In 1971, Patry and colleagues¹ first reported the EEG pattern of continuous spike and waves during slow-wave sleep in 6 children. They called the EEG pattern electrical or subclinical status epilepticus because it was not associated with any clinical signs when it occurred during sleep. All of these children had moderate to severe cognitive impairment, and 5 had epileptic seizures when the ESES pattern was first observed.

As other cases were reported, it became clear that ESES was an epileptic encephalopathy; the onset of it was most often associated with or followed by neurologic regression and seizures. Epileptic encephalopathies are conditions in which the epileptiform EEG abnormalities themselves are thought to contribute to a progressive disturbance in cerebral function.² In 1977, Tassinari and colleagues³ proposed that the abbreviation, ESES, should stand for encephalopathy with status epilepticus during sleep. More recent classifications by the International League Against Epilepsy (ILAE) call it “epileptic encephalopathy with continuous spike and wave during sleep (CSWS).”^4,5

The ILAE classification defines the ESES syndrome as an age-related and self-limited disorder characterized by 1) epilepsy with focal and apparently generalized seizures (unilateral or bilateral clonic seizures, tonic-clonic seizures, absences, partial motor seizures, complex partial seizures, or epileptic falls); 2) neuropsychological impairment in the form of global or selective regression of cognitive functions; 3) motor impairment in the form of ataxia, dyspraxia, dystonia, or unilateral deficit; and 4) typical EEG findings with a pattern of diffuse spike wave (or more or less unilateral or focal occurring up to 85% of slow-wave sleep and persisting on 3 or more recordings over a period of at least 1 month).² The percentage of NREM sleep occupied by spike-wave discharges varies in the literature from greater than 25% to greater than 85%.^6–8 Fig. 1 shows an example of ESES during NREM sleep.

Fig. 1 An example of ESES during NREM sleep.

ESES syndrome is a rare age-related condition occurring only in childhood, with a suggested incidence of 0.2% to 0.5% of childhood epilepsies.⁹ The first clinical symptoms usually emerge between 5 and 9 years of age.¹⁰ In most cases, the clinical course can be divided into 3 stages.^9,11–13 The first stage of ESES syndrome is usually heralded by the onset of seizures between 1 and 10 years of age (peak 4–5 years). The first seizure occurs in sleep in half of the cases, and in 40% it consists of unilateral convulsions that can last more than 30 minutes (hemiclonic status epilepticus).¹³ Other seizure types observed include focal motor, myoclonic, atypical absence, and generalized tonic-clonic. Seizures during the first stage tend to be infrequent and occur primarily in sleep.¹³ Tonic seizures are never seen in patients with ESES at any stage in the disease and when present warrant consideration of another diagnosis.

The second stage is often observed 1 to 2 years after epilepsy onset with the development of ESES with specific or global neuropsychological deterioration or behavioral problems. Habitual seizures become more frequent; and new seizure types are often observed, such as hemifacial, hemiconvulsive, atypical absences, and negative myoclonus (an interruption of tonic muscular activity time locked to a spike on the EEG without evidence of an antecedent myoclonus). Convulsive seizures continue to occur primarily during sleep. The neuropsychological regression tends to be gradual and progressive. Other neurologic deficits that occur in the second phase include ataxia, hemiparesis, or dyspraxia. Some develop an acquired epileptiform opercular syndrome characterized by dysarthria, drooling, face/tongue weakness, or speech arrest. The third stage of ESES syndrome is residual stage with alleviation of epilepsy and ESES by puberty, but permanent neuropsychological sequelae remain in half of the patients.^9,10

In the prospective longitudinal study of 32 children with ESES syndrome, 53% (17) had a symptomatic cause, 6 (19%) had atypical rolandic epilepsy, and 9 (28%) had Landau-Kleffner syndrome (LKS).¹⁴ Eleven children had congenital hemiplegia, 8 had unilateral thalamic injury on magnetic resonance imaging (MRI), and 5 had obstructive hydrocephalus. The mean age of epilepsy onset was 3.1 years, which was earlier in the symptomatic group than in the idiopathic group. Twenty (63%) of the children were cognitively normal before the development of ESES. Clinical symptoms of ESES syndrome (motor, language, behavioral, or cognitive deterioration) emerged at a mean age of 4.4 years. Symptoms of encephalopathy most often observed were deterioration of motor functions, including oral motor problems, combined with marked cognitive and behavioral problems in the symptomatic group. Mean delay from symptom onset to diagnosis of ESES was 1.0 year (0.1–4.8 years). In 7 children with a symptomatic cause and previous neuropsychological evaluation, the mean drop of the IQ by the time of the diagnosis of ESES syndrome was 29 points. Within the whole group of 32 children, the mean subsequent reduction of the IQ score during ESES, despite active treatment, was 23 points.

Others report at least one-third of the patients with ESES syndrome have symptomatic focal epilepsy with prenatal and perinatal problems or deviations in early development or structural abnormalities on brain imaging.^10,15 MRI abnormalities reported in children with ESES include unilateral or diffuse cortical atrophy, focal porencephaly, and cortical malformations. Cases of ESES in children with congenital hemiplegia either with prenatal/perinatal vascular or dysgenetic cause,^14–19 obstructive hydrocephalus,^16,17 or thalamic injury^14,20 have been reported. However, epidemiologic data on ESES syndrome in children with these conditions are not available.

ESES syndrome may occur in children with normal previous development and with normal brain structure in MRI. Some cases of ESES syndrome seem to evolve from idiopathic focal epilepsies of childhood, such as benign epilepsy of childhood with centrotemporal spikes^16,21,22 and the benign occipital epilepsy of childhood.²³ The risk of atypical evolution in idiopathic focal epilepsies seems to be low, less than 1%.²¹ Other idiopathic epilepsies that may be associated with ESES include the opercular syndrome with oral motor dysfunction, drooling, and epileptic negative myoclonus²⁴ and atypical benign partial epilepsy with frequent atypical absences.^25,26 The ESES syndrome needs to be distinguished from the acquired epileptic aphasia syndrome of LKS defined primarily by a gradually acquired aphasia combined with marked activation of primarily temporal epileptiform activity in sleep.^27–31 The clinical features of these syndromes are discussed in greater detail in this issue in the article authored by Bruni and colleagues.

The EEG pattern that defines the ESES syndrome is characterized by continuous spike-wave discharges during NREM sleep that are usually generalized and symmetric repeating at frequencies varying from 1.5 to 2.0 Hz, the pattern appearing as soon as the child falls asleep. The discharges may be asymmetrical, lateralized, or relatively focal, often frontally or centrally maximum, and sometimes consisting of sharp, spike discharges.^9,32 Discharges in wakefulness are infrequent, focal, or multifocal spikes or spike waves. In some, atypical absences are seen in wakefulness. During REM sleep, spike waves are far less frequent, occupying less than 25% of the REM sleep times. Discharges during REM sleep are often focal and similar to those in the wake EEG.⁹ Focal or multifocal spikes or spike waves occur infrequently.

The typical EEG finding in these patients before ESES develops are focal spikes or spike waves predominantly in centrotemporal or frontotemporal regions, sometimes with generalized spike waves that occur mainly in sleep.⁹ Some investigators suggest EEG features that increase the risk a child with benign idiopathic epilepsy could evolve to ESES include (1) focal spike-wave activity that spreads to adjacent regions or to the contralateral hemisphere and (2) focal slowing in the region of major epileptiform activity.³³ As the ESES pattern begins to resolve, the spike-wave discharges in sleep become shorter, less frequent, and more fragmented. The EEG typically normalizes, often 3 to 5 years after the onset of the syndrome. Rare focal discharges may persist in a few.

Investigators have used the spike-wave index (SWI) to quantify the percentage of NREM sleep occupied by spike-wave discharges. The SWI is usually defined by total minutes of spike waves multiplied by 100 and divided by the total minutes of NREM sleep without spike waves.¹⁵ The SWI is usually greater than 85% of the total duration of NREM sleep. Other investigators have defined ESES with lower SWI of greater than 25% to greater than 60%, justifying this by as the discharges are markedly activated by sleep. The duration of the sleep recording period needed to define the SWI varies from whole night sleep, first sleep cycle, and daytime nap.^7,8 Computerized digital EEG techniques allow semiautomated calculation of the SWI,³⁴ making analysis of it far less laborious. In 2009, Scheltens-deBoer³⁵ proposed quantitative and qualitative methods for classifying the EEG in patients with ESES that could make the comparison and interpretation of the published studies easier and possibly facilitate multicenter studies for this rare condition.

Sleep spindles, K-complexes, or vertex waves are seldom recognizable during ESES. The SWI often lessens across the night, and later NREM cycles contain lower percentages of spike-wave discharges (such that the average SWI for all NREM sleep is greater than 85%, with much higher percentages in earlier NREM sleep periods). The onset of REM sleep is often recognized by the disappearance of ESES. It is fairly easy to score REM sleep then because discharges are much less frequent. When the ESES pattern is fragmented, sleep architecture seems to be preserved with approximately 80% of the sleep time spent in NREM sleep and the remaining 20% in REM sleep.^13,15 Sleep organization and sleep stages are normal after the ESES pattern disappears.

At first glance, the ESES pattern is typically generalized and focal features are often evident. Initially, the ILAE classified the epilepsy associated with ESES as “undetermined as to whether it is focal or generalized.”³⁶ In 1994, Kobayashi and colleagues³⁷ argued that ESES has a focal cortical origin that is secondarily generalized in NREM sleep. The synchronizing nature of NREM sleep leads to focal discharges that seem widespread (a term called secondary bilateral synchrony).³⁸ ESES is now regarded as a focal epilepsy; the discharges generalized during NREM sleep are focal (or multifocal) during wake and REM sleep.

Some investigators argue that the neuropsychological deficits in ESES syndrome reflect the localization of the spikes. Cognitive dysfunction in children with frontal or prefrontal ESES often results in frontal lobe dysfunction with hyperkinesia, disinhibition, inattention, aggression, psychosis, or dementia, whereas temporal lobe ESES tends to produce prominent language deficits, especially for the expression of it (as compared with comprehension).

Treatment choices for ESES syndrome are based primarily on case reports and small cases series; no randomized controlled studies to treat it exist. Various antiepileptic drugs (AEDs), such as valproate (VPA), ethosuximide (ESM), benzodiazepines, sulthiame, and levetiracetam and intravenous immunoglobulin (IV-IG) or corticosteroids have been reported to abolish the ESES pattern from the EEG.^{7,8,16,39–48} Carbamazepine, oxcarbazepine, and phenobarbital may aggravate seizures and ESES and should be avoided.^7,49 Carbamazepine may provoke generalization of the spike-wave discharges.^11,13,49

Kramer and colleagues¹⁶ (2009) reported treatment responses in 30 children with ESES syndrome treated between 1994 and 2007 in 4 pediatric neurology outpatient clinics. The antiepileptic drugs that were found to be efficacious were levetiracetam (41%), clobazam (31%), and sulthiame (17%). In this case series, VPA, lamotrigine, topiramate, and ESM showed no efficacy. Corticosteroids were effective in 65%, and immunoglobulins were efficacious in a third. A third of the patients responded to high-dose diazepam, but this effect was only temporary.

The author (EL) prospectively evaluated the efficacy of VPA in all 32 children and a combination of VPA and ESM in children with bilaterally synchronous ESES or atypical absences.¹⁴ The primary treatment response was defined by total abolition of ESES, although permitting possible residual focal spiking. No response to VPA as the sole AED therapy (monotherapy) was observed, whereas ESES disappeared in 3 (18%) of the 17 children treated with the combination of VPA and ESM. In all, ESES disappeared with drug treatment in 16 children (50%) using different combinations of antiepileptic drugs and prednisone.

Treatment with oral corticosteroids, adrenocorticotropic hormone, or IV-IG is tried most often in patients who do not respond to AEDs. Some patients have clinical and EEG improvement. One case series treated 44 children with ESES with hydrocortisone (5 mg/kg/d during the first month, 4 mg/kg/d the second, 3 mg/kg/d the third, 2 mg/kg/d during months 4 to 12, then slowly tapering over a total treatment period of 21 months.⁴² Seizures or neuropsychological deficits improved in 34 patients (77%). Seizures were completely controlled in 77%, EEG normalized in 21 (47%), and the long-term remission rate was 45%. Only a few case reports of immunoglobulin therapy improving ESES syndrome have been reported.^48,50,51

Several small case series have recently been published reporting the benefits of epilepsy surgeries on ESES refractory to medical treatment.^52–56 The author’s (EL) group recently reported the benefits of epilepsy surgery in 13 children with medically refractory ESES syndrome.⁵² The group found that after surgery (1) the ESES EEG pattern terminated in 2 patients, restricted to 1 region in 1 patient, and lessened after surgery in 4 patients; (2) cognitive deterioration was halted in 12 patients; and (3) cognitive catch-up of greater than 10 IQ points was seen in 3 patients (all of whom had shown a first measured IQ of >75).⁵² Loddenkemper and colleagues (2009)⁵³ reported a beneficial outcome of epilepsy surgery on 8 children with ESES. Symptomatic causes for ESES were a perinatal infarction in 7 patients and a cortical malformation in 1 patient. Six patients became seizure free after resection, and 2 patients continued to have rare seizures. The postoperative EEG demonstrated resolution of generalized interictal epileptic discharges (IEDs) and ESES in all. Formal preoperative and postoperative neuropsychological testing showed overall improvement of age-equivalent scores.

Epilepsy surgery should be considered in patients with a unilateral brain lesion, even when the EEG activity shows no localizing features. Successful treatment of epilepsy and ESES by hemispherectomy or functional hemispherectomy and resective surgery report overall improvements in one-half of the patients undergo them.^52,53,55,57 The frequency of atypical absences was markedly reduced in the case series of children with ESES syndrome who had anterior or total corpus callosotomy.⁵²