a potential predictive value if analyzed early.

A randomized phase III trial of adjunctive zonisamide in pediatric patients with partial epilepsy.

PURPOSE: To assess the efficacy and safety/tolerability of adjunctive zonisamide treatment in pediatric patients with partial epilepsy. METHODS: In this phase III, double-blind, randomized, placebo-controlled, multicenter trial, 207 patients (age 6-17 years) with partial epilepsy, receiving one or two antiepileptic drugs, were randomized to receive adjunctive zonisamide or placebo. Zonisamide was initiated at 1 mg/kg/day, titrated to a target dose of 8 mg/kg/day over 8 weeks (one down-titration permitted), and maintained for 12 weeks. The primary efficacy end point was the proportion of responders (≥ 50% seizure frequency reduction from baseline) during the 12-week maintenance period. Safety/tolerability assessments included the incidence of treatment-emergent adverse events (TEAEs). KEY FINDINGS: In total, 93 (86.9%) of 107 patients randomized to zonisamide and 90 (90.0%) of 100 patients randomized to placebo completed the trial. Responder rates were 50% for zonisamide versus 31% for placebo (p = 0.0044; intention-to-treat population, last observation carried forward). The overall incidence of TEAEs was similar for zonisamide (55.1%) versus placebo (50.0%), with low rates of serious TEAEs with zonisamide and placebo (3.7% vs. 2.0%) and TEAEs leading to withdrawal (0.9% vs. 3.0%). TEAEs reported more frequently with zonisamide versus placebo were decreased appetite (6.5% vs. 4.0%), decreased weight (4.7% vs. 3.0%), somnolence (4.7% vs. 2.0%), vomiting (3.7% vs. 2.0%), and diarrhea (3.7% vs. 1.0%). SIGNIFICANCE: Adjunctive zonisamide treatment was shown to be effective and well tolerated in pediatric patients with partial epilepsy. No new or unexpected safety findings emerged.

A pharmacokinetic study and correlation with clinical response of rufinamide in infants with epileptic encephalopathies.

AIM: To evaluate the relationship between the pharmacokinetic (PK) parameters and therapeutic and adverse effects of rufinamide (RUF) in children with epileptic encephalopathies (EE) aged <4 years. METHODS: PK analysis was conducted at the steady state using a previously validated liquid chromatography tandem-mass spectrometric method in 15 children aged 6-42 months treated with RUF in add-on. Responders were defined as patients who achieved >50% decrease of seizures. Tolerability was evaluated by analysis of a parental report of adverse effects, a clinical examination and laboratory tests. RESULTS: Maximum plasma concentration (47.40 ± 35.36 mg/l), average plasma concentration (39.94 ± 24.53 mg/l) and half-life (13.66 ± 4.43 h) were extremely variable and considerably higher than those reported in older children treated with the same dose regimen. At the last evaluation, 9 patients (60%) were responders. CONCLUSION: RUF is efficacious and is well tolerated in children with EE. Nonetheless, a correlation between dose, serum concentration and efficacy could not be demonstrated. The variability in measured concentrations may be related to polytherapy that is necessary for controlling seizures in this very severe form of epilepsy, in which the off-label use of RUF is justified.

Making memories: the development of long-term visual knowledge in children with visual agnosia.

There are few reports about the effects of perinatal acquired brain lesions on the development of visual perception. These studies demonstrate nonseverely impaired visual-spatial abilities and preserved visual memory. Longitudinal data analyzing the effects of compromised perceptions on long-term visual knowledge in agnosics are limited to lesions having occurred in adulthood. The study of children with focal lesions of the visual pathways provides a unique opportunity to assess the development of visual memory when perceptual input is degraded. We assessed visual recognition and visual memory in three children with lesions to the visual cortex having occurred in early infancy. We then explored the time course of visual memory impairment in two of them at 2 years and 3.7 years from the initial assessment. All children exhibited apperceptive visual agnosia and visual memory impairment. We observed a longitudinal improvement of visual memory modulated by the structural properties of objects. Our findings indicate that processing of degraded perceptions from birth results in impoverished memories. The dynamic interaction between perception and memory during development might modulate the long-term construction of visual representations, resulting in less severe impairment.

A registry for Dravet syndrome: The Italian experience.

OBJECTIVES: We describe the Residras registry, dedicated to Dravet syndrome (DS) and to other phenotypes related to SCN1A mutations, as a paradigm of registry for rare and complex epilepsies. Our primary objectives are to present the tools and framework of the integrative platform, the main characteristics emerging from the patient cohort included in the registry, with emphasis on demographic, clinical outcome, and mortality. METHODS: Standardized data of enrolled pediatric and adult patients were collected in 24 Italian expert centers and regularly updated at least on a yearly basis. Patients were prospectively enrolled, at registry starting, but historical retrospective data were also included. RESULTS: At present, 281 individuals with DS and a confirmed SCN1A mutation are included. Most patients have data available on epilepsy (n = 263) and their overall neurological condition (n = 255), based on at least one follow-up update. Median age at first clinical assessment was 2 years (IQR 0-9) while at last follow-up was 11 years (IQR 5-18.5). During the 7-year activity of the registry, five patients died resulting in a mortality rate of 1.84 per 1000-person-years. When analyzing clinical changes over the first 5-year follow-up, we observed a significant difference in cognitive function (P < 0.001), an increased prevalence of behavioral disorders including attention deficit (P < 0.001), a significant worsening of language (P = 0.001), and intellectual disability (P < 0.001). SIGNIFICANCE: The Residras registry represents a large collection of standardized national data for the DS population. The registry platform relies on a shareable and interoperable framework, which promotes multicenter high-quality data collection. In the future, such integrated platform may represent an invaluable asset for easing access to cohorts of patients that may benefit from clinical trials with emerging novel therapies, for drug safety monitoring, and for delineating natural history. Its framework makes it improvable based on growing experience with its use and easily adaptable to other rare and complex epilepsy syndromes.

Benign childhood focal epilepsies.

The idiopathic focal epilepsies comprise a group of syndromes characterized by focal-onset seizures for which there is no detectable structural brain abnormality and for which there is a proposed functional mechanism for the epilepsy and electroencephalography (EEG) abnormalities. This group includes benign rolandic epilepsy (BRE), benign epilepsy with occipital paroxysms (both early onset and late-onset types), idiopathic photosensitive occipital lobe epilepsy, and some less well-defined syndromes. The limits of the early onset idiopathic occipital epilepsy syndrome are not clear, and perhaps this entity represents part of a larger syndrome group of "autonomic" age-related epilepsies. The term "idiopathic" implies absence of a structural brain lesion and a genetic propensity to seizures. The term "benign" implies that the epileptic seizures are easily treated or require no treatment, show remission without sequelae with ultimate and definitive remission before adulthood, do not have severe or exceedingly disturbing seizures, and have no associated serious intellectual or behavioral disturbances. It may be that a syndrome is benign only when it can be recognized early with reasonable certainty, thereby avoiding unnecessary investigations, overtreatment, and lifestyle restrictions. Although BRE has such characteristic clinical and EEG features to make early recognition possible, this is less constantly so in the other focal idiopathic epilepsy syndromes, where the term "benign" may be inappropriate. Mild and selective neuropsychological impairment may occur even in those with typical syndromes but it is unclear whether such selective deficits outlast the active phase of epilepsy. Sometimes the clinical course may be complicated by obvious cognitive and language impairments. In such cases, the term benign is obviously inappropriate, even when seizures are rare. In most patients with the typical focal idiopathic epilepsy syndromes, medication is not necessary.

Impaired object identification in idiopathic childhood occipital epilepsy.

PURPOSE: To investigate whether children with epilepsy primarily affecting the occipital cortex exhibit impairment of visual object identification and to what extent such a hypothesized dysfunction is related to an interfering functional, rather than structural, process. METHOD: We studied nine children with idiopathic childhood occipital epilepsy (ICOE) and compared them to eight children with lesional posterior cortex epilepsy (PCEs) and to 60 age-matched controls. We applied an "ascendent" paradigm of object identification, using a coarse-to-fine order procedure, which gradually integrated spatial frequency information from the most blurred image to the complete figure. In children with ICOE, we explored how epilepsy-related variables might be related to object identification task. KEY FINDINGS: Children with ICOE and those with PCEs needed more physical information than controls to identify visual stimuli. There was a decreasing accuracy from controls to children with ICOE and from children with ICOE to those with PCEs. Children with ICOE demonstrated slight selective impairment in visuospatial processing and those among them having experienced a higher number of seizures or in whom interictal electroencephalography (EEG) discharges had been present for a longer time, required a higher level of physical information to recognize objects. SIGNIFICANCE: The observation that children with ICOE performed worse than controls in object identification, although better than children with PCEs, might indicate that functional disruption caused by epileptiform EEG abnormalities and seizures, can interfere per se with perceptual processes, even in the absence of a lesion. This effect appears to be detected only by perceptual and cognitive screening.

Seizure Outcome of Temporal Lobe Epilepsy Surgery in Adults and Children: A Systematic Review and Meta-Analysis.

BACKGROUND: Temporal lobe epilepsy (TLE) surgery is associated with the best seizure outcome in adults, although its long-term results remain suboptimal. Retrospective pediatric studies suggest better figures whose determinants are poorly understood. OBJECTIVE: To conduct a systematic review and meta-analysis of studies on the efficacy of TLE surgery in children (age younger than 18 years) and adults. METHODS: We searched MEDLINE, Embase, and Cochrane Library for TLE surgery original research from January 1, 1990, until May 12, 2020. The outcome measures were seizure freedom since surgery and seizure freedom either at last or longest follow-up. We meta-analyzed the proportion of children and adults achieving either Engel I/International League Against Epilepsy (ILAE) 1 or Engel IA/ILAE 1A outcome by follow-up duration, type of surgery, histopathology, neuroimaging, quality of the studies, and publication period. We used a random effects model with Freeman-Tukey double arcsine transformation of proportions. RESULTS: From 40 409 records identified, we included 277 studies (30 848 patients). The proportions of patients achieving Engel I/ILAE 1 and Engel IA/ILAE 1A outcomes were 0.74 (95% CI, 0.69-0.78) and 0.61 (0.48-0.74) for children and 0.69 (0.67-0.71) and 0.56 (0.52-0.60) for adults. Histopathology significantly influenced Engel I/ILAE 1 outcome in adults but not in children ( P < .0001), while the type of surgery significantly influenced Engel I/ILAE 1 outcome in children but not in adults. CONCLUSION: The proportion of seizure freedom after TLE surgery was higher in children, although not significantly. Histopathology and the surgical approach can influence seizure outcome, with age-related variability.

Patterns and predictors of language representation and the influence of epilepsy surgery on language reorganization in children and young adults with focal lesional epilepsy.

Mapping brain functions is crucial for neurosurgical planning in patients with drug-resistant seizures. However, presurgical language mapping using either functional or structural networks can be challenging, especially in children. In fact, most of the evidence on this topic derives from cross-sectional or retrospective studies in adults submitted to anterior temporal lobectomy. In this prospective study, we used fMRI and DTI to explore patterns of language representation, their predictors and impact on cognitive performances in 29 children and young adults (mean age at surgery: 14.6 ± 4.5 years) with focal lesional epilepsy. In 20 of them, we also assessed the influence of epilepsy surgery on language lateralization. All patients were consecutively enrolled at a single epilepsy surgery center between 2009 and 2015 and assessed with preoperative structural and functional 3T brain MRI during three language tasks: Word Generation (WG), Rhyme Generation (RG) and a comprehension task. We also acquired DTI data on arcuate fasciculus in 24 patients. We first assessed patterns of language representation (relationship of activations with the epileptogenic lesion and Laterality Index (LI)) and then hypothesized a causal model to test whether selected clinical variables would influence the patterns of language representation and the ensuing impact of the latter on cognitive performances. Twenty out of 29 patients also underwent postoperative language fMRI. We analyzed possible changes of fMRI and DTI LIs and their clinical predictors. Preoperatively, we found atypical language lateralization in four patients during WG task, in one patient during RG task and in seven patients during the comprehension task. Diffuse interictal EEG abnormalities predicted a more atypical language representation on fMRI (p = 0.012), which in turn correlated with lower attention (p = 0.036) and IQ/GDQ scores (p = 0.014). Postoperative language reorganization implied shifting towards atypical language representation. Abnormal postoperative EEG (p = 0.003) and surgical failures (p = 0.015) were associated with more atypical language lateralization, in turn correlating with worsened fluency. Neither preoperative asymmetry nor postoperative DTI LI changes in the arcuate fasciculus were observed. Focal lesional epilepsy associated with diffuse EEG abnormalities may favor atypical language lateralization and worse cognitive performances, which are potentially reversible after successful surgery.

A 7 Mb duplication at 22q13 in a girl with bipolar disorder and hippocampal malformation.

We identified a duplication of 22q13.1-q13.2 in a 10-year-old girl and demonstrated that this duplication was the recombinant product of a maternal intrachromosomal insertion. Phenotypic characteristics included prominent forehead, small low-set ears, hypertelorism, epicanthal folds, small palpebral fissures, short philtrum, and syndactyly. MRI of the brain revealed high signal abnormalities in the periventricular white matter, a hypoplastic corpus callosum, under-rotated hippocampus on the left and atrophic hippocampus on the right. Since age 5, the child's behavior has shown cyclic maniacal episodes with severely disorganized mood and behavior. Psychiatric and cognitive assessment led to a diagnosis of bipolar disorder not otherwise specified, manic episodes, attention deficit hyperactivity disorder and moderate mental retardation. Array-CGH revealed an interstitial duplication of 6.9 Mb at chromosome 22q: dup(22)(q13.1q13.2). FISH using BAC clones confirmed the array-CGH results and demonstrated that the duplication was inverted. G-banding analysis in the proposita's mother revealed a banding pattern suggestive of an intrachromosomal insertion, as demonstrated by dual-color FISH with BACs that were duplicated in the proposita and multicolor-banding (MCB) based on microdissection derived region-specific libraries for chromosome 22. Our findings suggest that in both seemingly de novo deletions and duplications, the parent transmitting the imbalance should be investigated for possible balanced rearrangements. This report reinforces previous evidence that chromosome imbalances, and thus gene dosage effects, may be at the basis of some psychiatric disorders. Stringent correlations between submicroscopic imbalances, specific behavioral phenotypes and brain imaging will possibly help in dissecting complex behavioral traits.

Unilobar surgery for symptomatic epileptic spasms.

OBJECTIVE: To assess factors associated with favorable seizure outcome after surgery for symptomatic epileptic spasms and improve knowledge on pathophysiology of this seizure type. METHODS: Inclusion criteria were: (1) age between 6 months and 15 years at surgery; (2) active epileptic spasms; (3) follow-up after surgery >1 year. RESULTS: We retrospectively studied 80 children (aged 1.3 ± 2 years at seizure onset; 5.8 ± 4 years at surgery, 11.7 ± 5.7 years at last follow up). Magnetic resonance imaging (MRI) revealed structural abnormalities in 77/80 patients (96.3%; unilateral in 69: 89.6%). We performed invasive recordings in 24 patients (30%). In 21 patients in whom MRI or histopathology detected a lesion, electrodes exploring it constantly captured initial ictal activity at spasm onset. Fifty-eight patients (72.5%) underwent unilobar and 22 (27.5%) multilobar or hemispheric procedures. At last follow-up, 49 patients (61.3%) were in Engel class I. Multivariate logistic models showed completeness of resection of the seizure onset zone (OR = 0.016, 95%CI: 0.002, 0.122) and of the MRI visible lesion (OR = 0.179, 95% CI: 0.032, 0.999) to be significantly associated with Engel class IA outcome. Unfavorable outcome was associated with an older age at surgery, when it reflected a longer duration of epilepsy (OR = 1.383, 95% CI: 0.994,1.926). INTERPRETATION: Data emerging from invasive recordings and the good seizure outcome following removal of discrete epileptogenic lesions support a focal cortical origin of spasms. In patients with discrete epileptogenic lesions, the pragmatic approach to surgery should follow the same principles applied to focal epilepsy favoring, whenever possible, unilobar, one-stage resections.