Pharmacological treatment for continuous spike-wave during slow wave sleep syndrome and Landau-Kleffner Syndrome.

BACKGROUND: Continuous spike-wave during slow wave sleep syndrome (CSWS) and Landau-Kleffner syndrome (LKS) are two epileptic encephalopathies that present with neurocognitive regression, aphasia, and clinical seizures, typically presenting in children around five years of age. The pathophysiology of these conditions is not completely understood. Some studies suggest a common origin for both. No systematic reviews have assessed the efficacy of pharmacological interventions for these conditions. OBJECTIVES: To assess the benefit and adverse effects of pharmacological interventions for the treatment of CSWS and LKS. SEARCH METHODS: On 8 September 2020, we searched the Cochrane Register of Studies (CRS Web) and MEDLINE Ovid (1946 to September 04, 2020). We applied no language restrictions. CRS Web includes randomised or quasi-randomised, controlled trials from CENTRAL, PubMed, Embase, ClinicalTrials.gov, and the World Health Organization International Clinical Trials Registry Platform. SELECTION CRITERIA: Randomised controlled trials, quasi-randomised controlled trials, and cluster-randomised trials comparing antiepileptic drugs alone, or with steroids or intravenous immunoglobulins, or both versus other antiepileptic drugs, or placebo, or no treatment, administered to children with CSWS and LKS. We planned to compare treatments for the two conditions separately. DATA COLLECTION AND ANALYSIS: Two review authors independently assessed studies identified by the search strategy for inclusion. The primary outcomes considered in this review were neuropsychological-neurolinguistic functions. MAIN RESULTS: Our search strategy yielded 18 references. Two review authors independently assessed all references. We did not find any completed studies to include. We identified one ongoing trial, which was terminated because of lack of enrolment. AUTHORS' CONCLUSIONS: There was no evidence from trials to support or refute the use of pharmacological treatment for continuous spike-wave during slow wave sleep syndrome or Landau-Kleffner syndrome. Well-designed randomised controlled trials are needed to inform practice.

Inhibition of epileptiform activity by neuropeptide Y in brain tissue from drug-resistant temporal lobe epilepsy patients.

In epilepsy patients, drug-resistant seizures often originate in one of the temporal lobes. In selected cases, when certain requirements are met, this area is surgically resected for therapeutic reasons. We kept the resected tissue slices alive in vitro for 48 h to create a platform for testing a novel treatment strategy based on neuropeptide Y (NPY) against drug-resistant epilepsy. We demonstrate that NPY exerts a significant inhibitory effect on epileptiform activity, recorded with whole-cell patch-clamp, in human hippocampal dentate gyrus. Application of NPY reduced overall number of paroxysmal depolarising shifts and action potentials. This effect was mediated by Y2 receptors, since application of selective Y2-receptor antagonist blocked the effect of NPY. This proof-of-concept finding is an important translational milestone for validating NPY-based gene therapy for targeting focal drug-resistant epilepsies, and increasing the prospects for positive outcome in potential clinical trials.

Current and Emerging Therapies of Severe Epileptic Encephalopathies.

In this article, we review the treatment options for the pediatric epileptic encephalopathies and provide an update on the new and emerging therapies targeted at the underlying pathophysiology of many of these syndromes. We illustrate how the identification of the specific genetic and autoimmune causes has made possible the evaluation and development of novel, better targeted therapies, as and at times, avoidance of potentially offending agents.

Landau-Kleffner syndrome: an uncommon dealt with case in Southeast Asia.

An 11-year-old boy was admitted with fever followed by convulsions. He had developed aphasia subsequent to this illness. His birth history was unremarkable, and he had normal growth and development including of language, hearing and vision. His neurological examination was normal except for aphasia. Investigations including cerebrospinal fluid study and MRI were normal. However, EEG was abnormal and the boy was diagnosed as a case of Landau-Kleffner syndrome (LKS) and treated with sodium valproate, levetiracetam and steroids. He responded well to treatment and has been on follow-up for the last 4 months. We present this case of LKS to increase awareness about early diagnosis and to highlight the importance of appropriate management for a better outcome.

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.

[Efficacy of methylprednisolone therapy for electrical status epilepticus during sleep in children].

OBJECTIVE: To evaluate the therapeutic effect of methylprednisolone for electrical status epilepticus during sleep (ESES) in children. METHOD: The clinical and EEG data of 82 epilepsy patients with ESES, which included benign childhood epilepsy with centro temporal spikes (BECT) variants, epilepsy with continuous spikes and waves during slow sleep (CSWS) , Landau-Kleffner syndrome (LKS) collected from department of pediatrics, Peking University First Hospital were analyzed from July 2007 to September 2012. During ESES period, all patients received methylprednisolone treatment for three courses, which included methylprednisolone intravenous infusion for three days, followed by oral prednisone for four days every time. After three courses, prednisone [1-2 mg/(kg × d)] were taken by all patients for 6 months. The ESES phenomenon and seizures were observed before and after treatment. The efficacy of corticosteroid on ESES suppression, seizure control of three epilepsy syndrome were analyzed. RESULT: Thirty-nine cases were male and 43 cases were female. The epilepsy syndromes included 49 patients diagnosed as benign childhood epilepsy with centrotemporal spike (BECT) variants, 27 patients diagnosed as epilepsy with continuous spikes and waves during slow sleep (CSWS), and 6 patients diagnosed as LKS. Age of onset ranged from 1 year and 4 months to 11 years. The age of ESES newly monitored was from 2 years to 10 years and 8 months. The total effective rate of corticosteroid was 83% (68/82) for ESES, BECT variants was 82% (40/49), CSWS was 81% (22/27), LKS was 100% (6/6). There was no statistically significant difference in effective rates between the front two (χ² = 0.09, P > 0.05). The seizures were improved in the first month after methylprednisolone treatment in 3 epilepsy syndromes. The recurrence rate of BECT variants was 47% (23/49) , CSWS was 59% (16/27) , LKS was 50% (3/6) after 1 year follow up. There was no association between disease parameters, including age at seizure onset, duration of ESES and the treatment effect of ESES examined by Kruskal-Wallis method (χ² = 3.585, 0.932, P > 0.05). CONCLUSION: Methylprednisolone was effective for improving ESES and seizures in 3 epilepsy syndromes combined with ESES. There was no significant correlation between age at seizure onset, duration of ESES and treatment effect of ESES.

Serial EEG study in a girl with Landau-Kleffner syndrome associated with continuous spikes and waves during slow sleep.

Landau-Kleffner syndrome (LKS) is rare epileptic encephalopathy in childhood, characterized by both acquired epileptic aphasia and abnormal epileptiform discharges in electroencephalogram (EEG). We herein report a serial EEG study in LKS. A 22-month old girl was referred to our hospital because of frequently partial seizures in her left upper limb. On EEG performed and multiforcal spikes were recognized. Oral treatment of carbamazepine was started but her seizures were not controlled. Her language ability did not progress after 2 years of her age. At age 4 years, carbamazepine was switched to valproic acid, leading to reduction in the frequency of seizure episodes. She was able to speak two-word sentences at 4 years of age, but her word output gradually decreased. At 5 years of age, addition of zonisamide further reduced the frequency of seizure episodes, but failed to achieve complete control of seizures. She increasingly asked for questions to be repeated. Auditory brainstem response testing performed at the department of otolaryngology revealed normal hearing ability. She was diagnosed as having intellectual deficits with an intelligence quotient (IQ) of 61 at 7 years of age. The EEG at 8 years of age showed continuous spikes and waves during slow sleep (CSWS), leading to a diagnosis of LKS. After age 11 years, the CSWS on EEG improved without requiring a change in antiepileptic drugs (AEDs). Treatment with the oral AEDs was discontinued at 13 years of her age. Her IQ at 13 years of age was in the low 70s.

Episodic epileptic verbal auditory agnosia in Landau Kleffner syndrome treated with combination diazepam and corticosteroids.

We report 2 pediatric patients who presented initially with seizures followed by subacute language regression characterized by a verbal auditory agnosia. These previously normal children had no evidence of expressive aphasia during their symptomatic periods. Further, in both cases, auditory agnosia was associated with sleep-activated electroencephalographic (EEG) epileptiform activity, consistent with Landau-Kleffner syndrome. However, both cases are unique since the episodic auditory agnosia and sleep-activated EEG epileptiform activity rapidly responded to combination therapy with pulse benzodiazepine and corticosteroids. Further, in each case, recurrences were characterized by similar symptoms, EEG findings, and beneficial responses to the pulse benzodiazepine and corticosteroid therapy. These observations suggest that pulse combination high-dose corticosteroid and benzodiazepine therapy may be especially effective in Landau-Kleffner syndrome.

Acquired auditory agnosia in childhood and normal sleep electroencephalography subsequently diagnosed as Landau-Kleffner syndrome: a report of three cases.

AIM: We report three cases of Landau-Kleffner syndrome (LKS) in children (two females, one male) in whom diagnosis was delayed because the sleep electroencephalography (EEG) was initially normal. METHOD: Case histories including EEG, positron emission tomography findings, and long-term outcome were reviewed. RESULTS: Auditory agnosia occurred between the age of 2 years and 3 years 6 months, after a period of normal language development. Initial awake and sleep EEG, recorded weeks to months after the onset of language regression, during a nap period in two cases and during a full night of sleep in the third case, was normal. Repeat EEG between 2 months and 2 years later showed epileptiform discharges during wakefulness and strongly activated by sleep, with a pattern of continuous spike-waves during slow-wave sleep in two patients. Patients were diagnosed with LKS and treated with various antiepileptic regimens, including corticosteroids. One patient in whom EEG became normal on hydrocortisone is making significant recovery. The other two patients did not exhibit a sustained response to treatment and remained severely impaired. INTERPRETATION: Sleep EEG may be normal in the early phase of acquired auditory agnosia. EEG should be repeated frequently in individuals in whom a firm clinical diagnosis is made to facilitate early treatment.

Acquired opercular epilepsy with oromotor dysfunction: magnetoencephalographic analysis and efficacy of corticosteroid therapy.

The authors describe herein the magnetoencephalographic findings and long-term outcome of a girl with acquired opercular epilepsy with oromotor dysfunction. She presented with brief episodes of unconsciousness, tremulous movements of the upper limbs, and negative myoclonus, in addition to convulsive seizures. She also had prolonged episodes of dysarthria and oral motor dysfunction, a gradual decrease in speech output, impairment of finger movements, and deterioration in cognitive performance over several years. Her electroencephalography (EEG) recordings showed notable continuous sharp or sharp-slow discharges during sleep. Brain magnetic resonance images revealed no structural anomalies. Magnetoencephalographic analysis showed broadly distributed epileptic foci around the sylvian fissure, including a secondary source, explaining the specific prolonged neurological dysfunction. Antiepileptic drugs could control her seizures; however, they did not improve the other neurological symptoms or epileptiform discharge on EEG. Administration of low-dose prednisolone over a long period was effective for improving the neurological impairments of this patient.

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.

Long-term outcome of 32 children with encephalopathy with status epilepticus during sleep, or ESES syndrome.

PURPOSE: To prospectively evaluate the efficacy of drug treatment and long-term cognitive outcome in children with encephalopathy with status epilepticus during sleep (ESESS). METHODS: Thirty-two children were diagnosed and prospectively followed up for at least 3 years at our unit between 1991 and 2007. Twenty-seven children were included in the prospective treatment study with valproate (VPA) and 17 with VPA combined with ethosuximide (ESM). Treatment response of disappearance of electrical status epilepticus during sleep (SES) was documented with overnight EEG recordings. Neuropsychological follow up for at least 5 years was available in 18 patients. RESULTS: Six children had atypical rolandic (AR) epilepsy, nine Landau-Kleffner syndrome (LKS), and 17 symptomatic epilepsy. Before ESESS, 20 children were cognitively normal. Prospective treatment with VPA and ESM was effective in 3 of the 17 children (18%) treated. Abolition of SES with drug treatment was observed in 16 patients. In all, 10 children (31%), 4 with AR (67%), 3 with LKS (33%), and 3 with symptomatic etiology (19%), including 9 with treatment response regained the pre-ESESS cognitive level. Unfavorable cognitive outcome was predicted by younger age at ESESS diagnosis, lower IQ at the time of the diagnosis, and no response to drug treatment when compared with those with favorable cognitive outcome. Eight of the 16 nonresponders underwent epilepsy surgery. DISCUSSION: Treatment response with VPA combined with ESM was observed more often than with other drug combinations. Most children with ESESS experienced permanent cognitive impairment. Cognitive outcome depends on treatment response on electroencephalography (EEG) and seizures, and on underlying etiology.

Levetiracetam as add-on therapy in different subgroups of "benign" idiopathic focal epilepsies in childhood.

Several recent studies have shown that levetiracetam (LEV) can be beneficial in the treatment of children with typical rolandic epilepsy (RE). Reports about the effectiveness of LEV in the treatment of children with the less benign variants in the spectrum of "benign" idiopathic focal epilepsies are still rare. Little is known about the effect of LEV on interictal epileptiform discharges in these syndromes. We report on LEV therapy in 32 children (mean age: 10.6 years, range: 4-14) with RE or variants like atypical benign idiopathic partial epilepsy of childhood (ABIPEC), Landau-Kleffner syndrome (LKS), and continuous spikes and waves during sleep (CSWS) and in children with benign idiopathic focal epileptiform discharges of childhood (BIFEDC). Cognitive and behavioral problems, not seizures, may be related to the pathological EEG. Patients with a reduction in seizure frequency >50% and/or reduction in BIFEDC >90% 3 months after having started LEV therapy were defined as responders. The average dose of LEV was 39 mg/kg body wt per day; LEV was given in monotherapy to 31.3% of the patients. Overall, 20 of 32 patients (62.5%) did benefit: 12 of 24 patients had a >50% reduction in seizure frequency; 2 of 24 patients (8.3%) were completely seizure free; 18 of 32 patients (56.3%) had a >90% reduction in BIFEDC (including CSWS); 6 of 32 (18.8%) had an EEG completely free of epileptiform discharges; and 17 of 32 (53.1%) showed improvement in cognition and/or language functions and/or behavior. Surprisingly, LEV tended to be more helpful in atypical rolandic epilepsies and other variants.

Landau-Kleffner syndrome and CSWS syndrome: treatment with intravenous immunoglobulins.

This study reports results of therapy with immunoglobulin in children with Landau-Kleffner syndrome (LKS) or the syndrome of continuous spikes and waves during sleep (CSWS syndrome). In a prospective study, children diagnosed between 2002 and 2006 with either LKS or CSWS syndrome were treated soon after diagnosis with intravenous courses of immunoglobulin (IVIg). We compared the results with those reported in the literature and with data from a retrospective survey of our earlier patients. Six children (two girls), aged 4-9 years, were included. Three had LKS, and three had CSWS syndrome. One child-with typical LKS-had been treated with prednisone before (without response). No patient had seizures during IVIg treatment and follow-up. Their electroencephalography (EEG) findings did not improve. Neuropsychological improvement occurred in one child with CSWS syndrome. Three children did not show any beneficial effect; they were subsequently treated with steroids, one with a clearly positive result. We conclude that successful treatment of LKS and CSWS syndrome with IVIg occurs occasionally. However, the improvement cannot always be clearly attributed to this. It might also reflect the natural course of the disease. Although the temporal relation between IVIg treatment and clinical improvement cannot be denied in individual patients, its real value remains to be determined.

Rational treatment options with AEDs and ketogenic diet in Landau-Kleffner syndrome: still waiting after all these years.

Antiepileptic drugs (AEDs) remain a first treatment approach in Landau-Kleffner syndrome (LKS) and related syndromes. In the current literature, only class IV evidence is available. Inclusion criteria and outcome parameters are ill-defined. Most commonly, valproate, ethosuximide, and/or benzodiazepines are used. More recent case series show that sulthiame and especially levetiracetam can be considered as effective drugs. Smaller studies also point to the ketogenic diet as a valuable treatment option in LKS.

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.

[Adrenocorticotropic hormone therapy in acquired childhood epileptic aphasia]. / Szerzett gyermekkori epilepszias beszédzavar kezelése adrenokortikotrop hormonnal.

Although Landau-Kleffner syndrome, a childhood-acquired epileptic aphasia, is frequently studied either the underlying pathophysiology or the optimal therapy remained unknown. In our study we aimed to investigate the efficacy of ACTH therapy in Landau-Kleffner syndrome. We have analysed retrospectively the documentation of five children treated by ACTH, who suffered from Landau-Kleffner syndrome. We studied the longitudinal changes of the four most characteristic symptoms and signs of the syndrome: epileptiform EEG, speech and behaviour disorders, seizures together with the ACTH regimes. Besides, we analysed the relation between the starting date of the therapy and its efficacy. Before giving ACTH, epileptiform EEG and speech disorders were observed in all the five children, seizures in four of them, behaviour disorders in three of them. In two patients the speech disorder had been persisting for years before. Due to the starting ACTH stoss-therapy (20 E/day for one-two weeks) all the four examined signs disappeared or showed quick softening in all the five children in maximum two weeks. We adjusted long-term low dose maintenance therapy to avoid relapses in the long-term follow-up. Epileptiform EEGs have normalised in one case and have decreased in four cases. Speech disorders have disappeared in two and have softened in three children. Behaviour disorders have cured in 3/4 cases, softened in one case. Seizures have disappeared in all cases. One child is totally asymptomatic, four of them lives with softened symptoms. Analysing our data we found that the earlier the therapy starts, the more effective it is. On the basis of our data ACTH is an effective treatment for Landau-Kleffner syndrome. After giving it for only a short period, relapses often occur, to avoid relapses adjustment of long term low dose maintenance therapy is advisable.