Developmental and epileptic encephalopathies …

Epilepsy & Seizures

Updated 02.25.2024
Released 11.11.2003
Expires For CME 02.25.2027

Developmental and epileptic encephalopathies

Authors: Parmpreet Dhillon MD, Elissa G Yozawitz MD

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Editor: Solomon L Moshé MD

Developmental and epileptic encephalopathies

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Introduction

Overview

Developmental and epileptic encephalopathy is an epilepsy syndrome diagnosis in individuals whose developmental impairment occurs directly from their presumed genetic mutation (developmental encephalopathy) as well as developmental consequences related to frequent epileptic activity (epileptic encephalopathy). A pathologic genetic variant may be identified in a significant proportion of patients with developmental and epileptic encephalopathy. When the genetic mutation is known, this term can be replaced by the gene name associated with developmental and epileptic encephalopathy, such as KCNQ2-DEE. Prognosis may be etiology-dependent, though generally with drug-resistant epilepsy and significant developmental delay.

Key points

	• Developmental and epileptic encephalopathy encompasses a wide range of severe epilepsy syndromes often beginning in infancy and childhood.
	• Clinical presentation typically includes early onset epilepsy with developmental impairment and abnormal EEG.
	• The term developmental and epileptic encephalopathy can be used in whole or in part when appropriate.
	• “Developmental and epileptic encephalopathy” is used when both developmental and epileptic encephalopathy play a role in the patient’s clinical presentation.
	• Genetic testing, including whole-exome sequencing, may yield diagnosis in a significant proportion of patients.
	• Aggressive treatment of seizures may improve a component of epileptic encephalopathy but does not improve developmental encephalopathy.

Historical note and terminology

This section defines the terminology of developmental encephalopathy, epileptic encephalopathy, and developmental and epileptic encephalopathy.

Developmental encephalopathy describes a developmental impairment or intellectual disability that is static though the degree of disability may become more evident with age (17). Genetic causes of developmental encephalopathy are many, and patients may have a higher risk of epilepsy than the general population; however, there is no epileptic activity associated with developmental regression or further slowing of development (16). For example, a child or adult with intellectual disability without frequent epileptiform activity would be consistent with developmental encephalopathy (18).

An epileptic encephalopathy was first described by Dr. WJ West in 1841 in his letter to the editor of Lancet in which he wrote of his child with epileptic spasms, hypsarrhythmia, and developmental plateauing or regression, a triad that is now known as West syndrome. The term “epileptic encephalopathy” was coined by Dr. Charlotte Dravet in her 1965 thesis to describe the notion of abundant epileptic activity contributing to neurodevelopmental impairment, in the syndrome now known as Lennox-Gastaut (10).

The 2001 ILAE classification of epilepsy syndromes included epileptic encephalopathies of infancy and childhood as electroclinical syndromes with onset in early childhood and poor prognosis in terms of seizure control and neurodevelopmental outcome (10). In the 2010 ILAE Commission on Classification and Terminology, Berg and colleagues redefined the term epileptic encephalopathy as an electroclinical syndrome in which “the epileptic activity itself may contribute to severe cognitive and behavioral impairments above and beyond what might be expected from the underlying pathology alone (eg, cortical malformation)” (03). The epileptiform activity can cause regression in an individual with normal development or preexisting developmental delay who then shows developmental plateauing or regression, which can worsen over time. Notably, amelioration of epileptiform activity may improve the developmental consequences of the disorder (16).

In contrast, many severe genetic disorders have developmental consequences arising directly from the effect of the genetic mutation in addition to the effect of the frequent epileptic activity on development (19). The 2017 ILAE Commission for Classification and Terminology of the Epilepsies added the term “developmental and epileptic encephalopathy” to recognize these patients (16).

It may be difficult to separate whether the epileptic or developmental component is the more important contributor in a patient’s presentation (16).

A genetic mutation may cause a range of phenotypes from a self-limited epilepsy without developmental impairment to a developmental and epileptic encephalopathy. When a genetic etiology is identified, developmental and epileptic encephalopathies may be referred to by their gene name together with the word encephalopathy, such as KCNQ2 encephalopathy (16).

The previously used term “symptomatic generalized epilepsy” includes a heterogenous group of patients with developmental encephalopathies and epilepsy, epileptic encephalopathies, developmental and epileptic encephalopathies, generalized epilepsy, or combined generalized and focal epilepsy.

The 2017 ILAE Commission for Classification and Terminology and 2022 Classification papers allow for a more precise classification of a patient’s epilepsy syndrome.

This terminology is expanded in the 2022 ILAE position papers on the classification and definition of epilepsy syndromes in infancy and childhood into those with infantile, childhood, and variable onset. The 2022 position papers also proposed to include epilepsy syndromes with progressive neurologic deterioration into this category of developmental and epileptic encephalopathy, recognizing that cognitive impairment in Rasmussen syndrome and progressive myoclonic epilepsies may be due to the underlying etiology, superimposed epileptic activity, or both (21).

Clinical manifestations

Presentation and course

In general, the clinical course may be variable based on etiology and genetic or phenotypic heterogeneity. The majority of the developmental and epileptic encephalopathies begin in infancy and childhood (17), though this term can be applied to individuals of any age. Family, pregnancy, and birth history, including head size, may be normal. Neurologic examination may be abnormal with central hypotonia and cortical visual impairment. Developmental impairment and epilepsy typically occur early. The semiology of the seizures can include multiple seizure types: focal tonic, generalized tonic, myoclonic, focal clonic, atonic seizures, sequential seizures, and epileptic spasms.

Some developmental and epileptic encephalopathies may present with (1) preexisting developmental delay followed by developmental plateauing or regression with seizure onset, (2) an initial period of normal development, with developmental slowing emerging prior to the presence of frequent epileptic activity on EEG, or (3) epilepsy that may be controlled relatively early but with developmental consequences that may remain profound.

ILAE 2022 position papers divide developmental and epileptic encephalopathy syndrome classifications by age of onset: early infantile, infantile, childhood, and variable age of onset (14; 19; 22). Several specific syndromes are listed below, though details may be described in separate MedLink articles.

Infantile-onset developmental and epileptic encephalopathies are divided into those with exclusive onset under 3 months of age (early infantile developmental and epileptic encephalopathy, EIDEE) and those that may present either in early or late-infantile periods or usually after 3 months of age (22). EIDEE is characterized by onset of refractory epilepsy in the first 3 months of life with moderate to profound developmental impairment that becomes evident with time, and it includes neonates and infants previously classified as Ohtahara syndrome and early myoclonic encephalopathy (22). Later infantile-onset developmental and epileptic encephalopathies include epilepsy in infancy with migrating focal seizures, infantile epileptic spasms syndrome, and Dravet syndrome (22).

Developmental and epileptic encephalopathies with onset in childhood include epilepsy with myoclonic atonic seizures (previously known as Doose syndrome), Lennox-Gastaut syndrome, developmental and epileptic encephalopathy-spike wave activity in sleep, and hemiconvulsion-hemiplegia-epilepsy.

Developmental and epileptic encephalopathies that present at a variable age include febrile infection-related epilepsy syndrome (FIRES), Rasmussen syndrome, and progressive myoclonic epilepsies (14). FIRES may present in previously healthy children aged 3 to 15 years with a nonspecific febrile illness followed by prolonged refractory status epilepticus that may have a biphasic presentation with an acute phase of seizure activity lasting 1 to 12 weeks followed by a chronic phase of refractory seizure clusters every 2 to 4 weeks. Rasmussen syndrome presents with unilateral inflammation of the cerebral cortex with drug-resistant focal epilepsy, progressive hemiplegia, and cognitive decline with unihemispheric brain atrophy (17; 20; 14).

Additional articles have included the Neuronal Ceroid Lipofuscinosis which can have variable age of onset (07).

Prognosis and complications

Prognosis may depend on the specific underlying etiology of the patient’s developmental and epileptic encephalopathy, and there may be phenotypic variability within etiologies. Developmental and epileptic encephalopathies typically involve a developmental delay or regression and frequent seizures that may be drug resistant.

Status epilepticus and sudden unexplained death in epilepsy may differ for commonly occurring genetic developmental and epileptic encephalopathies (DEEs), but overall in those with intractable epilepsy may be higher than the average person with epilepsy (05).

Systemic concerns may include respiratory issues such as aspiration, recurrent pneumonia as a complication from severe delay, abnormal tone, and frequent seizures. Underlying etiology may cause movement disorders. Patients may also have gastrointestinal issues, such as dysphagia, gastroesophageal reflux, and constipation, increasing risk of aspiration, and pneumonia; they may need placement of a feeding tube and Nissen fundoplication. Orthopedic concerns are common, including hip dislocation and scoliosis. Limited mobility and chronic use of antiseizure medications leads to increased risk of bone fractures. Sleep issues can include excessive daytime sleepiness, problems with sleep maintenance, and sleep apnea.

Life expectancy may be decreased related to significant neurologic disability; in many cases, death is due to pneumonia, occasionally sudden unexplained death in epilepsy, or seizure-related injury or status epilepticus.

Diagnostic workup

Diagnostic evaluation should exclude structural or metabolic causes of provoked seizures.

Interictal and ictal EEG findings may be specific to the epilepsy syndrome. Interictal EEG will usually be abnormal (rarely can be normal at the onset of seizures) and may include diffuse slowing, multifocal discharges, or a burst-suppression pattern.

In EIDEE, background may include a burst suppression pattern or diffuse slowing with multifocal discharges. In infantile epileptic spasms syndrome, background will include hypsarrhythmia or multifocal discharges. In Lennox-Gastaut syndrome, EEG shows a slow background with frontally predominant slow spike-wave (< 2.5 Hz) and paroxysmal fast activity in sleep. Developmental and epileptic encephalopathy with spike-wave activation in sleep is characterized by marked activation of epileptiform abnormalities in sleep, with nearly continuous diffuse spike-and-wave complexes in the clinical context of cognitive regression.

Neuroimaging, including MRI if available, is used to evaluate for injury that may have occurred early in life or structural brain changes as a result of abnormal brain development (cortical dysplasia or hypothalamic hamartoma). In Rasmussen syndrome, MRI will show unihemispheric atrophy (though it may not be apparent early in the course).

If seizures are focal and MRI is unrevealing, PET and MEG may be performed to identify a resectable lesion. In certain genetic etiologies, imaging is often normal initially or may show cerebral volume loss or evidence of white matter hypo- or dysmyelination; over time, cerebral atrophy may develop.

If no structural abnormality is found, metabolic evaluation should be considered, particularly in patients with EIDEE, including urine organic and amino acids (s-sulfocysteine), urine alpha aminoadipic semialdehyde, plasma amino acids, lactate, uric acid, copper or ceruloplasmin, ammonia, acylcarnitine profile, transferrin isoelectric focusing, very long chain fatty acids, CSF glucose, lactate, pyruvate, amino acids, and neurotransmitters (22).

Genetic evaluation should be considered as a causative pathogenic variant can be identified in a significant proportion of patients with developmental and epileptic encephalopathy, with a higher yield in neonatal onset. This genetic evaluation may include chromosomal microarray, karyotype, gene panel, or whole-exome or genome sequencing.

With the increasing availability of whole-exome sequencing, studies suggest that yield of early targeted whole-exome sequencing in this population ranges from 10% to 72%. A study of 103 patients identified genetic etiology through whole exome sequencing in 41% of children with seizure onset under 2 years old and in 18% of those with older onset (15). Notably, “finding the molecular cause led to management changes in 36% of patients with DEEs.” Studies of cost-effectiveness suggest that early whole-exome sequencing in this population yields more diagnoses for lower cost (09; 01; 12).

Management

Optimizing treatment for a specific epileptic encephalopathy may ameliorate the effect of the epileptic encephalopathy on a patient’s long term-outcome with the potential to reverse some developmental slowing, depending on the age of the patient, their comorbidities, concurrent medications, and, most importantly, the underlying etiology.

No specific antiseizure medications have proven effective for this broad heterogenous group of disorders, and seizures may be medically refractory. If an underlying etiology is found, treatment can potentially be more targeted.

Specific relevant treatments for developmental and epileptic encephalopathy include the following.

A trial of pyridoxine and biotin supplementation, as well as others, are typically considered in medically intractable infants to identify vitamin-responsive seizures. Metabolic disorders may respond to a specific supplement or diet. Ketogenic diet may be helpful in specific etiologies, such as GLUT1 deficiency due to SLC2A1 mutations.

Adrenocorticotropin hormone, oral steroids, or vigabatrin are trialed first line in infantile epileptic spasms syndrome over traditional antiseizure medications.

Stiripentol, fenfluramine, and cannabidiol have been shown to be effective in patients with Dravet syndrome.

In other cases, the same medications may be more helpful, such as sodium channel-blocking agents in KCNQ2-DEE encephalopathy, SCN2A-DEE, and SCN8A-DEE (02). Other channel-targeted treatments include quinidine in KCNT1-DEE (06) and 4-aminopyridine in KCNA1-DEE (08).

Immunotherapy is considered in developmental and epileptic encephalopathies with potential immunologic etiology (Rassmusen, FIRES). Some children with an identified structural cause may be candidates for epilepsy surgery, which should be done early to prevent further neurologic regression.

Precision treatment may also involve enzyme replacement (CLN2) or genetic treatments (04).

All patients should receive treatment of seizures as well as comprehensive care to address learning, behavioral, movement, sleep, respiratory, gastrointestinal, and orthopedic concerns (including supplementation of vitamin D when appropriate).

Genetic counseling and expectations regarding prognosis are driven by genetic diagnosis.

Outcomes

Outcomes may depend on the specific underlying etiology of the patient’s developmental and epileptic encephalopathy.

Treatment with antiseizure medications may improve control of epilepsy and some degree of developmental impairment in an epileptic encephalopathy.

With the relative component of developmental encephalopathy, it is important to manage expectations of the impact of antiseizure treatment on neurodevelopmental impairment, which may not be reversible. This can limit the potentially harmful adverse effects of antiseizure medications on behavior and cognition that can occur with futile aggressive antiepileptic treatment (10).

References

01: Aaltio J, Hyttinen V, Kortelainen M, et al. Cost-effectiveness of whole-exome sequencing in progressive neurological disorders of children. Eur J Paediatr Neurol 2022;36:30-6. PMID 34852981
02: Ademuwagun IA, Rotimi SO, Syrbe S, Ajamma YU, Adebiyi E. Voltage gated sodium channel genes in epilepsy: mutations, functional studies, and treatment dimensions. Front Neurol 2021;12:600050. PMID 33841294
03: 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(4):676-85. PMID 20196795
04: Bertocchi I, Cambiaghi M, Hasan MT. Advances toward precision therapeutics for developmental and epileptic encephalopathies. Front Neurosci 2023;17:1140679. PMID 37090807
05: Donnan AM, Schneider AL, Russ-Hall S, Churilov L, Scheffer IE. Rates of status epilepticus and sudden unexplained death in epilepsy in people with genetic developmental and epileptic encephalopathies. Neurology 2023;100(16):e1712-22. PMID 36750385
06: Fitzgerald MP, Fiannacca M, Smith DM, et al. Treatment responsiveness in KCNT1-related epilepsy. Neurotherapeutics 2019;16(3):848-57. PMID 31054119
07: 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(1):433-513. PMID 35951482
08: Hedrich UBS, Lauxmann S, Wolff M, et al. 4-Aminopyridine is a promising treatment option for patients with gain-of-function KCNA2-encephalopathy. Sci Transl Med 2021;13(609):eaaz4957. PMID 34516822
09: Howell KB, Eggers S, Dalziel K, et al. A population-based cost-effectiveness study of early genetic testing in severe epilepsies of infancy. Epilepsia 2018;59(6):1177-87. PMID 29750358
10: 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(2):216-222. PMID 29356691
11: Lado FA, Rubboli G, Capovilla G, Avanzini G, Moshé SL. Pathophysiology of epileptic encephalopathies. Epilepsia 2013;54 Suppl 8(0 8):6-13. PMID 24571111
12: Lavelle TA, Feng X, Keisler M, et al. Cost-effectiveness of exome and genome sequencing for children with rare and undiagnosed conditions. Genet Med 2022;24(6):1349-61. PMID 35396982
13: Poke G, Stanley J, Scheffer IE, Sadleir LG. Epidemiology of developmental and epileptic encephalopathy and of intellectual disability and epilepsy in children. Neurology 2023;100(13):e1363-75. PMID 36581463
14: Riney K, Bogacz A, Somerville E, et al. International League Against Epilepsy classification and definition of epilepsy syndromes with onset at a variable age: position statement by the ILAE Task Force on Nosology and Definitions. Epilepsia 2022;63(6):1443-74. PMID 35503725
15: Scheffer IE, Bennett CA, Gill D, et al. Exome sequencing for patients with developmental and epileptic encephalopathies in clinical practice. Dev Med Child Neurol 2023;65(1):50-57. PMID 35701389
16: 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(4):512-21. PMID 28276062
17: Scheffer IE, Liao J. Deciphering the concepts behind "epileptic encephalopathy" and "developmental and epileptic encephalopathy." Eur J Paediatr Neurol 2020;24:11-4. PMID 31926847
18: Specchio N, Curatolo P. Developmental and epileptic encephalopathies: what we do and do not know. Brain 2021;144(1):32-43. PMID 33279965
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;63:1398-42. PMID 35503717
20: Varatharaj A, Pollak TA, Nicholson TR, et al. Characterising neuropsychiatric disorders in patients with COVID-19: authors' reply. Lancet Psychiatry 2020;7(11):934-5. PMID 33069310
21: Wirrell EC, Nabbout R, Scheffer IE, et al. Methodology for classification and definition of epilepsy syndromes with list of syndromes: report of the ILAE Task Force on Nosology and Definitions. Epilepsia 2022;63(6):1333-48. PMID 35503715
22: 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(6):1349-97.** PMID 35503712

Contributors

All contributors' financial relationships have been reviewed and mitigated to ensure that this and every other article is free from commercial bias.

Authors

Parmpreet Dhillon MD

Dr. Dhillon of Montefiore Health System has no relevant financial relationships to disclose.
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Elissa G Yozawitz MD

Dr. Yozawitz of the Albert Einstein College of Medicine received consulting fees from IQVIA and advisory board honoraria from Sermo.
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Editor

Solomon L Moshé MD

Dr. Moshé of Albert Einstein College of Medicine has no relevant financial relationships to disclose.
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Former Authors

C P Panayiotopoulos MD PhD

Patient Profile

Age range of presentation: 0 to 15 years
Sex preponderance: male=female
Heredity: autosomal recessive
Occupation groups selectively affected: none selectively affected

ICD & OMIM codes

ICD-10: Generalized idiopathic epilepsy and epileptic syndromes: G40.3

Encephalopathy, unspecified: G93.4-

Metabolic encephalopathy: G93.41

Mild intellectual disabilities: F70

Moderate intellectual disabilities: F71

Severe intellectual disabilities: F72

Profound intellectual disabilities: F73
OMIM: CNL8 gene: *607837

CLN8 late infantile variant: #600143

Developmental and epileptic encephalopathy 1; DEE1: # 308350

Developmental and epileptic encephalopathy 2; DEE2: # 300672

Developmental and epileptic encephalopathy 89; DEE89: # 619124

Progressive epilepsy with mental retardation (EPMR): #610003

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Developmental and epileptic encephalopathies

Associated Disorders

epilepsy
developmental encephalopathy

Differential Diagnosis

developmental encephalopathy

Also Relevant

Dravet syndrome
Early infantile epileptic encephalopathies
Epilepsy
Epilepsy in infancy with migrating focal seizures
GLUT1DS-related developmental and epileptic encephalopathy
- Intellectual disability
- Lennox-Gastaut syndrome
- Rasmussen syndrome
- West syndrome

Clinical Categories

Epilepsy & Seizures

Developmental and epileptic encephalopathies …

Developmental and epileptic encephalopathies

Introduction

Overview

Key points

Historical note and terminology

Clinical manifestations

Presentation and course

Prognosis and complications

Biological basis

Etiology and pathogenesis

Pathogenesis

Epidemiology

Prevention

Differential diagnosis

Confusing conditions

Associated or underlying disorders

Diagnostic workup

Management

Outcomes

Special considerations

Anesthesia

References

Contributors

Authors

Editor

Former Authors

Patient Profile

ICD & OMIM codes

This is an article preview.
Start a Free Account
to access the full version.

Questions or Comment?

Also in This Category

Anti-LGI1 encephalitis

Self-limited (familial) neonatal epilepsy

Alcohol withdrawal seizures

Epileptic lesions due to malformation of cortical development

Epileptic spasms

Sleep and epilepsy

Neocortical temporal lobe seizures

Jacksonian seizures

Developmental and epileptic encephalopathies

Introduction

Overview

Key points

Historical note and terminology

Clinical manifestations

Presentation and course

Prognosis and complications

Biological basis

Etiology and pathogenesis

Pathogenesis

Epidemiology

Prevention

Differential diagnosis

Confusing conditions

Associated or underlying disorders

Diagnostic workup

Management

Outcomes

Special considerations

Anesthesia

References

Contributors

Authors

Editor

Former Authors

Patient Profile

ICD & OMIM codes

This is an article preview. Start a Free Account to access the full version.

Questions or Comment?

Also in This Category

Anti-LGI1 encephalitis

Self-limited (familial) neonatal epilepsy

Alcohol withdrawal seizures

Epileptic lesions due to malformation of cortical development

Epileptic spasms

Sleep and epilepsy

Neocortical temporal lobe seizures

Jacksonian seizures

This is an article preview.
Start a Free Account
to access the full version.