Transient microstructural brain anomalies and epileptiform discharges in mice defective for epilepsy and language-related NMDA receptor subunit gene Grin2a.

OBJECTIVE: The epilepsy-aphasia spectrum (EAS) is a heterogeneous group of age-dependent childhood disorders characterized by sleep-activated discharges associated with infrequent seizures and language, cognitive, and behavioral deficits. Defects in the GRIN2A gene, encoding a subunit of glutamate-gated N-methyl-d-aspartate (NMDA) receptors, represent the most important cause of EAS identified so far. Neocortical or thalamic lesions were detected in a subset of severe EAS disorders, and more subtle anomalies were reported in patients with so-called "benign" phenotypes. However, whether brain structural alterations exist in the context of GRIN2A defects is unknown. METHODS: Magnetic resonance diffusion tensor imaging (MR-DTI) was used to perform longitudinal analysis of the brain at 3 developmental timepoints in living mice genetically knocked out (KO) for Grin2a. In addition, electroencephalography (EEG) was recorded using multisite extracellular electrodes to characterize the neocortical activity in vivo. RESULTS: Microstructural alterations were detected in the neocortex, the corpus callosum, the hippocampus, and the thalamus of Grin2a KO mice. Most MR-DTI alterations were detected at a specific developmental stage when mice were aged 30 days, but not at earlier (15 days) or later (2 months) ages. EEG analysis detected epileptiform discharges in Grin2a KO mice in the third postnatal week. SIGNIFICANCE: Grin2a KO mice replicated several anomalies found in patients with EAS disorders. Transient structural alterations detected by MR-DTI recalled the age-dependent course of EAS disorders, which in humans start during childhood and show variable outcome at the onset of adolescence. Together with the epileptiform discharges detected in young Grin2a KO mice, our data suggested the existence of early anomalies in the maturation of the neocortical and thalamocortical systems. Whereas the possible relationship of those anomalies with sleep warrants further investigations, our data suggest that Grin2a KO mice may serve as an animal model to study the neuronal mechanisms of EAS disorders and to design new therapeutic strategies.

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.

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.

Neurophysiological activity underlying altered brain metabolism in epileptic encephalopathies with CSWS.

We investigated the neurophysiological correlate of altered regional cerebral glucose metabolism observed in children with epileptic encephalopathy with continuous spike-waves during sleep (CSWS) by using a multimodal approach combining time-sensitive magnetic source imaging (MSI) and positron emission tomography with [(18)F]-fluorodeoxyglucose (FDG-PET). Six patients (4 boys and 2 girls, age range: 4-8 years, 3 patients with Landau-Kleffner syndrome (LKS), 3 patients with atypical rolandic epilepsy (ARE)) were investigated by FDG-PET and MSI at the acute phase of CSWS. In all patients, the onset(s) of spike-waves discharges were associated with significant focal hypermetabolism. The propagation of epileptic discharges to other brain areas was associated with focal hypermetabolism (five patients), hypometabolism (one patient) or the absence of any significant metabolic change (one patient). Interestingly, most of the hypometabolic areas were not involved in the epileptic network per se. This study shows that focal hypermetabolism observed at the acute phase of CSWS are related to the onset or propagation sites of spike-wave discharges. Spike-wave discharges propagation can be associated to other types of metabolic changes, suggesting the occurrence of various neurophysiological mechanisms at the cellular level. Most of the hypometabolic areas are not involved in the epileptic network as such and are probably related to a mechanism of remote inhibition. These findings highlight the critical value of combining FDG-PET with time-sensitive functional neuroimaging approaches such as MSI to assess CSWS epileptic network when surgery is considered as a therapeutic approach.

Epileptic encephalopathy with continuous spike-waves during slow-wave sleep including Landau-Kleffner syndrome.

Epileptic encephalopathy with continuous spike-waves during slow-wave sleep (CSWS) is a spectrum of epileptic conditions best defined by the association of cognitive or behavioral impairment acquired during childhood and not related to another factor other than the presence of abundant interictal epileptiform discharges (IED) during sleep, which tend to diffuse over the whole scalp. It is part of the childhood focal epileptic syndromes, some cases being idiopathic and overlapping with benign rolandic epilepsy, and others being symptomatic of a structural brain lesion. Landau-Kleffner syndrome (LKS) is a particular presentation where acquired aphasia is the core symptom. Clinical, neurophysiological, and cerebral glucose metabolism data support the hypothesis that IED play a prominent role in the cognitive deficits by interfering with the neuronal networks at the site of the epileptic foci but also at distant connected areas. Therefore, the treatment should aim to suppress IED. This may be achieved using conventional antiepileptic drugs, but corticosteroids seem to have more pronounced and sustained efficacy. Outcome for epilepsy is usually good, CSWS being an age-dependent EEG pattern, whereas outcome for cognition, language, and behavior is variable. Rehabilitation represents an important part of the treatment and visual forms of language should be encouraged in children with LKS.

BECTS evolving to Landau-Kleffner Syndrome and back by subsequent recovery: a longitudinal language reorganization case study using fMRI, source EEG, and neuropsychological testing.

By means of a longitudinal case study, we demonstrated the course of cerebral reorganization of language representation due to epilepsy in a child with benign epilepsy with centro-temporal spikes (BECTS) evolving to Landau-Kleffner Syndrome (LKS) and returning to BECTS. The child underwent the following procedures at the ages of 8.2, 8.6, and 9.3 years: 3D source EEG imaging, language fMRI (sentence generation and reading), and neuropsychological testing. He had a follow-up testing at the age of 10.8 years. Further, 24-h EEGs were regularly performed. At the age of around 8 years, the child was diagnosed initially with left-hemispheric BECTS, which evolved to LKS with continuous bilateral discharges. In addition, 3D source imaging data revealed a left anterior temporal focus with a spreading to the right parietal and left centro-parietal areas. The patient had verbal agnosia with poor verbal yet good performance indices. Functional magnetic resonance imaging (fMRI) showed a left-hemispheric reading network but sentence generation was impossible to perform. After initiation of adequate treatment, continuous discharges disappeared, and only very rare left-hemispheric centro-temporal spikes remained. Verbal IQ and performance IQ increased at the age of 8.6 years. Functional magnetic resonance imaging showed, at this time, a right-hemispheric language activation pattern for sentence generation and reading. At the ages of 9.3 and 10.8 years, language tasks remained right-hemispheric and verbal IQ remained stable, but right-hemispheric non-verbal functions decreased due to possible crowding-out mechanisms.

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.

Landau-Kleffner syndrome with lateral temporal focal cortical dysplasia and mesial temporal sclerosis: a 30-year follow-up.

A 39-year-old man, who presented at age 312 with Landau-Kleffner syndrome, had persisting oral and written language deficits into adulthood. Seizures were easily controlled in childhood, but reemerged in adulthood as medication-refractory complex partial seizures. Abnormal T2 signal hyperintensity was seen in the left mesial temporal area on brain MRI. Later, left temporal lobectomy revealed focal cortical dysplasia in the lateral temporal neocortex and gliosis plus neuronal loss in the hippocampus. This case suggests that focal cortical microdysgenesis may be a cause of the Landau-Kleffner syndrome. Persistent seizures in this illustrative case may have led to the evolution of dual-temporal-lobe pathology with mesial temporal sclerosis.

Possible involvement of the tip of temporal lobe in Landau-Kleffner syndrome.

Landau-Kleffner syndrome (LKS) is a childhood disorder of unknown etiology characterized by an acquired aphasia and epilepsy. We have performed comprehensive neurofunctional studies on an 8-year-old girl with typical LKS, with the aim of identifying lesions that may be responsible for her condition. 18F-fluoro-D-glucose (FDG) positron emission computed tomography (PET), 11C-Flumazenil (FMZ) PET, 99mTc-hexamethylpropyleneamine oxime single photon emission computed tomography (SPECT) and magnetoencephalography were performed before and after changes to the patient's medication led to a clinical improvement. Interictal SPECT showed hypoperfusion in the left frontal, left temporal, and left occipital lobes. 18F-FDG PET demonstrated a decrease in glucose metabolism medially in both temporal lobes and superiorly in the left temporal lobe. 11C-FMZ PET revealed a deficit in benzodiazepine receptor binding at the tip of the left temporal lobe. Magnetoencephalography demonstrated equivalent current dipoles located superiorly in the left temporal lobe. Our results suggest that the tip of the left temporal lobe plays an important role in the pathogenesis of LKS in our patient.

Afasias adquiridas: síndrome de Landau-Kleffner y otros / No disponible

Objetivo. Presentar las características clínicas-EEG del síndrome de Landau-Kleffner (SLK) o afasia epilépticaadquirida, discutir sus aspectos etiopatogénicos y sus relaciones con la epilepsia rolándica y la epilepsia con punta onda continuadurante el sueño lento (EPOCSL), y establecer el diagnóstico diferencial con otras afasias adquiridas y trastornos delespectro autista (TEA). Desarrollo y conclusiones. El SLK es un síndrome epiléptico raro con fenotipo clínico-EEG bien establecido–agnosia auditiva con crisis epilépticas, en un alto porcentaje, de buen pronóstico, otros trastornos neuropsicológicos,y EEG con punta onda continua en sueño lento (POCSL)– y una etiopatogenia no bien delimitada. La mayoría de loscasos son criptogénicos y en pocos casos se han encontrado agentes causales diversos, destacando entre ellos microdisgenesiascorticales. La afasia de recepción está originada por las POCSL que ocurren en periodos críticos de la maduración cerebral,durante la sinaptogénesis cortical bitemporal, cuando se establecen los circuitos funcionales elementales lingüísticos.Es probable que haya un factor genético implicado que, activado por factores medioambientales, desencadene el síndrome. ElSLK se relaciona por la edad de comienzo, anomalías del EEG intercrítico y activación por el sueño con otros síndromes que,a veces, se solapan entre ellos, como la epilepsia rolándica y la EPOCSL, con los cuales constituyen un continuo neurobiológicocuya expresión clínica neuropsicológica se relaciona con el punto de partida de las descargas, y la gravedad, con la activaciónen sueño. En el diagnóstico diferencial con otras afasias adquiridas y TEA, aparte de matices clínicos, a veces claros,los hallazgos del EEG en sueño son definitivos. El tratamiento incluye fármacos antiepilépticos y/o corticoides, apoyo psicopedagógicoy, en ocasiones, cirugía

No disponible

Bilateral volume reduction of the superior temporal areas in Landau-Kleffner syndrome.

No specific anatomic abnormalities have been detected in typical Landau-Kleffner syndrome (LKS), an acquired epileptic aphasia with language regression in children. In four children with typical LKS without obvious anatomic abnormalities, the authors performed MRI volumetric analysis of various neocortical regions and subcortical substructures. Volume reduction was detected in bilateral superior temporal areas (26 to 51%), specifically in planum temporale (25 to 63%) and superior temporal gyrus (25 to 57%), where receptive language is localized.

Accessibility of spoken, written, and sign language in Landau-Kleffner syndrome: a linguistic and functional MRI study.

Landau-Kleffner syndrome (LKS) is an acquired aphasia which begins in childhood and is thought to arise from an epileptic disorder within the auditory speech cortex. Although the epilepsy usually subsides at puberty, a severe communication impairment often persists. Here we report on a detailed study of a 26-year old, left-handed male, with onset of LKS at age 5 years, who is aphasic for English but who learned British Sign Language (BSL) at age 13. We have investigated his skills in different language modalities, recorded EEGs during wakefulness, sleep, and under conditions of auditory stimulation, measured brain stem auditory-evoked potentials (BAEP), and performed functional MRI (fMRI) during a range of linguistic tasks. Our investigation demonstrated severe restrictions in comprehension and production of spoken English as well as lip-reading, while reading was comparatively less impaired. BSL was by far the most efficient mode of communication. All EEG recordings were normal, while BAEP showed minor abnormalities. fMRI revealed: 1) powerful and extensive bilateral (R > L) activation of auditory cortices in response to heard speech, much stronger than when listening to music; 2) very little response to silent lip-reading; 3) strong activation in the temporo-parieto-occipital association cortex, exclusively in the right hemisphere (RH), when viewing BSL signs. Analysis of these findings provides novel insights into the disturbance of the auditory speech cortex which underlies LKS and its diagnostic evaluation by fMRI, and underpins a strategy of restoring communication abilities in LKS through a natural sign language of the deaf (with Video)

Epilepsy and epileptiform EEG: association with autism and language disorders.

The relationship between epilepsy, language, behavior, and cognition is not well understood. Developmental and acquired disabilities such as autistic spectrum disorders, Landau-Kleffner Syndrome, electrical status epilepticus in sleep, and developmental dysphasias have been associated with epileptiform abnormalities. These disorders share many common features and raise important questions regarding this intricate relationship. This article reviews these disorders and discusses the proposed interaction between epileptiform abnormalities and cognitive dysfunction. Diagnostic and treatment issues will also be reviewed.

Acquired aphasia in acute disseminated encephalomyelitis.

A 12-year-old boy developed a convulsion, hemiparesis, and acquired aphasia with paroxysmal electroencephalogram (EEG) abnormalities consisting of repetitive spikes and waves in the left centro-parietal region. T2-weighted magnetic resonance imaging disclosed high intensity lesions in the left pre-Sylvian and right frontal areas. He was diagnosed as having acute disseminated encephalomyelitis, and thus the oral administration of phenytoin and steroid pulse therapy were begun. With these treatments, his hemiparesis disappeared and the aphasia also improved gradually. Magnetic resonance imaging examination revealed the disappearance of the previously noted abnormalities, and the EEG abnormalities disappeared as well. This patient is a rare case of acute disseminated encephalomyelitis presenting an acquired aphasia. A focal lesion of acute disseminated encephalomyelitis may be responsible for the acquired aphasia. The distinction from Landau-Kleffner syndrome is also discussed.