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International Journal of Molecular... Sep 2020Developmental and epileptic encephalopathies (DEEs) are the spectrum of severe epilepsies characterized by early-onset, refractory seizures occurring in the context of... (Review)
Review
Developmental and epileptic encephalopathies (DEEs) are the spectrum of severe epilepsies characterized by early-onset, refractory seizures occurring in the context of developmental regression or plateauing. Early infantile epileptic encephalopathy (EIEE) is one of the earliest forms of DEE, manifesting as frequent epileptic spasms and characteristic electroencephalogram findings in early infancy. In recent years, next-generation sequencing approaches have identified a number of monogenic determinants underlying DEE. In the case of EIEE, 85 genes have been registered in Online Mendelian Inheritance in Man as causative genes. Model organisms are indispensable tools for understanding the in vivo roles of the newly identified causative genes. In this review, we first present an overview of epilepsy and its genetic etiology, especially focusing on EIEE and then briefly summarize epilepsy research using animal and patient-derived induced pluripotent stem cell (iPSC) models. The model, which is characterized by easy gene manipulation, a short generation time, low cost and fewer ethical restrictions when designing experiments, is optimal for understanding the genetics of DEE. We therefore highlight studies with models for EIEE and discuss the future development of their practical use.
Topics: Animals; Drosophila melanogaster; Phenotype; Spasms, Infantile
PubMed: 32899411
DOI: 10.3390/ijms21176442 -
Neurobiology of Disease Jan 2021Mouse models have made innumerable contributions to understanding the genetic basis of neurological disease and pathogenic mechanisms and to therapy development. Here we... (Review)
Review
Mouse models have made innumerable contributions to understanding the genetic basis of neurological disease and pathogenic mechanisms and to therapy development. Here we consider the current state of mouse genetic models of Developmental and Epileptic Encephalopathy (DEE), representing a set of rare but devastating and largely intractable childhood epilepsies. By examining the range of mouse lines available in this rapidly moving field and by detailing both expected and unusual features in representative examples, we highlight lessons learned in an effort to maximize the full potential of this powerful resource for preclinical studies.
Topics: Animals; Disease Models, Animal; Epileptic Syndromes; Gain of Function Mutation; Humans; Infant; Loss of Function Mutation; Mice; Mutation, Missense; Phenotype; Seizures; Spasms, Infantile
PubMed: 33301879
DOI: 10.1016/j.nbd.2020.105220 -
Developmental Medicine and Child... Jun 2022To estimate the prevalence, and evaluate presentation, treatment response, treatment side effects, and long-term seizure outcomes in all known cases of children with...
AIM
To estimate the prevalence, and evaluate presentation, treatment response, treatment side effects, and long-term seizure outcomes in all known cases of children with Down syndrome and infantile spasms on the island of Ireland.
METHOD
This was a 10-year retrospective multicentre review of clinical records and investigations, focusing on treatment response, side effects, and long-term outcomes.
RESULTS
The prevalence of infantile spasms in Down syndrome was 3.0% during the study period. Fifty-four infants were identified with median age of spasm onset at 201 days (interquartile range [IQR] 156-242). Spasm cessation was achieved in 88% (n=46) at a median of 110 days (IQR 5-66). The most common first-line medications were prednisolone (n=20, 37%), vigabatrin (n=18, 33.3%), and sodium valproate (n=9, 16.7%). At follow-up (median age 23.7mo; IQR 13.4-40.6), 25% had ongoing seizures and 85% had developmental concerns. Treatment within 60 days did not correlate with spasm cessation. Seventeen children (31%) experienced medication side effects, with vigabatrin accounting for 52%.
INTERPRETATION
Prednisolone is an effective and well-tolerated medication for treating infantile spasms in Down syndrome. Despite the high percentage of spasm cessation, developmental concerns and ongoing seizures were common.
Topics: Adult; Anticonvulsants; Child; Down Syndrome; Humans; Infant; Prednisolone; Seizures; Spasm; Spasms, Infantile; Treatment Outcome; Vigabatrin; Young Adult
PubMed: 35092693
DOI: 10.1111/dmcn.15153 -
Seizure Apr 2021Dravet Syndrome (DS) is a rare and severe infantile-onset epileptic encephalopathy. DS research focuses mainly on children. We did a systematic review, completed on... (Review)
Review
Dravet Syndrome (DS) is a rare and severe infantile-onset epileptic encephalopathy. DS research focuses mainly on children. We did a systematic review, completed on January 18, 2021, examining the number of clinical DS studies. We show that there are 208 studies on children exclusively, 28 studies on adults exclusively, and 116 studies involving adults and children combined. This 7:1 ratio of children to adult studies exclusively shows the dearth of research that addresses long-term natural history of DS into adulthood. Through this systematic review, we examine the most up-to-date information in DS adults as it pertains to seizures, electroencephalogram, imaging, treatment, motor abnormalities, cognitive and social behavior outcomes, cardiac abnormalities, sleep disturbances, diagnosis in adults, and mortality. Overall, the frequency of seizures increases in the first decade of life and then myoclonic, atypical absences and focal seizures with impaired awareness tend to decrease in frequency or even disappear in adulthood. Adults tend to have a notable reduction in status epilepticus, especially after 30 years of age. Parkinsonian features were seen in patients as young as 19 years old and are more severe in older patients, suggesting a progression of the parkinsonian symptoms. In adulthood, patients continue to present with behavior problems, associated with a lower health-related quality of life. The leading reported cause of death in DS adults is Sudden Unexpected Death in Epilepsy (SUDEP). Further studies in older adults are needed to understand the long-term outcomes of patients with DS.
Topics: Adult; Epilepsies, Myoclonic; Humans; Infant; Mutation; NAV1.1 Voltage-Gated Sodium Channel; Quality of Life; Spasms, Infantile; Young Adult
PubMed: 33677403
DOI: 10.1016/j.seizure.2021.02.025 -
Epilepsia Open Sep 2020Considering the dearth of literature on West syndrome (WS) from South Asian countries, this study aimed to evaluate the management practices in South Asia by an online...
OBJECTIVES
Considering the dearth of literature on West syndrome (WS) from South Asian countries, this study aimed to evaluate the management practices in South Asia by an online survey and meta-analysis.
METHODS
An online questionnaire was sent to 223 pediatric neurologists/pediatricians in India, Pakistan, Myanmar, Sri Lanka, Bhutan, Nepal, and Bangladesh. Their responses were evaluated and supplemented by a meta-analysis.
RESULTS
Of 125 responses received (response rate: 56%), around 60% of responders observed male preponderance and an approximate lead-time-to-treatment (LTTT) of 4-12 weeks. The commonest etiology observed was a static structural insult (88.6% of responders). Most commonly used first-line drug (country-wise) was as follows: India-adrenocorticotropin hormone (ACTH, 50%); Pakistan-oral steroids (45.5%); Myanmar, Sri Lanka, and Nepal-oral steroids (94.4%); Bangladesh-ACTH (2/2); Bhutan-vigabatrin (3/5). ACTH and vigabatrin are not available in Myanmar and Nepal. The most commonly used regime for ACTH was maximal-dose-at-initiation-regime in India, Sri Lanka, and Bangladesh and gradually escalating-regime in Pakistan. Maximum dose of prednisolone was variable-most common response from India: 3-4 mg/kg/d; Pakistan, Bhutan, and Bangladesh: 2 mg/kg/d; Sri Lanka, Nepal, and Myanmar: 5-8 mg/kg/d or 60 mg/d. The total duration of hormonal therapy (including tapering) ranged from 4 to 12 weeks (67/91). Most responders considered cessation of spasms for four weeks as complete response (54/111) and advised electroencephalography (EEG; 104/123) to check for hypsarrhythmia resolution. Difficult access to pediatric EEG in Bhutan and Nepal is concerning. More than 95% of responders felt a need for more awareness. The meta-analysis supported the preponderance of male gender (68%; confidence interval [CI]: 64%-73%), structural etiology(80%; CI 73%-86%), longer LTTT (2.4 months; CI 2.1-2.6 months), and low response rate to hormonal therapy(18% and 28% for ACTH and oral steroids respectively) in WS in South Asia.
SIGNIFICANCE
This study highlights the practices and challenges in the management of WS in South Asia. These include a preponderance of male gender and structural etiology, a longer LTTT, difficult access to pediatric EEG, nonavailability of ACTH and vigabatrin in some countries, and low effectiveness of hormonal therapy in this region.
PubMed: 32913954
DOI: 10.1002/epi4.12419 -
Biomedicine & Pharmacotherapy =... Nov 2020Progressive encephalopathy with edema, hypsarrhythmia, and optic atrophy (PEHO) syndrome is a genetic neurological condition characterized by extreme cerebellar atrophy.... (Review)
Review
Progressive encephalopathy with edema, hypsarrhythmia, and optic atrophy (PEHO) syndrome is a genetic neurological condition characterized by extreme cerebellar atrophy. PEHO-Like syndrome is comparable to PEHO syndrome, with the exception that there is no typical neuro-radiologic or neuro-ophthalmic findings. PEHO spectrum disorders are highly clinically and genetically heterogeneous, and this has challenged their diagnosis. This scoping review aims to summarize and discuss common clinical and genetic features of these syndromes to help future researches. This study was performed according to a six-stage methodology structure and PRISMA guideline. A systematic search of seven databases was performed to find eligible publications prior to June 2020. Articles screening and data extraction were independently performed by two reviewers and quantitative and qualitative analyses were conducted. Thirty-eight articles were identified that fulfill the inclusion criteria. Cerebellar atrophy was the main clinical difference between the two groups but data on optic atrophy and infantile spasms/hypsarrhythmia were not consistent with the previously essential diagnostic criteria. Genetic analysis was performed in several studies, leading to identification of pathogenic variants in different genes that caused these conditions due to different mechanisms. Genetic studies could revolutionize the diagnosis process and our understanding of the etiology of this challenging group of patients by providing targeted sequencing panels and exome- or genome-scale studies in the future.
Topics: Brain Edema; Cerebellum; Humans; Neurodegenerative Diseases; Optic Atrophy; Spasms, Infantile
PubMed: 33152950
DOI: 10.1016/j.biopha.2020.110793 -
Genes Feb 2024Infantile epileptic spasms syndrome (IESS) is a devastating developmental epileptic encephalopathy (DEE) consisting of epileptic spasms, as well as one or both of... (Review)
Review
Infantile epileptic spasms syndrome (IESS) is a devastating developmental epileptic encephalopathy (DEE) consisting of epileptic spasms, as well as one or both of developmental regression or stagnation and hypsarrhythmia on EEG. A myriad of aetiologies are associated with the development of IESS; broadly, 60% of cases are thought to be structural, metabolic or infectious in nature, with the remainder genetic or of unknown cause. Epilepsy genetics is a growing field, and over 28 copy number variants and 70 single gene pathogenic variants related to IESS have been discovered to date. While not exhaustive, some of the most commonly reported genetic aetiologies include trisomy 21 and pathogenic variants in genes such as , , , , , and . Understanding the genetic mechanisms of IESS may provide the opportunity to better discern IESS pathophysiology and improve treatments for this condition. This narrative review presents an overview of our current understanding of IESS genetics, with an emphasis on animal models of IESS pathogenesis, the spectrum of genetic aetiologies of IESS (i.e., chromosomal disorders, single-gene disorders, trinucleotide repeat disorders and mitochondrial disorders), as well as available genetic testing methods and their respective diagnostic yields. Future opportunities as they relate to precision medicine and epilepsy genetics in the treatment of IESS are also explored.
Topics: Animals; Precision Medicine; Spasms, Infantile; Epilepsy; Epileptic Syndromes; Spasm
PubMed: 38540325
DOI: 10.3390/genes15030266 -
Epilepsia Sep 2021The classical description of Dravet syndrome, the prototypic developmental and epileptic encephalopathy, is of a normal 6-month-old infant presenting with a prolonged,...
OBJECTIVE
The classical description of Dravet syndrome, the prototypic developmental and epileptic encephalopathy, is of a normal 6-month-old infant presenting with a prolonged, febrile, hemiclonic seizure and showing developmental slowing after age 1 year. SCN1A pathogenic variants are found in >80% of patients. Many patients have atypical features resulting in diagnostic delay and inappropriate therapy. We aimed to provide an evidence-based definition of SCN1A-Dravet syndrome in readiness for precision medicine trials.
METHODS
Epilepsy patients were recruited to the University of Melbourne Epilepsy Genetics Research Program between 1995 and 2020 by neurologists from around the world. Patients with SCN1A pathogenic variants were reviewed and only those with Dravet syndrome were included. Clinical data, including seizure and developmental course, were analyzed in all patients with SCN1A-Dravet syndrome.
RESULTS
Two hundred and five patients were studied at a median age of 8.5 years (range 10 months to 60 years); 25 were deceased. The median seizure-onset age was 5.7 months (range 1.5-20.6 months). Initial seizures were tonic-clonic (52%) and hemiclonic (35%), with only 55% being associated with fever. Only 34% of patients presented with status epilepticus (seizure lasting ≥30 minutes). Median time between first and second seizure was 30 days (range 4 hours to 8 months), and seven patients (5%) had at least 6 months between initial seizures. Median ages at onset of second and third seizure types were 9.1 months (range 3 months-25.4 years) and 15.5 months (range 4 months-8.2 years), respectively. Developmental slowing occurred prior to 12 months in 27%.
SIGNIFICANCE
An evidence-based definition of SCN1A-Dravet syndrome is essential for early diagnosis. We refine the spectrum of Dravet syndrome, based on patterns of seizure onset, type, and progression. Understanding of the full spectrum of SCN1A-Dravet syndrome presentation is essential for early diagnosis and optimization of treatment, especially as precision medicine trials become available.
Topics: Adolescent; Adult; Child; Child, Preschool; Delayed Diagnosis; Epilepsies, Myoclonic; Epilepsy; Epileptic Syndromes; Humans; Infant; Middle Aged; Mutation; NAV1.1 Voltage-Gated Sodium Channel; Precision Medicine; Seizures; Spasms, Infantile; Young Adult
PubMed: 34338318
DOI: 10.1111/epi.17015 -
Frontiers in Neurology 2022Early diagnosis and treatment are critical for young children with infantile spasms (IS), as this maximizes the possibility of the best possible child-specific outcome.... (Review)
Review
Early diagnosis and treatment are critical for young children with infantile spasms (IS), as this maximizes the possibility of the best possible child-specific outcome. However, there are major barriers to achieving this, including high rates of misdiagnosis or failure to recognize the seizures, medication failure, and relapse. There are currently no validated tools to aid clinicians in assessing objective diagnostic criteria, predicting or measuring medication response, or predicting the likelihood of relapse. However, the pivotal role of EEG in the clinical management of IS has prompted many recent studies of potential EEG biomarkers of the disease. These include both visual EEG biomarkers based on human visual interpretation of the EEG and computational EEG biomarkers in which computers calculate quantitative features of the EEG. Here, we review the literature on both types of biomarkers, organized based on the application (diagnosis, treatment response, prediction, etc.). Visual biomarkers include the assessment of hypsarrhythmia, epileptiform discharges, fast oscillations, and the Burden of AmplitudeS and Epileptiform Discharges (BASED) score. Computational markers include EEG amplitude and power spectrum, entropy, functional connectivity, high frequency oscillations (HFOs), long-range temporal correlations, and phase-amplitude coupling. We also introduce each of the computational measures and provide representative examples. Finally, we highlight remaining gaps in the literature, describe practical guidelines for future biomarker discovery and validation studies, and discuss remaining roadblocks to clinical implementation, with the goal of facilitating future work in this critical area.
PubMed: 35968272
DOI: 10.3389/fneur.2022.960454 -
Epilepsy Research Nov 2020In the wake of the pandemic COVID-19 and nationwide lockdowns gripping many countries globally, the national healthcare systems are either overwhelmed or preparing to...
In the wake of the pandemic COVID-19 and nationwide lockdowns gripping many countries globally, the national healthcare systems are either overwhelmed or preparing to combat this pandemic. Despite all the containment measures in place, experts opine that this novel coronavirus is here to stay as a pandemic or an endemic. Hence, it is apt to be prepared for the confrontation and its aftermath. From protecting the vulnerable individuals to providing quality care for all health conditions and maintaining essential drug supplies, it is going to be a grueling voyage. Preparedness to sustain optimal care for each health condition is a must. With a higher risk for severe COVID-19 disease in infants, need of high-dose hormonal therapy with a concern of consequent severe disease, presence of comorbidities, and a need for frequent investigations and follow-up; children with West syndrome constitute a distinctive group with special concerns. In this viewpoint, we discuss the important issues and concerns related to the management of West syndrome during COVID-19 pandemic in the South Asian context and provide potential solutions to these concerns based on the current evidence, adeptness, and consensus. Some plausible solutions include the continuation of containment and mitigation measures for COVID-19, therapeutic decision- making for West syndrome based on risk stratification, and tele-epileptology.
Topics: Adrenal Cortex Hormones; Adrenocorticotropic Hormone; Anticonvulsants; Antiviral Agents; Betacoronavirus; COVID-19; Clinical Decision-Making; Coronavirus Infections; Delivery of Health Care; Drug Interactions; Humans; Infant; Pandemics; Pneumonia, Viral; SARS-CoV-2; Spasms, Infantile; Telemedicine; Time-to-Treatment; Vigabatrin
PubMed: 32927329
DOI: 10.1016/j.eplepsyres.2020.106453