Clinical manifestations

Presentation and course

Epilepsy with continuous spike-and-waves during slow sleep syndrome is a heterogeneous epileptic disorder, is age dependent (with a peak onset around 4 to 7 years), and includes deterioration of motors skills and neuropsychological functions associated with, or independent from, the epileptic disorder.

According to the International League Against Epilepsy proposal, it may be defined as an age-related and self-limited disorder, characterized by the following features (30):

Epilepsy. Seizures may or may not be present before the stage of electrical status epilepticus during slow sleep. When the disease has started as epilepsy (80%), seizures usually start 3 to 5 years before the syndrome. Seizures are frequently nocturnal, motor focal, or secondarily generalized. Once the electrical status epilepticus during slow sleep is developed, children present different types of seizures, focal or secondarily generalized, diurnal and nocturnal, and predominating seizures with falls (usually due to negative myoclonus), or even status of absences during the day (08; 129). In a series of 10 patients, nocturnal motor seizures were predominant, and all of them also had atonic seizures (53). Tonic seizures during sleep or while awake are always absent in this syndrome.

Neuropsychological development. Normal neuropsychological development at the beginning of the disease is present in 60% to 75% of cases (21; 87; 88; 125). Rapid cognitive and behavioral deterioration is followed after the appearance of electrical status epilepticus during slow sleep, with deterioration of IQ, language, cognitive functions, and behavior. Patients can show a profound decrease in intellectual level, poor memory, impaired temporospatial orientation, reduced attention span, hyperkinesis, aggressive behavior, and even psychosis (58; 125). A comprehensive study of language development in 10 right-handed children and adolescents with continuous spike-and-wave sleep syndrome was reported. Severe language impairments in lexical and syntactic skills were found (27). In a retrospective study of 16 patients with idiopathic continuous spike-and-waves during slow sleep (CSWS), neuropsychological outcome was better than behavioral outcome, and the lexical-semantic route in reading and writing resulted more severely affected compared to the phonological route (22). Mental and behavioral deterioration evoking a frontal lobe syndrome has also been described in children with spikes or spike-waves discharges in the frontal lobe that can even persist after resolution of electrical status epilepticus during slow sleep in the EEG (108; 135).

Motor impairment. Motor impairment, including dyspraxia, dystonia, ataxia, or unilateral deficit, has been emphasized as one of the outstanding disturbances occurring in this syndrome (21; 92). Another peculiar phenomenon present in these patients is epileptic negative myoclonus during wakefulness. Epileptic negative myoclonus is a motor disorder characterized by a sudden, brief loss of postural tone associated with a paroxysmal EEG abnormality (usually a spike) without any clinical or polygraphic evidence of an antecedent positive motor phenomenon in the agonist and antagonist muscles (110; 10; 99). Epileptic negative myoclonus can be bilateral, in relation to diffuse paroxysmal activity, or focal, associated with a spike in the central region of the contralateral hemisphere (49). Clinical manifestations of epileptic negative myoclonus vary in location and intensity and may be head-drops, brief atonia of hands causing the dropping of objects, or falls due to epileptic negative myoclonus in lower limbs (96). In some cases, these “inhibitory seizures” in lower limbs are subtle and may cause difficulty walking. Even episodes of fecal incontinence were reported in two children as manifestations of epileptic negative myoclonus in the pelvic floor muscles (10). An easy maneuver to use to detect epileptic negative myoclonus in the upper limbs is to ask the child to extend both arms to the front and observe if there are brief and partial drops of the limbs. The diagnosis of epileptic negative myoclonus relies on the polygraphic demonstration of a brief interruption of the tonic EMG activity, time-locked to a cortical spike.

Motor impairment is never permanent; in nonsymptomatic cases the most disabling impairments are gait difficulties due to negative myoclonus in lower limbs. Orofacial dysfunction with dysarthria and dyspraxia (associated with persisting sialorrhea) has been reported in relation to electrical status epilepticus during slow sleep arising from Rolandic spikes (35; 19). In a particularly symptomatic case of electrical status epilepticus during slow sleep that appeared years after West syndrome, unilateral electrical status epilepticus during slow sleep was associated with a transitory “motor neglect” of one arm that lasted during the morning hours and disappeared during the evening (136).

Prognosis and complications

Epilepsy outcomes. Prognosis in terms of epilepsy, independent of etiology or severity, is good. The seizures in electrical status epilepticus during slow sleep are self-limited and disappear in the mid-teens or around puberty. Good seizure outcome is independent of the etiology and is observed also in cases with cortical malformations such as multilobar polymicrogyria (21; 88; 50; 09; 129; 14).

The characteristic EEG patterns during slow wave sleep also disappear at approximately the same time, with an average persistence until 11 years of age (127), but focal interictal spikes may persist (87; 08; 14).

The disappearance of the clinical seizures and CSWS may be simultaneous, or seizures may disappear before or after disappearance of the CSWS pattern on the EEG. In series with large follow-up, the duration of epilepsy ranged from 4 to 14 years, and in 44% of the cases, seizures disappeared before the end of electrical status epilepticus during slow sleep (09; 129).

Electroclinical parameters in the pre-CSWS period that have been proposed to predict a poor outcome are early-onset seizures, appearance of new seizures, and a significant increase in seizure frequency. From the electrical point of view, an increase in the frequency of the interictal EEG paroxysms while awake and during sleep and bilateral spike-and-wave paroxysms may also be predictive of a poor evolution in CSWS (14).

Neurocognitive outcomes. When CSWS disappears, neurocognitive and behavioral status may improve, but in most patients, residual moderate to severe neurocognitive impairments remain. Up to 50% of patients experience impairments severe enough to limit independent functioning (18). Therefore, despite the disappearance of seizures and improvement of the EEG, the persistence of neuropsychological impairments should lead one to be cautious regarding the prognosis, even when a certain degree of improvement in cognition, language, and behavior is seen.

In a previously mentioned study of 10 children with continuous spike-and-wave sleep syndrome, excluding symptomatic cases and patients with Landau-Kleffner syndrome, the results suggested that even patients who appeared to be in remission still had severe language disorders. Long-term language impairment seemed to be greater when epileptic activity occurred during a critical period in language acquisition (27). In a long-term follow-up of 25 patients, low IQ scores and behavioral disturbances persisted in 50% (129). The majority of affected children never return to normal levels, particularly in the verbal area and attention (86; 108). Neuropsychological tests of 25 children diagnosed with CSWS were reviewed in a long-term evolution study (101). Permanent cognitive impairment was found in 44% of them. The authors state that outcome seemed to depend on treatment response, disease duration, and underlying etiology.

The poor prognosis seems to be unrelated to the age of discovery of electrical status epilepticus during slow sleep or to the severity of epilepsy, but may be related to the duration of electrical status epilepticus during slow sleep. It has also been reported that poorer cognitive outcomes are associated with higher percentages of spike-wave activity during slow-wave sleep (77). In nonlesional epilepsy, cognitive recovery after cessation of the CSWS depends on the severity and duration of the initial regression. Overall, the duration of the CSWS seems to be the most important predictor of cognitive outcome (86; 108; 14). Therefore, early diagnosis is essential for minimizing long-term deficits, and delays in treatment are associated with poorer outcomes (18).

Etiology may play a role in prognosis as well, as structural lesions associated with CSWS are associated with more significant neurocognitive dysfunction and more severe impairment (15; 18). Cognitive outcomes are overall better in patients with EE-SWAS of unknown or idiopathic etiology (132).

Of note, during a follow-up of four cases for more than 8 years, no case of epilepsy with continuous spike-and-waves during slow sleep syndrome evolved into another epileptic syndrome (88).

Biological basis

Etiology and pathogenesis

The cause of electrical status epilepticus during slow sleep is unknown. Some patients with self-limited childhood epilepsy with centrotemporal spikes may present with atypical evolutions evolving into atypical benign partial epilepsy of childhood, status of benign childhood epilepsy with centrotemporal spikes, Landau-Kleffner syndrome, or epilepsy with continuous spike-and-waves during slow sleep. Other patients have preexisting encephalopathy, such as congenital hemiparesis, hemiplegia, spastic quadriplegia, diffuse hypotonia, and ataxia (symptomatic cases), before onset of the disorder. This preexisting encephalopathy may be due to prenatal, perinatal, or postnatal factors.

Tassinari and colleagues postulated that prolonged focal epileptic activity during sleep (as it occurs in ESES) interferes with local slow-wave activity and the site of epileptic focus, impairing the neural processes and, possibly, the local plastic changes associated with learning and other cognitive functions (123). Disruption of the normal maturation of neuronal networks may also alter normal processes of brain development, leading to an age-related pattern of electroclinical expression of ESES (112).

Thalamic lesions are the most commonly reported MRI abnormality in patients with ESES (65), and thalamic network dysfunction is hypothesized to play a role in the pathogenesis of ESES. Interactions between cortical and subcortical areas and the thalamus are known to play a role in the development of cognition, behavioral flexibility, and memory processes (66), so a disruption of these networks may result in neurocognitive disorders. The mechanism of epileptic discharges during sleep is hypothesized to be related to a disruption of the thalamocortical circuit acting on a hyperexcitable, immature cortex (43). It has also been hypothesized that dysfunction of the reticular nucleus of the thalamus can potentiate oscillatory discharges typically seen in the corticothalamic network during sleep, which may contribute to this physiologic dysfunction (66; 144). Furthermore, vascular lesions of the thalamus during early development have been identified in relation to electrographic patterns in ESES (66; 145). One study identified decreased thalamic volume and NAA/Cr ratio on magnetic resonance spectroscopy (MRS) in patients with ESES, further supporting the theory that a metabolic-induced thalamic dysfunction may play a role in epileptogenesis in this disease (66).

Other theories include the finding of prefrontal lobe growth in a patient with CSWS using 3-dimensional MRI-based volumetry and the reduction of the growth after improvement of CSWS in the child, suggesting that children with CSWS may be prone to frontal lobe dysfunctions (61).

Several reports have appeared with new information regarding the influence of genetic factors. The authors propose several genes that could contribute to the phenotype (95). In a study using array-based comparative genomic hybridization (aCGH) in a multicenter cohort of 61 patients with CSWS (41 patients) and Landau-Kleffner syndrome (20 patients), several potentially pathogenic alterations were detected. A large number of these corresponded to genomic regions or genes (ATP13A4, CDH9, CDH13, CNTNAP2, CTNNA3, DIAPH3, GRIN2A, MDGA2, SHANK3) that have been either associated with autism spectrum disorders for most of them, or involved in speech or language impairment, or in rolandic epilepsy. Particularly, copy number variations encoding cell adhesion proteins (cadherins, protocadherins, contactins, catenins) were detected with high frequency (72).

Sixteen studies reported 11 monogenic mutations: SCN2A, NHE6/SLC9A6, DRPLA/ATN1, Neuroserpin/SRPX2, OPA3, KCNQ2, KCNA2, GRIN2A, CNKSR2, SLC6A1, and KCNB1 (64). Ten studies reported 89 copy number variations including nine recurrent ones: Xp22.12 deletion encompassing CNKSR2, 16p13 deletion encompassing GRIN2A, 15q11.2-13.1 duplication, 3q29 duplication, 11p13 duplication, 10q21.3 deletion, 3q25 deletion, 8p23.3 deletion, and 9p24.2. Sixty-eight of the reported genetic etiologies including monogenic mutations and copy number variations were detected in patients with electrical status epilepticus during slow-wave sleep/continuous spike-wave of slow sleep/epilepsy aphasia spectrum solely. The most common underlying pathway was channelopathy (64). These findings will be of great interest to understand the pathophysiology of CSWS and Landau-Kleffner syndrome and the relationship with autism spectrum disorders.

The mechanism generating electrical status epilepticus during slow sleep. Secondary bilateral synchrony is the actual proposed mechanism underlying continuous spike-and-waves during slow sleep. In this respect the apparently generalized seizures (absences, tonic-clonic attacks) occurring in this condition have, in fact, a focal onset (120), as demonstrated by interhemispheric peak latencies of their EEG correlates (87; 90; 89), phase reversal of spikes on unilateral frontal regions (86), and studies of coherence and phase analyses (67). Localized metabolic abnormality has been revealed also by PET studies (78; 25). Overall, most evidence supports a predominance of focal or multifocal abnormalities during wakefulness that increase and become more diffuse during REM sleep (43).

The mechanism of neuropsychological impairment. Long-lasting persistence of continuous spike-waves during sleep is postulated to be responsible for the neuropsychiatric abnormalities in electrical status epilepticus during slow sleep. Three main arguments are in favor of this hypothesis:

The above observations suggest that electrical status epilepticus during slow sleep is a model for prolonged cognitive impairment induced by so called "interictal paroxysmal activity" (120). "Interictal paroxysmal activity" may interfere with different cognitive processes, as demonstrated by neurophysiological, neuropsychological, and biochemical studies (06; 140; 115; 126).

Longer duration of electrical status epilepticus during sleep appears to be the major predictor of poor outcome, and this might be explained by aberrant synapse formation due to abnormal neuronal activity during a critical period for synaptogenesis (93). Using a neuropsychological approach, it was conceived that the possible mechanisms underlying neuropsychological disorders in CSWS may be double as NREM sleep interictal epileptic discharges induce both a pathological activation in epileptogenic areas and a pathologic deactivation of default mode networks beyond the epileptogenic zone (37).

In 10 children between 6 and 9 years of age with epilepsy with CSWS, high-frequency oscillations in scalp EEG spikes during slow-wave sleep were investigated through temporal expansion of the EEG traces with a low-cut frequency filter at 70 Hz as well as through time-frequency power spectral analysis (68). The authors speculate that epileptic high-frequency oscillations may interfere with higher brain functions in epilepsy with CSWS. Regarding neurophysiology mechanisms of CSWS, it was suggested that facilitation of epileptic activity during sleep is mediated by high-amplitude slow waves. According to these authors, epileptic discharges appear more associated with synchronization than with excitability (40). A paper on abnormalities of coherence in EEG reported that coherence of EEG activity is altered during slow-wave sleep in children with ESES when compared to typically developing children (91). Abnormalities of coherence in EEG are a measure of the consistency of the phase difference between two EEG signals when compared over time, are an important feature of brain oscillations, and play a role in cognition and behavior. ESES was associated with remarkably high coherences at all bandwidths and most electrode pairs. Whether these increases in coherence correlate with the cognitive and behavioral abnormalities seen in children with this EEG pattern remains to be determined.

Epidemiology

Epileptic encephalopathy with spike-wave activation during sleep is a rare disorder. It is estimated that the incidence of EE-SWAS is 0.2% to 0.6% in children with epilepsy and 4.6% to 5.8% of children with self-limited epilepsy with centro-temporal spikes (76). This percentage could be higher if we consider that some patients with electrical status epilepticus during slow sleep do not present seizures at the beginning of the syndrome. A slight preponderance in males has been reported (87; 122; 125; 129).

Prevention

Because the etiology and physiopathology are not clear, it is not possible to prevent electrical status epilepticus during slow sleep. However, some risk factors raise the suspicion that a child could eventually develop electrical status epilepticus during slow sleep:

Differential diagnosis

Besides the differential diagnosis with other epilepsy syndromes, the first clinical obligation is to rule out acquired psychosis and progressive encephalopathies with mental deterioration.

The following are the main epilepsy syndromes to differentiate from epilepsy with continuous spike-and-waves during slow sleep syndrome:

Lennox-Gastaut syndrome. Age onset, atypical absence seizures, deterioration of intellectual level, and behavioral and language disturbances are seen both in Lennox-Gastaut syndrome and electrical status epilepticus during slow sleep, even though the electro-clinical characteristics of Lennox-Gastaut syndrome and the pathognomonic EEG in electrical status epilepticus during slow sleep are sufficiently well defined that the differential diagnosis should not be difficult. A key difference between Lennox-Gastaut syndrome and electrical status epilepticus during slow sleep is the lack of tonic seizures with the EEG correlation of rapid rhythms.

Epilepsy with myoclonic astatic seizures. In epilepsy with myoclonic astatic seizures, the EEG patterns are different and the neuropsychological impairment that may be seen in around one third of the patients with epilepsy with myoclonic astatic seizures takes much more time to become evident than in epilepsy with continuous spike-and-waves during slow sleep syndrome (32). Frequently, the differential diagnosis of epilepsy with myoclonic astatic seizures can be difficult with Lennox-Gastaut syndrome because of the presence of tonic seizures. A good clinical history, EEG analysis, predominant myoclonic component, and presence of genetic factors (febrile convulsions, family history) usually can give the clue.

Acquired epileptic aphasia. The distinction between epilepsy with continuous spike-and-waves during slow sleep syndrome and the Landau-Kleffner syndrome or acquired epileptic aphasia is disputed. All-night EEGs reveal that many children diagnosed with Landau-Kleffner syndrome actually have or went to an electrical status epilepticus during slow sleep. In Landau-Kleffner syndrome, however, acquired aphasia with auditive agnosia is the most predominant neuropsychological symptom; bilateral temporal EEG spikes are present but epileptic seizures do not always occur. Some consider electrical status epilepticus during slow sleep and Landau-Kleffner syndrome to be two facets of a same entity, in which the type of neuropsychological dysfunction depends on the location (frontal in continuous spike-and-waves during slow wave sleep and temporal in Landau-Kleffner syndrome) of interictal foci (120; 23).

Self-limited focal epilepsies in childhood. Similarities between self-limited focal epilepsy in childhood and electrical status epilepticus during slow sleep are the predominance of nocturnal seizures (at the beginning in electrical status epilepticus during slow sleep) and interictal focal spikes with a marked activation of the discharges during sleep. Self-limited focal epilepsies are seen usually in children without severe behavioral or cognitive deterioration. However, when neuropsychological impairment, motor impairment, or both occur, the electrical status epilepticus during slow sleep pattern should be looked for (21; 19). Epilepsy with continuous spike-and-waves during slow sleep syndrome has also been reported in children with the Gastaut type of childhood occipital epilepsy and in children with Panayiotopoulos syndrome (36; 131; 13; 33).

Diagnostic workup

EEG. The characteristic feature of this disorder is the continuous spike-wave discharges during slow sleep. Most researchers assert that more than 85% of NREM sleep is occupied by spike-wave discharges (58). A quantitative measure of the EEG abnormalities is the spike-wave index, which represents the sum of all the minutes with spike-wave discharges multiplied by 100 and divided by the total NREM recorded minutes (41). Persistence of electrical status epilepticus during slow sleep during 85% to 100% of slow sleep was initially considered an essential criterion for diagnosis (100; 121), but it was later accepted that epilepsy with continuous spike-and-waves during slow sleep syndrome can be diagnosed in cases with a spike-wave index of less than 85% (05; 143; 04).

Meanwhile, REM sleep has been shown to have a suppressive effect on epileptic activity in ESES (43). During REM sleep, the spike-wave index decreases, and focal spike discharges may become more prominent. Cases with relatively focal, albeit continuous, discharges mainly involving the temporal or frontal regions or markedly asymmetrical spike-wave activity over the two hemispheres have been also described (05; 86).

The typical EEG changes appear 1 to 2 years after the first seizure and are associated with behavioral deterioration. Generalized or focal interictal spikes that usually involve the frontotemporal or the centrotemporal region occur before this time and persist during wakefulness and REM sleep with a clear increase in NREM sleep. In symptomatic cases with unilateral or predominantly unilateral involvement, a background asymmetry can be seen (121). After "electrical status" develops, the awake EEG patterns do not differ much from the previous ones, except that both the diffuse and focal abnormalities tend to increase in frequency. Tassinari and coworkers emphasized the occurrence of diffuse spike waves at 2 to 3 Hz, organized in bursts, with or without clinical manifestations (121; 122; 125). When the affected child falls asleep, however, the characteristic continuous bilateral and diffuse slow spike-waves (electrical status) appear abruptly, lasting throughout almost the entirety of slow wave sleep.

Because some patients do not have evident seizures at the beginning of the syndrome, and instead present only neuropsychological deterioration, knowledge of the electrical status epilepticus during slow sleep and an additional high level of suspicion are necessary for identifying the syndrome. One must be aware that in every child with newly appearing bizarre behaviors or language impairment, a sleep EEG is mandatory. Diagnosis of electrical status epilepticus during slow sleep can be suspected with brief sleep recordings, but all-night sleep recordings must be performed.

Furthermore, a comprehensive neuropsychological study should be performed early in order to evaluate evolution and results of treatments.

Magnetoencephalography has been used in several patients with Landau-Kleffner syndrome, mainly before deciding on surgery for these patients (118), but there are no reports describing epileptic encephalopathy with spike-wave activation during sleep.

Imaging. Regarding imaging, a CT (computerized tomography) scan may be unremarkable or show unilateral or bilateral atrophic features (86).

However, brain MRI is mandatory, as neuroradiological abnormalities can be found in 33% to 60% of the cases with electrical status epilepticus during slow sleep, most commonly thalamic lesions and cortical malformations, including polymicrogyria and hydrocephalus (98; 65). To identify the relationship between thalamic volume and electrical status epilepticus in sleep, a study involving 15 patients with ESES, 15 patients with benign childhood epilepsy with centrotemporal spikes, and 30 healthy controls, all with normal brain MRIs, underwent analysis of subcortical gray matter volume (98). After correcting for total brain volume, volumes were compared with a group of healthy controls and patients with benign childhood epilepsy with centrotemporal spikes (BECTS, now termed SeLECTS). It revealed the total relative thalamic volume was significantly lower in patients with ESES than in the healthy controls, and in patients with ESES than in those with BECTS. There was no significant difference between patients with BECTS and healthy controls (98). Another study comparing thalamic volume on MRI evaluated 18 ESES patients, 29 refractory epilepsy controls, and 51 healthy controls (113). Similarly, these results showed that patients with ESES and normal magnetic resonance imaging have smaller relative thalamic volume controlling for age and total brain volume.

Many functional cerebral studies (PET) have been performed in patients with epileptic encephalopathy with spike-wave activation in sleep. Focal cerebral abnormalities are often identified, most frequently being decreased metabolic activity in the frontal regions. This could explain some characteristic neuropsychological features observed in these children. However, results are heterogeneous and not conclusive, probably because of the small and heterogeneous groups studied (treated and not treated patients, different evolution time, etc.) (78; 106; 46; 80; 25). One study reviewed PET studies using [18F]–fluorodeoxyglucose (FDG) were performed in nine children during acute and recovery phases of continuous spike-and-waves during slow sleep (CSWS). At the individual level, CSWS recovery was characterized by a complete or almost complete regression of both hypermetabolic and hypometabolic abnormalities observed during the acute phase. The authors state that the neurophysiological effects of CSWS activity are not restricted to the epileptic foci but spread via the inhibition of remote neurons within connected brain areas (26)

Management

Although seizures and epilepsy with continuous spike-and-waves during slow sleep on EEG are age dependent and self-limiting, epilepsy with continuous spike-and-waves during slow sleep is often difficult to treat before adolescence, and the urgent suppression of this EEG abnormality is necessary to prevent the progression of neuropsychological impairment.

A study designed to describe treatment choices made by clinicians caring for patients with CSWS in North America concluded that most clinicians thought prominent sleep-potentiated epileptiform activity should be treated; however, there was no agreement on best treatment (111).

A meta-analysis evaluating 13 randomized controlled trials has shown that combining corticosteroids and antiseizure medications is the most effective treatment for ESES. Their study concludes that this combination provides the most clinical improvement, EEG discharge improvement, and improvement in cognitive intelligence score (145). The most used and most effective seizure medications for ESES include benzodiazepines, valproic acid, ethosuximide, and levetiracetam, all of which involve GABA receptor-mediated inhibition (65; 144).

Corticosteroids. Steroid treatment was most successful in improving cognitive performance (133). Methylprednisolone pulse therapy has a marked efficiency in reducing clinical seizures and EEG discharges in children with ESES and can improve intelligence and behavior development, but the recurrence rate remains high (83).

A randomized control trial compared children with EE-SWAS taking clobazam versus high-dose corticosteroids (132). This study showed steroids to be more effective in improving IQ outcomes, although there were no significant differences in cognitive sum score outcomes, which is a comprehensive measure of overall cognitive functioning. There were no major differences in adverse effects identified. Of note, this trial was terminated prematurely for feasibility reasons, and therefore, the large sample size was not met.

A retrospective review of 33 children with ESES found that electrical status epilepticus in sleep initially resolved in 76%, but 56% had subsequent relapse. Interestingly, the relapse was higher for steroids (89%) and benzodiazepines (60%) as compared with nonbenzodiazepine antiepileptic drugs (29%). It is hypothesized that prolonging the steroid weaning period may potentially reduce the relapse rate, although this has to be considered against the side effect profile of prolonged steroid courses (142).

Benzodiazepines. There are consistent references about the preference of benzodiazepines to treat benign focal epilepsies of childhood because they seem to cause a reduction in EEG discharges (24; 23; 84; 104; 31). Chronic oral treatment with clobazam (70), lorazepam (07), and clonazepam (143) have been recommended. Clonazepam controlled spike-wave activities in two children with electrical status epilepticus during slow sleep but had no effect on cognitive and motor disorders, preventing a proper diagnosis (03). In two cases of continuous spike-and-wave sleep, intravenous injection of flunitrazepam at a dose of 0.02 mg/kg cleared up the EEG discharges (62). Twenty-nine patients with CSWS received a total of 48 high-dose diazepam treatment cycles: of the 29 cycles that responded in the short term, 20 had persistent responses on follow-up (114).

Valproate and ethosuximide. In 15 patients with electrical status epilepticus during slow sleep, including one case with Landau-Kleffner syndrome, a strategy with a sequential order of different treatments was presented: (1) high-dose valproate; (2) a combination of valproate and ethosuximide; (3) short cycles of high-dose diazepam for 7 days; (4) intramuscular synthetic adrenocorticotropic hormone-Z therapy for 11 to 43 days. A remission of epilepsy with continuous spike-and-waves during slow sleep in the EEG was achieved by high-dose valproate in 7 of 15 trials, by valproate plus ethosuximide in three of seven trials, by short cycles of high-dose diazepam in two of four trials, and by adrenocorticotropic hormone-Z therapy in two of five trials. A permanent remission of electrical status epilepticus during slow sleep syndrome was only achieved with high-dose valproate or a combination of valproate plus ethosuximide in 10 patients (56).

In another long-term follow-up of 32 children with encephalopathy with status epilepticus during slow sleep, treatment response with valproic acid combined with ethosuximide was better than with other drugs (73).

Other antiseizure medications. Levetiracetam was tried in 12 children with epilepsy with continuous spike-and-waves during slow sleep syndrome, including cryptogenic and symptomatic cases (01). The study was retrospective, and four patients showed retention of the drug after 1 year of treatment. The authors recognized that additional studies are needed in order to assess levetiracetam in the treatment of these epileptic conditions. Preference for levetiracetam and clobazam was also reported (69).

Lacosamide add-on treatment was reported to be effective in six out of eight children with CSWS syndrome (44).

Perampanel has been suggested as an effective add-on treatment for ESES, which acts as a noncompetitive antagonist on AMPA glutamate receptors (144).

Six children with Landau-Kleffner syndrome and CSWS were treated with acetazolamide. Three of them demonstrated complete resolution of electrical status in sleep, and five of the six children had subjective improvement in hyperactivity and attention (38).

Amantadine was tried in 20 patients with ESES-associated syndromes at a median dosage of 2.1 mg/kg/d and a median duration of therapy of 11.5 months with reduction in spike-wave index (141). Thirty percent of these patients exhibited complete (or nearly complete) resolution of ESES. A majority of patients exhibited subjective cognitive, linguistic, or behavioral benefits. Amantadine was generally well-tolerated.

According to several reports, sulthiame seems to be the oldest drug of choice (45; 71; 138; 29; 34; 60; 55). However, in an update on therapy for ESES/CSWS syndrome, this alternative was not recommended (137).

Treatment with other antiseizure drugs, such as phenytoin, phenobarbital, and carbamazepine, may be effective against seizures, but at present, this treatment is not recommended because these drugs may worsen the EEG discharges and neuropsychological deficit (12; 49; 48; 47; 34). Lamotrigine was involved in inducing electrical status epilepticus during slow sleep in a couple of cases (16; 17), and topiramate was also involved in one report (85). Of note, even valproate has been shown to induce continuous spike-wave discharges and worsening of clinical features in patients with atypical evolutions of benign focal epilepsies of childhood (102; 34; 103).

Intravenous immunoglobulins. Although anecdotal cases treated successfully with intravenous immunoglobulins have been reported, there were initially no sufficient data to consider it as a possible treatment (36; 131). In a report of immunoglobulin treatment for severe childhood epilepsy, six of 12 patients with ESES showed full or partial improvement (42). Immunotherapy in five consecutive patients (four males, age range 6 months to 13 years) with molecularly confirmed GRIN-related epileptic encephalopathies (four with GRIN2A-related epilepsy-aphasia spectrum/epileptic encephalopathy with CSWS accompanied by verbal, communicative, and behavioral regression, and one patient with GRIN2D-related infantile developmental-epileptic encephalopathy), all of whom received monthly infusions of IVIG 2 g/kg for 6 months and two of whom were also treated with high-dose corticosteroids, produced normalization or near normalization of the EEG in three patients (52). Two had mild improvement in verbal abilities and communication skills.

Ketogenic diet. Regarding the use of ketogenic diet, five children with continuous spike-and-waves during slow sleep refractory to antiepileptic drugs and steroids were prospectively evaluated (94). Resolution of electrical status epilepticus during sleep was observed in one patient, and mild reduction in the spike-wave index in another. The ketogenic diet did not influence the neuropsychological outcome. In a retrospective study of 65 patients with ESES syndrome, 12 of them were placed on the ketogenic diet and were followed for a minimum of 18 months. The authors suggest that a ketogenic diet is a well-tolerated treatment option and should be considered in the management of these patients (105).

Surgical treatments. In a pooled analysis of surgical treatments for epileptic encephalopathy related to SWAS including disconnection procedures and varying resective procedures, 80% of 575 patients had reported cognitive improvement after surgery, which was considered comparable to that reported after treatment with steroids (82). Of note, three cases reported evidence of focal cortical dysplasia that was seen on pathological evaluation of resected tissue, which had not been evident on MRI. There was less supporting evidence for multiple subpial transections (21% with improvement). Other studies that used formal neuropsychological testing as an endpoint identified either an arrest of decline, gains in performance, or stability of function following disconnection or resective surgeries in 64% of cases (82).

In a series of 11 patients, focal cortical resections were performed in seven children and hemispherectomies in four children (139). Postoperatively, nine children experienced decreased seizure frequency, eight had neuropsychological improvement, and nine had resolution of electrographic ESES. A series of eight patients with refractory epilepsy, hemiparesis, and developmental delay with electrical status epilepticus during sleep underwent hemispherectomy (six patients) or focal reception (two patients), and six patients became seizure free (74). Because cognitive impairment may be aggravated by the persistence of electrical status epilepticus during sleep, these procedures may have developmental benefits.

Of 14 patients who underwent surgery for epilepsy and ESES including hemispherotomy (10), temporo-parieto-occipital disconnection, frontal lobectomy, and parieto-occipital resection, 12 had long-term seizure freedom, resolution of ESES, and stabilization of cognitive and behavioral functioning (79).

Nine patients with electrical status epilepticus in sleep associated with a unilateral structural lesion amenable to surgery underwent hemispherotomy (59). All children had preoperative neuropsychological impairments. Developmental regression was halted postoperatively; none of the children returned to their original pre-electrical status epilepticus in sleep baseline. Four children demonstrated academic gains.

Eighteen patients with unilateral polymicrogyria and drug-resistant ESES (to at least three antiepileptic drugs) had hemispherotomy at a mean age of 7.2 years and showed that ESES disappeared in all patients whereas 16 of 18 became seizure-free. An improvement of behavior and cognitive condition was observed in all (39).

In cases of electrical status epilepticus during sleep with severe language impairment, namely children with Landau-Kleffner syndrome, a progressive and long-lasting improvement of language function has been obtained using the surgical procedure of multiple subpial transections in the region of focal epileptic discharges (90; 89; 57). Considering these antecedents, and because all studies suggest that electrical status epilepticus during slow sleep is mainly a focal epilepsy with secondary hypersynchronies, this treatment could be a good future choice.

Outcomes

There is known to be a significant correlation between reduction of the spike-wave index and seizure control, as well as a significant correlation between neurocognitive/behavior scores before and after treatment, seizure control, and EEG recovery (65). Therefore, it is recommended that ESES be treated as soon as possible.