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BACKGROUND: Autism spectrum disorder (ASD) is a childhood-onset complex neurodevelopmental disorder characterized by problems with communication and social interaction and restricted, repetitive, stereotyped behavior. The prevalence of ASD is one in 36 children. The genetic architecture of ASD is complex in spite of its high heritability. To identify the potential candidate genes of ASD, we carried out a comprehensive genetic study of monozygotic (MZ) twins concordant or discordant for ASD. METHODS: Five MZ twins and their parents were recruited for the study. Four of the twins were concordant, whereas one was discordant for ASD. Whole exome sequencing was conducted for the twins and their parents. The exome DNA was enriched using Twist Human Customized Core Exome Kit, and paired-end sequencing was performed on HiSeq system. RESULTS: We identified several rare and pathogenic variants (homozygous recessive, compound heterozygous, de novo) in ASD-affected individuals. CONCLUSION: We report novel variants in individuals diagnosed with ASD. Several of these genes are involved in brain-related functions and not previously reported in ASD. Intriguingly, some of the variants were observed in the genes involved in sensory perception (auditory [MYO15A, PLEC, CDH23, UBR3, GPSM2], olfactory [OR9K2], gustatory [TAS2R31], and visual [CDH23, UBR3]). This is the first comprehensive genetic study of MZ twins in an Indian population. Further validation is required to determine whether these variants are associated with ASD.
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Transtorno do Espectro Autista , Sequenciamento do Exoma , Gêmeos Monozigóticos , Humanos , Transtorno do Espectro Autista/genética , Gêmeos Monozigóticos/genética , Masculino , Feminino , Criança , Doenças em Gêmeos/genética , Pré-EscolarRESUMO
OBJECTIVES: To evaluate the effect of antiepileptic medications prescribed to mothers during pregnancy on the development and behavior of children. METHODS: From the Kerala Registry of Epilepsy and Pregnancy, 98 children between the ages of 1½ to 2½ y were consecutively chosen. Children of mothers who did not have epilepsy during pregnancy and not exposed to antiseizure medications (ASMs) antenatally were selected as comparator group. Developmental assessment of the children was performed using Developmental Assessment Scale for Indian Infants (DASII) and Receptive-Expressive Emergent Language Scale (REELS). Behavior outcomes were assessed using Child Behavior Checklist. RESULTS: A significant delay in expressive language skills was seen in children exposed to antiseizure medication with an odds ratio of 2.539 (95% CI 1.10, 5.85, P = 0.026). A delay in expressive language skills was seen in polytherapy with clobazam (odds ratio 6.83; 95% CI 2.17, 21.56, P < 0.001). Also, delay was seen in receptive language skills in the same polytherapy group (odds ratio of 7.333; 95% CI 2.16, 24.92, P < 0.001). There were no statistically significant differences between study and comparative groups in motor and mental quotient domains and behavioral outcomes. CONCLUSIONS: The finding of speech delay in children exposed to ASMs is significant since individuals with a history of childhood speech or language disorders may experience long-term difficulties in mental health, social well-being, and academic outcomes.
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This practice guideline provides updated evidence-based conclusions and recommendations regarding the effects of antiseizure medications (ASMs) and folic acid supplementation on the prevalence of major congenital malformations (MCMs), adverse perinatal outcomes, and neurodevelopmental outcomes in children born to people with epilepsy of childbearing potential (PWECP). A multidisciplinary panel conducted a systematic review and developed practice recommendations following the process outlined in the 2017 edition of the American Academy of Neurology Clinical Practice Guideline Process Manual. The systematic review includes studies through August 2022. Recommendations are supported by structured rationales that integrate evidence from the systematic review, related evidence, principles of care, and inferences from evidence. The following are some of the major recommendations. When treating PWECP, clinicians should recommend ASMs and doses that optimize both seizure control and fetal outcomes should pregnancy occur, at the earliest possible opportunity preconceptionally. Clinicians must minimize the occurrence of convulsive seizures in PWECP during pregnancy to minimize potential risks to the birth parent and to the fetus. Once a PWECP is already pregnant, clinicians should exercise caution in attempting to remove or replace an ASM that is effective in controlling generalized tonic-clonic or focal-to-bilateral tonic-clonic seizures. Clinicians must consider using lamotrigine, levetiracetam, or oxcarbazepine in PWECP when appropriate based on the patient's epilepsy syndrome, likelihood of achieving seizure control, and comorbidities, to minimize the risk of MCMs. Clinicians must avoid the use of valproic acid in PWECP to minimize the risk of MCMs or neural tube defects (NTDs), if clinically feasible. Clinicians should avoid the use of valproic acid or topiramate in PWECP to minimize the risk of offspring being born small for gestational age, if clinically feasible. To reduce the risk of poor neurodevelopmental outcomes, including autism spectrum disorder and lower IQ, in children born to PWECP, clinicians must avoid the use of valproic acid in PWECP, if clinically feasible. Clinicians should prescribe at least 0.4 mg of folic acid supplementation daily preconceptionally and during pregnancy to any PWECP treated with an ASM to decrease the risk of NTDs and possibly improve neurodevelopmental outcomes in the offspring.
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Anticonvulsivantes , Epilepsia , Transtornos do Neurodesenvolvimento , Complicações na Gravidez , Efeitos Tardios da Exposição Pré-Natal , Feminino , Humanos , Recém-Nascido , Gravidez , Anormalidades Induzidas por Medicamentos/prevenção & controle , Anticonvulsivantes/uso terapêutico , Anticonvulsivantes/efeitos adversos , Epilepsia/tratamento farmacológico , Transtornos do Neurodesenvolvimento/prevenção & controle , Transtornos do Neurodesenvolvimento/epidemiologia , Transtornos do Neurodesenvolvimento/induzido quimicamente , Complicações na Gravidez/tratamento farmacológico , Teratogênese/efeitos dos fármacosRESUMO
Microstate analysis is a spatiotemporal method where instantaneous scalp potential topography represents the current state of the brain. The temporal evolution of these scalp topographies gives an understanding of quasi-stable periods of long-range coherence between distant electrodes, reflecting functional coordination within large-scale cortical networks. It has been proven potential in identification and characterization of neurophysiological indicators associated with neuropsychiatric conditions. Changes in microstates connected to symptoms and cognitive impairments of neuropsychiatric conditions. It is useful in the study of cognitive processes and disorders related to memory. Researchers may probe into the relationships between microstates and other cognitive processes, such as memory retrieval and encoding. This is a tool for clinicians to enhance the precision of diagnosis and inform possibilities for treatment by acquiring information regarding individual diversity in microstates could lead to tailored medical methods. Customizing treatment according to a patient's microstate patterns could improve the efficacy of treatment. The papers selected for the review span a broad-spectrum including memory related disorders, psychiatry and neurological disorders. A section in the review article has been dedicated to source localization of EEG microstates. The selection of review papers shed light on the importance and huge potential of application of EEG microstate analysis in various neuropsychological processes. The review concludes with the need for standardization of microstate analysis. It suggests the incorporation of widely accepted machine learning techniques for increasing the accuracy, reliability and acceptability of microstate analysis as reliable biomarkers for neurological conditions in the future.
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Disfunção Cognitiva , Eletroencefalografia , Humanos , Eletroencefalografia/métodos , Reprodutibilidade dos Testes , Encéfalo/fisiologia , Mapeamento Encefálico/métodosRESUMO
Importance: Women with epilepsy (WWE) require treatment with antiseizure medications (ASMs) during pregnancy, which may be associated with an increased risk of major congenital malformations (MCMs) in their offspring. Objective: To investigate the prevalence of MCMs after prenatal exposure to 8 commonly used ASM monotherapies and changes in MCM prevalence over time. Design, Setting, and Participants: This was a prospective, observational, longitudinal cohort study conducted from June 1999 to October 2022. Since 1999, physicians from more than 40 countries enrolled ASM-treated WWE before pregnancy outcome was known and followed up their offspring until 1 year after birth. Participants aged 14 to 55 years who were exposed to 8 of the most frequently used ASMs during pregnancy were included in this study. Data were analyzed from April to September 2023. Exposure: Maternal use of ASMs at conception. Main Outcomes and Measures: MCMs were assessed 1 year after birth by a committee blinded to type of exposure. Teratogenic outcomes across exposures were compared by random-effects logistic regression adjusting for potential confounders and prognostic factors. Results: A total of 10â¯121 prospective pregnancies exposed to ASM monotherapy met eligibility criteria. Of those, 9840 were exposed to the 8 most frequently used ASMs. The 9840 pregnancies occurred in 8483 women (mean [range] age, 30.1 [14.1-55.2] years). MCMs occurred in 153 of 1549 pregnancies for valproate (9.9%; 95% CI, 8.5%-11.5%), 9 of 142 for phenytoin (6.3%; 95% CI, 3.4%-11.6%), 21 of 338 for phenobarbital (6.2%; 95% CI, 4.1%-9.3%), 121 of 2255 for carbamazepine (5.4%; 95% CI, 4.5%-6.4%), 10 of 204 for topiramate (4.9%; 95% CI, 2.7%-8.8%), 110 of 3584 for lamotrigine (3.1%; 95% CI, 2.5%-3.7%), 13 of 443 for oxcarbazepine (2.9%; 95% CI, 1.7%-5.0%), and 33 of 1325 for levetiracetam (2.5%; 95% CI, 1.8%-3.5%). For valproate, phenobarbital, and carbamazepine, there was a significant increase in the prevalence of MCMs associated with increasing dose of the ASM. Overall prevalence of MCMs decreased from 6.1% (153 of 2505) during the period 1998 to 2004 to 3.7% (76 of 2054) during the period 2015 to 2022. This decrease over time was significant in univariable logistic analysis but not after adjustment for changes in ASM exposure pattern. Conclusions and Relevance: Of all ASMs with meaningful data, the lowest prevalence of MCMs was observed in offspring exposed to levetiracetam, oxcarbazepine, and lamotrigine. Prevalence of MCMs was higher with phenytoin, valproate, carbamazepine, and phenobarbital, and dose dependent for the latter 3 ASMs. The shift in exposure pattern over time with a declining exposure to valproate and carbamazepine and greater use of lamotrigine and levetiracetam was associated with a 39% decline in prevalence of MCMs, a finding that has major public health implications.
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Anormalidades Induzidas por Medicamentos , Anticonvulsivantes , Epilepsia , Complicações na Gravidez , Humanos , Feminino , Anticonvulsivantes/efeitos adversos , Anticonvulsivantes/uso terapêutico , Adulto , Gravidez , Adulto Jovem , Adolescente , Epilepsia/tratamento farmacológico , Epilepsia/epidemiologia , Anormalidades Induzidas por Medicamentos/epidemiologia , Anormalidades Induzidas por Medicamentos/etiologia , Pessoa de Meia-Idade , Estudos Longitudinais , Complicações na Gravidez/tratamento farmacológico , Complicações na Gravidez/epidemiologia , Estudos Prospectivos , Ácido Valproico/efeitos adversos , Ácido Valproico/uso terapêutico , Efeitos Tardios da Exposição Pré-Natal/epidemiologia , Efeitos Tardios da Exposição Pré-Natal/induzido quimicamente , Fenitoína/efeitos adversos , Fenitoína/uso terapêutico , Lamotrigina/efeitos adversos , Lamotrigina/uso terapêutico , Carbamazepina/efeitos adversos , Fenobarbital/efeitos adversos , Fenobarbital/uso terapêutico , Estudos de Coortes , Oxcarbazepina/efeitos adversos , Oxcarbazepina/uso terapêutico , PrevalênciaRESUMO
Background: Developmental language disorder (DLD) is a neurodevelopmental disorder. Considering the pivotal role of epigenetics in neurodevelopment, we examined any altered DNA methylation between DLD and control subjects. Materials & methods: We looked into genome-wide methylation differences between DLD and control groups. The findings were validated by quantitative PCR (qPCR). Results: In the DLD group, differential methylation of CpG sites was observed in the Wnt signaling regulator genes APCDD1, AMOTL1, LRP5, MARK2, TMEM64, TRABD2B, VEPH1 and WNT2B. Hypomethylation of APCDD1, LRP5 and WNT2B was confirmed by qPCR. Conclusion: This is the first report associating Wnt signaling with DLD. The findings are relevant in the light of the essential role of Wnt in myelination, and of the altered myelination in DLD.
Developmental language disorder (DLD), previously called specific language impairment, is a neurodevelopmental disorder affecting approximately 7% of school-age children. Affected children fail to develop normal speech and language skills; this is a major public health concern as it adversely impacts their communication, academic and social skills. Human brain development is complex, and the accurate temporal and spatial regulation of the expression of multiple genes is essential for proper brain development. Epigenetic factors such as DNA methylation can modulate gene expression without altering the DNA sequence and are considered key regulators of the expression of genes involved in neurodevelopment. We examined any genome-wide methylation differences between children with DLD and control subjects. The findings were validated by real-time qPCR. The DLD group showed differential methylation of CpG sites in several Wnt signaling regulator genes (APCDD1, AMOTL1, LRP5, MARK2, TMEM64, TRABD2B, VEPH1, WNT2B) compared with the control group. Among these, hypomethylation of APCDD1, LRP5 and WNT2B was confirmed by qPCR. This is the first report associating Wnt signaling with DLD. The findings are relevant in the light of the essential role of Wnt in neuronal myelination and the altered myelination in DLD revealed by magnetic resonance imaging.
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Metilação de DNA , Transtornos do Desenvolvimento da Linguagem , Humanos , Via de Sinalização Wnt , Epigênese Genética , Genes Reguladores , Angiomotinas , Peptídeos e Proteínas de Sinalização IntracelularRESUMO
Background and Objective: For 1.3 billion population in India, there are only scarce reports on disability of epilepsy using disability-adjusted life year (DALY) as a measure. Our objective was to estimate DALY using real-life data over a period of time for a cohort of people with epilepsy (PWE) admitted to an Epilepsy Monitoring Unit (EMU) of a tertiary care epilepsy center. Materials and Methods: : We ascertained survival status as on December 31, 2016 of all eligible admissions to the EMU between 01/01/2005 and 12/31/2015. We examined the medical records of randomly selected 200 of the 1970 survivors and all the expired PWE (n = 40) for clinical characteristics. The cumulative real-life DALY (cr-DALY) for individual was calculated as the sum of the years lost to disability (YLD) and the years of life lost (YLL). Annual population-based DALY (p-DALY) was estimated from the cr-DALY, total patient-years of follow-up, and regional population prevalence. Results: The cr-DALY per PWE was 17.63 (generalized seizures only). The cr-DALY increased by 23.7% when all seizure types were considered (23.12). PWE with epilepsy onset <10 years of age, focal epilepsy (particularly, extratemporal lobe epilepsy), and premature death had significantly higher cr-DALY. Those who underwent surgery for epilepsy or achieved remission had significantly lower cr-DALY. The computed p-DALY was 583/1,00,000 population (generalized epilepsy contributed 165/1,00,000 population; focal epilepsy contributed 418/1,00,000 population). Conclusion: Our study had identified, for the first time, several determinants that reduced DALY significantly. Real-life DALY, rather than prevalence-based DALY, captures the cumulative disability of affected individuals. Epilepsy leads to loss of 23 years of disability-adjusted life span for the affected person. This can be extrapolated to substantial economic benefits.
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Epilepsias Parciais , Epilepsia , Humanos , Anos de Vida Ajustados por Qualidade de Vida , Efeitos Psicossociais da Doença , Anos de Vida Ajustados por Deficiência , Epilepsia/epidemiologia , Convulsões , PrevalênciaRESUMO
Following accidental release of valproate into ambient air during manufacture at a French production site in 2018, concerns were raised for inhabitants of the surrounding area. As no toxicological reference value (TRV) was available, the risks could not be properly assessed. The French Agency for Food, Environmental and Occupational Health and Safety (ANSES) was mandated to determine a TRV by inhalation to be used for risk assessment. Major congenital malformations (MCMs) in offsprings of mothers exposed to valproate during pregnancy have been reported in international scientific literature. As these adverse effects were the most sensitive effect identified, they were retained as the critical effect to be used for the TRV. The data from a robust registry on MCMs established by the International Registry of Antiepileptic Drugs and Pregnancy (EURAP) were modellized and support a strong DRR between the prevalence of MCMs in the fetus and in utero exposure. A benchmark dose (BMD) was then calculated as the dose that may trigger a 5% increase in this risk. A lower 95% confidence limit (BMD5%L95%) of 2.26 mg/kg/day, leading to an oral TRV of 0.08 mg/kg/day and a respiratory TRV of 0.26 mg.m-3 after applying an uncertainty factor of 30, was determined.
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Anormalidades Induzidas por Medicamentos , Complicações na Gravidez , Gravidez , Feminino , Humanos , Ácido Valproico/toxicidade , Benchmarking , Valores de Referência , Anticonvulsivantes/toxicidade , Medição de Risco , Complicações na Gravidez/induzido quimicamente , Complicações na Gravidez/tratamento farmacológicoRESUMO
Mitochondria have a crucial role in brain development and neurogenesis, both in embryonic and adult brains. Since the brain is the highest energy consuming organ, it is highly vulnerable to mitochondrial dysfunction. This has been implicated in a range of brain disorders including, neurodevelopmental conditions, psychiatric illnesses, and neurodegenerative diseases. Genetic variations in mitochondrial DNA (mtDNA), and nuclear DNA encoding mitochondrial proteins, have been associated with several cognitive disorders. However, it is not yet clear whether mitochondrial dysfunction is a primary cause of these conditions or a secondary effect. Our review article deals with this topic, and brings out recent advances in mitochondria-oriented therapies. Mitochondrial dysfunction could be involved in the pathogenesis of a subset of disorders involving cognitive impairment. In these patients, mitochondrial dysfunction could be the cause of the condition, rather than the consequence. There are vast areas in this topic that remains to be explored and elucidated.
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Doenças Neurodegenerativas , Transtornos do Neurodesenvolvimento , Humanos , Mitocôndrias/metabolismo , DNA Mitocondrial/genética , DNA Mitocondrial/metabolismo , Doenças Neurodegenerativas/genética , Doenças Neurodegenerativas/metabolismo , Transtornos do Neurodesenvolvimento/genética , Transtornos do Neurodesenvolvimento/complicações , Transtornos do Neurodesenvolvimento/metabolismo , CogniçãoRESUMO
Polymicrogyria (PMG) is a relatively common complex malformation with cortical development, characterized by an exorbitant number of abnormally tiny gyri separated by shallow sulci. It is a neuronal migration disorder. Familial cases of PMG and the manifestation of PMG in patients with chromosomal aberrations and mutations indicate their important role of genetics in this disorder. The highly stereotyped and well-conserved nature of the cortical folding pattern in humans is suggestive of the genetic regulation of the process. The chromosomal abnormalities observed in PMG include deletions, duplications, chromosomal rearrangements, and aneuploidies. Two of the most common deletions in PMG are 22q11.2 deletion and 1p36 deletion. Further, mutations in several genes such as GPR56, TUBB2B, SRPX2, PAX6, EOMES, WDR62, TUBA8, KIAA1279, and COL18A1 are known to be associated with PMG. Intriguingly, these genes are responsible only for a small number of cases of PMG. The protein products of these genes are implicated in diverse molecular and cellular functions. Taken together, PMG could be the result of the disruption of several biological pathways. Different modes of Mendelian inheritance and non-Mendelian inheritance are seen in PMG. We have suggested a gene panel that can be used for the detection of malformations of cortical development.
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We carried out a systematic review of published information on transfer of antiseizure medications (ASMs) into breastmilk, ASM serum concentrations in breastfed infants, and the wellbeing of infants breastfed by mothers on ASM treatment. Information was extracted from 85 relevant articles. No data on ASM levels in breastmilk or in breastfed infants was identified for cannabidiol, cenobamate, clobazam, eslicarbazepine-acetate, everolimus, felbamate, fenfluramine, retigabine, rufinamide, stiripentol, tiagabine, and vigabatrin. For ASMs, with available information on levels in breastfed infants, very low concentrations (in the order of 10% or less of maternal serum concentrations) were reported for carbamazepine, gabapentin, levetiracetam, oxcarbazepine, phenytoin, valproate, and clonazepam. Slightly higher levels (up to approximately 30% of maternal serum concentrations) have been observed with lamotrigine and topiramate, and in single case reports for brivaracetam, lacosamide, and perampanel. High infant levels (30% up to 100% of maternal serum concentrations) have been reported with ethosuximide, phenobarbital and zonisamide. Adverse infant effects during breastfeeding by mothers on ASMs appear to be rare regardless of the type of ASM, but systematic study is limited. Prospective long-term follow-up studies of developmental outcomes among children who have been breastfed by mothers taking ASMs are sparse and have mainly involved children whose mothers were taking carbamazepine, lamotrigine, levetiracetam, phenytoin or valproate as monotherapy while breastfeeding. Although these studies have not indicated poorer outcome among breastfed children compared with those who were not breastfed, further data on long-term outcomes are needed to draw firm conclusions. It is concluded that breastfeeding should in general be encouraged in women taking ASMs, given the well-established benefits of breastfeeding with regard to both short- and long-term infant health in the general population. Counselling needs to be individualized including information on the current knowledge regarding the woman's specific ASM treatment.
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Canabidiol , Epilepsia , Aleitamento Materno , Carbamazepina/uso terapêutico , Criança , Clobazam/uso terapêutico , Clonazepam/uso terapêutico , Epilepsia/tratamento farmacológico , Etossuximida/uso terapêutico , Everolimo/uso terapêutico , Felbamato/uso terapêutico , Feminino , Fenfluramina/uso terapêutico , Gabapentina/uso terapêutico , Humanos , Lactente , Lacosamida , Lamotrigina/uso terapêutico , Levetiracetam/uso terapêutico , Oxcarbazepina , Fenobarbital/uso terapêutico , Fenitoína/uso terapêutico , Estudos Prospectivos , Tiagabina , Topiramato , Ácido Valproico/uso terapêutico , Vigabatrina/uso terapêutico , Zonisamida/uso terapêuticoRESUMO
OBJECTIVE: In a prospective cohort of children (13-21 years) of women with epilepsy (CWWE), we compared those exposed to antiseizure medications (ASM) in utero to those without exposure to ASM regarding their language proficiency and intelligence. We also compared their educational performance with state-wide averages. METHODS: Research staff blinded to the ASM exposure of CWWE administered the Clinical Evaluation of Language Fundamentals IV and the Wechsler Intelligence Scale for Children IV to test their language proficiency and intelligence. We assessed their educational performance with a questionnaire. CWWE without antenatal exposure to ASM served as comparators for language and intelligence tests. The educational performance of CWWE (regardless of ASM exposure) was compared with the state-wide averages published by the government. RESULTS: In total, 446 children (mean age 16.5 ± 2.2 years; 236 girls) participated in the study. Their ASM exposure involved monotherapy for 272 (61%), polytherapy for 133 (29.8%) and none for 41 (9.2%). The commonly used ASMs (mono & polytherapy) were carbamazepine (n = 192), valproate (n = 124), phenobarbitone (n = 95), and phenytoin (n = 73). The full-scale intelligence quotient of CWWE (n = 146) with antenatal exposure to ASM (89.2 ± 21.5) was significantly lower (p = 0.03) than that of CWWE (n = 11) unexposed to ASM (96.9 ± 8.8). The CELF core language scaled score for the exposed CWWE (n = 132) was significantly lower than that of unexposed children (n = 12; 99.2 ± 19.9). Compared with state-wide averages, CWWE (n = 386) had delayed initiation of education (2.6% vs. 0.1%), increased dropout rates (1% vs. 0.11%), increased usage of special assistance during examinations (4.4% vs. 0.1%) and a lower rate (19.9% vs. 37%) of enrolment in universities. CONCLUSION: The language and intelligence functions of CWWE with exposure to older ASMs were lower than those of unexposed CWWE. Compared to state-wide averages, a significantly higher proportion of CWWE had difficulties with education, and only a smaller proportion enrolled in higher education.
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Epilepsia , Complicações na Gravidez , Efeitos Tardios da Exposição Pré-Natal , Adolescente , Anticonvulsivantes/efeitos adversos , Criança , Epilepsia/tratamento farmacológico , Feminino , Humanos , Inteligência , Idioma , Gravidez , Complicações na Gravidez/tratamento farmacológico , Efeitos Tardios da Exposição Pré-Natal/epidemiologia , Estudos Prospectivos , Sistema de RegistrosRESUMO
OBJECTIVE: We aimed to determine a possible association between motor and mental development in infants of women with epilepsy and antenatal exposure to antiseizure medication (ASM). METHODS: Developmental paediatricians who were blinded to antenatal ASM exposure evaluated motor and mental development of infants (>12 months) using the Developmental Assessment Scale for Indian Infants (an Indian adaptation of the Bayley Scale of Infant Development). Motor (MODQ) and mental development quotients (MEDQ) were computed as ratios of respective developmental age to the chronological age of the child. We employed linear mixed models to study the relationship between antenatal exposure to ASM and the development quotients after adjustment for malformation status and age of the baby, maternal education and seizure type. RESULTS: We studied 1,357 infants with mean age of 15.3±4.0 months (71.2% of all eligible infants). Infants were classified as having monotherapy or polytherapy, or unexposed in 840, 407 and 110 participants, respectively. The MEDQ of the polytherapy (92.9±14.9) and monotherapy (96.9±13.9) groups was lower than that of unexposed infants (99.8 12.5). Similarly, the MODQ of polytherapy (91.1±19.3) and monotherapy (96.6±17.5) groups was lower than that of unexposed infants (97.6 16.6). The differences in adjusted mean MEDQ were -7.4 (-11.4 to -4.3, p=0.001), -9.6 (-11.3 to -6.0, p=0.001) and -6.4 (-9.2 to -3.7, p=0.001) for valproate monotherapy, polytherapy with valproate and polytherapy without valproate, respectively. The adjusted mean MODQ also showed a similar trend. Those exposed to levetiracetam (n=62) had higher or similar adjusted MODQ (110.4±14.3; p=0.001) and MEDQ (104.3±9.1; p=0.09), compared to unexposed infants. A dose-dependent decrease in developmental indicators was observed for valproate and phenobarbitone. SIGNIFICANCE: Antenatal exposure to ASM, especially valproate and phenobarbitone, adversely affects motor and mental development of exposed infants. Early developmental screening of high-risk infants is desirable.
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Epilepsia , Efeitos Tardios da Exposição Pré-Natal , Anticonvulsivantes/efeitos adversos , Criança , Epilepsia/tratamento farmacológico , Feminino , Humanos , Lactente , Fenobarbital/uso terapêutico , Gravidez , Ácido Valproico/efeitos adversosRESUMO
Background: Prediction of outcome of West syndrome (WS) in relation to etiology and electrophysiology remain pertinent challenges. Objective: This study aimed to compare electro-clinical and imaging characteristics between WS of "unknown-etiology"; "symptomatic"WS; to gauge the evolution and impact of electroencephalographic (EEG) patterns on seizure outcomes. Materials and Methods: Electro-clinico-radiological data of 76 children with WS who were followed up for atleast 1 year was collected for reviewing clinical, therapeutic and EEG profiles (sub-typed as typical and modified hypsarrhythmia [HA]). Quantified seizure scores were assessed. Results: Among 76 children included in this retrospective analysis, 31 (40.8%) were of unknown-etiology and 45 (59.2%) were "symptomatic" (structural cause/developmental-encephalopathy). Children with symptomatic WS (p = 0.037), specifically with gliosis on imaging (p = 0.05) and typical HA (including the multifocal subtype; P = 0.023) were more likely to have other seizure types before onset of spasms and exhibit prior delay or regression in milestones (p = 0.017). There was negative correlation between time to diagnosis and reduction in seizure scores (r = -0.32; p = 0.005).Significant reduction was noted in seizure scores with pharmacotherapy, irrespective of etiology (P < 0.001 in unknown-etiology and symptomatic subgroups). Seizure freedom rates did not differ between typical and modified HA groups (p = 0.215) with a higher proportion of children with meaningful reduction in seizure scores in the former sub-group (p = 0.030). Children who failed to achieve seizure remission were more likely to exhibit developmental impairment (p = 0.019). Conclusions: Early diagnosis and initiation of optimal therapy is crucial towards improving outcome, irrespective of etiology (which impacts pre-spasm development) and HA subtypes.
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Espasmos Infantis , Criança , Eletroencefalografia , Humanos , Lactente , Encaminhamento e Consulta , Estudos Retrospectivos , Espasmos Infantis/tratamento farmacológico , Resultado do TratamentoRESUMO
India is considered the diabetes capital of the world and has the highest burden of mucormycosis. Bacterial, viral and fungal co-infections are increasingly being reported in severe acute respiratory syndrome virus 2 (SARSCoV-2) infected patients. India is one of the worst affected countries during the second wave of the COVID-19 pandemic. This combination of diabetes mellitus, COVID-19 and mucormycosis has led to the drastic upsurge of COVID-19-associated mucormycosis (CAM) in India. Immunosuppression, iron disequilibrium, endothelial injury, ketoacidosis and hypoxia are some of the other COVID-19-related risk factors for CAM. There has been an increase in the proportion of mucormycosis affecting paranasal sinuses and central nervous system (CNS) in CAM compared to pre-COVID-19 literature due to the SARSCoV-2-related pathophysiological mechanisms, complications and treatment strategies. CAM is a medical and surgical emergency, and it can present with non-specific symptoms and signs initially resulting in diagnostic delay. High index of suspicion and regular screening for features of CAM are of paramount importance to prevent lethal consequences. Rapid action with a tripod approach consisting of withdrawal of immunomodulators, early antifungal therapy and extensive surgical debridement is considered the best possible treatment model. We review the published data to give a detailed account of the predisposing factors and their mechanisms, diagnostic work-up, treatment modalities and prevention strategies of CAM with special emphasis on CNS mucormycosis.
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COVID-19 , Diabetes Mellitus , Mucormicose , COVID-19/complicações , Diagnóstico Tardio , Humanos , Mucormicose/diagnóstico , Mucormicose/epidemiologia , Mucormicose/etiologia , Pandemias , Fatores de Risco , SARS-CoV-2RESUMO
Objective: To explore novel word learning via fast mapping (FM) and explicit encoding (EE) in temporal lobe epilepsy (TLE). Methods: 16 right and 16 left temporal lobe epilepsy (RTLE and LTLE) patients along with 32 normal controls (NC) underwent learning of 24 novel object name pairs through standard FM and EE techniques. Their learning was assessed via a three-choice alternate delayed recognition task on the day of learning and on the following day. Recognition scores were compared using nonparametric statistics across the groups with P value set at <.05. Results: RTLE and NC performed similarly, while LTLE and NC differed significantly in novel word learning irrespective of the method of encoding. LTLE and RTLE differed in EE-based novel word learning alone. Further, with respect to encoding techniques, all groups performed better on EE compared to FM. The novel word associations learned via FM showed a lesser decline compared to EE following overnight integration in RTLE and NC. Conclusion: Novel word learning via FM did not facilitate learning above EE in TLE patients or NC. But FM-based words could better overcome forgetting following overnight integration in RTLE and NC. Hence, it is possible that FM has the potential to improve retention of novel information following overnight integration in RTLE as in NC. However, its efficacy in improving retention in LTLE needs further evidence.
RESUMO
PURPOSE: To study if one can conceptualize the scalp ictal onset pattern through analysis of interictal spike domain analysis in temporal lobe epilepsy (TLE). METHODS: Seventy-four patients with unilateral mesial temporal sclerosis (MTS) were categorized into "type A" interictal epileptiform discharges (IEDs) with negativity over infero-lateral scalp electrodes over temporal region and contralateral central region showing positivity; all IEDs other than type A were categorized as type B. The ictal electrographic patterns was termed "focal" when confined to side of MTS, was "regional" when lateralized to the ipsilateral hemisphere; "diffuse" if nonlateralized/localized; and ictal onset contralateral to MTS termed as "discordant." RESULTS: A total of 377 seizures and 5,476 spikes were studied. These were divided into four types: (1) type A IEDs ipsilateral to MTS (44 patients), (2) type A IEDs bitemporally (16 patients), (3) type A IEDs contralaterally (7 patients) and type B IEDs ipsilaterally, and (4) bilateral type B IEDs (7 patients). The ictal pattern was either focal or regional in 51 of 60 patients (85%) with type A IEDs; it was "diffuse" in 9 patients (15%). Diffuse ictal onset was seen in 12 of 14 (86%) with either ipsilateral/bitemporal type B IEDs. Ictal onset on the opposite hemisphere was noted in 2 (14%). CONCLUSIONS: Type A IEDs signify a focal ictal onset and type B IEDs suggest a diffuse ictal onset in patients with MTS on one side. SIGNIFICANCE: Interictal spike domain analysis helps predicting ictal patterns in temporal lobe epilepsy.
Assuntos
Epilepsia do Lobo Temporal , Eletroencefalografia , Epilepsia do Lobo Temporal/diagnóstico , Lateralidade Funcional , Humanos , Imageamento por Ressonância Magnética , Convulsões , Lobo TemporalRESUMO
OBJECTIVES: We aim to report the major congenital malformation (MCM) rates for new and old anti-epileptic drugs (AED) exposures during the first trimester of pregnancy in women with epilepsy (WWE). METHODS: We extracted relevant data on drug exposure and malformation rate from the records of a prospective observational registry (Kerala Registry of Epilepsy and Pregnancy) for all completed pregnancies between 1998 and 2019. A comprehensive and uniform criterion with detailed guideline was used for assessment of malformations. We employed generalised linear model to generate adjusted incidence rate ratios (aIRR) of MCM in AED exposed group as compared to AED unexposed group, after adjustment for age and educational status of mothers' and epilepsy classification. RESULTS: The unadjusted MCM rate was 6.2% for all the infants included in the study (148/2328); 4.7% for the unexposed group (16/340), and 6.6% for the exposed group (132/1988). The aIRR of MCM as compared to unexposed group was similar for all monotherapies; lamotrigine (0.50; 95% CI 0.07-3.68), levetiracetam (1.16; 0.43-3.11), oxcarbazepine (1.61; 0.62-4.21) valproate (1.71, 0.93-3.19), phenytoin (1.21, 0.51-2.90), carbamazepine (0.99, 0.54-1.82), and phenobarbitone (1.20, 0.52-2.74). However, the point estimates suggest least risk with lamotrigine and highest risk with valproate. Polytherapy with high-dose valproate carried significantly higher risk of MCM as compared to the unexposed group (aIRR=4.12; 2.18-7.79, p<0.001). The aIRR of GTCS during pregnancy was 1.63 (95% CI 1.12-2.37, p = 0.011) for monotherapy with new AEDs (lamotrigine, levetiracetam or oxcarbazepine) as compared to old AEDs (phenobarbitone, phenytoin, carbamazepine, or valproate). CONCLUSION: The MCM risk was significantly higher for polytherapy with high dose valproate. It did not differ substantially between different AED monotherapies although point estimate was lowest with lamotrigine. Pregnant women on new AEDs report higher likelihood of GTCS than women on old AEDs during pregnancy.
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Anormalidades Induzidas por Medicamentos , Epilepsia , Preparações Farmacêuticas , Complicações na Gravidez , Anormalidades Induzidas por Medicamentos/epidemiologia , Anormalidades Induzidas por Medicamentos/etiologia , Anticonvulsivantes/efeitos adversos , Epilepsia/tratamento farmacológico , Epilepsia/epidemiologia , Feminino , Humanos , Gravidez , Complicações na Gravidez/tratamento farmacológico , Complicações na Gravidez/epidemiologia , Sistema de RegistrosRESUMO
PURPOSE: The objective of the study was to evaluate the frequency, clinical, and video-electroencephalographic (VEEG) predictors of convlusive status epilepticus (CSE) in the epilepsy-monitoring unit (EMU). METHODS: The data of all patients who had CSE in our EMU between 2008 and 2017 were reviewed. For each case, two age- and diagnosis-matched subjects who underwent VEEG and did not develop CSE were taken as internal controls. Electro-clinical data of both the groups were compared. Predictors of CSE were assessed using logistic regression analysis. RESULTS: Out of 11,188 video-telemetries were conducted between 2008-17, forty-three events of CSE (0.38%) were recorded. On comparisons with 86 internal controls no differences were apparent on prevalence of cognitive impairment, structural lesion, number of baseline anti-seizure medications (ASM), ASM taper schedule, ictal patterns, and duration of VEEG monitoring. Inter-ictal rhythmic periodic patterns had significantly higher prevalence in cases (pâ¯=â¯0.028). Logistic regression analysis revealed that odds of CSE were higher with past history of SE [pâ¯=â¯0.008; adjusted odds ratio (OR)â¯=â¯5.48 (confidence intervals {CI} 1.55-19.28)] and in presence of rhythmic spike and wave discharges [pâ¯=â¯0.016, ORâ¯=â¯33.518(CIâ¯=â¯1.93-581.4)]; the odds were lower if the first two seizures recorded did not evolve into CSE [pâ¯=â¯0.009, ORâ¯=â¯0.247 (CIâ¯=â¯0.08-0.70)] and if there was prior history of daily seizures [pâ¯=â¯0.02, ORâ¯=â¯0.250 (CIâ¯=â¯0.07-0.84)]. CONCLUSION: CSE is a rare yet important adverse event in EMU. Clinical predictors are more relevant in comparison to EEG variables. Extent of ASM withdrawal may not directly account for occurrence of CSE; factors inherent to a patient's epilepsy are deterministic.