ILAE classification and definition of epilepsy syndromes with onset in neonates and infants: Position statement by the ILAE Task Force on Nosology and Definitions

Self-limited (familial) neonatal epilepsy (SeLNE)

Self-limited neonatal epilepsy and self-limited familial neonatal epilepsy have similar clinical and electrical features but can be distinguished on the basis of family history (Table 1).^29-31 These entities have similar genetic etiologies, with de novo pathogenic gene variants responsible for nonfamilial cases. A family history should be carefully sought as it can support diagnosis and guide decisions on investigation, treatment, and prognosis. The familial syndrome was known previously as benign familial neonatal seizures or convulsions.

Seizures typically start between days 2 and 7 of life and often have focal tonic or focal clonic features or may progress to have sequential features.³ Focal seizures may alternate sides from seizure to seizure. Seizures can recur over hours to days. Developmental milestones are usually normal.³¹

Epidemiology:

The estimated incidence of SeLNE is 5.3/100 000 live births.⁹

Clinical context:

These syndromes present between days 2 and 7 of life.^29-31 If children are born prematurely, seizures may occur within days of the corrected gestational age of 40 weeks. Both sexes are affected equally.

Pregnancy and birth history are unremarkable. Infants appear otherwise developmentally appropriate for age. Head size and neurological examination are normal.

Course of illness:

Seizures usually remit by 6 months of age, the majority ceasing by 6 weeks of age. If antiseizure medication has been commenced, it can often be stopped within weeks. Developmental progress is usually normal, although a minority of cases may have learning difficulties or mild motor impairment. Studies report that up to one third of individuals have seizures in later life.³⁰ These include febrile seizures, clusters of focal seizures, isolated generalized tonic-clonic seizures, and in a minority, self-limited epilepsy with centrotemporal spikes.^{29, 30, 32} Some patients with specific pathogenic gene variants may have myokymia (continuous muscle activity causing stiffness and subtle twitching), which may present later in infancy.³³

Seizures:

Seizures are characterized by focal tonic features at onset, affecting the head, face, and limbs.^{29, 30, 34} These may progress in a sequential pattern with tonic, clonic, myoclonic, and autonomic features following each other without a single predominant feature. There is often changing lateralization within or between seizures. Vocalization and/or automatisms may be seen. Autonomic features such as apnea and cyanosis are present in one third of seizures and may be the predominant manifestation. A recent paper comparing the presenting features of genetic epilepsies and acute provoked seizures in the neonate reports that seizures in genetic epilepsies (primarily KCNQ2-related SeLNE) tend to have later onset and be of shorter duration than acute provoked seizures associated with stroke or hypoxic ischemic encephalopathy.³⁵ Clusters of seizures in self-limited neonatal epilepsy may occur over hours or days, with the neonate behaving normally between events.³⁶ Clinical examination is normal between events except in the immediate post-ictal period or if the infant is sedated by medication.

EEG:

The EEG background may be normal or may show minor nonspecific abnormalities.³⁴ Focal interictal epileptiform abnormalities can be seen in approximately two thirds of cases, most commonly in the central, centrotemporal, or frontotemporal regions with a normal background.^{34, 35} During periods of more active seizures, focal or widespread slowing may be seen; however, in contrast to KCNQ2-DEE, a burst-suppression pattern, or more marked, persistent slowing is not observed.

A typical ictal pattern has been described with an initial attenuation of the EEG lasting up to 20 s, followed by repetitive spike discharges (mainly centrotemporal, although other regions can be affected; Figure 2), which are often bilateral but asynchronous and with shifting laterality.^{34, 37} The topography can change from one seizure to the next.

Imaging:

Neuroimaging does not show a causal lesion for the epilepsy.

Genetics:

Autosomal dominant inheritance patterns are seen within families (sometimes with incomplete penetrance). SeLNE may be due to de novo pathogenic variants in the same genes, KCNQ2 and KCNQ3, as self-limited familial neonatal epilepsy. The KCNQ2 and KCNQ3 genes code for potassium channel subunits, which come together to form a heterotetrameric potassium ion channel (the M channel).^38-40

A family history of SeLNE is required for self-limited familial neonatal epilepsy. There is often variability in the duration of the epilepsy in affected family members. In more than 90% of families, a pathogenic variant is identified.³⁰ Pathogenic variants in KCNQ2 are the most common cause of the syndrome, being present in over 80%, and include stop codons, deletions, and frameshift mutations resulting in haploinsufficiency, as well as certain missense variants that cause mild to moderate loss of channel function.^{41, 42} KCNQ3 and SCN2A pathogenic variants are much less frequent.

Self-limited familial neonatal-infantile epilepsy (SeLFNIE)

SeLFNIE is an autosomal dominant syndrome with onset in the neonatal or infantile period in different family members (Table 2).⁴³ This disorder was identified in families and found to be due to dominantly inherited SCN2A pathogenic variants.⁴⁴ In addition, rare families have KCNQ2 pathogenic variants.⁴⁵ De novo pathogenic gene variants are likely to cause nonfamilial cases. This syndrome can only be distinguished from the SeLNE or SeLIE if there is a family history documenting onset of self-limited epilepsy in some family members in the neonatal period, and others in the infantile period. Seizures start between day 2 and 7 months of life and have a semiology that is similar to self-limited neonatal epilepsy, with focal clonic or focal tonic features, often occurring in clusters. Seizures can recur over hours to days. Developmental milestones are typically normal.

Epidemiology:

The estimated incidence is unknown.

Clinical context:

SeLFNIE presents from 1 day to 23 months of life (mean 11 weeks, median 13 weeks).⁴⁶ Both sexes are affected equally. Perinatal history is unremarkable. Infants are developmentally appropriate for age with normal examination and head circumference. No other clinical features are seen (such as movement disorders).

Course of illness:

Seizure frequency varies, with some infants having only a few seizures and not requiring treatment, whereas others have clusters of many seizures per day. Seizures cease by age 12–24 months, with no recurrences later in life. Seizures are readily controlled with antiseizure medications.

Seizures:

Initially focal tonic features are observed with head and eye deviation, followed by other tonic and clonic features. Some have prominent apnea and staring. Seizures vary in duration from 20 s to 4 min. Seizures with fever are rare.

EEG:

The EEG background is typically normal. During periods of more active seizures, focal discharges, which are mainly in posterior regions, or widespread slowing may be seen.⁴⁷

Imaging:

Neuroimaging does not show a causal lesion for the epilepsy.

Genetics:

Autosomal dominant inheritance with high penetrance is seen with different family members showing a mixture of neonatal and infantile onset. This syndrome is associated primarily with pathogenic variants in the sodium channel subunit gene: SCN2A. Some families with self-limited seizures associated with KCNQ2 may have individuals presenting outside the neonatal period.^{43, 45}

Self-limited (familial) infantile epilepsy (SeLIE)

SeLIE, formerly called benign familial (and nonfamilial) infantile seizures, is a syndrome characterized by the onset of seizures in the infantile period (Table 3). Seizures are often frequent and may be difficult to control at onset, but they resolve spontaneously. Children have normal developmental progress. The syndrome was first described in families with a dominant inheritance of infantile seizures.⁴⁸ Later, it was expanded to include the familial syndrome of Infantile Convulsions Choreo-Athetosis with a movement disorder of paroxysmal kinesigenic dyskinesia/dystonia, with affected family members having either seizures or movement disorder, or both.⁴⁹

De novo and familial SeLIE are clinically identical except for the presence of a family history in the latter. Pathogenic variants in PRRT2 are the most common genetic etiology. Familial cases show autosomal dominant inheritance, with incomplete penetrance.

Epidemiology:

SeLIE is relatively common, accounting for 7%–9% of all epilepsies beginning prior to 2 years of age.⁵⁰ The incidence is estimated at 14.2/100 000 live births.⁹

Clinical context:

Age at onset ranges from 3 to 20 months with a peak of 6 months. The antenatal, birth, and neonatal history is typically normal. Head size and neurological examination are normal.

Course of illness:

Seizures may be frequent at onset but usually remit within 1 year from onset. In untreated cases there can be isolated or brief clusters of seizures within the period from onset to remission.⁵¹ A minority of individuals may have epilepsy persisting into later life.

Patients with proline rich transmembrane protein 2 (PRRT2) pathogenic variants may develop paroxysmal kinesigenic dyskinesia/dystonia beginning from childhood to adult life.^{52, 53} Symptoms of the movement disorder should be sought for specifically as the events are very brief, lasting seconds, and the diagnosis is often missed.

Seizures:

Focal seizures are mandatory for diagnosis, and occur with behavioral arrest, cyanosis, staring with impaired awareness, automatisms, head/eye version, and clonic movements. Focal clonic seizures may alternate from one side to the other and progress to a bilateral tonic-clonic seizure but do not migrate from one side to another within the same seizure. Seizures are brief (<3 min) but can be frequent (eg, 5–10 per day over 1–3 days at onset). One third of patients present with a single isolated seizure 10–15 days before frequent seizures commence. Longer seizures can occur but are rare. Seizures remit but recur after 1–3 months in a third of patients.⁵⁴

Epileptic spasms and/or myoclonic seizures are exclusionary for this diagnosis.

EEG:

The background EEG is normal, although focal slowing may occur postictally.⁵⁵ The interictal EEG is typically normal, but a variant with midline spikes during slow sleep has been described.^56-58 If there is persistent focal slowing in one area, a structural brain abnormality should be considered. Diffuse, persistent slowing would suggest a different syndrome.

The ictal recording is characterized by focal discharges, which often have onset in the temporal or posterior head regions, and which may spread to both hemispheres (Figure 3).⁵⁵ The seizure onset may vary from lobe to lobe or from hemisphere to hemisphere in different seizures in the same patient. However, the ictal pattern within the same seizure does not show a migrating pattern.

Imaging:

Neuroimaging does not show a causal lesion for the epilepsy. If the electroclinical diagnosis is clear and there is a family history, and/or a PRRT2 pathogenic variant, neuroimaging is not mandatory.

Genetics:

PRRT2 is the most commonly implicated gene.^{9, 41, 53} Other genes rarely associated with this syndrome include SCN8A, in which a movement disorder is also observed.⁵⁹ Infantile onset is also seen in patients with pathogenic variants in SCN2A (see above section on SeLFNIE). In familial cases, inheritance is autosomal dominant with high penetrance. A genetic etiology can be identified in about 80% of cases.⁹

Genetic epilepsy with febrile seizures plus (GEFS+) spectrum

GEFS+ was described initially as an autosomal dominant familial epilepsy with variable penetrance.⁶⁰ GEFS+ includes a spectrum of epilepsy phenotypes including epilepsy with myoclonic atonic seizures, DS,⁶¹ idiopathic and other genetic generalized epilepsy syndromes,⁶² and focal epilepsies,⁶³ with heterogeneous phenotypes, usually present in the same family. Although febrile seizures are the hallmark of GEFS+ and occur in many affected family members, not all affected family members have febrile seizures. GEFS+ has heterogeneous genetic etiologies, with pathogenic variants in several genes identified.

Although the most common phenotype in GEFS+ is classical febrile seizures, the next most common phenotype is Febrile Seizures plus (FS+). Children with FS+ may have several different presentations: the most frequent is where typical febrile seizures continue beyond the age of 6 years, the typical age at which most febrile seizures stop. In infancy, a strong family history of GEFS+ phenotypes suggests this diagnosis, but more recently, cases with FS+ phenotypes have been identified without a family history and a de novo pathogenic variant in a GEFS+ gene.⁶⁴

Epidemiology:

GEFS+ is a common familial syndrome; however, epidemiological data on the incidence are lacking.

Clinical context:

The following describe the specific FS+ phenotype. Specific syndromes are described elsewhere.

Febrile seizures in GEFS+ families may begin prior to 6 months of age unlike typical febrile seizures (which begin after age 6 months and mainly after 12 months) and persist beyond 6 years of age.^{60, 65} FS+ is the term used to describe febrile seizures persisting after 6 years of age and/or evolving to afebrile seizures. Other afebrile seizure types may develop at various ages. Prolonged focal clonic (hemiclonic) seizures with fever prior to 15 months, particularly if recurrent, should suggest DS. Neurological examination and cognitive abilities are usually normal.

Course of illness:

Seizures in FS+ are typically responsive to antiseizure medications, although not all patients require prophylactic treatment. Patients presenting with only FS+ usually have a self-limited epilepsy with resolution of seizures by puberty.⁶⁰ The course of illness for individuals presenting other epilepsy types or epilepsy syndromes within the spectrum of GEFS+ depends on the type of epilepsy or syndrome.

Seizures:

Febrile seizures, which may be generalized or focal, are mandatory for diagnosis. In addition, a variety of other generalized or focal afebrile seizures may be seen.^{60, 62, 63, 65, 66}

EEG:

The background EEG is normal. Occasionally focal or generalized spike and wave may be seen. The ictal EEG varies according to the seizure type.

Imaging:

Brain magnetic resonance imaging (MRI), if done, does not show a causal etiology in patients with GEFS+ syndromes.

Genetics:

Inheritance is autosomal dominant, with variable penetrance.^{60, 62, 65} Members of the same family may present with different types of seizures or epilepsy syndromes that may or may not be associated with fever or febrile seizures.^{60, 65, 66}

Although SCN1B was the first gene identified,⁶⁷ it is not the most common gene associated with GEFS+, with SCN1A pathogenic variants identified in ~10% of GEFS+ families.^{62, 68} Other gene variants encoding voltage-gated sodium, calcium, and potassium channels, and ligand-gated ion channels including nicotinic cholinergic receptor subunits, the γ-aminobutyric acid (GABA) A receptor subunits, and syntaxin 1B (STX1B) have also been linked to the syndrome.^{69, 70}

Myoclonic epilepsy in infancy (MEI)

This syndrome presents with myoclonic seizures at onset, which may be activated by sudden noise, startle, or touch, and less commonly by photic stimulation (Table 4). Some authors propose that the term “Reflex Myoclonic Epilepsy in Infancy” should be used if myoclonic seizures are activated by triggering factors such as sudden noise or startle, and they propose that children with this syndrome have a slightly earlier age at onset, better response to antiseizure medication, higher remission rate, and more favourable cognitive outcome.⁷¹ However, this syndrome could be considered a subgroup of MEI. Seizures are self-limiting in most cases. An EEG, ideally with video and electromyography (EMG), is mandatory to confirm the epileptic nature of the myoclonus and to exclude Infantile Epileptic Spasms Syndrome (IESS), which is much more common and severe than MEI.

Epidemiology:

MEI is a rare disorder, accounting for less than 0.8% of children with epilepsy treated at a specialty center.⁷² It accounted for 1.1% of all epilepsy with onset prior to 36 months of age in a population-based cohort.⁹

Clinical context:

The syndrome begins between the ages of 4 months and 3 years, with a peak age of 6–18 months. Males are more commonly affected, with a M:F ratio of ~2:1.⁷² Development prior to seizure onset is usually normal. However, mild cognitive or behavioral or motor difficulties may coexist at onset and should not exclude the diagnosis, as they might be incidental. Neurological examination is normal.

Course of illness:

Myoclonic seizures remit in nearly all cases, within 6 months to 5 years from onset, and most children can discontinue antiseizure therapy. Rarely, generalized tonic-clonic seizures may be seen in later life. Approximately 10% develop other epilepsies in late childhood or adolescence—mostly juvenile myoclonic epilepsy.⁷² Patients with photosensitivity may have seizures that are more difficult to control. At long-term follow-up, developmental outcome was normal in 63%–85% of cases.^72-77 Occasionally, mild intellectual disability, learning disorders, or attention problems evolve over time. Rarely, moderate to severe intellectual disability can be seen, and it is not necessarily correlated with seizure frequency.

Seizures:

Myoclonic seizures are mandatory for diagnosis and involve the head and the upper arms. They usually occur multiple times per day, both in wakefulness and sleep. They can occur in clusters and can lead to falls. Reflex-induced myoclonic seizures are seen in about one third of cases and are triggered by sudden noise, touch, or startle.⁷² Febrile seizures are present in up to one third of cases⁷² and may either precede or follow myoclonic seizures. Epileptic spasms, tonic, absence, and focal seizures are exclusionary. In addition, generalized tonic-clonic or generalized clonic seizures present at epilepsy onset are exclusionary.

EEG:

The EEG background in wakefulness is normal. Interictally, generalized discharges in the form of spike-and-wave, or less frequently, polyspike-and-wave, may be seen, and are more common in the early stages of sleep (Figure 4). Photic stimulation does not provoke spike-wave discharge without concomitant myoclonus, but a photoparoxysmal response can be seen after disappearance of myoclonic seizures in a minority of patients. The ictal EEG shows brief bursts of generalized spike-and-wave, polyspike, and polyspike and wave at ~3 Hz during myoclonus. Myoclonic seizures are more commonly recorded from sleep, and may be triggered by sudden noise, touch, or startle, or occasionally by intermittent photic stimulation.^{73, 78} Concurrent EMG recording facilitates diagnosis.

Imaging:

Brain MRI does not show a causal lesion for the epilepsy.

Genetics:

A family history of epilepsy or febrile seizures is reported in ~10% of cases.⁷² No causal genes have been found.

Differential diagnosis:

Early-infantile developmental and epileptic encephalopathy (EIDEE)

Predominant seizure types include focal tonic, generalized tonic, myoclonic, focal clonic, and epileptic spasms. Sequential seizures may occur.^{3, 79} EIDEE includes neonates and infants previously classified as Ohtahara syndrome and Early Myoclonic Encephalopathy.^{79, 80} The syndrome may have many and varied underlying etiologies including genetic, metabolic, and structural. The electroclinical descriptions of Ohtahara syndrome (predominantly burst suppression EEG pattern and tonic seizures) and Early Myoclonic Encephalopathy (predominantly myoclonic seizures and either burst-suppression or other significant EEG abnormalities) have been extremely valuable in epilepsy classification.^{81, 82} This nomenclature allowed clinicians and researchers to study the causes, outcomes, and treatment of neonates and infants with severe early onset epilepsy and provided families with crucial information on prognosis. However, the electroclinical features of these two syndromes have considerable overlap and furthermore share similar underlying etiologies.^{80, 83-85} The Task Force proposed that separating EIDEE into individuals with Ohtahara vs. Early Myoclonic Encephalopathy no longer provides valuable information for clinical decision-making or determination of prognosis.

Epidemiology:

The incidence of EIDEE is estimated as 10/100 000 live births.⁹

Clinical context:

This syndrome begins in the early infantile period (range 0–3 months) and affects boys and girls equally. The neurological examination is often severely abnormal, with abnormalities of tone (most frequently central hypotonia), posture, and motor behavior with cortical visual impairment. Abnormal neurological behavior or development often presents prior to onset of seizures but may be challenging to recognize due to extremely early onset (review of early videos can be helpful). Most children have moderate to profound developmental impairment. Family, pregnancy, and birth history are usually normal. Head size varies dependant on etiology but may be normal at birth.

Course of illness:

The seizures are usually drug resistant unless metabolic or genetic targets for precision therapy or structural abnormalities amenable to surgery are identified.^{86, 87} For instance, patients with pathogenic variants in SCN2A or SCN8A show seizure response to sodium channel agents, often at high dose.^88-90 EIDEE, regardless of whether epileptic spasms are a presenting seizure type, may evolve into IESS with the burst-suppression or multi-focal EEG abnormalities evolving in some cases to a hypsarrhythmia pattern. In very young neonates and infants, the extent of any developmental impairment may be difficult to assess; however, almost all infants with EIDEE will have moderate to profound intellectual disability. The exceptions include some individuals with early effective treatment of the underlying etiology, as may be the case in pyridoxine dependant epilepsy or pyridox(am)ine 5'-phosphate deficiency.⁹¹

Infants with EIDEE often have comorbid movement disorders including myoclonus, chorea, dystonia, and tremor. These may present prior to seizure onset, early in the evolution of the syndrome, or develop with time. Differentiating paroxysmal movement disorders from seizures can be challenging, particularly in the context of a severely abnormal interictal EEG. In such cases, prolonged video-EEG with EMG leads recordings should be considered to confirm the type of the paroxysmal event.⁸⁷

Comorbidities associated with global neurological disability including cortical visual impairment, motor impairment, orthopaedic concerns, behavioral problems, feeding difficulties, and early and increased mortality are recognized associations with the syndrome.⁹²

Seizures:

Tonic seizures are frequent and can occur in isolation or in clusters with 10–20 clusters a day. If these occur in clusters, distinguishing features from spasms include (1) tonic seizures usually occur independent of the sleep cycle, unlike epileptic spasms that are often appear upon awakening; and (2) tonic seizures last longer than epileptic spasms, which last <3 s. Tonic seizures are focal or asymmetric in the neonatal period.

Focal or multifocal myoclonus may be the predominant seizure type. The frequency of the myoclonus varies from occasional to almost continuous. Myoclonus can be erratic or massive and bilateral. Erratic myoclonus is asynchronous, asymmetric, and random. It can occur in the face or extremities or may be restricted to only an eyebrow, lip, or finger. It occurs during both wakefulness and sleep. Erratic myoclonus is more commonly associated with a metabolic etiology.

Epileptic spasms occur in some patients. They are more frequently seen beyond the first month of life. They usually occur in clusters—often on awakening.

Sequential seizures are characterized by several seizure manifestations occurring in sequence during a seizure.³ For example, an event may begin with focal tonic features followed by focal clonic features and then epileptic spasms without one predominant manifestation. In addition to the above seizure types, focal motor seizures may also occur.

EEG:

Interictal: The background is abnormal and may show burst-suppression, multifocal spikes/spike waves/sharp waves with or without slowing, discontinuity and/or diffuse slowing (Figure 5). The background abnormalities may be scarce very early in the course in rare patients but will deteriorate quickly with increasing seizure frequency. The burst-suppression pattern consists of high-voltage bursts (150-300uV) of mixed spikes, and sharp and slow waves lasting 1–5 s, alternating with periods of marked suppression (<5 μV) lasting 3–10 s; however, the duration might be influenced by concomitant medications. It is usually seen both in wakefulness and sleep and is unresponsive to stimulation. A burst- suppression pattern is usually bilateral but can be asymmetric, asynchronous, or even unilateral. Random focal attenuation can sometimes be seen. In some children, an abnormal EEG background pattern may be seen prior to seizures with the burst-suppression pattern becoming obvious only postictally. The burst-suppression pattern may disappear with age, but the EEG will remain abnormal. For infants who evolve to IESS, hypsarrhythmia may appear with age. If the etiology is treatable (metabolic or structural lesion amenable to surgery), the EEG may improve or even normalize.

Ictal: The pattern depends on seizure type. In the neonatal period, ictal patterns are focal or asymmetric. With tonic seizures the burst-suppression pattern attenuates with the emergence of low-voltage, high-frequency fast activity. Myoclonus may have a spike/sharp wave correlate. Erratic/fragmented myoclonus may not have an ictal correlate. Focal seizures are associated with a focal ictal recruiting rhythm. The ictal pattern in a sequential seizure will change through the seizure as the clinical manifestations change. Epileptic spasms are accompanied by a high-voltage generalized or focal sharp or slow wave followed by low-amplitude fast activity and attenuation. Furthermore, ictal EEG patterns may be seen with or without clinical seizures.

Imaging:

Structural brain abnormalities are an important and frequent cause of EIDEE and should be sought in all children. Where seizures are drug resistant and focal features are prominent, further imaging modalities should be considered to exclude a surgically remediable lesion. For certain genetic etiologies, imaging is often normal initially or may show reduced brain volume or evidence of white matter hypo-/dysmyelination. Over time cerebral atrophy may develop.

Genetics:

Causative pathogenic gene variants can be identified in more than half of patients with EIDEE.^{9, 84}

The seizure type(s) and EEG with other phenotypic features may predict genotype:

Metabolic studies:

Metabolic studies should be strongly considered, particularly if a clear structural abnormality is not found on imaging.⁸⁶ Furthermore, imaging or EEG features may suggest a specific metabolic etiology. Other sources should guide detailed neurometabolic testing; however, investigations should include urine organic and amino acids (including s-sulfocysteine), urine alpha aminoadipic semialdehyde, plasma amino acids, lactate, uric acid, copper/ceruloplasmin, ammonia, acylcarnitine profile, transferrin isoelectric focusing, very long-chain fatty acids, and CSF glucose, lactate, pyruvate, amino acids, and neurotransmitters.

Epilepsy of infancy with migrating focal seizures (EIMFS)

EIMFS is a rare developmental and epileptic encephalopathy beginning with drug-resistant, focal seizures in the first year of life, with associated severe encephalopathy (Table 6). Focal seizures can arise in both hemispheres and migrate from one cortical region to another within a seizure. Seizures are often prolonged with episodes of status epilepticus.¹⁰⁵ The cause is mainly genetic with KCNT1¹⁰⁶ as the major gene and more than 25 other genes linked to this syndrome.¹⁰⁷ Prognosis is poor, with severe neurological disability and reduced life expectancy, which may be, in part, related to the specific genetic mutation,^{105, 108} although a milder evolution has been reported in a few children.

Epidemiology:

EIMFS has an estimated prevalence of ~0.11/100 000 children.¹⁰⁹

Clinical context:

This syndrome usually begins in the first 6 months (mean 3 months), with rare cases beginning in the latter half of the first year of life.^{105, 108, 110} Males and females are equally affected. Head size and neurological examination are usually normal at onset. Most patients develop microcephaly by 1 year of age.^{110, 111} Development may be normal at onset; however, regression and subsequent severe delay is typical.¹⁰⁵

Course of illness:

Prognosis is poor, with ongoing drug-resistant seizures, severe neurological developmental and motor disability, and reduced life expectancy,^{105, 110} although a milder evolution has been reported in a few children. Some patients are also affected by severe gut dysmotility and may have a movement disorder,¹⁰⁹ as is common to many genetic developmental epileptic encephalopathies.

Seizures:

Focal motor clonic or tonic seizures are mandatory for diagnosis. These are initially sporadic, but the frequency rapidly increases in the weeks and months after seizure onset. Seizures may also be more subtle, with behavioral arrest with or without head and eye version, and prominent autonomic features.^{105, 112}

Focal seizures show a migration pattern on EEG, which might be missed if a prolonged video-EEG is not performed.^{108, 112, 113} Clinically, migration is characterized by unilateral focal tonic or clonic activity at seizure onset, which then evolves to contralateral focal tonic or clonic activity over the course of the seizure. Status epilepticus is common.¹¹² Rare cases with a history of epileptic spasms have been reported.^{109, 114-116} Myoclonic seizures are exclusionary.

EEG:

The EEG background can be normal at onset; however, diffuse slowing of the background occurs with time.^{105, 109, 112} Multifocal discharges appear with time in all cases. The EEG abnormality is enhanced by sleep deprivation and by sleep. Rarely hypsarrhythmia is reported.^{109, 115}

The ictal EEG correlates with clinical semiology, and there is involvement of multiple independent cortical regions consecutively in the same single seizure event (Figure 6).^{112, 113} The ictal EEG is characterized by monotonous activity in the 4–10 Hz band, beginning in the temporo-occipital regions with a specific and pathognomonic pattern of propagation migration.^{112, 113} Recently, two EEG markers have been developed to differentiate EIMFS seizures due to KCNT1 from other focal seizures seen in neonates and infants, with variance in time and coherence of ictal rhythms of seizures.¹¹³

Imaging:

Neuroimaging is normal at the outset, with reports of mild to moderate enlargement of subarachnoid and ventricular spaces. Brain atrophy, predominantly in the cerebellar region, has been reported on follow-up of some cases. Delayed myelination with white matter hyperintensity on MRI and decreased N-acetyl aspartate on MR spectroscopy are often reported.^{106, 109, 110}

Genetics:

Familial inheritance is rare showing interfamilial variability (mildly affected parents with infants with EIMFS).^{117, 118} De novo gene abnormalities are most commonly implicated. KCNT1 is the major gene and is reported in almost half of cases.^{106, 107, 119} Other genes associated with this syndrome include mainly SCN1A, SCN2A, SLC12A5, BRAT1, and TBC1D24.¹⁰⁷

Metabolic testing:

Some children presenting with EIMFS have been found to have underlying congenital disorders of glycosylation.¹²⁰

Infantile epileptic spasms syndrome (IESS)

IESS is a term proposed to encompass both West syndrome as well as infants presenting with epileptic spasms who do not fulfil all the criteria for West syndrome (Table 7). West syndrome classically referred to the triad of epileptic spasms, hypsarrhythmia, and developmental stagnation or regression.¹²¹ However, infants with IESS often lack one of these three criteria. For example, the developmental impact may not be apparent or typical hypsarrhythmia may not be present. This concern was previously identified by the West Delphi group, who proposed the term Infantile Spasms syndrome for all cases of infantile spasms, regardless of EEG findings, and retained the term West syndrome for cases in which hypsarrhythmia was associated, regardless of developmental regression.¹²² This change emphasizes the importance of early diagnosis and therapy because shorter lag time to treatment is associated with a better outcome.¹²³ The addition of the term “epileptic” to the name of the syndrome was done upon the request of many pediatric neurology/epilepsy experts in order to avoid any confusion with nonepileptic spasms and to emphasize the epileptic nature of this syndrome.

IESS is characterized by the onset of epileptic spasms between 1 and 24 (peak 3 and 12) months of age, although later onset may occur. Infants may have no antecedent history, or the antecedent history may reflect the underlying cause, for example, acquired structural brain or genetic abnormality. In some cases, infants with EIDEE or other early onset epilepsies (usually with focal seizures) may evolve to have clinical and EEG features of IESS after 3–4 months of age.¹²⁴

Epidemiology:

The estimated incidence of IESS is 30/100 000 liveborn infants, with some studies suggesting higher incidence rates with higher geographic latitudes (Sweden, Finland, Denmark).^{9, 125-127} A population-based cohort showed that IESS accounted for 10% of epilepsies that begin prior to 36 months.^{9, 41} Both sexes are affected, with a higher incidence in males.^{8, 38}

Clinical context:

IESS has onset between 3 and 12 months, with a range of 1–24 months. If onset occurs prior to 3 months, other early-onset developmental and epileptic encephalopathies should be considered. Prior to the onset of IESS the development can be normal, but there is often a history of preceding clear or suspected abnormal development. Developmental slowing, arrest, or regression is seen with the onset of spasms, although it may not be apparent very early in the course. Parents may report isolated regression in visual attention or altered social responsiveness in the days or weeks preceding the onset of spasms. Developmental plateauing and regression usually worsen without urgent and effective treatment. Although head size and examination may be normal, careful neurological examination may provide clues to the etiology, including abnormal head size or neurological exam findings. In addition, dermatological exam (for stigmata suggestive of a neurocutaneous disorder such as tuberous sclerosis complex), ophthalmologic assessment, and examination for dysmorphic features are important as they can suggest an underlying cause.

Course of illness:

IESS frequently evolves to other epilepsy types or syndromes, especially Lennox-Gastaut syndrome, or drug-resistant focal epilepsies. Although there are no precise data, it has been suggested that about 30% of patients with IESS may evolve to Lennox-Gastaut syndrome.^128-136 Some infants may begin with focal epilepsy that evolves to IESS, and then, as the child ages or in response to therapy, revert back to focal epilepsy. In such cases, focal features are often seen on EEG and typical hypsarrhythmia may be absent. Coexisting focal seizures, asymmetric epileptic spasms, and consistent focal features on EEG should also raise the possibility of a structural brain abnormality.

Epileptic spasms may persist in some cases, particularly with some of the genetic or structural encephalopathies. In some individuals, they resolve with effective therapy and subsequent epilepsy is not seen.

Developmentally, many infants are left with poor developmental outcome, regardless of seizure outcome. The severity of developmental delay relates predominantly to etiology and promptness of treatment. Prognosis is more favorable for infants with preceding normal development, no known cause, and prompt initiation of syndrome-specific treatment.^{123, 125}

Seizures:

Epileptic spasms are mandatory for the diagnosis of IESS, and consist of brief tonic contractions of axial muscles, each typically lasting <3 s, which may be flexor, extensor, or mixed. These usually occur in series or clusters, with increasing prominence of the motor features through the cluster, often over a period of minutes (although clusters may last 30 min or longer) and are often seen on awakening. These may be symmetric or asymmetric and may be subtle, with minor head nods, or eye or chin movements.

Focal seizures may also be seen and may co-occur in an infant with spasms, particularly in the setting of a structural etiology, for example, tuberous sclerosis or focal cortical dysplasia. Focal seizures may occur either independently of spasms or may precede, occur during, or follow a cluster of epileptic spasms, or even occur throughout the series of epileptic spasms. Tonic seizures at onset are atypical and should raise concern for another early onset developmental and epileptic encephalopathy.

EEG:

Interictally, hypsarrhythmia (chaotic, high amplitude, excessive slowing, multifocal epileptiform discharges) is often seen and the yield of detection is greatest if non-REM (rapid eye movement) sleep is recorded (Figure 7A). Some infants may have a very active multifocal epileptiform EEG without the chaotic background that typifies hypsarrhythmia. A consistent focal epileptiform discharge or focal fast activity should suggest an underlying structural abnormality. Very early in the course, or in older children, hypsarrhythmia may also be absent. Clinicians should not withhold standard therapy for children with IESS who do not have hypsarrhythmia.

The ictal recording of an epileptic spasm is characterized by a high amplitude, generalized, sharp or slow wave followed by low amplitude, fast activity, which may appear as a brief electrodecrement (Figure 7B). Hypsarrhythmia typically attenuates or stops during a series of epileptic spasms. EMG helps to distinguish epileptic spasms from myoclonic seizures and tonic seizures (see Figure 8).¹³⁷ A burst-suppression pattern on EEG is suggestive of EIDEE.

Neuroimaging:

Neuroimaging is strongly recommended to clarify the etiology, which may impact treatment decision-making. Brain MRI is abnormal in one half to two thirds of children with IESS,^{9, 138-142} and can show either acquired or congenital lesions that are focal, multifocal, or diffuse. Early imaging should be repeated after 2 years of age when myelination is likely to be complete, if there is a suspicion of a focal structural lesion, or in infants with refractory infantile spasms of unknown etiology. Optimized imaging and analysis for the detection of subtle focal cortical dysplasia may be necessary, and modalities such as fluorodeoxyglucose positron emission tomography or arterial spin labeling can be useful to detect focal structural anomalies in the presence of an apparently normal MRI.^{143, 144} Such children should be referred early for epilepsy surgical assessment. In addition, MRI abnormalities may point to specific metabolic disorders.

Genetics:

Genetic studies should be considered if no etiology is found after clinical examination and MRI.^145-147 In addition, genetic testing should be considered for patients with structural brain disorders known to be associated with a genetic basis.

Pathogenic variants in many genes have been associated with IESS and often are de novo in the child. A genetic etiology can be defined in up to 41% of cases.^{9, 41} Etiologies include Trisomy 21, ARX, CDKL5, STXBP1, IQSEC2, TSC1, TSC2, and many others. A genetic mutation can be inherited from a parent with mild symptoms or an unaffected parent. In addition, a range of chromosomal abnormalities and copy number variants have been associated with IESS, so chromosomal microarray and routine karyotype should be considered.

Metabolic and other lab studies:

Metabolic etiologies are a rare but important cause of IESS. Metabolic testing should be considered if an etiology is not found on clinical examination and no structural abnormalities are seen on MRI. In the absence of a known etiology, pyridoxine dependency should be considered. If laboratory studies are unavailable to rapidly exclude this diagnosis, infants should be considered for a trial of pyridoxine.¹⁴⁸ However, given the rarity of this disorder, such a trial should be given at the same time as the first-line therapy.

Differential diagnosis:

Dravet syndrome (DS)

DS (previously known as Severe Myoclonic Epilepsy of Infancy), presents in the first year of life in a normal child with prolonged, febrile and afebrile, focal clonic (usually hemiclonic), or generalized clonic seizures (Table 8).¹⁴⁹ Other seizure types including myoclonic and atypical absence seizures appear between the age of 1 and 4 years. Seizures are usually intractable, and from the second year of life children demonstrate cognitive and behavioral impairments.¹⁴⁹ Gait abnormalities including a characteristic crouch gait are usually seen by late childhood.¹⁵⁰ The clinical diagnosis is supported by the identification of pathogenic variants in the sodium channel gene SCN1A (found in over 80% of cases).¹⁵¹

Epidemiology:

DS affects ~6.5/100 000 live births.^{9, 41, 152}

Clinical context:

Onset of seizures is typically between 3 and 9 months, with a mean and median age of 6 months.^{149, 153, 154} Rare cases can present as early as 1 month of age, or as late as 20 months of age in a few reported cases; however, onset before 2 months or after 15 months should alert the clinician to review the diagnosis and consider further investigations to exclude other conditions. Development appears normal at seizure onset.^153-155 The neurological examination is normal at seizure onset. Walking may be slightly delayed (mean 16–18 months) and gait instability may be present. Head size is normal during the first years. Significant developmental delay, neurological examination abnormalities, movement disorders, or microcephaly at the time of seizure onset suggests an alternative diagnosis.

Course of illness:

Seizures are drug resistant and present through life. Episodes of status epilepticus are more frequent before 5 years of age. They can, however, occur later, even into adult life, especially with an illness or fever.¹⁵³ By adolescence/early adulthood, status epilepticus and atypical absences are rare—seizures are predominantly brief, with various types (focal with loss of awareness, clonic, generalized tonic-clonic, myoclonic, and atypical absences). Nocturnal seizures tonic and tonic-clonic may appear at this age and become the predominant seizure type.^{156, 157} Over time, developmental progress slows and delay may be evident from 12 to 60 months following onset of seizures.^158-160 Speech delay is predominant. Most patients manifest a degree of intellectual disability ranging from mild to severe (50%).^{155, 158} Many patients develop behavior disorders and some have inattention and hyperactivity.^{153, 160, 161} Developmental regression can be seen following episodes of status epilepticus. In most patients, however, the pattern is more of developmental slowing and consequent intellectual impairment.¹⁵⁸ Over time, most patients develop subtle pyramidal signs and gait disorder evolving to crouch gait, typically by late childhood to adolescence.¹⁵⁰

Seizures:

By this age, in addition to illness, seizures can also be triggered by physical activity, change in environmental temperature, visual patterns (rarely), photic stimulation (15% of patients), and excitement.^{139, 153, 159} Tonic and tonic-clonic seizures mainly in sleep and in clusters, may appear later in the course of the disease, from around age 4–5 years, and become more evident in adult life.^{156, 157, 162} Epileptic spasms are exclusionary. Seizures are exacerbated with the use of sodium channel–blocking drugs (this can be a clue to the diagnosis) such as carbamazepine, lamotrigine, oxcarbazepine, and phenytoin.¹⁴⁵ However, lamotrigine may rarely have a role in older patients as suggested in one small case series.¹⁶³

EEG:

Background may be normal or slow prior to age 2 years. Slowing is typical after 2 years of age.^{154, 159, 164} Interictal discharges are often focal, multifocal, and generalized, and appear after 2 years of age.¹⁶⁴ In patients with sleep clusters of seizures, interictal frontal discharges are often seen.^{162, 164} A photoparoxysmal response occurs in 15% of patients and is more frequent in younger children.¹⁶⁴ Ictal recordings depend on seizure type.

Neuroimaging:

MRI is normal at seizure onset.¹⁶⁵ Over time, mild cerebral and cerebellar atrophy may evolve. A minority of patients have hippocampal sclerosis^{165, 166}; however, epilepsy surgery is not indicated.

Genetics:

Genetic testing is recommended at all ages, including in adults in whom the diagnosis is suspected but details of history in infancy may be difficult to access. A pathogenic variant in SCN1A is present in more than 80%–85% of cases.¹⁵¹ Most are de novo; however, up to 10% of patients who are thought to have a de novo mutation will have one parent who is mosaic for the variant.¹⁶⁷ This carries implications for reproductive counseling. DS may occur in one member of a family with GEFS+. SCN1A pathogenic variants may be found in other epilepsy syndromes such as GEFS+ and early infantile SCN1A encephalopathy with profound impairment. The diagnosis of DS requires the typical clinical features and cannot be made on the basis of the genetic variant alone, and the absence of a gene variant should not preclude a clinical diagnosis of the syndrome.¹⁶¹ Treatment should not be delayed in the setting of a clinical diagnosis.

Other genes have rarely been associated with DS including dominant, pathogenic variants in GABRG2, GABRA1, STXBP1, and rare recessive cases with SCN1B variants.¹⁶⁸

A family history of febrile seizures or other epilepsies may be seen in 30%–50% of cases, and the semiology may be suggestive of GEFS+.

Metabolic and other lab studies:

No consistent abnormalities found.

Differential diagnosis:

KCNQ2-DEE

KCNQ2-DEE causes a neonatal onset encephalopathy and is due to de novo missense variants that produce a disorder distinct from self-limited neonatal epilepsy. Seizures may respond to sodium channel blockers (Table 9).

Epidemiology:

The incidence of KCNQ2-DEE is unknown.

Clinical context:

Seizure onset is within the first few days of life in the context of a severe neonatal encephalopathy with abnormal neurological examination and behavior.^{93, 97, 171-176} Seizures are typically not responsive to first-line medications such as phenobarbitone. Sodium channel–blocking agents such as carbamazepine and phenytoin should be considered early in this clinical context.⁸⁸

Course of illness:

Seizures may respond partially or completely to sodium channel blockers. Epilepsy frequently remits; however, developmental outcome is typically moderately to severely impaired.¹⁷⁴ Over half of patients will become seizure-free, varying from a few months of age to several years.¹⁷⁴ As genetic testing becomes more readily available it is likely that more cases with intermediate outcome between self-limited neonatal epilepsy and KCNQ2-DEE will be identified. Milder phenotypes may be seen in cases with mosaicism.

Seizures:

Focal tonic seizures are seen most frequently, although other seizure types including focal clonic and myoclonic may also be seen.^{97, 172, 174} Autonomic features, apnea, and ictal crying may be prominent during seizures. Epileptic spasms have been recorded in some individuals; however, the evolution to IESS is seen less frequently in KCNQ2-DEE than in other severe EIDEEs. The seizure semiology in neonates is similar to that seen in SeLNE; however, seizure frequency, EEG background abnormalities, and abnormal neurological examination in KCNQ2-DEE allow the syndromes to be distinguished.¹⁷⁴

EEG:

In more than 60% of cases the EEG shows a burst suppression pattern, which may be asymmetric at times (Figure 5).^{96, 173} In other cases, multifocal abnormalities including spikes, sharp waves, and hemispheric suppression may be seen.

Neuroimaging:

MRI signal abnormalities may be seen in the basal ganglia or thalamus during the neonatal period. In some cases, hyperintensities seen on T1 sequences in the globus pallidus may disappear with time.^{90, 92} Mild atrophy of the frontal lobe and thin corpus callosum have been reported.^{94, 96}

Genetics:

De novo missense variants in particular regions (hot spots) of the KCNQ2 gene produce a dominant negative, more severe loss of channel function than is seen in SeLNE.^{173, 175, 176}

Pyridoxine-dependent (ALDH7A1)-DEE (PD-DEE) and pyridox(AM)INE 5'-phosphate deficiency (PNPO)-DEE (P5PD-DEE)

PDE-DEE and P5P-DEE are caused by genetic-metabolic defects within the same lysine degradation pathway (Table 10).¹⁷⁷ Seizure control can be achieved in almost all cases with pharmacological doses of pyridoxine and pyridoxal-5'-phosphate, respectively, emphasizing the importance of early recognition. Some infants with P5PD-DEE respond partially or completely to pyridoxine therapy.¹⁷⁷

Epidemiology:

Estimates of incidence are available only for PD-DEE due to pathogenic variants in ALDH7A1 and vary from 1 in 65 000 births, 1 in 273 000 births, to 1 in 783 000 births.^178-180 The incidence of P5P-DEE is unknown.

Clinical context:

Patients with PD-DEE and P5P-DEE present shortly after birth with encephalopathy and seizures or with intrauterine convulsions. However, up to 25% of patients with pyridoxine-dependent epilepsy may present outside the newborn period, mainly in the first 3 years of life, although new onset of seizures has been reported at 17 years of age.^{181, 182} Patients with P5PD-DEE are often born prematurely, and those with either PD-DEE and P5PD-DEE may show signs of neonatal distress, irritability, and vomiting at times with acidosis and low Apgar scores, leading to a misdiagnosis of neonatal hypoxic-ischemic encephalopathy.^{182, 183} There may be a family history of EIDEE, infertility, and death in siblings.¹⁸⁴ Seizures are resistant to standard antiseizure medications.

Course of illness:

Evidence from small case series and observational studies suggests that lysine reduction therapies including a lysine-restricted diet and L-arginine therapy may provide additional benefit in terms of seizure control and cognitive outcome.¹⁴⁸ Despite adequate seizure control, the majority of people have varying degrees of intellectual disability from mild to severe.^{185, 186} Later-seizure onset is associated with better cognitive outcome; however, this can be normal for patients with onset at any age with both PD-DEE and P5PD-DEE, emphasizing the importance of early and adequate treatment.¹⁸⁷ Seizure relapse may occur during febrile illnesses, and treatment doses of pyridoxine may be doubled at these times.¹⁴⁸ Withdrawal of pyridoxine leads to a recurrence of seizures; therefore, treatment should be lifelong with dose adjustments as needed. Chronic use of pyridoxine may result in peripheral neuropathy, but this is rare if doses do not exceed 200 mg/day and can be monitored through testing of deep tendon reflexes and nerve conduction studies.¹⁸⁸ People with P5PD-DEE may be exquisitely sensitive to dosing and timing of pyridoxal-5-phosphate, with some benefiting from multiple doses per day.

Cirrhosis of the liver has been reported in P5PD-DEE and surveillance for this association is appropriate.¹⁸⁹

Seizures:

Seizures may manifest antenatally as excessive fetal movements and typically present in the first hours to days of life. Infants may be acidotic and hypotonic; however, seizures may manifest as frequent, at times continuous, multifocal myoclonus affecting limbs, trunk, eyes, and facial muscles. A variety of seizure types may occur including focal seizures, spasms, and generalized tonic-clonic seizures.¹⁴⁸ The semiology of a hyperkinetic, seemingly distressed and agitated infant with multifocal myoclonus and spasms should alert the clinician to the possibility of PD-DEE or P5PD-DEE. In older infants, presentation may be with febrile or febrile generalized tonic-clonic seizures, status epilepticus, or clusters of focal seizures. If doses of pyridoxal-5-phosphate are missed or not tolerated during vomiting illnesses, patients with P5PD-DEE may present with semiology, suggesting occipital network involvement, including colored lights, ictal blindness, and darting eye movements. Presentation with infantile spasms later in infancy is rare but has been reported in PD-DEE.¹⁹⁰ The wide variety of seizure types at presentation necessitates that PDE-DEE and P5PD-DEE be considered in all infants with drug-resistant seizures in infancy. Some children with PDE-DEE may be partially responsive to antiseizure medications.

EEG:

EEG in PD-DEE and P5PD-DEE in neonates with severe encephalopathy prior to treatment can show a burst-suppression pattern. In other cases, focal or multifocal discharges may be seen against a background of slow rhythms. If pyridoxine is given intravenously to an encephalopathic patient (ideally this should be done under EEG control), it must be done in a setting where the child can be intubated for respiratory support should treatment cause apnea. A burst-suppression EEG or EEG with multifocal sharp or spike complexes can become diffusely suppressed following pyridoxine administration and may take many hours or days to return to show normal background rhythms. Hypsarrhythmia has been reported in 1 of 30 patients in one series.¹⁸¹

Neuroimaging:

Neuroimaging may be normal, but in both PD-DEE and P5PD-DEE, over half of patients have MRI abnormalities. These including white matter edema in severely encephalopathic cases.^{181, 183} Intraventricular hemorrhage, ventricular dilatation, and corpus callosum hypoplasia can lead to misdiagnosis of a structural etiology for the epilepsy.¹⁸¹

Genetics:

Most cases of PD-DEE are associated with biallelic variants in ALDH7A1, also known as antiquitin, with a minority associated with biallelic variants in PLBP (previously known as PROSC).^{184, 186, 191} Pyridox(am)ine 5' phosphate deficiency is associated with biallelic variants in the PNPO gene.¹⁹¹ The disorder, previously termed folinic acid responsive epilepsy, is a form of PD-DEE associated with variants in ALDH7A1 and has a better response to pyridoxine than folinic acid alone.⁹¹ If a single pathogenic variant is identified, in the appropriate clinical context, then multiplex ligation probe amplification and chromosomal microarray should be undertaken to identify intragenic or whole gene deletions, or duplications involving the relevant gene on the other allele. If variants of uncertain significance are identified, metabolic investigations will help in assessment of pathogenicity. Antenatal genetic testing and maternal treatment with pyridoxine should be considered in subsequent pregnancies.

Metabolic testing

The biomarkers ⍺-aminoadipic semialdehyde (⍺-AASA) and pipecolic acid are elevated in urine, plasma, and CSF.¹⁴⁸ Ideally urine and plasma samples should be taken prior to treatment with pyridoxine; however, this should not delay therapy in suspected cases.¹⁸⁸ Following treatment, these biomarkers may be reduced but typically remain elevated. ⍺-AASA is considered the more reliable test. With the use of biomarkers and gene testing, withdrawal of therapy as a diagnostic test is now obsolete.

CDKL5-DEE

CDKL5-DEE, also known as CDKL5 deficiency disorder, is a DEE that is the result of pathogenic variants in the cyclin-dependent kinase like 5 (CDKL5) gene. It is an important cause of very early-onset epilepsy (median age 6 weeks) with pronounced hypotonia (Table 11). The combination of clusters of infantile spasms and tonic seizures in the first few months of life is characteristic, but multiple seizure types can occur. Seizures often have multiple phases, with a classic sequential hypermotor (hyperkinetic)-tonic-spasms seizure. Severe to profound global delay is present in essentially all cases.

Epidemiology:

CDKL5-DEE is rare, with estimated incidence of between 1/40 000 and 1/60 000 live births.^{41, 192, 193} It is X-linked and females outnumber males by a ratio of 4:1.^{194, 195}

Clinical context:

The median age of seizure onset is 6 weeks, and 90% of cases have onset before 3 months.^{196, 197} Developmental concerns are present at the time of seizure onset but become more pronounced with time. True regression is rare.¹⁹⁴ Neurological examination shows diffuse hypotonia but normal head circumference at onset.^{18, 194} Cortical visual impairment, with poor eye contact and lack of visual tracking is common.¹⁹⁴ Subtle dysmorphic features with deep set eyes, broad forehead, prominent lips, deep philtrum, and puffy phalanges with tapered fingers have also been described.¹⁹⁴

Course of illness:

Epilepsy typically remains drug resistant and most patients are left with severe intellectual disability. Most patients continue to have daily seizures, although occasional periods of seizure freedom up to 2 months or longer are seen in less than half of cases.¹⁹⁴ Independent walking and ability to speak single words is achieved in less than one quarter of cases.¹⁹⁴ Movement disorders including choreoathetosis, akathisia, dystonia, and parkinsonism can affect a minority of patients.¹⁹⁴ Males are more severely affected.

Seizures:

The initial seizure type can vary, but most commonly tonic seizures, spasms, generalized tonic-clonic seizures, or focal seizures are seen.¹⁹⁵ Over time, other seizure types can occur. The majority will have epileptic spasms and/or tonic seizures. One characteristic seizure type, seen in many but not all cases, is hypermotor(hyperkinetic)-tonic-spasms sequence seizures.¹⁹⁸ The first part of this seizure begins with a hypermotor phase with rocking, kicking, and vocalization that lasts 10–60 s. This is followed by a tonic phase, either with extension of all limbs or extension of the upper limbs and flexion of the lower limbs lasting 20–45 s. The seizure evolves to a series of extensor spasms, which lasts 1–15 minutes. Similar seizures that involve multiple phases with clustering of tonic seizures and spasms, but with variable order of seizures' types, are common.¹⁹⁵ Autonomic features are commonly seen with the above seizures, with facial flushing, pupillary dilatation, and irregular respirations. Myoclonic, clonic, absence, and atonic seizures may be seen with time.

EEG:

In Stage 1, the interictal EEG is normal but ictal recordings show generalized attenuation followed by fast activity in frontal or central head regions during the tonic seizure.¹⁹⁹ A burst-suppression pattern is not seen in this stage. In Stage 2, the interictal EEG is severely abnormal, showing bilateral or generalized slowing with spikes or polyspikes.¹⁹⁹ A burst-suppression pattern has rarely been reported in this stage.²⁰⁰ In Stage 3, the interictal recording shows diffuse, high-amplitude delta slowing with pseudo-periodic bursts of spikes, polyspikes, and spike-wave complexes that are maximal in the central, temporal, or temporal-occipital regions.¹⁹⁹

Genetics:

A pathogenic or likely pathogenic variant in the CDKL5 gene is required to confirm the diagnosis of CDKL5-DEE, and multiple variants have been reported in affected individuals. There are limited data on genotype-phenotype correlation; however, missense variants may correlate with a slightly less-severe disorder than truncating variants.¹⁹⁴

PCDH19 clustering epilepsy

PCDH19 Clustering Epilepsy is an X-linked disease, seen predominantly in females, caused by pathogenic variants in the PCDH19 gene (Table 12). Few males are reported. Epilepsy onset is often during the first year of life (mostly during the first 3 years), and the most characteristic feature is clusters of seizures often induced by fever. Intellectual disability and psychiatric symptoms are reported in about two thirds of cases. The severity of the phenotype seems to be correlated with the age of epilepsy onset.^{22, 201}

Epidemiology:

Data on incidence are limited but one study reports an estimated incidence of 1/42 000 live births.⁴¹ Large cohorts of females with seizure clusters triggered by fever show rates of PCDH19 pathogenic variants ranging from 2% to 20%.²²

Clinical context:

Seizure onset is typically before 1 year of age, with a mean age of 10 months (1.5–60 months in females).^{21, 202} Development and neurological examination are normal at seizure onset. Head circumference is normal.

Course of illness:

Seizures occur in clusters, which are triggered by fever and often drug resistant. After the first decade, a decrease in the frequency of the seizure clusters generally occurs regardless of the treatment, and remission of seizures may occur in at least one quarter, usually in adolescence to mid-adulthood.^{21, 22, 202-204}

Signs of intellectual disability and autism spectrum disorder, affecting up to 70%, emerge during the second year of life and often become the most relevant symptoms after the first decade. Behavioral disorders, with prominent hyperactivity and possible psychosis in up to 25% of women, are often problematic in adolescence and adults.²⁰⁵

Seizures:

At onset, seizures are focal impaired aware with tonic extension of the upper arms, deviation of head and eyes, pallor of the face, expression of fear, and screaming reported in half of the patients.^{21, 202}

Atypical absences may also be seen.²⁰² Seizures occur in clusters, often related to fever, and status epilepticus has been reported.²⁰⁶

EEG:

Interictal EEG showed slow background activity with rare focal spikes and slow waves that increase in frequency during clusters. With age, background activity may normalize. One third of patients show a photoparoxysmal response and few patients had generalized bursts of spike and waves.^{21, 202}

Seizures recorded on ictal EEG often arise from temporal regions, but parieto-occipital, frontal, or central onset may also be seen. In half of cases, seizures appear focal but are not well lateralized or localized on EEG.²¹

Neuroimaging:

MRI is typically normal at seizure onset.

Genetics:

PCDH19 pathogenic variants were initially recognized in large pedigrees in which only females were affected by epilepsy and intellectual disability (Epilepsy in Females with Mental Retardation). Currently, approximately half of reported cases are de novo.²²

Although the PCDH19 gene is located on Xq22, this condition has an unusual X-linked mode of inheritance sparing transmitting males. Only heterozygous female and mosaic males are affected due to presumed cellular interference. Few affected males with a similar phenotype are reported to date (nine cases reported in the literature).^{201, 207}

SMC1A DEE can mimic PCDH19 Clustering Epilepsy and can present with prolonged clusters of multiple focal and generalized seizures resistant to antiseizure medication, sometimes lasting days. Infants with this disorder have a severe developmental encephalopathy and mild dysmorphic features.²⁰⁸

Metabolic and other lab studies:

No consistent metabolic abnormalities are found.

Glucose transporter 1 deficiency syndrome (Glut1DS)

Glut1DS is a complex neurological disorder associated with a range of neurological symptoms including infantile onset epilepsy, movement disorders, and intellectual disability (Table 13).^{209, 210} Epilepsy is the most common presenting feature of Glut1DS and is a drug-resistant unless treated with the ketogenic diet.^211-213 The syndrome is associated with pathogenic variants in the SLC2A1 gene encoding the glucose transporter type 1, impairing glucose transport across the blood-brain barrier.²⁰⁹

Epidemiology:

The estimated incidence of Glut1DS presenting as epilepsy in infancy is 1/24 000 live births; however, the syndrome as a whole may be more common, as individuals may present later in childhood and with symptoms other than seizures.⁴¹

Clinical context:

Infants may present with many different seizure types but generalized-onset seizures are more common than focal.^{211, 214} In any child presenting with epilepsy and a movement disorder Glut1DS should be considered.²¹⁵ A history of seizures associated with fasting or in the early morning may be present. Other clues to diagnosis include eye-head gaze saccades (consisting of rapid, multidirectional eye movements, accompanied by head movements in the same direction) in early infancy and microcephaly (present in 50% of cases) or deceleration of head growth.^{209, 213, 216} Diagnosis is confirmed by lumbar puncture identifying low CSF glucose with normal or low CSF lactate after a 4–6 hour fast in the context of a normal blood glucose.²¹⁷ In Glut1DS, CSF glucose fifth percentile values range from 1.8–2.9 mmol/L, and CSF/plasma glucose ratio fifth percentile values range from 0.41–0.510. In the presence of a highly typical phenotype with a pathogenic SLC2A1 variant, a lumbar puncture may not be necessary.²¹³ In later-onset epilepsy associated with GLUT1DS, CSF glucose levels may not be as low.²¹⁸

Course of illness:

Seizures vary in frequency from multiple per day to only a few per year and are resistant to antiseizure medications. Seizure frequency tends to decline later in childhood and adult life, where intellectual disability, movement disorders, and migraine may be the predominant features.^{213, 219} Ketogenic diet with adequate ketosis may completely control seizures. Although this therapy may ameliorate further cognitive decline, many patients are still left with variable degrees of intellectual disability.

Seizures:

Generalized seizures are typically myoclonic, myoclonic-atonic, generalized tonic-clonic, or atypical or early onset absences. Early onset absences (less than age 4 years), often seen with a myoclonic component, should be investigated by lumbar puncture and genetic testing.²²⁰ In addition, this disorder should be considered in persons with epilepsy with myoclonic-atonic seizures or drug-resistant absence epilepsy, particularly if cognitive concerns are present. Epileptic spasms and generalized tonic-clonic status epilepticus have also been reported.⁴¹

EEG:

Interictal EEG is often normal. There is some evidence for age-specific changes, with focal or generalized slowing of background rhythms in infancy with or without intermittent focal or generalized spike and wave. In children older than 2 years, generalized 2.5–4 Hz spike-wave is seen.²²¹ In some cases, pre-prandial EEG abnormalities may be improved during the recording by feeding as glucose crosses the blood-brain barrier and EEG background rhythms may be less abnormal on the ketogenic diet.²²²

Neuroimaging:

Approximately 25% of patients have neuroimaging abnormalities including hyperintensity of subcortical U fibers, prominence of perivascular Virchow spaces, prominent ventricles, and delayed myelination for age.^{209, 223, 224} 18F-Deoxyglucose positron emission tomography may show a specific imaging signature including reduced signal from cerebral cortex, cerebellum, and thalamus with apparent increased glucose in the striatum.²²⁵

Genetics and other investigations:

Gene sequence analysis identifies heterozygous and less commonly recessive pathogenic variants in SLC2A1 in 81%–89% of cases.²⁰⁹ Another 11%–14% of cases with deletions or duplications in the gene may be identified by multiplex-ligation probe amplification and chromosomal microarray.²⁰⁹ With a highly suspicious clinical phenotype, but nondiagnostic lumbar puncture and genetic testing, other investigations including erythrocyte uptake tests and measurement of glucose transporter type 1 on the surface of red blood cells should be considered.^{225, 226}

Sturge-Weber syndrome (SWS)

SWS is a congenital neurocutaneous syndrome defined by the association of a facial capillary malformation referred to as a port-wine stain birthmark with ipsilateral leptomeningeal angioma and frequent ipsilateral glaucoma. It is caused by somatic activating mutations in the guanine nucleotide–binding protein alpha-q (GNAQ) gene (Table 14).²²⁷ The prognosis of SWS is highly variable and related to the potential complications that develop often in early childhood, including epilepsy, focal neurological deficits, and glaucoma.²²⁸ The diagnosis is confirmed by brain imaging showing direct or indirect evidence of the leptomeningeal angioma.

Epidemiology:

The estimated incidence of SWS is 1/20 000 to 1/50 000 live births. Patients with a facial port-wine stain on the forehead and/or the upper eyelid have an estimated risk of 20%–70% of developing SWS.^{229, 230}

Clinical context:

The diagnosis of SWS is suspected at birth in newborns presenting a facial port-wine stain covering the forehead and/or the upper eyelid. Careful examination under the hairline is important to detect more subtle lesions. Contrast-enhanced MRI can detect the leptomeningeal angioma before 3 months of age.²³¹ Rarely, the facial angioma may be absent.²³²

Seizures are usually the first manifestation, affecting 75% to 85% of patients at a median age of 6 months.²³³ Rare cases with onset of seizures in adulthood have also been reported.²³³ In addition to epilepsy, 40% to 60% of SWS patients will develop glaucoma with a risk of early visual impairment.²³³

Course of illness:

Natural history is highly variable but is usually marked by a progressive course with age-dependent neurological manifestations. Early manifestations during infancy include epilepsy, hemiparesis, psychomotor delay, and stroke-like events. Later signs and symptoms at school age include headaches, academic difficulties, and behavioral problems. In adulthood, psychiatric disorders including depression can be significant, and epilepsy and stroke-like events can continue throughout life.

Early seizure onset (before age 12 months), high seizure frequency, and drug resistance are the most reliable predictors of poor outcome.^{233, 234} Extensive unilateral or bilateral intracranial involvement is associated with earlier onset of seizures and worse cognitive development compared to unilateral leptomeningeal angioma.²³⁵ Presurgical evaluation should be considered in patients with unilateral disease who are drug resistant.²³⁶

Seizures:

The first seizures are usually focal motor.²³⁷ Focal autonomic seizures with variable degrees of impaired awareness are also frequent.²³⁸ Seizures can be subtle, and their prompt recognition is important because prolonged seizures and status epilepticus can occur frequently.²³⁷ About 30% of cases may have onset of seizures during febrile episodes and there is an increased susceptibility of fever-induced seizures at any age.²³⁷ Infantile spasms, myoclonic atonic seizures, and gelastic seizures have also been reported.²³⁹ Seizure clustering following a prolonged period of seizure freedom is common (40% of cases).^{238, 239}

Due to the high incidence of early-onset seizures and their potential deleterious effects on the developing brain, parental education in early seizure recognition and individualized emergency plans including the use of rescue benzodiazepine therapy is recommended.²⁴⁰

EEG:

The EEG characteristically shows asymmetric reduction in voltage and slowing of the background over the affected hemisphere (Figure 9).²⁴¹ The background might be normal, however, during the first year of life. Interictal epileptiform abnormalities may appear later and consist of focal sharp waves or frequent spike-wave bursts.²⁴¹ Such interictal epileptiform abnormalities before seizure onset might be a useful marker to identify patients with SWS who are at risk of developing epilepsy.²⁴² Ictal activity varies depending on seizure focus.

Neuroimaging:

Contrast-enhanced, cerebral MRI confirms the diagnosis of SWS by the direct visualization of leptomeningeal enhancement (Figure 10). Detection can be challenging in very young infants. Other imaging features such as ipsilateral choroid plexus enlargement, enlarged transmedullary veins, and T2 shortening of the white matter can help establish the diagnosis.²³¹ Cortical calcifications and cerebral atrophy appear over time.

Genetics:

Isolated port-wine stain and SWS have a common genetic etiology, with a somatic mosaic pathogenic variant recently identified in the GNAQ gene.²²⁷

Gelastic seizures with hypothalamic hamartoma

Hypothalamic hamartomas are very rare, congenital, non-neoplastic lesions, which are characteristically associated with gelastic (laughing episodes without mirth) or, less commonly, dacrystic (crying) seizures that typically begin in infancy or early childhood (Table 15). Other seizure types including focal impaired awareness or various generalized seizures may evolve, and with time there is progressive cognitive plateauing or regression and progressive behavioral abnormalities including impulsiveness and aggression. Precocious puberty is present in some cases. Seizures remain drug resistant but may improve significantly with surgical intervention. Early surgical therapy should be considered for seizure control and to prevent progressive cognitive and behavioral decline.

Epidemiology:

A single study documented a prevalence of hypothalamic hamartoma with gelastic seizures of 0.5/100,000 in children <20 years of age.²⁴³

Clinical context:

Onset is in the first year of life in ~85% of cases.²⁴⁴ A minority of cases can begin in early to mid-childhood.^{243, 245} There is no sex predisposition. Neurological examination is normal; however, general physical examination may reveal features of precocious puberty.

Course of Illness:

Epilepsy due to hypothalamic hamartoma is drug resistant. There is progression over time in most cases, with development of focal impaired awareness and generalized seizures.^{246, 247} Some patients may develop tonic, atonic, or atypical absences suggestive of Lennox-Gastaut syndrome. Surgical therapy targeting the hypothalamic hamartoma can mitigate this unfavorable evolution. Cognition is typically normal at seizure onset, but over time, developmental plateauing or regression is usually seen. Children can also develop progressive behavioral problems including aggression, impulsivity, hyperactivity, and autism spectrum disorder.

Seizures:

Gelastic seizures are the distinctive seizure type and mandatory for diagnosis. They are seen at epilepsy onset, and are brief, typically lasting less than 1 minute. They consist of mechanical and mirthless laughter, inappropriate to context. Awareness is often not impaired and postictal confusion is absent. Seizure frequency is high, typically multiple per day, and seizures may cluster. Seizures with smiling alone, but without distinctive mirthless laughter, are not gelastic seizures. Dacrystic seizures, characterized by stereotypic lacrimation, and sobbing, grimacing, or yelling, inappropriate to context may also be present. The combination of gelastic and dacrystic seizures in the same patient is particularly suggestive of a hypothalamic hamartoma. Other seizure types that can occur include focal seizures with frontal or temporal lobe semiology and rarely, epileptic spasms. Later in childhood, tonic and drop attacks, as well as atypical absences, may develop.

EEG:

The background is usually normal. Interictal discharges typically appear after infancy and initially are most commonly seen in the temporal regions, although focal spikes from any region may be present. Children with infantile spasms may show a hypsarrhythmia pattern.²⁴⁸

By later childhood, generalized slow spike-wave, or generalized spike or spike-wave can occur, in addition to focal or multifocal discharges.

Ictal recordings of gelastic seizures may show no change, or alternatively may show subtle and nonspecific changes, such as a decrease in amplitude, or reduction in frequency of interictal spikes. On scalp recording, seizures may appear to localize to the temporal or frontal region. However, depth electrodes in the hamartoma will confirm it as the focus of ictal onset,^{244, 249} and thus surgery should target the hamartoma, as opposed to focal temporal or frontal resection. By later childhood, patients with generalized seizure types will show generalized ictal onset.

Neuroimaging:

MRI shows a pedunculated or sessile lesion (Figure 11) that lies between the infundibular stalk anteriorly and the mammillary bodies posteriorly.²⁵⁰ The lesions are typically isointense to slightly hypointense to gray matter on T1-weighted studies, and hyperintense on T2-weighted studies. They usually do not enhance with contrast. In cases of suspected gelastic seizures, thin slices through the hypothalamic region should be obtained.

Genetics:

Most cases are sporadic. Approximately 5% of cases have Pallister Hall syndrome with a GL13 pathogenic variant.²⁵¹