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The International League Against Epilepsy (ILAE) distinguishes three main groups of neonatal epilepsy syndromes: (1) self-limiting neonatal, neonatal-infantile and infantile (familial or not familial) epilepsies, (2) developmental and epileptic encephalopathies (DEE) and (3) etiology-specific epilepsies. The DEEs are characterized by a combination of severe developmental disorders, neurological abnormalities and treatment-resistant seizures. This article focuses on early infantile DEEs, which manifest within the first 3 months of life. The underlying causes are mostly genetic, structural, and/or metabolic factors, with expanded diagnostic tools enabling identification in up to 80% of cases. Clinically, affected infants present with drug-resistant seizures of various semiologies, abnormal movement patterns and pathological interictal EEG patterns, such as a burst-suppression pattern or others. Epilepsy with migrating focal seizures in infancy is a rare form of DEE. It is characterized by focal motor, tonic-clonic seizures, which appear in EEG recordings as migrating onset epileptic activity. Among the etiology-specific DEEs, KCNQ2-related DEE, pyridoxine-dependent (ALDH7A1) and pyridoxamine-5-phosphate (PNPO)-dependent DEE as well as CDKL5-related DEE, are particularly associated with an onset in the neonatal and early infantile period. The treatment options for neonatal DEEs have improved due to advances in precision medicine. Specific genetic variants (e.g., KCNQ2, SCN2A and KCNT1 mutations) can be targeted with sodium channel blockers or other specific medications.; however, the prognosis remains poor, especially in severe treatment-resistant forms. Early genetic, structural, and metabolic diagnostics are crucial for initiating optimal treatment and improving long-term outcomes.
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Seizures are more common in neonates, with an incidence of 1–5/1000 births, than at any other age over the course of a lifetime [1]. However, 85% of these seizures are symptomatic, most commonly occurring in the context of hypoxic–ischemic encephalopathy. Neonatal epilepsy syndromes are therefore much rarer: It is estimated that 75 out of 100,000 neonates develop epilepsy within the first 6 months of life [2]. The incidence is assumed to be even higher in less resource-rich regions of the world [3].
In the neonatal period, a distinction is made between three groups of epilepsy syndromes [4]:
Self-limiting neonatal, neonatal-infantile, and infantile (familial or not familial) epilepsy syndromes, which are highly likely to show spontaneous remission.
Developmental and epileptic encephalopathies (DEEs), in which developmental disorders and neurological abnormalities are attributable, on the one hand, to the underlying cause, and on the other, to uncontrollable epilepsy, either in terms of the number of seizures or the high discharge activity [5].
Etiology-specific epilepsy syndromes, which also represent DEEs in this age group.
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The aim of this article is to present DEEs that occur within the first 3 months of life using summary tables (Table 1, 2, 3, 4, and 5): These are outlined in red in Fig. 1.
Fig. 1
Presentation by the International League Against Epilepsy (ILAE) Taskforce: three main groups of epilepsy syndromes with onset in the neonate and infantile periods [4]: The neonatal developmental and epileptic encephalopathies are outlined in red
Early infantile developmental and epileptic encephalopathies
Early-infantile DEEs include Ohtahara syndrome and early myoclonic encephalopathy, which were previously considered two distinct entities, but whose designations were abandoned in the latest ILAE position statement on the different epilepsy syndromes [4]. The etiologies are therefore highly diverse, most commonly being genetic, structural, and/or metabolic. By definition, seizure onset must be within the first 3 months of life, and abnormalities on neurological examination (of tone, posture, or movement), a developmental disorder (which may still be difficult to detect), frequent seizures, and pharmacoresistance must be present. The interictal electroencephalogram (EEG) is highly abnormal, showing a burst-suppression pattern, a discontinuous pattern, diffuse slowing, or multifocal discharges [4]. Further diagnostic tests such as cerebral imaging and genetic and metabolic analyses enable an accurate etiologic classification in up to 80% of affected neonates and infants ([6]; Table 1).
Table 1
Early infantile developmental and epileptic encephalopathy (DEE)
With an incidence of 10/100,000 live births, early-infantile DEE is rare. The first seizures occur within the first 3 months of life. These children do not become seizure-free with conventional antiseizure therapies and, as mentioned earlier, show abnormalities on neurological examination and in their development [5].
Precision medicine now allows certain gene variant-specific therapies to be used, such as sodium channel blockers, often in high doses, for KCNQ2 (and KCNQ3, both loss of function), SCN2A, and SCN8A (gain of function) and quinidine for KCNT1 [7‐10].
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On the other hand, epilepsy surgery should always be discussed if the prerequisites are met.
Seizures, electroencephalogram patterns, and movement disorders
Seizure semiologies in the context of early-infantile DEEs include tonic, myoclonic, and epileptic spasms, as well as sequential seizures (i.e., multiple semiologies in succession within a seizure, typically KCNQ2 with tonic onset).
Various interictal patterns are possible, but typically a burst-suppression pattern is seen, i.e., high-voltage burst activity (150–300 µV) consisting of spikes, sharp waves, sharp and slow waves alternating with a suppressed phase (amplitude < 5 µV). The duration of the suppressed phase is also influenced by the administration of barbiturates, for example, or by the child’s state of alertness. However, discontinuous patterns, multifocal spikes, sharp waves, sharp and slow waves, and diffuse slowing are also possible (examples in Figs. 2, 3, 4, 5, 6, 7, and 8).
Fig. 2
Ictal and interictal electroencephalogram (age 1 week, amplitude 15 µV): burst-suppression pattern in metabolic early-infantile developmental and epileptic encephalopathy due to a cholesterol metabolism disorder. Clinical presentation: erratic myoclonus during bursts (first half of the image), tonic seizures, and movement disorders (not shown)
Ictal electroencephalogram (age 3 days, amplitude 7 µV): sequential seizure with a a tonic phase, b a clonic phase (first half of the image, bilateral spikes and waves) followed by another tonic phase (second half of the page, bilateral flattening of amplitude and rapid activity), and c an autonomic phase with apnea (note absence of abdominal movement in the second half of the image) due to a KCNQ2 variant
Interictal electroencephalogram (age 4 months, amplitude 10 µV): diffuse slowing with superimposed sharp waves and sharp-and-slow wave complexes in the right hemisphere due to a CDKL5 variant. Clinical presentation: tonic seizures
In addition to epileptic seizures, neonates and infants with early-infantile DEE also exhibit movement disorders with chorea, non-epileptic myoclonus, dystonia, and tremor [5].
Epilepsy of infancy with migrating focal seizures
Epidemiology and clinical presentation
Epilepsy of infancy with migrating focal seizures is very rare, with a prevalence of approximately 0.1/100,000 infants. The seizures occur within the first 6 months (mean: 3 months). The children usually develop secondary microcephaly. Initial development is usually normal, but becomes severely impaired as the disease progresses (Table 2).
Table 2
Infantile epilepsy with focal migratory seizures
Onset
In the first 6 months of life (mean: 3 months)
Prevalence
0.11/100,000 infants
Normal initial development, followed by regression and microcephaly during the first year of life
Prognosis
Poor, although specific therapies can have a positive effect; milder spectrum possible
EEG
Typical: pattern of migration on EEG, i.e., the focus migrates, not to be confused with propagation
EEG background activity normal at onset, followed by diffuse slowing over time
Seizure semiology
Focal clonic and tonic, rarely spasms, status epilepticus is also common
Most common genetic causes
KCNT1, SCN2A, less frequently SCN1A, SLC12A5, BRAT1, TBC1D24, metabolic: CDG
Specific therapies
For KCNT1 and SCN2A
EEG electroencephalogram
Seizures and electroencephalogram
Focal motor tonic–clonic seizures that show a pattern of migration on EEG during a seizure are required for the diagnosis of this syndrome. The focus migrates, i.e., seizures are generated repeatedly at different locations during the course of a seizure; if seizures initially start on one side, the contralateral hemisphere also becomes active. However, this is not simply a propagation of epileptic activity [11, 12]. Seizures can also manifest exclusively with eye deviation to the side or with autonomic semiology [12‐14]. Spasms are relatively rare, and myoclonus argues against this diagnosis. Status epilepticus is also common. Prolonged EEGs are required in order to recognize and diagnose these as migrating focal seizures.
While the background activity is usually normal at the outset, it often slows down over the following months. Seizures show a typical EEG correlate with the aforementioned migrating focus [12].
Magnetic resonance imaging and metabolic diagnostics
Imaging is initially unremarkable, but signs of atrophy may become apparent over time. Metabolic evaluation is also essential, as a congenital disorder of glycosylation may be the cause in rare cases [15].
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Prognosis
The prognosis tends to be poor, with a clearly increased risk of sudden unexpected death in epilepsy (SUDEP) and mortality, although specific treatment options can somewhat influence the outcome [14].
KCNQ2-DEE (developmental and epileptic encephalopathy) [16, 17]
Onset
First days of life
Prevalence
Unknown. Loss-of-function variants, whereby self-limiting epilepsies and DEEs are also possible. (Caution: Gain-of-function variants show completely different clinical symptoms)
Prognosis
With rapid use of sodium channel blockers, seizures can decrease significantly, but developmental disorders are usually moderate to severe
EEG
Typical: suppression–burst pattern or multifocal spikes and sharp waves
Seizure semiology
Focal tonic, clonic, autonomic, therefore typically sequential, spasms are possible
Specific therapies
Sodium channel blockers (high doses sometimes necessary)
EEG electroencephalogram
Table 4
Pyridoxine-dependent (ALDH7A1) and pyridoxamine-5-phosphate (PNPO)-dependent developmental and epileptic encephalopathy (DEE) [18, 19]
Urine/plasma/cerebrospinal fluid elevated
Defect in the lysine degradation pathway; therefore, metabolic markers: alpha-aminoadipic semialdehyde and pipecolic acid
Onset
Immediately after birth, or in some cases even intrauterine. Patients may initially be acidotic, hypotonic, irritable, followed by rapid onset of seizures
Incidence
1/65,000–1/273,000 Births for ALDH7A1 variant-associated DEE, unknown for P5P-DEE
Prognosis
Depending on how quickly treatment is administered, mild to severe mental disability
EEG
Burst-suppression pattern or multifocal discharges with slowed background activity
Seizure semiology
Multifocal myoclonus (affecting the trunk, eyes, facial muscles), focal seizures, spasms, bilateral tonic, bilateral clonic, generally hyperkinetic and highly irritable to encephalopathic, vomiting
Most common genetic causes
ALDH7A1 for pyridoxine-dependent DEE, less commonly also biallelic variant in PLBP (pyridoxine-dependent DEE), PNPO for pyridoxamine-5-phosphate deficiency
Specific therapies
Pyridoxine and pyridoxal phosphate (see above). In addition, for causative ALDH7A1 variants, lysine reduction and L‑arginine administration to reduce neurotoxic lysine metabolites
EEG electroencephalogram
Table 5
CDKL5-DEE (developmental and epileptic encephalopathy) [20‐22]
Gene-associated DEE
Cyclin-dependent kinase-like 5 DEE
Onset
In the first few weeks, on average 6 weeks, primarily hypotonic, then seizures
Incidence
1/40,000–1/60,000 births, X‑linked, therefore F:M 4:1. M more severely affected than F
Prognosis
Severe global developmental disorder, movement disorder with choreoathetosis and dystonia
EEG
Initially interictally normal, bilateral flattening and rapid activity ictally. From stage 2: severe encephalopathic slowing, spikes and polyspikes. From stage 3: global slowing, pseudoperiodic, spikes, polyspikes. Spike-and-wave complexes
Seizure semiology
Clusters of spasms and tonic seizures. Stage 1: short tonic seizures. Facial flushing. Stage 2: encephalopathy with tonic seizures and spasms. Hypermotor–tonic spasm sequence. Stage 3: multifocal epilepsy, myoclonus, tonic seizures, absences
MRI
Progressive brain atrophy
Specific therapies
Refractory to therapy, ganaxolone
M men, F women, EEG electroencephalogram, MRI magnetic resonance imaging
Treatment options for neonatal developmental and epileptic encephalopathies
Although neonates and infants with neonatal DEEs are typically considered pharmacoresistant and their prognosis is still deemed poor, precision medicine has led to a improvement in outcomes for specific genetic variants in recent years, particularly in the field of monogenic epilepsies. Drug therapy options are now also potentially available for the neonatal and early-infantile period that may enable a better response. This underscores once again the considerable importance of rapid genetic, structural (using cranial magnetic resonance imaging [cMRI]), and metabolic evaluation in order to be able to initiate optimal treatment as early as possible.
This applies in particular to genetic variants in the KCNQ2 (DEE or self-limiting) and KCNQ3 (self-limiting) genes, SCN2A (self-limiting and DEE) and SCN8A (self-limiting), KCNT1 (DEE), and, of course, metabolic epilepsies such as ALDH7A1, biallelic variants in PLBP (pyridoxine-dependent DEE), and PNPO (pyridoxal phosphate-dependent DEE; Fig. 9). Furthermore, this also applies to rarer DEEs such as pyrimidine synthesis defects with evidence of a CAD variant, which can be treated with uridine monophosphate, or molybdenum cofactor deficiency, which can be treated with cyclic pyranopterin monophosphate. There are also therapies that can improve symptoms, such as sodium benzoate for glycine encephalopathy or ganaxolone for CDKL5 variants. Numerous new therapeutic approaches are the focus of research with the aim of offering gene variant-specific messenger RNA (mRNA) therapy or even gene therapy in the future [10, 23‐25].
Fig. 9
Treatment options for neonatal developmental and epileptic encephalopathies depending on whether the genetic variant represents a gain or a loss of function. (Adapted from Guerrini et al. [10, 23])
Developmental and epileptic encephalopathies (DEEs) are characterized by a combination of severe developmental disorders, neurological abnormalities, and seizures that are difficult to treat.
Early-infantile DEE is usually caused by genetic, structural, and/or metabolic factors, which can be identified in up to 80% of cases using advanced diagnostics.
Treatment options for neonatal DEEs have improved thanks to advances in precision medicine. Nevertheless, the prognosis often remains poor, especially in difficult-to-treat forms.
Early genetic, structural, and metabolic diagnostics are crucial for initiating optimal treatment and thus improving long-term outcomes.
Declarations
Conflict of interest
A.N. Datta declares the following: Consulting activities for Idorsia, Neurocrine, Epilog, Takeda, Biocodex and advisory board activities for Idorsia, Eisai, Jazz Pharmaceuticals, UCB, Angelini, Neuraxpharm. No conflict of interest.
For this article no studies with human participants or animals were performed by any of the authors. All studies mentioned were in accordance with the ethical standards indicated in each case.
The supplement containing this article is not sponsored by industry.
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Ronen GM, Penney S, Andrews W (1999) The epidemiology of clinical neonatal seizures in Newfoundland: a population-based study. J Pediatr 134(1):71–75CrossRefPubMed
2.
Symonds JD, Elliott KD, Shetty J et al (2021) Early childhood epilepsies: epidemiology, classification, aetiology, and socio-economic determinants. Brain 144(9):2879–2891CrossRefPubMedPubMedCentral
3.
Newton CR, Garcia HH (2012) Epilepsy in poor regions of the world. Lancet 380:1193–1201CrossRefPubMed
4.
Zuberi SM, Wirrell E, Yozawitz E et al (2022) ILAE classification and definition od epilepsy syndromes with onset in neonates and infants: Position statemnent by the ILAE Task force on Nosology and Definitions. Epilepsia: 1349–1397
5.
Scheffer IE, Berkovic S, Cappovilla et al (2017) ILAE classification of the epilepsies: Position paper of the ILAE Commission for Classification and Terminology. Epilepsia 58:512–521CrossRefPubMedPubMedCentral
6.
Howell KB, Freeman JL, Mackay MT et al (2021) The severe epilepsy syndromes in infancy: a population-based study. Epilepsia 62:358–370CrossRefPubMed
7.
Pisano T, Numis, Heavin SB (2015) Early and effective treatment od KCNQ2 encephalopathy. Epilepsia 56:685–691CrossRefPubMed
8.
Howell KB, Mc Mahon JM, Carvill GL et al (2015) SCN2A encephalopathy. Neurology 85:258–266CrossRef
9.
Wolff M, Johannsen KM, Hedrich UBS (2017) Genetic and phenotypic heterogeneity suggest therapeutic imlications in SCN2A related disorders. Brain 140:1316–1336CrossRefPubMed
10.
Guerrini R, Balestrini S, Wirrell E, Walker M (2021) Monogenetic epilepsies. Neurology 26:817–831CrossRef
11.
Coppola G (2009) Mailgnant migrating partial seizures in infancy. Epilepsia 50:49–51CrossRefPubMed
12.
Kuchenbuch M, Benquet P, Kaminska A (2019) Quantitative analysis and EEG markers of KCNT1 epilepsy in infancy with migrating focal seizures. Epilepsia 60:20–32CrossRefPubMed
13.
Caraballo RH, Fontana E, Darra F et al (2008) Migrating focal seizures in infancy. J Child Neurology 23:497–506CrossRef
14.
Kuchenbuch M, Barcia G, Chemaly N et al (2019) KCNT1 epilepsy with focal migrating seizures in infancy. Brain 142:2996–3008CrossRefPubMed
15.
Barba C, Darra F, Cusmai R et al (2016) Congenital disoreder of glycosilationpresenting as epileptic encephalopathy with migrating focal seizures in infancy. Dev Med Child Neurol 58:1085–1091CrossRefPubMed
16.
Pisano T, Numis AL, Haevin SB et al (2015) Early and effective treatment of KCNQ2 encephalopathy. Epilepsia 56:685–691CrossRefPubMed
17.
Goto A, Ishii A, Shibata M et al (2019) Characteristics of KCNQ2 variants causing either benign neonatal epilepsy or developmental and epileptic encephalopathy. Epilepsia 60:1870–1880CrossRefPubMedPubMedCentral
18.
Plecko B (2013) Pyridoxin and Pyridoxalphosphate-dependent epilepsies. Handb Clin Neurol 113:1811–1817CrossRefPubMed
19.
Couglin CR, Swanson MA, Spector E et al (2019) The genotypic spectrum of ALDH7A mutatios resulting in pyridoxin dependent epilepsie; Inherit Metab. Dis 42:252–261
20.
Bahi-Buisson N, Kaminska A, Boddaert N et al (2008) The tree stages of epilepsy in patients with CDKL5 mutations. Epilepsia 49:1027–1037CrossRefPubMed
21.
Klein KM, Yendle SC, Harvey AS et al (2011) A distinctive seizure type in patients with CDKL5 mutations. Hypermotor-tonic spasms sequence. Neurology 76:1436–1438CrossRefPubMed
22.
Hoy SM (2025) Ganaxolone: A Review in Epileptic Seizures Associated with Cyclin-Dependent Kinase-Like 5 Deficiency Disorder. Paediatr Drugs 27:111–118CrossRefPubMed
23.
Guerrini R, Conti V, Mategazza M et al (2023) Developmental and epileptic encephalopathies: From genetic heterogeneity to phenotypic continuum. Physiol Rev 103:433–513CrossRefPubMed
24.
Byrne S, Entight N, Delanty M (2021) Precision therapy in the genetic epilepsies of childhood. Dev Med Child Neurol 63(11):1276–1282CrossRefPubMed
25.
Datta AN, Kroell J (2020) Rational antiepileptic treatment in childhood NeuroPsychopharmacotherapy. In: Riederer P, Laux G, Mulsant B, Le Weidong, Nagatsu T (Hrsg)
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