Current Status of Treatments for Children with Electrical Status in Slow-Wave Sleep (ESES/CSWS)

Commentary

Treatment of Electrical Status Epilepticus in Sleep: A Pooled Analysis of 575 Cases.

van den Munckhof B, van Dee V, Sagi L, Caraballo RH, Veggiotti P, Liukkonen E, Loddenkemper T, Sánchez Fernández I, Buzatu M, Bulteau C, Braun KP, Jansen FE. Epilepsia 2015;56:1738–1746.

OBJECTIVE: Epileptic encephalopathy with electrical status epilepticus in sleep (ESES) is a pediatric epilepsy syndrome with sleep-induced epileptic discharges and acquired impairment of cognition or behavior. Treatment of ESES is assumed to improve cognitive outcome. The aim of this study is to create an overview of the current evidence for different treatment regimens in children with ESES syndrome. METHODS: A literature search using PubMed and Embase was performed. Articles were selected that contain original treatment data of patients with ESES syndrome. Authors were contacted for additional information. Individual patient data were collected, coded, and analyzed using logistic regression analysis. The three predefined main outcome measures were improvement in cognitive function, electroencephalography (EEG) pattern, and any improvement (cognition or EEG). RESULTS: The literature search yielded 1,766 articles. After applying inclusion and exclusion criteria, 112 articles and 950 treatments in 575 patients could be analyzed. Antiepileptic drugs (AEDs, n = 495) were associated with improvement (i.e., cognition or EEG) in 49% of patients, benzodiazepines (n = 171) in 68%, and steroids (n = 166) in 81%. Surgery (n = 62) resulted in improvement in 90% of patients. In a subgroup analysis of patients who were consecutively reported (585 treatments in 282 patients), we found improvement in a smaller proportion treated with AEDs (34%), benzodiazepines (59%), and steroids (75%), whereas the improvement percentage after surgery was preserved (93%). Possible predictors of improved outcome were treatment category, normal development before ESES onset, and the absence of structural abnormalities. SIGNIFICANCE: Although most included studies were small and retrospective and their heterogeneity allowed analysis of only qualitative outcome data, this pooled analysis suggests superior efficacy of steroids and surgery in encephalopathy with ESES.

The syndrome of electrical status epilepticus during sleep, otherwise known as ESES, was first identified by Patry et al (1) in 1971 to describe an epilepsy syndrome in young children presenting with global developmental regression and seizures whose sleep EEG showed a striking increase in diffuse or generalized spike-wave discharges. The spike-wave discharges are nearly continuous, occupying >85% of slow-wave sleep, sometimes obscuring K-complexes and vertex waves. The term “continuous spikes in slow wave” (CSWS) is more appropriate as these children are not truly in status epilepticus. The terms ESES and CSWS have been used interchangeably in the ensuing literature. Some propose using ESES to describe the EEG abnormalities, reserving the term CSWS to describe children exhibiting with this EEG pattern along with global cognitive regression (2). A subset of patients with CSWS who have pronounced language regression are categorized as having Landau-Kleffner syndrome. Seizures occur in both CSWS and LKS but are overshadowed by the behavioral and language regression (2, 3). The criterion of spikes occupying >85% of slow-wave sleep is now thought to be overly restrictive, and many authors believe the syndrome may be diagnosed in the right clinical setting with spikes occupying between 50% and 85% of slow-wave sleep. One must also take care to differentiate true ESES from the pattern seen in children with sleep-activated benign focal epileptiform discharges of childhood, which sometimes occur synchronously in both hemispheres. Reduction of spike-wave discharges with treatment often results in clinical improvement in most patients (2–4).

One-third of patients with CSWS have had prior antecedents such as neonatal encephalopathy, meningitis, or cortical malformations; in others no clear cause is found. Although the continuous spiking begins to wane during adolescence, focal spikes as well as cognitive and language deficits often persist, especially in those with longer duration (>3 years) of ESES (4). Studies of neuronal networks using functional and effective connectivity suggest that the medial parietal cortex, precuneus, and thalamus act as a central hub, interacting with the temporal and frontal cortices (5). CSWS has been reproduced in a mouse model of focal cortical dysplasia induced by single freeze lesions in the primary sensory cortex (6).

Autoimmune mechanisms have been invoked based on the response to steroids and immunosuppressants. A number of inflammatory markers have been found in serum of patients with CSWS, in particular interleukin 6, which dropped in patients treated successfully with immunotherapy. Recently, GRIN2A mutations were found in a subset of patients. GRIN2A is involved in neural development and cell adhesion (7)/Memantine, an (NMDA) receptor antagonist has been reported to improve seizures and CSWS (8).

A meta-analysis of 112 published papers involving 950 treatments in 575 patients with ESES/CSWS has been published (9). Patients were included if there was sufficient data to allow analysis of individual treatment effects on EEG and cognition before and after treatment (see table above; modified from (van den Munckhof et al [9]).

TABLE.

Effects of Analyzed Treatments on Cognition and EEG in Patients with ESES/CSWS

These results indicate that steroids and surgery are the most effective treatments for ESES/CSWS. Normal development prior to onset of ESES and shorter treatment lag were associated with better outcomes. Patients without a structural lesion fared better than those with a lesion (except for those treated surgically).

Other treatments reported to be effective include lacosamide, levetiracetam, ketogenic diet, acetazolamide, sulthiame, and vagus nerve stimulation. Oxcarbazepine and carbamazepine should be avoided as they may worsen ESES. In the presence of a focal cortical lesion, focal resection or hemispherectomy are often successful in eliminating ESES, thereby resulting in cognitive improvement. Multiple subpial transections may be helpful in selected patients with Landau-Kleffner syndrome.

A 2014 survey of 232 neurologists from North America regarding their treatment preferences in a patient with CSWS found that their preferred first choice was high-dose benzodiazepines (47%), followed by valproate (26%) and corticosteroids (15%) (10). Respondents chose ketogenic diet over resective surgery even in the presence of a focal lesion! This survey highlights the disconnect between what neurologists are practicing and what the best available evidence shows. Multicenter controlled trials are needed to evaluate treatments for CSWS, then formal treatment guidelines can be developed.

In summary, CSWS is an epileptic encephalopathy of childhood requiring prompt diagnosis and aggressive treatment (analogous to how one might manage a child with West syndrome). Close follow-up and serial overnight EEGs are helpful to assess the effects of a treatment and may be done cost-effectively using ambulatory EEG. Children not responding to high-dose benzodiazepines and/or valproate should receive a 3-month course of prednisone. Children not responding to steroids or showing steroid dependence (ie, their symptoms reemerge upon weaning steroids) may benefit from intravenous immunoglobulin. Refractory patients should be evaluated at an epilepsy center to determine if they may be candidates for focal resection. Ketogenic diet and vagus nerve stimulation are also useful options. Early reports suggest that patients with CSWS and GRIN2A mutations may benefit from treatment with NMDA receptor antagonists (11).