Biological Bases of Symptomatic Generalized Epilepsies in Children

2017 ◽  
Author(s):  
Dragos A. Nita ◽  
Miguel A. Cortez ◽  
Jose Luis Perez Velazquez ◽  
O. Carter Snead
Keyword(s):  
Mental Retardation ◽  
Intractable Epilepsy ◽  
Epileptic Encephalopathy ◽  
Global Developmental Delay ◽  
Epilepsy Syndrome ◽  
Mortality And Morbidity ◽  
Age Related ◽  
Ohtahara Syndrome ◽  
Brain Involvement ◽  
Myoclonic Encephalopathy

Symptomatic generalized epilepsies represent a group of challenging epilepsy syndromes, most often seen in children, which share the hallmark of a triad encompassing multiple seizure types, electroencephalographical (EEG) evidence of diffuse brain involvement, and dysfunction in the intellectual domain (global developmental delay or mental retardation). SGEs include the early myoclonic encephalopathy, early infantile epileptic encephalopathy (Ohtahara syndrome), West syndrome, epilepsy with myoclonic-astatic seizures, epilepsy with myoclonic absence, Lennox-Gastaut syndrome, and the progressive myoclonic epilepsies. SGEs may arise from various genetic, developmental, or acquired brain pathologies and also can be associated with other cerebral or systemic defects and thus being part of a broader epilepsy syndrome phenotype. SGEs are associated with significant mortality and morbidity and most patients with SGE grow up to have intractable epilepsy, mental retardation, and depend on parents and institutions for the activities of the daily living. The mechanisms of SGE are numerous and heterogeneous and the EEG findings usually reflect the age-related changes as the brain matures.

scholarly journals Ohtahara syndrome progressing to West syndrome

2021 ◽  
Vol 8 (5) ◽  
pp. 941
Author(s):  
Tapan Patel ◽  
Shivani Patel
Keyword(s):  
Mental Retardation ◽  
Epileptic Encephalopathy ◽  
Infantile Spasms ◽  
West Syndrome ◽  
Epilepsy Syndrome ◽  
Ohtahara Syndrome ◽  
Severe Epilepsy

West syndrome is a severe epilepsy syndrome composed of the triad of infantile spasms, hypsarrhythmia on electroencephalography (EEG) and mental retardation. It is sometimes due to the progression of a rare and fatal condition called early infantile epileptic encephalopathy (Ohtahara syndrome). Here we describe the case of a 3 year old male, who is a known case of West syndrome, presenting with recurrent breakthrough convulsions.

scholarly journals Epileptic Encephalopathies: An Overview

2012 ◽  
Vol 2012 ◽  
pp. 1-8 ◽  
Author(s):  
Sonia Khan ◽  
Raidah Al Baradie
Keyword(s):  
Slow Wave Sleep ◽  
Epileptic Encephalopathy ◽  
Dravet Syndrome ◽  
Management Options ◽  
Epileptic Encephalopathies ◽  
Age Related ◽  
Ohtahara Syndrome ◽  
Cerebral Dysfunction ◽  
Epileptic Syndromes

Epileptic encephalopathies are an epileptic condition characterized by epileptiform abnormalities associated with progressive cerebral dysfunction. In the classification of the International League Against Epilepsy eight age-related epileptic encephalopathy syndromes are recognized. These syndromes include early myoclonic encephalopathy and Ohtahara syndrome in the neonatal period, West syndrome and Dravet syndrome in infancy, myoclonic status in nonprogressive encephalopathies, and Lennox-Gastaut syndrome, Landau-Kleffner syndrome, and epilepsy with continuous spike waves during slow wave sleep in childhood and adolescences. Other epileptic syndromes such as migrating partial seizures in infancy and severe epilepsy with multiple independent spike foci may be reasonably added. In this paper, we provide an overview of epileptic encephalopathies including clinical neurophysiological features, cognitive deterioration, and management options especially that these conditions are generally refractory to standard antiepileptic drugs.

scholarly journals Boricua Founder Variant in FRRS1L Causes Epileptic Encephalopathy With Hyperkinetic Movements

2020 ◽  
Vol 36 (2) ◽  
pp. 93-98
Author(s):  
Imane Abdelmoumen ◽  
Sandra Jimenez ◽  
Ignacio Valencia ◽  
Joseph Melvin ◽  
Agustin Legido ◽  
...  
Keyword(s):  
Movement Disorder ◽  
Puerto Rican ◽  
Cerebellar Atrophy ◽  
Intractable Epilepsy ◽  
Brain Magnetic Resonance Imaging ◽  
Epileptic Encephalopathy ◽  
Pathogenic Variant ◽  
Global Developmental Delay ◽  
Neurodevelopmental Outcomes ◽  
Developmental Regression

Objective: To describe a founder mutation effect and the clinical phenotype of homozygous FRRS1L c.737_739delGAG (p.Gly246del) variant in 15 children of Puerto Rican (Boricua) ancestry presenting with early infantile epileptic encephalopathy (EIEE-37) with prominent movement disorder. Background: EIEE-37 is caused by biallelic loss of function variants in the FRRS1L gene, which is critical for AMPA-receptor function, resulting in intractable epilepsy and dyskinesia. Methods: A retrospective, multicenter chart review of patients sharing the same homozygous FRRS1L (p.Gly246del) pathogenic variant identified by clinical genetic testing. Clinical information was collected regarding neurodevelopmental outcomes, neuroimaging, electrographic features and clinical response to antiseizure medications. Results: Fifteen patients from 12 different families of Puerto Rican ancestry were homozygous for the FRRS1L (p.Gly246del) pathogenic variant, with ages ranging from 1 to 25 years. The onset of seizures was from 6 to 24 months. All had hypotonia, severe global developmental delay, and most had hyperkinetic involuntary movements. Developmental regression during the first year of life was common (86%). Electroencephalogram showed hypsarrhythmia in 66% (10/15), with many older children evolving into Lennox-Gastaut syndrome. Six patients demonstrated progressive volume loss and/or cerebellar atrophy on brain magnetic resonance imaging (MRI). Conclusions: We describe the largest cohort to date of patients with epileptic encephalopathy. We estimate that 0.76% of unaffected individuals of Puerto Rican ancestry carry this pathogenic variant due to a founder effect. Children homozygous for the FRRS1L (p.Gly246del) Boricua variant exhibit a very homogenous phenotype of early developmental regression and epilepsy, starting with infantile spasms and evolving into Lennox-Gastaut syndrome with hyperkinetic movement disorder.

scholarly journals Management of Infantile Spasms: An Updated Review

2020 ◽  
Vol 06 (01) ◽  
pp. 04-14
Author(s):  
Mary Iype ◽  
Kiren George Koshy
Keyword(s):  
Early Recognition ◽  
Intractable Epilepsy ◽  
Epileptic Encephalopathy ◽  
Infantile Spasms ◽  
Response To Treatment ◽  
High Dose ◽  
Ohtahara Syndrome ◽  
Oral Steroids ◽  
Antiepileptic Medications ◽  
Infancy And Early Childhood

AbstractInfantile spasms remain the most challenging of the epileptic encephalopathies of childhood. Infantile spasms are classified as an epileptic encephalopathy, as the adverse cognitive and behavioral burden of the condition is out of proportion to the burden one would expect from the underlying etiology or the accompanying magnetic resonance imaging. The ictal and interictal electroencephalographic (EEG) activity is presumed to contribute to the progressive cerebral dysfunction. In many of these children, the underlying etiology also contributes to the severe mental subnormality and autistic behavior. Though it is the syndromic approach that guides the pediatric epileptologist, it is best to keep in mind that one syndrome may evolve into another in infancy and early childhood. A baby with Ohtahara syndrome may, after 2 to 7 months, begin to have spasms. Lennox-Gastaut syndrome with its typical seizure types and EEG may evolve in a child with infantile spasms.The unique modalities used in the treatment of infantile spasms make early recognition important. It is, however, also of paramount importance to make an etiological diagnosis as the underlying etiology may be eminently treatable. The treating physician cannot abandon them as wholly “intractable” epilepsy. The excellent response to treatment in the few who just cannot be defined or accurately predicted drives the physician to exercise his brain. Use of the two well-accepted modalities of treatment; vigabatrin and adrenocorticotrophic hormone singly or in combination, oral steroids in high dose, ketogenic diet, the conventional antiepileptic medications, and strategies to target the basic cause have been tried out by various clinicians. Here, we have made an attempt to collate evidence and describe the progress in the management of infantile spasms.

scholarly journals Current Pharmacologic Strategies for Treatment of Intractable Epilepsy in Children

2021 ◽  
Vol 25 (Suppl 1) ◽  
pp. S8-18 ◽  
Author(s):  
Ja Un Moon ◽  
Kyung-Ok Cho
Keyword(s):  
Ion Channels ◽  
Molecular Mechanisms ◽  
Intractable Epilepsy ◽  
Epileptic Encephalopathy ◽  
New Drugs ◽  
Dravet Syndrome ◽  
Ohtahara Syndrome ◽  
Voltage Gated Ion Channels ◽  
Related Proteins ◽  
Gated Ion Channels

Epileptic encephalopathy (EE) is a devastating pediatric disease that features medically resistant seizures, which can contribute to global developmental delays. Despite technological advancements in genetics, the neurobiological mechanisms of EEs are not fully understood, leaving few therapeutic options for affected patients. In this review, we introduce the most common EEs in pediatrics (i.e., Ohtahara syndrome, Dravet syndrome, and Lennox-Gastaut syndrome) and their molecular mechanisms that cause excitation/inhibition imbalances. We then discuss some of the essential molecules that are frequently dysregulated in EEs. Specifically, we explore voltage-gated ion channels, synaptic transmission-related proteins, and ligand-gated ion channels in association with the pathophysiology of Ohtahara syndrome, Dravet syndrome, and Lennox-Gastaut syndrome. Finally, we review currently available antiepileptic drugs used to treat seizures in patients with EEs. Since these patients often fail to achieve seizure relief even with the combination therapy, further extensive research efforts to explore the involved molecular mechanisms will be required to develop new drugs for patients with intractable epilepsy.

SLC25A22 and Its Related Epileptic Encephalopathies

2021 ◽  
Author(s):  
Francesca Patanè ◽  
Elisa Pasquetti ◽  
Federica Sullo ◽  
Monica Tosto ◽  
Laura Sciuto ◽  
...  
Keyword(s):  
Epileptic Encephalopathy ◽  
Epileptic Encephalopathies ◽  
Psychomotor Delay ◽  
Brain Functions ◽  
Ohtahara Syndrome ◽  
Inherited Metabolic Disorders ◽  
Solute Carrier ◽  
Disease Modifying Treatment ◽  
Myoclonic Encephalopathy ◽  
Migrating Partial Seizures

AbstractEpileptic encephalopathy is a condition in which seizures, electroencephalographic epileptiform abnormalities lead to a progressive deterioration of brain functions causing a significant psychomotor delay. One of the typical features of this heterogeneous and large group of severe disorders is the extremely early onset of seizures. The main causes of the epileptic encephalopathies include structural brain defects, inherited metabolic disorders; in this aspect, more than 100 genetic defects, including mutations in the solute carrier family 25 (SLC25A22) gene which encodes a mitochondrial glutamate carrier. To date, the main clinical phenotypes related to mutations of this gene are Ohtahara syndrome (or early infantile epileptic encephalopathy), early myoclonic encephalopathy and migrating partial seizures in infancy. In all the cases, prognosis is poor and no disease-modifying treatment is available in the present days.

scholarly journals Genetic Etiologies in Developmental and/or Epileptic Encephalopathy With Electrical Status Epilepticus During Sleep: Cohort Study

2021 ◽  
Vol 12 ◽  
Author(s):  
Pan Gong ◽  
Jiao Xue ◽  
Xianru Jiao ◽  
Yuehua Zhang ◽  
Zhixian Yang
Keyword(s):  
Cohort Study ◽  
Status Epilepticus ◽  
Genetic Disorders ◽  
Epileptic Encephalopathy ◽  
Related Factors ◽  
Pathogenic Variants ◽  
Age Related ◽  
Ohtahara Syndrome ◽  
Related Feature ◽  
The Mean

BackgroundRecently, the electroencephalogram pattern of electrical status epilepticus during sleep (ESES) had been reported in some genetic disorders, and most of them were noted with developmental and epileptic encephalopathy (DEE) or epileptic encephalopathy (EE). This study aimed to determine the genetic etiologies and clinical characteristics of ESES in DEE/EE.MethodsWe performed a cohort study in cases of DEE or EE with ESES. Tio-based genetic testing was performed in 74 cases and was analyzed to identify underlying variants.ResultsPathogenic or likely pathogenic variants were identified in 17/74 cases, including KCNQ2 (n = 6), KCNA2 (n = 5), GRIN2A (n = 3), SLC9A6 (n = 1), HIVEP2 (n = 1), and RARS2 (n = 1). Eleven were boys. The median age at seizure onset was 6 months. ESES occurred at the mean age of 2.0 ± 1.2 years, predominant in the Rolandic region in 14 years. Twelve of 17 cases had the first stage of different epilepsy preceding ESES: 2/12 were diagnosed as Ohtahara syndrome, 2/12 were diagnosed as infantile spasms, 3/12 were diagnosed as DEE, and 5/12 were diagnosed as EE without the epileptic syndrome.ConclusionMonogenic variants explained over 20% of DEE/EE with ESES. ESES could be an age-related feature in genetic disorders and occurred after the first stage of different epilepsy. Both age-related factors and genetic etiology were suggested to play a role in the occurrence of ESES in genetic DEE/EE.

scholarly journals Neonatal neuronal WWOX gene therapy rescues Wwox null phenotypes

2021 ◽  
Author(s):  
Srinivasarao Repudi ◽  
Irina Kustanovich ◽  
Sara Abu-Swai ◽  
Shani Stern ◽  
Rami I. Aqeilan
Keyword(s):  
Gene Therapy ◽  
Autosomal Recessive ◽  
Viral Vector ◽  
Intractable Epilepsy ◽  
Epileptic Encephalopathy ◽  
Global Developmental Delay ◽  
The Central Nervous System ◽  
Biallelic Mutations ◽  
Brain Hyperexcitability ◽  
Wwox Gene

AbstractWW domain-containing oxidoreductase (WWOX) is an emerging neural gene regulating homeostasis of the central nervous system. Germline biallelic mutations in WWOX cause WWOX-related epileptic encephalopathy (WOREE) syndrome and spinocerebellar ataxia, and autosomal recessive 12 (SCAR12), two devastating neurodevelopmental disorders with highly heterogenous clinical outcomes, the most common being severe epileptic encephalopathy and profound global developmental delay. We recently demonstrated that neuronal ablation of murine Wwox recapitulates phenotypes of Wwox-null mice leading to intractable epilepsy, hypomyelination and postnatal lethality. Here, we designed and produced an adeno-associated viral vector harboring murine Wwox or human WWOX cDNA and driven by the human neuronal Synapsin I promoter (AAV-SynI-WWOX). Testing the efficacy of AAV-SynI-WWOX delivery in Wwox null mice demonstrated that specific neuronal restoration of WWOX expression rescued brain hyperexcitability and seizures, hypoglycemia, and myelination deficits as well as the premature lethality of Wwox-null mice. These findings provide a proof-of-concept for WWOX gene therapy as a promising approach to curing children with WOREE and SCAR12.

scholarly journals How to Help Your Patients Enroll in the New-Onset Refractory Status Epilepticus (NORSE) and Febrile Infection-Related Epilepsy Syndrome (FIRES) Family Registry, and Other Rare Epilepsy Registries

2021 ◽  
pp. 153575972199832
Author(s):  
Karnig Kazazian ◽  
Marissa Kellogg ◽  
Nora Wong ◽  
Krista Eschbach ◽  
Raquel Farias Moeller ◽  
...  
Keyword(s):  
Status Epilepticus ◽  
Refractory Status Epilepticus ◽  
Epilepsy Syndrome ◽  
Neurologic Disorder ◽  
Mortality And Morbidity ◽  
Refractory Status ◽  
Rigorous Research ◽  
Active Epilepsy ◽  
New Onset

New-onset refractory status epilepticus (NORSE) is a rare clinical presentation of refractory status epilepticus (RSE) that occurs in people without active epilepsy or preexisting neurologic disorder. Febrile infection-related epilepsy syndrome (FIRES) is a subcategory of NORSE. New-onset refractory status epilepticus/FIRES are becoming increasingly recognized; however, information pertaining to disease course, clinical outcomes, and survivorship remains limited, and mortality and morbidity are variable, but often high. The objective of the NORSE/FIRES Family Registry is to (1) provide an easily accessible and internationally available multilingual registry into which survivors or NORSE/FIRES surrogates or family members of people affected by NORSE/FIRES or their physicians can enter data in a systematic and rigorous research study from anywhere in the world where internet is available; and (2) to examine past medical history, outcomes, and quality of life for people affected by NORSE/FIRES.

scholarly journals Towards a Treatment for Neuroinflammation in Epilepsy: Interleukin-1 Receptor Antagonist, Anakinra, as a Potential Treatment in Intractable Epilepsy

2021 ◽  
Vol 22 (12) ◽  
pp. 6282
Author(s):  
Gaku Yamanaka ◽  
Yu Ishida ◽  
Kanako Kanou ◽  
Shinji Suzuki ◽  
Yusuke Watanabe ◽  
...  
Keyword(s):  
Receptor Antagonist ◽  
Small Sample Size ◽  
Interleukin 1 ◽  
Intractable Epilepsy ◽  
Evidence Base ◽  
Small Sample ◽  
Epilepsy Syndrome ◽  
Interleukin 1 Receptor Antagonist ◽  
Epileptic Syndromes ◽  
Systemic Symptoms

Febrile Infection-Related Epilepsy Syndrome (FIRES) is a unique catastrophic epilepsy syndrome, and the development of drug-resistant epilepsy (DRE) is inevitable. Recently, anakinra, an interleukin-1 receptor antagonist (IL-1RA), has been increasingly used to treat DRE due to its potent anticonvulsant activity. We here summarized its effects in 38 patients (32 patients with FIRES and six with DRE). Of the 22 patients with FIRES, 16 (73%) had at least short-term seizure control 1 week after starting anakinra, while the remaining six suspected anakinra-refractory cases were male and had poor prognoses. Due to the small sample size, an explanation for anakinra refractoriness was not evident. In all DRE patients, seizures disappeared or improved, and cognitive function improved in five of the six patients following treatment. Patients showed no serious side effects, although drug reactions with eosinophilia and systemic symptoms, cytopenia, and infections were observed. Thus, anakinra has led to a marked improvement in some cases, and functional deficiency of IL-1RA was indicated, supporting a direct mechanism for its therapeutic effect. This review first discusses the effectiveness of anakinra for intractable epileptic syndromes. Anakinra could become a new tool for intractable epilepsy treatment. However, it does not currently have a solid evidence base.

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