CHAPTER

Epilepsy Syndromes

Richard P. Morse

CLASSIFICATION OF EPILEPTIC SYNDROMES AND THE EPILEPSIES

There are many reasons why classification of the epilepsies matters. A standardized classification and terminology for epileptic syndromes is needed for organizing and differentiating the epilepsies. The International League Against Epilepsy (ILAE)-standardized classification facilitates clinical practice, trials of seizure medications and other therapies, research and epidemiological studies of the epilepsies.

Historically, there have been multiple revisions of the classification schemes, and the process continues as scientific advances add to our understanding. Most recently, the impact of neuroradiology and neurogenetics has prompted attempts to revise the historical classification schemes. In this chapter, a brief historical overview is followed by terminology and definitions, principles considered by the committees charged with revising the classification, and presentation of the most current tables of the epilepsies. No classification system has yet emerged that is perfect and all encompassing, due to the competing needs of those using a classification system. There is a balance between a detailed, precise, and somewhat cumbersome classification system, and a clinically applicable, practical, and useful system that may oversimplify the complexity of the epilepsies and thus hinder our understanding. Nevertheless, for a system to be useful, certain compromises are inevitable.

HISTORICAL OVERVIEW

The International League Against Epilepsy (ILAE) has approached the classification of epileptic seizures and the epilepsies as a body from early on. The first meeting occurred in 1964 and led to a preliminary classification, which in turn was submitted to a Commission on Terminology for consideration. This commission published a proposed scheme of classification in Epilepsia in 1964. After additional input from neurologists, the proposal was reviewed again by the members of the Commission on Terminology in 1967, and a revised scheme of classification was published in 1969 (1), despite the lack of agreement in regard to certain terms. Despite the limitations, the executive committee of the ILAE recommended the classification system be used in hopes of bringing more uniformity in the use of diagnostic terms, to facilitate the comparison of cases, and to improve methods of evaluating therapy and eventually further the understanding of the causes of epileptic seizures.

Infancy

Epilepsy of Infancy With Migrating Focal Seizures.  Epilepsy of infancy with migrating focal seizures is an infantile epileptic encephalopathy characterized by normal early development, refractory multifocal seizures arising independently from both hemispheres, and severe, progressive psychomotor retardation. In the revised ILAE terminology, it has been classified as an “electroclinical syndrome of unknown cause” with onset in infancy. Diagnostic criteria for epilepsy of infancy with migrating focal seizures include: (a) normal development before seizure onset, (b) onset before 6 months, (c) migrating focal motor seizures at onset, lasting for the first several months, often including autonomic manifestations such as apnea, cyanosis, or flushing, (d) multifocal seizures starting between 1 and 12 months that become intractable. Seizures tend to occur in daily multiple clusters, and may even be nearly continuous at times, (e) intractable to conventional antiseizure medications, (f) no identified etiology, and (g) profound psychomotor retardation, noted between 1 and 5 years of age. It is a rare syndrome and has been reported in a small number of infants. Although the seizures may become less frequent over time, there are frequent seizure recurrences during intercurrent illnesses. Outcome is poor, with global developmental delay.

West Syndrome.  West syndrome (WS) is one of the pediatric age–related epileptic encephalopathies (11). The syndrome includes the triad of infantile spasms, an EEG showing hypsarrhythmia and psychomotor retardation. Infantile spasms (IS) occur only in infancy and early childhood. IS are myoclonic-like movements (sudden, brief) that usually begin in the first year of life, typically between 4 and 8 months, with 90% beginning under a year of age. Spasms can be flexor, extensor, or a mixture of both. The spasms primarily consist of a sudden pitching forward from the waist with extension and stiffening of the arms and legs; some children have truncal extension rather than flexion. Various series give the incidence of mixed spasms at 40% to 50%, flexor spasms 35% to 40%, and extensor spasms 20% to 25%. Spasms tend to occur during state transitions, upon awakening or while falling asleep, and often occur in clusters. Infants may have dozens of clusters and hundreds of spasms per day. IS usually end by age 5, but other types of seizures often replace the spasms. WS leads to developmental regression and is associated with a specific EEG pattern known as hypsarrhythmia, which consists of high-amplitude, polymorphic delta, and multifocal and generalized spikes with a chaotic and disorganized background.

Many underlying causes and disorders, such as birth injury, metabolic disorders, and genetic disorders, can cause infantile spasms, which are more of an age-related manifestation of seizures than reflective of any specific cause. As there are many etiologies for IS, it is important to search for an underlying cause. About 10% of infants have no identifiable etiology. Almost any disorder causing brain damage can be associated with IS. Neonatal hypoxic ischemic brain injury is the most common cause. Other conditions associated with the development of IS include hydrocephalus, congenital or acquired microcephaly, brain malformations, Sturge-Weber syndrome, tuberous sclerosis, and other genetic syndromes (such as Aicardi syndrome, trisomy 21, other trisomies), prenatal/congenital infections, trauma, meningitis, encephalitis, intracranial hemorrhage, pyridoxine dependency (seizures may begin prenatally in this disorder), maple syrup urine disease, phenylketonuria, neurodegenerative diseases, biotinidase deficiency, and others. Increasingly, underlying genetic causes of IS are being identified. For example, MECP 2 mutations, the cause of Rett syndrome in girls, have been associated with IS in affected males. Idiopathic IS are diagnosed if normal psychomotor development precedes the onset of symptoms; no underlying disorders or definite presumptive causes are present; and no neurological or neuroradiological abnormalities exist. If a cause presents itself, the syndrome is referred to as symptomatic WS, as the seizures manifest as a symptom of another problem. Almost any cause of brain damage can be associated with IS.

The pathophysiology mediating WS and IS remains unknown. There are hypotheses that the syndrome results from dysregulation of GABA transmission, or results from an overexpression of corticotropin-releasing hormone receptors. Various attempts to create an animal model have so far been unsuccessful at reliably reproducing infantile spasms.

Outcome depends on etiology. Early detection and prompt effective treatment have been shown to improve neurodevelopmental outcomes, especially in idiopathic cases. However, in most outcome series, between 70% and 90% of infants have psychomotor delay or regression (12).

Myoclonic Epilepsy in Infancy.  Myoclonic epilepsy in infancy (MEI) accounts for about 2% of epilepsies that start before 3 years of age. Onset is 6 months to 3 years, and infants are neurologically normal. Seizures include myoclonic jerks, singular or in clusters. Consciousness most often remains normal during the seizures, but it may be affected during a longer cluster. Simple febrile seizures occur in 10% of these infants and other seizure types are not reported. About 20% have photosensitivity and another 10% may have stimulus-sensitive (sound or touch) seizures. Seizures tend to occur during transition from waking to sleep, and vice versa. The baseline EEG is usually normal, but during a seizure may show generalized polyspike and slow-wave or spike-wave discharges. Seizures are outgrown in the majority of infants within 1 to 2 years from onset. Up to 20% develop infrequent generalized tonic–clonic seizures in their early teens, and a similar number may have mild neurological deficits (cognitive, behavioral, or motor). EEG photosensitivity may continue after remission of seizures. Treatment with valproic acid has been most successful. Patients with acoustic and somatosensory-evoked myoclonus may not need treatment at all.

Benign Infantile Epilepsy (BIE).  Benign infantile epilepsy (BIE) is also known as benign infantile seizures (BIS). Several types of BIE have been described. The ILAE classified the syndrome into familial and nonfamilial forms, though other forms have been described in the literature. Affected children, who have no other health or developmental problems, develop seizures during infancy. The seizures have a focal origin, but may spread to become generalized seizures. The seizures may occur several times a day, often groups in clusters over 1 to 3 days followed by a gap of 1 to 3 months. Treatment with antiseizure medications is not necessary but they are often prescribed and are effective at controlling the seizures. This form of epilepsy resolves after 1 or 2 years, and appears to be completely benign. The EEG of these children, between seizures, is normal. The brain appears normal on MRI scan.

The familial and nonfamilial forms have overlapping features and the presence of a family history of infantile seizures may be the only distinguishing criterion. The nonfamilial form has a larger range of the onset of seizures, from 3 to 20 months with most occurring between 5 and 6 months. With benign familial infantile epilepsy, the seizure onset is from 4 to 8 months of age.

Benign Familial Infantile Epilepsy.  Benign familial infantile epilepsy (BFIE), also known as benign familial infantile seizures (BFIS), is an autosomal dominant (ie, genetic) epilepsy characterized by onset at age of 4 to 8 months. The neurologic prognosis is excellent. BFIS have been linked to chromosome 19q. Related infantile convulsions and choreoathetosis syndrome, in which BFIE are associated with paroxysmal choreoathetosis, have been linked to chromosome 16p12. Seizure types vary from simple partial seizures and complex partial seizures to generalized seizures beginning between 2 months and 2 years of age. Infants generally have normal neurologic examinations, and any neurologic studies are normal. There is no etiology identifiable. Family history is typically positive for seizures beginning at about the same age. Seizures tend to be brief and occur during the waking state, and are present in clusters in about half of patients. Interictal EEG is normal in nearly all infants.

Dravet Syndrome.  Dravet syndrome (DS; also known as severe myoclonic epilepsy of infancy or SMEI) is a rare, genetic epileptic encephalopathy that begins in infancy. Seizures appear during the first year of life with prolonged febrile seizures or fever-related seizures. In the second year of life, afebrile seizures emerge, including myoclonic, eyelid myoclonia, absence, and generalized tonic–clonic. Susceptibility to hyperthermia-induced seizures persists, with febrile episodes often triggering status epilepticus. All seizure types may be prolonged or lead to status epilepticus. Seizures in DS are frequently resistant to treatment. The majority of children with DS show stimulus-provoked seizures, with a high degree of photosensitivity and emotional triggers (stress) being frequently observed.

Children with DS typically have developmental regression or delay, with developmental quotients in the 50 range (normal 100), with a high incidence of behavioral problems (hyperactivity, oppositionality) and disturbed sleep. Development is normal before the onset of afebrile seizures, as is the EEG during the first year. However, in the second year, development tends to arrest and subsequently may regress. The EEG changes in the second or third year of life, showing generalized spike, polyspike, and polyspike and slow-wave paroxysms. EEG studies should avoid using photic stimulation in these children due to the high risk of inducing a seizure.

As children with DS get older, their decline in cognitive function stabilizes, and in many, improves slightly. Neurologic impairment involves the development of ataxia and what is been termed “crouched gait.” Severe learning disabilities are persistent. Seizures tend to be not only nocturnal but also persistent. There is a higher incidence of sudden unexpected death in epilepsy (SUDEP) associated with DS, with ongoing research into the possible association of the underlying channelopathy affecting the heart.

The drug stiripentol is considered the drug of choice for DS. It is typically used in combination with valproic acid and clobazam or another benzodiazepine. Stiripentol has been granted orphan drug status by the FDA, but is not generally available yet. The ketogenic diet has also been beneficial. For children with severe photosensitivity, specialized lenses may be of benefit. Certain antiseizure medications may exacerbate seizures and should be avoided, including carbamazepine, phenytoin, and lamotrigine (13).

Myoclonic Encephalopathy in Nonprogressive Disorders.  Myoclonic encephalopathy in nonprogressive disorders (also termed myoclonic status epilepticus in nonprogressive encephalopathy, or MSNE) is characterized by early onset of repeated myoclonic status in infants and young children. The EEG shows continuous diffuse epileptiform abnormalities. The outcome from myoclonic encephalopathy is poor. This is a difficult-to-diagnose entity and needs to be distinguished from progressive myoclonic epilepsies and other infantile myoclonic epilepsies. Most often there is an underlying genetic defect, such as Angelman syndrome, history of hypoxic ischemic encephalopathy, or brain malformation. Seizure onset most often occurs around 1 to 2 years of age, with a range from 0 to 7 years.

Childhood

Febrile Seizures Plus.  Febrile seizures plus (FS+, generalized epilepsy with febrile seizures plus, GEFS+) refers to a genetic syndrome in which febrile seizures tend to start earlier than typical febrile seizures (less than 1 year) and persist longer than the usual 6 years. The syndrome is heterogeneous, and includes generalized epilepsy with febrile seizures plus (GEFS+). Children are neurologically normal otherwise, and may outgrow their epilepsy around age 10, or, in the case of GEFS+, may develop afebrile seizures (13%) including absence, myoclonic, atonic, or even focal seizures.

Because of a common genetic basis (primarily mutations in sodium channels, SCN1A and others) with DS, FS+/GEFS+ is considered a spectrum diagnosis by many. There is remarkable heterogeneity within this disorder, which has autosomal dominant inheritance with incomplete penetrance. EEGs range from normal to having generalized epileptiform discharges (spike-wave, polyspike wave). Development is normal or with mild disabilities. Treatment is standard for recurrent febrile seizures (rescue medication or “mini” prophylactic approach), and other seizure types are also treated in a standard manner, though the association with absence, myoclonic-astatic, and Dravet phenotypes suggests avoiding carbamazepine, lamotrigine, and phenytoin.

Panayiotopoulos Syndrome.  Panayiotopoulos syndrome (PS) is the preferred name for what was previously termed “early-onset benign childhood occipital epilepsy.” PS accounts for up to 13% of 3 to 6 year olds and 6% of 1 to 14 year-olds with seizures. PS occurs only in children, and almost all seizures occur during sleep. A hallmark feature of PS is the prominent autonomic manifestations of the seizures, including vomiting, respiratory and temperature changes, pallor, mydriasis, urinary incontinence, and cardiac changes. Vomiting occurs in 75% of the seizures. Headache is also typical. Syncopal-like seizures with unresponsiveness and whole-body limpness are common. About half of the seizures end with convulsive activity. There is a great deal of variety in this epileptic syndrome. Seizures are described as typically prolonged, with more than half lasting more than 30 minutes, most often as autonomic status epilepticus. Despite the dramatic seizure, manifestation, and duration, the prognosis is excellent, the child typically returning to normal after a few hours of sleep. MRIs are normal. EEGs show marked variability, ranging from normal to multifocal spikes, and serial EEGs may change over time. Occipital spikes do occur but are not necessary for diagnosis. There may be frontal or central temporal spikes as well as generalized discharges. EEG abnormalities do not appear to be related to clinical course or prognosis. In PS, the cortical hyperexcitability is presumed maturational. PS is frequently misdiagnosed as a typical migraine, syncope, cyclic vomiting syndrome, or other nonepileptic disorders. Most patients have between one and five seizures, with only a third of patients having more than five seizures. The risk of developing epilepsy as an adult does not appear to be increased over the general population. Treatment is more likely needed for those children whose seizures are frequent, and there is no recommendation for any specific treatment that is likely to be superior.

Epilepsy With Myoclonic Atonic Seizures.  This syndrome was previously known as myoclonic-astatic epilepsy or Doose syndrome. In this epilepsy, myoclonic atonic seizures are the defining symptom (100%), with symmetrical myoclonic jerks immediately followed by a loss of muscle tone. More than half of these children have brief absence seizures often associated with the atonic seizures. This epilepsy has its onset from 7 months to 6 years, peaking at 2 to 4 years. Affected children are neurologically normal prior to the onset of seizures. Seizures tend to be frequent, and tonic seizures are exclusion criteria (tonic seizures are a distinguishing feature of Lennox-Gastaut syndrome). In two-thirds, generalized tonic–clonic seizures may appear months before the myoclonic-astatic seizures, and one-third of these children are affected by nonconvulsive status epilepticus. EEGs usually show a normal background (again contrast to Lennox-Gastaut syndrome) with frequent generalized spike and polyspike and slow-wave discharges at a 2 to 3 Hz frequency. About half of the patients will outgrow their epilepsy and have normal development or minor neurologic impairment, and the remaining continue with seizures, more severe impairment of cognitive functions, and behavioral abnormalities. The most successful treatment has been with valproic acid, and levetiracetam, ethosuximide, clonazepam, or other benzodiazepines.

Treatment may or may not be needed in this epileptic syndrome. Any antiseizure medication, preferably given as a once-daily nighttime dose, will usually control the seizures. Whether or not treatment of a centrotemporal spike (with or without seizures) found on an EEG will alter the learning profile remains the subject of great controversy and a much needed study.

Autosomal Dominant Nocturnal Frontal Lobe Epilepsy.  Historically, autosomal dominant nocturnal frontal lobe epilepsy (ADNFLE) was one of the first epilepsies to have a genetic basis described (14). Inheritance is autosomal dominant with 70% penetrance. Linkage to the long arms of chromosomes 20 and 15 has been demonstrated, with mutations in genes encoding subunits of a neuronal nicotinic acetylcholine receptor causative of the epilepsy. ADNFLE has a markedly homogeneous clinical phenotype. In ADNFLE, seizures occur nearly exclusively during sleep (hypnagogic state or shortly before awakening). The seizures are hypermotoric, semiologically identical to seizures from the supplementary somatosensory area, occur frequently (often multiple times a night), and are brief (20–50 seconds). The hyperkinetic movements are associated with dystonic posturing or tonic stiffening of the limbs and body, often with superimposed clonic components. Patients may be thrown out of bed and injuries may occur. Consciousness may be preserved. Secondarily generalized tonic–clonic seizures do occur in two-thirds of patients but are infrequent. Patients are neurologically normal, although there is an increased incidence of psychiatric disorders, likely due to the frequent misdiagnoses of the nocturnal seizures as a sleep disorder (benign nocturnal parasomnias, night terrors, and nightmares), obstructive sleep apnea syndrome, psychiatric or other medical disorder. Sleep is often fragmented because of the frequent nocturnal seizures, and thus excessive daytime somnolence is not uncommon. “Nocturnal paroxysmal dystonia” and “hypnic tonic postural seizures of frontal lobe origin” are diagnostic entities used in the past, which likely were given to patients with ADNFLE. Brain imaging is normal, as is the interictal EEG, though frontal lobe epileptiform abnormalities may occur in sleep. Interestingly, the ictal EEG is often not informative, or may show rhythmic slowing over the frontal region. Seizures tend to persist over the lifetime of the patient, waxing and waning in frequency, and ranging from mild to severe in an individual. The most common treatment used has been carbamazepine, but a number of patients may not respond, and alternatives include levetiracetam and lamotrigine.

Epilepsy With Myoclonic Absences.  Epilepsy with myoclonic absences (EMA), also known as Tassinari syndrome, is rare and accounts for less than 1% of patients with epilepsy. Up to 70% of patients are male, a contrast to the female preponderance seen in childhood absence epilepsy. Although originally considered a symptomatic generalized epilepsy under the 1989 classification (due to the variable and often poor prognosis), EMA is currently considered among the idiopathic generalized epilepsies. This in part is because two types of EMA have been described, one with a more benign course and eventual disappearance of seizures (which tend to be exclusively myoclonic absence in type), the other with a poor prognosis, seen in patients who generally have myoclonic absence seizures in conjunction with other seizure types. About a third of the time there is an etiologic factor identified, including prematurity, perinatal brain injury, congenital hemiparesis, and chromosomal disorders, and these patients tend to have a poorer outcome.

Seizure onset ranges between 11 months and 12 years of age. Clinically, there are absence seizures with accompanying rhythmic bilateral myoclonic jerks, often severe. There is variable impairment of consciousness, and there may be apnea as well. The myoclonic movements involve shoulders, arms, and legs and last from 10 to 60 seconds, occurring many times a day. They may be precipitated by falling asleep or awakening. In about a third of patients, myoclonic absences are the only seizure type. Neurologic examination tends to be normal, though up to 45% will have a developmental disability of varying degree even before the onset of the epilepsy. Cognitive disabilities may worsen or even appear during the course of the epilepsy, in contrast to typical childhood absence epilepsy. The EEG usually has a normal background with generalized spike-wave discharges. During a seizure, there is a typical generalized 3 Hz spike wave, as seen in absence. In about a third of patients, the myoclonic absence seizures remit after about 5 years; the remaining two-thirds of patients continue with seizures. The duration of myoclonic absences has been tied to the likelihood of cognitive disability.

A subtype of EMA is eyelid myoclonia with absence epilepsy, also called Jeavons syndrome. The main seizure type is a brief absence, lasting less than 2 seconds, and associated with 4 to 6 Hz eyelid myoclonia, or eye rolling or jerking upward in a way that is distinctive from the typical eyelid fluttering that happens in childhood absence epilepsy. The seizures typically begin around 2 to 3 years of age, but due to their brevity (generally <10 seconds) may go undiagnosed until later. Most patients have generalized tonic–clonic seizures during the course of their epilepsy. The seizures become quite frequent and may occur 30 or more times a day. There is a high degree of photosensitivity with light stimulus triggering seizures. Generalized tonic–clonic seizures are infrequent but may occur. Neurologic examination and outcome are normal in this epilepsy though seizures often persist into adult life. The EEG detects photosensitivity, and commonly polyspike discharges will be precipitated by eye closure. Fast (3 to 6 Hz) spike and polyspike and slow-wave generalized discharges may be recorded during seizures. The antiseizure medications, valproic acid, lamotrigine, and ethosuximide, are most helpful in management of these patients. Levetiracetam and clobazam may also be used. Carbamazepine, phenytoin, and vigabatrin should be avoided, as they may exacerbate the seizures.

Lennox-Gastaut Syndrome.  Lennox-Gastaut syndrome (LGS) designates a syndrome with multiple types of seizures, especially tonic (stiffening), atonic (drop), and atypical absence. LGS is one of the age-related epileptic encephalopathies. Development is usually, but not always, impaired, and the onset of LGS may be associated with developmental regression or arrest. The EEG shows characteristic patterns of background slowing and spike-wave bursts at frequencies of less than 3 per second (slow spike wave). LGS accounts for 2% to 5% of childhood epilepsies, and typically appears between ages 2 and 5 years. There are many underlying causes of this condition, but in about 25% to 35% of cases, no cause can be identified. Lennox-Gastaut syndrome has been associated with perinatal brain injury, prematurity, infections (encephalitis/meningitis, prenatal TORCH (Toxoplasmosis, Other [syphilis, varicella-zoster, parvovirus B19], Rubella, Cytomegalovirus, and Herpes) infections, brain malformations, genetic disorders, and a preceding history of infantile spasms. These children are often normal at the time of seizure onset, but soon show psychomotor retardation in association with uncontrolled seizures. Behavioral problems are common. Nonconvulsive status epilepticus occurs not infrequently (spike wave stupor or prolonged atypical absence), as does convulsive status epilepticus. Most devastating are the tonic and atonic seizures, both of which place the patient at high risk for head injury from falls. Treatment is difficult, because the seizures tend to be resistant to antiseizure medications, and the intellectual changes do not respond to any currently available intervention. The epilepsy persists through adulthood, requiring long-term care and frequently institutional placement. Treatment has traditionally been with valproic acid, lamotrigine (often in combination with valproic acid), topiramate, felbamate, clonazepam, rufinamide, clobazam, and others, including the ketogenic diet. Vagal nerve stimulators are often used in patients with LGS, and there have been some encouraging reports of deep brain stimulation. For refractory drop attacks, corpus callosotomy may be of great benefit.

Landau-Kleffner Syndrome.  Landau-Kleffner syndrome (LKS) is a rare childhood neurological disorder characterized by the sudden or gradual development of aphasia (receptive greater than expressive) in association with an abnormal EEG. The disorder usually appears between ages 5 and 7 years, with a preceding normal neurological profile and a progressive loss of language skills for no obvious reason. Many of the children have seizures but some do not. LKS is often misdiagnosed as autistic spectrum disorder, hearing impairment, learning disability, auditory/verbal processing disorder, mental retardation, emotional problems, or even attention deficit disorder. Treatment is difficult and often confers no benefit. Antiseizure medicines, corticosteroids, and multiple subpial transections (MSTs) have been tried, but none of them is reliably effective. The prognosis for LKS is variable, with some children having a severe permanent language disturbance and others regaining their language skills, at least partly.

Childhood Absence Epilepsy.  Childhood absence epilepsy (CAE) is an idiopathic generalized epilepsy occurring in otherwise normal children. Onset is between 4 and 10 years of age, with a peak of 5 to 7 years of age. Absence seizures are marked by an abrupt and complete behavioral arrest with impairment of consciousness. They last 4 to 20 seconds and can occur hundreds of times a day. The child will stare, sometimes blink, and there may be an associated mild loss of body tone and gentle clonic movements as the seizure ends. Absence seizures occur without aura and are not followed by any discernible postictal period. Automatisms are frequent as are mini rhythmic eye blinking movements (3 Hz). The EEG shows a generalized 3 Hz spike-wave pattern on a normal background. Hyperventilation will reliably provoke a seizure in the majority of children with CAE. The majority of children are neurologically normal, though school performance may be affected due to attentional deficits and slower processing speeds, attributable to the interictal, frequent subclinical discharges that may disrupt normal neuronal activity. About 50% of these children will have a generalized tonic–clonic seizure during the course of their epilepsy. The prognosis is excellent with seizures being outgrown in roughly 80% of patients, depending mostly on the age of onset.

Adolescence – Adults

Juvenile Absence Epilepsy.  Juvenile absence epilepsy (JAE) is in the spectrum of the absence epilepsies, with later age of onset (peaking between 9 to 13 years of age in 70% of patients) a much higher incidence of generalized tonic–clonic seizures, and a lower likelihood of outgrowing the epilepsy. There are myoclonic jerks in 20% of patients. The seizure type is predominantly typical absence, but they tend to be less frequent and of longer duration than in CAE. Seizures are often daily, lasting up to 30 seconds, and are longer than those seen in CAE. Children with JAE have a high rate of generalized tonic–clonic seizures over their lifetime, and are subject to absence status epilepticus /spike-wave stupor episodes, during which they may wander around and act confused. The epilepsy tends to be lifelong, but easily controlled with medication in the vast majority of patients (up to 80%). Seizures are precipitated by hyperventilation, sleep deprivation, fatigue, stress, and alcohol. The EEG shows a normal background with generalized spike and polyspike discharges, and the ictal EEG shows generalized 3 to 4 Hz spike or polyspike and slow-wave discharges. Valproic acid is the most effective antiseizure medication, with lamotrigine and levetiracetam as alternatives.

Epilepsy With Generalized Tonic–Clonic Seizures Alone.  The prevalence of this epileptic syndrome is unknown. It appears to be genetically determined and has shown linkage to the EJM1 locus for generalized tonic–clonic seizures on awakening, the best studied of the epilepsies grouped under this syndrome. By definition, all patients have generalized tonic–clonic seizures. These tend to occur within a few hours after awakening from sleep, but may also occur during relaxation or drowsiness. Seizure triggers include sleep deprivation, fatigue, stress, and alcohol consumption. The EEG is usually has a normal background with superimposed generalized spike and polyspike discharges in about half of the patients. About 15% have photosensitivity. The epilepsy tends to last for a lifetime with an 80+ percent likelihood of relapse on withdrawing treatment. Almost any of the antiseizure medications can be used, though for patients who have associated absence or myoclonic jerks as part of their epileptic manifestation, avoidance of carbamazepine, phenytoin, and oxcarbazepine is recommended.

Progressive Myoclonus Epilepsies.  Progressive myoclonus epilepsies (PME) are rare and most often occur as part of a neurodegenerative disorder. They typically involve both myoclonus (nonepileptic), tonic–clonic, and frequently myoclonic epileptic seizures. Other clinical features mainly rest on the underlying diagnosis, but typically involve progressive mental deterioration, cerebellar ataxia, and involuntary movements. The PME are seen in a variety of disorders, including mitochondrial disorders (myoclonic epilepsy and ragged red fibers), Unverricht-Lundborg syndrome (with Baltic and Mediterranean types), Lafora disease, Ramsay-Hunt syndrome (dentatorubral atrophy), sialidosis, Gaucher disease, and neuronal ceroid lipofuscinosis (NCL), especially the juvenile form. The PME are a heterogeneous group of disorders with very different clinical features, and only superficially similar, and such their classification as syndromic remains controversial.

Autosomal Dominant Epilepsy With Auditory Features (ADEAF).  Autosomal dominant epilepsy with auditory features (ADEAF) includes autosomal dominant lateral temporal lobe epilepsy (ADLTE) and autosomal dominant partial epilepsy with auditory features (ADPEAF). ADEAF is characterized by autosomal dominant transmission, age of onset in late adolescence, focal and secondarily generalized tonic–clonic seizures with auditory hallucinations, no brain anatomic abnormality, and a good outcome. It has been linked to chromosome 10q22-24. Similar mutations have been described in a low percentage of patients with sporadic cases of idiopathic partial epilepsy with auditory features.

Other Familial Temporal Lobe Epilepsies.  This designation reflects an emerging number of large pedigree/family genetic studies in which partial epilepsies, particularly of the temporal lobe, are found to have a genetic basis. As a group, these forms of epilepsy are found in otherwise neurologically normal individuals. Undoubtedly, as additional genetic information becomes available, this will be a rich source of understanding in terms of the pathophysiology of seizures, and will challenge the classification system in terms of the diversity of clinical expression and the genotype/phenotype correlation.

Less Specific Age Relationships

Familial Focal Epilepsy With Variable Foci (Childhood to Adult).  Familial focal epilepsy with variable foci represents another subset of the inherited partial epilepsies. The clinical features of the seizures and the EEG interictal foci show great variability, with frontal, temporal, occipital, and central parietal seizures associated with corresponding foci on EEG. The main age of seizure onset is 12 to 14 years, although it can vary from infancy to middle age. Familial focal epilepsy with variable foci most likely has autosomal dominant inheritance. Patients are normal, neurologically, and have normal imaging studies.

Distinctive Constellations

Mesial Temporal Lobe Epilepsy With Hippocampal Sclerosis

Mesial temporal lobe epilepsy with hippocampal sclerosis (MTLE with HS) is listed as a constellation rather than a syndrome, as it is a very common epilepsy seen in adults, has overlapping clinical features, is amenable to surgical management, but is heterogeneous as to etiology. There are familial forms of MTLE, and retrospective studies from surgical series have associated sporadic hippocampal sclerosis and MTLE development with preceding historical events such as febrile seizures, trauma, hypoxia, and intracranial infection, usually at an early age (less than 5 years). As HS has been demonstrated to develop over time, early identification of patients is difficult for studies of the natural history of HS. Data emerging from the febrile status epilepticus longitudinal multi-center study (FEBSTAT) supports an association between the occurrence of a prolonged febrile seizure in early childhood and the subsequent development of MTLE with HS. Whether there are additional genetic susceptibility factors involved or not remains to be determined, but they are strongly suspected. The seizure onset tends to be between ages 4 and 16 years of age for the majority of patients. The diagnosis is made when there is HS on MRI and a progressive course. Seizure semiology is typically that of a complex partial seizure with a preceding aura, mostly nausea or a rising epigastric sensation. The second most common aura is fear, either alone or accompanying the nausea. The seizure typically begins with a stare and oral alimentary automatisms, during which the patient is typically unresponsive. Dystonic posturing is contralateral, while automatisms are ipsilateral to the side of seizure onset. Early head deviation is ipsilateral, while head deviation later in the seizure is contralateral. Postictal aphasia reflects seizure origin in the language-dominant hemisphere. Seizures often become medically intractable. Precipitating factors include stress, sleep deprivation, and menstrual cycle-associated hormonal changes. Neurological profiles are typically normal, with the exception of memory deficits, which are often progressive.

Rasmussen Syndrome

Rasmussen syndrome (also called Rasmussen encephalitis, or RE) is a rare, progressive epileptic disorder that results in hemiatrophy of the brain, contralateral progressive hemiplegia, and cognitive deterioration, in association with intractable, progressive seizures. It most often begins in middle childhood and may have a protracted course punctuated with episodic status epilepticus. RE is associated with epilepsia partialis continua, an unusual form of seizure activity that may wax and wane over months or years, marked by arrhythmic twitching of a finger, toe, mouth, or other focal area. There is evidence to support that RE has an autoimmune basis rather than a genetic one. A viral etiology has been suggested by the pathology that includes cortical inflammation, neuronal loss, and gliosis confined to one hemisphere, and due to the similarity of RE to Russian spring summer meningoencephalitis, caused by a flavivirus. However, to date, there has been no viral agent identified. EEG tends to be abnormal, showing slowing and epileptiform discharges over the affected hemisphere; there may be no EEG correlate associated with epilepsia partialis continua. MRI shows progressive atrophy over the affected hemisphere, usually appearing and progressing within 6 months of the onset of seizures. Treatment is unsatisfactory, as the epilepsy rarely responds to medication. IVIG has been used as well as other immunomodulatory approaches, including chemotherapeutic agents, but the definitive intervention still remains (early) hemispherectomy.

Gelastic Seizures With Hypothalamic Hamartoma

This entity is listed as a constellation because of the high association of gelastic seizures (laughing seizures, often diabolical, forced laughter not affectively congruent) and hypothalamic hamartomas. Gelastic seizures can rarely come from other anatomical sites, such as the temporal lobe. Hypothalamic hamartomas can present with other seizure types in addition to gelastic seizures, most often complex partial seizures. The pathophysiology of seizures in hypothalamic hamartomas is not entirely understood, but intracranial monitoring studies have demonstrated that the seizures do originate and propagate from the hypothalamic hamartoma and adjacent structures.

Hemiconvulsion-Hemiplegia-Epilepsy

Epilepsies Attributed to and Organized by Structural-Metabolic Causes

Epilepsy associated with trauma, stroke, brain tumors, metastases, autoimmune disorders, electrolyte imbalance, sepsis, CNS infection, neurodegenerative disorders, uremia, etc., varies from individual to individual and reflects the structural-metabolic underlying process. These epilepsies fall into the “symptomatic” category under the previous (1989) classification scheme.

Malformations of Cortical Development

Malformations of cortical development include hemimegalencephaly, heterotopias, polymicrogyria, schizencephaly, lissencephaly, focal cortical dysplasia, types I and II, pachygyria, and others. Many brain malformations are highly epileptogenic. As there is a great deal of variety and unpredictability in how and whether a given malformation will be associated with epilepsy, it is more important to recognize the high frequency of brain malformations as a cause of epileptic seizures. Focal cortical dysplasia has emerged as a very common cause of focal seizures in children and frequently can be addressed surgically. Because of the high rate of malformations underlying epilepsy in children, MRI has become essential in the evaluation process.

Neurocutaneous Syndromes

Neurocutaneous syndromes include tuberous sclerosis complex (TSC), Sturge-Weber, incontinentia pigmenti, neurofibromatosis, hypomelanosis of Ito, and linear nevus sebaceous syndrome. They are classically associated with an increased incidence of epilepsy, especially TSC. Each of the neurocutaneous syndromes involves clinical dermatological findings in association with CNS abnormalities. There is a great deal of variety in terms of the clinical presentation and findings. TSC is highly associated with infantile spasms in infants and typically has abnormalities on MRI that are diagnostic (multifocal cortical dysplasia called “tubers”) in addition to skin findings (hypopigmented macules, facial angiofibromata, ungual fibromata, shagreen patches). There are two genes (TSC1 and TSC2) identified in TSC, and their associated protein products, hamartin and tuberin, respectively, act as tumor suppressor genes. The epileptogenicity of tubers is well understood and results from disruption of internal cell signaling pathways, as well as, neuronal connections within tubers and in the adjacent peri-tuber cortex. Sturge-Weber syndrome usually is identified because of a port-wine stain in the newborn that involves division I of the trigeminal nerve; MRI is diagnostic as it identifies the pial angiomatosis and progressive underlying cortical atrophy. Neurofibromatosis type I (NF-1), with multiple café au lait spots, neurofibromata, plexiform neuromas, and optic nerve gliomas, has an increased incidence of epilepsy over the general population; up to 10% of patients have epilepsy for various reasons. Most of the neurocutaneous syndromes involve CNS structural/anatomic malformations as the cause of the epilepsy.

Tumor

Brain tumors and metastatic tumors are both causes of recurrent seizures (epilepsy), usually considered symptomatic epilepsy. Generalizations are not of any great benefit, as the seizures reflect the site of origin and potential to spread to larger parts of the brain. Some brain tumors are quite epileptogenic, though, as a general rule, tumors do not tend to present with seizures in children, whereas in adults the two are commonly associated (about 50% of adults with brain tumors involving the hemispheres will experience seizures). However, gangliogliomas and developmental neuroectodermal tumors often present in childhood with seizures as their main manifestation. Hypothalamic hamartomas are another tumor highly associated with epilepsy. There is a growing awareness of subclinical seizures that may be associated with brain tumors, and the treatment of tumors (surgery, radiation, chemotherapy) may contribute to the development of epilepsy as well.

Infection

CNS infections, including encephalitis and meningitis/meningoencephalitis, vasculitis, are all associated with a high risk of seizures, and postinfectious epilepsy occurs at an overall increased rate. Encephalitis carries about a 20% risk of developing epilepsy, and meningitis about half of that, if there are seizures during the acute illness. If there are no acute seizures, the risks are much lower, about 10% for encephalitis and 2.5% for meningitis. Acute seizures in the course of a CNS infection are considered provoked, symptomatic, and not epilepsy, but late-occurring seizures are considered unprovoked and more likely associated with epilepsy.

Trauma

Angioma and Other Vascular Lesions

Arteriovenous malformations (AVMs), developmental venous malformations (DVMs), and cavernous angiomas, are all associated with an increased risk of epilepsy, both due to their tendency to bleed and due to peri-lesion associated brain malformations. The epilepsy typically involves partial seizures reflecting the anatomy.

Perinatal Insults

Benign Neonatal Seizures

Benign neonatal seizures (BNS) are defined as seizures with onset after birth through day 28 in an otherwise healthy child with no other known medical or neurologic problems. Such cases may be familial or isolated. Psychomotor development should be normal for a full-term or near-full-term infant with benign convulsions. Between seizures, findings on neurologic examination should be normal. Clinically, the seizures are frequent and brief, occasionally occurring many times within a day. BNS have been called “fifth day fits” after the likelihood of the seizures occurring then. BNS is rare, and must be distinguished from BFNC; BNS has a higher rate of status epilepticus and also has an EEG pattern known as trace pointu alternant. This pattern is frequently reported but not exclusively found in BNS, and consists of persistent discontinuous theta activity with intermixed sharp waves that are unreactive and often asynchronous. The pattern occurs in all states and it may persist until the 12th day of life, even after the seizures have ceased. The seizures usually last only a few days but may continue for a few months. Neurologic outcome is normal.

Febrile Seizures

Febrile seizures (FS) are very common, affecting up to 5% of children between 6 months and 6 years, peaking at 14 to 16 months. This is not considered epilepsy but an age-related susceptibility and an expression of symptomatic seizures. Febrile seizures are classified as simple or complicated, the former carrying only a slightly increased risk of epilepsy, about two times that of the general population. Complicated febrile seizures can be associated with an increased risk of epilepsy and generally warrant additional investigation. A simple febrile seizure is defined as one that is generalized, lasts less than 15 minutes, and occurs as an isolated, single event during a febrile illness. Complicated febrile seizures are defined as focal, lasting longer than 15 minutes, and recurrent within a febrile illness. Each of the features carries increased risk of developing afebrile seizures/epilepsy. In addition, prolonged febrile seizures (status epilepticus, defined historically as seizures >30 minutes) have been associated with subsequent development of temporal lobe epilepsy with mesial temporal sclerosis in a subset of children (16). Most children with febrile seizures, even complicated febrile seizures, require no treatment. Rectal benzodiazepines may be offered for seizures more than 5 minutes and recurrent febrile seizures may be treated with a “mini-preventive” approach using an oral benzodiazepine for 48 to 72 hours. Chronic antiseizure treatment should be reserved for those children diagnosed with epilepsy.