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 seizure type(s) and specific findings on EEG. Epilepsy syndromes often begin (and may remit) at specific ages. Identification of an epilepsy syndrome may provide important clues to the likely cause, the most effective treatment and the risk of comorbidities such as learning problems, intellectual disability, ADHD or other problems.[1]
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]
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.[3]
- 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):
- a. Syndromes with onset in neonates and infancy – this group of syndromes begins prior to 2 years of age.[4]
- b. Syndromes with onset in childhood.[5]
- c. Syndromes that begin at a variable age. This group includes syndromes that can begin either in childhood or adulthood.[6]
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. Almost two thirds of these syndromes are developmental and epileptic encephalopathies, which are associated with significant developmental impairment and frequent seizures which often respond poorly to antiseizure medication. Of the remainder of infants with an epilepsy syndrome, most will have a self-limited focal epilepsy, which will not impact development, and which are typically outgrown by early childhood.
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. 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.[4]
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 MRI scan will show evidence of a prior brain injury or abnormal brain development. Genetic causes are also relatively common and can include a large number of genetic variants. Metabolic causes are less commonly found. 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.[4]
Dravet syndrome
{{main|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 Charlotte Dravet, a French psychiatrist and epileptologist, while working at the Centre Saint Paul at the University of Marseille. The prevalence of this disorder is approximately 1/16,00 live births.[7] Seizures begin before 20 months of age and in most cases, the first seizures occur with fever and are generalized tonic-clonic (grand mal) or unilateral (one-sided) convulsions. These seizures are often prolonged, and may lead to status epilepticus, a medical emergency. In time, seizures increase in frequency and begin to occur without fever. Additional seizure types appear, most often these are myoclonic, atypical absence, and focal seizures. Seizures persist despite treatment with medication, however several medications including valproic acid, stiripentol, clobazam, fenfluramine and pharmaceutical grade Cannabidiol are often helpful to decrease seizure burden. Development is normal at the time of seizure onset, however developmental typically plateaus around age 2 years, and by adulthood, intellectual disability of varied severity is seen. Additional features that are seen in significant numbers of patients with Dravet syndrome may include a crouch gait, autism spectrum disorder, sleep problems, dysautonomia, and problems with growth and nutrition.[17] Persons with Dravet syndrome also have an increased risk of early death, particularly due to SUDEP (Cooper et al. 2016, Epilepsy Res 2016;128:43-7).
Syndromes not appearing in the 2017 ILAE classification
The latest 2017 ILAE classification of epilepsy syndromes no longer includes several syndromes included in earlier classifications. These are now included under other syndromes in the new classification, or are no longer regarded as syndromes, but are retained here for reference.
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.[8] These genes encode various nicotinic acetylcholine receptors.[citation needed]
Rolandic epilepsy
Benign centrotemporal lobe epilepsy of childhood or benign Rolandic epilepsy is an idiopathic localization-related epilepsy that occurs in children between the ages of 3 and 13 years, with peak onset in prepubertal late childhood. Apart from their seizure disorder, these patients are otherwise normal. This syndrome features simple focal seizures that involve facial muscles and frequently cause drooling. Although most episodes are brief, seizures sometimes spread and generalize. Seizures are typically nocturnal and confined to sleep. The EEG may demonstrate spike discharges that occur over the centrotemporal scalp over the central sulcus of the brain (the Rolandic sulcus) that are predisposed to occur during drowsiness or light sleep. Seizures cease near puberty.[9] Seizures may require anticonvulsant treatment, but sometimes are infrequent enough to allow physicians to defer treatment.
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 EEG in BOEC shows spikes recorded from the occipital (back of head) regions. The EEG and genetic pattern suggest an autosomal dominant transmission as described by Ruben Kuzniecky, et al.[10] Lately, a group of epilepsies termed Panayiotopoulos syndrome[11] that share some clinical features of BOEC.
Childhood absence epilepsy
Childhood absence epilepsy (CAE) is a genetic generalized epilepsy that affects children between the ages of 4 and 12 years of age, although peak onset is around five to six years old. These patients have recurrent absence seizures, brief episodes of unresponsive staring, sometimes with minor motor features such as eye blinking or subtle chewing. The EEG finding in CAE is generalized 3 Hz spike and wave discharges. Some go on to develop generalized tonic-clonic seizures. This condition carries a good prognosis because children do not usually show cognitive decline or neurological deficits, and the seizures in the majority cease spontaneously with ongoing maturation.[citation needed]
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
Frontal lobe epilepsy, usually a symptomatic or cryptogenic localization-related epilepsy, arises from lesions causing seizures that occur in the frontal lobes of the brain. These epilepsies can be difficult to diagnose because the symptoms of seizures can easily be confused with nonepileptic spells and, because of limitations of the EEG, be difficult to "see" with standard scalp EEG. Juvenile absence epilepsy is an idiopathic generalized epilepsy with later onset than CAE, typically in prepubertal adolescence, with the most frequent seizure type being absence seizures. Generalized tonic-clonic seizures can occur. Often, 3 Hz spike-wave or multiple spike discharges can be seen on EEG. The prognosis is mixed, with some patients going on to a syndrome that is poorly distinguishable from JME.
Juvenile myoclonic epilepsy
Juvenile myoclonic epilepsy (JME) is a genetic generalised epilepsy that occurs in patients aged 8 to 20 years. Patients have normal cognition and are otherwise neurologically intact. The most common seizure is myoclonic jerks, although generalized tonic-clonic seizures and absence seizures may occur as well. Myoclonic jerks usually cluster in the early morning after awakening. The EEG reveals generalized 4–6 Hz spike wave discharges or multiple spike discharges. These patients are often first diagnosed when they have their first generalized tonic-clonic seizure later in life, when they experience sleep deprivation (e.g., freshman year in college after staying up late to study for exams). Alcohol withdrawal can also be a major contributing factor in breakthrough seizures, as well. The risk of the tendency to have seizures is lifelong; however, the majority have well-controlled seizures with anticonvulsant medication and avoidance of seizure precipitants.[citation needed]
Lennox-Gastaut syndrome
Lennox-Gastaut syndrome (LGS) is a is a rare and severe form of epilepsy. It is a generalized epilepsy that consists of a triad of developmental delay or childhood dementia, mixed generalized seizures, and EEG demonstrating a pattern of approximately 2 Hz "slow" spike-waves. Onset occurs between two and 18 years.
As in West syndrome, LGS result from idiopathic, symptomatic, or cryptogenic causes, and many patients first have West syndrome. Authorities emphasize different seizure types as important in LGS, but most have astatic seizures (drop attacks), tonic seizures, tonic-clonic seizures, atypical absence seizures, and sometimes, focal seizures. Anticonvulsants are usually only partially successful in treatment.[citation needed]
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.[12]
Reflex epilepsies
About 6% of those with epilepsy have seizures that are often triggered by specific events, known as reflex seizures.[13] A number of epilepsy syndromes, known as reflex epilepsies, have seizures that are only triggered by specific stimuli.[14] Common triggers include: flashing lights and sudden noises.[13]
Those with photosensitive epilepsy can have seizures triggered by flashing lights. Other precipitants can trigger an epileptic seizure in patients who otherwise would be susceptible to spontaneous seizures. For example, children with childhood absence epilepsy may be susceptible to hyperventilation. In fact, flashing lights and hyperventilation are activating procedures used in clinical EEG to help trigger seizures to aid diagnosis. Finally, other precipitants can facilitate, rather than obligately trigger, seizures in susceptible individuals. Emotional stress, sleep deprivation, sleep itself, heat stress, alcohol and febrile illness are examples of precipitants cited by patients with epilepsy. Notably, the influence of various precipitants varies with the epilepsy syndrome.[15] Likewise, the menstrual cycle in women with epilepsy can influence patterns of seizure recurrence. Catamenial epilepsy is the term denoting seizures linked to the menstrual cycle.[16]
Primary reading epilepsy is a reflex epilepsy classified as an idiopathic localization-related epilepsy. Reading in susceptible individuals triggers characteristic seizures.[17] Catamenial epilepsy (CE) is when seizures cluster around certain phases of a woman's menstrual cycle.
Progressive myoclonic epilepsies
Progressive myoclonic epilepsies define a group of symptomatic generalized 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.
Rasmussen's encephalitis
Rasmussen's encephalitis, or Rasmussen's syndrome is a symptomatic localization-related epilepsy that is a progressive, inflammatory lesion affecting children with onset before the age of 10. Seizures start as separate focal seizures and may progress to epilepsia partialis continua (simple partial status epilepticus). Neuroimaging shows inflammatory encephalitis on one side of the brain that may spread if not treated. Dementia and hemiparesis are other problems. The cause is hypothesized to involve an immulogical attack against glutamate receptors, a common neurotransmitter in the brain.[18]
Temporal lobe epilepsy
Temporal lobe epilepsy (TLE) is not a classic syndrome but mentioned here because it is the most common epilepsy of adults. It is a symptomatic localization-related epilepsy and in most cases the epileptogenic region is found in the midline (mesial) temporal structures (e.g., the hippocampus, amygdala, and parahippocampal gyrus). Seizures begin in late childhood and adolescence. Most of these patients have focal seizures sometimes preceded by an aura, and some TLE patients also have secondary generalized tonic-clonic seizures. Often seizures do not sufficiently respond to medical treatment with anticonvulsants and epilepsy surgery may be considered.[19]
West syndrome
West syndrome is a triad of developmental delay, seizures termed infantile spasms, and EEG demonstrating a pattern termed hypsarrhythmia. Onset occurs between three months and two years, with peak onset between eight and nine months. West syndrome may arise from idiopathic, symptomatic, or cryptogenic causes. The most common cause is tuberous sclerosis. The prognosis varies with the underlying cause. In general, most surviving patients remain with significant cognitive impairment and continuing seizures and may evolve to another eponymic syndrome, Lennox-Gastaut syndrome. It can be classified as idiopathic, syndromic, or cryptogenic depending on cause and can arise from both focal or generalized epileptic lesions.
See also
References
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