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 (39):

	(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 with global or selective regression of cognitive functions.
	(3) Transient motor impairment with ataxia, dyspraxia, dystonia, or unilateral deficits.
	(4) Typical EEG findings with diffuse or more or less unilateral electrical status epilepticus during slow sleep occurring in up to 85% of slow sleep.

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 secondary 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 (12; 160). In a series of 10 patients, nocturnal motor seizures were predominant, and all of them also had atonic seizures (69). Tonic seizures during sleep or while awake are always absent in this syndrome.

Based on seizure patterns, 3 groups have been proposed: (1) patients with rare and nocturnal motor seizures (11%); (2) patients with unilateral and/or generalized motor seizures occurring during sleep and also absences during wakefulness (44.5%); and (3) patients with rare nocturnal motor seizures and frequent atonic seizures leading to falls while awake (159; 160).

Neuropsychological development. Normal neuropsychological development at the beginning of the disease is the norm in 60% to 75% of cases (29; 109; 110; 156).

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 (77; 156). Mental and behavioral deterioration evoking a frontal lobe syndrome has been described in children with spikes or spike-waves discharges in the frontal lobe (136) that can even persist after resolution of electrical status epilepticus during slow sleep in the EEG (171). 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. Their language profile was different from that observed in Landau Kleffner syndrome (36). 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 as a result of abnormal neuronal activity during a critical period for synaptogenesis (116). Fourteen patients with ESES were evaluated in 2010 (131). Eleven children had behavioral issues, and 7 showed evidence of cognitive impairment. Interestingly, 2 patients with acquired Kanji dysgraphia were presented with continuous spike waves in the occipito-temporal region during slow-wave sleep (91). A long-term follow-up of cognitive functions in 61 patients with continuous spike-waves during sleep had the objective to identify variables that predispose patients to a poorer long-term neuropsychological outcome. One of the conclusions was that CSWS/ESWS is a complex pathology and that many variables contribute to the outcome (99).

In a retrospective study of 16 CSWS idiopathic patients, neuropsychological outcome was better than the behavioral one, and the lexical-semantic route in reading and writing resulted were more severely affected compared to the phonological route (30).

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 (52).

Motor impairment. Motor impairment, including dyspraxia, dystonia, ataxia, or unilateral deficit, has been emphasized as 1 of the outstanding disturbances occurring in this syndrome (29; 115).

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 (138; 15; 124). 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 (65). 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 (119). In some cases these “inhibitory seizures” in lower limbs are subtle and may cause difficulty walking. Even episodes of fecal incontinence were reported in 2 children as manifestations of epileptic negative myoclonus in the pelvic floor muscles (15). 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 (49; 27). 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 1 arm that lasted during the morning hours and disappeared during the evening (172).

Prognosis and complications

Prognosis in terms of epilepsy, independent of etiology or severity, is good, with disappearance of seizures in almost all cases (29; 110; 13; 160). 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 (13; 160). Electrical status epilepticus during slow sleep also disappears in all cases, with an average persistence until 11 years of age (158). Focal abnormalities, instead, may persist for a longer time (12).

Despite the disappearance of seizures and the 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 most of the patients. In a long-term follow-up of 25 patients, low IQ scores and behavioral disturbances persisted in 50% (160). The poor prognosis seems to be not related 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. The majority of affected children never return to normal levels, particularly in the verbal area and attention (108; 136).

A comprehensive and long-term follow-up of 1 case showed details about evaluation of the boy’s behavior, language, and cognitive functions suggesting a dysexecutive syndrome (71). During the follow-up of 4 cases for more than 8 years, no case of epilepsy with continuous spike-and-waves during slow sleep syndrome evolved into another epileptic syndrome (110). In an 8-year-old boy with occipitotemporal epilepsy with continuous spike-and-waves during slow sleep followed up for 2 years, major deficits in visual perception with normal verbal intelligence were found (41). Moreover, persistence of electrical status epilepticus during slow sleep during 17 months without behavioral changes was also reported (59).

Out of 10 children with electrical status epilepticus during sleep and global or specific deterioration with long-term follow-up, 7 had epilepsy with continuous spike-and-waves during slow sleep syndrome and 3 had Landau-Kleffner syndrome. Electrical status epilepticus during sleep persisted for 5 to 9 years in epilepsy with continuous spike-and-waves during slow sleep syndrome, and therapy was disappointing (144).

Outcome at adulthood has been reported in 7 young adults, 5 of whom had continuous spike-and-waves during slow sleep syndrome and 2 had Landau-Kleffner syndrome in childhood. The authors emphasized the role of location of interictal EEG focus and age of onset as prognostic factors (128).

In an already 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 (36).

Neuropsychological tests of 25 children diagnosed with CSWS were reviewed in a long-term evolution study (127). 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 seizures in electrical status epilepticus during slow sleep are self-limited and disappear in the midteens. Good seizure outcome is independent of the etiology and is observed also in cases with cortical malformations such as multilobar polymicrogyria (66). The characteristic EEG patterns during slow wave sleep also disappear at approximately the same time, but focal interictal spikes may persist (109; 12). Improvement in language dysfunction, mental retardation, and psychiatric disturbances generally occur, but improvement is variable and individualized.

A long-term follow-up of 27 patients with polymicrogyria/CSWS was reported. It included patients with unilateral (multilobar or more localized), bilateral, and perisylvian polymicrogyria. The authors also found thalamic hypoplasia in these patients and presented them as examples of the syndrome of polymicrogyria, thalamic hypoplasia, and epilepsy with CSWS. An important clinical finding was that this syndrome is characterized by remission of epilepsy within early adolescence (05).

In a special issue of the Journal of Pediatric Epilepsy, our experience with atypical evolutions of idiopathic focal epilepsies in childhood was reported (45). This included the follow-up of 28 patients with atypical benign focal epilepsies of childhood, 13 patients with status of idiopathic focal epilepsies in childhood (IFEC), 21 patients with idiopathic CSWS/ESES, and 5 patients with mixed forms of atypical evolutions of IFEC. Treatment of atypical evolutions of IFEC was also updated in the same journal (46).

Clinical seizures tend to remit spontaneously around puberty independent of the etiological lesion (23). The CSWS also disappears in all cases. Focal abnormalities instead may persist for some time after the disappearance of CSWS. 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. 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. When CSWS disappears, neurocognitive and behavioral status improve, but in most patients, residual moderate to severe neurocognitive impairments remain. In nonlesional epilepsy, cognitive recovery after cessation of the CSWS depends on the severity and duration of the initial regression. The duration of the CSWS seems to be the most important predictor of cognitive outcome (23).

Biological basis

Etiology and pathogenesis

The cause of electrical status epilepticus during slow sleep is unknown. The affected children may have either normal psychomotor development, as is the case in patients with benign childhood epilepsy with centrotemporal spikes who present 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, or, abnormal signs, indicating 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.

We also want to call attention to the fact that a number of patients with benign childhood epilepsy with centrotemporal spikes evolve into a different kind of epilepsy with continuous spike-and-waves during slow sleep syndrome that we termed “mixed forms of atypical evolutions” because the patients presented electrical status epilepticus during slow sleep associated with clinical features of atypical benign partial epilepsy of childhood, status of benign childhood epilepsy with centrotemporal spikes, Landau-Kleffner syndrome, and typical epilepsy with continuous spike-and-waves during slow sleep syndrome (48; 47). That is to say that the same children present electrical status epilepticus during slow sleep with alternating periods of inhibitory seizures, plus absences and myoclonia, with learning disorders, but without language or behavioral problems, periods of status of Rolandic seizures during wakefulness and sleep (status of benign childhood epilepsy with centrotemporal spikes), periods of acquired epileptic aphasia (Landau-Kleffner syndrome), and periods of bizarre behavior with or without seizures (epilepsy with continuous spike-and-waves during slow sleep syndrome). Obviously, the same mixed forms may be seen in children with symptomatic origin. We presented a series of 59 patients with unilateral polymicrogyria, of whom 44 (78%) presented epilepsy. Thirty-three of these 44 patients started with focal seizures at a median age of 22 months and showed a severe worsening of epilepsy with continuous spike-and-wave sleep at a median age of 5.5 years (21). This conjunction of neurologic signs and atypical evolution of epilepsy might be considered as a distinct syndrome. In a large series of patients with different types of polymicrogyria, 4 of them showed electrical status epilepticus of sleep, and the fourth patient had right hemispheric polymicrogyria (162). A study of 66 patients with congenital hemiparesis, unilateral polymicrogyria, and epilepsy with or without status epilepticus during sleep with long-term follow-up was presented (22). A multicenter study including 117 patients with ESES-CSWS showed that this epileptic encephalopathy presents similar electroclinical findings in children with a spike-wave index greater than 85% and in those with a spike-wave index less than 85% (22). A case of association of continuous spike-and-wave sleep with vacuolating megalencephalic leukoencephalopathy was reported (79). Nine children with early-onset hydrocephalus and epileptic encephalopathy with continuous spike-and-waves during sleep were reported. Onset of epilepsy occurred at a median age of 14 months, with focal seizures, but neuropsychological and behavioral deterioration appeared between 6 and 13 years of age in association with electrical status epilepticus during sleep (19).

There is a report of 5 out of 7 patients with Mowat-Wilson syndrome, a rare genetic disease having anterior ESES pattern with spike-and-wave index of more than 85% on an overnight EEG (11). The architecture of sleep was abnormal. An ESES-related regression of cognitive and motor functions with impact on daily activities (ESES-related syndrome) was demonstrated in 3 out of 5 (60%) patients.

Perinatal thalamic injury can be followed by electrical status epilepticus in sleep based on thalamic and total brain volumes obtained and diffusion characteristics assessed on MRI and EEGs performed in sleep (168). Thalamic volume and diffusion characteristics correlated to neurodevelopmental outcome.

Seizure aggravation and negative myoclonus associated with continuous spikes-and-waves during slow sleep were induced by levetiracetam in 2 patients, 1 with Dravet syndrome and another with cryptogenic focal epilepsy (20).

The case of an 8-year-old boy was presented, which suggested that onconeuronal antibodies may be involved in the pathogenesis of CSWS syndrome (72).

Familial antecedents of epilepsy (including febrile convulsions) have been mentioned in about 15% of cases (158). In general, genetic factors seem to play a minor role in this syndrome. Two families associating benign childhood epilepsy with centrotemporal spikes and epileptic syndrome with epilepsy with continuous spike-and-waves during slow sleep in first-degree relatives were reported (34).

However, in the last few years several reports have appeared with new information regarding the influence of genetic factors. Array-based comparative genomic hybridization (aCGH) was used to identify copy number variations in 13 children with electrical status epilepticus in sleep syndrome to identify possible underlying risk factors (86). Array comparative genomic hybridization has again been used to start the study of phenotype-genotype correlations in 17 new patients with severe intellectual disability, language impairment, and age-related epileptic syndromes, including continuous spikes-and-waves during slow sleep. The authors propose several genes that could contribute to the phenotype (118). Seven copy number variations were detected in 4 of the 13 patients. Two patients with an unbalanced translocation between chromosomes 8p and 9p presented intellectual disabilities, dysmorphic features, and localization-related epilepsies evolving into ESES (114). One child with karyotype 47,XYY was also presented with rolandic spikes, atypical evolution with continuous spikes, and waves during slow sleep (26). Genomic dissection in patients with epileptic encephalopathies of the Landau-Kleffner and CSWS types were reported to be linked with autism. In a study using aCGH in a multicenter cohort of 61 patients with CSWS (41 patients) and Landau-Kleffner syndrome (20 patients), the 61 patients could be subdivided into 4 main groups (94). Twenty-five patients were diagnosed with idiopathic CSWS in the absence of any brain lesion; 16 patients were classified as symptomatic CSWS in the presence of severe psychomotor delay or acute fetal distress or PMG. Five patients had Landau-Kleffner syndrome with ESES, and 15 had Landau-Kleffner syndrome with EEG abnormalities but did not show the typical EEG pattern of ESES. Whereas the patients showed highly heterogeneous in genomic architecture, 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.

Sixteen studies reported 11 monogenic mutations: SCN2A, NHE6/SLC9A6, DRPLA/ATN1, Neuroserpin/SRPX2, OPA3, KCNQ2, KCNA2, GRIN2A, CNKSR2, SLC6A1, and KCNB1 (85). Ten studies reported 89 copy number variations including 9 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 (85).

These findings will be of great interest to understand the pathophysiology of CSWS and Landau-Kleffner syndrome and the relationship with autism spectrum disorders. In a patient with Christianson syndrome, a novel splice site mutation (IVS10-16> A) in SLC9A6 was detected and interpreted as a new cause of ESES syndrome (182). This was also reported in 3 of 5 male patients from 3 unrelated families with Christianson syndrome caused by a pathogenic nucleotide variation or a copy number variation involving SLC9A6 (104). ESES was present in 3 out of the 5 patients in the critical age window between 4 and 8 years, leading to the observation that ESES could be a constitutive feature of Christianson syndrome.

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; however, quantitative studies of different sleep stages and of temporal evolution of this EEG disturbance have not been carried out (77).

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 (151).

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 (151; 152; 156). 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. 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 (57). Persistence of electrical status epilepticus during slow sleep during 85% to 100% of slow sleep was initially considered an essential criterion for diagnosis (125; 151), 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% (07; 181; 06). 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 2 hemispheres have been also described (07; 108).

The cyclic percentage organization of sleep, however, remains grossly unchanged.

Studies describing quantitative aspects of the spike-and-wave discharges are overrepresented in literature, whereas qualitative aspects are relatively undervalued. Guidelines for evaluation of these EEG abnormalities in continuous spike-and-waves during slow sleep (CSWS), focusing on both aspects, have been presented (143). Functional and effective connectivity within the network generating the delta activity in the background sleep EEG in 15 patients with CSWS showed that, independent of etiology and severity of epilepsy, background EEG pattern in patients with CSWS before treatment is associated with a complex network of coherent sources in different areas of the brain (76). In a retrospective cross-sectional study of 22 CSWS patients, the location of the epileptic focus is related to age and follows a posterior-anterior course (10).

In 10 children between 6 and 9 years of age with epilepsy with CSWS, high-frequency oscillations (HFOs) 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 (88). This is the first report on the detection of HFOs from scalp EEG recordings in epileptic patients. The authors speculate that epileptic HFOs 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 (56).

A paper on abnormalities of coherence in EEG, which is a measure of the consistency of the phase difference between 2 EEG signals when compared over time, is an important feature of brain oscillations, and plays a role in cognition and behavior, reported that coherence of EEG activity is altered during slow-wave sleep in children with ESES when compared to typically developing children (113). 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 (113).

Computing an integrated root mean square over multiple electrodes during steady NREM sleep in 10 patients with CSWS was considered to offer a stable and reliable parameter for evaluating the strength of spikes in CSWS (126).

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 (150), as demonstrated by interhemispheric peak latencies of their EEG correlates (109; 112; 111), phase reversal of spikes on unilateral frontal regions (108), and studies of coherence and phase analyses (87). Localized metabolic abnormality has been revealed also by PET studies (100; 33).

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:

	(1) There is a close temporal association between electrical status epilepticus during slow sleep and neurologic regression (the latter beginning at the time electrical status epilepticus during slow sleep is discovered and improving after the disappearance of electrical status epilepticus during slow sleep) (151).
	(2) The duration of electrical status epilepticus during slow sleep is correlated with the final neuropsychological outcome (137).
	(3) There is a strict association between the pattern of neuropsychological dysfunction and the location of the interictal focus (137). A deterioration of language is observed in cases showing the predominance of paroxysmal abnormalities over 1 or both temporal regions (07), whereas a mental deterioration evoking a frontal lobe syndrome has been described in children exhibiting interictal frontal foci or clear cut anterior predominance of the discharges (136). On the other hand, causative factors for motor impairment in the form of dyspraxia, dystonia, ataxia, or unilateral deficit observed in some children during the period of continuous spike-and-waves during slow sleep would be a predominant involvement of motor areas by continuous spike-wave activity and the appearance of negative myoclonus during wakefulness (29; 115).

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" (150).

"Interictal paroxysmal activity" may interfere with different cognitive processes, as demonstrated by neurophysiological, neuropsychological, and biochemical studies (08; 177; 145; 157).

The finding of prefrontal lobe growth in a patient with CSWS using 3-dimensional magnetic resonance imaging-based volumetry, and the reduction of the growth after improvement of CSWS in the child, suggests that children with CSWS may be prone to frontal lobe dysfunctions (81).

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 (153). 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 (140).

Regarding etiology and pathophysiology of CSWS, an issue of Epilepsia included controversial results in 2 of the published papers: thalamic abnormalities in children with continuous spike-wave during slow-wave sleep (02); and no evidence of thalamic metabolic abnormality associated with continuous spike-and-wave during sleep (164).

Physiopathology of atypical evolutions of idiopathic focal epilepsies in childhood was updated (166).

Continuous spike-waves during slow-wave sleep were seen in a mouse model of focal cortical dysplasia (FCD). This was the first report of an in vivo animal focal cortical dysplasia model that induces chronic spontaneous electrographic brain seizures (149).

Epidemiology

Electrical status epilepticus during slow sleep is a rare disorder. The study of Morikawa and colleagues showed an incidence of 0.5% among 12,854 children evaluated during a 10-year period (109). In a cohort of 440 consecutive pediatric patients with at least 2 seizures, Kramer and colleagues found “epilepsy with ESES” in 0.2% (89). 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 (109; 152; 156; 160).

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:

	(1) Children with certain brain pathologies are more prone to develop secondary bilateral synchronies and electrical status epilepticus during slow sleep. Thalamic lesions and shunted hydrocephalus have been associated with symptomatic epilepsy with continuous spike-and-waves during slow sleep syndrome suggesting involvement of thalamocortical circuitry (170; 67; 83). In a series with 60 patients with early thalamic injury, CSWS was again found as a frequent complication related to cognitive outcome (97). Many cases with cortical malformations, especially polymicrogyria, also have been related to electrical status epilepticus during slow sleep (66; 121; 16).
	(2) Patients with benign childhood epilepsy with centrotemporal spikes with an atypical evolution also may risk evolution into Landau-Kleffner syndrome or electrical status epilepticus during slow sleep (03; 49; 48).
	(3) Certain EEG abnormalities can strongly suggest a possible evolution to electrical status epilepticus during slow sleep. Different interictal EEG patterns have been described as indicators of risk (103).
	(4) There are also some reports in children with focal symptomatic epilepsies or idiopathic focal epilepsies in which classic antiepileptic drugs, such as carbamazepine, oxcarbazepine, phenobarbital, or phenytoin, may induce the appearance of electrical status epilepticus during slow sleep; these should be avoided (17; 65; 64; 48). Valproic acid, lamotrigine, and topiramate have also been involved in sporadic cases, but more data are necessary (129; 24; 107; 25).

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. The clue 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 neuropsychologic 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 (43). 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. In our opinion, electrical status epilepticus during slow sleep and Landau-Kleffner syndrome are 2 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 (150; 31).

Benign focal epilepsies in childhood. Similarities between benign 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. Benign focal epilepsies are seen usually in normal children, with family antecedents and absence of 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 (29; 27). 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 (50; 163; 18; 47).

Diagnostic workup

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.

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

CT may be unremarkable or show unilateral or bilateral atrophic features (108).

Brain magnetic resonance is mandatory, considering that neuroradiological abnormalities can be found up to 60% of the cases with electrical status epilepticus during slow sleep, particularly thalamic lesions and cortical malformations.

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, none of whom were receiving antiepileptic drugs at the time of the MRI (which were considered within normal limits), analyzed subcortical gray matter volumes in patients with an ESES pattern on their electroencephalographs using high resolution T1-weighted 3-dimensional MPRAGE scans (122). These scans were assessed for segmentation and quantitative volumetric analysis of the brain by using the "volBrain" method. After correcting for total brain volume, volumes were compared with a group of healthy controls and patients with benign childhood epilepsy with centrotemporal spikes. 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 healthy controls and patients with BECTS. Both right and left relative thalamic volumes were lower in patients with ESES than in healthy controls and in patients with ESES than in patients with BECTS. However, there was no significant difference between the healthy controls and patients with BECTS (122).

A study of 18 ESES patients, 29 refractory epilepsy controls and 51 healthy controls, in which thalamic and total brain volumes were calculated using an algorithm for automatic segmentation and parcellation of magnetic resonance imaging, found that patients with ESES and normal magnetic resonance imaging have smaller relative thalamic volume controlling for age and total brain volume (141).

A study of 16 right-handed children aimed at evaluating the relationship of epileptic foci estimated from magnetoencephalography with cognitive functions at the period of diagnosis in nonlesional epilepsy with continuous spikes and waves during slow sleep, excluding those with Landau-Kleffner syndrome, estimated dipole clusters on the right Rolandic area in 4 patients (25%), right supramarginal gyrus in 3 (19%), left Rolandic area in 2 (13%), left supramarginal gyrus in 2 (13%), bilateral Rolandic area in 3 (19%), and multiple anatomical locations in 2 (13%) (98). The age at epilepsy onset had the strongest prognostic effect and full-scale intelligence quotient was relatively less affected if the cluster was found on the supramarginal gyrus (β = 14.7, p = 0.031). Cases with only a right-side cluster exhibited reduced impairment of perceptual organization compared with those with only a left-side cluster or bilateral clusters (β = 17.48, p = 0.02). In 12 of these patients, long-term intellectual prognosis was evaluated and was associated with intellectual level at the period of ECSWS diagnosis. The authors summarized that in nonlesional epilepsy with continuous spikes and waves during slow sleep, the relationship between epileptic focus and cognitive deficits differed from that observed in adults. Rather, it was similar to epilepsies associated with congenital or early infantile brain insults in that the left epileptic foci in right-handed patients were associated with lower nonverbal functions (98).

Magnetoencephalography has been used in several patients with Landau-Kleffner syndrome, mainly before deciding on surgery for these patients (148), but there are not reports in electrical status epilepticus during slow sleep.

Functional imaging studies have been performed so far related to the technique of neuroimaging performed and to the variability of the clinical phenotype, leading to results that are not always consistent. Most consistent findings are, depending of the method used, activations or increased regional glucose metabolism in the epileptogenic regions and deactivations, hypometabolism, or decreased functional connectivity in cortical regions that belong to the default mode network. Functional changes are either transitory, temporally related to the occurrence of interictal epileptiform discharges, or permanent, persisting across interictal epileptiform discharge-free periods. Some studies have shown that the more severe phenotype, ie, epileptic encephalopathy with CSWS, displays the more profound functional disturbances. Taken together, functional imaging studies support the concept that interictal epileptiform discharges impact cognition in epilepsy syndromes of childhood with sleep activation. However, the precise chronology between the occurrence of interictal epileptiform discharges and the functional disturbances, the neuropsychological correlates of the functional disturbances, and the effects of the antiepileptic treatments on interictal epileptiform discharges, functional disturbances, and cognition needs to be further studied (165).

Many functional cerebral studies (PET) have been performed in patients with electrical status epilepticus during slow sleep, identifying focal cerebral abnormalities in most of them, mainly frontal decreased metabolic activity that 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.) (100; 134; 62; 102; 33). PET studies using [18F]–fluorodeoxyglucose (FDG) were performed in 9 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 (35).

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.

Unfortunately, even knowing the strong relationship between the occurrence of paroxysmal activity and the onset of neuropsychological deterioration, electroencephalographic abnormalities of electrical status epilepticus during slow sleep respond poorly to treatment and until now, there is no proved therapeutic scheme able to control them definitively. Systematic studies of a large number of patients and various kinds of electrical status epilepticus during slow sleep-related disorders have not yet been published. This is why many aggressive therapies have been tried. It has been suggested that the suppression of subclinical epileptiform activity by an early and effective treatment could stop and revert this disorder affecting behavior, cognition, and language. Nevertheless, only few and limited studies have been conducted to evaluate the real influence of antiepileptic drug therapy on the clinical course of children with this infrequent syndrome. Indeed, reduction in polytherapy has been reported to improve the clinical picture (169).

Treatment with standard antiepileptic 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 (17; 63; 65; 64; 48). Instead, valproate, ethosuximide, and the benzodiazepines can be effective and deserve a trial before attempting treatments with higher risks. However, 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 (129; 48; 130).

There are consistent references about the preference of benzodiazepines or sulthiame to treat benign focal epilepsies of childhood because they seem to cause a reduction in EEG discharges (32; 31; 106; 132; 40). Chronic oral treatment with clobazam (92), lorazepam (09), and clonazepam (181) have been recommended. Incidentally, the power of benzodiazepines to reduce rapidly the EEG discharges was considered misleading for diagnosis of distinct syndromes within the electrical status epilepticus during slow sleep spectrum. Clonazepam controlled spike-wave activities in 2 children with electrical status epilepticus during slow sleep but had no effect on cognitive and motor disorders, preventing a proper diagnosis (04). In 2 cases of continuous spike-and-wave sleep, intravenous injection of flunitrazepam at a dose of 0.02 mg/kg cleared up the EEG discharges (82).

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 (142).

Sulthiame seems to be the oldest drug of choice according to several reports (61; 93; 175; 38; 48; 80; 73). However, in a update on therapy of ESES/CSWS syndrome, this alternative was not recommended (173).

As for the new antiepileptic drugs, lamotrigine was involved in inducing electrical status epilepticus during slow sleep in a couple of cases (Catania el al 1999; 25). Topiramate was also involved in 1 report (107). 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 4 patients showed retention of the drug after 1 year of treatment. The authors recognized that additional studies are needed in order to assess the place of levetiracetam in the treatment of these epileptic conditions. Preference for levetiracetam and clobazam was also reported (90). Lacosamide add-on treatment was reported to be effective in 6 out of 8 children with CSWS syndrome (60). Six children with Landau-Kleffner syndrome and CSWS were treated with acetazolamide. Three of them demonstrated complete resolution of electrical status in sleep, and 5 of the 6 children had subjective improvement in hyperactivity and attention (53). 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 (178). Thirty percent of these patients exhibited complete (or nearly complete) resolution of ESES. A majority of patients exhibited subjective cognitive, linguistic, or behavioral benefit. Amantadine was generally well-tolerated.

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. There was no agreement on best treatment (139).

Use of adrenocorticotrophics hormone or steroids has also shown some positive effects, but unfortunately, most of the results have been self limited (84; 07; 108; 150; 180). Steroid treatment was most successful in improving cognitive performance (167). 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 (105).

Although anecdotal cases treated successfully with intravenous immunoglobulins had been reported, there was initially no sufficient data to consider it as a possible treatment (50; 163). In a report of immunoglobulin treatment for severe childhood epilepsy, 6 of 12 patients with ESES showed full or partial improvement (58). Immunotherapy in 5 consecutive patients (4 males, age range 6 months-13 years) with molecularly confirmed GRIN-related epileptic encephalopathy (4 with GRIN2A-related epilepsy-aphasia spectrum/epileptic encephalopathy with CSWS, accompanied by verbal, communicative, and behavioral regression, and 1 patient with GRIN2D-related infantile developmental-epileptic encephalopathy), all of whom received monthly infusion of IVIG 2g/kg for 6 months, 2 of whom were also treated with high-dose corticosteroids, produced normalization or near normalization of the EEG in 3 patients, from whom 2 had mild improvement in verbal abilities and communication skills (68).

In 15 patients with electrical status epilepticus during slow sleep, including 1 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 3 of 7 trials, by short cycles of high-dose diazepam in 2 of 4 trials, and by adrenocorticotropic hormone-Z therapy in 2 of 5 trials. A permanent remission of electrical status epilepticus during slow sleep syndrome was only achieved with high-dose valproate and/or combination of valproate plus ethosuximide in 10 patients (74).

In a study where complete data were available in 33 children, the age at ESES diagnosis ranged from 32 to 165 months with a median of 76 months (179). The median duration of follow-up was 33 months. Two thirds of the children were on 1 or more antiepileptic drugs at ESES diagnosis. Antiepileptic drugs were used as first treatment for ESES in 24 of 33 (73%). Electrical status epilepticus in sleep initially resolved in 76% but 56% had subsequent relapse. The relapse rate was higher for steroids (89%) and benzodiazepines (60%) as compared with nonbenzodiazepine antiepileptic drugs (29%). At last follow-up, ESES using EEG criteria resolved in 21 children (64%). Electrical status epilepticus in sleep resolution was associated with seizure freedom (179).

In a 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 (95).

In a retrospective study of 21 cases with CSWS (3 were symptomatic), a significant number of them achieved clinical and EEG improvement (174).

Regarding the use of ketogenic diet, 5 children with continuous spike-and-waves during slow sleep refractory to antiepileptic drugs and steroids were prospectively evaluated (117). Resolution of electrical status epilepticus during sleep was observed in 1 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 (133).

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 (112; 111; 75). 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. No reports have been done as yet.

A series of 8 patients with refractory epilepsy, hemiparesis, and developmental delay with electrical status epilepticus during sleep underwent hemispherectomy (6) or focal reception (2), and 6 patients became seizure free (96). Because cognitive impairment may be aggravated by the persistence of electrical status epilepticus during sleep, these procedures may have developmental benefits.

In a series of 11 patients, focal cortical resections were performed in 7 children and hemispherectomies in 4 (176). Postoperatively, 9 children experienced decreased seizure frequency, 8 had neuropsychological improvement, and 9 had resolution of electrographic ESES.

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 (101).

Nine patients with electrical status epilepticus in sleep associated with a unilateral structural lesion amenable to surgery underwent hemispherotomy (78). 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 3 antiepileptic drugs) had hemispherotomy at a mean age of 7.2 years and showed that ESESS disappeared in all patients whereas 16 of 18 became seizure-free. An improvement of behavior and cognitive condition was observed in all (54).

The treatment strategy that we recommend in children with any of the epileptic encephalopathies with electrical status epilepticus during slow sleep, including the symptomatic cases, is (47):

(1) Discontinue the antiepileptic that the patient is taking and introduce benzodiazepines, ethosuximide (120; 14), or sulthiame. A combination of 2 of these may also be used. One alternative is to admit the patient, stop the antiepileptic drugs supposedly involved in the aggravation of the disease or at least have shown no benefit, and administrate high oral doses of diazepam for 1 or 2 weeks. Thereafter, the patient may be followed with ambulatory controls with diazepam, or switched to clobazam, or lowering progressively the doses of diazepam and adding ethosuximide or sulthiame. In our experience, good results were obtained with sulthiame in doses up to 20 mg/kg per day. If the case does not merit a hospital admission, or if there are difficulties or resistance to doing it, the switch should be done more cautiously, adding clobazam, ethosuximide, or sulthiame with a slow titration while the previous antiepileptic drugs are being discontinued. In fact, in a study of sulthiame add-on therapy in 53 children with focal epilepsies associated with encephalopathy related to ESES that were refractory to antiepileptic drugs, 10 of 28 patients in the symptomatic group became seizure free (44). Nine of the 28 patients showed a significant reduction in the number of seizures and presented spikes, but no ESES on EEG. The other 9 cases presented no clinical nor EEG improvement. Twenty-one of the 25 patients in the idiopathic group became seizure free and without ESES in less than 3 months after add-on sulthiame. Sulthiame may be a first-line drug as monotherapy in children with symptomatic or idiopathic ESES syndrome.

(2) If no significant improvement is seen, the following indication is steroids in high doses. Steroids have to be maintained for several months at least, and sometimes improvement starts to be seen after 2 months. In our first 2 cases with status of benign childhood epilepsy with centrotemporal spikes, steroids were clearly effective in stopping status, and after a couple of weeks they were discontinued (49).