Evidence for normal letter-sound integration, but altered language pathways in a case of recovered Landau-Kleffner Syndrome.

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 HG 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.

Epileptic encephalopathies: new genes and new pathways.

Epileptic encephalopathies represent a group of devastating epileptic disorders that occur early in life and are often characterized by pharmaco-resistant epilepsy, persistent severe electroencephalographic abnormalities, and cognitive dysfunction or decline. Next generation sequencing technologies have increased the speed of gene discovery tremendously. Whereas ion channel genes were long considered to be the only significant group of genes implicated in the genetic epilepsies, a growing number of non-ion-channel genes are now being identified. As a subgroup of the genetically mediated epilepsies, epileptic encephalopathies are complex and heterogeneous disorders, making diagnosis and treatment decisions difficult. Recent exome sequencing data suggest that mutations causing epileptic encephalopathies are often sporadic, typically resulting from de novo dominant mutations in a single autosomal gene, although inherited autosomal recessive and X-linked forms also exist. In this review we provide a summary of the key features of several early- and mid-childhood onset epileptic encephalopathies including Ohtahara syndrome, Dravet syndrome, Infantile spasms and Lennox Gastaut syndrome. We review the recent next generation sequencing findings that may impact treatment choices. We also describe the use of conventional and newer anti-epileptic and hormonal medications in the various syndromes based on their genetic profile. At a biological level, developments in cellular reprogramming and genome editing represent a new direction in modeling these pediatric epilepsies and could be used in the development of novel and repurposed therapies.

Neurobiology of continuous spike-wave in slow-wave sleep and Landau-Kleffner syndromes.

BACKGROUND: Several pediatric seizure disorders have common electrophysiological features during slow-wave sleep that produce different syndromes based on which part of the developing brain is involved. These disorders, of which continuous spike-wave in slow-wave sleep and Landau-Kleffner are the most common, are characterized by continuous spike-wave activity during slow-wave sleep, developmentally regulated onset and termination of abnormal electrical activity, and loss of previously acquired skills. Over the last 20 years, a variety of basic science findings suggest how spike-wave activity during sleep can cause the observed clinical outcomes. METHODS: Literature review and analysis. RESULTS: The role of slow-wave sleep in normal cortical plasticity during developmental critical periods, how disruption of slow-wave sleep by electrographic seizures could affect cortical maps and development, and the organization and functional connectivity of the thalamic structures that when damaged are thought to produce these seizure disorders are reviewed. CONCLUSIONS: Potential therapeutic directions are proposed based on the mechanisms of plasticity and anatomical structures involved in cortical plasticity during slow-wave sleep.

Landau-Kleffner syndrome: a study of 29 patients.

PURPOSE: The aim of the study was to retrospectively analyze the electroclinical features, etiology, treatment, and prognosis of 29 patients with Landau-Kleffner syndrome (LKS) with a long-term follow-up. METHODS: Inclusion criteria were a diagnosis of LKS with: (1) acquired aphasia or verbal auditory aphasia; (2) with or without focal seizures, secondarily generalized tonic-clonic seizures, absences, or atonic seizures. RESULTS: Mean follow-up was 12 years. All cases except six had seizures. Before the onset of aphasia, developmental language and behavioral disturbances were present in 19 and 14 patients, respectively. All patients had verbal auditory agnosia. Aphasia was severe in 24 patients and moderate in five. Nonlinguistic cognitive dysfunctions were moderate in 14 patients. Behavioral disturbances were found in 16 patients. During the continuous spike-and-wave discharges during slow sleep phase, the spike-wave index was >85% in 15, 50-85% in eight, and 30-50% in four. In two patients, the EEG recording showed occasional bilateral spikes, without continuous spike-and-wave discharges during slow sleep. In this phase, the awake EEG recording showed more frequent interictal abnormalities, predominantly in the temporal regions. Eight patients recovered language completely, but the remaining patients continue to have language deficits of different degrees. CONCLUSION: Landau-Kleffner syndrome is an epileptic encephalopathy characterized by acquired verbal auditory aphasia and seizures in most of the patients associated with continuous or almost continuous spike-and-wave discharges during slow wave sleep. The most commonly used treatments were clobazam, ethosuximide, sulthiame. High-dose steroids were also administered. Adequate and early management may avoid language and cognitive deterioration.

Serial auditory-evoked potentials in the diagnosis and monitoring of a child with Landau-Kleffner syndrome.

BACKGROUND: A boy, aged 2 1/2 yr, experienced sudden deterioration of speech and language abilities. He saw multiple medical professionals across 2 yr. By almost 5 yr, his vocabulary diminished from 50 words to 4, and he was referred to our speech and hearing center. PURPOSE: The purpose of this study was to heighten awareness of Landau-Kleffner syndrome (LKS) and emphasize the importance of an objective test battery that includes serial auditory-evoked potentials (AEPs) to audiologists who often are on the front lines of diagnosis and treatment delivery when faced with a child experiencing unexplained loss of the use of speech and language. RESEARCH DESIGN: Clinical report. RESULTS: Interview revealed a family history of seizure disorder. Normal social behaviors were observed. Acoustic reflexes and otoacoustic emissions were consistent with normal peripheral auditory function. The child could not complete behavioral audiometric testing or auditory processing tests, so serial AEPs were used to examine central nervous system function. Normal auditory brainstem responses, a replicable Na and absent Pa of the middle latency responses, and abnormal slow cortical potentials suggested dysfunction of auditory processing at the cortical level. The child was referred to a neurologist, who confirmed LKS. At age 7 1/2 yr, after 2 1/2 yr of antiepileptic medications, electroencephalographic (EEG) and audiometric measures normalized. Presently, the child communicates manually with limited use of oral information. CONCLUSIONS: Audiologists often are one of the first professionals to assess children with loss of speech and language of unknown origin. Objective, noninvasive, serial AEPs are a simple and valuable addition to the central audiometric test battery when evaluating a child with speech and language regression. The inclusion of these tests will markedly increase the chance for early and accurate referral, diagnosis, and monitoring of a child with LKS which is imperative for a positive prognosis.

Landau-Kleffner syndrome: a rare auditory processing disorder series of cases and review of the literature.

OBJECTIVE: To describe the clinical presentation and treatment of 3 children with an Auditory Processing Disorder with an identifiable neurological cause: Landau-Kleffner syndrome. This classical syndrome is well recognized in pediatric neurology but the diagnosis is less well known to Pediatric Otolaryngology, Speech Language Pathology and Audiology services. METHODS: Retrospective chart review of three patients with Landau-Kleffner syndrome. RESULTS: In all cases, pharmacological intervention led to clinical and electroencephalographic improvement, but all patients had long-term difficulty with understanding sounds in a noisy environment. Magnetic Resonance Imaging (MRI) of the brain was normal in all three patients. Their language disturbance improved over time. Speech language intervention was helpful in addressing communication difficulties arising from the auditory processing/receptive and expressive language disorder. CONCLUSION: A multidisciplinary assessment is the key for early diagnosis, treatment and follow-up in patients with this syndrome.

[Neurocognitive dysfunction in electrical status epilepticus during slow-wave sleep syndrome: Can the natural course of the syndrome be modified with early pharmacological treatment?]. / Disfunción neurocognitiva en el síndrome de estado de mal eléctrico durante el sueño lento: podemos modificar la evolución natural del síndrome con un tratamiento farmacológico precoz?

INTRODUCTION: Epileptic syndromes with continuous spike wave in slow-wave sleep (CSWS), including electrical status epilepticus in sleep (ESES) and Landau-Kleffner syndrome, are true epileptic encephalopathies where sustained epileptic activity is related to cognitive and behavioural decline. AIMS: To review the natural course of ESES, to define the general principles of treatment of epileptic syndromes with CSWS, to delineate the different options that are currently available for treating these epileptic encephalopathies, and to analyze the prognostic factors linked to pharmacological treatment of ESES. DEVELOPMENT: Epileptic syndromes with CSWS are initially treated with a pharmacologic intervention with polytherapy of antiepileptic drugs in most cases. However, due to the poor response that CSWS often have to antiepileptic drugs, non-pharmacologic treatment options are an important part of a comprehensive treatment plan for this group of children. This article discusses the use of corticosteroids, intravenous immunoglobulins, ketogenic diet, vagus nerve stimulation, and epilepsy surgery in the treatment of patients with epileptic syndromes with CSWS. CONCLUSIONS: Treatment of ESES extends beyond just control of the seizures; amelioration of the continuous epileptiform discharge must occur to improve neuropsychological outcome. There is a significant correlation between the length of the ESES period and the extent of residual intellectual deficit at follow-up. According to this knowledge, there is a well defined therapeutic interval where our different strategies of treatment may be useful, and the upper limits of this time frame to a critical period of 12-18 months.

Electrical status epilepticus in sleep.

Electrical status epilepticus in sleep (ESES) describes an electroencephalographic pattern showing significant activation of epileptiform discharges in sleep. The terms continuous spike wave in slow-wave sleep (CSWS) and Landau-Kleffner syndrome (LKS) describe the clinical epileptic syndromes seen with ESES. Although there is an overlap between these 2 syndromes, children with CSWS present with a more global regression have more problematic epilepsy and have EEG foci located predominantly in frontotemporal or frontocentral regions. In contrast, children with LKS present with an acquired auditory agnosia, fewer seizures, and EEG foci in the posterotemporal regions. ESES requires a high degree of clinical suspicion because slow-wave sleep must be recorded to confirm this diagnosis. Treatment of ESES extends beyond just control of the seizures; amelioration of the continuous epileptiform discharge must occur to improve neuropsychological outcome. Although there is little evidence to guide treatment, conventional antiepileptic drugs play only a minimal role. Steroid therapy and high-dose benzodiazepines are most commonly used, but other therapies including intravenous gamma-globulin, the ketogenic diet, and surgical therapy with multiple subpial transaction have shown efficacy in small case series. Although epilepsy resolves with time in most cases, many children are left with significant cognitive or language impairment. Longer duration of ESES appears to be the major predictor of poor outcome; markedly abnormal neuronal activity during a critical period for synaptogenesis may result in aberrant synapse formation, explaining the poorer neuropsychological outcome. Early recognition and effective therapy are necessary to improve long-term prognosis in this condition.

Síndrome de Landau-Kleffner / Landau-Kleffner syndrome

El síndrome de Landau-Kleffner es un trastorno poco frecuente en niños, que debe sospecharse en pacientes que presentan regresión del lenguaje adquirido y muchas veces se asocian otras manifestaciones como crisis convulsivas, trastornos de conducta y alteraciones psiquiátrica. En este artículo se publica una revisión actualizada de esta patología, para que los pediatras consideren este diagnóstico en un niño con afasia.

Landau-Kleffner syndrome with mitochondrial respiratory chain-complex I deficiency.

Landau-Kleffner syndrome is characterized by epileptic aphasia associated with electrical status epilepticus of slow wave sleep. A 5-year-old female, who had manifested normal developmental progress, was referred with principal complaints of fluctuating sensory aphasia and bizarre behavior during the preceding 4 months. Landau-Kleffner syndrome was confirmed by clinical and electroencephalographic features; in addition, the patient's mitochondrial respiratory chain-complex I deficiency was confirmed by fibroblast culture with the evidence of energy metabolism disorder. This patient's seizures were intractable to many antiepileptic drugs, adrenocorticotrophic hormone, and intravenous immunoglobulin, with catastrophic cognitive and behavioral decline, but the seizures were successfully controlled by ketogenic diet with supplementary mitochondrial cocktail including coenzyme Q10, riboflavin, L-carnitine, and high-dose multivitamins. The patient finally regained fully normal cognitive functioning. Landau-Kleffner syndrome with mitochondrial respiratory chain-complex I deficiency was controlled in this case by ketogenic diet and supplementary mitochondrial cocktail therapy.

Landau-Kleffner syndrome is not an eponymic badge of ignorance.

In a 1992 editorial article, Landau expressed the hope of collective agreement in the medical community about Landau-Kleffner syndrome (LKS) in terms of diagnosis criteria, etiology, pathophysiology and rational therapy. Since then, neurophysiological and neuroimaging studies have led to the view that LKS is an acquired aphasia, secondary to an epileptic disturbance affecting a cortical area involved in verbal processing. This fits with the hypothesis of a "functional ablation" caused by epileptic activity. Under these criteria, epileptic aphasia becomes a subgroup of the continuous spike-waves syndrome in which epileptic discharges originate from the temporal cortex. Genetic predisposition for KLS could be related to hyperexcitability and synchronization of interneurons within the perisylvian cortices, which generate the spike-waves. Activation of these waves during NREM sleep, following thalamo-cortical uncoupling, might then alter the blood brain barrier and provoke an autoimmune reaction. Interneuron hyperactivity might in turn have an antiepileptic protective effect, associated with the inhibition of a specific function, and spike-waves activity over the long term might eventuate in focal atrophy. This morphological defect might explain the poor verbal outcome in some cases of LKS. From this study we recommend a multicenter control study of good design and methodology be carried out to compare the efficacies of early versus delayed (3 months) corticosteroid treatment in patients with typical LKS that is being treated by clobazam (or diazepam) monotherapy.

Management of Landau-Kleffner syndrome.

Landau-Kleffner syndrome (LKS) is an acquired epileptic aphasia disorder in which children, usually 3-8 years of age who have developed age-appropriate speech, experience language regression with verbal auditory agnosia, abnormal epileptiform activity, behavioral disturbances, and sometimes overt seizures. There are no controlled clinical trials investigating the therapeutic options for LKS. Only open-label data are available. Early diagnosis and initiation of prompt medical treatment appear to be important to achieving better long-term prognosis.Several antiepileptic drugs have been reported to be beneficial in treating this syndrome. These include valproic acid (valproate sodium), diazepam, ethosuximide, clobazam, and clonazepam. Reports on the efficacy of lamotrigine, sultiame, felbamate, nicardipine, vigabatrin, levetiracetam, vagal nerve stimulation, and a ketogenic diet are few and more experience is needed. Carbamazepine and possibly phenobarbital and phenytoin have been reported to occasionally exacerbate the syndrome. As initial therapy, valproic acid or diazepam is often empirically chosen. Subsequently, other antiepileptic drugs, corticosteroids, or intravenous immunoglobulin (IVIG) therapy are often used. Corticosteroid therapy should probably not be delayed more than 1-2 months after the initial diagnosis. Various corticosteroid regimens including oral prednisone and, recently, high doses of intravenous pulse corticosteroids, as well as corticotropin (adrenocorticotropic hormone) have been reported to be effective in LKS. Oral corticosteroids are used more often and usually need to be maintained for a long period of time to prevent relapses. The use of IVIG has been associated with an initial dramatic response in only a few patients. In our experience, a long-term worthwhile improvement has been noted in only 2 of 11 patients. These two patients had an immediate response to IVIG initially and after relapses before eventually achieving a long-term sustained remission. Surgical treatment by multiple subpial transection, which is reserved for patients who have not responded to multiple medical therapies, has been followed in selected cases by a marked improvement in language skills and behavior. However, a widely accepted consensus about suitable candidates for this surgery and about its efficacy is still lacking. Speech therapy, including sign language, and a number of classroom and behavioral interventions are helpful in managing LKS, and should be used in all patients.

Afasia epiléptica adquirida o síndrome de Landau Kleffner: a propósito de un caso / Acquired epileptic aphasia or landau kleffner syndrome: a case study

La Afasia Epiléptica adquirida o Síndrome de Landau Kleffner, es una afección que se caracteriza por agnosia auditiva adquirida, EEG paroxísticos, crisis epilépticas (67,6 por ciento), problemas conductuales y cognoscitivos. La observación de un infante preescolar de 4 años de edad, sexo femenino, quien presentó crisis convulsiva de carácter tónico-clónico generalizadas, con dificultad para la comprensión del lenguaje hablado y presencia en el EEG de sueño compatible con status eléctrico durante el sueño lento. Con la administración de ácido valproico, clobazan, fenobarbital y ACTH, se obtuvieron resultados satisfactorios, desapareciendo el cuadro convulsivo y mejorando el lenguaje. El diagnóstico temprano de este síndrome permite una atención y manejo adecuado, ofreciéndole un mejor pronóstico al niño

Síndrome de landau kleffner: a propósito de un caso / Syndrome of landau kleffner: a purpose of a case

Síndrome Landau Kleffner es una enfermedad neurológica poco común de la infancia, presente en niños 3-7 años con desarrollo normal, caracterizándose por perdida gradual del lenguaje, crisis convulsivas, regresión neurológica, anormalidades electroencefalográficas. Caso clínico; escolar masculino 7 años que acude a consulta privada presentando convulsiones tónico clónicas generalizadas, afasia, perdida gradual de mortalidad, desarrollo normal hasta los 4 años, posterior a crisis convulsiva evidenciamos regresión neurológica progresiva. Realizamos EEG observando complejos punta onda multifocales, disminución en el trazado, reafirmando el diagnóstico, instaurándose tratamiento: Valproato y Clonazepan, obteniendo buena evolución

Epilepsy, antiepileptic drugs (AEDs) and cognition.

People with epilepsy are at increased risk of cognitive deficits as a result of various factors: the effect of seizures themselves, psychosocial factors and adverse effects of AEDs. It is crucial that, following early diagnosis of the correct epileptic syndrome, patients are treated with the appropriate drugs, as incorrect AEDs can exacerbate symptoms. By discussing various epileptic syndromes and performing a broad review of the available evidence, it is possible to make recommendations concerning prescription of AEDs with respect to cognition. An interesting advance in this area is the increasing use of AEDs such as valproate (in some countries divalproex is indicated), carbamazepine or lamotrigine (lamotrigine has been filed for approval in this indication) for bipolar disorders. Children and the elderly are especially vulnerable to adverse effects on cognition. This review highlights advantages of valproate in these populations; it is well tolerated and produces few cognitive side effects.