Epileptic Encephalopathy

Epileptic encephalopathy describes severe forms of epilepsy where the seizure activity itself contributes to serious cognitive and behavioral problems beyond what the underlying brain condition might cause alone, often beginning in early childhood and requiring prompt, specialized treatment.

Table of contents

• What is Epileptic Encephalopathy?
• Recognized Epileptic Encephalopathy Syndromes
• Causes and Contributing Factors
• How Doctors Diagnose the Condition
• Treatment Approaches

What is Epileptic Encephalopathy?

Epileptic encephalopathy is the name used to describe severe cases of epilepsy that result in reduced cognitive and behavioral function^[1]. This condition is defined as one in which abnormal electrical brain activity is believed to contribute to progressive disturbance in brain function^[2]. In simpler terms, both the seizures themselves and the abnormal brain waves between seizures can cause or worsen problems with thinking, behavior, and development.

Epileptic encephalopathy typically occurs early in a child’s life, starting in infancy, and can be characterized by generalized seizures (abnormal activity in both halves of the brain) or focal seizures (starting in one part of the brain) that are recurrent, severe and often resistant to antiepileptic medications^[1]. These conditions vary in their age of onset, developmental outcome, causes, neuropsychological deficits, electrical brain patterns, seizure types, and outlook^[3].

Damage to the brain from the frequent seizure activity often leads to delays in development or the loss of developed skills^[1]. However, in some cases, a child’s development impairment can also be a result of the underlying condition causing the epilepsy. These conditions are referred to as Developmental Epileptic Encephalopathies (DEE) to acknowledge the presence of multiple causes for the developmental damages^[1].

The International League Against Epilepsy (ILAE) first recognized epileptic encephalopathies as a distinct category in 2001^[3]. Later in 2010, researchers refined the definition to emphasize that the epileptic activity itself may contribute to severe cognitive and behavioral impairments above and beyond what might be expected from the underlying condition alone, and that these can worsen over time^[3].

Recognized Epileptic Encephalopathy Syndromes

While encephalopathy can occur in any epileptic condition, there are eight severe epileptic syndromes that are commonly associated with epileptic encephalopathy according to the International League Against Epilepsy^[2]. These syndromes are usually age-related and are extremely difficult to treat, with characteristic generalized seizures and massive epileptic brain wave abnormalities^[2].

West Syndrome, also known as infantile spasms, is characterized by seizures that last a few seconds and occur in clusters (up to 150 seizures at a time). Some babies will experience up to 60 clusters in a day^[1].

Dravet Syndrome, formerly called severe myoclonic epilepsy of infancy, is a genetic condition characterized by frequent, prolonged seizures that are commonly triggered by high body temperature. It typically begins within the first year of a child’s life^[1].

Early Myoclonic Encephalopathy (EME), also referred to as neonatal myoclonic encephalopathy, usually occurs in newborn infants. It is characterized by frequent drug resistant seizures that cause severe developmental damage resulting in reduced life expectancy^[1]. Epileptic encephalopathies are conditions in which neurologic deterioration results mainly from epileptic activity, which can be due to very frequent or severe seizures, or to nearly continuous abnormal electrical activity between seizures^[5].

Ohtahara Syndrome, also known as Early Infantile Epileptic Encephalopathy (EIEE), is a severe form that begins within the first 3 months of life. Neonates have poor suckling reflexes, low muscle tone and manifest with generalized and symmetrical tonic spasms that can appear in clusters or singly and can last for up to 10 seconds^[6]. The pattern of these spasms remains unchanged during wakefulness and sleep and they can occur hundreds of times per day^[6]. The characteristic brain wave pattern displays a suppression burst pattern, which is comprised of bursts of high amplitude spikes that alternate with periods of low voltage basic rhythm^[6].

Continuous Spike Wave of Sleep (CSWS) typically begins in children ages 2-12 years old and affects boys more often than girls. While various types of seizures are experienced within this syndrome, they all often result in a noticeable slowing of cognitive function 1-2 years after the seizure onset^[1].

Electrical Status Epilepticus During Slow-Wave Sleep (ESES) is sometimes used interchangeably with CSWS, but this condition is identified through the specific brain wave pattern. Children who suffer from these epilepsies experience epileptic activity during non-REM sleep that produces a pattern of near continuous spike waves^[1].

Landau-Kleffner Syndrome (LKS) is an extremely rare epilepsy syndrome that typically presents between 3 and 6 years. Early signs of LKS include epileptic seizures and difficulty understanding and speaking words^[4]. Challenges understanding conversation and recognizing voices will continue to persist and may worsen over time, with the child not being able to discern non-language based sounds such as doorbells, singing or dogs barking. This is called verbal auditory agnosia^[4].

Lennox-Gastaut Syndrome is also recognized as one of the eight syndromes^[2]. Other epileptic syndromes such as migrating partial seizures in infancy and severe epilepsy with multiple independent spike foci may be reasonably added to this list^[2].

Causes and Contributing Factors

Epileptic encephalopathy may result from different causes. Many cases have been associated with structural brain abnormalities^[6]. Some cases are due to metabolic disorders, such as cytochrome C oxidase deficiency or carnitine palmitoyl transferase II deficiency, or brain malformations, such as porencephaly or hemimegalencephaly, that may or may not be genetic in origin^[6].

Genetic variants of epileptic encephalopathy have been associated with mutations in certain genes such as ARX, CDKL5, SLC25A22 and STXBP1, among others^[6]. The genetic abnormalities are thought to lead to epileptic encephalopathy as they are related to neuronal dysfunction or brain development problems^[6]. The cause of some syndromes, like Landau-Kleffner Syndrome, is unknown^[4].

How Doctors Diagnose the Condition

Diagnosis is based on clinical findings and brain wave testing. The characteristic test is an electroencephalogram (EEG), which is a procedure that records the brain’s electrical activity. It is performed by attaching electrodes to the scalp^[4]. An EEG conducted over a longer period of time, specifically during sleep, will be most effective at capturing abnormalities^[4]. An EEG can also be used to monitor progress and help determine treatment over time^[4].

Magnetic resonance imaging (MRI) and computed tomography (CT) brain scans may also be used to better understand the abnormalities and determine treatment^[4]. Structural abnormalities can often be identified through brain imaging^[6].

Additionally, it is important for children with epileptic encephalopathy to receive speech, behavioral and educational assessments, to best determine interventions and long-term treatment plans^[4]. Genetic and metabolic testing may also be conducted to identify underlying causes^[6].

Treatment Approaches

The goals of treatment are not only to control seizures, but also to prevent or reverse neurologic loss of function^[7]. Early diagnosis and initiation of treatment appear to be important in achieving better long-term outcomes^[9]. In general, time is of the essence in diagnosis, and experienced specialists should promptly design a treatment plan^[7].

A common feature of epileptic encephalopathies is that these disorders are usually difficult to treat with standard antiepileptic drugs^[2]. As a result, more aggressive use of medications considered effective in suppressing abnormal brain waves between seizures, such as benzodiazepines, valproic acid, and lamotrigine, is often considered^[2]. In general, antiepileptic drugs that are considered “spike suppressors” such as valproic acid, benzodiazepines, ethosuximide, levetiracetam, and lamotrigine may be preferable^[9].

Hormonal and immune therapies are at the forefront of treatment in many cases, with traditional antiepileptic drugs and surgery playing a limited role^[7]. Adrenocorticotropic hormone (ACTH) or corticosteroids may be used, usually after standard antiepileptic drugs have failed^[9]. Immunomodulatory therapies such as intravenous immunoglobulin (IVIG) and plasmapheresis may also be considered^[2].

A ketogenic diet may be helpful for some patients^[2]. Surgical options are often considered when an identifiable lesion is present^[7]. Vagus nerve stimulation and epilepsy surgery may be appropriate in select cases^[9].

However, it is important to note that for most of these disorders, there are no controlled clinical trials investigating the therapeutic options, and only open-label data are available^[9]. Antiepileptic drugs must be used carefully, as they may aggravate seizures or worsen cognitive function^[9]. The degree of correlation between brain wave abnormalities and neuropsychological deficits requires better description in most of these syndromes. However, often a goal of treatment is to improve the brain wave pattern while monitoring for concurrent cognitive improvement to confirm that treatment is indeed worthwhile^[9].

Early diagnosis and proper intervention are key to success^[4]. Vigilance in monitoring baseline and progression of cognitive status in these disorders is required to gauge the effects of treatment on thinking abilities^[9]. Ongoing clinical and basic research may lead to better understanding of these devastating conditions and to better and more effective therapies^[7].