Epileptic and Epileptiform Encephalopathies 

Updated: Jul 26, 2022
Author: Masanori Takeoka, MD; Chief Editor: Stephen L Nelson, Jr, MD, PhD, FAACPDM, FAAN, FAAP, FANA 

Overview

Background

The term epileptic encephalopathy describes a heterogeneous group of epilepsy syndromes associated with severe cognitive and behavioral disturbances. These disorders vary in their age of onset, developmental outcome, etiologies, neuropsychological deficits, electroencephalographic (EEG) patterns, seizure types, and prognosis, but all may have a significant impact on neurological development.[1, 2]

In 2001, 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, recognized epileptic encephalopathies as a distinct category.[3, 4]

The ILAE defined an epileptic encephalopathy as a condition in which "the epileptiform EEG abnormalities themselves are believed to contribute to a progressive disturbance in cerebral function."

Later in 2010, researchers defined epileptic encephalopathy as a condition where the epileptic activity itself may contribute to severe cognitive and behavioral impairments above and beyond what might be expected from the underlying pathology alone (e.g., cortical malformation), and that these can worsen over time.[5]

This category includes the following epilepsy syndromes:

  • Early myoclonic encephalopathy (EME)

  • Early infantile epileptic encephalopathy (EIEE/Ohtahara syndrome)

  • Infantile Spasm (West Syndrome)

  • Dravet syndrome (severe myoclonic epilepsy in infancy; SMEI) 

  • Malignant epilepsy with migrating partial seizures in infancy

  • Doose syndrome (myoclonic astatic epilepsy)

  • Myoclonic status in nonprogressive encephalopathies

  • Lennox-Gastaut syndrome (LGS)

  • Landau-Kleffner syndrome (LKS)

  • Epilepsy with continuous spike-waves during slow sleep (CSWS)

  • Rasmussen's encephalitis

Because this concept is evolving, this listing is not definitive; other epilepsy syndromes, such as some cases of benign focal childhood epilepsy with centro-temporal spikes (benign rolandic epilepsy) and autism with epileptiform EEG abnormalities, may also fit under this rubric.[6] These 2 conditions are not currently considered epileptic encephalopathies, but there is increasing evidence that epilepsy or epileptiform activity may contribute to encephalopathy in a subset of cases.

"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. In contrast, the term epileptiform encephalopathies describes those conditions in which the interictal epileptiform EEG abnormalities may be more prominent than the clinical seizures.

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.[7] 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 (see image below).

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

In clinical practice, the ability to distinguish between epileptiform activity and an epileptic disorder 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 LKS).

The quantity of epileptiform activity does not correlate well with seizure severity. However, 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. (See Treatment and Management, as well as Medications.)

At this time, it remains unclear how much of the dysfunction seen in these disorders is due to epileptiform EEG activity and how much is due to the underlying cause of the epilepsy syndrome. Consequently, a useful guideline is to "treat the patient, 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.

For more information, see Epilepsy and Seizures and First Pediatric Seizure.

Terminology and definitions

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

Epileptic denotes the presence of epilepsy.

Epileptic seizure is a clinical event associated with a transient, hypersynchronous neuronal discharge and represents only the symptom of a potential underlying brain pathology, not the actual disease.

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

Epileptiform 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 is 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.

Although the term epileptic aphasia has been used for 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.

Pathophysiology

The epileptic encephalopathies are a group of age-specific epilepsy syndromes of diverse etiologies that share the potential for causing significant cognitive impairment. 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 include the following:

  • 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

  • Genetic factors

Electrical dysfunction

It remains unclear how much electrical dysfunction contributes to the neuropsychological impairments seen in these disorders. 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.[8, 9]

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 CSWS; however, further studies are required to better quantify and characterize the evolution of these deficits with the various potential contributing factors. This characterization is complicated by the fact that evaluating subtle cognitive impairments from the involvement of noneloquent cortex requires testing of performance.

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.[10, 11, 12, 13, 14, 15, 16] Although challenging to demonstrate, this phenomenon 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 postictal states, which may last from minutes to days, depending in part on the severity of the seizure and the patient’s cognitive reserve. More chronic, potentially reversible dysfunction may also be seen, such as in the subset of children with benign focal epilepsy of childhood with centro-temporal spike discharges (BECTS) who demonstrate a variety of neuropsychological deficits that may be reversible.[17, 18, 19]

More chronic and permanent impairment may be seen in more severe disorders, such as LGS. The more severe epileptic encephalopathies fall into this category.

Epileptiform activity during sleep

In epileptic or epileptiform encephalopathies, ictal and/or interictal epileptiform activity often becomes more frequent during sleep.[20] When discharges are present in the awake state, this is termed sleep potentiation. If discharges are present only during sleep, this is termed sleep activation.

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, as follows, still await an answer:

  • What are the mechanisms involved in the generation of such significant, interictal, sleep activation?

  • 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 CSWS. Secondary bilateral synchrony, which 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.[21, 22, 23]

Thalamic injury

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.[24]

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. Patients in the second group had a typical asymmetry of spike and waves and the presence or reduction of spindles, plus other atypical features concerning synchronism and morphology of spike and waves.[24]

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.[24]

A case-control study was performed on early developmental lesions in children with clinical presentation consistent with CSWS, and prominent sleep-potentiated epileptiform activity. The study compared 100 children with such prominent sleep potentiated epileptiform activity (>50% spike percentage) to 47 children without such EEG findings. The children who had the prominent sleep potentiated spikes had a higher rate of having early brain injury, in particular early thalamic injury.[25]

Etiology

The causes of epileptic encephalopathy vary among the different syndromes.

Early myoclonic encephalopathy

The etiology is often unknown. Metabolic disorders, including nonketotic hyperglycinemia, have been described in early myoclonic encephalopathy and should be pursued. Structural lesions are rare.

Infantile spasms (West syndrome)

No clear etiology is found in approximately 40% of cases.[26] There is a broad range of potential causes, including cerebral malformations, infection, hemorrhage, hypoxic-ischemic injury, metabolic disorders, and genetic conditions (eg, Down syndrome).

Malignant epilepsy with migrating partial seizures in infancy

In most cases, there is no clear etiology or structural problems, suggesting genetic factors may be causative or contributory.

Severe myoclonic epilepsy of infancy (Dravet syndrome)

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.[27]

Myoclonic status in nonprogressive encephalopathies

A genetic cause is identifiable in approximately half of children, including Angelman syndrome and 4p- syndrome.[28] Other reported causes include hypoxic-ischemic injury and cortical dysplasia.

Myoclonic-astatic epilepsy (Doose syndrome)

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.

Lennox-Gastaut syndrome (LGS)

A broad range of acquired and developmental etiologies have been described, including cerebral malformations, encephalitis, and hypoxic-ischemic injury.[29]

Landau-Kleffner syndrome and epilepsy with continuous spikes-waves during slow sleep

Most cases of Landau-Kleffner syndrome are idiopathic, with normal results on neuroimaging; however, volumetric MRI analysis has revealed decreased volume in bilateral superior temporal gyrus and planum temporale in studied cases.[30] Symptomatic cases of LKS and CSWS are described and are likely more common in CSWS.

Benign childhood epilepsy with centro-temporal spike discharges (benign rolandic epilepsy)

A genetic etiology is suspected, and recent work has implicated that mutation of the Elongator Protein Complex 4 may confer genetic susceptibility.[31]

Autistic regression with epileptiform EEG findings

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 (eg, tuberous sclerosis, LKS), children may have some autistic features, though they usually do not meet full criteria for autism over time.

Proposed explanations for the coexistence of autism and epilepsy include the following:

  • They are independent conditions

  • The same underlying pathology results in an autistic phenotype and epilepsy

  • An epileptic process in early development impair the normal formation of networks involved in social skills and communication

  • A focal brain lesion affecting the frontal or limbic system may result in an autistic phenotype and the potential for epilepsy

  • Epilepsy may result in cognitive dysfunction and an "autistic withdrawal" in "vulnerable" children[32]

Epidemiology

In a 20-year epidemiological study of childhood epilepsy syndromes from Tel Aviv, Kramer et al reported the following distribution of epileptic encephalopathy cases[33] :

  • West syndrome - 9% of childhood epilepsy cases

  • Myoclonic seizures - 2.2%

  • Lennox-Gastaut syndrome - 1.5%

  • LKS, Ohtahara syndrome, myoclonic astatic epilepsy, and ESES - 0.2% each

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

Prognosis

The prognosis is related to the underlying disorder. The severity of developmental impairment varies with the type of epilepsy.

Early infantile epileptic encephalopathy (Ohtahara syndrome)

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

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.[34]

Infantile spasms (West syndrome)

Development remains unaffected only in a minority. Most children experience slowing, plateauing, or regression of their developmental trajectory. An extensive literature review revealed that 16% of patients had normal development and 47% had continued seizures at an average follow-up of 31 months.[26] No specific AED has been shown to affect long-term developmental outcome.

The developmental prognosis partially depends on the etiology. 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

Developmental regression is common. Death has been reported in infancy and childhood in severe cases.

Severe myoclonic epilepsy of infancy (Dravet syndrome)

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.[35] Seizures continue into adulthood, and mortality increases from epilepsy-related causes.

Myoclonic status in nonprogressive encephalopathies

Affected 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)

The prognosis is variable and difficult to predict. After several years, the seizures may remit in 54-89% of patients.[36] 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.[37]

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)

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.[38] 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

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.

Benign childhood epilepsy with centro-temporal spike discharges (benign rolandic epilepsy)

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, but 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.[19, 39, 40, 41, 42, 43] However, further investigations are needed to clarify these relationships and better define this aspect of this syndrome.

Patient Education

Input from a neurologist, developmental pediatrician, psychologist, neuropsychologist, audiologist, or speech pathologist is needed to determine the proper educational program.

For patient education information, see the Brain and Nervous System Center, as well as Epilepsy.

 

Presentation

History

The history in patients with epileptic encephalopathy varies with the specific syndrome.

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.[34]

Most children are symptomatic from structural brain abnormalities such as cerebral dysgenesis, although metabolic disorders are also reported.[44]

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 from EIEE, in which tonic seizures appear early.

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 hypsarrhythmia 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.

Malignant epilepsy with migrating partial seizures in infancy

Onset of this rare syndrome occurs in the first year of life, in some cases 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 nearly continuous.

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 occur when the patient is 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.

Myoclonic status in nonprogressive encephalopathies

This rarely reported disorder has onset in infancy or early childhood, with onset usually during the first year of life.[28] 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.

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 that increase in frequency. Frequent falls are characteristic and are due to myoclonic or atonic seizures or both. 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.

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.

A broad range of acquired and developmental etiologies has been described, including cerebral malformations, encephalitis, and hypoxic-ischemic injury.[29] From 70-78% of LGS cases are symptomatic (ie, have an identified cause). Development is often delayed in symptomatic cases, whereas development may be normal in idiopathic cases.

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.[45] It was first described in 1957, when Landau and Kleffner reported on 6 children who presented with aphasia after apparently normal language acquisition. Since then, 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), like LKS, is a rare epilepsy syndrome occurring in early childhood. Peak onset is between 3 and 5 years of age.[46] Most children have normal development until the syndrome manifests. In contrast to LKS, which primarily affects language, children with CSWS develop more global cognitive impairment.

CSWS and LKS are not always completely distinct; overlap is seen in some cases. In CSWS, deficits in attention, language, memory, and visuospatial skills are reported. As in LKS, behavioral problems may occur, including aggression, emotional lability, disinhibition, and hyperactivity.

With LKS 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.

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.

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.[47] Epilepsy is present in up to 38% of autistic children and more may have epileptiform abnormalities present on their EEG.[48]

Physical Examination

A thorough general and neurological evaluation may aid in identifying a specific underlying etiology; however, findings may be normal in some cases. An evaluation by a geneticist may be useful when dysmorphic features are present.

Complications

The complications of epileptic and epileptiform encephalopathies usually are secondary to the treatment, especially with antiepileptic drugs (AEDs) or high-dose steroids. However, the psychiatric and psychological problems associated with a neurological handicap, especially a neurodegenerative process, can have a great impact on both the child and the family. In LKS and some cases of CSWS, behavioral and emotional disturbances are the major problems encountered.

 

DDx

Diagnostic Considerations

In any neurological disorder, determining the etiology is important, since specific etiologies may require specific treatments. Excluding an underlying structural or metabolic disorder is especially important when regression in intellectual or motor milestones has occurred. A thorough evaluation, including appropriate laboratory studies, neuroimaging, and consultations, should be performed as indicated by the history and examination.

Differential Diagnoses

 

Workup

Approach Considerations

Genetic and metabolic testing should be guided by the clinical scenario. No specific testing can be recommended for all cases, given the variability between these disorders. A more aggressive search is usually undertaken when development is slowing, plateauing, or regressing.

Studies to be considered include EEG monitoring, potentially with video to characterize seizures, and magnetic resonance neuroimaging. Every effort should be made to characterize a patient's epilepsy syndrome so that a more focused evaluation may be undertaken.

Genetic and Metabolic Testing

Testing for specific conditions, particularly treatable ones, should always be performed. Many genetic and metabolic conditions, however, may have similar or nonspecific presentations. Thus, screening metabolic studies may be considered, including the following:

  • Complete blood count

  • Electrolytes, glucose

  • Hepatic enzymes

  • Creatine kinase

  • Lactic acid

  • Pyruvic acid

  • Serum amino acids

  • Urine organic acids

  • Endocrine tests

  • Cerebrospinal fluid evaluation

Screening genetic studies to consider would include karyotype, fragile X testing, and chromosomal microarray analysis. When a specific condition is suspected, testing specific to that condition should be performed because screening studies may be inconclusive, potentially more costly, and less sensitive, depending on the condition suspected. There are targeted epilepsy gene panels that may provide more specific diagnosis when there are specific pathological genetic variants in consideration (e.g., Dravet syndrome; SCN1A and other pathological genetic variants have been associated with this syndrome).

When indicated, consultation with a geneticist may aid in diagnosis.

Neuroimaging

In general, neuroimaging is necessary when evidence of focality is noted on either the clinical examination or the EEG. MRI, preferably at least 1.5-Tesla strength, is recommended. CT imaging may be useful in specific cases, such as when calcification may help clarify a diagnosis.[49]

When epilepsy surgery is a consideration, functional neuroimaging studies may be useful. These include single-photon emission computed tomography (SPECT) and positron emission tomography (PET) scans. SPECT measures cerebral blood flow, and PET measures cerebral metabolism.

Magnetoencephalography (MEG) detects the magnetic field of epileptic discharges, which are superimposed on MR imaging. EEG abnormalities from deeper cortical areas such as language cortex may not reach the surface; therefore, the EEG could potentially be unremarkable, whereas MEG can detect the discharges.

Electroencephalography

Epileptiform activity may occur only in sleep; therefore, an EEG obtained only in the awake state is considered incomplete. Long-term EEG monitoring (24-h EEG) is considered the best study, but may not be necessary if marked epileptiform activation is seen during sleep, in the routine EEG (eg, electrical status epilepticus of sleep [ESES]). A prolonged EEG may capture a suspicious clinical event, such as a staring spell, and help determine whether it is an actual seizure.

The advantage of quantified EEG (QEEG) with spike localization and steady-state frequency-modulated auditory-evoked response (FMAER) is that spike localization techniques may better map the exact location of the discharge. Steady-state FMAER tests reflect response from the auditory association cortex involved in receptive language function. See the image below.

Epileptic and epileptiform encephalopathies. Frequ Epileptic and epileptiform encephalopathies. Frequency-modulated auditory evoked response (FMAER), before and after treatment with prednisone. The left FMAER is absent. The right FMAER is normal following treatment.

Early infantile epileptic encephalopathy (Ohtahara syndrome)

Interictal EEG reveals a suppression-burst pattern during wakefulness 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.[50]

Early myoclonic encephalopathy

The interictal EEG reveals a burst-suppression pattern more pronounced in sleep, with longer periods of diffuse voltage suppression lasting up to 10 seconds.[34] The EEG may evolve to hypsarrhythmia or multifocal spike discharges and may then return to a suppression-burst pattern afterwards.

Infantile spasms (West syndrome)

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).

Malignant epilepsy with migrating partial seizures in infancy

The interictal EEG reveals multifocal epileptiform activity and slowing. The ictal EEG confirms multifocal onsets, which may shift from seizure to seizure.

Severe myoclonic epilepsy of infancy (Dravet syndrome)

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.

Myoclonic status in nonprogressive encephalopathies

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.

Myoclonic-astatic epilepsy (Doose syndrome)

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.

Lennox-Gastaut syndrome (LGS)

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 10 Hz) are common in sleep (see the image below).

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

Landau-Kleffner syndrome and epilepsy with continuous spikes-waves during slow sleep

The hallmark EEG finding of Landau-Kleffner syndrome (LKS) and continuous spikes-waves during slow sleep (CSWS) is ESES, consisting of near-continuous, diffuse, epileptiform discharges in non-REM sleep (see the first image below). Often, multifocal and frequent epileptiform activity may also be present (see the second image below).

EEG of a patient with Landau-Kleffner syndrome sho EEG of a patient with Landau-Kleffner syndrome showing electrical status epilepticus of sleep (ESES).
Epileptic and epileptiform encephalopathies. Wakin 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 during rapid eye movement (REM) sleep and waking as well. ESES was initially described as having an EEG spike wave quantity occupying 85% of non-REM sleep; this is not an absolute requirement, however, as fewer discharges (perhaps 50% spike wave index of sleep) may result in cognitive deficits.[51, 52, 53]

The term ESES is somewhat misleading, since the pattern is not a clear ictal pattern. However, it is believed to cause more impairment 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 LKS, the ESES discharges tend to be more posteriorly predominant (temporal or temporal-occipital), whereas in CSWS, frontotemporal or centrotemporal discharges are more common. In CSWS, frontotemporal 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 LKS, the frequent epileptiform discharges contribute to the cognitive impairments seen. The ictal EEG pattern depends upon the seizure type captured.

Benign focal epilepsy of childhood with centro-temporal spike discharges (benign rolandic epilepsy)

The interictal EEG pattern is characterized by frequent, sleep-potentiated, bilateral or unilateral, centrotemporal, sharp or spike-wave discharges. The EEG pattern may be seen in the absence of clinical seizures and is then termed the benign rolandic epilepsy (BRE) trait.

For more information, see Epileptiform Normal Variants on EEG, Generalized Epilepsies on EEG, Localization-RelatedEpilepsies on EEG, EEG in Common Epilepsy Syndromes, and EEG in Status Epilepticus.

Neuropsychological Examination

Preservation of nonverbal skills is an important diagnostic feature of LKS and may help differentiate LKS from other disorders, including autism.

 

Treatment

Approach Considerations

The treatment approaches to all epileptic and epileptiform encephalopathies share some similarity. Early diagnosis and initiation of treatment appear to be important in achieving better long-term prognosis. Notably, for most of these disorders, there are no controlled clinical trials investigating the therapeutic options, and only open-label data are available.

In general, antiepileptic drugs (AEDs) that are considered "spike suppressors" such as valproic acid, benzodiazepines, ethosuximide, levetiracetam, and lamotrigine may be preferable. AEDs must be used judiciously, as they may aggravate seizures and status epilepticus or worsen cognitive function.

Additionally, adrenocorticotropic hormone (ACTH) or corticosteroids may be used, usually after standard AEDs have failed. A ketogenic diet and intravenous immunoglobulin (IVIG) may also be helpful. Vagus nerve stimulation and epilepsy surgery may be appropriate in select cases.

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.

Vigilance in monitoring baseline and progression of cognitive status in these disorders is required to gauge the effects of treatment on cognition.

The evaluation and management of epileptic and epileptiform encephalopathies usually are performed on an outpatient basis. However, the initial long-term EEG and evaluation may be performed in the hospital. Patients with intractable seizures may need hospitalization at times for seizure control.

Related practice parameters, treatment guidelines, and diagnostic criteria are available from the American Academy of Neurology, Child Neurology Society, and American Epilepsy Society[54] and the American College of Radiology.[55]

Go to Epilepsy and Seizures and Antiepileptic Drugs for complete information on these topics.

Early Infantile Epileptic Encephalopathy (Ohtahara Syndrome)

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.

Early Myoclonic Encephalopathy

Seizures are intractable to medical treatment, including standard anticonvulsants and corticosteroids, although these are often tried. A ketogenic diet may be helpful.[56]

Infantile Spasms (West Syndrome)

Variation in study methodologies prohibits a clear recommendation for first-line treatment; however, ACTH and vigabatrin are usually used in practice.

There is no consensus on ACTH dosing for infants. In infantile spasms, a prospective single-blind study showed no difference in the effectiveness of high-dose, long-duration corticotropin (150 U/m2/d for 3 wk then taper over 9 wk) versus low-dose, short-duration corticotropin (20-30 U/d for 2-6 wk then taper over 1 wk) with respect to spasm cessation and improvement in patient's EEG; hypertension was more common with larger doses.

Corticosteroids may be effective, but less so than ACTH. However, few comparative studies have been performed between ACTH and prednisone. Vigabatrin may be more effective in tuberous sclerosis. Vigabatrin is approved by the FDA as monotherapy for children aged 1 month to 2 years with infantile spasms. Other useful agents 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.

Malignant Epilepsy with Migrating Partial Seizures in Infancy

Seizures in these patients are often difficult to control with standard AEDs. Bromides, stiripentol, and clonazepam may be helpful in some cases.

Severe Myoclonic Epilepsy of Infancy (Dravet Syndrome)

As in the other epileptic encephalopathies, seizures are difficult to control. Lamotrigine and carbamazepine at times may exacerbate seizures. Phenobarbital, valproate, benzodiazepines, and bromides may be helpful. Stiripentol, in combination with valproate and clobazam, was efficacious in a randomized placebo-controlled study.[57]  Stiripentol gained FDA approval for treatment of seizures associated with Dravet syndrome in patients aged 6 months and older who are taking clobazam. 

Cannabidiol (Epidiolex) have been approved by the FDA for seizures associated with LGS in children aged 1 year and older. Felbamate, rufinamide, and topiramate have gained approval as adjunctive therapy for LGS in young children. 

The ketogenic diet may reduce seizures.

Myoclonic Status in Nonprogressive Encephalopathies

Episodes of myoclonic status may respond to benzodiazepines. AEDs that may be efficacious include valproate with ethosuximide or clobazam.[28]

Myoclonic-astatic epilepsy (Doose syndrome)

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.[37, 58]

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.

Lennox-Gastaut syndrome (LGS)

Seizures are typically medically refractory. Standard AEDs and infrequently used agents, such as felbamate, vigabatrin, and rufinamide, may be effective in LGS. Immunomodulatory agents, including ACTH, corticosteroids, and IVIG, may be helpful. Rufinamide (Banzel) and cannabidiol (Epidiolex) have been approved by the FDA for seizures associated with LGS in patients aged 1 year and older. Clobazam is indicated for adjunctive treatment of LGS in patients aged 2 years and older. 

The ketogenic diet; vagus nerve stimulation; corpus callosotomy for atonic drop attacks; and, less frequently, focal resective surgery, may be beneficial.

Landau-Kleffner syndrome and epilepsy with continuous spikes-waves during slow sleep

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 the image below).

Epileptic and epileptiform encephalopathies. EEG i 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 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.

In their original paper, Landau and Kleffner discerned a relationship between treatment with AEDs and improvement in the aphasia.[59] In 1967, Deuel and Lenn reported a case with a clear relationship between AED treatment and language improvement, and subsequent reports have been published of improvement with various anticonvulsants.[60] No data exist that support the use of any one AED, and whether any one anticonvulsant is better than others is unclear. Treatment is similar for the syndrome of continuous spikes and waves during sleep.

Aeby et al treated 12 children with behavioral and/or cognitive deterioration associated with continuous spike-waves during slow wave sleep (CSWS) with levetiracetam 50 mg/kg/day as add-on treatment.[61] They found that levetiracetam had a positive effect on the EEG, behavior, and cognition. High-dose pulse diazepam therapy also has been effective, according to De Negri et al, especially in cryptogenic cases.[62] Rectal diazepam, dosed at up to 1 mg/kg qhs, followed by a gradual taper over months, has been reported to help in some children.[63]

Marescaux et al reported mixed results with valproic acid treatment for 5 patients with LKS.[64] In the first patient, comprehension and oral expression improved slightly during the first 2 months of treatment, concomitant with disappearance of spike and wave discharges for 3 months, but then the spike and wave discharges recurred. In their third patient, the spike and wave duration in sleep decreased from 80% to 45%. Treatment had no effect on behavior abnormalities, speech, or intellect in 4 of the children.

Both ACTH and prednisone have been used. In 1974, McKinney and McGreal reported that 3 children with LKS treated with steroids had improvement, whereas only 1 of 6 in those who were not treated had improvement.[45]

Subsequently, it was reported that the rapidity of the response and the resultant neurological sequelae depend on the duration and severity of the symptoms before treatment, that initial high steroid doses were more effective, and that brief periods of steroid treatment appeared ineffective or led to a high rate of relapse.[64, 65]

Current treatment protocols vary. Options include either a short or long course of steroids as well as low or higher dosages. It has been proposed that a longer course may prevent relapse.

Chez et al have advocated the use of pulse prednisone therapy, which achieves the therapeutic benefits while markedly reducing the adverse corticosteroid effects.[66] The daily dose is calculated and then converted to a weekly dose.

Tsuru et al successfully treated 2 children with LKS with antiepileptic drugs and a high-dose intravenous corticosteroid.[67] Epileptic seizures and EEG abnormalities were improved on a combination of valproate and a benzodiazepine, but speech disturbances persisted.

Both patients were treated with an intravenous infusion of high-dose methylprednisolone (20 mg/kg daily) for 3 consecutive days. The infusion was repeated 3 times with a 4-day interval between treatments, which resulted in a rapid improvement in speech ability. After intravenous therapy, prednisolone was given orally (2 mg/kg daily for 1 month, then gradually withdrawn), which maintained the clinical improvement in speech.

Sinclair and Snyder reported prolonged benefit with prednisone (1 mg/kg/d for 6 months) in 8 patients with LKS and in 2 patients with CSWS.[68] All but one patient manifested significant improvement in language, cognition, and behavior, which continued after the corticosteroid trial. Mean yearly follow-up was 4 years. Side effects were few and reversible, and benefits appeared to be long lasting.

CDKL5 Deficiency Disorder

Cyclin-dependent kinase-like 5 (CDKL5) deficiency disorder (CDD) is a rare developmental epileptic encephalopathy caused by mutations in the CDKL5 gene. 

Ganaxolone is a GABAA receptor positive modulator. It binds specifically to GABAA receptors to enhance their inhibitory effects. It is indicated for seizures associated with cyclin-dependent kinase-like 5 (CDKL5) deficiency disorder (CDD) in patients aged 2 years or older. CDD, a rare developmental epileptic encephalopathy, is largely a disease of pediatric and young adult patients. 

Approval was based on the phase 3 MARIGOLD trial. Patients treated with ganaxolone (n = 49) showed a median 30.7% reduction in 28-day major motor seizure frequency, compared with 6.9% reduction for those receiving placebo (n = 51) (p = 0.0036). In the open label extension study, patients treated with ganaxolone for at least 12 months (n = 48) experienced a median 49.6% reduction in major motor seizure frequency.[69]

Surgical Care

Some children who do not respond to medical therapy may be candidates for surgical treatment of their epilepsy. The most common procedure is focal cortical resection, in which an epileptic focus is identified and resected. The goal of this type of surgery is complete removal or disconnection of the epileptogenic network, while preserving eloquent cortical areas so that a neurological deficit does not occur. Areas of eloquent cortex include those vital to motor, sensory, language, memory, or visual function.[70]

Morrell devised the multiple subpial transection (MST) procedure, in which vertical incisions are made in the cortex, disconnecting the horizontal cortical layers while preserving vertical connections and thus eloquent cortical function. Cortical and subcortical connections remain intact. This contrast with a typical epilepsy surgery resection, in which the area of seizure origin is removed, eliminating the cortical and subcortical connections.

The indication for MST includes focal origination of epileptiform discharges; normal development of language, up to speaking in sentences for a nonautistic child; and muteness for at least 2 years, since spontaneous improvement may occur.[71] Morrell reported improvement in 11 of 14 children with LKS who underwent MST.[22]

Grote et al reported significant postoperative improvement on measures of receptive or expressive vocabulary in 11 of 14 children who underwent MST for treatment of LKS. They concluded that MST may allow for a restoration of speech and language abilities and that early diagnosis and treatment optimize outcome. Additionally, they pointed out that gains in language function are most likely to be seen years, rather than months, after surgery.[72]

Favorable outcome after MST was also described in 5 children with LKS by Irwin et al, who reported that behavior and seizure frequency improved dramatically after surgery in all 5. Improvement in language also occurred in all the children, although none improved to an age-appropriate level.[73] The experience with MST at other centers has been variable.

For more information, see Presurgical Evaluation of Medically Intractable Epilepsy and Epilepsy Surgery

Consultations

Management of epileptic and epileptiform encephalopathies may require a multispecialty team, including the following:

  • Neurologist, child neurologist, epileptologist

  • Pediatrician or developmental pediatrician

  • Psychologist, neuropsychologist

  • Psychiatrist, child psychiatrist, psychopharmacologist

  • Speech pathologist, audiologist

  • Physical therapist, occupational therapist

  • Ophthalmologist, when a metabolic disorder with ophthalmologic findings is in the differential diagnosis

  • Audiological testing to exclude hearing loss

 

Medication

Medication Summary

The goals of pharmacotherapy are to reduce morbidity and to prevent complications. The agents used in the treatment of epilepsy include anticonvulsants and adrenocorticotropic hormones.

Adrenocorticotropic hormones

Class Summary

These agents stimulate the adrenal cortex to release of corticosteroids.

Corticotropin (ACTH, Acthar)

Efficacy in epileptic encephalopathies is variable. However, ACTH is associated with serious, potentially life-threatening side effects. ACTH gel preparation is used in epilepsy and is the only anticonvulsant medication that must be administered by IM injection.

Prednisone (Deltasone, Meticorten, Orasone)

Prednisone may decrease inflammation by reversing increased capillary permeability and suppressing polymorphonuclear neutrophil (PMN) activity.

Anticonvulsant agents

Class Summary

These agents prevent seizure recurrence and terminate clinical and electrical seizure activity. If absence seizures are present, ethosuximide is the appropriate medication. This may be the case for patients with chronic absence epilepsy. These agents may be used in conjunction with an anticonvulsive AED, such as phenytoin (Dilantin), for patients at risk of tonic-clonic seizures in whom valproic acid is contraindicated.

Vigabatrin (Sabril)

Vigabatrin inhibits gamma-aminobutyric acid transaminase (GABA-T), increasing the levels of the inhibitory compound GABA within the brain.

Carbamazepine (Tegretol)

Carbamazepine appears to act by reducing polysynaptic responses and blocking posttetanic potentiation. Its major mechanism of action is to reduce sustained high-frequency repetitive neural firing.

Diazepam (Valium)

A long-acting benzodiazepine, diazepam has anxiolytic and anticonvulsant properties. Diazepam is effective for multiple seizure types, but is usually used for control of intermittent episodes of increased seizure activity in epilepsy patients on stable anticonvulsant regimens.

Diazepam's mechanism of action is based on inhibition of neuronal excitation through binding to gamma-aminobutyric acid (GABA) and more specifically to GABA-A receptors.

This agent is available in oral solution (5 mg/5 mL or 5 mg/mL), tablets (Valium) 2 mg, 5 mg, 10 mg, rectal gel (Diastat or Diastat AcuDial delivery system and injection), and solution (5 mg/mL).

Valproic acid (Depakote, Depakene, Depacon)

Valproic acid is chemically unrelated to other drugs used to treat seizure disorders.

Although its mechanism of action is not established, the activity of valproic acid may be related to increased brain levels of GABA or enhanced GABA action. This agent may also potentiate postsynaptic GABA responses, affect potassium channels, or have direct membrane-stabilizing effect.

For conversion to monotherapy, concomitant AED dosage ordinarily can be reduced by approximately 25% every 2 wk. Reduction may be started at initiation of therapy or delayed by 1-2 wk if concern that seizures are likely to occur with reduction. Monitor patients closely during this period for increased seizure frequency.

As adjunctive therapy, valproic acid may be added to the patient's regimen at a dosage of 10-15 mg/kg/d. The dosage may be increased by 5-10 mg/kg/wk to achieve optimal clinical response. Ordinarily, optimal clinical response is achieved at daily doses of less than 60 mg/kg/d.

Ethosuximide (Zarontin)

A succinimide AED, ethosuximide is effective only against absence seizures. It has no effect on generalized tonic-clonic, myoclonic, atonic, or partial seizures.

The mechanism of action of ethosuximide is based on reducing current in T-type calcium channels found on thalamic neurons. The spike-and-wave pattern during petit mal seizures is thought to be initiated in thalamocortical relays by activation of these channels.

Ethosuximide is available in large 250-mg capsules, which may be difficult for some children to swallow, and as syrup (250 mg/5 mL).

Zonisamide (Zonegran)

Zonisamide may stabilize neuronal membranes and suppress neuronal hypersynchronization through action at sodium and calcium channels. It does not affect GABA activity.

Lamotrigine (Lamictal, Lamictal ODT, Lamictal XR)

Lamotrigine is a thiazine derivative that inhibits the release of glutamate (an excitatory amino acid) and inhibits voltage-sensitive sodium channels

Levetiracetam (Keppra, Keppra XR, Spritam)

Levetiracetam has a mechanism of action that may involve inhibition of voltage-dependent, N-type calcium channels; facilitation of GABA-ergic inhibitory transmission through displacement of negative modulators; and reduction of the delayed rectifier potassium current.

Felbamate (Felbatol)

Felbamate is an oral antiepileptic agent with weak inhibitory effects on GABA-receptor binding and benzodiazepine receptor binding. It has little activity at the MK-801 receptor-binding site of the NMDA receptor-ionophore complex. However, felbamate is an antagonist at the strychnine-insensitive glycine recognition site of the NMDA receptor-ionophore complex.

Tiagabine (Gabitril)

The mechanism of action of tiagabine in antiseizure effects is unknown. It is believed to be related to its ability to enhance the activity of GABA, the major inhibitory neurotransmitter in the CNS.

Rufinamide (Banzel)

Rufinamide prolongs the inactive state of the sodium channels, thereby limiting repetitive firing of sodium-dependent action potentials, mediating anticonvulsant effects.

Clobazam (ONFI, Sympazan)

Benzodiazepine indicated for adjunctive treatment of seizures associated with Lennox-Gastaut syndrome in children aged 2 years or older.

Stiripentol (Diacomit)

Allylic alcohol that is unrelated to other anticonvulsants. The precise anticonvulsant effect in humans is unknown. Possible mechanisms of action include direct effects mediated through the GABA-A receptor and indirect effects involving inhibition of cytochrome P450 activity with resulting increase in blood levels of clobazam and its active metabolite. It is indicated for treatment of seizures associated with Dravet syndrome in patients aged 6 months and older who are taking clobazam. There are no clinical data to support the use of stiripentol as monotherapy in Dravet syndrome. 

Topiramate (Eprontia, Qudexy XR, Topamax)

Indicated as adjunctive therapy for treatment of seizures associated with Lennox-Gastaut syndrome in patients aged 2 years and older. Available as extended-release capsules that may be swallowed whole or opened and sprinkled on a spoonful of soft food.