Myoclonus epilepsy with ragged-red fibers
Nov. 06, 2023
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This article emphasizes the clinical and EEG features of epileptic encephalopathy with continuous spike-and-wave during sleep and the occurrence of secondary bilateral synchronies as a mechanism for the generalization of previously focal epileptic discharges. In addition, the article points out that this syndrome may appear in children, starting first with idiopathic focal epilepsies, and also in children with prenatal cerebral lesions. This article discusses language development and impairment in children and adolescents with the disorder.
Electrical status epilepticus during sleep in children was first reported in 1971 by Patry, Lyagoubi, and Tassinari (103). They described six patients with a peculiar EEG pattern characterized by apparently subclinical spike-and-waves occurring almost continuously during NREM sleep with dramatic improvement during awaking and REM sleep. Five of them had epileptic seizures and were intellectually impaired. An interesting feature was that one child never had seizures and had normal motor development but no acquisition of speech. A few years later, in 1977, Tassinari and colleagues introduced the terms “encephalopathy related to electrical status epilepticus during sleep” and “electrical status epilepticus during slow sleep” for this syndrome (135; 129).
Questions regarding the term of status without detectable simultaneous clinical signs as well as the finding of electrical status epilepticus during slow sleep in nonepileptic children prompted the use of the term “epilepsy with continuous spike and waves during slow sleep,” which was adopted by the Commission on Classification and Terminology of the International League Against Epilepsy in 1989 (88; 126; 19).
In 2001, the International League Against Epilepsy (ILAE) Task Force on Classification proposed a group of syndromes named epileptic encephalopathies, which included epilepsy with continuous spike-wave during slow sleep and Landau-Kleffner syndrome, among others (29). Many common features and possible similar physiopathological mechanisms of production between these two syndromes have been proposed, leading to questions of whether they are two distinct entities or subclasses of a single syndrome (27; 55; 22; 121; 112; 34; 132; 133; 122).
Interestingly, a group of patients with particular evolutive features was recognized: children with benign childhood epilepsy with centrotemporal spikes, now termed “self-limited epilepsy with centrotemporal spikes” (SeLECTS) (124), with initially typical clinical and EEG features who follow an atypical course (02) or later on develop a status of benign childhood epilepsy with centrotemporal spikes, Landau-Kleffner syndrome, or electrical status epilepticus during slow sleep (02; 35; 34). Of note, the new terminology, which replaces “benign childhood epilepsy with centrotemporal spikes” with the term “self-limited epilepsy with centrotemporal spikes,” was proposed to remove the term “benign” from the syndrome, as these patients may present with comorbidities, including attention-deficit/hyperactivity disorder or cognitive deficits related to language and executive function (124), further highlighting the clinical spectrum associated with epileptic encephalopathy with continuous spike-and-wave in sleep.
In 2022, the ILAE proposed new terminology to describe this syndrome. The newest classification describes developmental or epileptic encephalopathy (DEE) and epileptic encephalopathy (EE) with spike-and-wave activation in sleep (SWAS) as a spectrum of conditions that are characterized by combinations of cognitive, language, behavioral, and motor regression associated with marked spike-and-wave activation in sleep. This syndrome is intended to replace syndromes previously named “epileptic encephalopathy with continuous spike-and-wave in sleep” and “atypical benign partial epilepsy” (pseudo-Lennox syndrome). The term “Landau–Kleffner syndrome” is defined as a subtype of EE-SWAS in which there is a specific regression primarily affecting language with an acquired auditory agnosia (124).
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 (29):
(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 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; 134). In a series of 10 patients, nocturnal motor seizures were predominant, and all of them also had atonic seizures (54). Tonic seizures during sleep or while awake are always absent in this syndrome.
Based on seizure patterns, three groups have been proposed: (1) patients with rare and nocturnal motor seizures (11%); (2) patients with unilateral 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 (133; 134).
Neuropsychological development. Normal neuropsychological development at the beginning of the disease is present in 60% to 75% of cases (20; 89; 90; 130). 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 (60; 130). Mental and behavioral deterioration evoking a frontal lobe syndrome has been described in children with spikes or spike-waves discharges in the frontal lobe (113) that can even persist after resolution of electrical status epilepticus during slow sleep in the EEG (140). 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 (26). 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 (21). Fourteen patients with ESES were evaluated in 2010 (108). Eleven children had behavioral issues, and seven showed evidence of cognitive impairment. 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 (80).
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 (96). 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).
Motor impairment. Motor impairment, including dyspraxia, dystonia, ataxia, or unilateral deficit, has been emphasized as one of the outstanding disturbances occurring in this syndrome (20; 95). 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 (115; 10; 102). 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 (50). 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 (99). 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; 18). 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 (141).
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 (20; 90; 51; 09; 134; 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 (132), but focal interictal spikes may persist (89; 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; 134).
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. 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 long-term follow-up of 25 patients, low IQ scores and behavioral disturbances persisted in 50% (134). The majority of affected children never return to normal levels, particularly in the verbal area and attention (88; 113). 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. 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 (88; 113; 14).
A comprehensive and long-term follow-up of one case showed details about the evaluation of the boy’s behavior, language, and cognitive functions, suggesting a dysexecutive syndrome (56). During the 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 (90). In an 8-year-old boy with occipitotemporal epilepsy with continuous spike-and-waves during slow sleep followed for 2 years, major deficits in visual perception with normal verbal intelligence were found (31). Moreover, persistence of electrical status epilepticus during slow sleep during 17 months without behavioral changes was also reported (44). 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 (26). Outcome at adulthood has been reported in seven young adults, five of whom had continuous spike-and-waves during slow sleep syndrome and two who had Landau-Kleffner syndrome in childhood. The authors emphasized the role of location of interictal EEG focus and age of onset as prognostic factors (105). Neuropsychological tests of 25 children diagnosed with CSWS were reviewed in a long-term evolution study (104). 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 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 (128). 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 (117).
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 (69), 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 (69; 149). Furthermore, vascular lesions of the thalamus during early development have been identified in relation to electrographic patterns in ESES (69; 150). In patients with epilepsy, magnetic resonance spectroscopy (MRS) has been shown to identify a decreased N-acetylaspartate/creatine (NAA/Cr) ratio as a sign of neuronal cell loss or dysfunction. One study identified decreased thalamic volume and NAA/Cr ratio in patients with ESES, further supporting the theory that a metabolic-induced thalamic dysfunction may play a role in epileptogenesis in this disease (69). Of note, thalamic lesions are the most commonly reported MRI abnormality in patients with ESES (68).
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 (63).
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 (67). 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 (98). Seven copy number variations were detected in four 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 (94). One child with karyotype 47,XYY was also presented with rolandic spikes, atypical evolution with continuous spikes, and waves during slow sleep (17). In a study using 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 (76).
Sixteen studies reported 11 monogenic mutations: SCN2A, NHE6/SLC9A6, DRPLA/ATN1, Neuroserpin/SRPX2, OPA3, KCNQ2, KCNA2, GRIN2A, CNKSR2, SLC6A1, and KCNB1 (66). 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 (66). 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 (125), as demonstrated by interhemispheric peak latencies of their EEG correlates (89; 92; 91), phase reversal of spikes on unilateral frontal regions (88), and studies of coherence and phase analyses (70). Localized metabolic abnormality has been revealed also by PET studies (81; 24). 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:
(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) (126).
(2) The duration of electrical status epilepticus during slow sleep is correlated with the final neuropsychological outcome (114).
(3) There is a strict association between the pattern of neuropsychological dysfunction and the location of the interictal focus (114). A deterioration of language is observed in cases showing the predominance of paroxysmal abnormalities over one or both temporal regions (05), 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 (113). 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 (20; 95).
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" (125). "Interictal paroxysmal activity" may interfere with different cognitive processes, as demonstrated by neurophysiological, neuropsychological, and biochemical studies (06; 145; 120; 131).
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 (71). 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 (93). 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.
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 (89). In a cohort of 440 consecutive pediatric patients with at least two seizures, Kramer and colleagues found “epilepsy with ESES” in 0.2% (72). 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 (89; 127; 130; 134).
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 (139; 52; 65). In a series with 60 patients with early thalamic injury, CSWS was again found as a frequent complication related to cognitive outcome (79). Many cases with cortical malformations, especially polymicrogyria, also have been related to electrical status epilepticus during slow sleep (51; 100; 11).
(2) Patients with benign childhood epilepsy with centrotemporal spikes (now termed SeLECTs) with an atypical evolution also may risk evolution into Landau-Kleffner syndrome or electrical status epilepticus during slow sleep (02; 35; 34).
(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 (84).
(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 (12; 50; 49; 34). Valproic acid, lamotrigine, and topiramate have also been involved in sporadic cases, but more data are necessary (106; 15; 87; 16).
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 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 (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 (125; 22).
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 (20; 18). 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; 136; 13; 33).
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 (60). Meanwhile, REM sleep has been shown to have a suppressive effect on epileptic activity in ESES (43). REM sleep is defined by alternations between phasic (PREM) and tonic (TREM) sleep. PREM sleep is defined by burst soft eye movements, myoclonic skeletal muscle movements, middle ear contractions, irregular respiratory and cardiac activity, and a high state of cortical activity similar to active wakefulness. TREM sleep, however, is more similar to restful wakefulness; it is a more quiescent state, lasting for longer periods of time. When further evaluating REM sleep, the spike-wave-index (SWI) has been shown to be significantly reduced in PREM sleep when compared to TREM sleep. The mechanism of this suppressive effect is hypothesized to be due to increased acetylcholine levels during the PREM sleep phase.
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 (126). 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 (126; 127; 130). 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 (41). Persistence of electrical status epilepticus during slow sleep during 85% to 100% of slow sleep was initially considered an essential criterion for diagnosis (103; 126), 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; 148; 04). 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; 88).
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 (123), but there are no reports in electrical status epilepticus during slow sleep.
Imaging. Regarding imaging, a CT (computerized tomography) scan may be unremarkable or show unilateral or bilateral atrophic features (88).
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 (101; 68). 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 (101). 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 healthy controls and patients with BECTS (101). Another study comparing thalamic volume on MRI evaluated 18 ESES patients, 29 refractory epilepsy controls, and 51 healthy controls (118). 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.
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 on 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 (137).
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.) (81; 111; 47; 83; 24). 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 (25).
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 (116).
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 (150). 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 (68; 149).
In a study where complete data were available in 33 children (147), two thirds of the children were on one or more antiepileptic drugs at ESES diagnosis. Antiepileptic drugs were used as first treatment for ESES in 24 of 33 (73%) patients. 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.
Corticosteroids. Steroid treatment was most successful in improving cognitive performance (138). 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 (85).
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 (23; 22; 86; 109; 30). Chronic oral treatment with clobazam (74), lorazepam (07), and clonazepam (148) 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 (64). 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 (119).
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 (58).
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 (77).
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 (73).
Lacosamide add-on treatment was reported to be effective in six out of eight children with CSWS syndrome (45).
Perampanel has been suggested as an effective add-on treatment for ESES, which acts as a noncompetitive antagonist on AMPA glutamate receptors (149).
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 (146). 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.
According to several reports, sulthiame seems to be the oldest drug of choice (46; 75; 143; 28; 34; 62; 57). However, in an update on therapy for ESES/CSWS syndrome, this alternative was not recommended (142).
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; 50; 49; 48; 34). Lamotrigine was involved in inducing electrical status epilepticus during slow sleep in a couple of cases (15; 16), and topiramate was also involved in one report (87). 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 (106; 34; 107).
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; 136). 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 encephalopathy (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 (53). 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 (97). 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 (110).
Surgical treatments. In a series of 11 patients, focal cortical resections were performed in seven children and hemispherectomies in four (144). 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 (78). 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 (82).
Nine patients with electrical status epilepticus in sleep associated with a unilateral structural lesion amenable to surgery underwent hemispherotomy (61). 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 (92; 91; 59). 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.
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 (68). Therefore, it is recommended that ESES be treated as soon as possible.
All contributors' financial relationships have been reviewed and mitigated to ensure that this and every other article is free from commercial bias.
Donya Eizadkhah MD
Dr. Eizadkhah of Albert Einstein College of Medicine has no relevant financial relationships to disclose.See Profile
Solomon L Moshé MD
Dr. Moshé of Albert Einstein College of Medicine has no relevant financial relationships to disclose.See Profile
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