Epilepsy syndromes
An epilepsy syndrome is defined as "a characteristic cluster of clinical and EEG features, often supported by specific etiological findings (structural, genetic, metabolic, immune, and infectious)."[1]
Syndromes are characterized by certain
Not everyone with epilepsy can be defined as having an epilepsy syndrome.[1] Epilepsy syndromes are most commonly found in children with epilepsy onset before 3 years of age and are less common in adult-onset epilepsy.[2]
This article reflects the 2017 ILAE Classification of the Epilepsies, and its more detailed follow-up papers, produced for the International League Against Epilepsy by a number of specialist clinicians.[3] Some syndromes in earlier classifications have been renamed or redefined, but these are retained at the end of the article for convenience.
Classification of epilepsy syndromes
Epilepsy syndromes are now classified based on the type of epilepsy as well as by the age at onset.[1]
Type of epilepsy
Syndromes are characterized into 4 groups based on epilepsy type:[1]
- a. Generalized onset epilepsy syndromes. These epilepsy syndromes have only generalized-onset seizures and include both the idiopathic generalized epilepsies (specifically childhood absence epilepsy, juvenile absence epilepsy, juvenile myoclonic epilepsy and epilepsy with generalized tonic- clonic seizures alone), as well as other genetic generalized epilepsies.[4]
- b. Focal onset epilepsy syndromes. These epilepsy syndromes have only focal onset seizures and include both the self-limited focal epilepsies in infants and children as well as other focal epilepsy syndromes.
- c. Generalized and focal onset epilepsy syndromes. These syndromes have seizures which can be both of generalized or focal onset.
- d. Developmental and epileptic encephalopathies (DEEs) or syndromes with progressive neurological deterioration.[1] Developmental and epileptic encephalopathies are disorders that typically onset early in life and are associated with developmental impairment that is due to both the underlying cause of the epilepsy (developmental encephalopathy) as well as frequent seizures and/or epileptiform discharges on EEG (epileptic encephalopathy). Epilepsy syndromes associated with cognitive impairment or other neurological regression that begin after a period of prolonged normal development are termed syndromes with progressive neurological deterioration. Both the DEEs and syndromes with progressive neurological deterioration are amongst the most severe types of epilepsy, with frequent seizures and high rates of drug resistance.
Age at onset
Epilepsy syndromes are also classified based on age at onset when the syndrome first appears, syndromes with onset in neonates and infancy, beginning prior to 2 years of age[5], syndromes with onset in childhood,[6] and syndromes that begin at a variable age. This group includes syndromes that can begin either in childhood or adulthood.[7]
Epilepsy syndromes with onset in neonates and infants
Epilepsy syndromes are identified in over half of children with epilepsy onset before 2 years of age.
Self-limited neonatal, infantile or neonatal-infantile epilepsy
As their names suggest, these epilepsies begin at specific ages in otherwise healthy babies and are caused by changes (variants) in specific genes. In some cases, the genetic changes are passed on from parent to child, and thus the syndromes are said to be familial. In other cases, the genetic change occurs de novo in the baby and there is no family history of other persons with early life seizures. De novo means that the child is affected but neither parent has the genetic variant. De novo variants typically may occur in the egg or sperm, or in early embryonic life.[5]
Seizures are focal in onset but less commonly may progress to involve both sides of the body (focal to bilateral convulsive seizure. The babies have a normal examination and attain normal developmental milestones. The MRI, interictal EEG (between seizures) and bloodwork is normal however genetic testing often shows a causal genetic variant (most commonly KCNQ2 or KCNQ3 in self-limited neonatal epilepsy, PRRT2 or less commonly SCN2A or SCN8A in self-limited infantile epilepsy and SCN2A or KCNQ2 in self-limited neonatal-infantile epilepsy. These epilepsies are generally outgrown by the early preschool years and antiseizure medication is not needed after that time.[5]
Infantile epileptic spasms syndrome
Infantile epileptic spasms syndrome is the most common DEE that begins in early life. Infants present with a characteristic seizure type called infantile spasms (repetitive spells of body crunching, each spell lasting less than 2-3 seconds, but which occur in brief clusters). The EEG is always severely abnormal and often shows a pattern called hysarrhythmia. Many children will have a preceding history of developmental delay and neurological concerns however this syndrome can also affect previously healthy babies. Typically if the seizures are not controlled quickly, infants may have plateauing or even regression of their development. An underlying cause can be found in most babies with infantile epileptic spasms syndrome. In many cases, the
Infantile spasms are treated with specific types of medication, most commonly either oral steroid, ACTH or vigabatrin. The long-term outcome is often worrisome. While infantile spasms often stop with medication, many babies will develop other seizure types over time and most will be left with intellectual disability. The outcome is best predicted by the underlying cause of the spasms and whether the infant's development before onset of spasms. Rapid treatment with effective medication has also been shown to improve longterm developmental outcome.[5]
Dravet syndrome
Dravet syndrome is a DEE beginning in infancy and characterized by severe epilepsy that does not respond well to treatment. This syndrome was described in 1978 by
Seizures persist despite treatment with medication, however several medications including
Epilepsy syndromes with onset in childhood
Epilepsy syndromes can be identified in up to one third of children with epilepsy. Syndromes with onset at this age are divided into the self-limited focal epilepsies, the genetic generalized epilepsies (including childhood absence epilepsy) and the developmental and epileptic encephalopathies.[6]
A. Self-limited focal epilepsies (SeLFEs)
SeLFEs account for approximately one quarter of epilepsies that begin in childhood (Specchio et al. Epilepsia 2022;63:1398-1442). They occur in otherwise healthy children with normal development and are not correlated with any brain abnormality on MRI. In most cases, children outgrow this epilepsy type by adolescence and do not need long-term antiseizure medication. These epilepsy syndromes are associated with characteristic seizures and EEG findings, specific for each syndrome.[6]
i. Self-limited epilepsy with centrotemporal spikes (SeLECTS) SeLECTS, (previously known as benign epilepsy of childhood with centrotemporal spikes or benign Rolandic epilepsy) is a focal epilepsy of unknown cause that most commonly occurs in early to mid school-aged children. Apart from their seizure disorder, these patients are otherwise normal. Seizures usually involve facial muscles and frequently cause drooling and difficulty with speech, although the child is aware throughout the seizure. Although most episodes are brief, seizures that occur in sleep may spread to both sides of the body with convulsive activity. Seizures are typically associated with sleep, most commonly being seen shortly after falling asleep or just before waking. The EEG shows epileptic discharges that occur over the centrotemporal region and are most frequent during drowsiness or light sleep. Seizures are outgrown by puberty.[13] Seizures may require antiseizure medication treatment, but sometimes are infrequent enough to allow physicians to defer treatment.[6]
ii. Self-limitied epilepsy with autonomic seizures (SeLEAS) SeLEAS (formerly known as benign occipital epilepsy of childhood or Panayiotopoulos syndrome) is a focal epilepsy of unknown cause that most commonly presents in the preschool years. Seizures are typically infrequent although can be prolonged.Seizures typically have a prominent autonomic component, most commonly retching but also including pallor, nausea, abdominal pain or even syncope.Seizures may evolve with head and eye deviation to one side, followed by focal or bilateral convulsive activity. Children often have retained awareness early on, but as the seizure evolves, awareness is often impaired. The EEG shows a normal background with epileptiform discharges that are maximal over the posterior head region and typically occur in sleep. As seizures are not frequent, daily antiseizure medication is not needed in many cases. In most cases, this epilepsy type is outgrown within a few years after onset, and longterm antiseizure medication is not required.[6]
B. Genetic Generalized Epilepsy
Childhood absence epilepsy (CAE) is an idiopathic generalized epilepsy that presents in early to mid childhood (age 3-12 years) with typical absence seizures, characterized by abrupt loss of responsiveness, staring, sometimes with subtle motor features such as eye blinking or chewing. Seizures are brief, typically lasting 20 seconds or less, but occur very frequently (up to 20-50 times per day in the untreated child). The EEG shows generalized 3 Hz spike and wave discharges. In most cases, absence seizures are the only seizure type, however a minority will develop generalized tonic-clonic seizures, most commonly in adolescence. Children with CAE do not show cognitive decline or neurological deficits, however have higher rates of learning disorders and ADHD. Children require antiseizures medication, about 60% will outgrow CAE typically within a few years after onset.[4]
C. Developmental and Epileptic Encephalopathies
i.
The most characteristic seizure type is a tonic seizure, which consists of brief generalized body stiffening, and often occurs most prominently in sleep. Additionally, patients often have other seizures types including atonic (abrupt, brief events of loss of tone, often leading to falls), atypical absences (staring spells with more gradual onset and offset), myoclonic jerks, generalized tonic-clonic and/or focal seizures. While many antiseizure medications can reduce seizure burden, patients do not achieve seizure freedom. Epilepsy is very drug resistant and life long. Intellectual disability typically worsens with age, and autism, behavior problems, sleep problems, higher rates of SUDEP and other medical comorbidities are common.
ii. Epilepsy with myoclonic-atonic seizures (EMAtS) (formerly known as Myoclonic-Atonic Epilepsy or Doose syndrome) presents in developmentally normal, mid preschool to early school-aged children. The initial presentation is often with a febrile or afebrile generalized tonic-clonic seizure, however shortly thereafter, different seizure types also evolve and seizures become much more frequent. The most characteristic seizure is a myoclonic-atonic seizure, where the child will briefly jerk, often with a vocalization and then lose tone. Other seizure types which commonly co-exist include atypical absences and myoclonic seizures. Tonic seizures are rare early in the course but may present later on. Many children will go through a period of very frequent seizures with developmental stagnation or regression, known as a “stormy course”. The EEG usually shows 3-6 Hz generalized spike-wave discharge, although the frequency is often slower during the stormy phase. Approximately two thirds of children will eventually have remission of seizures and can stop medication, usually within several years after epilepsy onset.
iii. Developmental and epileptic encephalopathy/Epileptic encephalopathy with spike-wave activitation in sleep (DEE-SWAS or EE-SWAS). This group of disorders was formerly known by many names, including continuous spike-wave in sleep (CSWS), Electrographic status epilepticus is sleep (ESES), Landau-Kleffner syndrome or pseudo-Lennox syndrome. In this disorder, there is marked activation of epileptiform discharge in sleep associated with stagnation or regression of development. The term DEE-SWAS is used for children with pre-existing developmental delay while EE-SWAS is used if prior development was normal. This disorder typically presents in preschool or early school-aged children, and the EEG pattern of marked exacerbation of spike-wave discharge in sleep remits by puberty, although the EEG may remain abnormal. Seizures also typically reduce in frequency and often abate by puberty. Persons with DEE-SWAS or EE-SWAS may present with a variety of seizures types including focal seizures or generalized seizures, and rarely seizures may not be seen.
Certain medications such as steroids or high dose
Epilepsy syndromes with onset at a variable age
The majority of syndromes that onset at a variable age can be subdivided into the idiopathic generalized epilepsy syndromes, focal epilepsy syndromes or syndromes with progressive neurological deterioration.
A. Idiopathic generalized epilepsy syndromes
i. Juvenile absence epilepsy (JAE) typically presents in early to mid adolescence in developmentally normal teens with typical absence seizures. JAE is distinguished from CAE as the absence seizures are less frequent (typically up to 10/day at most), age at onset is older (typically >10 years) and higher association with generalized tonic-clonic seizures. The EEG shows generalized 3-4 Hz spike-wave discharge and the background is normal. Approximately 80% of patients will develop generalized tonic-clonic seizures, most commonly within a few years of onset of absence seizures. Persons with JAE do not show cognitive decline or neurological deficits, however have higher rates of learning disorders, depression, anxiety and ADHD. The likelihood of remission is significantly lower than CAE.[4]
ii. Juvenile myoclonic epilepsy (JME) presents in developmentally normal teens and young adults with myoclonic seizures, that often occur in the morning and can be triggered by sleep deprivation or flashing lights. The majority (over 90%) also will develop generalized tonic-clonic seizures, which are often heralded by a cluster of myoclonic jerks. Approximately 40% also develop typical absence seizures, however these are usually infrequent, very brief and may not have complete impairment in awareness. The EEG shows fast generalized spike-wave or polyspike and wave and the MRI, if done, is normal. Persons with JME do not experience neurocognitive regression but have higher rates of learning problems, depression and anxiety and ADHD.[4]
B. Focal epilepsy syndromes
i. Sleep-related hypermotor epilepsy (SHE) is a focal epilepsy syndrome characterized by clusters of complex motor movements such as hand clenching, arm or leg flailing, abnormal posturing, kicking or vocalizations (shouting, moaning etc) that arise during sleep. Seizures are generally brief but often occur multiple times each night. This epilepsy syndrome can occur both in children and adults and is by either a specific gene (including nicotinic acetylcholine receptor subunit genes, genes affecting the GATOR1 complex or KCNT1) or structural brain abnormalities (either developmental brain changes or acquired brain injury). Persons with this epilepsy syndrome are often misdiagnosed as having nightmares.[7]
ii. Mesial temporal lobe epilepsy with hippocampal sclerosis is one of the most common causes of drug resistant epilepsy in adults and can also be seen in children. Seizures arise from the mesial temporal structures (e.g., the hippocampus, amygdala, and parahippocampal gyrus) and often begin with autonomic (rising sensation from the abdomen to the chest, nausea, vomiting), cognitive (déjà vu, jamais vu), fear or sensory (bad smell or taste) symptoms. There is often gradual impairment in awareness and oral automatisms (chewing, lip-smacking) are common. With seizures that affect the dominant hemisphere for language, persons often have difficulty with language (inability to speak or garbled language) during and shortly after the seizure. Seizures may evolve to become bilateral convulsive seizures. Seizures most commonly begin in late childhood and adolescence but can occur at any age. The MRI shows evidence of hippocampal sclerosis (scarring of the hippocampus). Often seizures do not sufficiently respond to medical treatment with anticonvulsants and epilepsy surgery may be considered.[25][7]
c. Epilepsy syndromes with progressive neurological impairment
i.
ii. Progressive myoclonic epilepsy is a rare syndrome that comprised a group of underlying genetic epilepsies characterized by progressive dementia and myoclonic seizures. Tonic-clonic seizures may occur as well. Diseases usually classified in this group are Unverricht-Lundborg disease, myoclonus epilepsy with ragged red fibers (MERRF syndrome), Lafora disease, neuronal ceroid lipofucinosis, and sialdosis.[7]
Syndromes not appearing in the 2017 ILAE classification
The latest 2017
Autosomal dominant nocturnal frontal lobe epilepsy
Autosomal dominant nocturnal frontal lobe epilepsy (ADNFLE) is an idiopathic localization-related epilepsy that is an inherited epileptic disorder that causes seizures during sleep. Onset is usually in childhood. These seizures arise from the frontal lobes and consist of complex motor movements, such as hand clenching, arm raising/lowering, and knee bending. Vocalizations such as shouting, moaning, or crying are also common. ADNFLE is often misdiagnosed as nightmares. ADNFLE has a genetic basis.[10] These genes encode various nicotinic acetylcholine receptors.[citation needed]
Rolandic epilepsy
Benign centrotemporal lobe epilepsy of childhood or benign
Benign occipital epilepsy of childhood
Benign occipital epilepsy of childhood (BOEC) is an idiopathic localization-related epilepsy and consists of an evolving group of syndromes. Most authorities include two subtypes, an early subtype with onset between three and five years, and a late onset between seven and 10 years. Seizures in BOEC usually feature visual symptoms such as scotoma or fortifications (brightly colored spots or lines) or amaurosis (blindness or impairment of vision). Convulsions involving one half the body, hemiconvulsions, or forced eye deviation or head turning are common. Younger patients typically experience symptoms similar to migraine with nausea and headache, and older patients typically complain of more visual symptoms. The
Childhood absence epilepsy
Epilepsy in females with intellectual disability
Epilepsy in females with intellectual disability, is characterized by seizure onset in infancy or early childhood (6–36 months) and cognitive impairment in some cases. Seizures are predominantly generalized, including tonic-clonic, tonic and atonic seizures. The spectrum of phenotypes has been extended to include female patients with early onset epileptic encephalopathies resembling Dravet syndrome, FIRES, Generalized epilepsy with febrile seizures plus (GEFS+) or focal epilepsy with or without intellectual disability. The condition is caused by mutations in PCDH19 (protocadherin 19).[citation needed]
See Febrile infection-related epilepsy syndrome (FIRES)
Frontal lobe epilepsy
Juvenile myoclonic epilepsy
Ohtahara syndrome
Ohtahara syndrome is a rare but severe epilepsy syndrome usually starting in the first few days or weeks of life. The seizures are often in the form of stiffening spasms but other seizures including unilateral ones may be seen. The electroencephalogram (EEG) is characteristic. The prognosis is poor with about half of the infants dying in the first year of life; most if not all surviving infants are severely intellectually disabled and many have cerebral palsy. There is no effective treatment. A number of children have underlying structural brain abnormalities.[14]
Reflex epilepsies
About 6% of those with epilepsy have seizures that are often triggered by specific events, known as
Those with
Primary reading epilepsy is a
Progressive myoclonic epilepsies
Progressive myoclonic epilepsies define a group of symptomatic generalized epilepsies characterized by progressive
Temporal lobe epilepsy
West syndrome
See also
References
- ^ a b c d e f Wirrell EC, Nabbout R, Scheffer IE, Alsaadi T, Bogacz A, French JA, et al. "Methodology for classification and definition of epilepsy syndromes with list of syndromes: Report of the ILAE Task Force on Nosology and Definitions". Epilepsia. 2022; 63: 1333–1348. https://doi.org/10.1111/epi.17237
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- ^ [https://www.ilae.org/guidelines/definition-and-classification/classification-and-definition-of-epilepsy-syndromes "Classification and Definition of Epilepsy Syndromes", ILAE
- ^ a b c d Hirsch E, French J, Scheffer IE, Bogacz A, Alsaadi T, Sperling MR, et al. "ILAE definition of the Idiopathic Generalized Epilepsy Syndromes: Position statement by the ILAE Task Force on Nosology and Definitions", Epilepsia, 2022; 63: 1475–1499. https://doi.org/10.1111/epi.17236
- ^ a b c d e f g Zuberi SM, Wirrell E, Yozawitz E, Wilmshurst JM, Specchio N, Riney K, et al. "ILAE classification and definition of epilepsy syndromes with onset in neonates and infants: Position statement by the ILAE Task Force on Nosology and Definitions", Epilepsia. 2022; 63: 1349–1397. https://doi.org/10.1111/epi.17239
- ^ a b c d e Specchio N, Wirrell EC, Scheffer IE, Nabbout R, Riney K, Samia P, et al. "International League Against Epilepsy classification and definition of epilepsy syndromes with onset in childhood: Position paper by the ILAE Task Force on Nosology and Definitions", Epilepsia, 2022; 63: 1398–1442. https://doi.org/10.1111/epi.17241
- ^ a b c d e Riney K, Bogacz A, Somerville E, Hirsch E, Nabbout R, Scheffer IE, et al. "International League Against Epilepsy classification and definition of epilepsy syndromes with onset at a variable age: position statement by the ILAE Task Force on Nosology and Definitions", Epilepsia, 2022; 63: 1443–1474. https://doi.org/10.1111/epi.17240
- ^ Wu YW, Sullivan J, McDaniel SS, Meisler MH, Walsh EM, Li SX, Kuzniewicz MW, "Incidence of Dravet Syndrome in a US Population", Pediatrics 2015 Nov;136(5):e1310-5. doi: 10.1542/peds.2015-1807. Epub 2015 Oct 5. PMID: 26438699; PMCID: PMC4621800
- ^ a b Cooper MS, Mcintosh A, Crompton DE, McMahon JM, Schneider A, et al., "Mortality in Dravet syndrome", Epilepsy Research, 2016 Dec; 128:43-47, doi: 10.1016/j.eplepsyres.2016.10.006. Epub 2016 Oct 26. PMID: 27810515.
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