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

3.1.1 Epidemiology

SeLECTS is the most frequent SeLFE and accounts for approximately 6%–7% of all childhood epilepsies.^{5, 23} Its incidence is approximately 6.1 per 100 000 children aged <16 years per year.^{24, 25}

3.1.2 Clinical context

The age at onset is usually between 4 and 10 years (range = 3–14 years) in 90% of patients, with a peak at approximately 7 years.²⁶ Both sexes are affected, with a slight male predominance (60%).^{25, 27, 28}

Antecedent, birth, and neonatal history is typically normal. A history of febrile seizures is seen in 5%–15% of cases. Rarely, a history of SeLEAS may be present.²⁹ Development, cognition, neurological examination, and head size prior to seizure onset are typically normal. SeLECTS may be seen in children with a history of prior neurological injury or intellectual disability, but these features are considered coincidental and not causal. Prior to epilepsy onset, attention-deficit/hyperactivity disorder and specific cognitive function deficits, mainly related to language and executive function, may be seen.³⁰

3.1.3 Course of illness

Seizures usually resolve by puberty but can occasionally continue until 18 years of age.³¹ While the epilepsy is active, behavioral and neuropsychological deficits may rarely emerge or worsen, particularly in language and executive functioning.^{32, 33} These deficits often improve or resolve with age.³⁴ The social outcome in adults is very good.³⁵ Seizures typically respond well to ASM. The prognosis for seizure remission is excellent even for those whose seizures are initially difficult to control.³⁶

3.1.4 Seizures

Focal seizures with characteristic frontoparietal opercular features and/or nocturnal bilateral tonic–clonic seizures are mandatory for diagnosis. Seizures are brief, typically <2–3 min, usually few in number (most children have fewer than 10 lifetime seizures), and may occur sporadically, with frequent seizures seen over a few days or weeks and then several months passing before the next seizure.

Characteristic semiology of the focal seizures includes (1) somatosensory symptoms, with unilateral numbness or paresthesia of the tongue, lips, gums, and inner cheek²⁷; (ii) orofacial motor signs, specifically tonic or clonic contraction of one side of the face, mouth, and tongue, then involving one side of the face; (iii) speech arrest—children have difficulty or are unable to speak (dysarthria or anarthria) but can understand language; and (iv) sialorrhea, a characteristic ictal symptom—it is unclear whether this is due to increased salivation, swallowing disturbance, or both. In some cases, focal seizures in sleep evolve rapidly to tonic–clonic activity of the ipsilateral upper limb, to an ipsilateral hemiclonic seizure, or to a focal to bilateral tonic–clonic seizure. Todd paresis may occur postictally. In nocturnal seizures, the initial focal component may often not be witnessed.

Seizures occur during sleep in 80%–90% of patients and only while awake in <20% of children.³⁷ In seizures associated with SeLECTS, cognitive (e.g., gustatory hallucinations), emotional (e.g., fear), and autonomic features are not seen. Moreover, focal motor or focal to bilateral tonic–clonic status epilepticus, defined as seizure persisting for >30 min, is rare³⁷ and, if present, should lead to review of the diagnosis. The occurrence of atypical absence seizures, focal atonic seizures, and focal motor seizures with negative myoclonus with loss of balance and falls should suggest evolution to EE-SWAS, and evidence of cognitive impairment or regression should be sought.

Generalized tonic–clonic seizures, as distinct from focal to bilateral tonic–clonic seizures, during wakefulness are exclusionary, but may be difficult to differentiate clinically.

3.1.5 Electroencephalogram

Background activity is typically normal, with the presence of normal sleep architecture. If sustained focal slowing without centrotemporal spikes or diffuse slowing is recorded, another epilepsy syndrome or a structural lesion should be considered, and brain imaging is recommended.

High-amplitude (>200 μV, peak to trough),³⁸ centrotemporal sharp-and-slow-wave complexes that activate in drowsiness and sleep are mandatory for diagnosis. They are triphasic, high-voltage (100–300 µV) sharp waves (initial low-amplitude positivity, then high-amplitude negativity followed again by low-amplitude positivity), with a transverse dipole (frontal positivity, temporoparietal negativity), often followed by a high-voltage slow wave.^{37, 39} The abnormalities may be isolated or occur in trains of doublets and triplets, and focal, rhythmic, slow activity is occasionally observed in the same region as the spikes. The abnormalities may be unilateral or bilateral and independent (Figure 2A). There may be abnormalities seen outside the centrotemporal region (midline, parietal, frontal, occipital). If a continuous spike-and-wave pattern is present in sleep, the child should be evaluated for progressive language or cognitive impairment or regression. This EEG pattern should only lead to a diagnosis of EE-SWAS if developmental plateauing or regression is present.^{21, 40}

A marked increase in the frequency of epileptiform activity in drowsiness and sleep is typical. The EEG pattern may also change such that sharp waves or spike-and-wave complexes have a broader field and become bilaterally synchronous (Figure 2B). In 10%–20% of children, centrotemporal sharp waves or spike-and-wave complexes may be activated by sensory stimulation of the fingers or toes.⁴¹

Seizures are typically infrequent; it is rare to obtain an ictal recording, and there are few published reports in the literature.⁴² Seizures may be accompanied by a brief decrease in amplitude of the background EEG, followed by diffuse sharp wave abnormalities of increasing amplitude, predominantly in one centrotemporal region,⁴² followed by high-amplitude slowing and then a return to the usual interictal EEG (Figure 2C). With focal to bilateral tonic–clonic seizures, ictal rhythms may become bilaterally synchronous (as opposed to generalized) sharp wave or spike-and-wave activity.^43-45

3.1.6 Imaging

Neuroimaging is normal or may show nonspecific findings. If the electroclinical diagnosis of SeLECTS is made and there are no atypical features, neuroimaging is not required. If there are clinical, developmental, or EEG features or evolution inconsistent with this diagnosis, neuroimaging should be considered. Nonspecific MRI findings, such as hippocampal asymmetry, white matter abnormalities, and enlargement of the lateral ventricles, should not exclude a diagnosis of SeLECTS.⁴⁶ Patients with focal epilepsy due to structural abnormalities such as focal cortical dysplasia, heterotopia, or low-grade brain tumors may mimic SeLECTS but usually show atypical features such as unilateral EEG abnormality or drug resistance.

3.1.7 Genetics

Genetic factors play an important etiological role, as supported by the higher incidence of a positive family history for epilepsy or febrile seizures, and age-dependent, focal EEG abnormalities in the relatives of SeLECTS patients. Siblings may show the EEG trait of centrotemporal abnormalities in an age-dependent, autosomal dominant fashion without clinical seizures.²² However, the clinical epilepsy syndrome is likely complex in inheritance, as pedigrees with multiple individuals with SeLECTS are very rare.⁴² At this time, there are no identified pathogenic gene variants found in most children with SeLECTS. Heterozygous pathogenic variants in GRIN2A can be found in individuals with SeLECTS, who may show evolution to EE-SWAS, with associated language and cognitive impairment.^13-15 Also, copy number variants have been detected in rare cases.⁴⁷ Other genetic etiologies such as fragile X syndrome (FraX) should be considered.

3.1.8 Differential diagnosis

3.2.1 Epidemiology

The prevalence of SeLEAS depends on the age range studied. It accounts for 5% of childhood epilepsies between 1 and 14 years⁵¹ and 13% of childhood epilepsies between 3 and 6 years.⁵² SeLEAS is the most common cause of afebrile nonconvulsive status epilepticus in childhood.⁵³

3.2.2 Clinical context

The usual age at onset is between 3 and 6 years (70% of cases), and ranges from 1 to 14 years.⁵⁴ Both sexes are affected equally. Antecedent and birth history is normal. A history of febrile seizures is seen in 5%–17% of patients. Head size and neurological examination are normal. Development and cognition are normal.^{51, 55, 56}

3.2.3 Course of illness

Seizure frequency is typically low, with approximately 25% of children having a single seizure only, and the majority having fewer than five seizures in total.⁵⁷ Seizures typically remit within 1–2 years, with normal neurodevelopment, although approximately 20% of patients may evolve to other SeLFEs, most commonly SeLECTS.⁵⁷ Rarely, SeLEAS may evolve to EE-SWAS.

3.2.4 Seizures

Focal autonomic seizures, with or without impaired awareness, are mandatory for diagnosis. Autonomic features at onset may vary, but most frequently include retching, pallor, flushing, nausea, malaise, or abdominal pain. Vomiting, the most common autonomic manifestation, occurs in approximately 75% of children and leads to misdiagnosis of acute gastroenteritis or migraine. Additional autonomic features include pupillary (e.g., mydriasis), temperature, and cardiorespiratory (breathing, pallor, cyanosis, and heart rate) changes. Syncope may rarely occur. Seizures frequently evolve with eye and/or head deviation, generalized hypotonia, and focal clonic (hemiclonic) or focal to bilateral tonic–clonic seizure activity. Awareness is usually preserved at seizure onset and may fluctuate in degree of impairment as the seizure progresses. More than 70% of seizures occur from sleep. Seizures are often prolonged and can last longer than 30 min.¹⁷

3.2.5 Electroencephalogram

The background activity is normal. If persistent focal slowing is present, a structural brain abnormality should be sought as an alternative etiology. Diffuse slowing is not seen except in the postictal period.

Multifocal, high-voltage sharp waves or spike-and-wave complexes are typically seen, often over the posterior regions at disease onset. Abnormalities may show marked variability in terms of localization in sequential EEGs, and the predominance of abnormalities might move to either centrotemporal region or frontopolar region. Generalized abnormalities may also be seen.²⁹ EEG abnormalities are activated both by sleep deprivation and by sleep, when abnormalities often have a wider field and may be bilaterally synchronous (Figure S1A,B). Eye closure (elimination of central vision and fixation-off sensitivity) typically activates posterior abnormalities, but this finding is not pathognomonic of this syndrome.

If seizures are recorded, ictal onset varies, but most have posterior onset. The ictal pattern shows rhythmic slow activity intermixed with small spikes and/or fast activity (Figure S1C).⁵⁸

3.2.6 Imaging

Neuroimaging, if performed, shows no causal lesion. MRI should be considered in cases with recurrent seizures or atypical presentations. Nonspecific MRI findings should not exclude a diagnosis of SeLEAS.

3.2.7 Genetics

SeLEAS is probably genetically determined; however, no causative gene variants have been detected so far. There is a higher prevalence of febrile seizures in first-degree relatives and case reports of siblings with other SeLFEs.^{18, 51} There is no clear indication to perform genetic testing in most patients; however, rare cases with SCN1A pathogenic variants have been reported.^59-61

3.2.8 Differential diagnosis

3.3.1 Epidemiology

COVE has a prevalence of 0.3% of children with newly diagnosed, afebrile seizures.²⁶

3.3.2 Clinical context

Age at onset is typically at 8–9 years, with a range from 1 year to 19 years.⁶³ Both sexes are equally affected. Antecedent and birth history is normal. Patients have normal development and cognition, although mild cognitive impairment has been described. Head size and neurological examination are normal.⁶⁴

3.3.3 Course of illness

Remission occurs in 50%–80% of patients by puberty with or without administration of ASM.^{65, 66} Seizures are often responsive to ASM. Remission is more likely in the 90% of patients who only have focal seizures.⁶⁴ Occurrence of bilateral tonic–clonic seizures is associated with a lower rate of remission. Development usually remains normal.

3.3.4 Seizures

Focal sensory visual seizures during wakefulness are mandatory for diagnosis. They have abrupt onset, are brief (typically seconds, most lasting <3 min, rarely up to 20 min), and frequent without treatment. Typically, elementary visual phenomena occur, described as small multicolored circles seen in the peripheral vision, increasingly involving more of the visual field and moving horizontally across to the other side. This may be followed by deviation of the eyes or turning of the head (to the side ipsilateral to the hemisphere of seizure onset).⁶⁷

Other features consistent with occipital lobe onset may occur, including ictal blindness, complex visual hallucinations or illusions (such as palinopsia, micropsia, metamorphopsia), orbital pain, eyelid fluttering, or repeated eye closure.^{68, 69} The seizure may spread outside the occipital lobe, resulting in hemiparesthesia, impaired awareness (14%), and hemiclonic (43%) or focal to bilateral tonic–clonic (13%) seizure.⁶³ Typical absence seizures may rarely occur in some patients after onset of the focal sensory seizures.⁷⁰

There may be ictal or postictal headache, nausea, or vomiting. Postictal headache with migrainelike features is common (in 50% of patients) and may be associated with nausea and vomiting.

3.3.5 Electroencephalogram

The background activity is normal. Interictal occipital sharp waves or spike-and-wave complexes are typically seen but may only occur in sleep. Centrotemporal, frontal, or generalized abnormalities are also present in 20% of cases.⁷¹ Fixation-off sensitivity (facilitation of epileptiform abnormalities with elimination of central vision) is seen in 20%–90% of patients but is not pathognomonic of this syndrome.^{63, 66, 72} EEG abnormalities are enhanced by sleep deprivation and sleep (Figure S2A,B). COVE may rarely evolve to EE-SWAS; therefore, if cognitive regression occurs, a sleep EEG should be performed.

At ictal onset, there is a decrease in the usual background occipital spikes or spike-and-wave complexes with the sudden appearance of unilateral occipital fast rhythms with spikes of low amplitude. There may be slower spike-and-wave abnormalities during oculoclonic seizures or ictal blindness (Figure S2C).^{68, 69}

3.3.6 Imaging

Neuroimaging is normal. Brain MRI is required to exclude a structural brain abnormality.⁷³

3.3.7 Genetics

Genetic testing is not required, as there are no genes identified for this epilepsy syndrome. It is presumed that the etiology is genetic, and likely complex/polygenic in inheritance.¹⁸ A family history of febrile seizures or epilepsy occurs in up to one third of cases, and a family history of migraine is reported in 9%–16% of cases.^{63, 66}

3.3.8 Differential diagnosis

3.4.1 Epidemiology

The prevalence of POLE is low. Epidemiological data are limited, but estimates suggest that POLE accounts for 0.7% of childhood epilepsies.⁷⁴

3.4.2 Clinical context

Age at onset is between 1 and 50 years, but is most commonly between 4 and 17 years (mean = 11 years), although rare cases with adult onset are also reported.⁷⁵ There is a strong female predominance.⁷⁴ Antecedent and birth history is unremarkable, and development is normal. Head size and neurological examination are normal.

3.4.3 Course of illness

Prognosis varies; some patients will have only a few seizures, others have seizure remission over time, and others continue to have photic-induced seizures.⁷⁶

3.4.4 Seizures

Photic-induced, focal sensory visual seizures (induced for example by flickering sunlight) are mandatory for diagnosis and the main seizure type. Young children may find the aura hard to describe but they can sometimes draw a picture of what they see. Visual sensory symptoms include lights, colored spots, formed visual hallucinations, or visual blurring/loss that moves across the visual field. There is associated head and eye version in which the patient feels they are following the visual phenomenon. Seizures can be induced by video games or other photic stimuli, and in the past were often induced by older analog televisions with slower frequency outputs.⁷⁷

Seizures are typically brief (<3 min), although prolonged seizures may occur. Seizures may progress to a cephalic sensation (including headache), autonomic epigastric sensation or vomiting, and impaired awareness or to a focal to bilateral tonic–clonic seizure.^{74, 78} Infrequently, seizures can arise from sleep without photic induction. Some patients also have focal sensory visual occipital seizures without visual induction.⁷⁴ An overlap between this syndrome and the IGEs is well described,^79-81 and thus myoclonic, absence, and generalized tonic–clonic seizures may also be seen. The frequency of seizures is variable.

3.4.5 Electroencephalogram

The background EEG is normal. Interictal occipital spikes or spike-and-wave abnormalities may be seen. Generalized spike-and-wave complexes or centrotemporal spikes may coexist. Occipital spike-and-wave or polyspike-and-wave complexes are facilitated by eye closure and intermittent photic stimulation (Figure S3). Generalized spike-and-wave or polyspike-and-wave (with posterior predominance) complexes may also occur with photic stimulation.⁷⁴ Epileptiform activity is elicited by sleep deprivation and by sleep.

Ictal onset is in the contralateral occipital lobe to the visual field containing the visual sensory phenomena, and to the direction of head and eye deviation.^{74, 76} Occipital ictal patterns may spread to the ipsilateral temporal lobe or the contralateral occipital lobe.

3.4.6 Imaging

Neuroimaging is normal.

3.4.7 Genetics

A family history is reported in one third of patients.⁷⁴ A few families with affected members in multiple generations have been reported.^{79, 82, 83} There is considerable overlap with the IGEs and with SeLECTS.^{80, 84} No known gene exists.

3.4.8 Differential diagnosis

4.1.1 Overview

This syndrome (previously known as Jeavons syndrome) is characterized by the triad of frequent eyelid myoclonia, with or without absences, induced by eye closure and photic stimulation. Eyelid myoclonia is often most prominent on awakening (Table 6).

A subgroup of patients with EEM have prominent photic induction of eyelid myoclonia (with or without absence), and absence or myoclonic seizures.⁸⁶ This subgroup has previously been referred to as “sunflower syndrome,” due to sun-seeking behavior, as they may turn their faces to the sun as a light source at seizure onset.⁸⁷ This subgroup can be termed “EEM with prominent photic induction.”

4.1.2 Epidemiology

This syndrome is rare, and there are no population-based studies on incidence. Several studies from epilepsy centers have shown that it accounts for 1.2%–2.7% of all epilepsy cases seen.^{88, 89}

4.1.3 Clinical context

The peak age at onset is 6–8 years, with a range of 2–14 years.^89-91 There is a 2:1 female:male predominance.^89-91 Antecedent and birth history is normal. Development and cognition are often normal, although individuals with borderline intellectual functioning and intellectual disability are seen. In the subgroup with prominent photic induction, approximately half have intellectual disability or attentional problems, which may become more apparent with age.⁸⁷ Neurological examination is normal.

4.1.4 Course of illness

EEM is often, but not invariably, drug-resistant.^92-94 Generalized tonic–clonic seizures are often controlled with ASMs, whereas eyelid myoclonia are not fully controlled. In adult life, eyelid myoclonia alone may not be associated with EEG change, and thus represents a movement disorder.⁹⁵ EEM is often a life-long condition.^{93, 94}

In the subgroup with prominent photic induction, behavioral management may be important to avoid excessive medication, but is very challenging, particularly in those with intellectual disability. Environmental measures to reduce light exposure are important in these patients, which include wearing wide-brimmed hats and wrap-around sunglasses. Specific blue lenses (Z1) may attenuate the photosensitive response in some patients.⁹⁶

4.1.5 Seizures

Eyelid myoclonia, consisting of brief, repetitive, and often rhythmic 3–6-Hz myoclonic jerks of the eyelids, with simultaneous upward deviation of the eyeballs and extension of the head, is mandatory for diagnosis. These seizures are very brief (typically <1 to 3 s, always <6 s) and occur multiple times each day, even many times per hour. They are typically induced by involuntary or voluntary slow eye closure or exposure to bright light or sunlight.⁹⁷ During eyelid myoclonia, awareness may be intact or mildly impaired; impaired awareness may be subtle and not recognized by the patient.

Up to 20% of patients develop eyelid myoclonic status epilepticus, with repetitive, recurrent eyelid myoclonia associated with mildly impaired awareness and responsiveness. Eyelid myoclonia may also be associated with absence seizures, with mildly impaired awareness. In addition, some patients have typical absence seizures without eyelid myoclonia.

Generalized tonic–clonic seizures occur in the majority of cases but are usually infrequent. They may be provoked by sleep deprivation, alcohol, or photic stimulation.

In the patients with prominent photic induction, eyelid myoclonia (with or without absence), absence, or myoclonic seizures are typically associated with behaviors such as facing a light source and hand-waving in front of the eyes, rubbing the forehead, going up close to an analog television, or using other means to create a flickering effect of light.^{86, 87, 98} Sustained triggering can result in a generalized tonic–clonic seizure.

Febrile seizures occur in 3%–13% patients.^{92, 99} Patients may also have myoclonic and typical absence seizures even if at relatively lesser frequency than eyelid myoclonias. The presence of frequent limb myoclonus should suggest an alternative syndrome diagnosis. Focal seizures are exclusionary.

4.1.6 Electroencephalogram

The background activity is normal; significant EEG background slowing should suggest an alternative diagnosis. Interictally, brief bursts of fast (3–6 Hz) irregular generalized polyspike-and-wave complexes are frequent. Fixation-off sensitivity, which can be induced by eye closure, and intermittent photic stimulation activate the epileptiform abnormality and often elicit eyelid myoclonia with/without absence seizures (Figure 4).^{100, 101} Young patients typically show photic sensitivity, which becomes less apparent with age and ASM. Similarly, sensitivity to eye closure may reduce with age. The epileptiform activity is also elicited by hyperventilation.

In the subgroup with photic induction, generalized spike-and-wave abnormalities are also provoked by photic induction. In those patients, intermittent photic stimulation may trigger brief eyelid myoclonia, typical absence, or myoclonic seizures.

Bursts of generalized spike-and-wave activity often become briefer and fragmented in sleep. Fragmented generalized spike-and-wave complexes can appear as focal or multifocal spike-and-wave complexes but are not consistently localized to one area. The morphology of the focal spike-and-wave complexes resembles that of the generalized spike-and-wave pattern.

Ictal recordings of eyelid myoclonia show high-amplitude, irregular generalized polyspike or polyspike-and-wave complexes, which may be followed by rhythmic spike or polyspike-and-wave complexes at a frequency of 3–6 Hz. Eyelid myoclonia with/without absence is terminated with complete elimination of light. Eyelid myoclonia may or may not be associated with loss of awareness.

4.1.7 Imaging

An MRI is not required with a typical clinical presentation, but if done, shows no causal abnormality.

4.1.8 Genetics

This syndrome likely has shared genetic etiologies with other idiopathic generalized epilepsies. A family history of seizures or epilepsy is present in 25%–83% of cases, with nearly all affected relatives having generalized seizures.^{92, 99} In approximately 20% of cases, there is a family history of an IGE—CAE, juvenile absence epilepsy, juvenile myoclonic epilepsy, or generalized tonic–clonic seizure alone—and nearly half the patients have a family history consistent with genetic epilepsy with febrile seizures plus.⁹⁹

No single pathogenic gene variant is identified in the majority of patients. In patients with this syndrome in the setting of a DEE, several monogenic disease genes have been implicated, including CHD2,¹⁰² SYNGAP1¹⁰³ and NEXMIF¹⁰⁴ (formerly known as KIAA2022); some patients with pathogenic variants in these genes have this syndrome without a DEE.

4.1.9 Differential diagnosis

4.2.1 Epidemiology

The exact incidence is unknown. This syndrome accounted for 0.5%–1% of all epilepsies observed in a specialty epilepsy clinic, Saint Paul Center in Marseille.¹⁰⁵

4.2.2 Clinical context

Peak age at onset is approximately 7 years, with a range of 1–12 years, and males are more commonly affected (70%).^{105, 106} The antecedent and birth history is unremarkable; however, at presentation approximately half of patients have developmental impairment. Intellectual disability may become evident with age, and is ultimately seen in 70% of cases.^105-107 Neurological examination is typically normal.

4.2.3 Course of illness

The evolution of EMA is variable.^{105, 106} Remission occurs in approximately 40% of patients. In the remainder, myoclonic absences persist, or the epilepsy may evolve with the development of other generalized seizure types. Prognosis is more favorable if myoclonic absence seizures are the only seizure type and are controlled with medication.¹⁰⁵

4.2.4 Seizures

Myoclonic absence seizures are mandatory for diagnosis.¹⁰⁵ Absence seizures are associated with rhythmic 3-Hz jerks of the upper limbs, superimposed on tonic abduction of the arms during the seizure (giving a ratcheting appearance). The seizures have an abrupt onset and offset. The patient, if standing, typically bends forward during the seizure, but falling is uncommon. The myoclonic jerks are typically bilateral and symmetric but can be unilateral or asymmetric. Perioral myoclonia and rhythmic jerks of the head and legs may also occur. Seizures last 10–60 s and occur multiple times per day.¹⁰⁷ Alertness varies from complete loss of awareness to retained awareness. Occasionally, autonomic manifestations, such as a change in breathing or urinary incontinence¹⁰⁵ or complex gestural automatisms, may be seen.¹⁰⁸ Myoclonic absences are the only seizure type seen in one third of patients. Myoclonic absence status epilepticus is rare. Generalized tonic–clonic (seen in 45%), clonic, atonic, or typical absence seizures may also occur; multiple seizure types may indicate a more unfavorable prognosis. Only 4% of patients also have typical absence seizures without myoclonic jerks. Focal seizures are exclusionary.

4.2.5 Electroencephalogram

The background activity is normal. Occipital intermittent rhythmic delta activity is typically not seen.¹⁰⁵ Interictal 3-Hz generalized spike-and-wave and polyspike-and-wave abnormalities may occur (approximately one third of cases). Focal abnormalities that arise consistently from one region should raise consideration of an alternative diagnosis of a structural etiology.

Generalized spike-and-wave discharges may be provoked by hyperventilation, which may also trigger myoclonic absence seizures. Intermittent photic stimulation triggers generalized spike-and-wave abnormalities in a minority of patients (14%). Generalized spike-and-wave complexes are also activated by sleep deprivation, drowsiness, and sleep. Similar to other generalized epilepsies, generalized spike-and-wave complexes often become fragmented with sleep deprivation or sleep. The pattern may appear as focal or multifocal spike-and-wave complexes but is not consistently seen in a single area. The morphology of the focal abnormalities appears similar to the generalized spike-and-wave activity.

Regular 3-Hz generalized spike-and-wave complexes accompany myoclonic absence seizures. The 3-Hz discharge is time-locked with the myoclonic jerks (Figure 5). The electromyographic (EMG) recording shows that the myoclonic jerks precede the marked tonic contraction of both deltoids.¹⁰⁵

4.2.6 Imaging

An MRI should be considered to exclude other causes, but if done, it should be normal or may show mild diffuse atrophy.

4.2.7 Genetics

A family history (usually of generalized seizures) is present in 20% of cases. Rarely, there is a family history of febrile seizures. Although EMA is considered to be genetic, there are only isolated case reports of specific pathogenic genetic variants,^{109, 110} with most cases likely to be polygenic. This syndrome is presumed to have shared genetic etiologies with the IGEs.¹¹¹

4.2.8 Differential diagnosis

5.1.1 Epidemiology

EMAtS has an incidence of approximately 1 in 10 000 children and accounts for approximately 2% of childhood epilepsies.¹¹⁵

5.1.2 Clinical context

EMAtS typically begins at between 2 and 6 years (range = 6 months to 8 years). Boys are more commonly affected.¹¹⁶ Approximately one quarter of children have a history of a febrile seizure,^117-120 and such a history is associated with a more favorable long-term outcome.¹²⁰ Development prior to seizure onset is normal in two thirds of patients, and neurological examination is typically unremarkable at onset. Moderate to severe developmental delay preceding seizure onset should be considered as an alert for diagnosis.¹²¹

5.1.3 Course of illness

The onset of EMAtS is often abrupt, with explosive “stormy” onset of many seizures and seizure types often generalized tonic–clonic and myoclonic. In other cases, it evolves more slowly, requiring careful follow-up over the first year to distinguish it from LGS. Seizures often are drug-resistant, particularly during the high seizure frequency (explosive or stormy) phase, and recurrent bouts of nonconvulsive status epilepticus with increased frequency of other generalized seizure types are seen. During this phase, developmental plateauing or even regression, predominantly on behavior and executive functions, and ataxia are often evident. Behavior disorders such as hyperactivity and aggression, and sleep disturbances are also common during the active phase, and typically improve or remit after seizure control is achieved.

Despite seizures being drug-resistant initially, two thirds of children achieve remission, usually within 3 years of onset, and can be weaned off antiseizure therapies.^{120, 122} In the remaining third, persisting seizures, cognitive impairment, aggression, and hyperactivity are often seen. Once seizures are controlled and the EEG improves, developmental progress is seen. Development may return to premorbid levels of function, or the child may be left with a variable degree of intellectual disability. Factors predictive of poorer outcome include tonic seizures, recurrent nonconvulsive status epilepticus, and an EEG showing very frequent or nearly continuous irregular generalized spike-and-wave, slow spike-and-wave, or generalized paroxysmal fast activity.^{120, 122-125}

5.1.4 Seizures

Myoclonic–atonic seizures are mandatory for diagnosis and are characterized by a brief myoclonic jerk affecting the proximal muscles, often associated with a slight vocalization, followed by a very brief atonic component, which may be subtle, with a head nod, or more prominent, with an abrupt fall (Video S1). Conversely, pure atonic seizures, which are also commonly seen, lack the myoclonic component at onset, and lead to an abrupt but brief loss of axial tone, with head nods or a sudden fall.

Other seizures that are frequently seen include myoclonic (which are brief [<100 ms] and can also lead to falls),¹²⁶ absence, and generalized tonic–clonic seizures. The latter may occur with or without fever and are the presenting seizure type in approximately two thirds of cases.^{117, 119, 122}

Tonic seizures appear in some patients later in the course and are associated with a poorer long-term outcome.¹²⁰

Nonconvulsive status epilepticus is also common and may be inaugural. It manifests as impaired awareness, lasting hours to days, with atypical absence, myoclonic, and atonic features, associated with somnolence, unsteadiness, drooling, speech disorders, and erratic myoclonus predominating in the face and upper limbs. Recurrent nonconvulsive status epilepticus is associated with a less favorable outcome.^{120, 124} Epileptic spasms and focal seizures are exclusionary.

5.1.5 Electroencephalogram

The background activity shows a normal, age-appropriate posterior dominant rhythm at onset. Monomorphic, biparietal theta rhythms are characteristic of EMAtS but are not seen in all patients. With increased seizure frequency, generalized, higher amplitude background slowing may be seen.

Interictal abnormalities comprised of generalized 2–6-Hz spike-and-wave or polyspike-and-wave complexes often occurring in bursts lasting 2–6 s are seen (Figure 6A). Long sequences of generalized irregular spike-and-wave discharges should raise the question of nonconvulsive status epilepticus. The generalized discharges can become fragmented, and a consistent spike focus is not seen. Generalized spike-and-wave abnormalities are activated with sleep. Generalized paroxysmal fast activity, consisting of bursts of diffuse or bilateral fast (10 Hz or more) polyspikes during sleep, is rarely seen and should suggest LGS. Hyperventilation may elicit generalized spike-and-wave discharges and absence seizures. Photosensitivity is rare.

Ictal recordings of myoclonic–atonic seizures show generalized polyspike or spike discharges with the myoclonus, followed by a high-voltage slow wave accompanying the atonic component (Figure 6B,C). Simultaneous recording of EMG with EEG is recommended for ictal recordings; polyspikes correlate with brief myoclonus in the neck muscles, whereas the slow wave correlates with loss of muscle activity in the proximal limb muscles. Absence seizures are associated with 2–6-Hz generalized spike-and-wave complexes.

During nonconvulsive status epilepticus, the EEG shows long runs of high-amplitude, 2–3-Hz irregular, generalized spike-and-wave activity, with background slowing.

5.1.6 Imaging

The MRI is normal.

5.1.7 Genetics

A family history of epilepsy or febrile seizures is found in approximately one third of cases^{117, 119, 122, 123, 127} and is associated with a more favorable long-term outcome.¹²⁰ The familial epilepsy syndrome of genetic epilepsy with febrile seizures plus is seen in families of probands with EMAtS.^{128, 129}

In the majority of children, EMAtS has complex inheritance with a polygenic pattern. In some cases, pathogenic variants have been seen in genes including SCN1A,¹³⁰ SCN1B,¹³¹ SCN2A,¹³² STX1B,¹³³ SLC6A1,¹³⁴ CHD2,¹⁰² SYNGAP1,¹⁰³ NEXMIF¹⁰⁴ KIAA2022.¹³⁵ Approximately 5% of patients with EMAtS have GLUT1 deficiency associated with pathogenic variants in SLC2A1.⁸⁵

5.1.8 Differential diagnosis

5.2.1 Epidemiology

LGS accounts for approximately 1%–2% of all persons with epilepsy. In children, LGS is rarely diagnosed at initial seizure onset (0.6%). LGS often evolves from another severe infantile epilepsy syndrome or etiology, with approximately 20% of cases evolving from infantile epileptic spasms syndrome.¹³⁷ Ultimately, 3.6% of all children with epilepsy, and 19% of children with seizures starting in infancy, evolve to LGS.¹³⁸

5.2.2 Clinical context

LGS usually begins between 18 months and 8 years of age, with a peak age at onset of 3–5 years. Onset in the second decade is rare.¹³⁹ It is slightly more common in males. Abnormalities on neurological examination (for example pyramidal signs) are often found and are related to the underlying etiology. Most children have developmental impairment that predates seizure onset in LGS, but developmental stagnation or decline can occur with onset of frequent seizures. Less commonly, development and behavior may be normal at seizure onset.

5.2.3 Course of illness

LGS persists into adulthood in nearly all cases, and seizures remain drug-resistant.¹³⁹ Atypical absence and tonic seizures remain frequent in adults, whereas atonic seizures often settle.¹⁴⁰

Over time, there is developmental slowing, plateauing, or regression, culminating in moderate to severe intellectual disability in >90% of patients.^140-142 Behavior disorders such as hyperactivity, aggression, autism spectrum disorder, and sleep disturbances are common in childhood and adolescence.^{140, 141}

5.2.4 Seizures

Tonic seizures, consisting of a sustained increase in axial and limb muscle contraction lasting from 3 s to 2 min, are mandatory for diagnosis and are most prominent in sleep. They may be subtle, with slow upward eye rolling or deviation, at times with facial grimace or flexor movements of the head and/or trunk, or more clinically obvious, with a brief cry, apnea, abduction, and elevation of the limbs with a vibratory component and bilateral fist clenching. If occurring while the patient is standing, they may forcefully throw the patient off balance, leading to a fall (drop attack), with the patient often sustaining an injury. Tonic seizures may be exacerbated by medications that lead to increased sleepiness, such as acute use of high-dose benzodiazepines.

5.2.5 Electroencephalogram

Focal or multifocal slow spike-and-wave pattern may also be seen. Abnormalities are not typically activated by photic stimulation.

Tonic seizures, which are often subtle, and may not be recognized by families, are typically recorded on sleep EEG. The EEG pattern of tonic seizures consists of a burst of bilateral 10-Hz or higher frequency fast activity with a recruiting rhythm—an initial diffuse decrement followed by gradual increase in amplitude (Figure 7C). Polygraphic recordings during tonic seizures often show a brief apnea with electromyographic axial muscle contraction. Because of these characteristic findings, a sleep recording can be beneficial to distinguish LGS from other epilepsy syndromes.

Atypical absence seizures are associated with slow spike-and-wave (<3 Hz) complexes, although it can be challenging to clearly distinguish between ictal and interictal slow spike-and-wave patterns.

5.2.6 Imaging

As structural causes are the most common etiology, MRI at onset is strongly recommended, as this may impact on treatment decision-making.¹⁴⁶ A variety of structural etiologies may be found, including focal or diffuse cortical malformations, tuberous sclerosis complex, tumors, or acquired brain injury such as hypoxic–ischemic encephalopathy. Reinvestigation of older patients with LGS can result in identification of structural etiologies missed on previous imaging.¹⁴⁷ MRI may also be normal.

5.2.7 Genetics

Pathogenic variants in many genes have been associated with the etiologies that causes LGS and are usually de novo in the child.^{148, 149} A range of chromosomal abnormalities and copy number variants have been associated with LGS, so chromosomal microarray is essential. A range of next generation sequencing approaches can be taken, ideally with whole exome sequencing, or an epilepsy gene panel, particularly if no etiology is found after clinical examination and MRI. Furthermore, genetic testing should also be considered for patients with structural brain disorders suggestive of an underlying genetic cause.

5.2.8 Metabolic testing

Rarely, LGS can be due to a neurometabolic disorder. Metabolic testing should be considered if an underlying etiology is not found with imaging or genetic studies.

5.2.9 Differential diagnosis

5.3.1 Epidemiology

DEE-SWAS and EE-SWAS are rare, accounting for 0.5%–0.6% of all epilepsy presentations seen at pediatric tertiary epilepsy centers.^151-153

5.3.2 Clinical context

DEE-SWAS and EE-SWAS are characterized by onset of seizures at between 2 and 12 years of age (peak = 4–5 years), with the EEG developing spike-and-wave activation in sleep 1–2 years after seizure onset in association with cognitive/behavioral regression or plateauing. Both sexes are affected equally. Antecedent and birth history are often normal; however, structural brain lesions are a risk factor for DEE-SWAS and EE-SWAS. Specifically, thalamic injury in early life¹⁵⁴ and malformations such as bilateral perisylvian polymicrogyria are associated with this syndrome; therefore, neuroimaging, particularly MRI, is recommended whenever possible. Neurological examination and developmental level may be normal or reflect an underlying structural brain abnormality. Regression in cognitive, behavioral, or psychiatric functioning is the cardinal symptom of this syndrome. All cognitive domains can be affected, including language and communication, temporospatial orientation, attention, and social interaction. Motor regression with dyspraxia or dystonic features may also occur.¹⁵⁵ Follow-up visits with clinical assessment, EEGs, and neuropsychological testing should be scheduled at baseline and during the follow-up to assess the evolution.¹⁵⁶

5.3.3 Course of illness

Clinical seizures typically remit around puberty, even in patients with a structural lesion.¹⁵⁷ Resolution of clinical seizures may precede, coincide with, or follow the resolution of the EEG pattern.¹⁵⁷ The SWAS pattern on EEG also resolves, typically by adolescence.^{158, 159} Focal abnormalities may persist during both wakefulness and sleep. Sleep architecture normalizes with resolution of SWAS.¹⁵⁸

Neurocognitive and behavioral improvement is typically seen, with resolution of the SWAS on EEG.¹⁶⁰ However, many patients have residual impairment, which is severe enough to limit independent functioning in approximately half of the patients.^{161, 162} The duration and etiology of DEE-SWAS and EE-SWAS are the most important predictors of cognitive outcome; the risk of poor outcome is higher if it is present for >2 years.¹⁶³ Poorer outcomes are also seen with younger onset of DEE-SWAS.¹⁶³ Thus, early diagnosis is of paramount importance to enable initiation of treatment to improve long-term outcome even if some causes are not treatable (the etiology prevails), and there may be no clinical improvement for some when the EEG pattern is abolished. Nevertheless, residual deficits may remain following remission of seizures and SWAS, which may occur from months to 7 years after onset.

5.3.4 Seizures

There is no mandatory seizure type. Seizure type is dependent on the underlying etiology. Furthermore, EE-SWAS and DEE-SWAS may occur in patients who do not have clinical seizures.

In most patients, infrequent and drug-responsive seizures are observed during the initial phase at between 2 and 5 years of age. These early seizures are typically focal motor, with or without impaired awareness, and focal to bilateral tonic–clonic seizures. Seizures typically worsen with the evolution of multiple seizure types. These include focal seizures with or without impaired awareness, typical and atypical absence seizures, atonic seizures, and focal motor seizures with negative myoclonus.

5.3.5 Electroencephalogram

The EEG pattern depends on the underlying etiology. The background activity during wakefulness may show focal or diffuse slowing and often contains focal or multifocal abnormalities, but it may be normal (Figure 9A). Epileptiform abnormalities during wakefulness are not continuous. In drowsiness and sleep, there is marked activation of epileptiform activity, with slow (1.5–2 Hz) spike-and-wave complexes in N-REM sleep. Typically, this activity is also seen in Stage II sleep (Figure 9B). SWAS is usually diffuse but may occur more focally (typically frontally) or multifocally. In rapid eye movement sleep, the abnormalities become less frequent or may even be absent. Normal sleep architecture (vertex sharp waves, sleep spindles, and K complexes) is absent or difficult to distinguish. An overnight sleep EEG may be required, as slow wave sleep may not be achieved on an outpatient sleep EEG. The ictal EEG correlates with the seizure type.

5.3.6 Imaging

Neuroimaging may be normal or demonstrate underlying structural brain abnormalities that may be developmental (e.g., perisylvian polymicrogyria) or acquired (thalamic abnormalities can be observed).

5.3.7 Genetics

Some cases have a genetic basis and may follow monogenic or complex inheritance. A family history of seizures is seen in up to 50% patients with DEE-SWAS or EE-SWAS.¹⁶⁴ The major monogenic cause is GRIN2A, which encodes the N-methyl-D-aspartate (NMDA) receptor glutamate receptor alpha 2 subunit.¹² Pathogenic variants are associated with a range of severity of DEE-SWAS phenotypes.^13-15 These individuals have a characteristic speech pattern, which may persist into adult life.¹⁶⁵

5.3.8 Differential diagnosis

5.4.1 Epidemiology

This is a rare syndrome, which is likely underrecognized, with an estimated incidence of 1 per million.¹⁷⁰

5.4.2 Clinical context

FIRES occurs most commonly in school-aged children (mean = 8 years) with a typical range of 2–17 years.^{166, 169, 171} It is exceedingly infrequent under the age of 2 years and can begin at a variable age, but may rarely occur in young adulthood. Both sexes are affected, with a slight male predominance.¹⁷¹ Perinatal history is typically normal. At presentation, children are developmentally normal, without a history of prior neurological disease including epilepsy, and have normal head size.

All children have a history of a prior febrile infection, most commonly upper respiratory or gastrointestinal, between 24 h and 2 weeks before onset of refractory status epilepticus. At the time of seizure onset, patients may still be febrile, or may have had recent resolution of the fever.

At presentation, patients are typically encephalopathic and have frequent seizures despite ASMs. Head size is normal. Persistent focal abnormalities on examination are unusual, but transient Todd paresis may be seen.

5.4.3 Course of illness

The prognosis is variable but often poor.¹⁷¹ Mortality is approximately 10% in the acute phase, due to intensive care complications such as sepsis, or uncontrolled status epilepticus. Following the acute phase, most children are left with drug-resistant, multifocal epilepsy.

Developmentally, in the acute stage, most children regress, and at follow-up, in the chronic phase, the majority are left with varying degrees of intellectual disability.¹⁷¹ Approximately one third of survivors have normal or borderline cognition (often learning disorders), one third have mild to moderate intellectual disability, and one third have severe to profound disability or are vegetative. Poorer outcome was associated with longer duration of medically induced burst-suppression coma and younger age at onset.¹⁷¹ Attention and behavior problems, including aggression, are also common in survivors.

In the chronic phase, many patients will have evidence of motor dysfunction.

5.4.4 Seizures

Focal or multifocal seizures are mandatory for diagnosis and may evolve to bilateral tonic–clonic seizures. Common ictal symptoms are eye deviation and hemifacial twitching. Seizures progress in frequency and severity rapidly to culminate in superrefractory status epilepticus (defined as >24 h) in the acute phase.

5.4.5 Electroencephalogram

The EEG background activity is typically abnormal, with slowing and multifocal abnormalities. Recurrent extreme delta brush, consisting of a paroxysmal beta–delta complex of 15–18-Hz beta superimposed on 1–3-Hz delta in the frontal and central head regions, is often seen (Figure S4A,B).¹⁷² This pattern may be modified by anesthetic agents used for the treatment for status epilepticus.

Prolonged video-EEG monitoring at diagnosis shows a gradual increase in seizure burden over the first days to week of illness. Initially, seizure burden may be low, but over time, frequent, multifocal subclinical and clinical seizures are recorded, usually with a frequency of several per hour.¹⁷² A typical seizure pattern, consisting of focal activity of >10 Hz of low to moderate amplitude, evolving to well-formed, rhythmic spikes and spike-and-wave complexes, is seen, and ictal activity often shifts from one hemisphere to the other (Figure S4C).¹⁷²

5.4.6 Neuroimaging

During the acute stage, the MRI is normal in approximately two thirds of cases. Approximately one third may show T2 hyperintense changes in bilateral temporal regions, insula, basal ganglia, and/or thalami, which may be subtle. Leptomeningeal enhancement may also be seen but is not specific to this syndrome.¹⁷³

During the chronic stage, the MRI usually shows variable degrees of diffuse cerebral atrophy, and/or signal changes over the temporal lobes, cerebral cortex, periventricular white matter, hippocampi, and basal ganglia.¹⁷³

5.4.7 Genetics

This disorder is not suspected to be genetic, and no causal genes have been identified. There is usually no family history of seizures.

5.4.8 Other laboratory studies

Examination of cerebrospinal fluid (CSF) is required to exclude infection. The CSF is typically normal but may show a mild pleocytosis. CSF protein and lactate are normal. Oligoclonal bands are negative. An immune etiology should be excluded, but in FIRES, no causal antibodies have yet been found.¹⁶⁹ Serum and CSF autoimmune panels are negative. It has been reported that Th1 chemokines (CXCL9, CXCL10, etc.) are predominantly upregulated in CSF, independently of interleukin-1 receptor (IL-1R) signaling.¹⁷⁴ Metabolic studies are unremarkable. In some cases, excessive neuroinflammation, which may be secondary to functional deficiency in IL-1R antagonist, has been reported.^{175, 176}

5.4.9 Differential diagnosis

5.5.1 Epidemiology

HHE is a rare syndrome and its incidence has declined markedly in resource-equipped countries over the past 30 years since the instigation of aggressive treatment for prolonged seizures or status epilepticus.¹⁷⁸

5.5.2 Clinical context

Age at onset is typically <4 years, and there is no sex predilection.^{178, 179} Birth and antecedent history are noncontributory, and previous development and neurological examination are normal. Children present with prolonged focal status epilepticus and then develop immediate hemiparesis. The diagnosis of HHE should be considered when a persistent hemiplegia is observed after febrile status epilepticus in a child younger than 4 years. Aphasia may also be present acutely in up to one quarter of cases, if the dominant hemisphere is involved.¹⁸⁰

5.5.3 Course of illness

The majority of children are left with a permanent motor deficit. However, this deficit may be minimal or resolve within 12 months in 20%.¹⁷⁷ If present, aphasia most commonly resolves within 2 months¹⁸⁰ but may persist.¹⁸¹ Subsequent focal seizures appear after a variable duration, with 85% having seizure onset within 3 years of the initial status epilepticus.¹⁷⁸ Focal seizures during the chronic phase are typically drug-resistant,¹⁷⁹ but may be amenable to surgical treatment, such as hemispherotomy.^{178, 182} Many children are also left with variable degrees of intellectual disability.¹⁷⁸

5.5.4 Seizures

The first seizure is typically focal clonic febrile status epilepticus. The clonic component may be subtle. There is typically a seizure-free period after the focal status epilepticus that can last months to years. After a variable period, focal motor seizures and/or focal to bilateral tonic–clonic seizures appear, and usually become drug-resistant. Seizures may localize solely to the temporal lobe or may arise from extratemporal regions or be multifocal.¹⁸²

5.5.5 Electroencephalogram

If an EEG is obtained during the acute focal status epilepticus, the ictal discharge is characterized by rhythmic (2–3 Hz) slow waves that are usually bilateral with higher amplitude over the affected hemisphere (Figure S5A,B).¹⁷⁸ In addition, over the affected hemisphere, recruiting rhythms (10 Hz) are frequently seen.¹⁷⁸ The background activity may be normal at onset, but during the chronic phase, there is excess slowing (often asymmetric) and epileptiform abnormalities, which are most prominent over the affected hemisphere, but may be bilateral.

5.5.6 Imaging

MRI immediately following the status epilepticus demonstrates diffuse hemispheric signal abnormalities with T2 hyperintensity and restricted diffusion, predominantly of the subcortical white matter of the affected hemisphere.¹⁸³ Edema of the affected hemisphere can be severe, leading to mass effect and possible herniation (Figure S5C–F).¹⁷⁸ If magnetic resonance spectroscopy is done, it shows decreased N-acetyl aspartate and mildly increased lactate in the affected hemisphere. On Day 8–15 after status epilepticus, cytotoxic edema decreases, with normalization of apparent diffusion coefficient images and ongoing T2 hyperintensity, with evolving volume loss. Within 1 month, atrophy of the affected cerebral hemisphere is clearly evident. Hippocampal sclerosis is also commonly seen (Figure S5G–J).¹⁸²

5.5.7 Genetics and other testing

Genetic testing and evaluation for coagulation, metabolic, infective, and immune disorders are typically normal.^{178, 184}

5.5.8 Differential diagnosis