Levetiracetam efficacy in epileptic syndromes with continuous spikes and waves during slow sleep: experience in 12 cases

PURPOSE: To assess the add-on efficacy of levetiracetam on the EEG, behavior, and cognition of children with continuous spikes and waves during slow sleep (CSWS). METHODS: Charts of children with behavioral and/or cognitive deterioration associated with CSWS who received levetiracetam at 50 mg/kg/day as add-on treatment were retrospectively reviewed. Awake and sleep EEG recordings and detailed neuropsychological and behavioral assessments were available at baseline and 2 months after levetiracetam initiation. In children showing clinical and/or electrophysiological improvement after 2 months, levetiracetam was continued with a new evaluation at 1 year. RESULTS: Twelve patients were included (9 cryptogenic and 3 symptomatic cases). Seven patients (58.3%) showed improvement of EEG record. Among these seven patients, neuropsychological evaluation was improved in three, and in the other four patients, not testable because of severe cognitive impairment, behavior was improved. Two patients improved in neuropsychological evaluation despite the lack of EEG improvement. Eight patients (66.6%) continued levetiracetam treatment after 2 months. After 1 year, four patients were still on levetiracetam, two because sustained effect on EEG and behavior and the two others because improvement in neuropsychological testing despite unchanged EEG. Levetiracetam was discontinued in the other four patients because of neuropsychological or behavioral deterioration associated with CSWS pattern, between 9 and 11 months after treatment initiation. CONCLUSIONS: This retrospective study suggests that levetiracetam has a positive effect on the EEG, the behavior, and the cognition of patients with epilepsy and CSWS. Additional studies are warranted in order to assess the place of this drug in these epileptic conditions.     

Observation of continuous spike-waves during slow sleep in children with myelomeningocele

Cases Two patients with myelomeningoceles (MMC) and shunt-treated hydrocephalus are reported. At 5 and 7 years respectively, when they began presenting mental deterioration and behavioural disorders, sleep EEG showed continuous spike-waves during slow sleep (CSWS). Discussion These are the first cases of CSWS described in patients with MMC. The mechanisms of CSWS are considered. The role of hydrocephalus and the thalamic injuries found in one of the patients is discussed in detail. The usefulness of monitoring sleep EEG in patients with hydrocephalus or thalamic lesions is stressed, considering the effects of CSWS on the cognitive competencies and the soft or subclinical course that epilepsy complicated with CSWS may follow.     

Corticosteroids as treatment of epileptic syndromes with continuous spike-waves during slow-wave sleep

To assess the efficacy and tolerability of steroids in epileptic syndromes with continuous spike-waves during slow-wave sleep (CSWS), charts of 44 children (25 boys) who received corticosteroids for cognitive and/or behavioral deterioration associated with CSWS were retrospectively reviewed. Awake and sleep electroencephalography (EEG) records, clinical and neuropsychological assessments were available before, during, and after corticosteroid therapy. Evaluation focused on effects on EEG, behavior, and cognition. All but two patients received hydrocortisone (initial dose of 5 mg/kg/day). The treatment was slowly tapered with a total duration of 21 months. There were 18 symptomatic and 26 cryptogenic cases. Mean age was 7 years and mean intelligence quotient/developmental quotient (IQ/DQ) was 65. Mean CSWS duration before corticosteroid treatment was 1.7 years. Twenty patients had tried more than two antiepileptic drugs (AEDs) before steroids. Positive response to steroids was found during the first 3 months of treatment in 34 of 44 patients (77.2%), with normalization of the EEG in 21 patients. Relapse occurred in 14 of them. Hence, 20 patients (45.4%) were long-term responders after a single but prolonged trial of steroids, including all four cases of Landau-Kleffner syndrome. Positive response to steroids was highly significantly associated with higher IQ/DQ. Shorter CSWS duration, but not age, etiology, or previous AED trials, was associated with positive response to steroids. Early discontinuation of the treatment for side effects was encountered in seven patients. We conclude that corticosteroids are safe and efficient for treatment of epilepsy with CSWS. Poor responders are patients with very low IQ and long duration of CSWS.     

Acquired cognitive dysfunction with focal sleep spiking activity

The syndrome of continuous spike-waves during slow sleep (CSWS) is considered an epileptic encephalopathy in which the epileptiform abnormalities may contribute to progressive cognitive dysfunction. The characteristic electroencephalographic feature of the syndrome occurs during non-REM sleep, and takes the form of continuous bilateral and diffuse slow spike-waves that persist through all slow sleep stages. Using a case study design including clinical, neuropsychological, electroencephalographic, and positron emission tomography with 18F-fluorodeoxyglucose (PET-FDG) investigations, we describe the clinical and electroencephalographic findings in two patients who presented with nonsymptomatic epilepsy with unilateral spike-waves during sleep. Both patients presented with a left unilateral motor neglect of the upper limb that was associated with unilateral CSWS activity over the right hemisphere, predominantly in the centrotemporal region. PET-FDG studies during the active phase of CSWS showed right centrotemporal hypermetabolism in both cases. After treatment, a regression of the CSWS activity and an improvement of the cerebral FDG pattern were paralleled by a remission of the motor neglect. These cases demonstrate that the electroencephalographic pattern of CSWS in nonsymptomatic epilepsies is not necessarily diffuse and bilateral, and that focal unilateral CSWS activity can be associated with focal neuropsychological deficits. These findings add further evidence that the spectrum of clinical conditions associated with the electroencephalographic pattern of CSWS can include different forms of acquired cognitive disturbances that may be focal in nature.     

Long-term follow-up of cognitive functions in patients with continuous spike–waves during sleep (CSWS)

Continuous spike–waves during sleep (CSWS) are associated with several cognitive, neurological, and psychiatric disorders, which sometimes persist after CSWS disappearance. The purpose of this retrospective study was to investigate the correlation between general (clinical and instrumental) and neuropsychological findings in CSWS, to identify variables that predispose patients to a poorer long-term neuropsychological outcome.Patients with spikes and waves during sleep with a frequency ≥ 25/min (spikes and waves frequency index — SWFI) were enrolled. There were patients presenting abnormal EEG activity corresponding to the classic CSWS and patients with paroxysmal abnormalities during sleep < 85% with SWFI ≥ 25/min that was defined as excessive spike–waves during sleep (ESWS). Clinical and instrumental features and neuropsychological findings during and after the spike and wave active phase period were considered. A statistical analysis was performed utilizing the Spearman correlation test and multivariate analysis. The study included 61 patients; the mean follow-up (i.e., the period between SWFI ≥ 25 first recording and last observation) was 7 years and 4 months.The SWFI correlated inversely with full and performance IQ during CSWS/ESWS. Longer-lasting SWFI ≥ 25 was related to worse results in verbal IQ and performance IQ after CSWS/ESWS disappearance. Other variables may influence the neuropsychological outcome, like age at SWFI ≥ 25 first recording, perinatal distress, pathologic neurologic examination, and antiepileptic drug resistance. This confirms that CSWS/ESWS are a complex pathology and that many variables contribute to its outcome.The SWFI value above all during CSWS/ESWS and long-lasting SWFI ≥ 25 after CSWS/ESWS disappearance are the most significant indexes that appear mostly to determine cognitive evolution. This finding underscores the importance of EEG recordings during sleep in children with a developmental disorder, even if seizures are not reported, as well as the importance of using therapy with an early efficacy.     

Cognitive deterioration and electrical status epilepticus during slow sleep

The results of long-term follow-up of 10 children with global or specific cognitive deterioration and, on the electroencephalogram, electrical status epilepticus during sleep (ESES) are described. They were referred because of cognitive deterioration and underwent repeated neurological and neuropsychological examinations and all-night electroencephalography. A previous cognitive level was known or could be estimated in all. Seven children had a continuous spikes and waves during sleep (CSWS) syndrome, with global cognitive deterioration in four and more specific cognitive decline in three, and another three children had Landau-Kleffner syndrome (LKS). Of the last three, two children never had seizures, while the other had localization-related epilepsy. No children experienced aggravation of clinical seizures. However, therapy was disappointing. Cognitive dysfunction did not respond to valproate and/or benzodiazepines in 9 of the 10 children. A frontal epileptic focus was found in 5 of 7 children with CSWS, and a left temporal focus in 2 of 3 children with LKS. The ESES persisted in CSWS for 5-9 years and in LKS for 1-5 years, and disappeared at puberty. Good cognitive recovery after disappearance of ESES occurred in only one child, and partial recovery in four. An unfavorable prognosis of cognitive deterioration seems to be related to long-duration ESES and/or early onset epileptic activity. The authors are of the opinion that cognitive deterioration in children, with or without manifest epileptic seizures, should mandate electroencephalographic investigation during sleep.     

Ictal and interictal EEG abnormalities in ADHD children recorded over night by video-polysomnography

In this paper we explore the prevalence of ictal and interictal epileptiform discharges (IEDs) and sleep disorders in ADHD children referred to a sleep clinic for all night video-PSG. Forty-two ADHD outpatients (35 males and 7 females) underwent video-PSG and a behavioural/neuropsychological assessment. Spearman correlation coefficients (p<0.05 criterion level) were used to assess the association between cognitive, behavioural, clinical (co-morbidity), sleep (sleep efficiency) and EEG (seizures, IEDs, localization of IEDs foci) variables. Sleep disorders were found in 86% of ADHD children; among these, 26% had RLS. 53.1% of ADHD children had IEDs (28.2% centro-temporal spikes, 12.5% frontal spikes, 9.3% temporal-occipital spikes and 2.3% generalized S-W). Nocturnal seizures were recorded in three patients: two with atypical interictal rolandic spikes and one with left frontal slow abnormalities. A significant relationship (p<0.05) emerges between nocturnal seizures and WISC-R IQ score and visual-spatial memory test and between some cognitive variables and interictal rolandic spikes. High levels of inattention, impulsivity/hyperactivity and oppositional behaviours were related (p<0.01 or 0.05) with Restless Leg Syndrome diagnosis. In conclusion, ADHD is a condition often associated with EEG epileptiform abnormalities. Seizures/IEDs presence seems to play a role on cognitive abilities, conversely sleep disorders have a stronger impact on behavioural rather than cognitive indicators.     

Long-term outcome after cognitive and behavioral regression in nonlesional epilepsy with continuous spike-waves during slow-wave sleep

Purpose: To present the long‐term follow‐up of 10 adolescents and young adults with documented cognitive and behavioral regression as children due to nonlesional focal, mainly frontal, epilepsy with continuous spike‐waves during slow wave sleep (CSWS). Methods: Past medical and electroencephalography (EEG) data were reviewed and neuropsychological tests exploring main cognitive functions were administered. Key Findings: After a mean duration of follow‐up of 15.6 years (range, 8–23 years), none of the 10 patients had recovered fully, but four regained borderline to normal intelligence and were almost independent. Patients with prolonged global intellectual regression had the worst outcome, whereas those with more specific and short‐lived deficits recovered best. The marked behavioral disorders resolved in all but one patient. Executive functions were neither severely nor homogenously affected. Three patients with a frontal syndrome during the active phase (AP) disclosed only mild residual executive and social cognition deficits. The main cognitive gains occurred shortly after the AP, but qualitative improvements continued to occur. Long‐term outcome correlated best with duration of CSWS. Significance: Our findings emphasize that cognitive recovery after cessation of CSWS depends on the severity and duration of the initial regression. None of our patients had major executive and social cognition deficits with preserved intelligence, as reported in adults with early destructive lesions of the frontal lobes. Early recognition of epilepsy with CSWS and rapid introduction of effective therapy are crucial for a best possible outcome.     

Are frequent spikep-waves during non-REM sleep in relation with an acquired neuro-psychological deficit in epileptic children ?

In a population of 11 children with frequent spike waves during non REM sleep who had no neurological symptoms between birth and their first symptom, 3 groups were compared according to their neuropsychological performances. In the first group, the children had no intellectual deficit, in the second group, they had an acquired aphasia as in the Landau-Kleffner syndrome and in the third they had severe behavioural disorder and mental deterioration. The non REM sleep paroxysmic activity density tended to be highest in the third group, variable in the second group and moderate in the first group, and their topography was always generalized in the acute phase in groups II and III but asymmetrical in group I. The EEG anomalies disappeared during adolescence but in group II and III children a moderate to severe delay in school work persisted.     

Early thalamic injury associated with epilepsy and continuous spike-wave during slow sleep

PURPOSE: Mechanisms inducing continuous spike-wave during slow sleep (CSWS) in encephalopathy with electrical status epilepticus during sleep are still unclear. Recently, some sporadic cases with early thalamic injury associated with CSWS have been reported. The aim of the study was to investigate in a population of patients with an early thalamic injury the presence of an activation of paroxysmal activities during sleep, their characteristics, and possible relations to neuroimaging and neuropsychological features. METHODS: Thirty-two patients with prenatal or perinatal thalamic injuries, mostly due to a vascular mechanisms, were fully examined, including neuroimaging, EEG monitoring, and cognitive follow-up. RESULTS AND CONCLUSIONS: Twenty-nine of 32 patients showed major sleep EEG activation. Among these 29 patients, two different groups were distinguished: the first included the more or less typical CSWS (12 cases), generally with symmetry of spike and waves (SWs) and often with no spindle at all. The other cases had an usual asymmetry of SWs and presence or reduction of spindles, plus other atypical features concerning synchronism and morphology of SWs. Behavioral disorders were significantly more present in patients with a true CSWS; their improvement (and in one case of the three thoroughly followed the improvement of cognitive competence) paralleled the disappearance of CSWS. The generally predominant injury of the lateral aspect of the thalamus included reticular nucleus and ventral nuclei. An imbalance of gamma-aminobutyric acid (GABA)(B)--versus GABA(A)--mediated receptors may be evoked as a cofactor predisposing to CSWS.     

Role of interictal epileptiform abnormalities in cognitive impairment

The epileptic encephalopathies are conditions in which neurological deterioration is attributable entirely or partly to epileptic activity and is due to very frequent or severe seizures or severely abnormal electroencephalograms (EEGs), or both. Evidence for the concept that seizures or the abnormal EEGs are responsible for the cognitive deterioration is the observation that patients can improve dramatically when therapy eliminates or reduces seizure frequency and improves or normalizes the EEG. For example, children with the syndrome of continuous spike-wave of sleep (CSWS) have electrical status epilepticus during sleep (ESES) and cognitive regression. Although seizures often occur in the disorder, there are indications that the EEG abnormalities are responsible for the cognitive regression. Interictal spikes, which correspond to a large intracellular depolarization with evoked action potentials, in many ways mimic a "miniseizure." Interictal spikes can result in transitory cognitive impairment with the type of deficit dependent on where in the cortex the spike arises. We suggest that interictal spikes, particularly if frequent and widespread, can impair cognitive abilities, through interference with waking learning and memory, and memory consolidation during sleep.     

Continuous spikes and waves during slow sleep: a 30 months follow-up study of neuropsychological recovery and EEG findings

An eight-year-old boy is reported who presented with a progressive mental deterioration in the years following a nocturnal asymmetrical generalized tonic-clonic seizure. The diagnosis of continuous spikes and waves during slow sleep (CSWS) was made. Once a month a sleep recording was made during twenty-two consecutive months and detailed neuropsychological studies were made over a period of 30 months. Intensive antiepileptic treatment resulted in the disappearance of the CSWS and in a recovery from intellectual-, language- and behavioural disturbances. The good results were still present at a follow-up examination 30 months later.     

Epileptic encephalopathy with continuous spikes and waves during sleep in children with shunted hydrocephalus: a study of nine cases

Purpose: We present a series of nine patients with early‐onset hydrocephalus who had seizures and continuous spikes and waves during slow sleep (CSWS) associated with neurocognitive and motor deterioration. Methods: Six boys and three girls aged 9–16 years (mean 11.3 years) were studied. [Correction added after online publication 12‐Apr‐2008: Number of girls and boys has been updated.] All patients underwent clinical examinations, electroencephalographic evaluations, neuroradiological imaging and neuropsychological assessment at first examination. Antiepileptic drugs (AEDs) were given in all cases and changed according to clinical and EEG evolution. Results: Onset of epilepsy occurred from age 8 to 60 months (mean 19.6 months and median 14 months) with focal seizures with or without secondary generalized tonic–clonic seizures. Between ages 6 and 13 years (mean 10.4 years and median 8 years), hyperkinesia, aggressiveness, and poor socialization appeared in all nine cases. Reduced attention span, deterioration of language, and temporospatial disorientation were found in three of them. Negative myoclonus was found in two patients. The EEG showed CSWS. Response to change in treatment was good in all patients. None of the patients had relapses, seven of them have remained seizure free, and two continued having sporadic focal motor seizures during 2–5 years (mean 3 years) of follow‐up. Conclusion: In children with early‐onset hydrocephalus, particularly with behavioral and language disturbances and/or motor deterioration, CSWS should be considered. Periodic EEG recordings during sleep should be done in these children. The early identification of this particular electroclinical picture is crucial to start adequate treatment to avoid progressive cognitive deterioration.     

Epilepsy and sleep: with special reference to nonconvulsive status epilepticus with continuous diffuse spike-waves during slow-wave sleep

There are numerous important problems concerning relationship between epilepsy and sleep. To clarify the clinical significance and pathophysiology of the nonconvulsive status epilepticus with continuous diffuse spike-waves during slow-wave sleep (CSWS) in EEG, this study was carried out on seven cases each of epilepsies with electrical status epilepticus during slow sleep (ESES) and with peculiar type of nonconvulsive status epilepticus in childhood (PNSE) and four cases of atypical benign partial epilepsy (ABPE). Mental deterioration was most frequently observed in ESES, less in PNSE but none in ABPE. In both ESES and PNSE, mentally deteriorated cases showed suppression of CSWS at significantly later ages than those without deterioration. And spike-wave indices during slow-wave sleep, which were the highest in ESES and lower in PNSE and ABPE, also had a strong relation to mental deterioration. In these three disorders, both clinical seizures and CSWS were suppressed at or before 16 years of age, although they were intractable before adolescence. This finding indicated age dependent evolutions of the three disorders. Coherence and phase analysis of CSWS was undertaken to differentiate primary and secondary bilateral synchrony in seven cases of these three disorders, which have both features of generalized and partial epilepsies. This analysis disclosed secondary bilateral synchrony as the nature of CSWS in six cases. And this analysis method was considered to provide a clue to their pathophysiology. Thus, in these disorders, importance of early diagnosis by EEG including deep sleep and early treatment was recognized.     

CSWS-related autistic regression versus autistic regression without CSWS

Continuous spike-waves during slow-wave sleep (CSWS) and Landau-Kleffner syndrome (LKS) are two clinical epileptic syndromes that are associated with the electroencephalography (EEG) pattern of electrical status epilepticus during slow wave sleep (ESES). Autistic regression occurs in approximately 30% of children with autism and is associated with an epileptiform EEG in approximately 20%. The behavioral phenotypes of CSWS, LKS, and autistic regression overlap. However, the differences in age of regression, degree and type of regression, and frequency of epilepsy and EEG abnormalities suggest that these are distinct phenotypes. CSWS with autistic regression is rare, as is autistic regression associated with ESES. The pathophysiology and as such the treatment implications for children with CSWS and autistic regression are distinct from those with autistic regression without CSWS.     

Continuous spikes and waves during sleep in children with shunted hydrocephalus

Focal epileptiform abnormalities in awake children submitted to ventricular shunting are well described in the literature, but there are few reports about EEG patterns during sleep. We studied 20 children affected by hydrocephalus of various aetiology and submitted to shunting during the first year of life. We found focal abnormalities in all the children and in 95% of cases they were on the same side as the shunt; in 65% of cases they had an amplitude of 300 mV or more. During sleep there was activation of abnormalities in all subjects, and in 33% we found continuous spikes and waves during slow sleep (CSWS). We discuss the aetiology of CSWS and its possible role in causing the neuropsychological disturbances of our patients. Received: 19 May 1997 Revised: 19 December 1997     

A review of the relationships between Landau-Kleffner syndrome, electrical status epilepticus during sleep, and continuous spike-waves during sleep

The goal of this report is to review the relationships between Landau-Kleffner syndrome (LKS), electrical status epilepticus during sleep (ESES), and continuous spike-waves during sleep (CSWS). LKS is a clinical syndrome involving mainly acquired aphasia and sometimes seizures. Other clinical findings include cognitive impairments and global regression of behavior. The EEG may evolve from more benign conditions into ESES (or CSWS), seen in 50% of patients with LKS, or may also show focal findings. Seizures include atypical absence, generalized tonic-clonic, atonic, and partial motor attacks. Effective medications are discussed. The EEG patterns CSWS and ESES are likely equivalent terms. CSWS is used by some authors, and ESES by others. Patients with these patterns usually show mental retardation, seizures, and global regression. More benign EEG patterns, like focal discharges, may develop into these more severe generalized patterns, which are associated with atypical absences, negative myoclonus, and cognitive disturbances. Memory disorders are common, because the nearly continuous generalized discharges in sleep do not allow for the memory consolidation that also occurs during sleep. Medications and possible etiologies are discussed.     

Encephalopathy with continuous spike‐waves during slow‐wave sleep: evolution and prognosis

Encephalopathy with continuous spike‐waves during slow‐wave sleep (CSWS) evolves over time, and three stages can be recognized: before the onset of CSWS, during CSWS, and after the CSWS period. Clinical seizures tend to remit spontaneously around puberty. This pattern is independent of the etiological lesion. 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 non‐lesional 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. Early recognition and effective therapy to reduce the seizures and resolve the CSWS may be crucial to improve long‐term prognosis. Cognitive recovery is observed in patients who respond well to AED treatment and outcome depends on the etiology.     

Encephalopathy related to Status Epilepticus during slow Sleep: a link with sleep homeostasis?

Encephalopathy related to Status Epilepticus during slow Sleep (ESES) is a childhood epilepsy syndrome characterized by appearance of cognitive and behavioural disturbances in conjunction with a striking activation of EEG epileptic abnormalities during sleep. The link between the extreme amount of epileptic discharges during sleep and the deterioration of cognitive functions and behavior is poorly understood. We hypothesize that the negative effects of ESES may depend on the impairment of the synaptic homeostasis processes occurring during normal sleep and that are particularly important in the developmental age. Sleep ensures synaptic homeostasis by promoting synaptic weakening/elimination after the increase of synaptic strength that occurs during wakefulness. Changes in synaptic strength are reflected in the EEG by changes of sleep slow wave activity (SWA). Recent studies in ESES have failed to show changes of sleep SWA, particularly at the site of the epileptic focus, suggesting a spike‐related impairment of the homeostatic recovery of sleep. This impaired synaptic homeostasis in the critical period of development may alter cortical wiring and thereby disrupt, often irreversibly, cognitive functions and behavior, leading to the neuropsychological compromise typical of ESES.     

SPECT and epilepsy with continuous spike waves during slow-wave sleep

Ten cases of epilepsy with continuous spike waves in slow-wave sleep (CSWS) were evaluated using single photon emission computed tomography (SPECT); in eight patients the EEG paroxysmal abnormalities showed a predominant localization. SPECT carried out using^99mTc-HMPAO allows study of cerebral blood flow (CBF); the examination was performed during phases of drowsiness and the results compared to the EEG data. In four cases SPECT revealed areas of low CBF in sites corresponding to those of the prevalent EEG discharges; in two cases the areas of hypoperfusion did not correspond to those indicated by the EEG; lastly, in four cases SPECT results were negative. The areas of hypoperfusion were predominantly located in the frontal, temporal, and parietal regions. Furthermore, the percentage of positive SPECT results was significantly higher (five cases out of six) in the group in which the CSWS phase was prolonged for at least 1 year, compared to the group in which this phase lasted less than 1 year. Thus, in this type of epilepsy, SPECT reveals focal cortical areas of decreased CBF which correlated generally to the predominant sites of EEG abnormalities. A longer duration of the CSWS phase seems to be associated with a more significant cortical disorder, documented by the presence of areas of hypoperfusion.