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Landau–Kleffner syndrome (LKS) is a rare epilepsy occurring in children usually between the ages of three and nine years, characterised by dramatic loss of language skills in association with epileptiform activity over the language centres during sleep. It may be associated with convulsive seizures and additional difficulties with behaviour, social interaction, motor skills and cognition. Early treatment to suppress the EEG abnormalities can at least partially reverse this regression in 60–70% but usually needs to be continued for some years. Management focuses on restoring communication so that the child continues to engage and learn. Therapy and education support are essential and need to be very flexible as the child's profile can fluctuate dramatically and may include signing when they cannot access language and may require considerable opportunities for consolidation and overlearning. The epileptiform activity usually resolves by puberty, often with continuing recovery in skills for some years that will benefit from ongoing support. Many have persisting deficits as adults which are more severe with earlier age of onset and a longer epileptiform period. It is important to recognise LKS as early multi-disciplinary management may improve outcomes.

In the last decade, a sufficient amount of data has accumulated that testifies to the ambiguity of the assertion about the «benignity» of benign childhood epilepsy with centro-temporal commissures («Rolandic»). More and more researchers are providing evidence of cognitive impairment associated with age-dependent epilepsy. A literature review is given on this problem, the main trends and main criteria the diagnosis of typical and atypical age-dependent epilepsy with centro-temporal commissures on the electroencephalogram are considered. It has been established that the main criteria for the atypical nature of age-dependent epilepsy include such signs as the intermittent focus of slow waves, multiple asynchronous peak waves, long peak wave clusters, generalized 3 Hz «absance-like» runs, the relationship of interictal paroxysms with negative or positive myoclonus, and abundance interictal finds during wakefulness and sleep. A continuum of conditions associated with the condition under consideration is highlighted, which includes a number of conditions from relatively favorable to severe and disabling. We have singled out the term «atypical rolandic epilepsy», which has already taken shape in the world literature and includes such signs of atypicality as: early debut of seizures (up to 4 years), the presence of daytime seizures, duration of seizures (more than 30 minutes), with a tendency to form status, changes in neuroimaging studies (both morphological - computed and magnetic resonance imaging - and functional - positron emission tomography), impaired cognitive and / or behavioral sphere (including Indra attention deficit hyperactivity disorder), disorders of motor development as well as the mental and speech development, atypical manifestations in the electroencephalogram (unusual localization rolandic spikes, their generalization, the presence of «3Hz absansopodobnyh runs»).

Landau–Kleffner syndrome (LKS) is a rare neurological disorder characterized by acquired aphasia. LKS presents with distinctive electroencephalography (EEG) findings, including diffuse continuous spike and wave complexes (CSW), particularly during sleep. There has been little research on the mechanisms of aphasia and its origin within the brain and how it recovers. We diagnosed LKS in a 4-year-old female with an epileptogenic zone located primarily in the right superior temporal gyrus or STG (nondominant side). In the course of her illness, she had early signs of motor aphasia recovery but was slow to regain language comprehension and recover from hearing loss. We suggest that the findings from our patient's brain imaging and the disparity between her recovery from expressive and receptive aphasias are consistent with the dual-stream model of speech processing in which the nondominant hemisphere also plays a significant role in language comprehension. Unlike aphasia in adults, the right-hemisphere disorder has been reported to cause delays in language comprehension and gestures in early childhood. In the period of language acquisition, it requires a process of understanding what the words mean by integrating and understanding the visual, auditory, and contextual information. It is thought that the right hemisphere works predominantly with respect to its integrating role.

INTRODUÇÃO: A Síndrome de Landau Kleffner (SLK) é um distúrbio neurológico raro, conceituado como uma afasia epiléptica adquirida, a qual inicialmente é apenas verbal e evolui para dificuldades em processar e interpretar informações. O atual desafio reside em um diagnóstico e abordagem precoces. METODOLOGIA: Foi realizada uma revisão de literatura com busca no PubMed. Utilizou-se o descritor (“Landau-Kleffner Syndrome”), sendo encontrados 136 artigos entre os anos de 1992 e 2020. Foram, então, selecionados estudos publicados na íntegra, no idioma inglês, entre 2015 e 2020, o que à utilização de seis artigos para o estudo. DISCUSSÃO: Entre 1957, quando da descrição do primeiro caso, até 2015 foram descritos mais de 350 casos de SLK, observando-se uma maior incidência em crianças entre 3 e 8 anos previamente hígidas. A etiologia exata da síndrome ainda é desconhecida, mas o fator genético é uma das teorias mais aceitas. Mutações do gene GRIN2A, responsável pela codificação da proteína GluN2A, crucial em áreas do cérebro da fala e linguagem, é responsável por disfunções do desenvolvimento neurológico. Existem também sugestões de possíveis causas autoimunes, visto que o uso de corticoides em algumas crianças é efetivo. Outros estudos encontraram achados de anticorpos contra o fator neurotrófico derivado do cérebro, o qual auxilia na regulação sináptica de áreas importantes para aprendizagem e memória. Os principais sinais clínicos são afasia adquirida e crises epilépticas, mas outros distúrbios comportamentais podem estar presentes, anormalidades eletroencefalográficas - principalmente na região temporal, responsável pela compreensão da fala - e em mais de dois terços dos pacientes convulsões foram descritas. O diagnóstico da SLK é baseado na história clínica e nos achados do eletroencefalograma. Não existe um tratamento universalmente aceito, mas foi observado boa evolução em alguns pacientes com uso de corticosteróides. Antiepilépticos e programas de comportamento e fala também são utilizados. CONCLUSÃO: A complexidade e raridade da doença dificultam o diagnóstico precoce e poucos exames podem diferenciar esta síndrome de outras condições associadas a distúrbios neurológicos. Assim, é importante que sejam desenvolvidas pesquisas para melhor entender as causas, amanifestação e a evolução da SLK e, assim, desenvolver um tratamento específico, visando um melhor prognóstico e um desenvolvimento adequado desses pacientes pediátricos.

Introduction: Continuous spikes and waves during slow sleep (CSWS) is an EEG pattern that appears during childhood, and is often associated with cognitive impairment. It can appear in the course of epileptic syndromes, as well as in benign epilepsy. The aim of this study is to analyse epidemiological and clinical characteristics of patients with CSWS, in order to describe possible predictive factors in their outcome. Methods: A retrospective study was conducted on paediatric patients with CSWS treated in a third-level hospital from November 1997 to November 2017. Results: The study included 25 patients (68% male), of whom 76% had abnormalities in the neuroimaging or suffered from psychomotor development disorder (secondary CSWS). The rest were healthy, or diagnosed with idiopathic epilepsy. The mean age of onset of CSWS was 6.7 years, but earlier in the secondary CSWS cases. Symptoms were present during the CSWS episode in 72% of cases. All of them were treated with antiepileptic drugs, which were effective in 36%. CSWS stopped in 72%, and remission was longer if the CSWS onset occurred at an older age. One-third (33%) presented with sequelae, mostly cognitive and behavioural alterations. Outcome was poorer in those with secondary CSWS and, in those whose CSWS started at an earlier age and lasted longer. Conclusion: The CSWS pattern, although rare, is still a therapeutic challenge. A close follow-up of the patients with epilepsy is important, especially if associated with cognitive impairment, in order to establish an early diagnosis and treatment. Resumen: Introducción: La punta-onda continua durante el sueño lento (POCS) es un trazado electroencefalográfico característico, que aparece en la infancia y que en ocasiones condiciona un deterioro cognitivo. Este patrón electroencefalográfico puede aparecer tanto en determinados síndromes epilépticos como en la evolución de epilepsias idiopáticas y sintomáticas. El objetivo de nuestro estudio es analizar las características epidemiológicas y clínicas de pacientes que presentan en algún momento de su evolución POCS, describir la respuesta a distintos tratamientos y estudiar factores predictores de su evolución. Métodos: Estudio observacional retrospectivo de pacientes pediátricos con POCS seguidos en un hospital terciario en el periodo de noviembre 1997 a noviembre 2017. Resultados: Obtuvimos una muestra de 25 pacientes (68% varones). El 76% presentaba de base alteraciones en pruebas de neuroimagen o retraso psicomotor (POCS secundaria). El 24% restante eran niños sanos o con epilepsias benignas (POCS primaria). La edad media al inicio de la POCS fue de 6,7 años, siendo menor en los casos secundarios. Durante el periodo de POCS, el 72% presentó alguna manifestación clínica añadida. Todos recibieron combinaciones de antiepilépticos, siendo eficaces en el 36%. La POCS cesó en el 72%, siendo más probable el cese cuanto más tarde se hubiera instaurado. Un tercio tuvo alguna secuela, principalmente alteraciones cognitivas y del comportamiento, más frecuentes en POCS secundaria y en los pacientes en que duró más tiempo. Conclusiones: El trazado electroencefalográfico de POCS, aunque infrecuente, supone un reto terapéutico. Es importante seguir a los pacientes con epilepsia, especialmente si asocia deterioro neurológico, para detectar la presencia POCS e iniciar tratamiento precoz.

Purpose Acquired epileptic aphasia (AEA) accompanied by electroencephalogram (EEG) abnormality is a rare disease; therefore, there are few studies investigating the prognostic factors and treatment efficacy. We aimed to determine the therapeutic effects and prognostic factors for clinical seizure and neuropsychological function in acquired aphasia patients. Methods We retrospectively studied cases of AEA diagnosed at Severance Children's Hospital from January 2013 to October 2017. We evaluated the efficacy of antiepileptic drugs, steroids, and ketogenic diets (KD) in treating acquired aphasia. The EEG patterns and prognostic factors were predicted by the background EEG and frequency of spike and wave during sleep (SWS). Results The study analyzed 20 patients, 11 male and 9 female, with AEA. Aphasia most commonly occurred at 4 years of age, and clinical seizure was most likely to occur between 2 and 4 years of age and focal seizures were the most common seizure type. KD was shown to be the best treatment for clinical seizure in AEA patients. Patients with normal EEG background showed better responses to clinical seizure treatment and improvements in neuropsychological function. Conclusion KD and steroids generate the best therapeutic effects for clinical seizure in AEA patients. Improvements in neuropsychological function in AEA patients may be related to the EEG background and the SWS patterns. Additionally, the results suggest that the response of clinical seizure to antiepileptic drugs may also be related to the EEG background. However, the current study had some limitations and further research is needed.

Epilepsy Aphasia Syndromes (EAS) are a spectrum of childhood epileptic, cognitive, and language disorders of unknown etiology.CNKSR2is a strong X-linked candidate gene implicated in EAS; however, there have been no studies of genetic models to dissect how its absence may lead to EAS. Here we develop a novelCnksr2KO mouse line and show that male mice exhibit increased neural activity and have spontaneous electrographic seizures.Cnksr2KO mice also display significantly increased anxiety, impaired learning and memory, and a progressive and dramatic loss of ultrasonic vocalizations. We find that Cnksr2 is expressed in cortical, striatal, and cerebellar regions and is localized at both excitatory and inhibitory postsynapses. Proteomics analysis reveals Cnksr2 anchors key binding partners at synapses, and its loss results in significant alterations of the synaptic proteome, including proteins implicated in epilepsy disorders. Our results validate that loss of CNKSR2 leads to EAS and highlights the roles of Cnksr2 in synaptic organization and neuronal network activity.SIGNIFICANCE STATEMENTEpilepsy Aphasia Syndromes (EAS) are at the severe end of a spectrum of cognitive-behavioral symptoms seen in childhood epilepsies, and they remain an inadequately understood disorder. The prognosis of EAS is frequently poor, and patients have life-long language and cognitive disturbances. Here we describe a genetic mouse model of EAS, based on the KO of the EAS risk geneCnksr2. We show that these mice exhibit electrophysiological and behavioral phenotypes similar to those of patients, providing an important new model for future studies of EAS. We also provide insights into the molecular disturbances downstream of Cnksr2 loss by usingin vivoquantitative proteomics tools.

To celebrate the 50th year since the publication of the seminal LKS paper by Drs. Landau and Kleffner, a small conference, “Fifty Years of Landau–Kleffner Syndrome International Symposium: A Tribute to William Landau and Frank Kleffner”, was held on November 1–3, 2007 at a beautiful castle located in the small village Biesen in Belgium. In this short chapter, the author introduced the program of this memorable international symposium.

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. (Less)

Landau-Kleffner syndrome (LKS) is a rare childhood neurological condition that causes developmental regression, loss of language skills and abnormal electroencephalogram (EEG) patterns. Its etiology is unknown. This report describes a case of a 13-year-old boy who at 3.5 years of age was bitten by a tick. Two months thereafter, he began losing previously acquired developmental and language skills, and developed seizures. The seizures subsided with valproic acid treatment, but the developmental delays persisted. Family history and disease progression reports obtained from the patient’s father revealed that the patient displayed repetitive behaviors prior to the age of three. Clinical observation also showed the patient having numerous repetitive vocalizations and movements along with difficulty with switching sets. His developmental age at the time of presentation was determined to be 3 to 4 years of age. During the course of diagnostic testing, we were able to rule out tick-borne encephalitis (TBE) and rule in LKS in a premorbidly autistic child. This case describes the similarities between the three conditions and the diagnostic investigations used to arrive at a final diagnosis.

The Landau-Kleffner syndrome (LKS), formerly known as acquired epileptic aphasia, is a rare syndrome that typically presents in early childhood with language regression and seizures. We report a case of LKS in an 7-year-old boy who presented with aggressive behavior, difficulty in maintaining posture, and language regression. Systemic examination, including neurological evaluation, was normal. Cerebrospinal fluid (CSF) analysis and magnetic resonance imaging (MRI) were normal. Electroencephalogram (EEG) showed abnormal findings associated with generalized seizure discharge during sleep with more spikes being noted in bilateral frontal and temporal regions. LKS was diagnosed and was treated with anticonvulsants and steroids. On follow-up, the child showed improvement in maintaining posture, was able to walk independently and had improved linguistic functions. This case adds another variant of LKS to the existing literature.

Objective Epilepsy-aphasia spectrum (EAS) are a group of epilepsy syndromes denoting an association between epilepsy, speech disorders and the EEG signature of centrotemporal spikes. Mutations in the GRIN2A gene, encoding the NMDA glutamate receptor α2 subunit were reported in focal epilepsy with speech disorder. We aimed to explore the role of GRIN2A mutations in patients with centrotemporal spikes related epileptic syndromes in a Chinese cohort. Methods Patients with Landau-Kleffner syndrome (LKS), epileptic encephalopathy with continuous spike-and-wave during sleep (ECSWS), atypical benign partial epilepsy (ABPE), and benign epilepsy with centrotemporal spikes (BECTS) were recruited. GRIN2A mutation screening was performed using PCR and Sanger sequencing. Results 122 patients, including 9 LKS, 26 ECSWS, 42 ABPE and 45 BECTS were enrolled. The mean age of seizure or aphasia onset was 5 years, ranging from 10 months to 11 years. Heterozygous GRIN2A mutations were detected in four patients (G760S, D1385Y, C455Y and C231R) GRIN2A mutation was found in 11.1% (1 out of 9 cases) of LKS, and in 7.1% (3 out of 42 cases) of ABPE, but in none with ECSWS and BECTS. No GRIN2A mutation was found in patients with a family history of febrile seizures or epilepsy. Conclusion GRIN2A mutation is a genetic cause in less than 11% patients with LKS or ABPE. GRIN2A gene is a rare causative gene in Chinese patients with EAS, suggesting the possibility of other gene involved in the pathogenesis.

Transient oromotor deficits in children with rolandic epilepsy (RE) have been described in literature. It has been reported that thalamic aphasia can be caused by thalamic infarction or hemorrhage; however, it has never been reported that thalamic aphasia can be caused by epileptic disorders. Here, we describe a 6-year-old right-handed boy who showed transient oromotor deficits and speech disturbance with worsening of both epileptic seizure and paroxysmal discharges on electroencephalogram. He had paucity of spontaneous speech, feeble speech, arrest of speech, and anomia, but his repetition skills were intact. A single-photon emission computed tomography (SPECT) scan using technetium-99m hexamethyl propylene amine oxime (99mTc-HMPAO) to measure regional cerebral blood flow showed a reduction in flow in the left thalamus and ipsilateral frontotemporal areas, which appeared concurrently with the speech dysfunction. We suggest that speech disturbance such as thalamic aphasia, which is similar to the symptoms of Landau-Kleffner syndrome, may occur due to epileptic disorders such as RE. It may be possible to miss speech disturbance implicated in the thalamus in cases complicated by oromotor dysfunction. It is important that speech disturbance implicated in the thalamus is not overlooked in patients with RE showing an atypical course.

We report a case of a 48-year-old woman who was diagnosed with Landau-Kleffner syndrome (LKS) at the age of 4 and reassessed by the same neurologist four decades later. While her seizures abated by the time she was 12 years old, she was left with chronic aphasia, despite receiving optimal care. Although she graduated from high school, started her own family, and was gainfully employed, she was vulnerable in situations that required clear communication. This case reflects successful management of an otherwise debilitating condition and reminds us of the vulnerability of adults with LKS and their need for a life-long support., Highlights • Acquired epileptiform aphasia, and LKS as its variant, has lifelong consequences. • Even those who recover relatively well from LKS face lifelong social, communication and economic challenges. • Educational and psychological support with effective social restructuring may be necessary for adults with LKS.

To evaluate the correlation between clinical spectrum and therapeutic outcomes and neuropsychological deficits in children with status epilepticus during sleep (SES).The clinical spectrum of patients with SES was defined as follows: status epilepticus of benign childhood epilepsy with centro-temporal spikes (SEBECTs), atypical benign focal epilepsy during childhood (ABFEC), non-idiopathic focal epilepsy (NIFE), and Landau-Kleffner syndrome (LKS). SES cases were divided into 4 groups according to neuropsychological findings before treatment: developmental delay/intellectual disability (DD/ID), cognitive impairment (CI), attention deficit and/or hyperactivity behaviors (AHD), and normal group (NG). The therapeutic outcomes were classified into 3 groups: satisfactory response, recurrence, and seizure control.A total of 39 cases (24 males and 15 females) were recruited, including 3 cases with SEBECTs, 26 with ABFEC, 8 with NIFE [2 with focal cortical dysplasia (FCD)], and 2 with LKS. There were 7 patients in the DD/ID group, 8 in the CI group, 19 in the AHD group, and 5 in the NG group. Neuropsychological outcomes were significantly different among clinical spectrum (P 0.001), and neuropsychological deficits frequently occurred in the ABFEC group or in the NIFE group. Besides, 18 patients in the satisfactory group had satisfactory response to medicine or surgery (2 out of 18 cases with FCD), whereas recurrence was observed at least one session within one year in 16 cases in the recurrence group, and no improvement in spike-wave index and cognition/behavior was noted in 5 patients in the seizure control group, although seizure could be controlled. There were significant differences in therapeutic outcomes among clinical spectrum (P = 0.041), with the worst outcomes in the NIFE group (only 1 out of 8 with satisfactory good response).It is important to categorize patients with SES into epilepsy syndromes, including SEBECTs, ABFPEC, NIFE, and LKS; the clinical spectrum may be a significant determinant to influence the outcomes of SES, including neuropsychological deficits and therapeutic outcomes.

Purpose Long-term ketogenic diet (KD) treatment has been shown to induce liver steatosis and gallstone formation in some in vivo and clinical studies. The aim of this retrospective study was to evaluate the hepatic side effects of KD in epileptic children. Method A total of 141 patients (mean age: 7.1±4.1years [2–18 years], 45.4% girls), receiving KD at least one year for intractable epilepsy due to different diagnoses (congenital brain defects, GLUT-1 deficiency, West syndrome, tuberous sclerosis, hypoxic brain injury, etc.) were included in the study. Serum triglyceride, cholesterol, aminotransferase, bilirubin, protein and albumin levels and abdominal ultrasonography were recorded before and at 1, 3, 6, and 12 months following after diet initiation. Results The mean duration of KD was 15.9±4.3months. At one month of therapy, three patients had elevated alanine and aspartate aminotransferase levels. These patients were receiving ketogenic diet for Doose syndrome, idiopathic epilepsy and GLUT-1 deficiency. Hepatosteatosis was detected in three patients at 6 months of treatment. Two of these patients were treated with KD for the primary diagnosis of tuberous sclerosis and one for Landau Kleffner syndrome. Cholelithiasis was detected in two patients at 12 months of treatment. They were receiving treatment for West syndrome and hypoxic brain injury sequelae. Conclusion Long-term ketogenic diet treatment stimulates liver parenchymal injury, hepatic steatosis and gallstone formation. Patients should be monitored by screening liver enzymes and abdominal ultrasonography in order to detect these side effects.

Landau–Kleffner syndrome (LKS) is a disease from the group of age-dependent epileptic encephalopathies with the phenomenon of prolonged spike–wave activity in slow-wave sleep, which is manifested by acquired sensorimotor aphasia, impaired higher mental functions concurrent with various epileptic seizures and diffuse electroencephalographic (EEG) epileptiform changes in the absence of cerebral structural changes. In 1957, W. M. Landau, a pediatric neurologist, and F. R. Kleffner, a logopedist, first described the clinical presentation of the disease in 6 patients. The author associated the occurrence of aphasia with epileptiform EEG activity rather than with epileptic seizures, i. e. they per se formulated the modern concept of epileptic encephalopathy. There has been currently evidence that prolonged diffuse epileptiform activity has a damaging effect on a child’s developing brain, which is seen in impairments of speech and other higher mental functions. The age of patients with manifestations of LKS (3–5 years) is a critical period for the development of speech function. According to the concept of H. Doose (2003), congenital brain maturation disorder underlies LKS. The paper considers ideas on the origin of the LKS, including the possible genetic bases of diseases, epidemiological aspects, clinical and EEG manifestations with a detailed description ictal and interictal EEG changes, and treatment approaches, including the author’s data. The disease is characterized by an electroclinical triad: seizures (may be absent or may be single in a history), impaired higher mental functions (with a predominance of aphasic disorders), epileptiform EEG activity (a combination of regional and diffuse patterns with an increase during sleep).

Landau–Kleffner syndrome (LKS) is an epileptic encephalopathy that is marked by sudden onset of verbal auditory agnosia and subsequent deterioration in expressive language. The primary deficit is in phonological processing, possibly at the level of impaired phonological short-term memory, and it appears to create a cascade of cognitive deterioration that impacts all aspects of speech comprehension. Inability to recognize nonverbal auditory stimuli may also be present but may not emerge until later in the condition. Language recovery may occur in about one-third of patients and appears to be precipitated by resolution of the EEG abnormalities. Nonverbal intelligence is typically normal, but language skills are globally impaired. Some studies suggest deficits in visual-spatial processing and/or visual-motor integration in up to 50% of cases, but other aspects of cognitive functioning, such as memory and executive functioning, have not been well studied. Auditory working memory, however, is a consistent area of difficulty for children with LKS and appears to persist regardless of functional outcome. Behavioral disturbance is also pervasive in LKS and can sometimes be the feature requiring the most clinical attention. Recent studies have emerged that provide more thorough neurodiagnostic information about the cognitive and behavioral features of LKS, but the reported literature on expected neuropsychological findings in LKS remains sparse.

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.

The article describes the phenomenon of dual pathology – a combination of structural changes in the brain and benign epileptiform discharge of childhood on electroencephalogram. The uniqueness lies in the observation that the child, since birth suffering from spastic form of cerebral palsy and severe epilepsy, demonstrated the development of Stevens–Johnson syndrome due to intolerance of one of the antiepileptic drugs. Therapeutic approaches to overcome a whole range of violations are discussed in the article.

Landau-Kleffner syndrome (LKS) has been demonstrated in the past to respond to immunotherapy. Recently, some cases of LKS have been shown to be secondary to glutamate receptor (GRIN2A) mutations. Whether such cases respond to immunotherapy is not known. Here, we present the case of a 3-year-old boy with LKS found to have a GRIN2A heterozygous missense mutation, whose clinical symptoms and EEG responded to a course of combination oral steroids and monthly infusions of intravenous immunoglobulin. He then relapsed after discontinuation of this therapy, and responded again after a second course of intravenous immunoglobulin. We conclude that immunotherapy should be considered as a therapeutic option in patients with LKS who are also found to harbour GRIN2A mutations.

We report a case study of cognitive linguistic treatment in a teenager with chronic severe Landau Kleffner Syndrome. The effect of speech and language therapy in LKS is rarely examined and our case is unique in that we use an effective approach in adult aphasia to treat language deficits in aphasia in LKS. The results show successful acquisition of a considerable amount of new words as well as improved communication in daily life. However, auditory verbal agnosia, the most prominent feature in LKS, persisted. Cognitive linguistic treatment seems a promising treatment to improve spoken language production in LKS, but more research is needed to optimize speech and language therapy of auditory verbal agnosia and auditory language comprehension in children with LKS

Objective The objective of the study was to investigate electroclinical and neuropsychological features, genetic background, and evolution of children with idiopathic encephalopathy with status epilepticus during slow sleep (ESES), including Landau–Kleffner syndrome (LKS). Material and methods All children diagnosed with idiopathic ESES at the Danish Epilepsy Centre between March 2003 and December 2014 were retrospectively reviewed. Repeated 24-hour electroencephalography (24-h EEG) recordings, neuropsychological assessments, and clinical–neurological evaluation were performed throughout the follow-up in all patients. In 13 children, genetic investigations were performed. Results We collected 24 children (14 males and 10 females). Mean age at ESES diagnosis was 6 years, and mean ESES duration was 2 years and 7 months. Twenty-one children had epileptic seizures. Three children had LKS. Topography of sleep-related EEG epileptic abnormalities was diffuse in 3 subjects, hemispheric in 6, multifocal in 9, and focal in 6. During the active phase of ESES, all children presented with a heterogeneous combination of behavioral and cognitive disturbances. In 14 children, a parallel between severity of the clinical picture and spike–wave index (SWI) was observed. We could not find a strict correlation between the type and severity of neurobehavioral impairment and the side/topography of sleep-related EEG discharges during the active phase of ESES. At the last follow-up, 21 children were in remission from ESES. Complete recovery from neurobehavioral disorders was observed in 5 children. Genetic assessment, performed in 13 children, showed GRIN2A variant in two (15.4%). Significance Our patients with idiopathic ESES showed a heterogeneous pattern of epileptic seizures, neurobehavioral disorders, and sleep EEG features. Only one-fourth of children completely recovered from the neuropsychological disturbances after ESES remission. Lack of correlation between severity/type of cognitive derangement and SWI and/or topography of sleep EEG epileptic abnormalities may suggest the contribution of additional factors (including impaired sleep homeostasis due to epileptic activity) in the neurobehavioral derangement that characterize ESES.

Objective To report a case with Landau-Kleffner syndrome (LKS) presenting with unusual clinical features. Methods The clinical features of the case including clinical manifestations, serial electroencephalography (EEG) outcomes, neuroimaging findings, neuropsychological outcomes, interventional approaches and long-term follow-up outcomes, were analyzed. Results This previously normal girl (3y10m), presented with progressive ataxia as an onset symptom, ensued with cognitive impairments and language regressions (characterized by verbal auditory agnosia and expressive aphasia), and autistic-like behaviors. She had no evidence of clinical seizures, with normal brain and spine MRI scans, intact auditory exams and normal brain auditory evoked potential, although the sleep- activated inter-ictal epileptiform discharges of EEG were revealed. The patient showed gradual resolution of symptoms with long-term high-dose steroids plus intravenous immunoglobulin (IVIG) regimens, in consistence with the gradual improvement of the outcomes of serial EEGs. She recovered and returned to normal kindergarten 1y1m after the onset of the disease, consistent with the normal EEG results. Her full-scale intelligence quotient (IQ) was 71 score, with verbal IQ 66 and performance IQ 81 respectively, tested at the time of 1y3m after the onset. The long-term prognosis of the case was good as she had good academic performance and was a monitor of the class at the time of her long-term follow-up of 5y8m after the onset. Conclusion LKS is heterogeneity entity, especially for those with the atypical onset such as ataxia, as well as absence of clinical seizures. The combination of long-term high-dose steroid plus IVIG regimens may be especially effective in LKS.

Speech and language development may be impaired in all forms of epilepsy involving specialized functional areas in the dominant cerebral hemisphere and their connections. The concept of epilepsy-aphasia clinical spectrum was recently proposed, but the notion of aphasia is quite conditional here as many of these patients demonstrate disorders of speech and language development from their infancy. Those forms of epilepsy are considered as continuum from the most severe Landau-Kleffner syndrome (LKS) and epilepsy with continuous spike-and-wave during sleep (CSWS) (also indicating as electrical status epilepticus during sleep - ESES) to intermediate epilepsy-aphasia disorders (with incomplete correspondence to diagnostic criteria of LKS and epilepsy with CSWS). The mild end of the spectrum is represented by benign childhood epilepsy with centrotemporal spikes (rolandic), which is often associated with speech and language disorders. The importance of genetic factors is discussed, including mutations in SRPX2, GRIN2A and other genes. The perspectives of individualized pharmacotherapy in epilepsy, co-morbid with neurodevelopmental disorders or impairments of speech and language development, are depending on the progress in genetic studies. In the new generation of antiepileptic drugs the positive influence on neuroplasticity mechanisms and higher cerebral functions are supposed for levetiracetam.Речь и ее развитие могут страдать при всех формах эпилепсии, затрагивающих специализированные центры в доминантном большом полушарии и их формирующиеся связи. В последние годы сформулирована концепция спектра расстройств 'эпилепсия-афазия', при этом указание на афазию представляется достаточно условным, поскольку у значительной части этих пациентов с раннего возраста отмечаются нарушения речевого развития. Соответствующие формы эпилепсии рассматриваются как клинический континуум, в котором самыми тяжелыми являются синдром Ландау-Клеффнера и эпилепсия с CSWS (также обозначается как эпилепсия с электрическим эпилептическим статусом медленноволнового сна - ESES), за ними следует промежуточная форма расстройства спектра 'эпилепсия-афазия' (с неполным соответствием критериям синдрома Ландау-Клеффнера и эпилепсии с CSWS), а наименьшей степенью тяжести обладает доброкачественная эпилепсия детства с центротемпоральными спайками (роландическая), при которой часто отмечаются речевые расстройства. Обсуждается роль генетических изменений при данных формах эпилепсии, в том числе мутаций генов SRPX2, GRIN2A и др. Перспективы индивидуализированной фармакотерапии эпилепсии, коморбидной с нарушениями нервно-психического развития и формированием речи, связаны с достижениями генетики. Среди современных эффективных противоэпилептических препаратов в аспекте положительного влияния на патогенез болезни выделен леветирацетам.

Developmental regression is characteristic of Rett syndrome and it also occurs in a number of other developmental disabilities. To assist clinicians in identifying promising therapeutic approaches, we identified 38 studies that sought to improve adaptive behavior functioning in cases where developmental regression had either already occurred or was likely to occur. Studies were summarized in terms of (a) participants, (b) intervention, (c) dependent variables, (d) outcomes, (e) study design, and (f) certainty of evidence. The available literature included 136 participants from preschoolers to adults. Most participants (n = 132) had Rett syndrome. Interventions targeted a range of dependent variables (e.g., challenging behavior, communication, motor, and play skills). Multi-component interventions derived from behavior analytic principles were the norm, suggesting the need for clinical expertise in the application of such principles. However, only 12 studies (with 44 participants) were rated as providing conclusive evidence of a positive intervention effect. Future research on the mechanisms underlying developmental regression might lead to new and more effective interventions.

Regression in children with epilepsy may involve loss of cognitive abilities, failure to progress or a slowing of developmental trajectory. A few seizures do not lead to regression. Large numbers of seizures may be associated with regression but the cause is an important cofounder. Individual spike discharges on EEG are associated with transient cognitive impairment and continuous spike discharges with regression. Regression may be global in continuous spike wave in slow sleep (CSWS) or specific (auditory agnosia) in Landau Kleffner syndrome. Regression is mild and transient in Rolandic Epilepsy or profound and permanent in West Syndrome. Epilepsy syndromes grouped under "epileptic encephalopathies" may lead to regression, although proof of this concept is not strong for many syndromes. The absence of cognitive assessment before epilepsy onset, the contribution of the cause and complications of treatment make for difficult methodological problems. The large majority of children with epilepsy do not have regression. There is need for more longitudinal studies of children with epileptic encephalopathies and other epilepsies associated with regression.

We overview here the new data about the epileptic spectrum disorders within the frame of perisylvian epileptic network since our first trial to synthetize knowledge about this system epilepsy (Halasz et al., 2005). We found evidences for a continual features relating together syndromes constituting this spectrum disorder in several fields: in sharing genetic origin, in common perisylvian human communication circuitry, in NREM sleep related potentiation of interictal epileptiform discharges of the centro-temporal spike phenomenon and in the discharge related cognitive impairment, reflecting functional deficits in human communication abilities. The transformation of a part of the children to develop into a malignant course with different degree of residual cognitive loss, through compromising sleep plastic functions, by the epileptic discharges during sleep, beside pure genetic origin, is still under research. Both factual data and new conceptual approaches helps understand better the developmental childhood epilepsies.

Functional evaluation assays using human induced pluripotent stem cell (hiPSC)-derived neurons can predict the convulsion toxicity of new drugs and the neurological effects of antiepileptic drugs. However, differences in responsiveness depending on convulsant type and antiepileptic drugs, and an evaluation index capable of comparing in vitro responses with in vivo responses are not well known. We observed the difference in synchronized burst patterns in the epileptiform activities induced by pentylentetrazole (PTZ) and 4-aminopryridine (4-AP) with different action mechanisms using multi-electrode arrays (MEAs); we also observed that 100 µM of the antiepileptic drug phenytoin suppressed epileptiform activities induced by PTZ, but increased those induced by 4-AP. To compare in vitro results with in vivo convulsive responses, frequency analysis of below 250 Hz, excluding the spike component, was performed. The in vivo convulsive firing enhancement of the high γ wave and β wave component were observed remarkably in in vitro hiPSC-derived neurons with astrocytes in co-culture. MEA measurement of hiPSC-derived neurons in co-culture with astrocytes and our analysis methods, including frequency analysis, appear effective for predicting convulsion toxicity, side effects, and their mechanism of action as well as the comparison of convulsions induced in vivo.

Benign epilepsy with centrotemporal spikes (BECTS) is the most common focal epilepsy of the childhood and also one of the best known. It has a proclivity to start at a particular age and remit spontaneously before adolescence. Majority of patients may avoid long-term treatment, because of the mild course and very good outcome. Only few patients may present cognitive deficits if the proper treatment is not implied. BECTS is a part of heterogeneous group of syndromes that consists of Landau-Kleffner Syndrome (LKS), Continuous Spike-and-Wave during Sleep (CSWS) and Atypical benign partial epilepsy (ABPE). These syndromes may be also a result of various trajectories that BECTS may evolve to. Disease is suggested to have genetic origins, as some patients have relatives with different types of epilepsy. The discovery of the pathogenic mechanism of the disease and implementation of targeted therapy belong to the main challenges in the treatment of these patients.

Purpose Electrical status epilepticus in sleep (ESES) is an electrographic abnormality linked to language abnormalities and cognitive dysfunction and specifically associated with Landau–Kleffner syndrome (LKS), the syndrome of continuous spike and wave in slow-wave sleep (CSWS), and autistic regression with epileptiform EEG (AREE). As first-line therapies for treatment of ESES display inadequate efficacy and confer substantial risk, we set out to describe our center's experience with amantadine in the treatment of ESES. Methods Patients with video-EEG-confirmed ESES who received amantadine were retrospectively identified in a clinical EEG database. Spike–wave index, before and after amantadine exposure, was compared in a pairwise fashion. In an exploratory analysis, we cataloged reported changes in language functioning, cognition, and autistic features, which accompanied treatment. Results We identified 20 patients with ESES-associated syndromes. Median cumulative weighted average amantadine dosage was 2.1 mg/kg/d (interquartile range (IQR): 1.1, 4.5), and median duration of therapy was 11.5 months (IQR: 7.8, 26.6). In comparison with median baseline spike–wave index (76%), post-amantadine spike–wave index (53%) was reduced, with P = 0.01. Six (30%) patients exhibited complete (or nearly complete) resolution of ESES. A majority of patients exhibited subjective cognitive, linguistic, or behavioral benefit. Amantadine was generally well-tolerated despite substantial dosage and duration of therapy. Conclusions This study suggests that amantadine may be effective in the treatment of ESES-associated syndromes but warrants replication in a more rigorous study.

The purpose of this review is to discuss rare neurological disorders with respect to communication difficulties typical of children. Firstly, communication disorders with special focus on rare communication neurological disorders are discussed. Secondly, on the basis of literature review, the authors explore clinical studies on the most typical rare children's communication neurological disorders. Thirdly, on the basis of the findings from the clinical studies, they set a few recommendations for their medical therapies and management. The methodology was based on the literature review of research studies exploring the research issue. The findings show that the intervention strategies appear to have positive effects on the improvement of speech and language production among children suffering from Landau-Kleffner syndrome and childhood apraxia of speech. Nevertheless, randomized control trials are needed in order to accelerate and facilitate an early and relevant diagnosis and treatment management. In addition, a multidisciplinary approach seems to be the most appropriate for the accurate diagnosis and comprehensive treatment.

Landau-Kleffner Syndrome (LKS) is a rare form of acquired aphasia in children, characterized by epileptic discharges, which occur mostly during sleep. After normal speech and language development, aphasia develops between the ages of 3-7 years in a period ranging from days to months. The epileptic discharges usually disappear after reaching adulthood, but language outcomes are usually poor if no treatment focused on restoration of (non-) verbal communication is given. Patients often appear deaf-mute, but sign language, as part of the treatment, may lead to recovery of communication. The neural mechanisms underlying poor language outcomes in LKS are not yet understood. In this detailed functional MRI study of a recovered LKS patient - that is, a patient no longer suffering from epileptic discharges, audiovisual multi-sensory processing was investigated, since LKS patients are often proficient in reading, but not in speech perception. In the recovered LKS patient a large difference in the neural activation to auditory stimuli was found in the left versus the right auditory cortex, which cannot be attributed to hearing loss. Compared to healthy proficient readers investigated earlier with the same fMRI experiment, the patient demonstrated normal letter-sound integration in the superior temporal gyrus as demonstrated by the multi-sensory interaction index, indicating intact STG function. Diffusion Tensor Imaging (DTI) based fiber tracking in the LKS patient showed fibers originating from Heschl's gyrus that seem to be left-right inverted with respect to FIG fiber pattern described in the literature for healthy controls. In the patient, in both hemispheres we found arcuate fibers projecting from (homologues of) Broca's to Wernicke's areas, and a lack of fibers from arcuate left inferior parietal and sylvian areas reported in healthy subjects. We observed short arcuate segments in the right hemisphere. Although speculative, our results suggest intact temporal lobe processing but an altered temporal to frontal connectivity. The altered connectivity might explain observed short-term verbal memory problems, disturbed (speech) sound-motor interaction and online feedback of speech and might be one of the neuronal factors underlying LKS. (c) 2015 Elsevier Inc. All rights reserved.

We reviewed the etiology, clinical symptoms, differential diagnosis, treatment and prognosis of the Landau-Kleffner syndrome. The Landau-Kleffner syndrome is a rare syndrome of unknown etiology. Onset occurs between 18 months and 13 years of age, with three-fourths of the cases appearing before the age of 7 years. Most patients appeared normal before the onset of the syndrome. The loss of acquired language is usually total, but nonverbal skills are generally completely or at least relatively preserved. Clinical seizures are experienced by 70% of patients at some time, although they do not necessarily appears at very beginning of disorder. Paroxysmal electroencephalography abnormalities are often very marked; such abnormalities tend to increase during slow wave sleep, often producing continuous spike and waves during slow wave sleep. Other characteristics associated with this syndrome include neurobehavioral symptoms such as autistic behavior, various degrees of cognitive regression and motor disorders. Treatment with standard anti-epileptic drugs is typically not effective. Adrenocorticotropic hormone is currently preferred due to its clinical and electroencephalographic efficacy. The prognosis is uncertain. Significant improvement is observed in most cases, although moderate or permanent speech deficiencies typically persist. Since proper treatment of Landau-Kleffner syndrome, once identified, can have profound consequences on a child's language development, it is important for the clinician to evaluate any child with alterations of speech development without a cause with an electroencephalogram that includes recording during sleep.

A child with Landau-Kleffner syndrome who changed to continuous spike wave discharges both during sleep as well as awake is reported in this communication. A 4.5-year-old boy developed rapidly progressive mixed aphasia with relative preservation of writing and drawing skills. Electroencephalogram showed 2-2.5 Hz spike wave discharges more marked during slow wave sleep. Single photon emission tomography revealed hypoperfusion of the left frontotemporoparietal area. The patient did not respond to methylprednisolone, intravenous immunoglobulin and a number of antiepileptic drugs. At 2 year follow up there was no clinical improvement and the EEG showed continuous spike wave discharges not only during sleep but also during waking. He was aphasic but had preservation of spatial intelligence. This case report highlights the severe and resistant form of Landau-Kleffner syndrome and the heterogeniety of the condition. (J Pediatr Neurol 2004; 2(3): 157-160).