eMedicine Specialties > Neurology > Pediatric Neurology

Epileptic and Epileptiform Encephalopathies

Author: Dean Patrick Sarco, MD, Instructor, Department of Neurology, Harvard Medical School; Assistant Physician, Department of Neurology, Division of Epilepsy and Clinical Neurophysiology, Children's Hospital Boston
Coauthor(s): Masanori Takeoka, MD, Assistant Professor, Department of Neurology, Harvard Medical School; Consulting Staff, Department of Neurology, Division of Epilepsy and Clinical Neurophysiology, Children's Hospital Boston
Contributor Information and Disclosures

Updated: Jul 29, 2009

Introduction

Background

Epilepsy, one of the most common neurologic conditions, is defined as a chronic condition characterized by spontaneous, recurrent seizures. An epileptic seizure is defined as a clinical event associated with a transient, hypersynchronous neuronal discharge and represents only the symptom of a potential underlying brain pathology and not the actual disease. Epileptic is a descriptive term used to denote the presence of an epileptic mechanism. Electroencephalography (EEG) typically is used to help in the diagnosis and classification of epileptic disorders. Encephalopathy refers to cerebral dysfunction of any cause.

Epilepsy is a heterogeneous condition with many etiologies, often unrelated. Similarly, the cognitive profiles of patients with epilepsy vary significantly and may be related to different factors including etiology, age of onset, seizure control, and adverse effects related to treatment.

Chatrian et al in their 1974 glossary of EEG terms defined the term epileptiform to describe distinct waves or complexes, distinguishable from the background activity, which resemble the waveforms recorded in a proportion of human subjects suffering from an epileptic disorder.1 In practice, the presence of epileptiform activity indicates a tendency toward epileptic seizures; however, the presence of epileptiform activity alone does not diagnose epilepsy. Epileptiform patterns include spike and sharp wave discharges, either alone or accompanied by slow waves, occurring singly or in bursts lasting at most a few seconds. These epileptiform patterns typically refer to interictal EEG activity (found in between seizures), and not ictal EEG activity (found during an electrographic seizure). The probability of the association between epileptiform activity and actual epileptic disorder varies.

Earlier-onset epilepsy may potentially have a greater impact on a child's development than later-onset epilepsy. Age of epilepsy onset also varies and depends upon the underlying etiology. Seizures and cognitive function may vary over time, depending on the developmental stage of the child. Seizures may eventually remit in many children over time, but behavioral and cognitive problems may persist into adulthood.

Epileptic or epileptiform encephalopathies are characterized by slowing or regression of development that is attributed to ictal and/or interictal epileptiform activity, often becoming more frequent in sleep.2 (When discharges are present in the awake state, this is termed sleep-potentiation. If discharges are only present in sleep, then this is termed sleep-activation.) Hence, deviation from a normal developmental trajectory in the presence of epileptiform EEG activity, including delay, plateauing, or regression of cognitive abilities and/or behavioral regulation, should raise suspicion of a potential epileptic encephalopathy.

The International League Against Epilepsy (ILAE) Task Force on Classification and Terminology proposed a modified diagnostic scheme for epileptic seizures and epilepsy that, for the first time, recognizes a distinct category for the epileptic encephalopathies.3 The ILAE defines an epileptic encephalopathy as a condition where "the epileptiform EEG abnormalities themselves are believed to contribute to a progressive disturbance in cerebral function." This category includes the following epilepsy syndromes:

  • early myoclonic encephalopathy, early infantile epileptic encephalopathy (Ohtahara syndrome),
  • West syndrome, severe myoclonic epilepsy in infancy (Dravet syndrome), migrating partial seizures in infancy, myoclonic status in nonprogressive encephalopathies,
  • Lennox-Gastaut syndrome (LGS), Landau-Kleffner syndrome (LKS), and epilepsy with continuous spike-waves during slow wave sleep (CSWS).

Because this concept is evolving, other epilepsy syndromes such as some cases of benign rolandic epilepsy may also fit into this rubric.4

The term epileptic encephalopathy describes a heterogenous group of epilepsy syndromes associated with severe cognitive and behavioral disturbances. These disorders vary in terms of their ages of onset, developmental outcome, etiologies, neuropsychological deficits, EEG patterns, seizure types, and prognosis. Grouping these disorders is useful in recognizing that a subset of severe epilepsies in infancy or early childhood may have a significant impact on neurological development. "Epileptic encephalopathy" is the most commonly used phrase in the literature. Note that the term epileptic encephalopathy may refer to conditions with severe and frequent ictal EEG activity (actual seizures) as a more prominent component, as opposed to epileptiform encephalopathies, or those conditions where the interictal epileptiform EEG abnormalities may be more prominent than the actual seizures.

This ability to make these distinctions in clinical practice may be challenging as variability may be seen within each epilepsy syndrome and within a given child over time. However, in some cases, severe developmental regression may be seen in the context of few seizures but severe interictal epileptiform abnormalities, as in some cases of Landau-Kleffner syndrome (LKS). The quantity of epileptiform activity does not correlate well with seizure severity. Observational and anecdotal evidence correlate the quantity of epileptiform activity with the degree of cognitive impairment. Additional well-designed studies are needed to sufficiently quantify and correlate interictal epileptiform activity with neuropsychological and developmental measures.

Inherent in the notion of an epileptic encephalopathy is that limiting or suppressing EEG ictal and/or interictal activity may improve cognitive and behavioral outcome. Anecdotal and small series data support this concept; however, this remains controversial due to the lack of data from larger well-designed studies. A common feature is that these disorders are usually refractory to standard antiepileptic drugs (AEDs). As a result, more aggressive use of AEDs considered effective in suppressing interictal epileptiform discharges (eg benzodiazepines, valproic acid, lamotrigine), immunomodulatory therapies (eg, corticosteroids, intravenous immunoglobulin [IVIG], plasmapheresis), ketogenic diet, and surgical options are often considered.

At this time, it remains unclear how much of the dysfunction seen in these disorders is secondary to epileptiform EEG activity or secondary to the underlying cause of the epilepsy syndrome. An additional understanding of these mechanisms is required in order to make more specific treatment recommendations. For these reasons, these authors advocate "treating the patient, and not the EEG." Data are insufficient to recommend treatment for the sole purpose of minimizing interictal epileptiform activity at this time, especially when the clinical symptoms of the epileptiform activity on the patient are unclear.

The prototypical example of an epileptic encephalopathy is Lennox-Gastaut syndrome, characterized by a mental retardation, a generalized slow spike and wave EEG pattern, and a mixed seizure disorder, which includes tonic, atonic, and myoclonic seizures. Most children with Lennox-Gastaut syndrome have symptomatic epilepsy that is medically intractable. Seizures may be as frequent as hundreds per day. In this and similar disorders, the frequency and severity of seizures may have a greater impact on cognition than is seen in other disorders. Other identifiable factors that likely contribute include the underlying etiology and adverse effects from AEDs.

Terminology and definitions

Epilepsy: This is a chronic condition with spontaneous, recurrent seizures; a seizure is defined as a clinical event associated with a transient, hypersynchronous neuronal discharge.

Epileptic: This term denotes the presence of epilepsy.

Encephalopathy: This refers to a disturbance in brain functioning, particularly in intellectual activity or higher cortical functioning as used in this review.

Epileptiform: This refers to spike waves, sharp waves, spike and wave activity, or other rhythmic waveforms that imply epilepsy or may be associated with epilepsy. However, epileptiform activity alone does not confirm a diagnosis of epilepsy.

Epileptic or epileptiform encephalopathy: A category of severe epilepsy syndromes of infancy or early childhood, in which the epileptiform EEG abnormalities themselves are believed to contribute to a progressive disturbance in cerebral function. More precisely, the term epileptic encephalopathies may be used to refer to those syndromes characterized by very frequent seizures, where as epileptiform encephalopathies may be used to refer to those syndromes that generally occur later and where the EEG epileptiform activity is more prominent than clinical seizures.

Epileptic aphasia and epileptiform aphasia: Although the term epileptic aphasia has been used for Landau-Kleffner syndrome (LKS), epileptic aphasia by its strict definition refers to an aphasia caused by an actual seizure, or in other words, an ictal aphasia. Epileptiform aphasia refers to a language disorder, expressive, receptive, or mixed, associated with epileptiform features on EEG. The terms congenital aphasia, developmental aphasia, or acquired aphasia are used with this to describe whether the condition is developmental or acquired. Acquired aphasia implies previously normal language development with subsequent regression. Note that regression might occur even in developmental language disorders or the congenital aphasias.

Each of the following disorders considered epileptic encephalopathies are reviewed:

  • Early myoclonic encephalopathy
  • Early infantile epileptic encephalopathy (Ohtahara syndrome)
  • Migrating partial epilepsy in infancy
  • West syndrome (infantile spasms)
  • Severe myoclonic epilepsy of infancy (Dravet syndrome)
  • Myoclonic status in nonprogressive syndromes
  • Myoclonic-astatic epilepsy (Doose syndrome)
  • Lennox-Gastaut syndrome (LGS)
  • Landau-Kleffner syndrome (LKS) and epilepsy with continuous spikes-waves during slow sleep (CSWS)

Briefly mentioned are two conditions not currently considered epileptic encephalopathies but for which evolving evidence and discussion are implicating that epilepsy or epileptiform activity may contribute to encephalopathy in a subset of cases:

  • Benign childhood epilepsy with centro-temporal spikes (benign rolandic epilepsy)
  • Autism with epileptiform EEG abnormalities

Pathophysiology

The underlying mechanisms of these disorders are still poorly understood. Identifiable factors that may influence the course and degree of cognitive and behavioral impairment in these disorders includes underlying etiology, age of onset of epilepsy, seizure frequency and severity, interictal epileptiform activity severity, treatment-related adverse effects, cumulative detrimental effects of severe chronic epilepsy, and genetic factors.   

It remains unclear how much electrical dysfunction contributes to the neuropsychological impairments seen in these disorders. In 1957, Landau and Kleffner suggested that "persistent convulsive discharges in brain tissue largely concerned with language communication" may be responsible for the deficits seen in LKS. This represents the basic concept that frequent seizures and/or interictal discharges may significantly disrupt the function of neuronal networks involved in language, learning, memory, behavioral regulation, and other higher cortical functions, resulting in either transient or permanent deficits. For example, continuous abnormal discharges during sleep may cause disruption of hippocampal function and interfere with learning and memory while awake and memory consolidation in sleep.5,6

The deficits seen in some epileptic encephalopathies appear to generally correlate with the location, frequency, and degree of spread of abnormal electrical activity, as in LKS and epilepsy with continuous spikes-waves during slow sleep (CSWS); however, further studies are required to better quantify and characterize the evolution of these deficits with the various potential contributing factors. Adding to the difficulty of this characterization is that the involvement of noneloquent cortex is more difficult to assess, given that performance must be tested in order to appreciate more subtle cognitive impairments. 

The duration of electrical dysfunction may in part determine the severity of the disorder. Impairment at the exact moment of an interictal discharge has been described and is termed transient cognitive impairment.7,8,9,10,11,12,13  Although challenging to demonstrate, this appears to be due to a temporary disruption of a cortical network involved in a particular function at the time of an interictal epileptiform discharge. 

Longer duration dysfunction may be seen during ictal and post-ictal states, which may last from minutes to days, depending in part on the severity of the seizure, and the cognitive reserve a patient may have. More chronic, potentially reversible dysfunction may also be seen, such as in the subset of children with benign childhood epilepsy with centro-temporal spike discharges (BCECTS) who demonstrate a variety of neuropsychological deficits that may be reversible.14,15,16  More chronic and permanent impairment may be seen in more severe disorders, such as Lennox-Gastaut syndrome (LGS). The more severe epileptic encephalopathies falls into the latter category.     

The role of sleep activation, particularly in electrical status epilepticus of sleep (ESES), offers an appealing and challenging paradigm that could lead to better understanding of the pathophysiologic basis of these conditions. Two crucial questions still await an answer: (1) what are the mechanisms involved in the generation of such significant, interictal, sleep activation; and (2) what are the mechanisms involved in the cognitive/developmental regression that accompanies these conditions.

Though still unclear, evidence suggests that defective mechanisms of synaptogenesis and thalamocortical circuit formation during a critical period may be involved in the generation of epilepsy with continuous spikes-waves during slow sleep (CSWS). Secondary bilateral synchrony, that is facilitated by the corpus callosum and that may involve the thalamocortical connections, was hypothesized as the possible mechanism for the generation of ESES discharges.17,18,19

An association between CSWS and early thalamic injury has been reported. A review of EEG abnormalities in 32 children with early thalamic injury, primarily due to vascular mechanisms, revealed that 29 out of the 32 patients showed significant sleep activation.20  Among these 29 patients, 2 different groups were distinguished: the first included typical CSWS (12 cases), generally with symmetry of spike and waves and often with no spindle at all. The other cases had an usual asymmetry of SWs and the presence or reduction of spindles, plus other atypical features concerning synchronism and morphology of SWs. Behavioral disorders were significantly more present in patients with a true CSWS; their improvement paralleled the disappearance of CSWS. Generally, the predominant injury was in the lateral aspect of the thalamus including reticular nucleus and ventral nuclei.

Frequency

International

In a 20-year epidemiological study of childhood epilepsy syndromes from Tel Aviv, Kramer et al reported that West syndrome occurred in 9%; myoclonic seizures in 2.2%; Lennox-Gastaut syndrome in 1.5%; and LKS, Ohtahara syndrome, myoclonic astatic epilepsy, and ESES in 0.2% each.21

Mortality/Morbidity

Mortality and morbidity relate to the underlying causes of these disorders, treatment, or both.

Age

Each of these childhood epilepsy syndromes has its own characteristic age of onset.

Clinical

History

Epileptic Encephalopathy Syndromes

  • Early infantile epileptic encephalopathy (Ohtahara syndrome)
    • Early infantile epileptic encephalopathy (EIEE) is a rare disorder characterized by early-onset seizures in the neonatal period, which may begin as early as the first few days of life.
    • Brief generalized tonic seizures typically occur first, occasionally in clusters. Focal motor and hemiconvulsive seizures may occur in up to half of cases.22
    • Interictal EEG reveals a suppression-burst pattern while awake and in sleep. Bursts of generalized high amplitude slowing with admixed multifocal spike discharges are separated by several seconds of diffuse voltage suppression. Ictal EEG reveals typical generalized electro-decrements during tonic seizures.
    • Most children are symptomatic from structural brain abnormalities such as cerebral dysgenesis, although metabolic disorders are also reported.23
    • Seizures are difficult to treat. Response to treatment is often poor. In addition to standard AEDs, ACTH, corticosteroids, the ketogenic diet, and epilepsy surgery may be helpful in some cases.
    • The prognosis is very poor. Most children either die or are severely neurologically impaired. All surviving children have global developmental delays. Some children may progress to West syndrome and Lennox-Gastaut syndrome. These 3 disorders are considered to be on a spectrum by some authors. Progression to hypsarrhythmia portends a poorer prognosis.
  • Early myoclonic encephalopathy
    • Early myoclonic encephalopathy (EME) is a rare disorder characterized by neonatal-onset seizures, usually within the first month of life.
    • Seizures are mostly myoclonic and partial motor seizures. Myoclonic seizures may be focal, occasionally very subtle, and may become frequent. Tonic spasms may develop later. This is different than early infantile epileptic encephalopathy (EIEE), in which tonic seizures appear early.
    • The interictal EEG reveals a burst-suppression pattern more pronounced in sleep, with longer periods of diffuse voltage suppression lasting up to 10 seconds.22 The EEG may evolve to hypsarrhythmia or multifocal spike discharges and may then return to a suppression-burst pattern afterwards.
    • The etiology is often unknown. Metabolic disorders, including nonketotic hyperglycinemia, have been described in EME and should be pursued. Structural lesions are rare. 
    • Seizures are medically intractable to treatment, including standard anticonvulsants and corticosteroids, which are often tried. A ketogenic diet may also be helpful.
    • The prognosis is poor. Neurological abnormalities are common, and most children have minimal developmental progress. Reported mortality is a high as 50% during the first year of life.22
  • Infantile spasms (West syndrome)
    • West syndrome usually occurs in the first year of life and consists of the triad of infantile spasms, developmental deterioration, and a hypsarrhthymia pattern on EEG.
    • The epileptic spasms are brief, generalized seizures involving extension and/or flexion axially and of the extremities. An individual spasm lasts seconds, often longer than typical myoclonic seizures, though not as long as most tonic seizures. The spasms may be subtle and may be isolated at onset, typically clustering later in the course. Several clusters per day, particularly in drowsiness, are characteristic.
    • Hypsarrhythmia, the typical interictal EEG finding, consists of a disorganized pattern with asynchronous, very high amplitude slowing and frequent multifocal spike and sharp wave discharges. The ictal EEG typically reveals a generalized slow wave followed by diffuse voltage attenuation (electro-decrement), which may associated with a spasm or be only electrographic (without clinical correlate).
    • No clear etiology is found in approximately 40% of cases.24 There is a broad range of potential causes, including cerebral malformations, infection, hemorrhage, hypoxic-ischemic injury, metabolic disorders, and genetic conditions, such as Down syndrome.
    • Variation in study methodologies prohibits a clear recommendation for first-line treatment; however, ACTH and vigabatrin are usually used in practice. Corticosteroids may be less efficacious than ACTH, although they are effective. Vigabatrin may be more efficacious in tuberous sclerosis. Other agents that are efficacious include valproate, levetiracetam, topiramate, zonisamide, lamotrigine, and benzodiazepines.
    • The ketogenic diet is helpful in most cases. Focal cortical resection or hemispherectomy may be considered for cases that are lesional and medically intractable.
    • Development remains unaffected only in a minority. Most children experience slowing, plateauing, or regression of their developmental trajectory. The developmental prognosis partially depends on the etiology. No specific AED has been shown to affect long-term developmental outcome. An extensive literature review revealed that 16% had normal development, and 47% had continued seizures at an average follow-up of 31 months.24 When classified by etiology, normal development was described in 51% of cryptogenic cases versus only 6% of symptomatic cases. Approximately 17% of cases evolved into Lennox-Gastaut syndrome.
  • Malignant epilepsy with migrating partial seizures in infancy
    • Onset of this rare syndrome occurs in the first year of life and may occur in the neonatal period. It is characterized by frequent partial seizures of multifocal onset, with autonomic or motor involvement. The seizures increase in frequency and may become near-continuous.
    • The interictal EEG reveals multifocal epileptiform activity and slowing. The ictal EEG confirms multifocal onsets, which may shift from seizure to seizure.
    • In most cases, there is no clear etiology or structural problems, suggesting genetic factors may be causative or contributory.
    • Seizures are often difficult to control with standard AEDs. Bromides, stiripentol, and clonazepam may be helpful in some cases.
    • Developmental regression is common, and death has been reported in infancy and childhood in severe cases.
  • Severe myoclonic epilepsy of infancy (Dravet syndrome)
    • Severe myoclonic epilepsy of infancy (SMEI) is an uncommon disorder with onset between 3 months and 2 years of age.
    • The epilepsy begins with recurrent simple febrile seizures, which later become of longer duration and afebrile. Myoclonic seizures, either focal or generalized, appear after age 1 year. Multiple seizure types develop, including hemiclonic, simple motor, complex partial, and atypical absence seizures. Episodes of status epilepticus are common.
    • The interictal EEG is initially normal and then deteriorates to a nonspecific pattern of multifocal epileptiform discharges and multifocal or generalized slowing. A photoparoxysmal response may occur early in childhood. Ictal EEG findings depend on the seizure type. The ictal focus may shift during some seizures.
    • Most cases are associated with various mutations in the sodium channel gene SCN1A. Mutations in SCN1A may also be seen in other conditions; thus, it is not a specific finding. Neuroimaging is either normal or reveals nonspecific abnormalities.
    • As in the other epileptic encephalopathies, seizures are difficult to control. Lamotrigine and carbamazepine at times may exacerbate seizures. Phenobarbital, valproate, benzodiazepines, topiramate, bromides, and felbamate may be helpful. Stiripentol, in combination with valproate and clobazam, was efficacious in a randomized placebo-controlled study.25 The ketogenic diet may reduce seizures.
    • Development is normal initially, followed by regression occurring by the second or third year of life and progressing to a significant mental retardation. Cognition is severely affected, and most patients have motor and coordination dysfunction. In a series of patients followed into adulthood, approximately half had an IQ below 50.26 Seizures continue into adulthood, and mortality increases from epilepsy-related causes.
  • Myoclonic status in non-progressive encephalopathies
    • This rarely reported disorder has onset in infancy or early childhood, with onset usually during the first year of life.27 Seizures typically begin with partial motor seizures, although myoclonic status may occur at onset. Myoclonic absences, massive myoclonias, and rarely generalized or hemiclonic seizures may occur. Myoclonias may be multifocal and occur with startles. Myoclonic status epilepticus may be recurrent. Motor abnormalities and movement disorders are common.
    • The interictal EEG consists of multifocal epileptiform discharges and background slowing. Epileptiform discharges are potentiated in sleep, in some cases similar to an ESES pattern. Ictal EEG recording may demonstrate generalized slow spike and wave, or an absence pattern, depending on the seizure type.
    • A genetic cause is identifiable in approximately half of children, including Angelman syndrome and 4p- syndrome.27 Other reported causes include hypoxic-ischemic injury and cortical dysplasia.
    • Episodes of myoclonic status may respond to benzodiazepines. AEDs that may be efficacious include valproate with ethosuximide or clobazam.27
    • Children have a poor prognosis, experiencing developmental regression, and eventual severe mental retardation. The repeated episodes of myoclonic status may contribute to cognitive deterioration.
  • Myoclonic-astatic epilepsy (Doose syndrome)
    • Myoclonic-astatic epilepsy (MAE) is a rare syndrome occurring in early childhood, usually before age 5 years. Children are previously normal, and there is a slight male predominance to the syndrome. A history of febrile seizures or generalized epilepsy with febrile seizures "plus" (GEFS+) may be present.
    • Initial seizures are generalized tonic-clonic (GTC), followed by myoclonic seizures which increase in frequency. Frequent falls are characteristic and are due to either myoclonic, atonic, or a combination of myoclonic and atonic seizures. Multiple seizure types, including atypical absence and tonic seizures in addition to myoclonic, atonic, and GTC seizures, may occur. Nonconvulsive status epilepticus (NCSE) is common.
    • The EEG is initially normal or mildly abnormal, with worsening. Generalized spike and poly-spike wave discharges and excessive theta activity in the central-parietal regions, typically develop interictally. Myoclonic seizures demonstrate generalized spike or poly-spike wave discharges, and atonic seizures demonstrate poly-spike wave discharges with electromyogram (EMG) silence.
    • Most cases are idiopathic with normal neuroimaging. A genetic etiology has been hypothesized given it sometimes has an association with febrile seizures and GEFS+; however, no specific gene has been implicated.
    • AEDs effective in generalized epilepsies are the mainstay of treatment. Valproate is usually first-line treatment, with other options including lamotrigine, ethosuximide, levetiracetam, topiramate, zonisamide, and felbamate. Corticosteroids and IVIG may be helpful.28,29 Certain AEDs that may aggravated generalized or myoclonic epilepsies, such as carbamazepine, oxcarbazepine, vigabatrin, and tiagabine, and should be used cautiously. The ketogenic diet has also been helpful and should be considered.
    • The prognosis is variable and difficult to predict. After several years, the seizures may remit in 54-89%.30 The cognitive outcome ranges from no sequelae in most cases to progressive cognitive impairment in a minority. Approximately 18% may have a poor cognitive outcome.28 A family history of epilepsy and recurrent episodes of status epilepticus may portend a worse prognosis. Epilepsy longer than 3 years duration and nocturnal tonic seizures, characteristic of Lennox-Gastaut syndrome, may also suggest a worse prognosis in some patients.
  • Lennox-Gastaut syndrome (LGS)
    • Lennox-Gastaut syndrome (LGS) is a mixed seizure disorder with onset in early childhood and a very refractory course resulting in significant cognitive impairment. Onset is often before age 5 years.
    • The most commonly reported seizure types are tonic, atonic, and atypical absences. Myoclonic, GTC, and focal seizures may also occur. Seizures may begin with infantile spasms, which then evolve into multiple seizure types. Nocturnal tonic seizures are most characteristic, with atypical absences and atonic seizures also occurring in most patients. Tonic and atonic seizures may cause frequent falls and injury, resulting in the need for protective helmets for some patients. Seizures are very frequent, and episodes of convulsive and nonconvulsive status epilepticus are common.
    • The hallmark interictal EEG finding is generalized slow spike-wave discharges (usually 1.5-2 Hz), often with multifocal epileptiform discharges. Bursts of generalized fast spike discharges (approximately 10Hz) are common in sleep. (See Media file 1.) Ictal EEG findings depend on the seizure type captured. Tonic seizures demonstrate a diffuse electrodecrement pattern with superimposed low amplitude, fast spike discharges. A slow spike-wave pattern may be seen with atypical absences, and myoclonic seizures may have a diffuse spike or poly-spike wave pattern.
Epileptic and epileptiform encephalopathies. EEG ...

Epileptic and epileptiform encephalopathies. EEG showing an epileptiform beta frequency burst.

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Epileptic and epileptiform encephalopathies. EEG ...

Epileptic and epileptiform encephalopathies. EEG showing an epileptiform beta frequency burst.


    • From 70-78% of Lennox-Gastaut syndrome (LGS) cases are symptomatic, with a broad range of acquired and developmental etiologies described, including cerebral malformations, encephalitis, and hypoxic-ischemic injury.31 Development is often delayed in symptomatic cases, whereas development may be normal in idiopathic cases.
    • Seizures are typically medically refractory. Standard AEDs and infrequently used agents, such as felbamate, vigabatrin, and rufinamide, may be effective in Lennox-Gastaut syndrome. Immunomodulatory agents including ACTH, corticosteroids, and IVIG may be helpful. The ketogenic diet, vagus nerve stimulation, corpus callosotomy for atonic drop attacks, and less frequently focal resective surgery, may be beneficial.
    • The developmental outcome is poor. Symptomatic Lennox-Gastaut syndrome increases the risk of mental retardation, which is reported in up to 100% of symptomatic cases in long-term follow-up.32 Other factors increasing the risk of mental retardation include earlier age of onset and history of infantile spasms. Most patients continue having seizures. Early remission of epilepsy does not necessarily improve cognitive outcome.
  • Landau-Kleffner syndrome and epilepsy with continuous spikes-waves during slow sleep
    • Landau-Kleffner syndrome (LKS) is a rare epilepsy syndrome occurring in early childhood, with onset usually between 3 and 10 years of age.33 In 1957, Landau and Kleffner reported 6 children who presented with aphasia after apparently normal language acquisition. Since then, Landau-Kleffner syndrome (LKS) has been recognized as an epileptic syndrome characterized by language regression, an abnormal EEG, and absence of specific underlying brain pathology.
    • The disorder is more common in boys, and most children have previously normal development. Patients develop an acquired verbal auditory agnosia early in the course, mimicking difficulty hearing, or "word deafness". Aphasia and language regression follow, along with seizures and behavioral problems in most children. Most have normal preceding language development, and the loss of language function is considered to be secondary to the near continuous epileptiform discharges in the superior temporal gyrus and adjacent cortical areas. Behavioral problems reported include aggression, emotional lability, disinhibition, and hyperactivity.
    • Epilepsy with continuous spike-waves during slow sleep (CSWS) is a similarly rare epilepsy syndrome occurring in early childhood, with peak onset between 3 and 5 years.34 Most children have normal development and then develop more global cognitive impairment, in contrast to Landau-Kleffner syndrome (LKS), which primarily affects language; however, these syndromes are not always completely distinct, as overlap is seen in some cases. In CSWS, deficits in attention, language, memory, and visuo-spatial skills are reported. Similar to Landau-Kleffner syndrome, behavioral problems may occur, including aggression, emotional lability, disinhibition, and hyperactivity.
    • With Landau-Kleffner syndrome and CSWS, seizures may be either rare or very frequent and difficult to control. Multiple seizures types are characteristic. Atonic, absence, partial motor, and generalized convulsive seizures may occur.
    • The hallmark EEG finding of LKS and CSWS is electrical status epilepticus of sleep (ESES), consisting of near-continuous, diffuse, epileptiform discharges in non-REM sleep. (See Media file 2.) Often, multifocal and frequent epileptiform activity may also be present. (See Media file 3.)
EEG of a patient with Landau-Kleffner syndrome sh...

EEG of a patient with Landau-Kleffner syndrome showing electrical status epilepticus of sleep (ESES).

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EEG of a patient with Landau-Kleffner syndrome sh...

EEG of a patient with Landau-Kleffner syndrome showing electrical status epilepticus of sleep (ESES).


Epileptic and epileptiform encephalopathies. Waki...

Epileptic and epileptiform encephalopathies. Waking EEG in Landau-Kleffner syndrome, showing left posterior spikes.

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Epileptic and epileptiform encephalopathies. Waki...

Epileptic and epileptiform encephalopathies. Waking EEG in Landau-Kleffner syndrome, showing left posterior spikes.


    • These discharges are markedly sleep potentiated; however, epileptiform activity is often present in REM and waking as well. ESES was initially described as having an EEG spike wave quantity occupying 85% of non-REM sleep; however, this is not an absolute requirement as fewer discharges (perhaps 50% spike wave index of sleep) may result in cognitive deficits.35,36,37 The term ESES is somewhat misleading since the pattern is not a clear ictal pattern. However, it is believed to be more impairing than interictal activity in other disorders, thus representing a gray zone between the ictal and interictal states. Ictal EEG findings depend upon the seizure type recorded.
    • In Landau-Kleffner syndrome (LKS), the ESES discharges tend to be more posteriorly predominant (temporal or temporal-occipital), whereas in CSWS, fronto-temporal or centro-temporal discharges are more common. In CSWS, fronto-temporal discharges result in more executive function impairment and autistic behaviors, while a more central EEG focus (posterior frontal lobe involvement) may result in more motor impairment, including dyspraxia, dystonia, and ataxia. As in Landau-Kleffner syndrome (LKS), the frequent epileptiform discharges contribute to the cognitive impairments seen. The ictal EEG pattern depends upon the seizure type captured.
    • Most cases of Landau-Kleffner syndrome are idiopathic with normal neuroimaging; however, volumetric MRI analysis has revealed decreased volume in bilateral superior temporal gyrus and planum temporale in studied cases.38 Symptomatic cases of LKS and CSWS are described and are likely more common in CSWS.
    • In LKS and CSWS, there appears to be a close temporal association between the onset and resolution of the ESES and the cognitive impairment. As well, a longer duration of ESES may result in more severe impairment; thus, treatment is often aimed at improving the ESES pattern, in addition to controlling seizures. Standard AEDs with the ability to suppress epileptiform activity, including valproic acid, levetiracetam, lamotrigine, and benzodiazepines, may be helpful. Other medications that may be efficacious include ethosuximide, sulthiame, corticosteroids, higher doses of benzodiazepines, and IVIG. (See Media file 4.) The ketogenic diet may help, and, in select patients, multiple subpial transections, a surgical procedure meant to disrupt propagation of epileptiform activity, may be beneficial. Intensive developmental supports must also be provided.


Epileptic and epileptiform encephalopathies. EEG ...

Epileptic and epileptiform encephalopathies. EEG in Landau-Kleffner syndrome (LKS), before and after treatment with prednisone. The left EEG tracing shows electrical status epilepticus of sleep. The right tracing, obtained after 6 months of prednisone treatment, is normal.

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Epileptic and epileptiform encephalopathies. EEG ...

Epileptic and epileptiform encephalopathies. EEG in Landau-Kleffner syndrome (LKS), before and after treatment with prednisone. The left EEG tracing shows electrical status epilepticus of sleep. The right tracing, obtained after 6 months of prednisone treatment, is normal.


    • The prognosis is variable. The epilepsy and ESES pattern improve and may remit after several years, whereas most children are left with varying degrees of language and cognitive dysfunction. Neuropsychological assessments should be performed in order to gauge developmental progress and the effect of treatments over time.
Syndromes Sometimes Associated With Epileptiform Encephalopathy
  • Benign childhood epilepsy with centro-temporal spike discharges (benign rolandic epilepsy)
    • Benign rolandic epilepsy (BRE) is the most common epilepsy syndrome of childhood and has a peak onset between 7 and 10 years of age, with resolution by adolescence. The most common seizures are brief partial motor seizures involving the face and pharyngeal muscles, usually occurring at night. A tendency toward secondary generalized tonic-clonic seizures also exists. A genetic etiology is suspected, and recent work has implicated that mutation of the Elongator Protein Complex 4 may confer genetic susceptibility.39 The interictal EEG pattern is characterized by frequent, sleep potentiated, bilateral or unilateral centro-temporal sharp or spike-wave discharges. The EEG pattern may be seen in the absence of clinical seizures and is then termed the BRE trait.
    • Most children are developmentally normal and do not exhibit any obvious problems. However, a subset of children does experience cognitive impairment. An abundance of literature on benign rolandic epilepsy (BRE) has described a variety of neuropsychological deficits, however, with no uniform profile of impairment identifiable and variable study methodologies. Bilateral rolandic EEG discharges are associated with poorer cognitive function than unilateral discharges. Left hemisphere discharges have also been associated with verbal problems, while right hemisphere discharges have been associated with nonverbal difficulties.
    • Unfortunately, few studies have attempted to correlate EEG abnormalities, including spike discharge frequency, with neuropsychological deficits. EEG findings that have been correlated with cognitive problems include a high awake or sleep spike index and intermittent EEG slowing.40,41,42,43,44,45 However, further investigations are needed to clarify these relationships and better define this aspect of this syndrome.
  • Autistic regression with epileptiform EEG findings
    • An increased risk of epilepsy is associated with autism, but the role of epilepsy in this disorder remains unclear. In most autistic children, including the approximately one third with developmental regression, epilepsy does not play an obvious role in their symptoms. In children with autism, there is no difference in the incidence of regression between children with and without epilepsy, suggesting that epilepsy does not increase the risk of regression in autism.46 Epilepsy is present in up to 38% of autistic children and more may have epileptiform abnormalities present on their EEG.47
    • Epilepsy may aggravate autistic symptoms and interfere with developmental progress, independent of autism in some children; however, it is unclear if it is causative. In some conditions such as tuberous sclerosis or LKS, children may have some autistic features, though they usually do not meet full criteria for autism overtime. Proposed explanations for the coexistence of autism and epilepsy include the following: (1) they are independent conditions, (2) the same underlying pathology results in an autistic phenotype and epilepsy, (3) an epileptic process in early development impair the normal formation of networks involved in social skills and communication, (4) a focal brain lesion affecting the frontal or limbic system may result in an autistic phenotype and the potential for epilepsy, and (5) epilepsy may result in cognitive dysfunction and an "autistic withdrawal" in "vulnerable" children.48
Summary

The epileptic encephalopathies are a group of age-specific epilepsy syndromes of diverse etiologies sharing the potential for significant cognitive impairment. The reasons for developmental deterioration are multifactorial. Potential factors include the underlying etiology, AED adverse effects, recurrent clinical and subclinical seizures or status epilepticus, and interictal epileptiform discharges and slowing on EEG. Vigilance in monitoring baseline and progression of cognitive status in these disorders is required to gauge the effects of treatment on cognition.

The degree of correlation between EEG abnormalities and neuropsychological deficits requires better description in most of these syndromes. However, often a goal of treatment is to improve the EEG while monitoring for concurrent cognitive improvement to confirm that treatment is indeed worthwhile. Potential etiologies, including structural and metabolic disorders, must be thoroughly investigated. Treatment options generally include standard AEDs, in addition to corticosteroids, IVIG, ketogenic diet, vagus nerve stimulation, and epilepsy surgery in select cases. Judicious use of AEDs, which may aggravate seizures and status epilepticus, and monitoring for these adverse effects, may also limit worsening of cognitive function.

More on Epileptic and Epileptiform Encephalopathies

Overview: Epileptic and Epileptiform Encephalopathies
Differential Diagnoses & Workup: Epileptic and Epileptiform Encephalopathies
Treatment & Medication: Epileptic and Epileptiform Encephalopathies
Follow-up: Epileptic and Epileptiform Encephalopathies
Multimedia: Epileptic and Epileptiform Encephalopathies
References
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Further Reading

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Keywords

epileptic encephalopathy, epileptic encephalopathies, epileptiform encephalopathy, epileptiform encephalopathies, catastrophic epilepsy, catastrophic epilepsies, epileptiform aphasia, malignant epilepsy, malignant epilepsies, early myoclonic encephalopathy, early infantile epileptic encephalopathy, Ohtahara syndrome, migrating partial epilepsy, migrating partial epilepsy in infancy, West syndrome, infantile spasms, severe myoclonic epilepsy in infancy, Dravet syndrome, myoclonic status, myoclonic status in non-progressive syndromes, myoclonic astatic epilepsy, Doose syndrome, Lennox-Gastaut syndrome, Landau-Kleffner syndrome, LKS, acquired epileptiform aphasia, verbal auditory agnosia, language regression, word deafness, continuous spikes and waves during slow wave sleep, electrical status epilepticus of sleep, autism, autistic spectrum disorders, pervasive development disorder, PDD, transient cognitive impairment, benign childhood epilepsy with centro-temporal spikes, BCECTS, benignrolandic epilepsy

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Contributor Information and Disclosures

Author

Dean Patrick Sarco, MD, Instructor, Department of Neurology, Harvard Medical School; Assistant Physician, Department of Neurology, Division of Epilepsy and Clinical Neurophysiology, Children's Hospital Boston
Dean Patrick Sarco, MD is a member of the following medical societies: American Academy of Neurology, American Epilepsy Society, and Child Neurology Society
Disclosure: Nothing to disclose.

Coauthor(s)

Masanori Takeoka, MD, Assistant Professor, Department of Neurology, Harvard Medical School; Consulting Staff, Department of Neurology, Division of Epilepsy and Clinical Neurophysiology, Children's Hospital Boston
Masanori Takeoka, MD is a member of the following medical societies: American Academy of Neurology, American Epilepsy Society, American Medical Association, Child Neurology Society, and Massachusetts Medical Society
Disclosure: Nothing to disclose.

Medical Editor

Robert Baumann, MD, Program Director, Professor, Departments of Neurology and Pediatrics, University of Kentucky
Robert Baumann, MD is a member of the following medical societies: American Academy of Neurology, American Academy of Pediatrics, American College of Epidemiology, American Epilepsy Society, and Child Neurology Society
Disclosure: Nothing to disclose.

Pharmacy Editor

Francisco Talavera, PharmD, PhD, Senior Pharmacy Editor, eMedicine
Disclosure: eMedicine Salary Employment

Managing Editor

Jose E Cavazos, MD, PhD, FAAN, Associate Professor with Tenure, Departments of Neurology, Pharmacology, and Physiology, University of Texas Health Science Center at San Antonio; Co-Director, South Texas Comprehensive Epilepsy Center; Director of the Epilepsy Center, Audie L Murphy Veterans Affairs Medical Center
Jose E Cavazos, MD, PhD, FAAN is a member of the following medical societies: American Academy of Neurology, American Clinical Neurophysiology Society, American Epilepsy Society, and Society for Neuroscience
Disclosure: Nothing to disclose.

CME Editor

Selim R Benbadis, MD, Professor, Director of Comprehensive Epilepsy Program, Departments of Neurology and Neurosurgery, University of South Florida School of Medicine, Tampa General Hospital
Selim R Benbadis, MD is a member of the following medical societies: American Academy of Neurology, American Academy of Sleep Medicine, American Clinical Neurophysiology Society, American Epilepsy Society, and American Medical Association
Disclosure: Nothing to disclose.

Chief Editor

Amy Kao, MD, Assistant Professor, Department of Pediatrics, Division of Pediatric Neurology, Department of Neurology, Oregon Health and Science University; Consulting Staff, Shriners Hospital for Children
Amy Kao, MD is a member of the following medical societies: American Academy of Neurology, American Academy of Pediatrics, American Epilepsy Society, and Child Neurology Society
Disclosure: Nothing to disclose.

 
 
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