Koolen-de Vries syndrome associated with continuous spike-wave in sleep

Koolen-de Vries syndrome (KdVS) is a genetic condition caused by 17q21.31 microdeletions or pathogenic variants in KANSL1. Affected patients most commonly exhibit some or all of the following: neonatal hypotonia, developmental impairment, facial dysmorphic features, and congenital malformations. Epilepsy occurs in approximately half, often with phenotypes on the epilepsyaphasia spectrum. We describe six children with KdVS found to have continuous spike-wave in sleep (CSWS) on EEG, four of whom were diagnosed with epileptic encephalopathy with CSWS and two with Landau-Kleffner syndrome. When compared with other children with CSWS on EEG, patients with KdVS may present at slightly later ages and with a longer interval between seizure diagnosis and identification of CSWS. There is no clear best treatment for children with CSWS, but two patients in our cohort were trialed on a variation of the ketogenic diet, and both reported clinical improvement. In one of the patients, the response was dramatic, and CSWS recurred when weaning of the ketogenic diet was attempted. Based on our findings, an EEG capturing a prolonged period of sleep should be arranged in any child with KdVS presenting with developmental regression or plateau, particularly if they have a preceding history of seizures.

Aphasia and a Dual-Stream Language Model in a 4-Year-Old Female with Landau-Kleffner Syndrome.

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.

Cerebral dominance in an unusual case of Landau-Kleffner syndrome.

Landau-Kleffner syndrome (LKS) is described by the International Classification of Epileptic Syndromes since 1985 as a constellation of clinical and electrographic signs, including acquired aphasia, regression of language milestones and seizures, along with sleep-activated paroxysms on electroencephalogram which can progress to electrographic status epilepticus of sleep. In this case, a 7-year-old boy presented with an atypical history of new-onset aphasia and regression of language milestones with rare seizures. However, there was an electrographic mismatch in the form of right-sided epileptiform activity and continuous spike and wave of sleep pattern. Detailed speech analysis and perusal of the history revealed a possibly ambidextrous child with right hemispheric language dominance, and he was diagnosed with LKS and treated. This report illustrates the many pitfalls in the diagnosis and treatment of this rare epileptic syndrome.

Encephalopathy related to Status Epilepticus during slow Sleep: from concepts to terminology.

Five pediatric and adult neurologists with clinical and research interests in Encephalopathy related to Status Epilepticus during slow Sleep (ESES) express their opinions on definition, diagnostic assessment and terminology that may be considered for this condition. The aim of this "debate" is to identify aspects in which there is a shared opinion and areas where there are still controversies in the classification and suggest areas which demand further studies and research.

Update on the genetics of the epilepsy-aphasia spectrum and role of GRIN2A mutations.

Formerly idiopathic, focal epilepsies (IFE) are self-limiting, "age-related" diseases that mainly occur during critical developmental periods. Childhood epilepsy with centrotemporal spikes, or Rolandic epilepsy (RE), is the most frequent form of IFE. Together with the Landau-Kleffner syndrome and the epileptic Encephalopathy related to Status Epilepticus during slow Sleep syndrome (ESES), RE is part of a single and continuous spectrum of childhood epilepsies and epileptic encephalopathies with acquired cognitive, behavioral and speech and/or language impairment, known as the epilepsy-aphasia spectrum (EAS). The pathophysiology has long been attributed to an elusive and complex interplay between brain development and maturation processes on the one hand, and susceptibility genes on the other hand. Studies based on the variable combination of molecular cytogenetics, Sanger and next-generation sequencing tools, and functional assays have led to the identification and validation of genetic mutations in the GRIN2A gene that can directly cause various types of EAS disorders. The recent identification of GRIN2A defects in EAS represents a first and major break-through in our understanding of the underlying pathophysiological mechanisms. In this review, we describe the current knowledge on the genetic architecture of IFE.

The inhibitory effect of functional lesions on eloquent brain areas: from research bench to operating bed.

Objectives: Functioning, but injured cerebral connections are hypothesized to inhibit cortical plasticity. Study of neural networks can validate this hypothesis, and provide further practical clues for clinical and surgical options to restore function in eloquent brain areas. Material and methods: Cortical lesions in eloquent areas were simulated by means of artificial neural networks. Next, functional restoration of these networks after lesional bypass was studied. Results: The accuracy of network outputs was reduced from 92% to 72% (P-value < 0.001) when logical temporal connections with dysfunctional lesions were established. Restoration of function was almost totally achieved by bypassing the lesion, without any significant changes in network nodal weights. Estimated remaining functional fraction errors were trivial (0.0044%-1.4%). Discussion: Examples of functional decline due to disturbing signals are Todd's paralysis and Landau-Kleffner syndrome. Functional restoration after lesionectomy in eloquent areas of the brain is also practiced. Likewise, injured connections provide routes of influence for disturbing impulses. Conclusion: Herein, the proposed evidences provide theoretical clues to formulate new avenues in restorative functional neurosurgery. They may help to identify suitable lesions and suitable techniques for functional restoration including dissection of disturbing connections, bridging and bypassing lesions that can be corroborated by simulation.

Response to immunotherapy in a patient with Landau-Kleffner syndrome and GRIN2A mutation.

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.

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

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

Outcome following multiple subpial transection in Landau-Kleffner syndrome and related regression.

OBJECTIVE: To determine whether multiple subpial transection in the posterior temporal lobe has an impact on long-term outcome in children who have drug-resistant Landau-Kleffner syndrome (LKS) or other "electrical status epilepticus during sleep" (ESES)-related regression. Given the wide variability in outcomes reported in the literature, a secondary aim was to explore predictors of outcome. METHODS: The current study includes a surgery group (n = 14) comprising patients who underwent multiple subpial transection of the posterior temporal lobe and a nonsurgery comparison group (n = 21) comprising patients who underwent presurgical investigations for the procedure, but who did not undergo surgery. Outcomes were assessed utilizing clinical note review as well as direct assessment and questionnaires. RESULTS: The distribution of nonclassical cases was comparable between groups. There were some differences between the surgery and nonsurgery groups at presurgical investigation including laterality of discharges, level of language impairment, and age; therefore, follow-up analyses focused on change over time and predictors of outcome. There were no statistically significant differences between the groups in language, nonverbal ability, adaptive behavior, or quality of life at follow-up. There was no difference in the proportion of patients showing improvement or deterioration in language category over time for either group. Continuing seizures and an earlier age of onset were most predictive of poorer quality of life at long-term follow-up (F2,23 = 26.2, p = <0.001, R(2) = 0.714). SIGNIFICANCE: Both surgery and nonsurgery groups had similar proportions of classic LKS and ESES-related regression. Because no significant differences were found in the changes observed from baseline to follow-up between the two groups, it is argued that there is insufficient evidence to suggest that multiple subpial transection provides additional benefits over and above the mixed recovery often seen in LKS and related regressive epilepsies.

Las evoluciones atípicas de la epilepsia rolándica son complicaciones predecibles / The atypical developments of rolandic epilepsy are predictable complications

Introducción. Las evoluciones atípicas de la epilepsia rolándica son parte de un espectro clínico de fenotipos variables, idiopáticos, dependientes de la edad y con una predisposición genéticamente determinada. Objetivo. Estudiar las características electroclínicas sugestivas de una evolución atípica en la epilepsia rolándica. Pacientes y métodos. Se realizó una búsqueda retrospectiva de 133 niños diagnosticados de epilepsia focal benigna atípica (EFBA), síndrome de Landau-Kleffner y epilepsia de punta-onda continua durante el sueño (POCS). Se seleccionaron nueve pacientes que, en el trascurso de su epilepsia rolándica, presentaron un cuadro clínico atípico y un patrón electroencefalográfico (EEG) de estado epiléptico eléctrico durante el sueño (ESES). Resultados. El inicio de la epilepsia rolándica fue, en promedio, a los 5 años. Los pacientes presentaron un empeoramiento clínico y del EEG año y medio más tarde en promedio. En tres pacientes se observaron características de EFBA, y en seis, de POCS. No se encontraron casos de síndrome de Landau-Kleffner. El EEG en vigilia mostró una focalidad centrotemporal izquierda en seis pacientes, y derecha, en tres. Todos los pacientes presentaron un ESES en el EEG de sueño. En tres de ellos se observó un patrón atípico de ESES regional. Además, se detectaron alteraciones cognitivas y conductuales por déficits en áreas específicas del aprendizaje, como lenguaje, memoria, atención e inquietud. Conclusiones. El inicio precoz de la epilepsia rolándica, la aparición de nuevas crisis con un incremento en su frecuencia y una focalidad frontocentrotemporal en el EEG, que aumenta en frecuencia, tanto en vigilia como en sueño, son características electroclínicas sugerentes de una evolución atípica (AU)

Introduction. The development of atypical features in rolandic epilepsy is part of a clinical spectrum of phenotypes that are variable, idiopathic and age-dependent, as well as having a genetically determined predisposition. Aim. To study the electroclinical characteristics suggesting an atypical development in rolandic epilepsy Patients and methods. A retrospective search was performed in 133 children diagnosed with atypical benign focal epilepsy (ABFE), Landau-Kleffner syndrome and continuous spike-wave during sleep (CSWS). Nine patients were selected, all of whom presented atypical clinical features and an electroencephalogram (EEG) pattern of electrical status epilepticus during sleep (ESES) in the course of their rolandic epilepsy. Results. The average age at onset of rolandic epilepsy was 5 years. Patients showed a deterioration of both their clinical features and their EEG recording one and a half years later, on average. ABFE was observed in three of them and CSWS in six. No cases of Landau-Kleffner syndrome were found. The EEG in wakefulness showed the focus to be in the left centrotemporal region in six patients and in three of them it was on the right-hand side. All the patients presented ESES in the EEG during sleep. An atypical pattern was observed in the regional ESES in three of the patients. Moreover, cognitive and behavioural disorders were detected due to deficits in specific learning areas, such as language, memory, attention and restlessness. Conclusions. The early onset of rolandic epilepsy, the appearance of new seizures with an increased frequency and the frontocentrotemporal focus in the EEG, which increases in frequency, both in wakefulness and in sleep, are all electroclinical characteristics of an atypical development (AU)

Seizures and epilepsy: an overview for neuroscientists.

Epilepsy is one of the most common and disabling neurologic conditions, yet we have an incomplete understanding of the detailed pathophysiology and, thus, treatment rationale for much of epilepsy. This article reviews the clinical aspects of seizures and epilepsy with the goal of providing neuroscientists an introduction to aspects that might be amenable to scientific investigation. Seizures and epilepsy are defined, diagnostic methods are reviewed, various clinical syndromes are discussed, and aspects of differential diagnosis, treatment, and prognosis are considered to enable neuroscientists to formulate basic and translational research questions.

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.

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.

GRIN2A mutations cause epilepsy-aphasia spectrum disorders.

Epilepsy-aphasia syndromes (EAS) are a group of rare, severe epileptic encephalopathies of unknown etiology with a characteristic electroencephalogram (EEG) pattern and developmental regression particularly affecting language. Rare pathogenic deletions that include GRIN2A have been implicated in neurodevelopmental disorders. We sought to delineate the pathogenic role of GRIN2A in 519 probands with epileptic encephalopathies with diverse epilepsy syndromes. We identified four probands with GRIN2A variants that segregated with the disorder in their families. Notably, all four families presented with EAS, accounting for 9% of epilepsy-aphasia cases. We did not detect pathogenic variants in GRIN2A in other epileptic encephalopathies (n = 475) nor in probands with benign childhood epilepsy with centrotemporal spikes (n = 81). We report the first monogenic cause, to our knowledge, for EAS. GRIN2A mutations are restricted to this group of cases, which has important ramifications for diagnostic testing and treatment and provides new insights into the pathogenesis of this debilitating group of conditions.