Continuing Education Activity

Electrical status epilepticus in sleep (ESES) is a pediatric epileptic encephalopathy characterized by cognitive regression and significant activation of epileptiform activity during non-rapid eye movement sleep, resulting in an electroencephalography pattern marked by nearly continuous spike-wave discharges. The condition typically affects children between the ages of 2 and 12, with a peak incidence between 3 and 5 years. ESES is associated with various etiologies, which may or may not involve structural brain abnormalities. Clinically, affected children often present with infrequent seizures, either focal or generalized, and experience stagnation or regression in their developmental progress. The current treatment approach includes the use of traditional antiepileptic drugs, such as benzodiazepines and corticosteroids, as well as other therapies like epilepsy surgery, intravenous immunoglobulin, and the ketogenic diet.

Participants in this activity gain a comprehensive understanding of the evaluation and management of ESES. They learn about the critical importance of early diagnosis and intervention to prevent long-term cognitive decline and improve the quality of life for affected children. The activity emphasizes the value of an interprofessional team approach in managing ESES, where collaboration among neurologists, pediatricians, neuropsychologists, and other healthcare professionals enhances patient outcomes. By integrating knowledge from various specialties, the healthcare team can develop individualized treatment plans that address both the seizure control and cognitive development of the patient, ultimately leading to better clinical outcomes.

Objectives:

• Identify the early signs and symptoms of electrical status epilepticus in sleep in patients to facilitate prompt diagnosis and treatment.

• Assess the effectiveness of treatment plans for patients with electrical status epilepticus in sleep, and adjust them as necessary to optimize patient outcomes.

• Implement evidence-based treatment strategies, including pharmacologic and non-pharmacologic options, for managing electrical status epilepticus in sleep.

• Collaborate with an interprofessional team to create and execute individualized treatment plans for children with electrical status epilepticus in sleep.

Introduction

Electrical status epilepticus in sleep (ESES) is a childhood-onset epileptic encephalopathy characterized by epilepsy, cognitive regression, and marked activation of epileptiform activity during non-rapid eye movement sleep to produce an electroencephalography (EEG) pattern of near-continuous spike-wave discharges.[1][2] Though ESES terminology primarily describes the dramatic electrographic pattern, the International League Against Epilepsy introduced the more descriptive term continuous spikes and waves during slow sleep in 1989 to describe the full clinical phenotype.[3][4]

Etiology

Different etiologies, both with or without structural abnormalities of the brain, have been associated with ESES. An early developmental lesion, such as a perinatal infarct involving the thalamus, has been particularly correlated with the development of ESES. In a case-control study, results showed that 14% of the patients with epilepsy and sleep-activated EEG had early developmental lesions involving thalami, such as stroke, periventricular leukomalacia, and cortical malformation. However, only 2% of the patients in the control group had a thalamic lesion (patients with epilepsy but not with sleep-activated EEG).[5]

Recently, several genetic etiologies, including monogenic mutations or copy number variants, have been correlated with the development of ESES. Among monogenic mutations, including those in SCN2A, SLC9A6, DRPLA/ ATN1, neuroserpin/SRPX2, OPA3, KCNQ2, KCNA2, GRIN2A, CNKSR2, SLC6A1, and KCNB1, GRIN2A mutations, with possible dysfunction of N-methyl-D-aspartate receptor-mediated signaling, have most frequently linked with ESES.[6][7] Recurrent copy number variants were reported in association with ESES, such as Xp22.12 deletion, 16p13 deletion, 15q11.2-13.1 duplication, 3q29 duplication, 11p13 duplication, 10q21.3 deletion, 3q25 deletion, and 8p23.3 deletion.[8][9]

The exact reason for the sleep activation of the EEG abnormality is unknown. Some researchers correlated abnormal EEG with the abnormal hyperactivation of the thalamic oscillatory circuit: an interplay between inhibitory gamma-aminobutyric acidergic (GABA) reticular thalamic neurons and excitatory glutaminergic dorsal thalamic neurons. Researchers also hypothesized that the change in the thalamic oscillatory circuit might be due to a substitution from GABAa- to GABAb-mediated postsynaptic inhibition.[10] Sleep potentiation of epileptiform discharges may disrupt cortical information processing and trigger learning and memory impairments.[11]

Epidemiology

ESES is a rare condition. Results from a 20-year cohort from a pediatric neurology clinic in Israel revealed an ESES prevalence of 0.2% among 440 patients with epilepsy.[12] Another retrospective review of 1497 EEG records over five years identified 102 patients with an electrographic pattern consistent with ESES. Importantly, children with generalized spike-wave discharges were noted to have global or severe developmental issues compared with focal epileptiform discharges. Additionally, a spike-wave index of over 50% is more likely correlated with more widespread developmental disruption.[13]

History and Physical

Typically, children between 2 and 12 years, with a peak between 3 and 5 years, present with infrequent seizures (focal or generalized) and stagnation or regression of the development. Within 2 to 3 years of the onset of symptoms, further developmental regression occurs in association with more frequent generalized seizures, such as atonic or atypical absence seizures. Most children have normal development before disease onset, but developmental delay and cognitive impairment may be present from the beginning, depending on the underlying etiologies.[14] Rarely, neurocognitive regression may appear as the earliest feature without evidence of clinical seizures. Behavioral abnormalities, particularly hyperactivity, are commonly present with ESES.[15]

Evaluation

ESES is diagnosed by demonstrating bilateral, or rarely, unilateral, continuous or near-continuous slow (1.5 to 3 Hz), diffuse, or bilateral spike-wave discharges during non-rapid eye movement (NREM) sleep.[2] During wakefulness and rapid eye movement sleep, only intermittent focal or multifocal epileptiform discharges or slow waves are present; an inadequate sampling of EEG during NREM sleep may entirely miss the diagnosis.[2] Sporadic frontotemporal or centrotemporal interictal epileptiform discharges during wakefulness become significantly activated during sleep, disrupting the typical sleep background. There is controversy concerning the minimum threshold of spike-wave activity during NREM sleep for a formal diagnosis of ESES. Different study results have quoted a widely variable range of 25% to 85%, but most commonly, 85% or 50% spike-wave index thresholds have been accepted for diagnosis of ESES.[3]

Treatment / Management

Due to a lack of randomized controlled studies, current treatment options are primarily based on retrospective studies and expert opinions. The treatment goal—suppression of the EEG abnormalities, improvement of the seizure control, amelioration of the behavioral abnormalities, and reversal of cognitive regression—must be established at the time of the diagnosis. The existing treatment paradigm has its basis in uncontrolled studies and case series and primarily focuses on the use of traditional antiepileptic drugs (AEDs), including benzodiazepines and corticosteroids, epilepsy surgery, and other nonpharmacologic therapies such as the administration of IVIG or a ketogenic diet.

The most common AEDs used for ESES include valproate, ethosuximide, and levetiracetam.[16] In a placebo-controlled, double-blind, crossover study, researchers noted that levetiracetam decreased the spike-wave index to 37 (mean) from a baseline of 56 (mean) at the end of the treatment period (P < 0.0002).[17] Rarely, ethosuximide and sulthiame have been reported to improve ESES as a monotherapy, but as adjunctive and combination therapy, both have had extensive use. Although valproate has not been associated with worsening seizures in ESES, the definitive efficacy of this agent is unknown and should not be used as first-line therapy.[18]

Benzodiazepines, particularly diazepam and clobazam, have been extensively used when treating ESES. A group of researchers treated 29 children with ESES with oral high-dose diazepam (1 mg/kg; maximum of 40 mg) and noted a reduction of the spike-wave index from 76.7% to 40.8% within 24 hours. These patients received 0.5 mg/kg of diazepam for 3 weeks after the initial high dose before gradual tapering. Reversible side effects—sedation, dizziness, respiratory depression, hypotonia, paradoxical aggravation—occurred in approximately one-quarter of patients.[19] Larrieu et al first described the utility of clobazam in 1986.[20] Only rare reports of precipitation of absence status in ESES have appeared associated with clobazam.[21] Caraballo et al demonstrated that clobazam was effective in 5 of 117 patients and in combination with other agents in 86 of 117 patients.[22] A few specific antiepileptic drugs, such as phenytoin, phenobarbital, and carbamazepine, can worsen seizure control in ESES and require withdrawal in the presence of worsening drop or absence seizures.[23][24]

Corticosteroids (methylprednisolone, prednisolone, adrenocorticotropic hormone) have been utilized in different therapeutic regimens, both as long-term continuous therapy lasting for months or intermittent monthly high-dose treatment. Buzatu et al retrospectively reviewed the efficacy and safety of a 21-month regimen of hydrocortisone (5 mg/kg/day during the first month, 4 mg/kg/day during the second month, 3 mg/kg/day during the third month, 2 mg/kg/day for next 9 months, and slow taper during remaining of the treatment period) in 44 patients with a positive response in 34 patients during the first 3 months of the treatment, and with normalization of EEG in 21 patients. However, among 34 responders, 14 patients had a subsequent relapse. Higher intelligence and developmental quotients and shorter disease duration before initiating treatment were associated with a positive outcome. Due to side effects, 7 patients discontinued treatment early.[25] 

Chen et al reviewed the efficacy of a different regimen of corticosteroids that used a combination of intravenous methylprednisolone with oral prednisone for 6 months. This study has results reporting a high response rate but a high relapse rate at 1-year follow-up.[26] Due to fear of side effects from long-duration corticosteroid therapy, methylprednisolone pulse therapy (15 to 30 mg/kg/day for 3 days consecutively, once a month for 4 months) has also been used successfully.[27] A recent review calculated a response rate, defined as an improvement in the EEG or cognition, of 80% in response to steroid therapy in 575 patients compared to 49% with antiepileptic drugs and 68% from benzodiazepines.[28] 

The subgroup of patients with ESES and structural brain pathology, such as perinatal infarction or cortical malformation, may benefit from epilepsy surgery. Different surgical procedures (eg, multiple subpial transections, focal lesionectomies, and hemispherectomies) have mainly been used in patients with structural brain pathology. Children with unilateral brain pathology were frequently seizure-free after hemispherectomy or focal resection, with the disappearance of the EEG pattern and improvement in cognitive status.[29] However, more studies are needed to assess long-term neurocognitive status and determine the role of surgery. The ketogenic diet and intravenous immunoglobulin infusions have been studied in small numbers of patients, and no specific recommendations are possible regarding their efficacy.

Differential Diagnosis

Patients with Landau-Kleffner syndrome develop less frequent seizures and severe regression of language development (auditory agnosia) rather than the more global regression noted with ESES.[30] The EEG pattern in Landau-Kleffner syndrome is typically unilateral or lateralized.[31] Children with benign pediatric focal epileptic syndromes—benign childhood epilepsy with centrotemporal spikes and late-onset childhood occipital epilepsy, Gastaut type—can present with relatively easy-to-control seizures and milder neuropsychological deficits. The EEG of these patients shows potentiation of the epileptiform activities during sleep but is much less prominent compared with near-continuous spike-wave abnormalities of ESES.[32] During acute stages of ESES, children may experience intractable atonic and absence seizures, closely mimicking Lennox-Gastaut syndrome. However, the tonic seizures of Lennox-Gastaut syndrome are typically absent in patients with ESES.[33]

Prognosis

Clinical seizures and EEG abnormalities spontaneously improve after puberty, with only a partial reversal of cognitive deterioration.[34] A longer duration of ESES may be associated with a poor outcome regarding cognitive impairment; EEG may continue to show focal or multifocal interictal abnormalities.

Complications

Inadequate treatment and delayed diagnosis may lead to a worse cognitive outcome in patients with ESES.[34]

Deterrence and Patient Education

Antiepileptic drugs (AEDs), particularly levetiracetam, clobazam, and ethosuximide, can be used early after diagnosis. A few specific AEDs such as phenytoin, phenobarbital, carbamazepine, and oxcarbazepine are relatively contraindicated and should be discontinued. If there is no improvement in the EEG or cognition after 3 months of AED therapy, a corticosteroid regimen should merit consideration after carefully reviewing potential adverse events.[35] Polytherapy has been noted as effective in most patients. A select subgroup of patients with structural brain lesions may need evaluation for epilepsy surgery.

Enhancing Healthcare Team Outcomes

The diagnosis and management of ESES are very complex and best conducted by an interprofessional team. The diagnosis usually requires an EEG capturing NREM sleep.[3] The treatment approach is promptly initiating appropriate AEDs and escalating to a corticosteroid regimen if needed. Because all patients have neuropsychiatric features, a mental health nurse should be involved in the care, assisting in evaluating patients, monitoring treatment progress, counseling patients and families about the condition, and reporting any concerns to the treating clinician. The pharmacist should educate the patient and caregivers about the drugs, their adverse effects, and potential benefits, check for drug interactions, and verify all dosing. Recovery is slow, so social workers should be involved to ensure that the patient has adequate support services. Long-term monitoring by the interprofessional team is vital to prevent instances of morbidity.