The severe epilepsy syndromes of infancy: A population‐based study

Abstract

Objective To study the epilepsy syndromes among the severe epilepsies of infancy and assess their incidence, etiologies, and outcomes. Methods A population‐based cohort study was undertaken of severe epilepsies with onset before age 18 months in Victoria, Australia. Two epileptologists reviewed clinical features, seizure videos, and electroencephalograms to diagnose International League Against Epilepsy epilepsy syndromes. Incidence, etiologies, and outcomes at age 2 years were determined. Results Seventy‐three of 114 (64%) infants fulfilled diagnostic criteria for epilepsy syndromes at presentation, and 16 (14%) had "variants" of epilepsy syndromes in which there was one missing or different feature, or where all classical features had not yet emerged. West syndrome (WS) and "WS‐like" epilepsy (infantile spasms without hypsarrhythmia or modified hypsarrhythmia) were the most common syndromes, with a combined incidence of 32.7/100 000 live births/year. The incidence of epilepsy of infancy with migrating focal seizures (EIMFS) was 4.5/100 000 and of early infantile epileptic encephalopathy (EIEE) was 3.6/100 000. Structural etiologies were common in "WS‐like" epilepsy (100%), unifocal epilepsy (83%), and WS (39%), whereas single gene disorders predominated in EIMFS, EIEE, and Dravet syndrome. Eighteen (16%) infants died before age 2 years. Development was delayed or borderline in 85 of 96 (89%) survivors, being severe–profound in 40 of 96 (42%). All infants with EIEE or EIMFS had severe–profound delay or were deceased, but only 19 of 64 (30%) infants with WS, "WS‐like," or "unifocal epilepsy" had severe–profound delay, and only two of 64 (3%) were deceased. Significance Three quarters of severe epilepsies of infancy could be assigned an epilepsy syndrome or "variant syndrome" at presentation. In this era of genomic testing and advanced brain imaging, diagnosing epilepsy syndromes at presentation remains clinically useful for guiding etiologic investigation, initial treatment, and prognostication.

Modeling genetic epileptic encephalopathies using brain organoids

“…DEEs are a group of severe neurological syndromes whose underlying molecular pathology is unknown (Howell et al , 2021 ). Together with the lack of accessibility of human samples, it is not surprising that the current medical treatment is lacking.…”

“…Epilepsy affects around 50 million people worldwide and is considered the most frequent chronic neurological condition in children (Aaberg et al , 2017 ; Blumcke et al , 2017 ). Approximately 40% of seizures in the early years of life are accounted for by developmental and epileptic encephalopathy (DEE), previously known as early infantile epileptic encephalopathies (EIEEs) (Howell et al , 2021 ). These are pathologies of the developing brain, characterized by intractable epileptiform activity and impaired cerebral and cognitive functions (Lado et al , 2013 ; Shao & Stafstrom, 2016 ; Nashabat et al , 2019 ; Howell et al , 2021 ).…”

“…Approximately 40% of seizures in the early years of life are accounted for by developmental and epileptic encephalopathy (DEE), previously known as early infantile epileptic encephalopathies (EIEEs) (Howell et al , 2021 ). These are pathologies of the developing brain, characterized by intractable epileptiform activity and impaired cerebral and cognitive functions (Lado et al , 2013 ; Shao & Stafstrom, 2016 ; Nashabat et al , 2019 ; Howell et al , 2021 ). Several genes have been implicated in causing DEEs (McTague et al , 2016 ).…”

Epilepsy Syndromes in the First Year of Life and Usefulness of Genetic Testing for Precision Therapy

“…Next-generation sequencing has led to an explosion of gene discoveries in human disorders and up to 50% of monogenic epilepsies reach a precision diagnosis [ 2 ]. The highest diagnostic yield is usually amongst subjects with early-onset seizures and a global neurodevelopmental delay [ 3 , 4 ]. New techniques that enable investigation of the epigenetic regulation and longer read lengths [ 2 ] combined with functional testing of variants of unknown significance, even in known genes, and systematic match-making exchange [ 5 ] are needed to facilitate a genetic diagnosis for the remaining half.…”

Antiepileptogenic effects of rapamycin in a model of infantile spasms due to structural lesions

“…Infantile spasms (IS) are age‐specific seizures characterized by clusters of axial epileptic flexion and extension spasms in infancy 1–7 . In ~24% there is a genetic or genetic‐structural etiology, whereas in ~33% the cause is unknown 7–11 . In ~60% of affected infants, IS are associated with pre‐existing structural or metabolic brain pathologies, and have worse prognosis than IS of unknown etiology, including persistence of intellectual and other neurological deficits as well as epilepsies that are often drug‐resistant 4,5,7,12 .…”