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.

Biological basis

Etiology and pathogenesis

Developmental and epileptic encephalopathies are associated with a variety of underlying etiologies, including structural (hypothalamic hamartoma, hemimegalencephaly, tuberous sclerosis complex), metabolic, genetic, and immune.

Many have a genetic etiology (approximately 30%), which is often de novo, and may have marked genetic heterogeneity. In EIDEE, causative pathogenic gene variants can be identified in more than half of patients (22).

Pathogenesis

The underlying etiology’s contribution to the developmental component versus epileptic component of encephalopathy may vary with different genetic diseases and at different ages and stages of the disease process. It may be impossible to tease apart in neonatal onset developmental and epileptic encephalopathies, where development is never normal; seizures may cease in the first years of life in some patients, yet development remains severely affected (17).

Possible pathophysiological mechanisms of epileptic activity leading to neurologic and developmental compromise include interfering with neurogenesis, synaptogenesis, and normal network-organization as well as triggering neuroinflammation (16; 07).

Disruption of subcortical arousal centers regulating cortex early in life may lead to alterations of intracortical synapses that affect a critical period of cognitive development. Impairment of interneuronal function globally through the action of a genetic lesion similarly causes widespread cortical dysfunction manifesting as increased delta slow waves on EEG and as developmental delay or arrest clinically (11).

Epidemiology

As developmental and epileptic encephalopathy is a relatively new standardized term, epidemiological data specific for this term are just emerging.

The cumulative incidence of developmental and epileptic encephalopathy overall has been estimated to be 169 in 100,000 with a prevalence of 112 in 100,000 (13).

Prevention

No preventative or curative measures are available for any of the forms of developmental and epileptic encephalopathy, though prompt diagnosis and antiseizure treatment may improve control of epilepsy and some degree of developmental impairment in an epileptic encephalopathy.

Elucidation of the genetic basis will make carrier detection and prenatal diagnosis more feasible.

Differential diagnosis

Confusing conditions

Developmental encephalopathy. Developmental encephalopathy is a static disability, such as developmental delay or intellectual disability. There may be cognitive, neurologic, or psychiatric impairment; stagnation; or regression (14). This population may have a higher risk of epilepsy than the general population, but this does not mean that they have an epileptic encephalopathy. Genetic causes are also frequent. It is important to differentiate this group of patients from those with developmental and epileptic encephalopathies as epilepsy management may be more conservative (17).

Associated or underlying disorders

Associated disorders include epilepsy from developmental and epileptic encephalopathy and developmental encephalopathy from developmental and epileptic encephalopathy.

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).

Special considerations

Anesthesia

Anesthesiologists taking care of patients with developmental and epileptic encephalopathy, epilepsy, or uncontrolled seizures should be aware of perioperative seizure precautions and first aid. Anesthetic agents may have pro- or anticonvulsant properties, and anesthesiologists should understand the impact of anesthesia medications on seizures.