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BACKGROUND: Attention-Deficit/Hyperactivity Disorder (ADHD) is a highly heterogeneous diagnostic category, encompassing several endophenotypes and comorbidities, including sleep problems. However, no predictor of clinical long-term trajectories or comorbidity has yet been established. Sleep EEG has been proposed as a potential tool for evaluating the synaptic strength during development, as well as the cortical thickness, which is presumed to be altered in ADHD. We investigated whether the slope of the Slow Waves (SWs), a microstructural parameter of the sleep EEG, was a potential predictive parameter for psychiatric comorbidities and neuropsychological dimensions in ADHD. METHODS: 70 children (58 m; 8.76 ± 2.77 y) with ADHD who underwent psychiatric and neurologic evaluations and a standard EEG recording during naps were investigated. After sleep EEG analysis, we grouped the extracted SWs in bins of equal amplitude and then measured the associations, through generalized linear regression, between their maximum downward slopes (MDS) and the individual scores obtained from clinical rating scales. RESULTS: The presence of Multiple Anxiety Disorders was positively associated with MDS of medium amplitude SWs in temporo-posterior left areas. The Child Behavior Checklist scores showed negative associations in the same areas for small SWs. The presence of autistic traits was positively associated with MDS of high amplitude SWs in bilateral anterior and temporal left areas. The WISC-IV Processing Speed Index showed negative associations with MDS of small-to-medium SWs in anterior and temporal right areas, while positive associations in posterior and temporal left areas. CONCLUSIONS: Consistency of association clusters' localization on the scalp suggests that variations in the local MDS, revealing alterations of local synaptic strength and/or in daytime use of certain cortical circuits, could underlie specific neurodevelopmental trajectories resulting in different ADHD clinical phenotypes.
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Transtorno do Deficit de Atenção com Hiperatividade , Humanos , SonoRESUMO
Mutations in the EPM2A gene encoding laforin cause Lafora disease (LD), a progressive myoclonic epilepsy characterized by drug-resistant seizures and progressive neurological impairment. To date, rodents are the only available models for studying LD; however, their use for drug screening is limited by regulatory restrictions and high breeding costs. To investigate the role of laforin loss of function in early neurodevelopment, and to screen for possible new compounds for treating the disorder, we developed a zebrafish model of LD. Our results showed the epm2a-/- zebrafish to be a faithful model of LD, exhibiting the main disease features, namely motor impairment and neuronal hyperexcitability with spontaneous seizures. The model also showed increased inflammatory response and apoptotic death, as well as an altered autophagy pathway that occurs early in development and likely contributes to the disease progression. Early administration of trehalose was found to be effective for rescuing motor impairment and neuronal hyperexcitability associated with seizures. Our study adds a new tool for investigating LD and might help to identify new treatment opportunities.
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Doença de Lafora , Animais , Doença de Lafora/tratamento farmacológico , Doença de Lafora/genética , Doença de Lafora/metabolismo , Mutação , Proteínas Tirosina Fosfatases não Receptoras/genética , Proteínas Tirosina Fosfatases não Receptoras/metabolismo , Convulsões , Trealose/farmacologia , Ubiquitina-Proteína Ligases/genética , Peixe-Zebra/metabolismoRESUMO
A serotonergic dysfunction has been largely postulated as the main cause of depression, mainly due to its effective response to drugs that increase the serotonergic tone, still currently the first therapeutic line in this mood disorder. However, other dysfunctional pathomechanisms are likely involved in the disorder, and this may in part explain why some individuals with depression are resistant to serotonergic therapies. Among these, emerging evidence suggests a role for the astrocytic inward rectifier potassium channel 4.1 (Kir4.1) as an important modulator of neuronal excitability and glutamate metabolism. To discuss the relationship between Kir4.1 dysfunction and depression, a systematic review was performed according to the PRISMA statement. Searches were conducted across PubMed, Scopus, and Web of Science by two independent reviewers. Twelve studies met the inclusion criteria, analyzing Kir4.1 relationships with depression, through in vitro, in vivo, and post-mortem investigations. Increasing, yet not conclusive, evidence suggests a potential pathogenic role for Kir4.1 upregulation in depression. However, the actual contribution in the diverse subtypes of the disorder and in the comorbid conditions, for example, the epilepsy-depression comorbidity, remain elusive. Further studies are needed to better define the clinical phenotype associated with Kir4.1 dysfunction in humans and the molecular mechanisms by which it contributes to depression and implications for future treatments.
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Depressão/metabolismo , Depressão/fisiopatologia , Canais de Potássio Corretores do Fluxo de Internalização/metabolismo , Antidepressivos/farmacologia , Antidepressivos/uso terapêutico , Antidepressivos Tricíclicos/farmacologia , Antidepressivos Tricíclicos/uso terapêutico , Astrócitos/efeitos dos fármacos , Astrócitos/metabolismo , Fator Neurotrófico Derivado do Encéfalo/metabolismo , Depressão/tratamento farmacológico , Regulação para Baixo/efeitos dos fármacos , Humanos , Ketamina , Inibidores Seletivos de Recaptação de Serotonina/farmacologia , Inibidores Seletivos de Recaptação de Serotonina/uso terapêutico , Regulação para Cima/efeitos dos fármacosRESUMO
Mitochondrial diseases (MDs) are a large group of genetically determined multisystem disorders, characterized by extreme phenotypic heterogeneity, attributable in part to the dual genomic control (nuclear and mitochondrial DNA) of the mitochondrial proteome. Advances in next-generation sequencing technologies over the past two decades have presented clinicians with a challenge: to select the candidate disease-causing variants among the huge number of data provided. Unfortunately, the clinical tools available to support genetic interpretations still lack specificity and sensitivity. For this reason, the diagnosis of MDs continues to be difficult, with the new "genotype first" approach still failing to diagnose a large group of patients. With the aim of investigating possible relationships between clinical and/or biochemical phenotypes and definitive molecular diagnoses, we performed a retrospective multicenter study of 111 pediatric patients with clinical suspicion of MD. In this cohort, the strongest predictor of a molecular (in particular an mtDNA-related) diagnosis of MD was neuroimaging evidence of basal ganglia (BG) involvement. Regression analysis confirmed that normal BG imaging predicted negative genetic studies for MD. Psychomotor regression was confirmed as an independent predictor of a definitive diagnosis of MD. The findings of this study corroborate previous data supporting a role for neuroimaging in the diagnostic approach to MDs and reinforce the idea that mtDNA sequencing should be considered for first-line testing, at least in specific groups of children.
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Epilepsy is a common, often severe, feature of LAMA2-related muscular dystrophy (LAMA2-RD) and could represent its onset and main manifestation, even in the absence of overt muscle involvement. To date, there is no systematic characterization of epilepsy in LAMA2-RD, and its impact on neurodevelopment and on the clinical course remains poorly established. In view of this knowledge gap, we conducted a systematic review of the literature and, as an illustrative example, reported the clinical case of a boy with late-onset LAMA2-related limb-girdle muscular dystrophy presenting with severe epilepsy. Our analyses of the literature data revealed a mean age at first seizure of 8 years, with significant differences between early- versus late-onset disease (5.78 ± 4.11 and 9.00 ± 2.65 years, respectively; p = 0.0007), and complete versus partial merosin deficiency (5.33 ± 3.70 and 10.36 ± 5.49 years, respectively; p = 0.0176). A generalized onset was the most common seizure presentation, regardless of merosin expression levels or the timing of muscular distrophy onset. Cortical malformations were not significantly associated with an earlier epilepsy onset, and were found to be quasi-significantly associated with a greater incidence of focal, or focal and generalized, onset seizures. No clear conclusions could be reached on the electrophysiological and neurodevelopmental features of the disorder, or on the relative efficacy of anti-epileptic treatments; further research on these aspects is needed. This systematic review helps to show that epilepsy in LAMA2-RD may be more than an ancillary manifestation of the disease, but rather one of its core features. A targeted and prompt electroencephalographic and epilepsy assessment, in addition to the specific neuromuscular workup, is therefore mandatory in early clinical management to pursue the best possible outcome for affected children.
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Epilepsia , Distrofia Muscular do Cíngulo dos Membros , Distrofias Musculares , Criança , Eletroencefalografia , Epilepsia/genética , Humanos , Laminina/genética , Masculino , Distrofias Musculares/complicações , Distrofias Musculares/genéticaRESUMO
Attention deficit hyperactivity disorder (ADHD) is commonly associated with sleep problems, possibly due to shared pathophysiology. Microstructural sleep electroencephalographic (EEG) alterations may likely represent markers of disordered cortical maturation in ADHD, although literature data are still conflicting, deserving further assessment. After having systematically reviewed the literature, we included 11 studies from 598 abstracts, and assessed 23 parameters of cyclic alternating pattern (CAP), four parameters of sleep EEG power and one parameter of sleep graphoelements through 29 meta-analyses and, when possible, univariate meta-regressions. Slow wave activity (SWA) in ADHD was significantly higher in early childhood and lower in late childhood/adolescence compared to controls, with an inversion point at 10 years. Total CAP rate and CAP A1 index in non-rapid eye movement (NREM) stage 2 sleep, and CAP A1 rate in NREM sleep were significantly lower in ADHD patients than controls. SWA and CAP A1 changes are therefore possible markers of altered cortical maturation in ADHD, consistently with the neuropsychological deficits characterizing the disorder, likely fostering earlier detection of at-risk/milder conditions, and more tailored therapeutic interventions.
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Transtorno do Deficit de Atenção com Hiperatividade , Sono de Ondas Lentas , Adolescente , Criança , Pré-Escolar , Eletroencefalografia , Humanos , Polissonografia , SonoRESUMO
Psychogenic nonepileptic seizures (PNES) are episodic manifestations that mimic epileptic seizures (ES) although not associated with electroencephalogram (EEG) abnormalities. Psychogenic nonepileptic seizures and ES, however, can often cooccur. Emotional distress in adolescents can trigger PNES, but the psychopathological and personality features are still unknown. The aim of this study was to explore psychopathological features in a sample of referred youth with PNES, with or without ES, compared with a control group with ES. Thirty-four patients aged 12 to 21â¯years, 19 females and 15 males, were included in the study, 15 patients with PNES, 7 with PNES and ES, and 12 with ES. The three groups were compared according to psychiatric categorical diagnoses, psychopathological dimensions, life stressors, and personality traits, including alexithymia, interpersonal reactivity, and resilience, all assessed with structured measures. Patients with PNES, with or without ES, were more severely impaired, had a higher incidence of mood disorders, more frequent lifetime traumatic experiences, and lower resilience. All the three groups presented alexythimic traits and emotional dysregulation. Major limitations are the small sample size and the lack of a control group of healthy subjects. Disentagling psychopathological characteristics in PNES can help clinicians to focus diagnostic approaches and therapeutic interventions.
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Epilepsia , Transtornos Mentais , Adolescente , Adulto , Criança , Eletroencefalografia , Epilepsia/complicações , Feminino , Humanos , Masculino , Psicopatologia , Convulsões/complicações , Convulsões/diagnóstico , Adulto JovemRESUMO
OBJECTIVE: The use of music-based neuro-stimulation for treating seizures and interictal epileptiform discharges (IED) (the so-called "Mozart effect") remains a controversial issue. We have conducted an updated meta-analysis in order to systematically review literature evidence and provide further insights about the role of the Mozart effect in epilepsy. METHODS: Following the "Preferred Reporting Items for Systematic Reviews and Meta-Analyses" (PRISMA) guidelines, we searched three bibliographic databases from their date of inception to January 2020. Nine meta-analyses were performed according to both music stimulation protocols and outcome measures. We applied the Cochrane Q-test and the I2-index for heterogeneity evaluation, and either fixed-effect or random-effect models to compute mean differences and pool data. RESULTS: Of 147 abstracts, 12 studies were included and grouped according to stimulation protocols and outcome measures. The nine meta-analyses showed significant reductions in seizures and IED frequencies after long-term music treatment, and in IED frequency during and after a single music stimulus. CONCLUSIONS: Music-based neurostimulation may improve the clinical outcome of individuals with epilepsy, by reducing the frequency of seizures and IED. Further and stronger evidence will allow defining its potential in the different forms of epilepsy, and the most effective stimulation protocols. SIGNIFICANCE: Music therapy should be considered as a complementary, non-invasive approach for treating epilepsy and epileptiform discharges.
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Epilepsia/terapia , Musicoterapia/métodos , Adolescente , Ondas Encefálicas , Criança , Pré-Escolar , Epilepsia/fisiopatologia , Feminino , Humanos , Masculino , Musicoterapia/normasRESUMO
Mutations in the ATPase family 3-like gene (AFG3L2) have been linked to autosomal-dominant spinocerebellar ataxia type 28 and autosomal recessive spastic ataxia-neuropathy syndrome. Here, we describe the case of a child carrying bi-allelic mutations in AFG3L2 and presenting with ictal paroxysmal episodes associated with neuroimaging suggestive of basal ganglia involvement. Studies in skin fibroblasts showed a significant reduction of AFG3L2 expression. The relatively mild clinical presentation and the benign course, in spite of severe neuroimaging features, distinguish this case from data reported in the literature, and therefore expand the spectrum of neurological and neuroradiological features associated with AFG3L2 mutations.
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Proteases Dependentes de ATP/genética , ATPases Associadas a Diversas Atividades Celulares/genética , Ataxias Espinocerebelares/congênito , Criança , Humanos , Imageamento por Ressonância Magnética , Masculino , Ataxias Espinocerebelares/diagnóstico , Ataxias Espinocerebelares/genética , Ataxias Espinocerebelares/patologia , Ataxias Espinocerebelares/fisiopatologiaRESUMO
The study of sources and spatiotemporal evolution of ictal bursts is critical for the mechanistic understanding of epilepsy and for the validation of anti-epileptic drugs. Zebrafish is a powerful vertebrate model representing an excellent compromise between system complexity and experimental accessibility. We performed the quantitative evaluation of the spatial recruitment of neuronal populations during physiological and pathological activity by combining local field potential (LFP) recordings with simultaneous 2-photon Ca2+ imaging. We developed a method to extract and quantify electrophysiological transients coupled with Ca2+ events and we applied this tool to analyze two different epilepsy models and to assess the efficacy of the anti-epileptic drug valproate. Finally, by cross correlating the imaging data with the LFP, we demonstrated that the cerebellum is the main source of epileptiform transients. We have also shown that each transient was preceded by the activation of a sparse subset of neurons mostly located in the optic tectum.
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Cálcio/metabolismo , Fenômenos Eletrofisiológicos , Epilepsia/fisiopatologia , Imagem Molecular , Fótons , Peixe-Zebra/fisiologia , Potenciais de Ação , Animais , Feminino , Humanos , Masculino , Neurônios/patologia , Análise de Componente Principal , Estatística como Assunto , Fatores de Tempo , Ácido Valproico/farmacologiaRESUMO
Autosomal recessive spastic paraplegia 52 is caused by biallelic mutations in AP4S1 which encodes a subunit of the adaptor protein complex 4 (AP-4). Using next-generation sequencing, we identified three novel unrelated SPG52 patients from a cohort of patients with cerebral palsy. The discovered variants in AP4S1 lead to reduced AP-4 complex formation in patient-derived fibroblasts. To further understand the role of AP4S1 in neuronal development and homeostasis, we engineered the first zebrafish model of AP-4 deficiency using morpholino-mediated knockdown of ap4s1. In this model, we discovered several phenotypes mimicking SPG52, including altered CNS development, locomotor deficits, and abnormal neuronal excitability.
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Complexo 4 de Proteínas Adaptadoras/genética , Transtornos do Neurodesenvolvimento/genética , Transtornos do Neurodesenvolvimento/fisiopatologia , Paraplegia Espástica Hereditária/genética , Paraplegia Espástica Hereditária/fisiopatologia , Complexo 4 de Proteínas Adaptadoras/deficiência , Adolescente , Animais , Animais Geneticamente Modificados , Comportamento Animal/fisiologia , Paralisia Cerebral/genética , Pré-Escolar , Estudos de Coortes , Modelos Animais de Doenças , Epilepsia/genética , Epilepsia/fisiopatologia , Feminino , Sequenciamento de Nucleotídeos em Larga Escala , Humanos , Masculino , Peixe-ZebraRESUMO
Many aspects of epilepsy in mitochondrial disorders (MDs) need to be further clarified. To this aim, we explored retrospectively a cohort of individuals with MDs querying the "Nationwide Italian Collaborative Network of Mitochondrial Diseases" (NICNMD) database (1467 patients included since 2010 to December 2016). We collected information on age at epilepsy onset, seizure type and frequency, genetic findings, and antiepileptic drugs (AEDs). At the time of our survey, 147/1467 (10%) patients in the NICNMD database had epilepsy. Complete information was available only for 98 patients, 52 males and 46 females, aged 5-92 years (mean age 40.4 ± 18.4; 14/98 children/teenagers and 84 adults). Epilepsy was the presenting feature of MD in 46/98 (47%) individuals, with onset at a median age of 19 years (range, 0.2-68; < 3 years in 14/97 (14%), 3-19 years in 36/97 (37%), > 19 years in 47/97 (49%)). Moreover, 91/98 patients (93%) displayed multiple seizures, with daily or weekly frequency in 25/91 (28%). Interictal EEG was abnormal in 70/78 (90%) patients, displaying abnormal background (47/70; 67%) and/or interictal paroxysms (53/70; 76%). Eighty of 90 patients (89%) displayed a 50-100% reduction of seizures on AEDs; levetiracetam was the most commonly used. Forty-one patients (42%) carried the m.3243A>G mutation, 16 (16%) the m.8344A>G, and 9 (9%) nuclear DNA (nDNA) mutations. Individuals with early-onset seizures mainly carried nDNA mutations and had a more severe epilepsy phenotype, higher seizure frequency, and disorganized background EEG activity. A better definition of epilepsy in MDs may foster the diagnostic workup, management, and treatment of affected patients, and allow more homogeneous patient stratification.
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Epilepsia/epidemiologia , Doenças Mitocondriais/epidemiologia , Convulsões/epidemiologia , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Criança , Pré-Escolar , Estudos Transversais , Epilepsia/complicações , Feminino , Humanos , Itália/epidemiologia , Masculino , Pessoa de Meia-Idade , Doenças Mitocondriais/complicações , Estudos Retrospectivos , Convulsões/complicações , Inquéritos e Questionários , Adulto JovemRESUMO
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.
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Epilepsia/diagnóstico , Epilepsia/genética , Testes Genéticos/métodos , Epilepsia/patologia , Sequenciamento de Nucleotídeos em Larga Escala , Humanos , Mutação , Sequenciamento do ExomaRESUMO
STUDY OBJECTIVES: Recently, a role for gain-of-function (GoF) mutations of the astrocytic potassium channel Kir4.1 (KCNJ10 gene) has been proposed in subjects with Autism-Epilepsy phenotype (AEP). Epilepsy and autism spectrum disorder (ASD) are common and complexly related to sleep disorders. We tested whether well characterized mutations in KCNJ10 could result in specific sleep electrophysiological features, paving the way to the discovery of a potentially relevant biomarker for Kir4.1-related disorders. METHODS: For this case-control study, we recruited seven children with ASD either comorbid or not with epilepsy and/or EEG paroxysmal abnormalities (AEP) carrying GoF mutations of KCNJ10 and seven children with similar phenotypes but wild-type for the same gene, comparing period-amplitude features of slow waves detected by fronto-central bipolar EEG derivations (F3-C3, F4-C4, and Fz-Cz) during daytime naps. RESULTS: Children with Kir4.1 mutations displayed longer slow waves periods than controls, in Fz-Cz (mean period = 112,617 ms ± SE = 0.465 in mutated versus mean period = 105,249 ms ± SE = 0.375 in controls, p < 0.001). An analog result was found in F3-C3 (mean period = 125,706 ms ± SE = 0.397 in mutated versus mean period = 120,872 ms ± SE = 0.472 in controls, p < 0.001) and F4-C4 (mean period = 127,914 ms ± SE = 0.557 in mutated versus mean period = 118,174 ms ± SE = 0.442 in controls, p < 0.001). CONCLUSION: This preliminary finding suggests that period-amplitude slow wave features are modified in subjects carrying Kir4.1 GoF mutations. Potential clinical applications of this finding are discussed.
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Transtorno do Espectro Autista , Transtorno Autístico , Epilepsia , Canais de Potássio Corretores do Fluxo de Internalização , Transtorno do Espectro Autista/genética , Estudos de Casos e Controles , Criança , Epilepsia/genética , Humanos , Mutação/genética , Fenótipo , Canais de Potássio Corretores do Fluxo de Internalização/genética , SonoRESUMO
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.
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Eletroencefalografia/métodos , Epilepsia do Lobo Frontal/fisiopatologia , Epilepsia do Lobo Frontal/psicologia , Lobo Frontal/fisiopatologia , Transtornos do Neurodesenvolvimento/fisiopatologia , Transtornos do Neurodesenvolvimento/psicologia , Adolescente , Adulto , Atenção/fisiologia , Criança , Pré-Escolar , Cognição/fisiologia , Epilepsia do Lobo Frontal/diagnóstico por imagem , Feminino , Lobo Frontal/diagnóstico por imagem , Humanos , Masculino , Transtornos do Neurodesenvolvimento/diagnóstico por imagem , Convulsões/diagnóstico por imagem , Convulsões/fisiopatologia , Convulsões/psicologia , Adulto JovemRESUMO
OBJECTIVE: To delineate the epileptology, a key part of the SYNGAP1 phenotypic spectrum, in a large patient cohort. METHODS: Patients were recruited via investigators' practices or social media. We included patients with (likely) pathogenic SYNGAP1 variants or chromosome 6p21.32 microdeletions incorporating SYNGAP1. We analyzed patients' phenotypes using a standardized epilepsy questionnaire, medical records, EEG, MRI, and seizure videos. RESULTS: We included 57 patients (53% male, median age 8 years) with SYNGAP1 mutations (n = 53) or microdeletions (n = 4). Of the 57 patients, 56 had epilepsy: generalized in 55, with focal seizures in 7 and infantile spasms in 1. Median seizure onset age was 2 years. A novel type of drop attack was identified comprising eyelid myoclonia evolving to a myoclonic-atonic (n = 5) or atonic (n = 8) seizure. Seizure types included eyelid myoclonia with absences (65%), myoclonic seizures (34%), atypical (20%) and typical (18%) absences, and atonic seizures (14%), triggered by eating in 25%. Developmental delay preceded seizure onset in 54 of 56 (96%) patients for whom early developmental history was available. Developmental plateauing or regression occurred with seizures in 56 in the context of a developmental and epileptic encephalopathy (DEE). Fifty-five of 57 patients had intellectual disability, which was moderate to severe in 50. Other common features included behavioral problems (73%); high pain threshold (72%); eating problems, including oral aversion (68%); hypotonia (67%); sleeping problems (62%); autism spectrum disorder (54%); and ataxia or gait abnormalities (51%). CONCLUSIONS: SYNGAP1 mutations cause a generalized DEE with a distinctive syndrome combining epilepsy with eyelid myoclonia with absences and myoclonic-atonic seizures, as well as a predilection to seizures triggered by eating.
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Deficiências do Desenvolvimento/genética , Mutação/genética , Espasmos Infantis/genética , Proteínas Ativadoras de ras GTPase/genética , Adolescente , Adulto , Anticonvulsivantes/uso terapêutico , Encéfalo/diagnóstico por imagem , Encefalopatias/complicações , Encefalopatias/diagnóstico por imagem , Encefalopatias/genética , Criança , Pré-Escolar , Estudos de Coortes , Deficiências do Desenvolvimento/complicações , Deficiências do Desenvolvimento/diagnóstico por imagem , Eletroencefalografia , Feminino , Estudos de Associação Genética , Humanos , Lactente , Masculino , Espasmos Infantis/complicações , Espasmos Infantis/diagnóstico por imagem , Espasmos Infantis/tratamento farmacológico , Adulto JovemRESUMO
OBJECTIVE: PCDH19-related epilepsy is an epileptic syndrome with infantile onset, characterized by clustered and fever-induced seizures, often associated with intellectual disability (ID) and autistic features. The aim of this study was to analyze a large cohort of patients with PCDH19-related epilepsy and better define the epileptic phenotype, genotype-phenotype correlations, and related outcome-predicting factors. METHODS: We retrospectively collected genetic, clinical, and electroencephalogram (EEG) data of 61 patients with PCDH19-related epilepsy followed at 15 epilepsy centers. All consecutively performed EEGs were analyzed, totaling 551. We considered as outcome measures the development of ID, autistic spectrum disorder (ASD), and seizure persistence. The analyzed variables were the following: gender, age at onset, age at study, genetic variant, fever sensitivity, seizure type, cluster occurrence, status epilepticus, EEG abnormalities, and cognitive and behavioral disorders. Receiver operating characteristic curve analysis was performed to evaluate the age at which seizures might decrease in frequency. RESULTS: At last follow-up (median = 12 years, range = 1.9-42.1 years), 48 patients (78.7%) had annual seizures/clusters, 13 patients (21.3%) had monthly to weekly seizures, and 12 patients (19.7%) were seizure-free for ≥2 years. Receiver operating characteristic analysis showed a significant decrease of seizure frequency after the age of 10.5 years (sensitivity = 81.0%, specificity = 70.0%). Thirty-six patients (59.0%) had ID and behavioral disturbances. ASD was present in 31 patients. An earlier age at epilepsy onset emerged as the only predictive factor for ID (P = 0.047) and ASD (P = 0.014). Conversely, age at onset was not a predictive factor for seizure outcome (P = 0.124). SIGNIFICANCE: We found that earlier age at epilepsy onset is related to a significant risk for ID and ASD. Furthermore, long-term follow-up showed that after the age of 10 years, seizures decrease in frequency and cognitive and behavioral disturbances remain the primary clinical problems.
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Caderinas/genética , Síndromes Epilépticas/genética , Síndromes Epilépticas/terapia , Adolescente , Adulto , Idade de Início , Transtorno Autístico/complicações , Transtorno Autístico/psicologia , Criança , Pré-Escolar , Estudos de Coortes , Eletroencefalografia , Feminino , Humanos , Lactente , Deficiência Intelectual/complicações , Deficiência Intelectual/psicologia , Masculino , Fenótipo , Protocaderinas , Estudos Retrospectivos , Convulsões , Resultado do Tratamento , Adulto JovemRESUMO
Spreading depression (SD) is a neurophysiological phenomenon characterized by abrupt changes in intracellular ion gradients and sustained depolarization of neurons. It leads to loss of electrical activity, changes in the synaptic architecture, and an altered vascular response. Although SD is often described as a unique phenomenon with homogeneous characteristics, it may be strongly affected by the particular triggering event and by genetic background. Furthermore, SD may contribute differently to the pathogenesis of widely heterogeneous clinical conditions. Indeed, clinical disorders related to SD vary in their presentation and severity, ranging from benign headache conditions (migraine syndromes) to severely disabling events, such as cerebral ischemia, or even death in people with epilepsy. Although the characteristics and mechanisms of SD have been dissected using a variety of approaches, ranging from cells to human models, this phenomenon remains only partially understood because of its complexity and the difficulty of obtaining direct experimental data. Currently, clinical monitoring of SD is limited to patients who require neurosurgical interventions and the placement of subdural electrode strips. Significantly, SD events recorded in humans display electrophysiological features that are essentially the same as those observed in animal models. Further research using existing and new experimental models of SD may allow a better understanding of its core mechanisms, and of their differences in different clinical conditions, fostering opportunities to identify and develop targeted therapies for SD-related disorders and their worst consequences.
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Impairments of the dialog between excitation and inhibition (E/I) is commonly associated to neuropsychiatric disorders like autism, bipolar disorders and epilepsy. Moderate levels of hyperexcitability can lead to mild alterations of the EEG and are often associated with cognitive deficits even in the absence of overt seizures. Indeed, various testing paradigms have shown degraded performances in presence of acute or chronic non-ictal epileptiform activity. Evidences from both animal models and the clinics suggest that anomalous activity can cause cognitive deficits by transiently disrupting cortical processing, independently from the underlying etiology of the disease. Here, we will review our understanding of the influence of an abnormal EEG activity on brain computation in the context of the available clinical data and in genetic or pharmacological animal models.
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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.