Landau-Kleffner Research Articles

Landau Kleffner Syndrome and Misdiagnosis of Autism Spectrum Disorder: A Mini-Review

Autism spectrum disorders (ASD) is the name for a group of developmental disorders including a wide range of signs, symptoms and disability. Landau kleffner syndrome (LKS) or acquired epileptic aphasia is a pediatric disorder characterized by the association of epileptiform electroencephalographic (EEG) abnormalities and acquired aphasia. The early stages of the LKS may be manifested by the symptoms of the autism leading to misdiagnosis. Since LKS is a progressive disease, its misdiagnosis leads to a greater neurocognitive deterioration which may result in seizure in the final stages. The purpose of this review was to provide an overview of available researchs on ASD population and patients with LKS and relationship between these two diseases.

An aphasic child with behavioral abnormality: Landau–Kleffner syndrome

Acquired epileptic aphasia, otherwise known as Landau–Kleffner syndrome, is a childhood epilepsy syndrome, characterized by acquired aphasia, seizures, behavioral abnormalities, and abnormal electroencephalography (EEG), in various combinations. Sometimes, some intracranial pathologies, such as brain tumor, head injury, demyelination, and neurocysticercosis, have been found in association. Here, we report a case of a 5-year-old male child presenting with gradual loss of speech, behavioral abnormalities, such as hyperactivity, inattentiveness, and abnormal EEG findings, but without the classical seizures seen with this syndrome.

Speech and language neurodevelopmental disorders in epilepsy: pathophysiologic mechanisms and therapeutic approaches

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.

Lenneberg’s Contributions to the Biology of Language and Child Aphasiology: Resonation and Brain Rhythmicity as Key Mechanisms

This paper aims to re-evaluate the legacy of Eric Lenneberg’s monumental Biological Foundations of Language, with special reference to his biolinguistic framework and view on (child) aphasiology. The argument draws from the following concepts from Lenneberg’s work: (i) language (latent struc- ture vs. realized structure) as independent of externalization; (ii) resonance theory; (iii) brain rhythmicity; and (iv) aphasia as temporal dysfunction. Specifically, it will be demonstrated that Lenneberg’s original version of the critical period hypothesis and his child aphasiology lend themselves to elucidating a child aphasia of epileptic origin called Landau-Kleffner syndrome (LKS), thereby opening a possible hope for recovery from the disease. Moreover, it will be claimed that, to the extent that the language disorder in LKS can be couched in these terms, it can serve as strong “liv- ing” evidence in support of Lenneberg’s critical period hypothesis and his view on child aphasiology.

Epilepsy in patients with autism: links, risks and treatment challenges.

Autism is more common in people with epilepsy, approximately 20%, and epilepsy is more common in people with autism with reported rates of approximately 20%. However, these figures are likely to be affected by the current broader criteria for autism spectrum disorder (ASD), which have contributed to an increased prevalence of autism, with the result that the rate for ASD in epilepsy is likely to be higher and the figure for epilepsy in ASD is likely to be lower. Some evidence suggests that there are two peaks of epilepsy onset in autism, in infancy and adolescence. The rate of autism in epilepsy is much higher in those with intellectual disability. In conditions such as the Landau–Kleffner syndrome and nonconvulsive status epilepticus, the epilepsy itself may present with autistic features. There is no plausible mechanism for autism causing epilepsy, however. The co-occurrence of autism and epilepsy is almost certainly the result of underlying factors predisposing to both conditions, including both genetic and environmental factors. Conditions such as attention deficit hyperactivity disorder, anxiety and sleep disorders are common in both epilepsy and autism. Epilepsy is generally not a contraindication to treating these conditions with suitable medication, but it is important to take account of relevant drug interactions. One of the greatest challenges in autism is to determine why early childhood regression occurs in perhaps 25%. Further research should focus on finding the cause for such regression. Whether epilepsy plays a role in the regression of a subgroup of children with autism who lose skills remains to be determined.

GRIN2A mutations in epilepsy-aphasia spectrum disorders

ObjectiveEpilepsy-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. MethodsPatients 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. Results122 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. ConclusionGRIN2A 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.

The Clinical Spectrum of Benign Epilepsy with Centro-Temporal Spikes: a Challenge in Categorization and Predictability.

Benign epilepsy with centro-temporal spikes (BECTS) is the most common type of focal epilepsy in children; it is age-dependent and presumably genetic. Traditionally, children with BECTS have a very good prognosis, even without medical treatment, and are thought to show no neurological symptoms or cognitive deficits. However, many previous studies have shown that BECTS can present with various clinical and electroencephalographic characteristics that are commonly associated with neuropsychological deficits, including linguistic, cognitive, and behavioral impairment. The degree of the neuropsychological deficits appears to depend on the sleep cycle and the localization of epileptiform discharges. Furthermore, based on neurobiological studies, a complex interplay between the processes of brain maturation and the involvement of genes that confer susceptibility may contribute to a variety of different childhood epileptic syndromes with various neuropsychological deficits. Thus, BECTS, atypical benign focal epilepsy during childhood, status epilepticus of BECTS, Landau-Kleffner syndrome, and epileptic encephalopathy with continuous spike-and-wave during sleep are all considered different entities, but are part of a single spectrum of disorders. In clinical practice, we have to consider BECTS as benign only when there are no or only mild neuropsychological deficits before medical treatment.

Deficits in music processing in Landau–Kleffner syndrome: A follow-up adult investigation with four patients

Deficits in music processing in Landau–Kleffner syndrome: A follow-up adult investigation with four patients

The Implication of the Thalamus in Speech Disturbance in a Boy with Rolandic Epilepsy

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.

Adrenocorticotropic hormone protects learning and memory function in epileptic Kcna1-null mice

ACTH, a member of the melanocortin family of peptides, is often used in the treatment of the developmental epileptic encephalopathy spectrum disorders including, Ohtahara, West, Lennox Gastaut and Landau-Kleffner Syndromes and electrical status epilepticus of sleep. In these disorders, although ACTH is often successful in controlling the seizures and/or inter-ictal EEG abnormalities, it is unknown whether ACTH possesses other beneficial effects independent of seizure control. We tested whether ACTH can ameliorate the intrinsic impairment of hippocampal-based learning and memory in epileptic Kcna1-null (KO) mice. We found that ACTH − administered in the form of Acthar Gel given i.p. four times daily at a dose of 4 IU/kg (16 IU/kg/day) for 7days – prevented impairment of long-term potentiation (LTP) evoked with high-frequency stimulation in CA1 hippocampus and also restored spatial learning and memory on the Barnes maze test. However, with this treatment regimen, ACTH did not exert a significant effect on the frequency of spontaneous recurrent seizures. Together, our findings indicate that ACTH can ameliorate memory impairment in epileptic Kcna1-null mice separate from seizure control, and suggest that this widely used peptide may exert direct nootropic effects in the epileptic brain.

Prelingual auditory verbal agnosia, A rare condition

Auditory agnosia, agnosia for speech is a rare condition, caused mostly by stroke, in adults, while in children it is often a sequel of herpes simplex encephalitis or is associated with epilepsy, in Landau–Kleffner syndrome. This article presents a rare case of verbal auditory agnosia as a result of meningoencephalitis, caused probably by herpes simplex virus. The patient's developed encephalitis at the age of 1 year and 4 months. After her recovery, the family noticed the absence of language development. She was initially diagnosed with profound hearing loss, and the hearing aids did not help her. The speech therapy developed her lip-reading skills with a hard-to-understand pronunciation. Later, audiometry showed a nearly normal peripheral auditory system and magnetic resonance imaging revealed the characteristic brain lesions in both the temporal lobes, explaining the patient's evolution. Assessment of children with delayed speech development must consider the central hearing disorders as a differential diagnosis.

Delayed speech development in children: Introduction to terminology

There has been recently an increase in the number of children diagnosed with delayed speech development. There is delay compensation with age, but mild deficiency often remains for life. Delayed speech development is more common in boys than in girls. Its etiology is unknown in most cases, so a child should be followed up to make an accurate diagnosis. Genetic predisposition or environmental factors frequently influence speech development. The course of its delays is various. In the history of a number of disorders (childhood disintegrative disorder, Landau–Kleffner syndrome), there is evidence for the normal development of speech to a certain period and then stops or even regresses. By way of comparison, there are generally speech developmental changes in autism even during the preverbal stage (a complex of revival fails to form; babbling is poor, low emotional, gibberish; at the same time, the baby recipes whole phrases without using them to communicate). These speech disorders are considered not only as a delay, but also as a developmental abnormality. Speech disorders in children should be diagnosed as early as possible in order to initiative corrective measures in time. In this case, a physician makes a diagnosis and a special education teacher does corrective work. The successful collaboration and mutual understanding of the specialists in these areas will determine quality of life for a child in the future. This paper focusses on the terminology and classification of delays, which are necessary for physicians and teachers to speak the same language.

EFFICACY AND SAFETY OF LEVETIRACETAM IN CHILDREN WITH ELECTRICAL STATUS EPILEPTICUS DURING SLOW-WAVE SLEEP (ESES)

Electrical status epilepticus during slow-wave sleep (ESES) is an EEG pattern of continuous (85-100%) diffuse epileptiform activity in the sleep EEG. The morphology of the epileptiform complexes is identical to benign epileptiform discharges of childhood (BEDC). Epilepsy with ESES (or “Penelope Syndrome”) is a form of age-dependent epileptic encephalopathies with the phenomenon of continuous spike-waves during slow wave sleep. This group of epilepsies also includes Pseudo-Lennox syndrome, Landau-Kleffner syndrome, autistic epileptiform regression and some others. In most cases, the ESES pattern correlates with the severity of cognitive deficit in this population of epileptic children. The aim of this study was to evaluate the efficacy and safety of levetiracetam in children with the ESES pattern in the EEG. Materials and Methods. During the period of 2010-2016, 34 epileptic children with ESES patterns in the EEG (14 boys and 20 girls) treated with levetiracetam (33 in combined and 1 in monotherapy) were studied. Results. Twenty eight of the patients with ESES patterns in the sleep EEG were diagnosed with the ESES form of epilepsy. Among them, 7 idiopathic, 13 symptomatic, and 8 “symptomatic” cases of ESES (the latter resulted from “double pathology” of idiopathic + hypoxic-ischemic factors and these children had cerebral palsy). Among other ESES patients, 3 cases were of Pseudo-Lennox syndrome, 2 cases of Landau-Kleffner syndrome and one girl with autistic epileptiform regression. All 28 children received levetiracetam at therapeutic doses of 20-80 mg/kg/daily. Levetiracetam was highly effective in 67.6% of patients (n=23); of those, 2 children showed full clinical and electroencephalographic remission before reaching puberty, 9 children had clinical remission and 12 children had a significant decrease in seizures and epileptiform discharges. A low efficacy of levetiracetam was seen in 20.6% (n=7) of patients. Disease aggravation (seizures and epileptiform discharges) was found in 11.8% (n=4) of patients. Other negative effects were observed in only 4 (11.8%) children (3 cases of agitation and sleep disturbance and one case of allergic rash). In conclusion, levetiracetam is a highly effective medication (67.6% of cases) in combined antiepileptic therapy in children with ESES. However, the risk of exacerbation was as high as 11.8%. The most effective combinations of levetiracetam were those with valproates and ethosuximide.

Architecture of Human Language from the Perspective of a Case of Childhood Aphasia — Landau–Kleffner Syndrome

This paper addresses Landau–Kleffner syndrome (LKS), a childhood aphasia, from the perspective of I-language and the critical period for first language acquisition. LKS involves a language disorder and behavioral disturbances resembling autistic spectrum disorders due to electroencephalographic abnormalities with continuous spike-and-waves during sleep over the temporal regions. Comparing LKS with other childhood syndromes, the architecture of language is explored through elucidating the linguistic mechanisms behind the language disorder in LKS on the basis of Hickok & Poeppel’s (2007) dual-stream model of speech processing. It is claimed that early onset LKS provides further support for the critical period for first language acquisition and modularity of mind (the faculty of language), and that verbal auditory input during the critical period is most crucial for language recovery and development in LKS. Considering that electroencephalographic abnormalities affect cognitive/motor functions, ameliorating neural dysfunction in the affected brain areas with proper application of trans-cranial direct current stimulation is recommended.

Abstracts

Purpose: The GRIN2A gene has been associated with epilepsies ranging from benign focal childhood epilepsies to severe epileptic encephalopathies. The aim of this study was to evaluate genotypes and phenotypes in individuals with GRIN2A deletions or variants. Method: We compared genotypes and phenotypes in six newly identified patients with GRIN2A variants with those of 149 individuals with GRIN2A variants from the literature. Results: Six new patients with epilepsy, developmental and/or behavioral problems and GRIN2A deletions (n = 3), missense (n = 2) or splice-site variants (n = 1) are presented. In 125 (84%) of the 149 individuals with GRIN2A variants previously reported, a specific epilepsy syndrome was diagnosed, most often classified as Benign Epilepsy with Centro-Temporal Spikes (BECTS; n = 44) or Landau-Kleffner syndrome/ Continuous Spike-And-Waves during Slow-wave sleep (LKS/ CSWS; n = 42). Problems of speech and language development (81%), cognition (68%), motor skills (50%) or behavior (42%) were common. Missense variants were seen in 52% of the patients reported earlier, more often in individuals with BECTS (71%) compared to those with LKS/ CSWS (48%). Certain missense variants in or close to the ligand-gated ion channel domain were associated with a severe phenotype, as was also observed in two of our patients with severe epilepsy and cognitive impairment. Conclusion: Individuals with GRIN2A gene variants or deletions have an extremely variable phenotype without a clear genotype-phenotype correlation. Variants in or close to the ligand-gated ion channel can be associated with a severe phenotype.

Idiopathic focal epilepsies: the "lost tribe".

Idiopathic focal epilepsies: the "lost tribe".

後天性失語を呈し Landau-Kleffner 症候群と判明した幼児例

後天性失語を呈し Landau-Kleffner 症候群と判明した幼児例

Neuropsychological Assessment of Children with Landau-Kleffner Syndrome

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.

Treatment of Atypical Evolutions of Idiopathic Focal Epilepsies in Childhood

The relationship between continuous spike-and-wave discharges during slow sleep (CSWSS) and neuropsychological impairment (cognitive functions, memory consolidation, and language and behavior disturbances) has been clearly demonstrated. These phenomena occur not only in symptomatic cases of CSWSS or electrical status epilepticus in sleep (ESES) syndrome, but also in the different conditions that constitute the spectrum of atypical evolutions of idiopathic focal epilepsies of childhood (IFEC). In spite of continuous advances in treatment, management is still difficult and challenging. Treatment options of atypical evolutions of IFEC include benzodiazepines, sulthiame, levetiracetam, valproic acid, and ethosuximide. Other drugs such as lacosamide and acetazolamide have been proposed. Usual antiepileptic drugs such as carbamazepine, phenobarbital, phenytoin, oxcarbazepine, lamotrigine, and topiramate were proven to be capable of inducing ESES. Steroids and intravenous immunoglobulins were recommended in refractory cases. Surgery, ketogenic diet, and vagal nerve stimulation were also used in some cases. Our interest regarding a scheme of treatment in atypical evolutions of IFEC is centered on two questions: (1) Is it possible to prevent the evolution of IFEC into atypical focal epilepsies of childhood, status epilepticus of IFEC, Landau–Kleffner's syndrome, or ESES syndrome? (2) Which is the treatment of choice once one of these conditions is installed?

Neurocognitive and behavioral profiles of children with Landau-Kleffner syndrome

ABSTRACTThis is a retrospective study of 14 cases of children with Landau-Kleffner syndrome (LKS), the most prominent feature of which is acquired aphasia. These children were followed at a tertiary care pediatric epilepsy center. From the research data base, all LKS cases with neuropsychological evaluation were extracted. Children ranged in age from 6 to 13 years (M = 9.12; SD = 2.19) at the time of assessment (1 to 10 years post-onset). The majority of the children were white males, and all but one continued to experience seizure activity. Global intellectual functioning ranged from 59 to 101 (M = 82.07; SD = 12.14). Across the 14 cases reviewed, the neuropsychological profiles are considered in the context of neurological and syndrome-related factors. For these cases, 86% demonstrated continued expressive, and 50% had receptive language problems with 57% exhibiting poor auditory processing. Furthermore, 50 to 57% had deficits in auditory working memory and verbal memory. Academically, the majority had poor reading fluency and comprehension; 50% exhibited difficulty with mathematics. Finally, 57% evidenced attentional or other behavioral problems. Better understanding of LKS can assist in targeted assessment and intervention planning.