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.     

Electrical Status Epilepticus in Sleep: Clinical Presentation and Pathophysiology

Electrical status epilepticus in sleep involves an electroencephalographic pattern where interictal epileptiform activity is potentiated in the transition from wakefulness to sleep. Near-continuous spikes and waves that occupy a significant proportion of nonrapid eye movement sleep appear as a result of sleep-potentiated epileptiform activity. This electroencephalographic pattern appears in different electroclinical syndromes that present three common characteristics with different degrees of severity: seizures, sleep-potentiated epileptiform activity, and neuropsychologic regression. Continuous spikes and waves during sleep comprise the severest epileptic encephalopathy in the electroclinical spectrum. Landau-Kleffner syndrome presents with intermediate severity. Some “benign” pediatric focal epileptic syndromes represent the mildest end of this continuum. Based on published data, we provide a framework for clinical and electrical events. The underlying mechanisms leading to sleep potentiation of epileptiform activity in electrical status epilepticus in sleep are incompletely understood. A genetic basis or acquired early developmental insult may disrupt the normal maturation of neuronal networks. These factors may dynamically alter normal processes of brain development, leading to an age-related pattern of electroclinical expression of electrical status epilepticus in sleep.     

Response of status epilepticus induced by lithium and pilocarpine to treatment with diazepam

Status epilepticus (SE) was induced in rats by administration of 3 mmol/kg lithium chloride followed 24 h later by injection of 25 mg/kg pilocarpine. Treatment with 20 mg/kg diazepam was initiated at the time each of four EEG patterns was seen: (i) discrete electrographic seizures; (ii) waxing and waning epileptiform activity; (iii) continuous, high-amplitude, rapid spiking; and (iv) periodic epileptiform discharges (PEDs) on a relatively flat background. Success of diazepam in stopping all seizure activity was predicted by the EEG pattern seen at the time of treatment. All rats treated while displaying discrete electrographic seizures had status stopped with diazepam, but only three of six with waxing and waning epileptiform activity and one of six each with continuous spiking and PEDs. Rats which continued to seize had a decrease in spike amplitude of 74.8 +/- 18.25% following diazepam injection. These data confirm the clinical impression that the longer the duration of status epilepticus, the more difficult it is to control and suggest that the EEG pattern at the time of treatment predicts the probability of success.     

睡眠性癫癎患者动态脑电图的研究

目的探讨睡眠性癫疒间患者的24h动态脑电图(AEEG)的表现及其诊断价值。方法对91例仅于睡眠中发作癫疒间的患者进行AEEG检查,并对检查结果进行分析。结果AEEG发现疒间性放电71例(78.0%),其中4例出现于清醒状态,41例出现于睡眠状态,26例清醒和睡眠时均有放电;在67例睡眠时有疒间性放电的患者中,34例仅出现在浅睡期,33例整个睡眠中均出现疒间性放电。清醒时有癫疒间波的患者癫疒间发作频率明显高于无异常放电患者和仅睡眠时有疒间性放电的患者(均P<0.05)。结论睡眠中癫疒间发作患者于睡眠中疒间性放电出现率明显高于白天清醒时。AEEG容易发现睡眠性癫疒间患者的发作期和发作间歇期以及自然睡眠状态下的疒间样波。     

Definition of the neurological phenotype associated with dup (X)(p11.22-p11.23)

The aim of this study was to describe in detail the neurological features of nine patients carrying the recently reported microduplication at Xp11.22-11.23. Clinical and neurological examination, brain magnetic resonance imaging (except for two patients), electroencephalography and a neuropsychological assessment specific for language disturbances were performed in nine patients with microduplication at Xp11.22-11.23, disclosed by comparative genomic hybridisation array. Six patients were familial cases belonging to three unrelated pedigrees and three were sporadic cases. The patients had the following characteristics: mild dysmorphic facial features (except for two patients), mental retardation with moderate to severe global language deterioration, electroencephalographic epileptiform discharges during wakefulness and especially during sleep or electrical status epilepticus during slow sleep in younger cases, and negative brain magnetic resonance imaging. The main clinical features of this new microduplication syndrome were mild facial dysmorphisms, from increased electroencephalogram abnormalities during sleep to electrical status epilepticus during slow sleep, and mental retardation mainly involving language function in the absence of detectable brain lesions. In the absence of detectable brain lesions, speech delay may be associated with electrical status epilepticus during slow sleep or, alternatively, related to abnormal brain expression of a dosage-sensitive gene contained within the duplication region.     

240例睡眠/清醒不同发作时间癫痫患者24小时动态脑电图分析

目的:了解睡眠/清醒不同发作时间癫痫患者24小时动态脑电图特点。方法:回顾性分析240例癫痫患者的24小时动态脑电图资料。结果:仅于睡眠中发作的癫痫患者AEEG上仅在睡眠中放电的比例高于清醒期和睡眠/ 清醒均发作患者,额叶癫痫患者于睡眠中发作者以及AEEG上单纯夜间放电者均明显多于颞叶癫痫患者,差异具有显著性(P<0.01)。结论:额叶癫痫患者及临床上仅于睡眠中发作患者睡眠中放电明显高于其他癫痫患者,对此类睡眠中高发人群进行AEEG检查有助于提高诊断率。     

Electroencephalographic response to intravenous diazepam during status epilepticus

To determine the electroencephalographic (EEG) response to intravenous bolus administration of diazepam during status epilepticus (SE), we retrospectively evaluated the time to the disappearance of epileptiform activity in EEG recordings after 10 mg intravenous bolus administration of diazepam, and examined the relationship of this response time to the duration, etiology, and outcome of SE. Patients with SE who responded positively to diazepam administration (n = 53; 37 women, 16 men), aged 17–88 years were recruited from our SE registry. According to their response time to intravenous administration of diazepam, patients were divided into four subgroups: Group I response times ranged from 20 to 60 s, group II from 61 to 120 s, group III from 121–180 s, and group IV from 181 to 360 s. The duration of SE was 10.76 ± 3.46 h in the first group and 27.00 ± 12.57 h in the last group. According to the etiology, patients with central nervous system tumors and metabolic disorders were the fastest responders, whereas those with cerebrovascular diseases and withdrawal of antiepileptic drugs were the slowest responders. This study revealed a positive correlation between the response time to diazepam administration and seizure duration during status epilepticus. Response time may have a role in predicting outcome of status epilepticus treatment, in particular, the effects of diazepam. Thus, longer-duration EEGs are indicated.     

Treatment of epilepsy with electrical status epilepticus during slow sleep and its related disorders

To elucidate an effective therapeutic strategy for 'ESES syndrome', epilepsy with electrical status epilepticus during slow sleep (ESES) and its related epileptic disorders, we studied the effect of treatment on the EEG pattern of continuous spike-waves during slow wave sleep (CSWS) in 15 afflicted patients. Basically performed in the following order, the employed therapies included (1) high-dose valproate (VPA) therapy (serum level >100 microg/ml); (2) a combination therapy of VPA and ethosuximide (ESM); (3) short cycles of high-dose diazepam (oral or intrarectal DZP, 0.5-1 mg/kg per day for 6-7 days); and (4) intramuscular synthetic ACTH-Z therapy (0.01-0.04 mg/kg per day for 11-43 days). Regarding the initial EEG effect, a remission of CSWS was achieved by high-dose VPA therapy in 7 of 15 trials (47%), by the combination therapy of VPA and ESM in 3/7 trials (43%), by short cycles of high-dose DZP in 2/4 trials (50%), and by ACTH-Z therapy in 2/5 trials (40%). A permanent remission of ESES syndrome was achieved by high-dose VPA therapy and/or combination therapy of VPA and ESM in 10 patients (67%). The effects of short cycles of high-dose DZP and ACTH-Z therapy were at best temporary. Our strategy for the treatment of ESES syndrome is therefore considered valid.     

Clinical significance of periodic lateralized epileptiform discharges: relationship with status epilepticus

A retrospective study was carried out in 147 patients who had been found to have periodic lateralized epileptiform discharges (PLEDs). Clinical, laboratory, radiological, and pathological correlation was performed for all patients. As in previously published works, we found a high correlation with cerebrovascular accidents in our population. A large number of patients, however, had no evidence of focal central nervous system pathology. An attempt was made to find a temporal relationship between the onset of seizure activity (or neurological dysfunction in those patients without seizure activity) and the recording of an EEG with PLEDs. We found that most of the EEGs with PLEDs were obtained within the first 4 days of seizure activity or status epilepticus condition. We postulate that the EEG phenomenon of PLEDs could be considered a part of the status epilepticus condition. Suggestive of this was the fact that the first EEG record obtained in one-third of our patients showed electrographic partial status epilepticus. In a small percentage of our patients, a transitional record showed first status epilepticus and then PLEDs. We found that PLEDs usually disappeared from the EEG tracing within 9 days post-ictus flash status. They were most frequently replaced by focal slowing or random spike activity.     

Sphenoidal EEG recording in complex partial seizures

A prospective study was performed to evaluate the usefulness of sphenoidal EEG recording during wakefulness, as compared to routine tracings awake and asleep, for recognizing epileptic electroencephalographic foci in patients with complex partial seizures. Fifty patients were investigated. Following sleep deprivation a routine waking EEG, a sleep tracing and an awake recording with sphenoidal needles were obtained. In nine patients temporal epileptiform activity was apparent in all three conditions (wakefulness, sleep and with sphenoidal electrodes). In 21 patients temporal epileptiform activity was seen during sleep only, while the sphenoidal leads were non-contributory. In 20 patients epileptiform activity was not recorded under any of the above conditions. This study indicates that sphenoidal recording during wakefulness does not contribute to the detection of epileptic discharges in patients with complex partial seizures.     

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.     

Nocturnal epileptiform EEG discharges, nocturnal epileptic seizures, and language impairments in children: review of the literature

This review addresses the effect on language function of nocturnal epileptiform EEG discharges and nocturnal epileptic seizures in children. In clinical practice, language impairment is frequently reported in association with nocturnal epileptiform activity. Vice versa, nocturnal epileptiform EEG abnormalities are a common finding in children with specific language impairment. We suggest a spectrum that is characterized by nocturnal epileptiform activity and language impairment ranging from specific language impairment to rolandic epilepsy, nocturnal frontal lobe epilepsy, electrical status epilepticus of sleep, and Landau-Kleffner syndrome. In this spectrum, children with specific language impairment have the best outcome, and children with electrical status epilepticus of sleep or Landau-Kleffner syndrome, the worst. The exact nature of this relationship and the factors causing this spectrum are unknown. We suggest that nocturnal epileptiform EEG discharges and nocturnal epileptic seizures during development will cause or contribute to diseased neuronal networks involving language. The diseased neuronal networks are less efficient compared with normal neuronal networks. This disorganization may cause language impairments.     

Effects of drugs on the initiation and maintenance of status epilepticus induced by administration of pilocarpine to lithium-pretreated rats

The ability of various drugs to prevent the onset of status epilepticus induced by administration of the muscarinic agonist, pilocarpine, to lithium-pretreated rats was determined. Motor limbic seizures and status epilepticus occurred in 100% of rats administered pilocarpine (30 mg/kg, s.c.) 20 h after pretreatment with lithium (3 meq/kg, i.p.). The latency to spike activity and to status epilepticus was 20 +/- 1 min and 24 +/- 1 min, respectively. Atropine, diazepam, phenytoin, carbamazepine, phenobarbital, paraldehyde, and L-phenylisopropyladenosine (L-PIA) prevented all phases of seizure activity induced by lithium/pilocarpine treatment. The initiation of status epilepticus was significantly prolonged by pretreatment with sodium valproate. These findings indicate that the seizures induced by administration of lithium and pilocarpine accurately model generalized tonic-clonic epilepsy. The anticonvulsant activity of L-PIA was prevented by prior treatment with the adenosine antagonist, theophylline. The latency to spike and seizure activity was decreased by theophylline, indicating that endogenous adenosine may have a tonic inhibitory influence on cholinergic neurons. Atropine, diazepam, phenobarbital, phenytoin, sodium valproate, L-PIA, and carbamazepine did not interrupt seizure activity when administered 60 min after pilocarpine (approximately 35 min after initiation of status epilepticus). When rats were administered paraldehyde at this time, status epilepticus was rapidly terminated and all rats survived. Thus, status epilepticus induced by lithium and pilocarpine provides a seizure model that is not responsive to conventional anticonvulsants.     

Ictal catatonia as a manifestation of nonconvulsive status epilepticus.

Three patients with EEG documented ictal catatonia, a nonconvulsive status epilepticus, who responded dramatically to intravenous phenytoin are described. The EEG showed continuous bilateral pseudoperiodic sharp waves and spike discharges in one patient, spike and wave complexes were seen prominently in the right fronto-central region in another, and the EEG of the third patient showed periodic lateralising epileptiform discharges during the catatonic state. We postulate that such catatonia was due to involvement of the limbic system by seizure activity.     

Benign childhood epilepsy with Centro-Temporal spikes (BCECTSs), electrical status epilepticus in sleep (ESES), and academic decline — How aggressive should we be?

Since many of the children with BCECTSs display electrical status epilepticus during sleep and many present with different comorbidities, mainly ADHD and behavioral disturbances, clinicians are often confronted with the dilemma of how aggressive they should be with their efforts of normalizing the EEG. We conducted a retrospective study by screening medical records of all consecutive patients with BCECTSs, spike–wave index (SWI) > 30%, and ADHD/ADD that were evaluated in our pediatric epilepsy service and were followed up for at least two years. Patients with neurocognitive deterioration detected by formal testing were excluded. A total of 17 patients with mean age of 6.9 years at BCECTS diagnosis were identified. The patients' mean SWI was 60% and that dense electrical activity lasted 1.5 years on average (range: 1–4.5 years). Six children were formally diagnosed with learning disabilities in addition to ADD/ADHD. All of them were treated with an average of three antiepileptic medications, mainly for the purpose of normalizing the EEG, but none of them was treated with steroids or high-dose diazepam. The mean duration of follow-up was 5.5 years. A cognitive or behavioral deterioration was not detected in any of them. Our data suggest that when treating a child with BCECTSs, high SWI, and school difficulties, the most critical parameter that determines the necessity of using second-line antiepileptic agents such as steroids or high-dose diazepam is a formal psychological evaluation that proves cognitive (I.Q.) decline. Otherwise, these agents may be avoided.     

EEG abnormalities aid diagnosis of Rett syndrome

Nine girls with Rett syndrome had 22 electroencephalographic studies performed over 5 years. Nineteen waking tracings demonstrated moderate background slowing. Focal epileptiform activity was observed in 13 studies, 10 of which had bilateral independent foci. Spikes were invariably maximal in central regions, diphasic or triphasic, and of very short duration. In 3 patients, epileptiform activity preceded clinical seizures by up to 2 years. Two children had spontaneous hyperpnea preceding apnea during wakefulness with further background slowing. Video monitoring of 2 children revealed that episodic behavioral changes were not seizures. Ten of 12 sleep recordings had abnormal background activity with absent or rudimentary spindles. Normal activity occurred only in girls younger than years of age. Epileptiform activity was markedly increased during sleep in 8 tracings in which both wakefulness and sleep were obtained. It was characterized by bilaterally independent and bisynchronous spike-and-wave activity, maximal in parasagittal areas. One patient had bursts of high-voltage slow-wave activity followed by attenuation. No apneic episodes were recorded during sleep. In Rett syndrome, electroencephalographic abnormalities include background slowing, centrally located short-duration spikes, and increased epileptiform activity during sleep. This activity commonly preceded clinical seizures in patients studied at initial presentation.     

Disturbances of rapid-eye-movement sleep in 3 brothers with Pelizaeus-Merzbacher disease.

The electrophysiological features of 3 brothers with the classic form of Pelizaeus-Merzbacher disease (PMD) were studied. Two consecutive overnight polygraphic sleep recordings indicated a gross distortion of rapid-eye-movement (REM) sleep for all patients. A lower than normal percentage of REM sleep in these patients was consistent with their retarded intellectual development, which supports current thinking that REM sleep may be a sensitive index of brain function integrity. Non-rapid-eye-movement (NREM) sleep, in contrast to reported findings in 1 patient with PMD, was uniformly characterized by distinct stages in which the electroencephalograms contained frequent vertex waves and spindles. Tests of peripheral nerve conduction velocity, acoustic brainstem reflexes, and visual and auditory evoked potentials did not indicate any abnormalities, nor did electroencephalograms obtained during wakefulness. One patient did have epileptiform spikes and spike waves recorded during an all-night EEG, an unusual finding in a child with cerebral white matter disease.     

Nocturnal epileptiform EEG discharges,nocturnal epileptic seizures,and language impairments in children: Review of the literature

This review addresses the effect on language function of nocturnal epileptiform EEG discharges and nocturnal epileptic seizures in children. In clinical practice, language impairment is frequently reported in association with nocturnal epileptiform activity. Vice versa, nocturnal epileptiform EEG abnormalities are a common finding in children with specific language impairment. We suggest a spectrum that is characterized by nocturnal epileptiform activity and language impairment ranging from specific language impairment to rolandic epilepsy, nocturnal frontal lobe epilepsy, electrical status epilepticus of sleep, and Landau–Kleffner syndrome. In this spectrum, children with specific language impairment have the best outcome, and children with electrical status epilepticus of sleep or Landau–Kleffner syndrome, the worst. The exact nature of this relationship and the factors causing this spectrum are unknown. We suggest that nocturnal epileptiform EEG discharges and nocturnal epileptic seizures during development will cause or contribute to diseased neuronal networks involving language. The diseased neuronal networks are less efficient compared with normal neuronal networks. This disorganization may cause language impairments.     

Chloralhydrat versus Diazepam zur rektalen Behandlung von Anfallsserien und Status epileptici – eine Pilotstudie

Purpose To compare the effect of rectally administered diazepam and chloral hydrate on serial seizures or status epilepticus. Methods In an open prospective pilot study we compared the rectal administration of diazepam (0.4 mg/kg body weight) with a 20% solution of chloral hydrate (50mg/kg) inpatients of an epilepsy hospital with serial seizures or status epilepticus (grand mal-seizures excluded). Outcome criteria were defined as absence of seizures during the next 3 and 24 hours following administration of the study drug, as well as eventual necessity of an additional intervention in case of recurrent seizures. Results Analysis of 69 interventions (chloral hydrate, 32 and diazepam, 37) in 65 episodes of serial seizures and 4 episodes of status epilepticus showed no recurrence of seizures within 3 hours and within 24 hours in 78% and 41% of patients treated with diazepam compared to 72% and 48% of patients treated with chloral hydrate (p=0.58 and 0.81). After application of diazepam or chloral hydrate, additional intervention due to recurrent seizures was necessary in 14% and 22% respectively (p=0.53). Conclusions These results indicate comparable efficacy of both drugs. Chloral hydrate seems to be a useful alternative to diazepam in the treatment of serial seizures.