Acetazolamide for electrical status epilepticus in slow‐wave sleep

Electrical status epilepticus in slow‐wave sleep (ESES) is characterized by nearly continuous spike–wave discharges during non–rapid eye movement (REM) sleep. ESES is present in Landau‐Kleffner syndrome (LKS) and continuous spike and wave in slow‐wave sleep (CSWS). Sulthiame has demonstrated reduction in spike–wave index (SWI) in ESES, but is not available in the United States. Acetazolamide (AZM) is readily available and has similar pharmacologic properties. Our aims were to assess the effect of AZM on SWI and clinical response in children with LKS and CSWS. Children with LKS or CSWS treated with AZM at our institution were identified retrospectively. Pre‐ and posttherapy electroencephalography (EEG) studies were evaluated for SWI. Parental and teacher report of clinical improvement was recorded. Six children met criteria for inclusion. Three children (50%) demonstrated complete resolution or SWI <5% after AZM. All children had improvement in clinical seizures and subjective improvement in communication skills and school performance. Five of six children had subjective improvement in hyperactivity and attention. AZM is a potentially effective therapy for children with LKS and CSWS. This study lends to the knowledge of potential therapies that can be used for these disorders, which can be challenging for families and providers.     

Scalp‐recorded high‐frequency oscillations in childhood sleep‐induced electrical status epilepticus

Because high‐frequency oscillations (HFOs) may affect normal brain functions, we examined them using electroencephalography (EEG) in epilepsy with continuous spike‐waves during slow‐wave sleep (CSWS), a condition that can cause neuropsychological regression. In 10 children between 6 and 9 years of age with epilepsy with CSWS or related disorders, we investigated HFOs in scalp EEG spikes during slow‐wave sleep 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. HFOs (ripples) concurrent with spikes were detected in the temporally expanded traces, and the frequency of the high‐frequency peak with the greatest power in each patient’s spectra ranged from 97.7 to 140.6 Hz. This is the first report on the detection of HFOs from scalp EEG recordings in epileptic patients. We speculate that epileptic HFOs may interfere with higher brain functions in epilepsy with CSWS.     

Epilepsy with Electrical Status Epilepticus During Slow Sleep and Secondary Bilateral Synchrony

Summary: In 3 children with "epilepsy with electrical status epilepticus during slow sleep" (ESES), we estimated interhemispheric small time differences (TDs) during spike-wave activity in EEG by coherence and phase analysis by the two-dimensional autoregressive model to differentiate their continuous diffuse spike-waves during slow-wave sleep (CSWS) between primary bilateral synchrony and secondary bilateral synchrony (SBS). Maximal TDs at onset of apparently bilateral synchronous spike-wave bursts (BSSWs) during slow-wave sleep were 12·0–26·5 ms (mean 20·3 ms) with consistent leading hemispheres in eight bursts of the 3 patients, indicating SBS as pathophysiology of their CSWS. This suggestion was supported by their clinico-EEG findings, including the effect of a single oral dose of clobazam (CLB) on EEG. Three ictal BSSWs of atypical absence seizures in 2 patients were also analyzed to obtain maximal TDs of 17·9–41·7 ms (mean 26·3 ms) at onset, with the same leading sides as in sleep, also indicating SBS. Examination of intraburst TD variations showed no consistent disappearance of TDs during the latter part of the bursts, in either sleep or the ictal EEGs of atypical absences, and a role of the corpus callosum was suggested in the generation of SBS in ESES.     

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.     

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.     

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.     

Cognition and Paroxysmal EEG Activities: From a Single Spike to Electrical Status Epilepticus during Sleep

Summary:  Epileptic EEG paroxysms can interfere with cognitive processes producing transitory effects, such as those related to a single spike, as well as long-lasting effects, such as in electrical status epilepticus during slow-wave sleep (ESES). Focal spike-related disruption of cortical functions can produce transitory cognitive impairment, with neuroanatomical specificity between the site of the epileptic focus and the impaired cognitive tasks. ESES represents a model of the long-lasting effects of continuous spike-wave activity on higher cortical functions. The duration of ESES and the localization of interictal foci seem to play a major role in influencing the degree and type of cognitive dysfunction, suggesting that the ESES clinical picture results from a localized disruption of EEG activity caused by focal epileptic activity during sleep. Recently, Giulio Tononi's group reported that a local increase of slow-wave activity (SWA) during sleep after learning is associated with improved performance of the learned task after sleep (Huber et al., Nature 2004;430:78–81). On the basis of these findings, we can speculate that prolonged focal epileptic activity during sleep (as occurring in ESES) interferes with local SWA at the site of the epileptic focus, impairing the neural processes and, possibly, the local plastic changes associated with learning and other cognitive functions.     

EEG features in Encephalopathy related to Status Epilepticus during slow Sleep

Encephalopathy related to Status Epilepticus during slow Sleep (ESES) is a peculiar electro‐clinical condition, with variable etiologies, characterized by an age‐dependent phenomenon of extreme activation of epileptic activity during sleep, i.e. “status epilepticus during sleep”, that is strictly associated with the appearance of cognitive and behavioral disturbances. Even though the peculiar EEG picture is fundamental for the diagnosis of ESES, clear‐cut and shared diagnostic criteria for defining the EEG boundaries of this syndrome are still lacking. The diagnosis of ESES can be further complicated by the variability of the EEG findings, that during the course of the disease can change from diffuse to more or less focal and viceversa, depending both on the spontaneous clinical evolution of this condition and/or on the effects of medications. Given the complexity and the heterogeneity of EEG parameters during the ESES course, it is important to correlate the EEG findings with the concomitant cognitive and behavioral status, possibly taking into account not only the spike‐wave index, but also other parameters, such as for instance the topography of the epileptic abnormalities, their patterns of spread, and their fluctuations over time. Moreover, the epileptiform activity not only during sleep, but also during wakefulness, the presence of focal slowing, the organization of the EEG background and a derangement of the sleep architecture may play a role in determining the clinical picture.     

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.     

Epilepsy with Continuous Spike-Waves During Slow Sleep and Its Treatment

Five children with epilepsy with "continuous spike-waves during slow sleep" (CSWS) are reported. The main clinical features of CSWS include (a) onset between 5 and 7 years of age, (b) the occurrence of several types of seizure (i.e., partial motor, generalized motor, and atypical absence), and (c) the presence of language disturbances and abnormal behavior based on emotional impairment. The EEG findings were characterized by sleep tracings showing almost continuous (greater than 95%), diffuse slow spike and wave activity. After treatment with valproate (VPA) (or ethosuximide, ESM) and clonazepam (CZP), the spike and wave complex status disappeared. Symptoms and signs of the CSWS also decreased. We suggest that combined treatment is an appropriate treatment for CSWS.     

Functional brain connectivity in electrical status epilepticus in sleep

Aims. Electrical status epilepticus in sleep (ESES) is an age‐related, self‐limited epileptic encephalopathy. The syndrome is characterized by cognitive and behavioral abnormalities and a specific EEG pattern of continuous spikes and waves during slow‐wave sleep. While spikes and sharp waves are known to result in transient cognitive impairment during learning and memory tasks performed during the waking state, the effect of epileptiform discharges during sleep on cognition and behavior is unclear. There is increasing evidence that abnormalities of coherence, a measure of the consistency of the phase difference between two EEG signals when compared over time, is an important feature of brain oscillations and plays a role in cognition and behavior. The objective of this study was to determine whether coherence of EEG activity is altered during slow‐wave sleep in children with ESES when compared to typically developing children. Methods. We examined coherence during epochs of ESES versus epochs when ESES was not present. In addition, we compared coherence during slow‐wave sleep between typically developing children and children with ESES. Results. ESES was associated with remarkably high coherences at all bandwidths and most electrode pairs. While the high coherence was largely attributed to the spikes and spike‐and‐wave discharge, activity between spikes and spike‐and‐wave discharge also demonstrated high coherence. Conclusions. This study indicates that EEG coherence during ESES is relatively high. Whether these increases in coherence correlate with the cognitive and behavioral abnormalities seen in children with this EEG pattern remains to be determined.     

The effect of surgery in encephalopathy with electrical status epilepticus during sleep

Purpose: We analyzed clinical and electroencephalography (EEG) outcomes of 13 patients with pharmacoresistant encephalopathy with electrical status epilepticus during sleep (ESES) following epilepsy surgery. Methods: All patients had symptomatic etiology of ESES and preoperative neuropsychological deterioration. Ten patients had daily atypical absences. Clinical outcome was assessed at 6 months and at 2 years after surgery. Clinical and EEG data were reviewed retrospectively. The spike propagation pattern and area and source strength in source montage were analyzed from preoperative and postoperative EEG studies. Key Findings: Preoperative sleep EEG showed electrical status epilepticus during sleep (SES) with one‐way interhemispheric propagation in nine patients and with two‐way interhemispheric propagation in four. The age of the patients at the time of surgery ranged from 3.6–9.9 years. Focal resection (two patients) or hemispherotomy (one patient with postoperative EEG) either terminated SES or restricted the discharge to one region. Either reduced SES propagation area or source strength was found in four of eight callosotomy patients with postoperative EEG. Of patients who had seizures preoperatively, Engel class I–II seizure outcome was observed in two of three children after focal resection or hemispherotomy and in two of eight children after callosotomy. None of these patients with Engel class I–II outcome had SES with two‐way interhemispheric propagation on preoperative EEG. Cognitive deterioration was halted postoperatively in all except one patient. Cognitive catch‐up of more than 10 IQ points was seen in three patients, all of whom had shown a first measured IQ of >75. Significance: Patients with pharmacoresistant ESES based on symptomatic etiology may benefit from resective surgery or corpus callosotomy regarding both seizure outcome and cognitive prognosis.     

Medical Management With Diazepam for Electrical Status Epilepticus During Slow Wave Sleep in Children

ObjectiveOral diazepam, administered in varying doses, is among the few proposed treatment options for electrical status epilepticus during slow wave sleep in children. We sought to retrospectively evaluate the long-term efficacy of high-dose oral diazepam in reducing electrographic and clinical evidence of electrical status epilepticus during slow wave sleep in children. Additionally, we surveyed caregivers to assess safety and behavioral outcomes related to ongoing therapy.MethodsWe collected demographic and clinical data on children treated for electrical status epilepticus during slow wave sleep between October 2010 and March 2013. We sought to identify the number of patients who achieved at least a 50% reduction in spike wave index on electroencephalograph after receiving high-dose oral diazepam. We also administered a questionnaire to caregivers to assess for behavioral problems and side effects.ResultsWe identified 42 evaluable patients who received high-dose diazepam (range 0.23-2.02 mg/kg per day) to treat electrical status epilepticus during slow wave sleep. Twenty-six patients had spike reduction data and 18/26 (69.2%) children achieved a greater than 50% reduction in spike wave count from an average of 15.54 to 5.05 (P = 0.001). We received 28 responses to the questionnaire. Some patients experienced new onset of difficulties with problem-solving and speech and writing development. Sleep disturbances (50%) and irritability (57.1%) were the most frequent side effects reported. There did not appear to be a dose-related effect with electroencephalograph changes, behavioral effects, or side effects.ConclusionsHigh-dose oral diazepam significantly reduces the spike wave count on electroencephalograph in children with electrical status epilepticus during slow wave sleep. Although this therapy improves electroencephalograph-related findings, it can be associated with concerning neurological and behavioral side effects in some individuals, so further study is warranted.     

Ketogenic diet in the treatment of refractory continuous spikes and waves during slow sleep

Purpose: To evaluate the effect of the ketogenic diet on electroclinical characteristics and cognitive function in children with continuous spikes and waves during slow sleep (CSWS). Methods: Five children (four boys, one girl) aged between 8 and 13 years with CSWS refractory to conventional antiepileptic drugs (AEDs), including levetiracetam, and steroids were included. The prospective electroclinical assessment was performed prior to the ketogenic diet and once every 6 months post initiation during the 2‐year period. All children underwent neuropsychological testing prior to the ketogenic diet and four of the children again 12 months after the diet’s introduction. In case 4 the testing has been performed after 7 months and the diet was withdrawn after 9 months because of the lack of efficacy and the parent’s wishes. In two patients the cognitive functions were also evaluated after 24 months since the diet’s initiation. During the period on the ketogenic diet the concomitant AED treatment was unchanged. Results: Electrographic evaluation after 24 months on the ketogenic diet showed CSWS resolution in one patient, mild decrease of the spike–wave index in one, and lack of response in three patients. The ketogenic diet did not influence the neuropsychological outcome, and intelligence quotient (IQ) scores remained low at the end of the follow‐up period. However, in two patients an improvement in attention and behavior was demonstrated. Discussion: This is the first study evaluating the efficacy of the ketogenic diet in children with CSWS. Five presented cases were refractory to AEDs and steroids. Only one case responded with complete CSWS disappearance; in one the effect of the ketogenic diet was partial and intermittent, whereas in three patients no response has been observed. These results show that the ketogenic diet did not appear to influence the neuropsychological outcome; however, the absence of a control group makes it impossible to conclude with certainty.     

Measuring spike strength in patients with continuous spikes and waves during sleep: Comparison of methods for prospective use as a clinical index

ObjectiveTo compare methods of estimating spike strength as a potential index in the assessment of continuous spikes and waves during sleep (CSWS).MethodsSpikes were searched and averaged automatically from pre- and postoperative EEGs of ten patients with CSWS who underwent corpus callosotomy (eight) or resective epilepsy surgery (two). From the most prominent spike, we measured peak amplitude and root mean square (RMS) over ±150 ms window around the peak. In order to compensate for spatiotemporal instability of spikes, the cumulative amplitude and RMS were computed from the highest quartile of electrodes (Ampl-Q and RMS-Q, respectively). The stability of parameters was studied by comparing two ten minute epochs during the first hour of NREM sleep, as well as by analyzing overnight variation of indices in further ten patients with CSWS. The Ampl-Q and RMS-Q were compared between pre- and postoperative recordings.ResultsAll four measures, amplitude, RMS, Ampl-Q and RMS-Q, were correlated with each other and highly dependent on NREM/REM-sleep stage and arousals. Expectedly, Ampl-Q and RMS-Q had the greatest intra-individual stability. The amplitude had up to 71% intra-individual variation making it unhelpful for clinical use. Ampl-Q and RMS-Q were comparable in assessing change following surgical treatment.ConclusionsComputing an integrated RMS over multiple electrodes during steady NREM sleep offers a stable and reliable parameter for evaluating the strength of spikes in CSWS.SignificanceAnalyzing spike strength with RMS-Q may offer a clinically useful, supplementary index for EEG monitoring of CSWS where spike index has been of limited value.     

Encephalopathy related to status epilepticus during slow sleep (ESES) as atypical evolution of Panayiotopoulos syndrome: an EEG and neuropsychological study

Aim: We report two patients with Panayiotopoulos syndrome (PS) who developed encephalopathy related to status epilepticus during slow sleep (ESES) at the peak of their clinical course. Methods: Clinical charts and EEG data were reviewed. Results: The patients exhibited nocturnal autonomic seizures and occipital EEG foci, the latter of which later evolved into multifocal EEG foci with synchronous frontopolar and occipital spikes (Fp‐O EEG foci), and finally into continuous spikes‐waves during sleep (CSWS; spike‐wave index >85% based on whole‐night sleep recording) at eight years and seven years of age, respectively. The occipital spikes always preceded frontopolar spikes by 30～50 mseconds based on the analysis of CSWS. Neuropsychological ability, including IQ, deteriorated during the CSWS period in both patients. The autonomic seizures and focal to bilateral tonic‐clonic seizures were initially resistant to antiepileptic drugs (AEDs), and occurred more than 10 times in both patients. However, the seizures and EEG findings gradually resolved, and AEDs were successfully terminated in both patients. Conclusion: PS can progress to ESES if the clinical course exhibits atypical evolution. The initial autonomic symptom of the seizures and interictal Fp‐O EEG foci should be carefully monitored in patients with CSWS or ESES.     

Acquired epileptic frontal syndrome as long-term outcome in two children with CSWS

Continuous spikes and waves during slow sleep (CSWS) are a well-known EEG pattern that can be associated with cognitive and behavioural deterioration. We present the long-term clinical, neuropsychological and EEG follow-up of two patients who developed CSWS during childhood. In both the CSWS onset was followed immediately by rapid cognitive and behavioural deterioration. Later the CSWS fragmented or fluctuated and the spike-wave discharges diminished and this was associated with progressive clinical improvement. At the same time bilateral frontal EEG abnormalities appeared awake and in sleep. After the initial period of rapid cognitive and linguistic improvement both patients stabilised. The latest neuropsychological assessment showed a frontal syndrome. The presence of frontal EEG abnormalities superimposed on CSWS, their persistence after CSWS resolution and, in addition, the finding of subtle frontal-type neuropsychological alterations early in recovery may indicate poor long-term outcome.     

Jerking during absences: video‐EEG and polygraphy of epileptic myoclonus associated with two paediatric epilepsy syndromes

Objective: Epileptic myoclonus (EM) is reported in many paediatric epilepsies from neonatal period to adolescence. Myoclonus can be the only seizure type or may occur among others, independently or in combination as a single ictal event. We report two children presenting with absences associated with myoclonus, predominating on one side, in a setting of two different types of absence seizures and two different electro‐clinical syndromes. Methods: Patients were explored with long‐duration video‐EEG coupled to surface EMG polygraphy. EEG was visually analysed and complemented by jerk‐locked back‐averaging. Results: Two types of seizure, encompassing myoclonus and absence, were identified: myoclonic absences in the context of epilepsy with myoclonic absences and atypical absences with atonic component (negative myoclonus) in the context of encephalopathy related to status epilepticus during slow sleep (ESES). In the latter case, rhythmic upper limb jerking, mimicking positive myoclonus, corresponded to recovery of muscular tone after each negative myoclonus. Significance: Due to the rhythmic recovery of muscle tone, subsequent rhythmic negative myoclonus may exhibit a similar clinical picture to that of rhythmic positive myoclonus. Video‐EEG recording coupled to EMG polygraphy is essential in order to precisely characterize motor manifestations during seizures with myoclonus [Published with video sequences].