Developmental and Epileptic Encephalopathies: Progress in Understanding and Clinical Implications

Abstract

Developmental and epileptic encephalopathies (DEEs) are a group of complex pediatric epilepsies associated with adverse neurodevelopmental outcomes and multiaxial neurological morbidities. The understanding of DEE has evolved from its initial genetic underpinnings, to a clinically driven term encompassing a broader group of etiologies. Although individually rare, the DEEs constitute a sizeable group of pediatric epilepsies. It is especially important to recognize treatable or modifiable entities in this group. This review attempts to highlight the progress in understanding, along with the evolution of the conceptual framework of DEEs. A summary of the currently well-established DEE syndromes is provided along with available precision therapies, which might help the treating physician in the appropriate evaluation and management of the affected children.

 

MissingLinkText

Keywords

encephalopathy - epilepsy - development - DEE

Introduction

Developmental and epileptic encephalopathies (DEEs) are a niche group of mostly pharmacoresistant complex pediatric epilepsies associated with a plethora of neurological morbidities and often with devastating neurocognitive outcomes.[1] Conceptual understanding of DEEs is important for appropriate evaluation to reach an etiological diagnosis, realistic therapeutic goal setting, and consideration of precision medicine. With advances in molecular genetics, the list of recognized genes associated with DEE is growing exponentially. Better understanding of gene-function-disease relationship is expected to pave the way for novel treatment options in the form of targeted therapeutic interventions, like antiseizure medications with novel mechanisms of action and repurposing of drugs. This review will describe the conceptual framework of the DEE syndromes, highlighting the progress in understanding and current crossroads. Major features of the currently well-established DEE syndromes are tabulated with a clinical viewpoint along with the available precision therapies. However, detailed descriptions of each of the individual DEEs are considered beyond the scope of this review.

 

MissingLinkText

Evolution of Concepts

Encephalopathy refers to a global deterioration of cerebral function resulting in an altered mental state. Epileptic encephalopathy describes conditions in which epileptiform abnormalities themselves contribute to cognitive and neurological decline.[2] Although the term epileptic encephalopathy was formally included by the International League Against Epilepsy (ILAE) in the 2001 classification scheme, Gastaut et al had used it much earlier to describe the Lennox Gastaut Syndrome (LGS) as epileptic encephalopathy with slow spike and waves.[3] The initial concept of epileptic encephalopathy was based on the triad of seizures, electroencephalographic abnormalities, and cognitive decline. The 2010 ILAE revision better clarified the concept as “disorders where the epileptic activity is implicated in cognitive and behavioral impairment, above and beyond what might be expected from the underlying pathology alone and these might worsen over time.”[4] Treatment of the electroclinical syndromes with an improvement in the burden of the epileptiform abnormality was shown to reverse the cognitive slowing.[5] [6] The concept of epileptic encephalopathy is now actively considered in presurgical decision-making of well-defined focal epilepsies in children. The developmental stagnation or regression in this setting is considered as a clinical state attributable to a combination of frequent seizures, widespread interictal abnormalities, and the cognitive and behavioral effects of polytherapy. It is expected that the developmental trajectories of these affected children would be reversed or modified by successful resective surgeries.[7]

On the other hand, the term “developmental encephalopathy” was initially used to describe monogenic encephalopathies where the developmental impairment may be directly attributable to the underlying genetic defect.[8] This can be exemplified by the prototypic disorder, Rett syndrome. Epilepsy may coexist with these disorders; however, the burden of epilepsy or interictal epileptiform abnormalities is not considered significant enough to make a major contribution to the developmental status.

It was observed that certain genes responsible for childhood epileptic encephalopathies were also independently and directly detrimental to neurodevelopment and cognition. Many of these epileptic disorders might present with developmental delay even before the onset of seizures. With the advent of molecular genetics and functional studies, the role of these genes in the developing brain has been better elucidated. For example, DEEs related to CDKL5 and STXBP mutations have an independent contribution to poor cognition and development over and above the component of epilepsy.[9] Several such genes were subsequently discovered with significant involvement of neurocognitive domains both due to their abnormal function in the developing brain and also due to their contribution to the epilepsy. To encompass this unique group of genetic disorders, the term “epileptic encephalopathy” was revised, and the concept of DEE was officially incorporated into the epilepsy classification scheme by the ILAE (2017).[8] In this framework, developmental impairment is primarily attributed to the underlying pathology, which is often genetic, while epilepsy may further exacerbate developmental outcomes.[1] However, it is challenging to delineate the key driving force of encephalopathy and it has been proposed that both epilepsy and developmental impairment may be the epiphenomena of the underlying etiology. While controlling epilepsy may lead to better developmental outcomes, cognitive and behavioral impairments may persist due to the broader impact of the underlying pathology.

The clinical course of the DEEs remains variable. Most of these disorders might have a preexisting developmental delay with a superadded regression after seizure onset. In some, there may be an initial period of normal development, with developmental slowing emerging after the onset of epilepsy or with frequent epileptic activity in the electroencephalogram (EEG).[10] In disorders like PCDH19-related encephalopathy, the severity of epilepsy may be mild, while the developmental impact can be profound. These children typically present in early childhood (< 3 years) with febrile and afebrile seizure clusters followed by cognitive impairment, autistic traits, and behavioral abnormalities. In the long run, many of the DEEs may be associated with motor dysfunction, movement disorders, and psychiatric morbidities along with sleep, respiratory, and gastrointestinal problems. Thus, DEE may be considered as an umbrella term for a group of complex epileptic syndromes to help the treating physicians set realistic goals for epilepsy control, select appropriate antiseizure medications, choose disease-modifying therapies when available, and educate families regarding the long-term prognosis. It is also expected that such a concept will help the research community develop better mechanistically driven therapeutic options to ameliorate the downstream effects of the individual genetic variations, rather than concentrating merely on the symptomatic control of seizures by newer antiseizure medications.[11]

More than 900 genes have been identified as monogenic causes of DEE. Deficiencies in many cellular mechanisms including the ion channels, synaptic transmission, transporters, cell signaling, and epigenetics have been implicated in their pathophysiology.[11] [12] [Table 1] gives a classification of the common monogenic DEEs based on the dominant downstream effect of the genetic variation.[11] [13] Common monogenic causes of DEEs with the disease mechanisms, inheritance patterns, loss or gain of function, and phenotypic features have been listed in [Table 2].[11] [14] [15] [16] [17]

Table 1 Classification of DEE based on the genes involved in the pathomechanisms

Functional domain		Genes
Channelopathies	Sodium channelopathies	SCN1A, SCN2A, SCN8A, SCN3A, SCN1B
	Potassium channelopathies	KCNQ2, KCNQ3, KCNA1, KCNA2, KCNB1, KCNC1, KCNT1, KCNT2, KCNMA1, KCNJ10, HCN1
	Calcium channelopathies	CACNA1A, CACNA1B, CACNA1C, CACNA1D, CACNA1E
Synaptopathies	Presynaptic proteins	STXBP1, VAMP2, SNAP25, CPLX1, STX1B, DNM1, TBC1D24, SYNJ1, AP3B2, NECAP1
	Synaptic scaffold and post-synaptic density	SYNGAP1, IQSEC2, CNTNAP2, NRXN1, ADAM22, ARHGEF9, TANC2, SHANK3
Receptors	Glutamate receptor subunits	GRIA2, GRIN1, GRIN2A, GRIN2B, GRIN2D
	GABA receptor subunits	GABRA1, GABRA2, GABRB1, GABRB2, GABRB3, GABRG2, GABRD
Ion and solute transporters		ATP1A2, ATP1A3, SLC2A1, SLC1A2, SLC6A1, SLC12A5, SLC13A5, SLC25A22
mTOR pathway and cell growth/signaling		TSC1/2, MTOR, PTEN, AKT3, PIK3CA, DEPDC5, NPRL⅔, GNB1, GNAO1, PCDH19, RHOBTB2
Epigenetic regulation/Transcription regulators		MECP2, CHD2, EEF1A2, PURA, SETD1B, ARX, SMC1A, CDKL5
Cell metabolism		UBA5, KLHL20, WWOX

Abbreviations: DEE, developmental and epileptic encephalopathy; GABA, gamma-aminobutyric acid; mTOR, mammalian target of rapamycin.

Table 2 Common monogenic causes of DEE

Gene	Gene function	Functional effect	Clinical/Electroclinical phenotype	Seizure characteristics	Comorbidities
SCN1A (AD, DN)	Voltage-gated sodium channel α subunit Nav1.1 (GABAergic interneurons)	LOF	DS	Recurrent focal clonic (hemiclonic) febrile and afebrile seizures. Other seizure types- myoclonic seizures, focal seizures with impaired awareness, focal to bilateral tonic-clonic seizures, atypical absences, atonic seizures, and NCSE	ID, ADHD. Pyramidal signs Crouch gait Parkinsonism (later onset)
		GOF	EIDEE/Neonatal onset	Onset < 3 months, epileptic spasms, tonic seizures	Hyperkinetic movement disorders, arthrogryposis High risk for SUDEP
SCN2A (AD, DN)	Voltage-gated Na channel α subunit -generation and propagation of action potential	GOF	EIDEE EIMFS	Onset < 3 months Focal seizures, spasms in clusters	Hyperkinetic movement disorders Gastrointestinal dysmotility ID/ASD High risk for SUDEP
		LOF	Late-onset DEE
SCN8A (AD, DN)	Voltage-gated sodium channel – generation of action potential	GOF in DEE < 6 months; LOF -later onset DEE or IESS	EIDEE EIMFS	Focal seizures, tonic seizures associated with apnea, cyanosis, bradycardia, tonic-clonic seizures, myoclonic seizures, and absences	Hyperkinetic movement disorders ID/ASD Gait ataxia, sleep disorders Cortical visual impairment High risk for SUDEP
KCNQ2 (AD, DN)	Voltage-gated potassium channel - generation of neuronal muscarine-regulated M-type current	LOF Dominant Negative GOF rare Neonatal onset DEE	Neonatal DEE	Most common seizure type – focal tonic Others – clonic seizures, myoclonic seizures, epileptic spasms, autonomic features, apnea seizures remit after first year in 50%	Hyperkinetic movement disorders (dystonia, tremors) Hypotonia Cortical visual impairment Abnormal eye movements Feeding intolerance
KCNT1 (AD/DN)	Sodium-activated potassium channel - regulation of neuronal excitability	GOF	EIMFS Sleep-related hypermotor epilepsy	Migrating focal seizures evolving to focal status epilepticus	Microcephaly Cortical visual impairment, Hyperkinetic movement disorders Arrhythmia Autonomic features
CACNA1A (AD /AR)	Voltage-dependent calcium channel α1A subunit- modulates gene transcription, neurotransmitter release, neurite outgrowth, and enzyme activity	GOF	EIDEE EIMFS DS LGS	Early onset seizures with recurrent status epilepticus often triggered by fever Alternating focal seizures	Paroxysmal hemiplegia Ataxia GDD/ID
		LOF	DEE	Early onset refractory absence seizures with ID/GDD
GRIN1 (AD/DN)	NMDA receptor GluN1 (major conduit of fast excitatory transmission in the brain)	GOF LOF Dominant Negative	Neonatal onset DEE	Generalized seizures, tonic seizures, epileptic spasms, focal seizures	Profound GDD/ID Hypotonia Hyperkinetic movement disorders Oculogyric crisis Stereotypic hand movements Cortical visual impairment Microcephaly Cortical malformation in some patients
GRIN2A (AD/DN)	NMDA receptor GluN2A (major conduit of fast excitatory transmission in the brain) > 60% of variants inherited from unaffected or mildly affected parent.	GOF/LOF	DEE Epilepsy-aphasia spectrum including Landau–Kleffner syndrome DEE – spike wave activation in sleep (EE/DEE SWAS)	Seizures often temporo-rolandic with centrotemporal spikes	Hyperkinetic movement disorder - dystonia, or choreiform movements ADHD/ASD/ID Speech and language disorders
SLC2A1 (AD/DN)	Glucose transporter type 1 (glucose transporter at the blood–brain barrier)	LOF	Epilepsy with myoclonic atonic seizures	Generalized tonic clonic seizures, myoclonic seizures, atonic seizures, typical and atypical absences	Hyperkinetic movement disorders Acquired microcephaly Ataxia Paroxysmal exercise-induced dystonia Paroxysmal head and eye movements
STXBP1 (AD/DN)	Crucial role in SNARE assembly, complexes with syntaxin-1	LOF	EIDEE IESS DS LGS	Tonic seizures with epileptic spasms. May have focal seizures Seizures improve after first year in 50%	Hypotonia Ataxia Tremor, Dystonia, and other movement disorders – chorea, dyskinesia, bruxism ID/GDD
SYNGAP1 (AD/DN)	Interacts with NMDA receptor complex, AMPA receptor trafficking, dendritic spine modification	LOF	DEE Epilepsy with eyelid myoclonia Epilepsy with myoclonic atonic seizures IESS	Seizure onset > 2 years with eyelid myoclonia with absences, myoclonic seizures, atonic seizures (drop seizures), and atypical or typical absences. Reflex seizures provoked by eating in 25%. Photosensitivity and eye closure sensitivity	Gait abnormality ASD/ID/GDD Cognitive delay Feeding difficulty
GNAO1 (AD/DN)	Alpha (Gαo) subunit of inhibitory Go protein complex	LOF or dominant negative	IESS EIMFS DEE	Infantile spasms or nonspecific DEE	Hyperkinetic movement disorders – choreoathetosis, ballism and dystonia Stereotypies Self-injurious behavior Microcephaly
PCDH 19 (X-linked dominant females affected)	Protocadherin 19 (involved in signal transduction and cell adhesion)	LOF	DEE	Infantile onset clusters of seizures triggered with fever Focal seizures, Tonic-clonic seizures, atypical absences Status epilepticus	Cognitive impairment Autistic traits, Behavioral abnormalities in 70%
ARX (X-linked)	Aristaless-related homeobox protein (neuronal proliferation, intraneuronal migration, forebrain differentiation, testicular development)	LOF (truncation, expansion of polyalanine tract and missense)	EIDEE, IESS	Frequent tonic seizures or spasms beginning in infancy with a specific EEG finding of suppression-burst pattern	Microcephaly Cataract Genital dysfunction Hyperkinetic movement disorders
CDKL-5 (X Linked)	AKT/ GSK-3β signaling pathway (neuronal precursor proliferation, synaptogenesis)	LOF	EIDEE IESS	Epileptic spasms, tonic seizures. Events often have multiple phases classically described as sequential hyperkinetic–tonic spasms	Cortical visual impairment Hand stereotypes Hypotonia ASD Feeding intolerance Dysautonomia Breathing abnormalities
TSC1/2 (AD/DN)	Regulation of mTOR pathway	LOF	IESS DEE	Epileptic spasms, focal seizures	Cardiac rhabdomyoma, renal angiomyolipoma, intellectual disability, TAND

Abbreviations: AD, autosomal dominant; ADHD, attention deficit hyperactivity disorder; AR, autosomal recessive; ASD, autism spectrum disorder; DEE, developmental and epileptic encephalopathy; DN, de novo; DS, Dravet syndrome; EE, epileptic encephalopathy; EEG, electroencephalogram; EIDEE, early infantile developmental and epileptic encephalopathy; EIMFS, epilepsy of infancy with migrating focal seizures; GDD, global developmental delay; GOF, gain of function; ID, intellectual disability; IESS, infantile epileptic spasms syndrome; LGS; Lennox–Gastaut syndrome, LOF, loss of function; NCSE, non convulsive status epilpeticus; SUDEP, sudden unexpected death in epilepsy; SWAS, spike wave activation in sleep; TAND, tuberous sclerosis associated neuropsychiatric disorders.

DEEs are conceptually differentiated from progressive myoclonus epilepsies (PMEs), the disorders with a relentlessly progressive neurological dysfunction and loss of neurons in specific brain regions. In addition to the developmental regression and epilepsy, many other multiaxial neurological and multisystem findings might be seen in these disorders including progressive visual and hearing impairments, pyramidal, extrapyramidal or cerebellar dysfunction, neuropathy, organomegaly and skeletal anomalies.[18] However, it is often difficult to differentiate a slowly progressive PME from a DEE, especially in the initial stages. Moreover, with the advent of disease-modifying therapies like enzyme replacement, it might be possible to alter the progressive trajectory of many of these disorders, which will further blur the borderlands between these entities.

Lastly, acquired antenatal and/or perinatal insults like hypoglycemia and hypoxia may also present with poorly controlled complex epilepsies in infancy along with severe intellectual and neurodevelopmental disabilities. Compared with the static encephalopathies due to these remote insults, monogenic DEEs are expected to offer a therapeutic window during which a disease-modifying intervention might be able to ameliorate the ongoing downstream adverse effects of the genetic variations.

 

MissingLinkText

Electroclinical Syndromes

Even though most of the DEEs may be regarded as etiology-driven syndromes, some of the classical electroclinical syndromes (of unknown, genetic, and acquired origin) with significant deleterious potential on the developmental trajectories are also included in most of the current classification schemes of DEE. The electroclinical patterns, age of onset, seizure types, developmental course, and associated features define these syndromes. They have diverse or multifactorial etiologies. Common epilepsy syndromes presenting as DEE with the associated genetic variations are depicted in [Fig. 1]. With further progress in the understanding of the neurobiology of early-onset epilepsies, it is expected that more and more etiology specific DEEs might ultimately emerge from these electroclinical syndromes. A detailed description of these individual syndromes is beyond the scope of this review. Interested readers are encouraged to go through the recent ILAE position papers.[17] [19]

Fig. 1 Common genetic variations in well-known epilepsy syndromes presenting as developmental and epileptic encephalopathy (DEE). EIDEE, early infantile developmental epileptic encephalopathy; EIMFS, epilepsy of infancy with migrating focal seizures; EMAtS, epilepsy with myoclonic atonic seizures; IESS, infantile epileptic spasms syndrome; LGS, lennox gastaut syndrome; DEE-SWAS, developmental epileptic encephalopathy - spike wave activation in sleep.

 

MissingLinkText

Expanding Spectrum of DEE

In recent years, the term DEE has conceptually expanded to include varied etiologies. Many more diverse genetic and acquired disorders are now being recognized as DEE, whenever both brain dysfunction and epilepsy might be considered as independent components of an adverse developmental outcome.[11] Some of these etiologies encountered in the recent DEE literature are enumerated below.

Chromosomal disorders: Important examples of the chromosomal anomalies presenting as DEE include ring chromosome 20, Wolf–Hirschhorn syndrome, and 18 q- syndrome. Features of some common chromosomal disorders with DEE features are given in [Table 3].[20]

Table 3 Chromosomal disorders presenting as DEE

Chromosomal disorders	Key features	Seizure types
Wolf–Hirschhorn syndrome (Partial 4p deletion)	Greek helmet appearance of the nose, micrognathia, short philtrum, epicanthic folds, high forehead, prominent glabella, hypertelorism, cleft lip and palate, dysplastic ears, periauricular tags, microcephaly, heart defects, cleft lip and palate, Ig A deficiency	GTCS, hemiclonic seizures (fever triggered), epileptic spasms, atypical absences, and focal seizures
Miller–Dieker syndrome (17p13.3 microdeletion)	Short upturned nose, thickened upper lip with a thin vermillion upper border, frontal bossing, small jaw, low-set posteriorly rotated ears, sunken appearance in the middle of the face, widely spaced eyes, hypertelorism, prominent forehead with temporal hollowing, classical lissencephaly	IESS Focal/generalized seizures
Ring chromosome 20 syndrome	Intellectual disability Behavioral problems Seizures usually intractable	Focal seizures, NCSE, visual hallucinations (50%)
18 q- syndrome	Microcephaly, turricephaly, broad nasal bridge, high arched palate, deep set eyes. Cerebellar hypoplasia Aberrant myelination	Tonic-clonic seizures, epileptic spasms
Pallister–Killian syndrome (tetrasomy 12p)	Coarsened flat facies, reduced scalp hair, high forehead, broad nasal bridge, high arched palate, retrognathia, low set ears, cupid-shaped upper lip Cardiac, diaphragmatic, and ocular abnormalities	Tonic-clonic seizures, epileptic spasms
Angelman syndrome	Developmental delay, marked speech impairment, ataxia, tremor and seizures	Tonic clonic seizures, atypical absences, myoclonic seizures with status epilepticus

Abbreviations: DEE, developmental and epileptic encephalopathy; GDD, global developmental delay; GTCS, generalized tonic-clonic seizures; IESS, Infantile epileptic spasms syndrome; IgA, immunoglobulin A; NCSE, nonconvulsive status epilepticus.

Structural malformations of the brain: Genetic variations that disrupt neuronal growth and proliferation resulting in cortical developmental malformations are also presently included in the clinical spectrum of DEEs.[11] Tuberous sclerosis, Miller–Dieker syndrome, Sturge–Weber syndrome, lissencephaly-associated syndromes, agyria–pachygyria spectrum, and polymicrogyria are important examples under this category. [Table 4] represents the spectrum of DEE genes associated with malformations of cortical development and their neuroimaging characteristics.[21]

Table 4 Disorders of cortical malformation with their neuroimaging findings

Affected gene	Predominant imaging phenotype
ARX	Posteriorly predominant lissencephaly, pachygyria/agyria, corpus callosal dysgenesis, striatal and thalamic nuclei atrophy
DCX	Anteriorly predominant lissencephaly (males) Subcortical band heterotopia (female)
LIS1	Posteriorly predominant lissencephaly
TUBA1A / TUB2B	Posteriorly predominant lissencephaly, cerebellar dysplasia, dysmorphic basal ganglia, brainstem abnormalities
TUBB3 / TUBB5	Absent corpus callosum, polymicrogyria-like pattern
DYNCH1	Posteriorly predominant lissencephaly
RELN	Anterior predominant lissencephaly, severe hippocampal and cerebellar hypoplasia

Metabolic disorders: Neurometabolic disorders are an important cause of developmental delay and epilepsy. Even though most of the classical neurometabolic syndromes may present with episodic crisis and regression, a few of them might show clinical patterns of DEE. Classical examples are neonatal onset pyridoxine and pyridoxal-5 phosphate-dependent epilepsies. Early identification and prompt treatment might alter the trajectory of many of these syndromes. A detailed description of all these syndromes is beyond the scope of this review.

 

MissingLinkText

Approach to Diagnosis and Management

The diagnostic approach to a child with DEE is depicted in [Fig. 2]. The flowchart represents a broad diagnostic framework and highlights the core features of DEEs as against progressive neurological syndromes. However, it may not be possible to fit the entire spectrum of DEE syndromes in such a framework. Moreover, some classical features in a given DEE might immediately reveal the diagnosis, and the flowchart then becomes redundant. For example, mid-infantile onset epilepsy with fever-provoked hemiclonic seizures of shifting laterality and frequent episodes of status epilepticus might straight away clinch the diagnosis of SCN1A-related Dravet syndrome.

Fig. 2 Diagnostic approach to developmental and epileptic encephalopathy (DEE). DEE: developmental epileptic encephalopathy, PME – progressive myoclonic epilepsy, VUS – variant of unknown significance, SNHL – sensorineural hearing loss, ASD – autism spectrum disorder. The most prominent features for both DEE and PME are highlighted (*).

A stepwise genetic evaluation based on the clinical phenotype is equally important for arriving at an etiological diagnosis of DEE syndrome ([Fig. 1]). However, interpretation of detected variants and establishing pathogenicity are major clinical challenges. Inputs from an experienced clinical geneticist might be warranted at this stage. With evolution of the phenotype, need for reanalysis of genetic reports/additional genetic tests might also arise.

It is often challenging to tease out the deficits attributable to the etiology from the effects of ongoing epilepsy in an individual patient with DEE. Hence, interventions should be balanced against the realistic expectation for epilepsy control and neurocognitive improvement, but not at the cost of adverse effects from overtreatment. Nonetheless, as the implications of the epileptic activity occur during a critical time in brain development, it becomes imperative to treat timely and adequately. The burden of DEE extends beyond recurrent seizures and intellectual disability to include behavioral issues, movement disorders, gait difficulties, as well as issues related to feeding, gastrointestinal and autonomic systems, and sleep.

The general principles of instituting antiseizure medications remain similar to other childhood epilepsies. The antiseizure medications are tailored to the predominant seizure type, epilepsy syndrome, and sometimes the underlying etiology. For instance, in cases of nontuberous sclerosis-associated infantile spasms, hormonal therapy (ACTH or oral prednisolone) is used as first line while in tuberous sclerosis-related infantile spasms, vigabatrin is preferred. As DEEs are typically drug-resistant and often require polytherapy, it is essential to understand the pharmacological properties and possible drug interactions among the antiseizure medications. Apart from the traditional antiseizure medications, certain agents with a novel mechanism of action have proved beneficial in specific epilepsy syndromes.[22] Cannabidiol, which modulates G-protein coupled receptor 55 and transient receptor potential vanilloid 1, has shown efficacy in randomized control trials in Dravet syndrome and tuberous sclerosis complex.[23] [24] Likewise, drug repurposing has been proven useful in genetic DEEs. Fenfluramine, initially introduced as an appetite suppressant, has now shown to be effective in Dravet syndrome. The mechanism of action combines an enhancement of serotonergic transmission with a positive allosteric modulation of sigma-1 receptor.[25] [26]

Although the historical approach to epilepsy treatment is rather empirical, a change in the direction toward precision medicine has emerged to help in altering the disease course. For example, everolimus, an MTOR (Mammalian Target for Rapamycin) inhibitor has shown a possible disease modifying effect in tuberous Sclerosis associated neuropsychiatric disorder (TAND), in addition to its antiseizure effect.[27] However, precision medicine is not as simple as finding the pathogenic gene and tailoring treatment to the gene's function. The spectrum of diseases caused by the same gene defect can vary from self-limited epilepsies to severe DEEs, while also having an age-dependent expression. As DEEs are rare, evidences are mostly based on case reports and small case series. The experience with KCNT1 epilepsies and quinidine highlights the need for caution when drawing conclusions based on small patient cohorts.[28] [29] The rationale to fix the genetic defect with a specific gene therapy may seem straightforward. However, it is challenging as the gene needs to be introduced into the specific neuronal networks in a developing brain at a time before the downstream effects have become irreversible. Nonetheless, promising gene therapy candidates such as STK-001 and ETX-101 for Dravet syndrome are underway.[22] Phenotyping and confirming the etiology is crucial to aid targeted interventions such as specific antiseizure medications, avoidance of agents associated with seizure exacerbation, vitamin replacements, dietary therapy, and surgery. [Table 5] gives a list of currently available precision therapies in DEE.[22] [30]

Table 5 Precision therapy in DEE

DEE	Precision drug/approach
Dravet syndrome	Stiripentol, Fenfluramine, Cannabidiol Soticlestat, STK-001, Clemizole, Lorcaserin (undergoing trials) Avoid sodium channel blockers
SCN2A (onset < 3 months)	Sodium channel blockers
SCN2A (onset > 3 months)	Sodium channel blockers may exacerbate seizures
SCN8A	Sodium channel blockers, NBI 921352 (XEN901)
KCNQ2	Sodium channel blockers, Pyridoxine Retgabine (Ezogabine)
KCNT1	Quinidine
SYNGAP1	Perampanel
GRIN 2A/GRIN 2B	Memantine
GRIN2B	Radiprodil
CDKL-5	Ganaxolone
Tuberous sclerosis complex	Everolimus, Sirolimus, Vigabatrin (epileptic spasms)
GATORopathies (DEPDC5, NPRL2, NPRL3)	Everolimus, Sirolimus
GLUT-1 deficiency syndrome (SLC2A1)	Ketogenic diet
Pyridoxine-dependent epilepsy (ALDH7A1)	Pyridoxine
Pyridoxal-5-phosphate-dependent epilepsy (PNPO)	Pyridoxal phosphate
Biotinidase deficiency (BTD)	Biotin
Cerebral folate deficiency (FOLR1)	Folinic acid
Creatine deficiency syndrome (GAMT, SLC6A8, AGAT)	Creatine, arginine-restricted diet, ornithine

Abbreviation: DEE, developmental and epileptic encephalopathy.

It is well known that certain environmental factors like fever or hyperthermia trigger seizures in Dravet syndrome or PCDH19 related epilepsies. Fatigue, stress, or excitement, and environmental photic or pattern stimulation might trigger seizures in many DEEs. It is important to identify these factors during medical history and to counsel the families to avoid such precipitants. Caregivers should be instructed regarding seizure action plans and out-of-hospital rescue therapy. Parents also may need to be informed regarding the risk of status epilepticus and sudden unexpected death in epilepsy. The need for addressing other morbidities such as communication, behavior, daily activity, and motor skills, also need to be acknowledged. A multidisciplinary team is required to care for each of these aspects. In view of the potential chance for care giver burn outs due to the prolonged disease burden, quality of life measures should also include the parents and other immediate family members.

 

MissingLinkText

Gaps in the Conceptual Framework, Borderlands, and Future Challenges

The evolution of the term DEE as an offshoot of the term epileptic encephalopathy helped in better understanding the intricacies of adverse developmental outcomes in the monogenic epilepsy syndromes. Conceptualized as an etiologically driven term, DEE highlighted the potential impact of the genetic defect on the neurodevelopmental progress, irrespective of its epileptogenic potential. Moreover, the need for more holistic disease modifying therapies were also emphasized, addressing issues beyond mere seizure control.[11]

Reclassification and revision of terminologies are pivotal to the understanding of disease processes. There has been a trend toward expansion of this concept along with consideration of the term DEE in a broader clinical perspective including the epilepsies associated with acquired brain injuries, metabolic or autoimmune disorders. For example, a child with developmental delay and epileptic spasms occurring as a sequelae of perinatal asphyxia-related injury may be considered as a DEE, as the brain injury and the epilepsy independently contribute to the adverse neurocognitive outcomes. Similarly, neurometabolic disorders like aminoacidopathies presenting with myoclonic seizures and burst suppression on the EEG may also be considered as DEEs in view of the significant component of brain injury and epilepsy, both contributing to the devastating neurodevelopmental outcomes. This conceptualization emphasizes the recognition of etiology as the major factor responsible for the adverse neurodevelopmental outcomes, and hence makes a point for specific treatment strategies that may prevent or alleviate the downstream effects. Therapeutic hypothermia in perinatal asphyxia is a good example of a preventive strategy, while enzyme replacement therapies for neurometabolic disorders are targeted management options. However, such an approach expands the boundaries of the concept of DEE exponentially, leading to inclusion of a wide variety of neurobiologically diverse entities under this umbrella. The inherent fallacies of such an approach in relation to the concept of epileptic encephalopathy were well described earlier.[31] Moreover, with development of disease-modifying therapies changing the current natural history of both DEEs and other progressive epileptic syndromes like PME, the boundaries might further get blurred in future, necessitating the need for better refinement in terminolgies.

 

MissingLinkText

Conclusion

This article has attempted to describe the current understanding of DEEs with a futuristic perspective. Advances in molecular genetics and functional studies are rapidly expanding the database of genes related to DEEs, while precision and disease modifying treatments are changing the natural history and outcomes, albeit to a lesser extent. Better definition of the conceptual framework as well as development of newer terminologies might be warranted in the near future to reflect this phenomenal progress in the understanding of these disorders.

 

MissingLinkText

 

MissingLinkText

Conflict of Interest

None declared.

• References

• 1 Scheffer IE, Berkovic S, Capovilla G. et al. ILAE classification of the epilepsies: position paper of the ILAE Commission for Classification and Terminology. Epilepsia 2017; 58 (04) 512-521
• 2 Engel Jr J. International League Against Epilepsy (ILAE). A proposed diagnostic scheme for people with epileptic seizures and with epilepsy: report of the ILAE Task Force on Classification and Terminology. Epilepsia 2001; 42 (06) 796-803
• 3 Gastaut H, Roger J, Soulayrol R. et al. Childhood epileptic encephalopathy with diffuse slow spike-waves (otherwise known as “petit mal variant”) or Lennox syndrome. Epilepsia 1966; 7 (02) 139-179
• 4 Berg AT, Berkovic SF, Brodie MJ. et al. Revised terminology and concepts for organization of seizures and epilepsies: report of the ILAE Commission on Classification and Terminology, 2005-2009. Epilepsia 2010; 51 (04) 676-685
• 5 Kalser J, Cross JH. The epileptic encephalopathy jungle - from Dr West to the concepts of aetiology-related and developmental encephalopathies. Curr Opin Neurol 2018; 31 (02) 216-222
• 6 Trivisano M, Specchio N. What are the epileptic encephalopathies?. Curr Opin Neurol 2020; 33 (02) 179-184
• 7 Ma Y, Kaminski M, Kim A. Surgical treatment of epileptic encephalopathy with spike-and-wave activation in sleep: a systematic review and meta-analysis. Seizure 2024; 119: 78-83
• 8 Scheffer IE, Liao J. Deciphering the concepts behind “epileptic encephalopathy” and “developmental and epileptic encephalopathy”. Eur J Paediatr Neurol 2020; 24: 11-14
• 9 Specchio N, Curatolo P. Developmental and epileptic encephalopathies: what we do and do not know. Brain 2021; 144 (01) 32-43
• 10 Yozawitz EG, Dhillon P. Developmental and epileptic encephalopathies. Medlink. Last updated February 25, 2024. Accessed May 13, 2025 at: https://www.medlink.com/articles/developmental-and-epileptic-encephalopathies
• 11 Scheffer IE, Zuberi S, Mefford HC, Guerrini R, McTague A. Developmental and epileptic encephalopathies. Nat Rev Dis Primers 2024; 10 (01) 61
• 12 Oliver KL, Scheffer IE, Bennett MF, Grinton BE, Bahlo M, Berkovic SF. Genes4Epilepsy: an epilepsy gene resource. Epilepsia 2023; 64 (05) 1368-1375
• 13 Cavirani B, Spagnoli C, Caraffi SG. et al. Genetic epilepsies and developmental epileptic encephalopathies with early onset: a multicenter study. Int J Mol Sci 2024; 25 (02) 1248
• 14 Spagnoli C, Fusco C, Percesepe A, Leuzzi V, Pisani F. Genetic neonatal-onset epilepsies and developmental/epileptic encephalopathies with movement disorders: a systematic review. Int J Mol Sci 2021; 22 (08) 4202
• 15 Morrison-Levy N, Borlot F, Jain P, Whitney R. Early-onset developmental and epileptic encephalopathies of infancy: an overview of the genetic basis and clinical features. Pediatr Neurol 2021; 116: 85-94
• 16 Guerrini R, Conti V, Mantegazza M, Balestrini S, Galanopoulou AS, Benfenati F. Developmental and epileptic encephalopathies: from genetic heterogeneity to phenotypic continuum. Physiol Rev 2023; 103 (01) 433-513
• 17 Zuberi SM, Wirrell E, Yozawitz E. et al. ILAE classification and definition of epilepsy syndromes with onset in neonates and infants: position statement by the ILAE Task Force on Nosology and Definitions. Epilepsia 2022; 63 (06) 1349-1397
• 18 Vinayan KP, Jyotsna AS. Progressive Myoclonic epilepsies. Last updated December 31, 2023. Accessed May 13, 2025 at: https://www.medlink.com/articles/progressive-myoclonus-epilepsies
• 19 Specchio N, Wirrell EC, Scheffer IE. et al. International League Against Epilepsy classification and definition of epilepsy syndromes with onset in childhood: position paper by the ILAE Task Force on Nosology and Definitions. Epilepsia 2022; 63 (06) 1398-1442
• 20 Chromosomal Abnormalities-Epilepsy Diagnosis.org. Last Updated June 3, 2024. Accessed May 13, 2025 at: https://www.epilepsydiagnosis.org/aetiology/chromosomal-abnormalities-overview.html
• 21 Bartolini E. Inherited developmental and epileptic encephalopathies. Neurol Int 2021; 13 (04) 555-568
• 22 Johannessen Landmark C, Potschka H, Auvin S. et al. The role of new medical treatments for the management of developmental and epileptic encephalopathies: novel concepts and results. Epilepsia 2021; 62 (04) 857-873
• 23 Devinsky O, Cross JH, Laux L. et al; Cannabidiol in Dravet Syndrome Study Group. Trial of cannabidiol for drug-resistant seizures in the Dravet syndrome. N Engl J Med 2017; 376 (21) 2011-2020
• 24 Hess EJ, Moody KA, Geffrey AL. et al. Cannabidiol as a new treatment for drug-resistant epilepsy in tuberous sclerosis complex. Epilepsia 2016; 57 (10) 1617-1624
• 25 Ceulemans B, Boel M, Leyssens K. et al. Successful use of fenfluramine as an add-on treatment for Dravet syndrome. Epilepsia 2012; 53 (07) 1131-1139
• 26 Sourbron J, Smolders I, de Witte P, Lagae L. Pharmacological analysis of the anti-epileptic mechanisms of fenfluramine in scn1a mutant zebrafish. Front Pharmacol 2017; 8: 191
• 27 Previtali R, Prontera G, Alfei E. et al. Paradigm shift in the treatment of tuberous sclerosis: effectiveness of everolimus. Pharmacol Res 2023; 195: 106884
• 28 Borlot F, Abushama A, Morrison-Levy N. et al. KCNT1-related epilepsy: an international multicenter cohort of 27 pediatric cases. Epilepsia 2020; 61 (04) 679-692
• 29 Mullen SA, Carney PW, Roten A. et al. Precision therapy for epilepsy due to KCNT1 mutations: a randomized trial of oral quinidine. Neurology 2018; 90 (01) e67-e72
• 30 Myers KA, Scheffer IE. Precision medicine approaches for infantile-onset developmental and epileptic encephalopathies. Annu Rev Pharmacol Toxicol 2022; 62: 641-662
• 31 Howell KB, Harvey AS, Archer JS. Epileptic encephalopathy: Use and misuse of a clinically and conceptually important concept. Epilepsia 2016; 57 (03) 343-347

Publication History

Article published online:
11 August 2025