Overview of infantile epilepsy syndromes

INTRODUCTION — The International League Against Epilepsy (ILAE) has classified epilepsy syndromes (table 1) with the purposes of standardizing terminology and developing a more uniform understanding of the clinical features, diagnosis, and consequences of these disorders [1-6]. (See "ILAE classification of seizures and epilepsy".)

This topic review will discuss recognized infantile epilepsy syndromes. Neonatal epilepsy syndromes are reviewed elsewhere. (See "Overview of neonatal epilepsy syndromes".)

OVERVIEW OF EVALUATION — Infants with suspected seizures should first be evaluated for immediately treatable, provoked (symptomatic) causes of seizures (table 2 and table 3). First-line diagnostic testing includes electroencephalography (EEG) to characterize the interictal background, to confirm the events are seizures, and to classify the seizures. Brain magnetic resonance imaging (MRI) is also standard of care for infants with epilepsy and may help narrow the differential diagnosis and tailor the subsequent workup. Serum, urine, cerebrospinal fluid (CSF) studies, and genetic testing are obtained on a case-by-case basis.

SELF-LIMITED INFANTILE EPILEPSY SYNDROMES — Self-limited epilepsies are syndromes in which there is likely to be spontaneous remission of the seizures [6].

Self-limited (familial) infantile epilepsy — Self-limited (familial) infantile epilepsy (SeLIE) is relatively common, with an estimated incidence of 14.2 per 100,000 live births [7], and accounts for 7 to 9 percent of epilepsies with onset before age two years [6,8].

●Terminology – SeLIE was formerly called benign familial (and nonfamilial) infantile seizures.

●Genetics – Most cases of SeLIE are caused by pathogenic variants in the PRRT2 gene, though SCN2A, KCNQ2, and KCNQ3 have also been implicated. The nonfamilial form of SeLIE is due to de novo pathogenic variants in PRRT2. The inheritance pattern of familial cases is autosomal dominant with incomplete penetrance.

The phenotypic spectrum of PRRT2 pathogenic variants includes the syndrome referred to as infantile convulsions and (paroxysmal) choreoathetosis (ICCA) [9,10], fever-related infantile seizures, hemiplegic migraine, and episodic ataxia [11-17]. (See "Hemiplegic migraine", section on 'Pathophysiology and genetics'.)

Rare infants with SeLIE have pathogenic variants in SCN8A, and some of these individuals develop paroxysmal dyskinesia in adolescence [18].

●Clinical features – SeLIE is characterized by focal seizures in an otherwise normal infant. The seizures begin between ages 3 and 20 months, with a peak incidence at approximately 6 months of age [6,19]. Seizures may be frequent and difficult to control initially. Manifestations of focal seizures include behavioral arrest, impaired awareness, cyanosis, automatisms, versive head and eye movements, and/or clonic movements. Focal clonic seizures may progress to bilateral tonic-clonic seizures, or alternate sides from one focal seizure to another. Seizures may be frequent but typically last less than three minutes.

●Evaluation and diagnosis – Diagnostic criteria for SeLIE (table 4) require focal seizures as described above. Like other self-limited epilepsy syndromes, an evaluation for alternative diagnoses (table 2) is necessary for suspected cases of SeLIE. Neuroimaging is mandatory to exclude lesional epilepsy [6].

The interictal EEG is normal with SeLIE but may show postictal focal slowing [19]; midline spikes during slow wave sleep are reported as a variant [6,20-22]. The ictal EEG reveals focal discharges, predominantly in temporal or posterior regions; bilateral spread may be observed [19].

Brain imaging shows no cause of seizures [6].

●Treatment – Treatment for SeLIE includes standard antiseizure medications. There is evidence from case series to suggest that sodium channel blockers are the most effective antiseizure medication class for infants with PRRT2 [23,24]. The movement disorder associated with PRRT2 is also responsive to carbamazepine [25].

●Clinical course and outcomes – Seizures typically abate by the age of one year, and psychomotor development is normal. In some children and families with SeLIE caused by pathogenic variants in PRRT2, paroxysmal kinesigenic dyskinesia develops in childhood or adulthood [26,27].

Genetic epilepsy with febrile seizures plus — A group of genetic epilepsy syndromes, in which there is a family pedigree of seizures with heterogeneous semiology that often begin during the first year of life, is referred to as genetic epilepsy with febrile seizures plus (GEFS+) [28]. GEFS+ is characterized by multiple febrile seizures, generalized tonic-clonic seizures, and other seizure types including absences, myoclonic seizures, and even focal seizures. GEFS+ is reviewed in greater detail elsewhere. (See "Clinical features and evaluation of febrile seizures", section on 'Genetic epilepsies with febrile seizures'.)

Myoclonic epilepsy in infancy — Myoclonic epilepsy in infancy (MEI) is a rare condition characterized by myoclonic seizures at onset [6].

●Terminology – MEI was previously known as benign myoclonic epilepsy in infancy.

●Genetics – There is currently no known genetic cause.

●Clinical features – In MEI, myoclonic seizures begin between the ages of four months and three years. The peak onset is from 6 to 18 months [6]. There is a 2:1 male-to-female predominance. Development is usually normal prior to seizure onset, although mild developmental abnormalities may be present.

The myoclonic seizures of MEI typically involve the head and upper arms and occur during wakefulness and sleep [6]. These seizures may cluster and can result in falls. Reflex-induced myoclonic seizures, triggered by noise, touch, or startle, affect approximately one-third of patients [29]. Febrile seizures are also seen in approximately one-third of patients.

●Evaluation and diagnosis – Diagnostic criteria for MEI (table 5) require myoclonic seizures with onset from four months to three years [6].

The neurologic examination is normal. An EEG is necessary to confirm that the myoclonus is epileptic and to exclude the much more common and severe infantile epileptic spasms syndrome (IESS). (See "Infantile epileptic spasms syndrome: Clinical features and diagnosis".)

The EEG background is normal during wakefulness, while generalized spike-and-wave or polyspike-and-wave discharges are seen interictally during sleep [6]. Myoclonus correlates with brief bursts of generalized spike-and-wave and/or polyspike-and-wave at approximately 3 Hz during ictal EEG recording; myoclonic seizures are activated by drowsiness and sleep [30].

A brain MRI is required to exclude a lesional cause of epilepsy [6].

Epileptic myoclonus must be distinguished from other epileptic and nonepileptic conditions, including IESS (as noted above), tonic seizures, normal physiologic sleep myoclonus (hypnic jerks), and benign startle responses, among others. (See "Nonepileptic paroxysmal disorders in infancy".)

●Treatment – There is no evidence-based treatment guideline for MEI. Seizures are treated with standard broad-spectrum antiseizure medications (eg, levetiracetam, clobazam, valproate, and others) [31].

●Clinical course and outcomes – Myoclonic seizures usually resolve spontaneously within six months to five years from the onset of MEI, and most children are able to stop antiseizure medication [6]. Subsequent development of other epilepsies, most often juvenile myoclonic epilepsy, occurs in approximately 10 percent of patients. Most patients have normal neurodevelopmental outcomes, but some develop intellectual disability, learning disorders, or problems with attention.

DEVELOPMENTAL AND EPILEPTIC ENCEPHALOPATHIES — Developmental and epileptic encephalopathies are severe syndromes associated with refractory seizures and abnormal neurodevelopmental outcomes, which are related to both the underlying syndrome etiology and the seizures or epileptiform abnormalities [6].

Early infantile developmental and epileptic encephalopathy — Early infantile developmental and epileptic encephalopathy (EIDEE) is a rare syndrome, with an estimated incidence of 10 per 100,000 live births [7]. EIDEE is characterized by early onset, frequent seizures, abnormal neurologic examination, with burst-suppression pattern, slowing, and abundant multifocal discharges on EEG, along with developmental impairment.

●Terminology – In addition to etiology-specific epilepsies, EIDEE incorporates the epilepsy syndromes previously classified as Ohtahara syndrome and early myoclonic encephalopathy (EME) [6]. Ohtahara syndrome and EME are now known to have considerable overlap in clinical features and etiologies [6,32-34]. Thus, these syndrome names have been retired.

●Etiology – There are numerous causes of EIDEE, including structural brain abnormalities, metabolic disorders, and pathogenic gene variants. Genetic studies in patients with EIDEE have identified causative pathogenic variants in over one-half of patients [7,32].

●Clinical features – Onset is within the first three months of life. At onset, the neurologic examination is abnormal with hypotonia or spasticity, and often motor asymmetries [6]. Developmental delays are either apparent upon seizure onset or emerge quickly thereafter. Tonic or myoclonic seizures are required for this diagnosis. Additional seizure types include focal clonic seizures and epileptic spasms. Affected infants may have sequential seizures [35].

●Evaluation and diagnosis – The diagnosis of EIDEE requires the presence of tonic or myoclonic seizures, with onset from birth to three months of age, in an infant with developmental impairment prior to or shortly after seizure onset (table 6). In addition to EEG, the evaluation should exclude a provoked cause of seizures (eg, infection, acute metabolic disturbance, ischemic stroke, or intracranial hemorrhage) including imaging with a brain MRI, and metabolic and genetic investigations to identify the etiology. A thorough evaluation can identify the etiology of EIDEE in approximately 80 percent of patients [6,7,36].

The characteristic background EEG pattern in EIDEE is that of burst suppression, which may be present only in sleep but can also occur across all sleep-wake stages. There is sometimes no associated EEG seizure pattern when myoclonus is present, but clear seizures are visible on EEG when focal clonic or tonic seizures occur. Later in the disease course, in early infancy, the EEG may evolve to a hypsarhythmia pattern or to multifocal spikes and sharp waves.

Brain imaging with MRI is required to exclude a structural cause of seizures. Initial imaging may be normal with some genetic etiologies, or may reveal reduced brain volume, atrophy, and/or white matter abnormalities such as hypomyelination or dysmyelination.

Most infants should receive genetic testing with epilepsy gene panels or whole exome sequencing preferred [37,38]. Metabolic testing is appropriate when no etiology has been identified on initial evaluation.

Suggested genetic investigations include [6]:

•Chromosomal microarray and karyotype (particularly if the infant has dysmorphic features or co-occurring extracerebral malformations)

•Next generation techniques with an epilepsy gene panel, whole exome sequencing, or whole genome sequencing (preferred for infants without obviously dysmorphic features) [39,40]

Suggested metabolic studies may include the following [6]:

•Urine organic and amino acids (including s-sulfocysteine) and urine alpha aminoadipic semialdehyde

•Plasma amino acids, lactate, uric acid, copper/ceruloplasmin, ammonia, acylcarnitine profile, transferrin isoelectric focusing, and very long-chain fatty acids

•Cerebrospinal fluid (CSF) glucose, lactate, pyruvate, amino acids, and neurotransmitters

●Treatment – Seizures are initially treated with standard antiseizure medications but are usually resistant to pharmacologic therapy. There is increased interest and optimism in more tailored therapies as the genetic underpinnings of EIDEE are increasingly understood [41]. Patients with EIDEE who have pathogenic variants in KCNQ2, SCN2A, or SCN8A may respond to sodium channel antiseizure medications such as carbamazepine, oxcarbazepine, lacosamide, or phenytoin [6,42-44]. Certain metabolic conditions and vitamin-dependent epilepsies may be treatable [45]. The ketogenic diet can also be effective for some infants [46]. Select patients may respond to surgical treatment with hemispherectomy or more tailored resection of focal cortical dysplasia [47-50]. Early referral to a specialized epilepsy center is strongly recommended.

●Clinical course and prognosis – The overall outcome of EIDEE is poor, with severe developmental delay, motor disability, and reduced life expectancy [6,51]. Approximately 50 percent of affected patients die in infancy. In many infants, the EEG evolves to hypsarhythmia, which may be asymmetric if there is hemispheric or unilateral focal cortical dysplasia. In the remainder, the EEG evolves to consist of multifocal or unifocal spikes.

EIDEE is the earliest of the age-dependent encephalopathies that include infantile epileptic spasms syndrome (IESS) and Lennox-Gastaut syndrome [52]. The three share the following features:

•Specific age of onset

•Severe intellectual disability

•Abundant epileptiform EEG abnormalities

•Frequent, treatment-resistant seizures

•The potential to evolve sequentially from syndrome to syndrome depending upon the age of the patient

Thus, as the neonate or infant with EIDEE syndrome reaches a few months of age, the patient may develop IESS and then, in childhood, develop Lennox-Gastaut syndrome with the associated seizure types and prognosis.

IESS is discussed in detail separately. (See "Infantile epileptic spasms syndrome: Etiology and pathogenesis" and "Infantile epileptic spasms syndrome: Clinical features and diagnosis" and "Infantile epileptic spasms syndrome: Management and prognosis".)

Lennox-Gastaut syndrome is also discussed separately. (See "Lennox-Gastaut syndrome".)

Epilepsy of infancy with migrating focal seizures — Epilepsy of infancy with migrating focal seizures (EIMFS) is characterized by drug-resistant migrating focal seizures and developmental delay [6]. It is a rare disorder, with an estimated prevalence of approximately 0.1 per 100,000 children [53].

●Terminology – EIMFS was previously known as malignant migrating partial seizures of infancy.

●Etiology – EIMFS has multiple genetic causes, with more than 30 genes implicated [54]. Together, these known genetic etiologies account for approximately 70 percent of cases. Pathogenic variants in KCNT1 are the most common genetic etiology, and lead to a gain-of-function abnormality of the KCNT1 potassium channel [55]. De novo gene abnormalities account for most cases, as familial inheritance is rare [56,57].

●Clinical features – The hallmark of EIMFS is focal seizures that migrate from one hemisphere or cortical region to another within a single seizure [6]. Onset is within the first year of life, usually within the first six months (mean three months) [58-60]. Seizures are often prolonged, resistant to therapy, and commonly increase in frequency over weeks to months after epilepsy onset. Episodes of status epilepticus are frequent [58].

●Evaluation and diagnosis – The evaluation should exclude structural causes of seizures and a search for the underlying etiology. The diagnosis of EIMFS requires the occurrence of focal motor clonic or tonic seizures that migrate clinically from one hemisphere to another, along with an ictal EEG confirming a migrating pattern (table 7). Genetic testing with an epilepsy gene panel (at minimum) or whole exome or whole genome sequencing is strongly advised [39,40].

The interictal EEG may have a normal background at the time of seizure onset, but diffuse slowing develops over time, along with multifocal discharges. The ictal EEG shows a migrating pattern with consecutive involvement of multiple independent cortical regions in a single seizure event [61,62].

An MRI is required to exclude a structural cause of seizures. Imaging is typically normal at onset of EIMFS. Over time, patients may develop delayed myelination with white matter hyperintensities on MRI, while some patients develop cerebellar atrophy [53,55,60].

Metabolic testing may be useful to exclude other causes of seizures and to search for congenital disorders of glycosylation, which have been identified in some children with EIMFS [63]. (See "Overview of congenital disorders of glycosylation", section on 'Diagnosis'.)

●Treatment – Seizures in EIMFS are drug resistant, but observational data and anecdotal reports suggest that some patients respond favorably to stiripentol plus clonazepam, and/or levetiracetam [64,65]. Quinidine, a KCNT1 potassium channel blocker, has been proposed as a rational treatment for KCNT1-associated EIMFS, but benefit among several small studies has been inconsistent [66-70], and its use is in this setting is controversial. As with other pharmacoresistant epilepsies, the ketogenic diet may be helpful for children with EIMFS. Though off-label, vagus nerve stimulation may also be considered once children have grown sufficiently to accommodate the device.

●Clinical course and prognosis – Drug-resistant epilepsy, severe developmental delay and regression are characteristic of EIMFS, along with a reduced life expectancy. Some children will also have an associated gut dysmotility and a movement disorder [53].

Infantile epileptic spasms syndrome — IESS incorporates West syndrome (the triad of epileptic spasms, arrest of psychomotor development, and hypsarhythmia) and infants with epileptic spasms (also called infantile spasms) who do not fulfill all the criteria for West syndrome [6].

Infantile spasms are reviewed in detail elsewhere. (See "Infantile epileptic spasms syndrome: Etiology and pathogenesis" and "Infantile epileptic spasms syndrome: Clinical features and diagnosis" and "Infantile epileptic spasms syndrome: Management and prognosis".)

Dravet syndrome — Dravet syndrome (DS), previously known as severe myoclonic epilepsy of infancy, is a rare early-onset epilepsy syndrome characterized by refractory epilepsy and neurodevelopmental problems. Onset of seizures most commonly occurs between three and nine months. The clinical features of DS evolve over time (table 8).

DS is discussed in detail separately. (See "Dravet syndrome: Genetics, clinical features, and diagnosis" and "Dravet syndrome: Management and prognosis".)

Etiology-specific syndromes — Etiology-specific syndromes are characterized by an epilepsy etiology that is associated with a clearly defined, distinct phenotype and consistent EEG, neuroimaging, and genetic associations [6]. Most etiology-specific syndromes with neonatal or infantile onset are also developmental and epileptic encephalopathies (DEEs).

CDKL5 developmental and epileptic encephalopathy — Cyclin-dependent kinase-like 5 developmental and epileptic encephalopathy (CDKL5-DEE) is characterized by medically refractory seizures, typically with onset in the first two months of life, and severe neurodevelopmental impairment [71]. The estimated incidence is 1.7 to 2.5 per 100,000 live births [72-74].

●Terminology – CDKL5-DEE is also known as CDKL5 deficiency disorder.

●Genetics – CDKL5-DEE is an X-linked condition, with a 4:1 female-to-male ratio [75,76]. Males with pathogenic variants in CDKL5 have no normal CDKL5 gene, and as a result their syndrome is usually lethal during fetal life [77].

●Clinical features – Seizure onset occurs at a median age of 6 weeks, with onset by 12 months in 90 percent of patients; other early features include developmental delay, prominent hypotonia, and cortical visual impairment with poor eye fixation and avoidance of gaze; some patients have symptoms (eg, deceleration of head growth, stereotypies and hand apraxia) that overlap with those of Rett syndrome [6,71,78]. (See "Rett syndrome: Genetics, clinical features, and diagnosis", section on 'Atypical RTT'.)

Multiple seizure types can be seen, including tonic seizures, epileptic spasms, generalized tonic-clonic seizures, and focal seizures [6]. Clusters of epileptic spasms and tonic seizures may predominate in the first months of life. Seizures with multiple motor phases, including a specific sequence (hyperkinetic-tonic-spasms), have been reported in some patients [75,79,80].

The clinical and EEG features of CDKL5-DEE typically evolve over three successive stages [81]:

•Early epilepsy with brief tonic seizures (stage 1)

•Epileptic encephalopathy with tonic seizures and epileptic spasms (stage 2)

•Multifocal and myoclonic epilepsy with tonic seizures, myoclonus, absences, or multifocal seizures (stage 3)

●Evaluation and diagnosis – The interictal EEG may be normal initially (first stage) but later becomes severely abnormal with bilateral or generalized slowing and spikes or polyspikes (second stage), followed by high-amplitude, diffuse delta waves with pseudoperiodic bursts high amplitude spike, polyspikes, and spike and wave activity (third stage) [81]. Brain MRI may be normal or show delayed myelination and global atrophy [71,82]. Genetic testing with detection of pathogenic or likely pathogenic variants in CDKL5 confirms the diagnosis (table 9) [6].

●Treatment – Sustained benefit has not been shown with conventional antiseizure medications [78,83]. Small studies suggest possible short-term benefit with ketogenic diet [84] and vagus nerve stimulation [85].

For children ages two years and older, we suggest treatment with ganaxolone. Ganaxolone, a synthetic neuroactive steroid, is approved by the US Food and Drug Administration (FDA) to treat seizures in patients with CDKL5 deficiency disorder who are two years of age or older [86]. Approval was based on a controlled trial of 101 patients (ages 2 to 21 years; 78 percent female) with pathogenic variants in CDKL5 and ≥16 major motor seizures per 28 days at baseline [87]. Patients were randomly assigned to treatment in a 1:1 ratio with ganaxolone or placebo; the dose was titrated for four weeks (up to a maximum of 63 mg/kg per day for patients weighing ≤28 kg, or to a maximum of 1800 mg/day for patients weighing >28 kg) followed by 13 weeks of maintenance dosing. At the end of the 17-week double-blind treatment phase, the median reduction from baseline in the 28-day frequency of major motor seizures was greater with ganaxolone compared with placebo (31 versus 7 percent; estimated median difference -27.1 percent, 95% CI -47.9 to -9.6 percent). However, the proportion of patients with a reduction in seizure frequency of ≥50 percent showed only a nonsignificant trend to benefit with ganaxolone (24 versus 10 percent, estimated difference -14.7 percent, 95% CI -4.7 to 33.8 percent). Results from an open-label extension trial suggested that the reduction in major motor seizures was sustained [88].

The most common adverse effects with ganaxolone were somnolence, pyrexia, and upper respiratory tract infections [87,88].

Cannabidiol is not well studied for the treatment of CDKL5-DEE but is offered by some experts [89].

●Clinical course and prognosis – The prognosis of CDKL5-DEE is generally poor, with most patients having refractory epilepsy and severe intellectual disability; a minority of patients achieve independent walking [71].

PCDH19 clustering epilepsy — PCDH19 clustering epilepsy is characterized by focal and/or generalized seizures, commonly fever-induced and in clusters, as well as behavioral and psychiatric comorbidity and varying degrees of intellectual disability [6,90]. Females are mainly affected. The estimated incidence is approximately 2.5 per 100,000 live births [72].

●Genetics – PCDH19 clustering epilepsy is an X-linked syndrome associated with pathogenic variants in the PCDH19 gene, which encodes for protocadherin-19 [6]. Only heterozygous females and mosaic males are affected due to random X inactivation, which leads to somatic mosaicism and abnormal cellular interference between cells with and without protocadherin [90-92]. Males with hemizygote pathogenic variants produce only cells with a deficient subclass of protocadherin-19 but remain asymptomatic because of the absence of cellular interference.

●Clinical features – Seizure onset is usually within the first three years of life, most commonly in the first year (mean age 10 months) [93,94]. The seizures typically occur in clusters and may be triggered by fever. Seizures are focal with impaired awareness and may include tonic upper arm extension, head and eye deviation, facial pallor, fearful expression, and screaming; atypical absences are also reported [94]. A 2019 systematic review of 269 cases of PCDH19 clustering epilepsy found that approximately one-third had episodes of status epilepticus [95].

The neurologic examination and neurodevelopment is typically normal at seizure onset [6]. However, many affected patients develop cognitive impairment, autism, and/or behavioral abnormalities.

●Evaluation and diagnosis – The diagnosis is suspected in an infant female presenting with a cluster of febrile seizures (table 10) [6]. The EEG shows a slow background with epileptiform discharges (spikes and slow waves) during seizures. In approximately one-half of cases, seizures may be poorly localized on EEG [6,93]. Brain MRI, laboratory, and metabolic studies show no consistent abnormalities at seizure onset [6]. The diagnosis is confirmed by genetic testing that demonstrates a PCDH19 pathogenic variant.

●Treatment – PCDH19 clustering epilepsy is typically refractory to treatment with antiseizure medications [90]. There is low-quality retrospective evidence that bromide, clobazam, valproate, and levetiracetam may reduce the frequency of seizures [96,97]. Most patients are on polytherapy prior to possible age-dependent improvement of seizures.

●Clinical course and prognosis – Seizures are generally intractable during the first decade of life but tend to decrease in frequency after the first decade of life, and seizure remission during adolescence to adulthood occurs in up to 25 percent. Most patients develop intellectual disability and autism spectrum disorder, and some develop behavioral disorders, including attention deficit hyperactivity disorder, depression, and psychosis [6,98]. However, some patients have normal intellectual development [90].

Glut1 deficiency syndrome — Glucose transporter 1 deficiency syndrome (Glut1DS) leads to a progressive neurologic deterioration with epilepsy, movement disorders, and intellectual disability [6,99,100]. The estimated incidence of the classic Glut1DS phenotype (neonatal/infantile onset of epilepsy) is 4.2 per 100,000 live births [72]. However, the disorder may be more common, as affected individuals may present later in childhood with nonepileptic symptoms [6].

●Genetics – Glut1DS is caused by pathogenic variants in the SLC2A1 gene, which encodes the glucose transporter type 1 that facilitates glucose transport across the blood-brain barrier into the brain [101].

●Clinical features – The classic phenotype of Glut1DS is characterized by epilepsy, developmental delay, microcephaly or deceleration of head growth, and complex movement disorders [101]. Seizures generally begin before the age of three years with various types of generalized seizures (particularly myoclonic, myoclonic-atonic, generalized tonic-clonic) and focal seizures, including atypical or early-onset absence seizures [100,102]. Suggestive features of Glut1DS include seizures occurring in early morning or with fasting, and rapid, multidirectional eye movements with head movements in the same direction (ie, eye-head gaze saccades). Approximately 10 percent of children with early-onset (prior to age four years) absence epilepsy have Glut1DS; thus, children with this seizure profile should be evaluated for Glut1DS [103].

●Evaluation and diagnosis – The interictal EEG may be normal [104]. Infants may show background slowing, sometimes with focal slowing or epileptiform discharges; children older than age two years usually have generalized 2.5 Hz spike-wave pattern. Brain MRI abnormalities occur in approximately 25 percent, including subcortical U fiber hyperintensity, enlarged perivascular spaces, enlarged ventricles, and delayed myelination [6,101,105].

The diagnosis of Glut1DS can be confirmed after a four- to six-hour fast by lumbar puncture demonstrating low CSF glucose (hypoglycorrhachia) and normal blood glucose, or with molecular genetic testing that identifies an SLC2A1 pathogenic variant (table 11) [101].

●Treatment – For patients of all ages with Glut1DS, we recommend starting ketogenic dietary therapy (KDT) as early as possible after the diagnosis is made [100]. The ketogenic diet is effective for treating seizures associated with Glut1DS, but the primary goal is to slow or prevent neurodevelopmental decline. KDT provides ketones as an alternative energy source for the brain. Treatments other than KDT (eg, antiseizure medications) do not correct the underlying metabolic defect of Glut1DS. (See "Ketogenic dietary therapies for the treatment of epilepsy", section on 'GLUT-1 deficiency'.)

The preferred KDT for children under two years of age with Glut1DS is a modified classic ketogenic diet with a 3:1 lipid to nonlipid ratio [100]. The diet is continued for as long as tolerated. Unlike KDT for children with other epilepsy types, whose diet is titrated to seizure control, children with Glut1DS should have high-target serum ketones even after seizures are controlled in order to preserve brain development. (See "Ketogenic dietary therapies for the treatment of epilepsy", section on 'Classic ketogenic diet'.)

For adolescents and adults, and for younger patients unable to adhere to the classic ketogenic diet, the modified Atkins diet is an alternative [100]. (See "Ketogenic dietary therapies for the treatment of epilepsy", section on 'Modified Atkins diet'.)

The seizures in Glut1DS are generally resistant to therapy with antiseizure medications alone, unless also used in combination with KDT [6].

●Clinical course and prognosis – Although the ketogenic diet may control seizures, most affected patients have varying degrees of cognitive impairment [6,101].

Sturge-Weber syndrome — Sturge-Weber syndrome (SWS) is a rare congenital vascular disorder caused by somatic mosaic pathogenic variants in the GNAQ gene. SWS is characterized by facial capillary malformation (port wine stain) and associated capillary-venous malformations affecting the brain and eye. These vascular malformations are associated with specific ocular and neurologic abnormalities. Seizures are often the first symptom of SWS; seizure onset is typically in the first year of life.

SWS is reviewed in detail elsewhere. (See "Sturge-Weber syndrome".)

Gelastic seizures with hypothalamic hamartoma — Hypothalamic hamartomas are rare congenital brain lesions associated with widespread comorbidities [6,106]. Gelastic seizures are defined as focal seizures with uncontrollable stereotyped laughter (with or, most classically, without a sensation of mirth). They are characteristically associated with hypothalamic hamartomas but can also arise from other locations.

Epidemiologic data are scarce but suggest that the prevalence of gelastic seizures with hypothalamic hamartoma (GS-HH) is 0.5 per 100,000 children less than 20 years of age [107].

●Clinical features – Seizure onset is typically in the first year of life but can occur later in childhood [6,106-108]. Some patients have a combination of gelastic and dacrystic seizures, defined as focal seizures with paroxysmal stereotyped crying [109]. Additional seizure types may include other types of focal seizures and epileptic spasms. Most patients have multiple seizures per day, and seizures may occur in clusters.

●Evaluation and diagnosis – The EEG usually has a normal background [6]. Beyond infancy, interictal discharges may appear. Later in childhood, the EEG may show generalized slow spike and wave, or generalized spike or spike-wave. The diagnosis requires the presence of gelastic seizures and imaging confirmation of hypothalamic hamartoma (table 12) [6].

●Treatment – Seizures are resistant to pharmacologic therapy. Early surgical treatment of the hypothalamic hamartoma is optimal for both seizure control and prevention of cognitive and behavioral decline [6,110]. (See "Seizures and epilepsy in children: Refractory seizures", section on 'Epilepsy surgery'.)

●Clinical course and prognosis – Without surgery targeting the hypothalamic hamartoma, epilepsy worsens over time with development of focal impaired awareness seizures and generalized seizures, or even multiple seizure types similar to the Lennox-Gastaut syndrome (see "Lennox-Gastaut syndrome") [6,111,112]. Although usually normal at seizure onset, cognition may plateau or decline over time along with the development of behavioral problems. Comanagement with an endocrinologist is advised.

SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Seizures and epilepsy in children".)

SUMMARY AND RECOMMENDATIONS

●Self-limited syndromes

•Self-limited (familial) infantile epilepsy (SeLIE) – SeLIE is one of the more common infantile epilepsies. Most cases are caused by pathogenic variants in the PRRT2 gene. The nonfamilial form of SeLIE is due to de novo pathogenic variants in PRRT2. The inheritance pattern of familial cases is autosomal dominant with incomplete penetrance. SeLIE is characterized by the onset of focal seizures in an otherwise normal infant beginning from 3 to 20 months of age. The seizures may occur with behavioral arrest, impaired awareness, cyanosis, automatisms, versive head and eye movements, and/or clonic movements. Seizures may progress to bilateral tonic-clonic seizures, or alternate sides from one focal seizure to another (table 4). Seizures usually remit by one year of age, and neurodevelopment is typically normal. Some patients develop paroxysmal dyskinesia later in life. Treatment with sodium channel blockers can be effective for seizure control and also ameliorate the movement disorder. (See 'Self-limited (familial) infantile epilepsy' above.)

•Genetic epilepsy with febrile seizures plus (GEFS+) – GEFS+ encompasses a group of genetic epilepsy syndromes with a family pedigree of seizures with heterogeneous semiology that often begin during the first year of life. Phenotypes include multiple febrile seizures, generalized tonic-clonic seizures, absences, myoclonic seizures, and focal seizures. (See "Clinical features and evaluation of febrile seizures", section on 'Genetic epilepsies with febrile seizures'.)

•Myoclonic epilepsy in infancy (MEI) – MEI is a rare condition characterized by myoclonic seizures at onset, which occurs between the ages of four months and three years. The peak onset is from 6 to 18 months. Development is usually normal prior to seizure onset. The neurologic examination is also normal. An EEG is necessary to confirm that the myoclonus is epileptic and to exclude infantile epileptic spasms syndrome (IESS) (table 5); neuroimaging is also required. MEI is generally responsive to therapy with standard antiseizure medications. The seizures usually resolve from six months to five years after onset. Most but not all patients have normal neurodevelopment, and some go on to develop other epilepsies. (See 'Myoclonic epilepsy in infancy' above.)

●Developmental and epileptic encephalopathies (DEEs) – The DEEs are severe syndromes associated with refractory seizures and poor neurodevelopmental outcomes, which are related to both the underlying etiology independent of epileptiform activity and the epileptic encephalopathy. (See 'Developmental and epileptic encephalopathies' above.)

•Early infantile developmental and epileptic encephalopathy (EIDEE) – This syndrome is characterized by early onset, frequent refractory seizures, developmental impairment, and poor prognosis with reduced life expectancy (table 6). Infants with EIDEE may evolve to develop IESS and then in childhood may develop Lennox-Gastaut syndrome. (See 'Early infantile developmental and epileptic encephalopathy' above.)

•Epilepsy of infancy with migrating focal seizures (EIMFS) – This syndrome is characterized by drug-resistant migrating focal seizures, severe developmental delay, and a reduced life expectancy (table 7). (See 'Epilepsy of infancy with migrating focal seizures' above.)

•Infantile epileptic spasms syndrome (IESS) – This syndrome incorporates West syndrome (the triad of epileptic spasms, arrest of psychomotor development, and hypsarhythmia) and infants with epileptic spams (also called infantile spasms) who do not fulfill all the criteria for West syndrome. (See "Infantile epileptic spasms syndrome: Etiology and pathogenesis" and "Infantile epileptic spasms syndrome: Clinical features and diagnosis" and "Infantile epileptic spasms syndrome: Management and prognosis".)

•Dravet syndrome (DS) – This syndrome is characterized by refractory epilepsy and neurodevelopmental problems. The clinical features of DS evolve over time (table 8). (See "Dravet syndrome: Genetics, clinical features, and diagnosis" and "Dravet syndrome: Management and prognosis".)

●Etiology-specific syndromes – These are characterized by an epilepsy etiology that is associated with a clearly defined, distinct phenotype and consistent EEG, neuroimaging, and genetic associations; most etiology-specific epilepsy syndromes are also DEEs. (See 'Etiology-specific syndromes' above.)

•CDKL5-DEE – This disorder, also called CDKL5 deficiency disorder, is an X-linked condition characterized by female predominance, medically refractory seizures, typically with onset in the first two months of life, and severe neurodevelopmental impairment. Genetic testing with detection of pathogenic or likely pathogenic variants in CDKL5 confirms the diagnosis (table 9). For children ages two years and older with refractory epilepsy due to CDKL5-DEE, we suggest treatment with ganaxolone (Grade 2B), which may provide modest benefit for reducing the frequency of seizures. The seizures are generally unresponsive to standard antiseizure medications. (See 'CDKL5 developmental and epileptic encephalopathy' above.)

•PCDH19 clustering epilepsy – This is an X-linked condition characterized by refractory focal and/or generalized seizures, commonly fever-induced and in clusters, as well as behavioral and psychiatric comorbidity and varying degrees of intellectual disability. Only heterozygous females and mosaic males are affected. The diagnosis is suspected in a female infant presenting with a cluster of febrile seizures (table 10). Seizures tend to decrease in frequency after the first decade of life; seizure remission during adolescence to adulthood occurs in up to 25 percent. (See 'PCDH19 clustering epilepsy' above.)

•Glucose transporter 1 deficiency syndrome (Glut1DS) – The classic phenotype of Glut1DS is characterized by epilepsy, developmental delay, microcephaly or deceleration of head growth, and complex movement disorders. The diagnosis of Glut1DS can be confirmed by lumbar puncture demonstrating low cerebrospinal fluid (CSF) glucose (hypoglycorrhachia) and normal blood glucose, along with molecular genetic testing that identifies an SLC2A1 pathogenic variant (table 11). For patients of all ages with Glut1DS, we recommend ketogenic dietary therapy (KDT) started as early as possible (Grade 1B). KDT is effective for treating seizures and, importantly, supporting neurodevelopment. (See 'Glut1 deficiency syndrome' above and "Ketogenic dietary therapies for the treatment of epilepsy", section on 'GLUT-1 deficiency'.)

•Sturge-Weber syndrome (SWS) – SWS is caused by somatic mosaic pathogenic variants in the GNAQ gene and characterized by facial capillary malformation (port wine stain) and associated capillary-venous malformations affecting the brain and eye. Seizures are often the first symptom of SWS; seizure onset is typically in the first year of life. (See "Sturge-Weber syndrome".)

•Gelastic seizures with hypothalamic hamartoma (GS-HH) – Hypothalamic hamartomas are rare congenital brain lesions associated with widespread comorbidities including gelastic seizures. GS-HH is associated with a high seizure frequency with treatment-resistant epilepsy that worsens over time. The diagnosis of GS-HH is made with imaging demonstration of hypothalamic hamartoma (table 12). Early surgical treatment of the hypothalamic hamartoma is optimal for both seizure control and prevention of cognitive and behavioral decline. (See 'Gelastic seizures with hypothalamic hamartoma' above.)