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Neurotherapeutics : the Journal of the... Oct 2014Epileptic encephalopathies represent a group of devastating epileptic disorders that occur early in life and are often characterized by pharmaco-resistant epilepsy,... (Review)
Review
Epileptic encephalopathies represent a group of devastating epileptic disorders that occur early in life and are often characterized by pharmaco-resistant epilepsy, persistent severe electroencephalographic abnormalities, and cognitive dysfunction or decline. Next generation sequencing technologies have increased the speed of gene discovery tremendously. Whereas ion channel genes were long considered to be the only significant group of genes implicated in the genetic epilepsies, a growing number of non-ion-channel genes are now being identified. As a subgroup of the genetically mediated epilepsies, epileptic encephalopathies are complex and heterogeneous disorders, making diagnosis and treatment decisions difficult. Recent exome sequencing data suggest that mutations causing epileptic encephalopathies are often sporadic, typically resulting from de novo dominant mutations in a single autosomal gene, although inherited autosomal recessive and X-linked forms also exist. In this review we provide a summary of the key features of several early- and mid-childhood onset epileptic encephalopathies including Ohtahara syndrome, Dravet syndrome, Infantile spasms and Lennox Gastaut syndrome. We review the recent next generation sequencing findings that may impact treatment choices. We also describe the use of conventional and newer anti-epileptic and hormonal medications in the various syndromes based on their genetic profile. At a biological level, developments in cellular reprogramming and genome editing represent a new direction in modeling these pediatric epilepsies and could be used in the development of novel and repurposed therapies.
Topics: Brain; Epilepsies, Myoclonic; Epilepsy; Humans; Infant; Infant, Newborn; Landau-Kleffner Syndrome; Lennox Gastaut Syndrome; Sequence Analysis, DNA; Spasms, Infantile
PubMed: 25266964
DOI: 10.1007/s13311-014-0301-2 -
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 -
Pharmacology & Therapeutics Aug 2020Infantile spasms (IS or epileptic spasms during infancy) were first described by Dr. William James West (aka West syndrome) in his own son in 1841. While rare by... (Review)
Review
Infantile spasms (IS or epileptic spasms during infancy) were first described by Dr. William James West (aka West syndrome) in his own son in 1841. While rare by definition (occurring in 1 per 3200-3400 live births), IS represent a major social and treatment burden. The etiology of IS varies - there are many (>200) different known pathologies resulting in IS and still in about one third of cases there is no obvious reason. With the advancement of genetic analysis, role of certain genes (such as ARX or CDKL5 and others) in IS appears to be important. Current treatment strategies with incomplete efficacy and serious potential adverse effects include adrenocorticotropin (ACTH), corticosteroids (prednisone, prednisolone) and vigabatrin, more recently also a combination of hormones and vigabatrin. Second line treatments include pyridoxine (vitamin B6) and ketogenic diet. Additional treatment approaches use rapamycin, cannabidiol, valproic acid and other anti-seizure medications. Efficacy of these second line medications is variable but usually inferior to hormonal treatments and vigabatrin. Thus, new and effective models of this devastating condition are required for the search of additional treatment options as well as for better understanding the mechanisms of IS. Currently, eight models of IS are reviewed along with the ideas and mechanisms behind these models, drugs tested using the models and their efficacy and usefulness. Etiological variety of IS is somewhat reflected in the variety of the models. However, it seems that for finding precise personalized approaches, this variety is necessary as there is no "one-size-fits-all" approach possible for both IS in particular and epilepsy in general.
Topics: Adrenal Cortex Hormones; Adrenocorticotropic Hormone; Animals; Diet, Ketogenic; Disease Models, Animal; Drug Therapy, Combination; Humans; Infant; Spasms, Infantile
PubMed: 32417271
DOI: 10.1016/j.pharmthera.2020.107578 -
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 -
Epilepsia Jul 2022To determine the structural networks that constrain propagation of ictal oscillations during epileptic spasm events, and compare the observed propagation patterns across...
OBJECTIVE
To determine the structural networks that constrain propagation of ictal oscillations during epileptic spasm events, and compare the observed propagation patterns across patients with successful or unsuccessful surgical outcomes.
METHODS
Subdural electrode recordings of 18 young patients (age 1-11 years) were analyzed during epileptic spasm events to determine ictal networks and quantify the amplitude and onset time of ictal oscillations across the cortical surface. Corresponding structural networks were generated with diffusion magnetic resonance imaging (MRI) tractography by seeding the cortical region associated with the earliest average oscillation onset time, and white matter pathways connecting active electrode regions within the ictal network were isolated. Properties of this structural network were used to predict oscillation onset times and amplitudes, and this relationship was compared across patients who did and did not achieve seizure freedom following resective surgery.
RESULTS
Onset propagation patterns were relatively consistent across each patient's spasm events. An electrode's average ictal oscillation onset latency was most significantly associated with the length of direct corticocortical tracts connecting to the area with the earliest average oscillation onset (p < .001, model R = .54). Moreover, patients demonstrating a faster propagation of ictal oscillation signals within the corticocortical network were more likely to have seizure recurrence following resective surgery (p = .039). In addition, ictal oscillation amplitude was associated with connecting tractography length and weighted fractional anisotropy (FA) measures along these pathways (p = .002/.030, model R = .31/.25). Characteristics of analogous corticothalamic pathways did not show significant associations with ictal oscillation onset latency or amplitude.
SIGNIFICANCE
Spatiotemporal propagation patterns of high-frequency activity in epileptic spasms align with length and FA measures from onset-originating corticocortical pathways. Considering the data in this individualized framework may help inform surgical decision-making and expectations of surgical outcomes.
Topics: Child; Child, Preschool; Diffusion Tensor Imaging; Electroencephalography; Humans; Infant; Seizures; Spasm; Spasms, Infantile
PubMed: 35388455
DOI: 10.1111/epi.17251 -
BMC Pediatrics Jul 2012Infantile spasms (IS; West syndrome) is a severe form of encephalopathy that typically affects infants younger than 2 years old. Pediatricians, pediatric neurologists,... (Review)
Review
BACKGROUND
Infantile spasms (IS; West syndrome) is a severe form of encephalopathy that typically affects infants younger than 2 years old. Pediatricians, pediatric neurologists, and other pediatric health care providers are all potentially key early contacts for families who have an infant with IS. The objective of this article is to assist pediatric health care providers in the detection of the disease and in the counseling and guidance of families who have an infant with IS.
METHODS
Treatment guidelines, consensus reports, and original research studies are reviewed to provide an update regarding the diagnosis and treatment of infants with IS. Web sites were searched for educational and supportive resource content relevant to providers and families of patients with IS.
RESULTS
Early detection of IS and pediatrician referral to a pediatric neurologist for further evaluation and initiation of treatment may improve prognosis. Family education and the establishment of a multidisciplinary continuum of care are important components of care for the majority of patients with IS. The focus of the continuum of care varies across diagnosis, initiation of treatment, and short- and long-term needs. Several on-line educational and supportive resources for families and caregivers of patients with IS were identified.
CONCLUSIONS
Given the possibility of poor developmental outcomes in IS, including the emergence of other seizure disorders and cognitive and developmental problems, early recognition, referral, and treatment of IS are important for optimal patient outcomes. Dissemination of and access to educational and supportive resources for families and caregivers across the lifespan of the child with IS is an urgent need. Pediatric health care providers are well positioned to address these needs.
Topics: Adrenocorticotropic Hormone; Anticonvulsants; Continuity of Patient Care; Directive Counseling; Humans; Infant; Infant, Newborn; Parents; Patient Education as Topic; Pediatrics; Spasms, Infantile; Vigabatrin
PubMed: 22830456
DOI: 10.1186/1471-2431-12-108 -
Epilepsia Open Dec 2023Literature on the genotypic spectrum of Infantile Epileptic Spasms Syndrome (IESS) in children is scarce in developing countries. This multicentre collaboration...
OBJECTIVE
Literature on the genotypic spectrum of Infantile Epileptic Spasms Syndrome (IESS) in children is scarce in developing countries. This multicentre collaboration evaluated the genotypic and phenotypic landscape of genetic IESS in Indian children.
METHODS
Between January 2021 and June 2022, this cross-sectional study was conducted at six centers in India. Children with genetically confirmed IESS, without definite structural-genetic and structural-metabolic etiology, were recruited and underwent detailed in-person assessment for phenotypic characterization. The multicentric data on the genotypic and phenotypic characteristics of genetic IESS were collated and analyzed.
RESULTS
Of 124 probands (60% boys, history of consanguinity in 15%) with genetic IESS, 105 had single gene disorders (104 nuclear and one mitochondrial), including one with concurrent triple repeat disorder (fragile X syndrome), and 19 had chromosomal disorders. Of 105 single gene disorders, 51 individual genes (92 variants including 25 novel) were identified. Nearly 85% of children with monogenic nuclear disorders had autosomal inheritance (dominant-55.2%, recessive-14.2%), while the rest had X-linked inheritance. Underlying chromosomal disorders included trisomy 21 (n = 14), Xq28 duplication (n = 2), and others (n = 3). Trisomy 21 (n = 14), ALDH7A1 (n = 10), SCN2A (n = 7), CDKL5 (n = 6), ALG13 (n = 5), KCNQ2 (n = 4), STXBP1 (n = 4), SCN1A (n = 4), NTRK2 (n = 4), and WWOX (n = 4) were the dominant single gene causes of genetic IESS. The median age at the onset of epileptic spasms (ES) and establishment of genetic diagnosis was 5 and 12 months, respectively. Pre-existing developmental delay (94.3%), early age at onset of ES (<6 months; 86.2%), central hypotonia (81.4%), facial dysmorphism (70.1%), microcephaly (77.4%), movement disorders (45.9%) and autistic features (42.7%) were remarkable clinical findings. Seizures other than epileptic spasms were observed in 83 children (66.9%). Pre-existing epilepsy syndrome was identified in 21 (16.9%). Nearly 60% had an initial response to hormonal therapy.
SIGNIFICANCE
Our study highlights a heterogenous genetic landscape and phenotypic pleiotropy in children with genetic IESS.
Topics: Male; Humans; Child; Infant; Female; Down Syndrome; Cross-Sectional Studies; Spasms, Infantile; Seizures; Spasm; N-Acetylglucosaminyltransferases
PubMed: 37583270
DOI: 10.1002/epi4.12811 -
Boletin Medico Del Hospital Infantil de... 2023CDKL5 deficiency syndrome is caused by pathogenic variants in the CDKL5 gene, with a variable clinical spectrum ranging from patients with characteristics of autism...
BACKGROUND
CDKL5 deficiency syndrome is caused by pathogenic variants in the CDKL5 gene, with a variable clinical spectrum ranging from patients with characteristics of autism spectrum disorder to early-onset epilepsy refractory to treatment. Initially, until the gene was discovered, it was considered an atypical form of Rett syndrome. This study aimed to describe the clinical and molecular heterogeneity in CDLK5 disorders among three female patients with CDKL5 pathogenic variants.
CASE REPORTS
We reported three unrelated Mexican female patients evaluated for global developmental delay and epilepsy. All three cases were hemizygotes to a CDKL5 pathogenic variant. In one patient, we performed a 306 gene panel associated with epilepsy. In the other two cases, a human genomic microarray was performed. We describe their clinical features electroencephalogram and brain magnetic resonance evaluations.
CONCLUSIONS
CDKL5 deficiency syndrome represents a challenge for clinicians since the clinical manifestations, electroencephalographic and neuroimaging studies can be non-specific. This syndrome should be suspected in the presence of global developmental delay, autistic behavioral phenotype and epilepsy, associated or not with dysmorphia. Given the similarity between various epileptic encephalopathies, multigene panels including sequencing and duplication/deletion analysis should be requested in which this gene and its possible differential diagnoses are considered, without forgetting the usefulness of genomic techniques in unclear cases.
Topics: Humans; Female; Autism Spectrum Disorder; Spasms, Infantile; Epilepsy; Rett Syndrome
PubMed: 37490689
DOI: 10.24875/BMHIM.22000100 -
Seizure Oct 2022Infantile epileptic spasms syndrome (IESS) is the most common type of severe epilepsy in infants. However, etiological frequency and optimized therapy, particularly...
BACKGROUND
Infantile epileptic spasms syndrome (IESS) is the most common type of severe epilepsy in infants. However, etiological frequency and optimized therapy, particularly corticosteroid regimen and dose, remain unknown.
METHODS
An ambispective study of an IESS-diagnosed cohort was conducted. Etiologies were evaluated based on the 2017 International League Against Epilepsy classification system. Patients received intravenous dexamethasone or methylprednisolone for 3-5 consecutive days, followed by usual-dose (2 mg/kg/d) oral prednisone for 60-90 days with tapering doses for 1-2 months or high-dose (4 mg/kg/d) oral prednisone for 9-11 days with tapering doses for 2-4 weeks. Treatment responses were compared between the usual and high-dose prednisone groups after propensity score matching. Correlation analysis between treatment responses and underlying etiology was performed.
RESULTS
Of the 441 included participants, 218 (49.4%) cases had proven etiologies. The most common etiology of IESS was acquired-structural (23.6%), followed by genetic (15.4%) and congenital-structural (7.0%). Hypoxic-ischemic encephalopathy (55, 52.8%) was the most common acquired-structural etiology. Among the 242 patients administered corticosteroids, 95 received usual-dose oral prednisone and 147 received high-dose oral prednisone. After propensity score matching, 54 patients were included in the usual-dose and high-dose groups, respectively, and treatment effectiveness was compared. There were no significant differences in seizure freedom at days 13-14 (55.6% vs. 51.9%, p = 0.700) and continued seizure freedom between days 14-42 (29.6% vs. 38.9%, p = 0.311) post corticosteroid administration between the usual- and high-dose prednisone groups. The proportion of children achieving seizure cessation at days 13-14 (χ = 1.470, p = 0.698) and days 14-42 (χ = 0.928, p = 0.836) was similar in the different etiological subgroups. Unknown etiological group showed significantly higher resolution of hypsarrhythmia than other etiological groups (χ = 10.761, p = 0.009). Both usual-dose and high-dose group showed tolerance to full-dose corticosteroids and similar adverse events over the observation period.
CONCLUSION
IESS etiology was primarily related to structural causes. Clinical response in short-term follow-up was independent of prednisone dosage and underlying etiology. Better EEG responses may occur in patients with unknown etiology.
Topics: Adrenal Cortex Hormones; Child; Cohort Studies; Dexamethasone; Humans; Infant; Methylprednisolone; Prednisone; Spasm; Spasms, Infantile; Treatment Outcome
PubMed: 35952490
DOI: 10.1016/j.seizure.2022.07.019 -
Neuropediatrics Dec 2020Over the last several decades, significant progress has been made in the discovery of appropriate therapy in the management of infantile spasms (IS). Based on several... (Review)
Review
Over the last several decades, significant progress has been made in the discovery of appropriate therapy in the management of infantile spasms (IS). Based on several well-controlled studies, the American Academy of Neurology and the Child Neurology Society have published the current best practice parameters for the treatment of IS. However, dissemination and implementation of evidence-based guidelines remain a significant challenge. Though the number of well-performed controlled trials and systematic reviews is increasing exponentially, the proportion of valuable new information subsequently embedding into the routine clinical care is significantly lower. Planned and systematic implementation of evidence-based interventions in a given health care structure may outstrip the benefits of discovering a new insight, procedure, or drug in another controlled setting. Implementation problems can be broad-ranging to hinder effective, efficient, safe, timely, and patient-centered care without significant variation. The first part of this review article provides a detailed summary of some crucial comparative treatment studies of IS available in the literature. In the second part, practical challenges to mitigate the gap between knowledge and practice to improve outcomes in the management of IS has been explored, and a consolidated framework approach for systematic implementation research methodology has been discussed to implement evidence-based guidelines for the management of IS. Although large multicenter controlled studies will help gather quality evidence in the treatment of IS, a more comprehensive range of scientific methodologies, including qualitative research and mixed research methodologies, will hold the more considerable promise for implementing evidence-based practices in the health care system.
Topics: Clinical Trials as Topic; Disease Management; Humans; Implementation Science; Infant; Infant, Newborn; Spasms, Infantile
PubMed: 33049784
DOI: 10.1055/s-0040-1716901