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Epilepsy is a common neurological disorder that affects approximately 10.5 million children worldwide. Approximately 33% of affected patients exhibit resistance to all available antiseizure medications, but the underlying mechanisms are unknown and there is no effective treatment. Increasing evidence has shown that an abnormal gut microbiota may be associated with epilepsy. The gut microbiota can influence the function of the brain through multiple pathways, including the neuroendocrine, neuroimmune, and autonomic nervous systems. This review discusses the interactions between the central nervous system and the gastrointestinal tract (the brain-gut axis) and the role of the gut microbiota in the pathogenesis of epilepsy. However, the exact gut microbiota involved in epileptogenesis is unknown, and no consistent results have been obtained based on current research. Moreover, the target that should be further explored to identify a novel antiseizure drug is unclear. The role of the gut microbiota in epilepsy will most likely be uncovered with the development of genomics technology.
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OBJECTIVE: Lennox-Gastaut Syndrome (LGS) is characterized by the presence of multiple seizure types and encompasses a heterogenous group of etiologies. The aim of our study was to evaluate the etiological profile of LGS and investigate seizure outcomes based on different clinical variables. METHODS: The clinical features, neuroimaging findings, genetic testing and other testing results of LGS patients were systematically reviewed. The identifiable etiology was categorized as either acquired or nonacquired. Univariate and multivariate regression analyses were performed to explore the association between clinical variables and seizure outcome at the last follow-up. RESULTS: We enrolled 156 patients diagnosed with LGS, of whom 66% were male. The mean age of patients was 34.2 months and the median follow-up duration was 29.5 months (interquartile range = 14-56.25 months). The initial seizure type was epileptic spasm in 61 patients, among which 33 of them met the criteria for infantile epileptic spasm syndrome. All patients underwent neuroimaging test, with 25% falling into the acquired structural category. Etiology could be identified in 84 individuals, including pathogenetic variants found in 34 out of 117 patients with nonacquired etiology. CHD2 mutations were most frequently observed among these pathogenetic variants. At the last follow-up, favorable outcomes were observed in 27 patients. The identification of etiology emerged as a significant determinant influencing LGS outcome; specifically, patients with unknown etiology had a higher likelihood of experiencing favorable outcomes compared to those with known cause (p = 0.041). Early onset age and longer epilepsy duration significantly increased the odds of an unfavorable outcome (p = 0.006 and 0.024). SIGNIFICANCE: We present novel data on the clinical and etiological spectrum of LGS, with determined etiology observed in over half of the patients. Epileptic spasms were found to be more prevalent than tonic seizures as seizure onset types in LGS. The presence of a known etiology, earlier age at onset, and longer duration of epilepsy were associated with a poorer long-term epileptological outcome.
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Síndrome de Lennox-Gastaut , Humanos , Masculino , Síndrome de Lennox-Gastaut/fisiopatología , Femenino , Preescolar , Lactante , Niño , Estudios de Seguimiento , Estudios Retrospectivos , Espasmos Infantiles/etiología , Espasmos Infantiles/fisiopatología , ElectroencefalografíaRESUMEN
Two general protocols for the regioselective electrochemically enabled sulfonylation cyclization of N-alkenylacrylamides with sodium sulfinates or sulfonyl hydrazides were described. These methods were carried out under mild, chemical oxidant-free, and transition-metal-free conditions with a broad substrate scope and good functional group tolerance to provide sulfonyl-containing 4-pyrrolin-2-ones, which is readily scalable to the gram scale.
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BACKGROUND AND PURPOSE: To test the hypothesis that myoclonic seizures can evolve to tonic seizures, we documented the electroclinical features of this under-recognized seizure type. METHODS: We observed a distinct seizure pattern starting with myoclonus without returning to an interictal state, which subsequently evolved into generalized tonic seizures. The detailed symptomatic and electroencephalographic characteristics of this seizure were extracted, and the clinical manifestations, drug curative responses in patients with this seizure were reviewed and analyzed. RESULTS: The onset of all seizures was characterized by a preceding period of myoclonus and bursts of generalized spike or poly-spike slow wave discharges with high amplitude. This was closely followed by the occurrence of tonic seizures, which were distinguished by bursts of generalized fast activity at 10 Hz or higher frequency. This under-recognized seizure type has been designated as myoclonic-to-tonic (MT) seizure. The number of patients identified with MT seizures in this study was 34. The prevalence rate of MT seizures was found to be higher in males. While MT seizures typically included a tonic component, it should be noted that some patients experiencing this seizure type never presented with isolated tonic seizures. Generalized Epilepsy not further defined (GE) accounted for approximately one-third of the diagnosed cases, followed by Lennox-Gastaut syndrome and Epilepsy with Myoclonic-Atonic seizures. In comparison to other types of epilepsy, GE with MT seizures demonstrated a more favorable prognosis. CONCLUSIONS: The classification of myoclonic-to-tonic seizure represents a novel approach in comprehending the ictogenesis of generalized seizures and can provide valuable assistance to clinicians in epilepsy diagnosis.
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Electroencefalografía , Epilepsias Mioclónicas , Convulsiones , Humanos , Masculino , Femenino , Electroencefalografía/métodos , Adulto , Adolescente , Convulsiones/fisiopatología , Convulsiones/diagnóstico , Niño , Adulto Joven , Epilepsias Mioclónicas/fisiopatología , Epilepsias Mioclónicas/diagnóstico , Epilepsia Generalizada/fisiopatología , Epilepsia Generalizada/diagnóstico , Preescolar , Persona de Mediana Edad , Mioclonía/fisiopatología , Mioclonía/diagnóstico , LactanteRESUMEN
Objectives: This study aimed to investigate the clinical, radiological, and genetic features of POLR3-related leukodystrophy caused by mutations in POLR3A or POLR1C. Methods: Fourteen Chinese patients with POLR3-related leukodystrophy were enrolled in this cross-sectional observational study. The clinical manifestations, brain MRI and genetic tests of the patients were evaluated. Results: Thirteen patients had biallelic variants in POLR3A (92.9%), and one had biallelic variants in POLR1C (7.1%). The median age at disease onset was 9 months. A total of 85.7% of the patients presented with motor delay, abnormal gait, and intelligence disability in the first 2 years of life. Intellectual disability can be categorized based on its severity. It varied from mild (which involves difficulty concentrating) to very severe (with no smiling or laughing or never being able to speak since birth). Short stature was observed in all patients, and delayed dentition was observed in 64.3% of them. Furthermore, three out of 14 patients had myopia. Hypomyelination was invariably present in all patients, whereas myelination of the basal ganglia was preserved in only six out of 14 patients. All the mutations were compound heterozygous and included missense (n = 25), deletion (n = 1), and splice site variants (n = 2). A total of 78.6% of the patients with POLR3A were identified as carrying the c.1771-6C>G variant or the c.1771-7C>G variant. Conclusion: The phenotypic diversity of POLR3-HLD associated with pathogenic variants ranges from mild to very severe for neurological and non-neurological symptoms. Most patients presented symptoms in the first 2 years of life. The c.1771-6C>G or c.1771-7C>G variant is the most frequent mutation site in POLR3A in Chinese individuals.
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Background: Sleep-related facial mandibular myoclonus (SRFMM) remains rare in clinical practice. The aim of this study was to provide a comprehensive understanding of the electroclinical manner, therapeutic regimen, and prognosis of SRFMM. Methods: Twenty-three patients who were diagnosed with SRFMM by clinical manifestation, video-electroencephalography (EEG) and electromyography over bilateral masseter and temporalis muscles were enrolled. Clinical and electrophysiological evaluation as well as follow-up information were recorded and analyzed. Results: The cohort involved 4 infants and 19 adults with a mean onset age of 43.5 years for SRFMM, among whom 19 were male. Twenty-one patients complained of tongue injuries and disturbed night-time sleep. SRFMM in 4 patients were ascribed to oral aripiprazole, brainstem ischemia and brain trauma. In 62 SRFMM episodes, 93.5% occurred in NREM sleep and 6.5% in REM sleep, and all events were associated with EEG arousals. In 13 patients with or without clonazepam, the motor events gradually disappeared, and the rest turned to be sporadic. Conclusion: SRFMM is a characteristic parasomnia manifested by tongue biting and accompanying facial mandibular myoclonus, leading to disrupted sleep. Besides adults, infants can also experience SRFMM with spontaneous remission. Most patients respond well to clonazepam, eventually with favorable prognosis.
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BACKGROUND: PHACTR1 (phosphatase and actin regulators) plays a key role in cortical migration and synaptic activity by binding and regulating G-actin and PPP1CA. This study aimed to expand the genotype and phenotype of patients with de novo variants in PHACTR1 and analyse the impact of variants on protein-protein interaction. METHODS: We identified seven patients with PHACTR1 variants by trio-based whole-exome sequencing. Additional two subjects were ascertained from two centres through GeneMatcher. The genotype-phenotype correlation was determined, and AlphaFold-Multimer was used to predict protein-protein interactions and interfaces. RESULTS: Eight individuals carried missense variants and one had CNV in the PHACTR1. Infantile epileptic spasms syndrome (IESS) was the unifying phenotype in eight patients with missense variants of PHACTR1. They could present with other types of seizures and often exhibit drug-resistant epilepsy with a poor prognosis. One patient with CNV displayed a developmental encephalopathy phenotype. Using AlphaFold-Multimer, our findings indicate that PHACTR1 and G-actin-binding sequences overlap with PPP1CA at the RPEL3 domain, which suggests possible competition between PPP1CA and G-actin for binding to PHACTR1 through a similar polymerisation interface. In addition, patients carrying missense variants located at the PHACTR1-PPP1CA or PHACTR1-G-actin interfaces consistently exhibit the IESS phenotype. These missense variants are mostly concentrated in the overlapping sequence (RPEL3 domain). CONCLUSIONS: Patients with variants in PHACTR1 can have a phenotype of developmental encephalopathy in addition to IESS. Moreover, our study confirmed that the variants affect the binding of PHACTR1 to G-actin or PPP1CA, resulting in neurological disorders in patients.
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Secuenciación del Exoma , Estudios de Asociación Genética , Proteínas de Microfilamentos , Mutación Missense , Fenotipo , Espasmos Infantiles , Niño , Preescolar , Femenino , Humanos , Lactante , Masculino , Actinas/genética , Predisposición Genética a la Enfermedad , Genotipo , Proteínas de Microfilamentos/genética , Mutación Missense/genética , Enfermedades del Sistema Nervioso/genética , Proteína Fosfatasa 1/genética , Espasmos Infantiles/genéticaRESUMEN
BACKGROUND: The PACS gene family has been demonstrated to be related to intracellular vesicular trafficking. The phenotypic manifestations caused by the pathogenic variants of PACS include epilepsy, intellectual disability/developmental delay, and malformations, such as facial abnormalities. METHODS: We identified seven new cases with pathogenic or likely pathogenic PACS variants using next-generation sequencing. Detailed information obtained from these patients was analyzed along with that obtained from previously reported patients. RESULTS: With the inclusion of the newly diagnosed cases in this study, 103 cases with PACS gene family-related neurological diseases were reported, of which 43 were PACS2-related cases and the remaining were PACS1-related cases. Most patients had seizures, which have been reported to be effectively controlled by several types of anti-seizure medications (ASMs). The most efficacious and frequently prescribed ASMs included sodium valproate (43.3%, 13/30), oxcarbazepine/carbamazepine (26.7%, 8/30), and levetiracetam (20%, 6/30). Almost all patients had intellectual disability/developmental delay. The most common pathogenic missense variants were PACS1 p. Arg203Trp and PACS2 p.Glu209Lys. In addition, we report a patient carrying a likely pathogenic copy number variation (CNV) (de novo heterozygous deletion of chr14:105821380-106107443, 286 kilobase, destroyed part of the furin-binding region domain and the protein structure after it) with more severe and refractory late-onset epilepsy. CONCLUSIONS: The clinical phenotypes of the different PACS heterozygous missense variants were similar. The pathogenic variant sites of PACS1 and PACS2 were quite limited but located in different regions. A CNV destroying part of the PACS2 gene might also be pathogenic. These findings may provide an important clue for further functional studies on the pathogenic mechanism of neurological disorders related to the PACS gene family. Video Abstract (MP4 65767 kb).
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Epilepsia , Discapacidad Intelectual , Humanos , Discapacidad Intelectual/genética , Variaciones en el Número de Copia de ADN , Epilepsia/tratamiento farmacológico , Epilepsia/genética , Fenotipo , Genotipo , Proteínas de Transporte Vesicular/genéticaRESUMEN
BACKGROUND: To investigate electroclinical phenotypes and long-term photosensitivity outcome in a large pediatric cohort of patients with epilepsy with photosensitivity. METHODS: Patients with epilepsy with photosensitivity with four or more years of follow-up were included. Sustained terminal remission (STR) of photosensitivity (≥3.5 years) and seizure control were investigated, as well as the prognostic factors of photosensitivity. Furthermore, a cluster analysis was used to study the different subgroups of photoparoxysmal responses (PPR). RESULTS: We included 190 individuals with a median age at diagnosis of photosensitivity of 93.1 months (interquartile range [IQR] 62.8 to 120 months) and a median follow-up duration of 68.5 months (IQR 51.8 to 84 months). STR of photosensitivity was achieved in 97 (51.1%) patients, and the mean time from age at diagnosis of photosensitivity onset to STR was 16.5 months. Age at the last follow-up (9 to 18 years [P = 0.001]), a history of photoconvulsive response (PCR) (P = 0.009), and posterior epileptiform discharges (EDs) of PPRs (P = 0.05) were significantly associated with a lower chance of entering STR according to a Cox proportional hazards model. The subgroup of generalized epilepsy syndrome exhibited 46.2% of eye closure sensitivity and 47.7% of PCR. The rates of focal epilepsy syndrome (cluster 1), generalized epilepsy syndrome (cluster 2), and unclassified epilepsy (cluster 3) were similar and not statistically different in photosensitive outcome (P = 0.527). CONCLUSIONS: Age nine to 18 years, a history of PCR, and posterior EDs of PPRs were the adverse factors affecting photosensitivity, suggesting the effect of age-related brain changes in STR. There was no difference in the prognosis of photosensitivity in different epileptic syndromes.
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Epilepsias Parciales , Epilepsia Generalizada , Epilepsia , Síndromes Epilépticos , Humanos , Epilepsia/tratamiento farmacológico , ConvulsionesRESUMEN
OBJECTIVE: Bone metabolism can be influenced by a range of factors. We selected children with self-limited epilepsy with centrotemporal spikes (SeLECTS) and lifestyles similar to those of healthy children to control for the confounding factors that may influence bone metabolism. We aimed to identify the specific effects of epilepsy and/or anti-seizure medications (ASMs) on bone metabolism. METHODS: Patients with SeLECTS were divided into an untreated group and a monotherapy group, and the third group was a healthy control group. We determined the levels of various biochemical markers of bone metabolism, including procollagen type I nitrogenous propeptide (PINP), alkaline phosphatase (ALP), osteocalcin (OC), collagen type I cross-linked C-telopeptide (CTX), calcium, magnesium, phosphorus, parathyroid hormone (PTH), and vitamin D3 (VD3 ). RESULTS: A total of 1487 patients (from 19 centers) were diagnosed with SeLECTS; 1032 were analyzed, including 117 patients who did not receive any ASMs (untreated group), 643 patients who received only one ASM (monotherapy group), and 272 children in the healthy control group. Except for VD3 , other bone metabolism of the three groups were different (p < .001). Bone metabolism was significantly lower in the untreated group than the healthy control group (p < .05). There were significant differences between the monotherapy and healthy control group in the level of many markers. However, when comparing the monotherapy and untreated groups, the results were different; oxcarbazepine, levetiracetam, and topiramate had no significant effect on bone metabolism. Phosphorus and magnesium were significantly lower in the valproic acid group than the untreated group (adjusted p < .05, Cliff's delta .282-.768). CTX was significantly higher in the lamotrigine group than in the untreated group (adjusted p = .012, Cliff's delta = .316). SIGNIFICANCE: Epilepsy can affect many aspects of bone metabolism. After controlling epilepsy and other confounders that affect bone metabolism, we found that the effects of ASMs on bone metabolism differed. Oxcarbazepine, levetiracetam, and topiramate did not affect bone metabolism, and lamotrigine corrected some of the abnormal markers of bone metabolism in patients with epilepsy.
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PURPOSE: To investigate the risk factors of second primary malignant tumor (SPMT) in patients with differentiated thyroid cancer (DTC) and establish a competing risk nomogram to predict the probability of SPMT occurrence. METHODS: We retrieved data from the Surveillance, Epidemiology, and End Results (SEER) database for patients diagnosed with DTC between 2000 and 2019. The Fine and Gray subdistribution hazard model was employed to identify SPMT risk factors in the training set and develop a competing risk nomogram. Model evaluation was performed using area under the receiver operating characteristic curve (AUC), calibration curve, and decision curve analysis (DCA). RESULTS: A total of 112,257 eligible patients were included in the study and randomized into a training set (n = 112,256) and a validation set (n = 33,678). The cumulative incidence rate of SPMT was 15% (n = 9528). Age, sex, race, tumor multifocality, and TNM stage were independent risk factors of SPMT. The calibration plots showed good agreement between the predicted and observed SPMT risks. The 10-year AUCs of the calibration plots were 70.2 (68.7-71.6) in the training set and 70.2 (68.7-71.5) in the validation set. Moreover, DCA showed that our proposed model resulted in higher net benefits within a defined range of risk thresholds. The cumulative incidence rate of SPMT differed among risk groups, classified according to nomogram risk scores. CONCLUSION: The competing risk nomogram developed in this study exhibits high performance in predicting the occurrence of SPMT in patients with DTC. These findings may help clinicians identify patients at distinct levels of risk of SPMT and develop corresponding clinical management strategies.
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Adenocarcinoma , Neoplasias Primarias Secundarias , Neoplasias de la Tiroides , Humanos , Neoplasias de la Tiroides/epidemiología , Neoplasias Primarias Secundarias/epidemiología , Investigación , Área Bajo la Curva , Nomogramas , Programa de VERFRESUMEN
Structural rearrangements of chromosome 4p gives rise to a group of rare genomic disorders that mainly result in two different clinical entities: Wolf-Hirschhorn syndrome (WHS) and partial 4p trisomy. The severity of the phenotype depends on the size of the deletion or locus duplication. Here, we present two unrelated individuals with a copy number variation of chromosome 4p. Inverted duplication deletions (inv dup-del) in 4p are particularly rare. Case 1 describes a 15-year-old girl with a 1.055 Mb deletion of terminal 4p, distal to the recognized critical region of WHS, and a large duplication of 9.6 Mb in size from 4p16.3 to p16.1. She had postnatal development delay, intellectual disability (especially pronounced in speech), seizure/electroencephalogram anomalies, and facial dysmorphic features. This unusual chromosomal imbalance resulted in the WHS phenotype rather than the 4p trisomy syndrome phenotype. Case 2 describes a 21-month-old boy with a 1.386 Mb terminal 4p deletion who presented with slight developmental delay, borderline intellectual disability, and seizures. Combined with previous reported cases of 4 pter del-dup or pure 4p terminal deletions, our observations suggest that terminal chromosome 4p deletion is more pathogenic than the concomitant partial 4p duplication, and some regions of the 4p terminal may have regulatory effects on the remaining region of 4p. About nine cases have been reported thus far to date, and our study delineates further genotype-phenotype correlations about terminal 4p duplication-deletions for predicting disease prognosis and patient counseling.
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BACKGROUND: More than 50 loci are associated with spinocerebellar ataxia (SCA), and the most frequent subtypes share nucleotide repeats expansion, especially CAG expansion. OBJECTIVE: The objective of this study was to confirm a novel SCA subtype caused by CAG expansion. METHODS: We performed long-read whole-genome sequencing combined with linkage analysis in a five-generation Chinese family, and the finding was validated in another pedigree. The three-dimensional structure and function of THAP11 mutant protein were predicted. Polyglutamine (polyQ) toxicity of THAP11 gene with CAG expansion was assessed in skin fibroblasts of patients, human embryonic kidney 293 and Neuro-2a cells. RESULTS: We identified THAP11 as the novel causative SCA gene with CAG repeats ranging from 45 to 100 in patients with ataxia and from 20 to 38 in healthy control subjects. Among the patients, the number of CAA interruptions within CAG repeats was decreased to 3 (up to 5-6 in controls), whereas the number of 3' pure CAG repeats was up to 32 to 87 (4-16 in controls), suggesting that the toxicity of polyQ protein was length dependent on the pure CAG repeats. Intracellular aggregates were observed in cultured skin fibroblasts from patients. THAP11 polyQ protein was more intensely distributed in the cytoplasm of cultured skin fibroblasts from patients, which was replicated with in vitro cultured neuro-2a transfected with 54 or 100 CAG repeats. CONCLUSIONS: This study identified a novel SCA subtype caused by intragenic CAG repeat expansion in THAP11 with intracellular aggregation of THAP11 polyQ protein. Our findings extended the spectrum of polyQ diseases and offered a new perspective in understanding polyQ-mediated toxic aggregation. © 2023 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.
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Ataxias Espinocerebelosas , Expansión de Repetición de Trinucleótido , Humanos , Expansión de Repetición de Trinucleótido/genética , Ataxias Espinocerebelosas/genética , Proteínas/genética , Linaje , Proteínas Represoras/genéticaRESUMEN
Traditional conductive fabrics are prepared by the synthesis of conductive polymers and the coating modification of metals or carbon black conductive materials. However, the conductive fabrics cause a significant decline in performance after washing or mechanical wear, which limits their application. Moreover, the single function of the traditional conductive fabric is also the reason that limits its wide application. In order to prepare a wearable, stable, high-performance, washable, multifunctional conductive fabric, we have carried out related research. In this work, polydopamine was used as a bonding layer, an adsorption reduction layer, and a protective layer to improve the bonding between silver nanoparticles and carbon nanotubes (CNTs) on the polyester fabric surface so as to prepare a multifunctional conductive fabric with a high-stability "sandwich" structure, in which a Ag-NPS@CNT structure acting as an intermediate conductive layer formed on the inner layer PDA@CNT by electroless silver plating and the outermost layer PDA@CNT coated on the surface of the intermediate conductive layer by the impregnation-drying method. The sheet resistance of an E-Fabric can reach 2.11 Ω/â¡ due to the uniform and dense conductive path formed by the special structure Ag-NPs@CNT. At a low voltage of 1.5 V, the E-Fabric can reach 117 °C in 50 s and remain stable. The electrical conductivity and current heating properties of the E-Fabric remain good even after multiple washing or bending tests. Due to its stable and outstanding electrical conductivity, the E-Fabric has an electromagnetic shielding efficiency (SET) of 35.3 dB in the X-band (8.2-12.4 GHz). In addition, E-Fabric-based spin-coated poly(methyl methacrylate) or polydimethylsiloxane electrodes exhibit excellent performance in nanogenerators. Through the low-frequency friction of the human body, transient voltages up to 4 V can be generated from a 2 cm × 2 cm electrode sample. The output power of a single generator can reach about 12 nW/cm2. Therefore, an E-Fabric is considered to have great potential in the fields of electric heating, electromagnetic shielding, and smart wearable devices.
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This systematic review and meta-analysis aimed to evaluate the efficacy of vigabatrin (VGB) in treating infantile epileptic spasms syndrome (IESS). Databases of PubMed, Embase, Web of Science, MEDLINE, and Cochrane Library were systematically searched. All the relevant randomized controlled trials (RCTs) and observational studies (OSs) of VGB for IESS were included and analyzed separately. The primary outcome was the cessation of epileptic spasms (ES). Five RCTs and nine OSs compared the efficacy of VGB vs hormonal monotherapy for IESS. Meta-analysis of the five RCTs showed that hormonal monotherapy was significantly better than VGB monotherapy (OR = 0.37, 95% CI = 0.20-0.67) for patients with new-onset IESS. Meta-analysis of the nine OSs agrees with the result from RCTs (OR = 0.61, 95% CI = 0.43-0.85). VGB was more effective in patients with TSC than in those with other etiologies (five OSs, OR = 5.59, 95% CI = 2.17-14.41). There was no significant difference in the efficiency of VGB combined with hormonal therapy vs hormonal monotherapy for IESS (two RCTs, OR = 0.75, 95% CI = 0.09-6.45). Hormonal monotherapy is better than VGB monotherapy for non-TSC-associated IESS. But for patients with IESS due to TSC, VGB is the first choice. VGB combined with hormone therapy does not definitely increase ES control rates compared with that of hormonal monotherapy.
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Espasmos Infantiles , Vigabatrin , Humanos , Vigabatrin/uso terapéutico , Anticonvulsivantes/uso terapéutico , Espasmos Infantiles/tratamiento farmacológico , Síndrome , Espasmo/complicaciones , Espasmo/tratamiento farmacológicoRESUMEN
BACKGROUND: To summarize the clinical and genetic characteristics of patients with pyridox(am)ine-5'-phosphate oxidase (PNPO) deficiency. METHODS: Clinical and genetic data of the patients were collected and analyzed. RESULTS: Eighteen patients from 17 families with variants in PNPO were collected, and 15 cases survived to date. The age of onset ranged from 1 day to 5 months (median age 6.5 days) and seven of them presented with seizures <24 h. About 7/18 (39%) of patients showed seizure-free with pyridoxine (PN) or pyridoxal-5'-phosphate treatment. Two patients showed surprised therapeutic responses to antiseizure medications therapy: one could be controlled for up to 1 year and 5 months, and the other showed seizure-free for >8 years. The neurodevelopment was normal in one patient, mild delay in four, in whom responded well to PN. Severe delay could be seen in the remaining 10 surviving patients. Genetic analysis revealed 14 variants of PNPO, seven of which were novel. Five pairs of unrelated patients were observed to carry the same variants, respectively, and had similar developmental status and onset age of seizures in some degree in each pair, whereas also had differences. CONCLUSIONS: The clinical characteristics, including age of onset, treatment response and prognosis, were variable and difficult to classify into different types clearly. Patients with PNPO deficiency who used PN as their main treatment and being able to control seizures seemed to be associated with better outcomes. Patients with the same genotype tended to show the correlation of phenotype-genotype.
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Encefalopatías Metabólicas , Hipoxia-Isquemia Encefálica , Enfermedades Metabólicas , Piridoxaminafosfato Oxidasa , Humanos , Encefalopatías Metabólicas/genética , Hipoxia-Isquemia Encefálica/genética , Oxidorreductasas , Fosfatos/uso terapéutico , Fosfato de Piridoxal/uso terapéutico , Piridoxaminafosfato Oxidasa/deficiencia , Piridoxaminafosfato Oxidasa/genética , Piridoxina , Convulsiones/tratamiento farmacológico , Convulsiones/genéticaRESUMEN
Objectives: To investigate neonatal electroencephalography (EEG) background activity and electrographic seizures in patients in the pediatric intensive care unit (PICU) who underwent bedside video-electroencephalography (vEEG) monitoring. Methods: A total of 232 pediatric patients admitted or transferred to PICU that underwent vEEG monitoring were retrospectively enrolled in this study, and electrographic status epilepticus was observed after vEEG monitoring. Results: The median age was 1.56 years [95% confidence interval (CI) = 1.12-2.44]. Electrographic seizures occurred in 88 patients (37.9%), out of which 36 cases (40.9%) had electrographic status epilepticus. Prior epileptic encephalopathy diagnosis [odds ratio (OR) = 6.57, 95% CI = 1.91-22.59, p = 0.003], interictal epileptiform discharges (OR = 46.82, 95%CI = 5.31-412.86, p = 0.0005), slow disorganized EEG background (OR = 11.92, 95%CI = 1.31-108.71, p = 0.028), and burst-suppression EEG background (OR = 23.64, 95%CI = 1.71-327.57, p = 0.018) were the risk factors for electrographic seizures' occurrence. Of the 232 patients, the condition of 179 (77.2%) patients improved and they were discharged, 34 cases (14.7%) were withdrawn, and 18 cases (7.8%) died. The in-hospital death rate was 47.6% (10 in 21 cases) in patients with attenuated/featureless, compared to 0/23 with normal EEG background. Conclusions: Electrographic status epilepticus occurs in more than one-third of patients with electrographic seizures. vEEG is an efficient method to determine electrographic seizures in children. Abnormal EEG background activity is associated with both electrographic seizures' occurrence and unfavorable in-hospital outcomes.
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Objective: To analyze the genotypes and phenotypes of mosaic male patients with PCDH19-related epilepsy (PCDH19-RE) and explore the correlation between genotype, variant allele frequency (VAF), and phenotypic severity. Methods: Clinical data and peripheral blood samples of 11 male mosaic patients were collected and analyzed in our study. The VAF of the PCDH19 gene from peripheral blood was quantified using amplicon-based deep sequencing. Additional 20 mosaic male patients with PCDH19-RE were collected from the published literature, with 10 patients whose VAFs of the PCDH19 gene were available for analytic purposes. Results: In our cohort of 11 patients, 10 variants were identified, and four were novel. The VAF of the PCDH19 gene from peripheral blood ranged from 27 to 90%. The median seizure onset age was 6 months (range: 4-9 months). Clinical manifestations included cluster seizures (100%), fever sensitivity (73%), focal seizures (91%), developmental delay/intellectual disability (DD/ID, 82%), and autistic features (45%). Thirty-one mosaic male patients collected from our cohort and the literature developed seizures mostly (87%) within one year of age. Variant types included missense variants (42%), truncating variants (52%), splice variants (3%), and whole PCDH19 deletion (3%). Among 21 patients with a definite VAF from our cohort and the literature, nine had a low VAF ( ≤ 50%) and 12 had a high VAF (> 50%). Seventy-five percent of variants from the high VAF group were missense, whereas 89% of those from the low VAF group were truncations. The median seizure onset age was 6 months in the low VAF group and 9 months in the high VAF group (p = 0.018). Forty-four percent (4/9) of patients from the low VAF group achieved seizure-free for ≥1 year, whereas none of the 12 patients from the high VAF group did (p = 0.021). DD/ID was present in 83% (10/12) of the high VAF group and 56% (5/9) of the low VAF group (p = 0.331). Conclusion: The predominant variant types were truncating and missense variants. Missense variants tended to have higher VAFs. Patients with a high VAF were more likely to have a more severe epileptic phenotype. Our findings shed light on the phenotypic implications of VAF in mosaic males with PCDH19-RE.
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Objective: To determine the contribution of genetic etiologies in epilepsy with photosensitivity. Methods: A total of 35 epileptic patients with genetic photosensitivity from January 2019 to May 2021 were analyzed. Results: Pathogenic variants were identified in 35 patients, including SCN1A(7) CHD2(6), TPP1(3), SYNGAP1(3), GABRA1(2), GABRG2(1), KCTD7(1), MFSD8(1), KCNC1(1) GBA(1), CACNA1A(1), KCNMA1(1), FLNA(1), SZT2(1), SLC2A1(1), 5q33.2-34del(1), and mitochondrial variants(3). The predominant epileptic syndrome was progressive myoclonus epilepsy (PME) and Dravet syndrome, while the most common seizure type in both spontaneous seizures and photoconvulsive response (PCR) was myoclonic seizures. The abnormal EEG background and brain MRI were mainly seen in the PME patients. In PME, initial low-frequencies (1-6 Hz) photosensitivity was observed in 70% (7/10) of patients. Among the other patients, 12 patients (48.0%, 12/25) had photosensitivity at initial low -frequencies and 12 patients (48.0%, 12/25) had photosensitivity at initial middle frequencies (6-20 Hz). At the 1-year follow-up, 77.7% (21/27) still remained photosensitive. Conclusion: The most common genes for epilepsy with genetic photosensitivity are SCN1A and CHD2, and the most common syndromes are PME and Dravet syndrome. MFSD8, KCNMA1, SZT2, FLNA, and SLC2A1 variants might be candidate genes for photosensitivity. PPRs at initial low-frequencies may be a marker of PME, and the most typical feature of genetic photosensitivity may be low- or middle- frequencies induced PPRs. Photosensitivity in epilepsy with genetic photosensitivity may be difficult to disappear in a short period of time.
RESUMEN
OBJECTIVE: To study the relationship between eye closure sensitivity (ECLS), photosensitivity, and the mechanism of Jeavons syndrome (JS). METHODS: The interictal and the ictal epileptiform discharges (EDs) of 80 patients with electroencephalograms were classified (I: focal posterior EDs; II: the posterior spread into the frontal EDs; and III: generalized EDs) and analyzed under different provoked conditions. RESULTS: During the interictal and the ictal period, the positive rates of ECLS were higher than those of photosensitivity (100% vs 57.5%, P = 0.001; 97.5% vs 27.4%, P = 0.001). After a one-year interval, eyelid-myoclonia with ECLS remitted in 16 out of 21 patients (P = 0.002), and eyelid-myoclonia with photo-convulsion response (PCR) disappeared in all the previous six patients (P = 0.021). For the interictal EDs with ECLS, grade I accounted for 11.2%; grade I, II, and III 51.3%; and grade III 32.5%. Interictal EDs classification of photosensitivity showed a similar trend as that of ECLS. For the ictal EDs, grade I accounted for 10.2% of patients with ECLS and 6.7% of patients with PCR; grade I, II, and III, 33.3% of patients with ECLS and 46.6% of patients with PCR; and grade III, 53.9% of patients with ECLS and 40% of patients with PCR. CONCLUSION: ECLS was more common than photosensitivity in JS. Photosensitivity was more likely to disappear than ECLS. Both eye closure and intermittent-photic-stimulation could induce three grades of EDs, confirming that visual stimuli could trigger occipital cortex originating epileptic neural network to varying degrees, which further recognizes JS as another continuum epilepsy.