Landau-Kleffner syndrome (LKS): long-term follow-up and links with electrical status epilepticus during sleep (ESES)

We describe 11 patients affected by Landau-Kleffner syndrome (LKS) with a mean follow-up of 9 years and 8 months. EEG recordings during wakefulness, NREM and REM sleep showed a bitemporal electrical status epilepticus during sleep (BTESES) in all cases; four of them presented a shift from a BTESES towards an 'intercalated electrical status epilepticus during sleep' (IESES) accompanied by a global regression of cognitive and behavioural functions in 3/4 of cases. At the last observation, only 18.2% of cases presented a complete language recovery and mental retardation was evident in 63.6%. The prognosis of LKS in our cases may depend on the interaction of different negative factors such as onset of aphasia before 4 years, its duration for longer than 1 year, long-lasting duration and continuity without fluctuations of BTESES/IESES, probably preexisting mild speech delay. It is important for the prognosis to utilize antiepileptic treatment and possibly neurosurgical techniques to eliminate EEG paroxysmal abnormalities. At present, no similar cases with clinical-EEG evolution from LKS to electrical status epilepticus during sleep (ESES) have ever been described. Our observation demonstrates that LKS and ESES classified as different clinical-EEG syndromes represent two aspects of the same brain dysfunction and they may exist separately or pass one into the other with a change in the clinical-EEG picture. The common origin of the two syndromes is confirmed by recent functional brain imaging, neurophysiological and neurosurgical techniques.     

Landau-Kleffner and autistic regression: the importance of differential diagnosis

Some neurological disorders may present psychiatric signs and symptoms, therefore the search for an etiological diagnosis is crucial. The aim of this study is to report the case of a patient with a neurological disorder, diagnosed during a psychiatric admission. A boy with normal neuropsychomotor development until the age of 3 years, started presenting epileptic seizures, followed by behavioral disorder and language deterioration. During neurologic follow-up, the patient was referred to the Psychiatry Department with a diagnosis of autism, in this case an autistic regression (AR). During his admission, diagnosis of Landau-Kleffner syndrome (LKS) was established on clinical and EEG grounds. LKS is characterized by acquired aphasia, epilepsy, EEG abnormalities and behavioral changes, including autistic traits. Language regression is observed LKS and AR. We stress the main differences between these two entities because misdiagnosis may postpone early intervention and consequent benefits, as observed in our case.     

Episodic receptive aphasia in a child with Landau-Kleffner Syndrome: PET correlates

We report a four-year-old boy with Landau-Kleffner Syndrome (LKS) characterized by episodic receptive aphasia lasting for few weeks followed by gradual recovery of baseline language functions. Neuropsychological evaluation during an episode showed severe impairment in verbal skills and comprehension, but relative preservation of non-verbal skills. Although he could carry on a conversation during remission, neuropsychological evaluation demonstrated findings reflective of receptive language deficits. Prolonged EEG disclosed frequent sharp-wave activity in the left and right temporal regions but no electrographic seizures. Glucose metabolism PET scan during the fourth episode of aphasia revealed intense hypermetabolism in the left temporal neocortex. Awake EEG during the PET tracer uptake period showed 6.0 spikes/min in the left temporal region and 4.0 spikes/min in the right. A repeat PET scan during remission showed hypometabolism in the left temporal cortex. Awake EEG during the FDG uptake period showed 16.0 spikes/min in the right temporal region and 0.3 spikes/min in the left. During his fifth aphasic episode, EEG (without PET) showed 0.16 spikes/min in the right temporal region and none in the left. Intermittent short episodes of predominantly receptive aphasia with near-total recovery between episodes can be one of the clinical presentations of LKS. This case illustrates the dynamic changes of glucose metabolism in the temporal lobe during episodes of aphasia and remission in a case with LKS. The clinical course of our patient with transient EEG and PET findings suggest that glucose metabolism in LKS cannot be attributed solely to interictal epileptiform activities on scalp EEG.     

Acquired auditory agnosia in childhood and normal sleep electroencephalography subsequently diagnosed as Landau–Kleffner syndrome: a report of three cases

Aim We report three cases of Landau–Kleffner syndrome (LKS) in children (two females, one male) in whom diagnosis was delayed because the sleep electroencephalography (EEG) was initially normal. Method Case histories including EEG, positron emission tomography findings, and long‐term outcome were reviewed. Results Auditory agnosia occurred between the age of 2 years and 3 years 6 months, after a period of normal language development. Initial awake and sleep EEG, recorded weeks to months after the onset of language regression, during a nap period in two cases and during a full night of sleep in the third case, was normal. Repeat EEG between 2 months and 2 years later showed epileptiform discharges during wakefulness and strongly activated by sleep, with a pattern of continuous spike‐waves during slow‐wave sleep in two patients. Patients were diagnosed with LKS and treated with various antiepileptic regimens, including corticosteroids. One patient in whom EEG became normal on hydrocortisone is making significant recovery. The other two patients did not exhibit a sustained response to treatment and remained severely impaired. Interpretation Sleep EEG may be normal in the early phase of acquired auditory agnosia. EEG should be repeated frequently in individuals in whom a firm clinical diagnosis is made to facilitate early treatment.     

Hemispheric integrative therapy in Landau-Kleffner syndrome: applications for rehabilitation sciences

A case study is presented of a 14-year-old right-handed Caucasian female diagnosed with the Landau-Kleffner Syndrome (LKS) at the age 3 1/2 years. Her LKS symptoms presented with abrupt disruption in language after normal development, electroencephalogram (EEG) brain-wave abnormality, seizure activity, inability to read, and impairment in her motor skills. After 11 years of pharmacological and special education interventions with no significant improvement in any measurable area of function, a multimodal approach using techniques purportedly aimed at facilitating inter-hemispheric communication was provided. At completion of the program, EEG was controlled, reading, language, and auditory processing improved and objective behavioral-social measures improved significantly.     

HEMISPHERIC INTEGRATIVE THERAPY IN LANDAU-KLEFFNER SYNDROME: APPLICATIONS FOR REHABILITATION SCIENCES

A case study is presented of a 14-year-old right-handed Caucasian female diagnosed with the Landau-Kleffner Syndrome (LKS) at the age 3½ years. Her LKS symptoms presented with abrupt disruption in language after normal development, electroencephalogram (EEG) brain-wave abnormality, seizure activity, inability to read, and impairment in her motor skills. After 11 years of pharmacological and special education interventions with no significant improvement in any measurable area of function, a multimodal approach using techniques purportedly aimed at facilitating inter-hemispheric communication was provided. At completion of the program, EEG was controlled, reading, language, and auditory processing improved and objective behavioral-social measures improved significantly.     

Landau-Kleffner syndrome: long-term follow-up

Purpose

Landau–Kleffner syndrome (LKS) is a rare entity characterized by epilepsy and aphasia. It occurs in previously normal children, usually between three and seven years of age. The long-term outcome of LKS is not completely clear. The aim of this study is to verify the long-term follow-up of a group of patients with LKS, focusing on clinical and electroencephalographic (EEG) aspects, and quality of life. Methods: This was a transversal study. Between November 2006 and April 2007 seven patients with previous diagnosis of LKS were interviewed. They had had a follow-up of three to 16 years after their disease onset. They were all males between the ages of eight and 27 years old. All patients had normal MRI. Parents and/or patients were interviewed by one of the authors using a structured questionnaire. The Vineland Adaptive Behavior Scales, the Conner’s Rating Scales – Revised, and Short-Form Health Survey (SF 36) were used. Each patient had a prolonged interictal EEG recording. All patients had normal MRI. Results: The present investigation revealed that two patients still have seizures several years after epilepsy onset. One patient had total and three others had partial remission of language disturbance, while three patients still have aphasia and verbal auditory agnosia. With respect to quality of life, only one of our patients has a normal life at present. The remaining six patients with some sort of limitation consider the aphasia/agnosia to be the main difficulty in their lives. Five patients have normal EEGs. Conclusions: The long-term follow-up of patients with LKS shows that epilepsy and EEG abnormalities do not always disappear. Language disturbances tend to persist in most patients. The age of onset of language dysfunction does not seem to correlate with the prognosis for recovery of language function. Patients with LKS have an overall poor quality of life, mostly due to language difficulties.     

Multiple subpial transection in Landau-Kleffner syndrome

We have considered multiple subpial transection (MST) as a treatment option for Landau-Kleffner syndrome (LKS) for the past 6 years. The effect of this technique on language and cognitive ability, behaviour, seizures, and EEG abnormalities is analysed here. Five children (4 males, 1 female; aged 5.5 to 10 years) underwent MST with sufficiently detailed pre- and postoperative data for analysis. Behaviour and seizure frequency improved dramatically after surgery in all children. Improvement in language also occurred in all children, although none improved to an age-appropriate level. All five had electrical status epilepticus in sleep (ESES) before surgery, which was eliminated by the procedure. One child has had an extension of his MST due to the recurrence of ESES and accompanying clinical deterioration with good effect. An attempt is made to set the effect of MST against the natural history of the condition. MST is an important treatment modality in LKS, although the timing of this intervention and its effect on final language outcome remains to be defined.     

Outcome of multiple subpial transections for autistic epileptiform regression.

Treatment options for atypical forms of Landau-Kleffner syndrome (LKS) are not well delineated. Many patients with typical LKS fail to respond to antiepileptic drug treatment, but some benefit from multiple subpial transections (MSTs). The authors report seven patients with autism or autistic epileptiform regression who responded in varying degrees to MSTs after failed medical management. These patients derived from an original cohort of 36 children (29 males, seven females, ranging from 2 years, 3 months to 11 years, 3 months, mean age = 5 years, 8 months) with a history of language delay or regression, as well as varying degrees of social and behavioral abnormalities, who were evaluated with video-electroencephalogram (EEG) monitoring over a 2-year period. Fifteen patients had clinical seizures (11 of the 19 children with autistic epileptiform regression and four of 12 autistic children). Epilepsy was refractory to medication in seven. Surgical treatment variously involved MSTs of the left neocortex in temporal, parietal, and frontal regions, often including regions within the classic perisylvian language areas. One patient also had a left temporal lobectomy. In all seven patients, seizure control or EEG improved after MSTs. Language, social, and overall behavior improved to a moderate degree, although improvements were temporary in most. Autistic epileptiform regression resembles LKS in that both may respond to MST. MST is used to treat epilepsy in eloquent regions. The responsiveness of autistic epileptiform regression to MST buttresses the argument that autistic epileptiform regression is a form of focal epilepsy.     

Landau-Kleffner Syndrome: Consistent Response to Repeated Intravenous γ-Globulin Doses: A Case Report

Summary: Purpose: Although several treatments have been tried for Landau-Kleffner syndrome (LKS) too many patients are refractory to known therapies. We report an 8–year-old girl who failed other therapies but who had a consistent response after treatment with intravenous (i.v.) γ-globulin. Methods: We monitored the girl from the age of 6 years, when she presented with a 6–month history of loss of language with normal hearing, normal brain magnetic resonance imaging (MRI), increased cerebrospinal fluid (CSF) IgG index, and an EEG showing almost continuous, predominantly left-sided spike- and slow-wave complexes. She had no clinical seizures and did not respond to consecutive trials of valproate (VPA), clonazepam (CZP), prednisone, and carbamazepine (CBZ). She received three courses of intravenous (i.v.) γ-globulin; after each course, clinical and electrographic improvement lasted a few months. After each of the initial two eourses, clinical improvement lasted 3–4 months but was followed by recurrence of the spikes on the EEG and by speech deterioration. Results: However, her last remission has been continuous for the past 16 months. Her CSF IgG index became normal after the first i.v. γ-globulin infusion. Conclusions: Based on our experience with this patient and on other investigators' experience, we believe that further research into immunologic mechanisms and therapies of this syndrome are warranted.     

The assessment of auditory function in CSWS: Lessons from long-term outcome

In Landau-Kleffner syndrome (LKS), the prominent and often first symptom is auditory verbal agnosia, which may affect nonverbal sounds. It was early suggested that the subsequent decline of speech expression might result from defective auditory analysis of the patient's own speech. Indeed, despite normal hearing levels, the children behave as if they were deaf, and very rapidly speech expression deteriorates and leads to the receptive aphasia typical of LKS. The association of auditory agnosia more or less restricted to speech with severe language decay prompted numerous studies aimed at specifying the defect in auditory processing and its pathophysiology. Long-term follow-up studies have addressed the issue of the outcome of verbal auditory processing and the development of verbal working memory capacities following the deprivation of phonologic input during the critical period of language development. Based on a review of neurophysiologic and neuropsychological studies of auditory and phonologic disorders published these last 20 years, we discuss the association of verbal agnosia and speech production decay, and try to explain the phonologic working memory deficit in the late outcome of LKS within the Hickok and Poeppel dual-stream model of speech processing.     

Atypical Evolutions of Benign Localization‐Related Epilepsies in Children: Are They Predictable?

PURPOSE: To emphasize that, in some patients, different atypical evolutions occur in the course of so-called benign focal epilepsies of childhood (BFEC) and to promote interest in finding clinical and/or electroencephalographic (EEG) clues to which patients might be prone to these risky evolutions. METHODS: Twenty-six patients who started with the typical clinical and EEG features of benign childhood epilepsy with centrotemporal spikes (BCECTS) but who had reversible or persistent, serious epileptic events including status epilepticus and language, cognitive, or behavioral impairments were followed for 相似文献   

Brain Single Photon Emission Computed Tomography Imaging in Landau-Kleffner Syndrome

Summary: Five right–handed children with Landau-Kleffner syndrome (LKS) who had disease onset between the ages of 3 and 9 years were studied with EEG and single-photon emission computed tomography (SPECT) before and, in four cases, after 6 months of corticosteroid treatment. EEG findings included both focal and generalized spikes as well as spike-wave discharges with bilateral temporal predominance. These increased markedly during sleep in 1 child, and continuous spike-and-wave complexes appeared during slow-wave sleep in another patient. Neuropsychological testing demonstrated verbal auditory agnosia. Magnetic resonance imaging (MRI) was performed in 4 children and was normal. Brain SPECT imaging demonstrated abnormal perfusion in the left temporal lobe in all patients. The response to corticosteroid therapy was mixed. Our findings reinforce the concept that LKS is a functional disease affecting the language-dominant brain areas. We conclude that SPECT imaging may be of diagnostic assistance in the evaluation of this syndrome of unknown etiology.     

Intracranial EEG Monitoring in Landau-Kleffner Syndrome Associated with Left Temporal Lobe Astrocytoma

Summary: A 3½-year-old boy developed partial complex seizures with right-sided motor activity, occasionally secondarily generalized at age 18 months. Initial EEG showed left-sided focal epileptiform discharges. Seizures became refractory to antiepileptic drugs (AEDs). At age 3 years, there was severe language deterioration consistent with Landau-Kleffner syndrome (LKS). At that time, an EEG showed almost continual generalized spikes and poly spikes, worse during sleep. Video-EEG showed generalized tonic seizures associated with generalized EEG ictal activity. Magnetic resonance imaging (MRI) showed a cystic and solid lesion of the left hippocampal and parahippocampal gyri without surrounding edema. Subdural strip electrodes under the left temporal and overlying the left frontal lobes demonstrated interictal spikes simultaneously in all recording contacts. Ictal EEG activity occurred in the temporal electrodes 0.2–1 s before appearing in the frontal electrodes. After left temporal lobectomy with subtotal resection of a low-grade astrocytoma, he had an immediate marked decrease in seizures. In 1 month he was seizure-free, and in 6 months had no further seizures and markedly improved language. These findings provide further evidence that left temporal structural epileptogenic lesions may contribute significantly to the pathophysiology of LKS.     

Epileptic encephalopathy of late childhood: Landau-Kleffner syndrome and the syndrome of continuous spikes and waves during slow-wave sleep.

Landau-Kleffner syndrome (LKS) and the syndrome of continuous spikes and waves during slow wave sleep (CSWS) are two points on the spectrum of functional childhood epileptic encephalopathies. They are characterized by a severe paroxysmal EEG disturbance that may permanently alter the critical synaptogenesis by strengthening synaptic contacts that should have been naturally "pruned." The much more common benign epilepsy with centrotemporal spikes is also related to LKS and CSWS by a common pathophysiology. Although prognosis in LKS and CSWS for seizure control is good, cognitive function declines and permanent neuropsychologic dysfunction is seen in many cases. This permanent damage is most evident in those patients who had early-onset EEG abnormality and a prolonged active phase of continuous spike-and-wave discharges during sleep. If the active phase of paroxysmal activity persists for over 2 to 3 years, even successful treatment does not resolve neuropsychologic sequelae. In LKS, the paroxysmal activity permanently affects the posterior temporal area and results in auditory agnosia and language deficits; in CSWS, the frontal lobes are more involved and other cognitive disturbances predominate. Aggressive treatment should include high-dose antiepileptic drugs, corticosteroids, and surgery in specific cases.     

Epileptic encephalopathies of the Landau-Kleffner and continuous spike and waves during slow-wave sleep types: Genomic dissection makes the link with autism

Purpose: The continuous spike and waves during slow‐wave sleep syndrome (CSWSS) and the Landau‐Kleffner (LKS) syndrome are two rare epileptic encephalopathies sharing common clinical features including seizures and regression. Both CSWSS and LKS can be associated with the electroencephalography pattern of electrical status epilepticus during slow‐wave sleep and are part of a clinical continuum that at its benign end also includes rolandic epilepsy (RE) with centrotemporal spikes. The CSWSS and LKS patients can also have behavioral manifestations that overlap the spectrum of autism disorders (ASD). An impairment of brain development and/or maturation with complex interplay between genetic predisposition and nongenetic factors has been suspected. A role for autoimmunity has been proposed but the pathophysiology of CSWSS and of LKS remains uncharacterized. Methods: In recent years, the participation of rare genomic alterations in the susceptibility to epileptic and autistic disorders has been demonstrated. The involvement of copy number variations (CNVs) in 61 CSWSS and LKS patients was questioned using comparative genomic hybridization assays coupled with validation by quantitative polymerase chain reaction (PCR). Key Findings: Whereas the patients showed highly heterogeneous in genomic architecture, several potentially pathogenic alterations were detected. A large number of these corresponded to genomic regions or genes (ATP13A4, CDH9, CDH13, CNTNAP2, CTNNA3, DIAPH3, GRIN2A, MDGA2, SHANK3) that have been either associated with ASD for most of them, or involved in speech or language impairment, or in RE. Particularly, CNVs encoding cell adhesion proteins (cadherins, protocadherins, contactins, catenins) were detected with high frequency (≈20% of the patients) and significant enrichment (cell adhesion: p = 0.027; cell adhesion molecule binding: p = 9.27 × 10^?7). Significance: Overall our data bring the first insights into the possible molecular pathophysiology of CSWSS and LKS. The overrepresentation of cell adhesion genes and the strong overlap with the genetic, genomic and molecular ASD networks, provide an exciting and unifying view on the clinical links among CSWSS, LKS, and ASD.     

Landau-Kleffner syndrome and CSWS syndrome: Treatment with intravenous immunoglobulins

This study reports results of therapy with immunoglobulin in children with Landau-Kleffner syndrome (LKS) or the syndrome of continuous spikes and waves during sleep (CSWS syndrome). In a prospective study, children diagnosed between 2002 and 2006 with either LKS or CSWS syndrome were treated soon after diagnosis with intravenous courses of immunoglobulin (IVIg). We compared the results with those reported in the literature and with data from a retrospective survey of our earlier patients. Six children (two girls), aged 4–9 years, were included. Three had LKS, and three had CSWS syndrome. One child—with typical LKS—had been treated with prednisone before (without response). No patient had seizures during IVIg treatment and follow-up. Their electroencephalography (EEG) findings did not improve. Neuropsychological improvement occurred in one child with CSWS syndrome. Three children did not show any beneficial effect; they were subsequently treated with steroids, one with a clearly positive result. We conclude that successful treatment of LKS and CSWS syndrome with IVIg occurs occasionally. However, the improvement cannot always be clearly attributed to this. It might also reflect the natural course of the disease. Although the temporal relation between IVIg treatment and clinical improvement cannot be denied in individual patients, its real value remains to be determined.     

GRIN2A mutations in epilepsy-aphasia spectrum disorders

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.

Factors predicting seizure outcome of anterior temporal lobectomy for patients with mesial temporal sclerosis.

PURPOSE: To investigate the factors, including those associated with ictal scalp EEG results, related to surgical outcome in patients with pathologically proven mesial temporal sclerosis. METHODS: We studied 51 consecutive patients who underwent anterior temporal lobectomy and had at least 4 years of follow-up. Surgical outcome was classified as being seizure-free or not seizure-free during the first two and the subsequent two postoperative years. Clinical variables and scalp EEG parameters were subjected to statistical analysis. RESULTS: Of the 51 patients, 36 (70.6%) were seizure-free during postoperative years 3 and 4. Logistic regression analysis revealed that seizure remission for the first 2 years (p = 0.002) and contralateral propagated ictal discharges (p = 0.015) were independently related to seizure outcome at 4 years. Patients who were seizure-free at 2 years had an 86.5% chance of remaining seizure-free at 4 years. Of the patients without bitemporal asynchrony or switch of lateralization, 88.9% were seizure free at 4 years, compared with 54.5% of patients with asynchrony or switch of lateralization (p = 0.007). These two factors, however, were not predictive of seizure outcome at 2 years. CONCLUSIONS: Contralateral propagated ictal discharges, including bitemporal asynchrony and switch of lateralization, unfavorably influence long-term seizure outcome. Long-term seizure control is best when the patient has no such propagation patterns of ictal discharges and is seizure-free during the first 2 years after temporal lobectomy.     

CSWS-related autistic regression versus autistic regression without CSWS

Continuous spike-waves during slow-wave sleep (CSWS) and Landau-Kleffner syndrome (LKS) are two clinical epileptic syndromes that are associated with the electroencephalography (EEG) pattern of electrical status epilepticus during slow wave sleep (ESES). Autistic regression occurs in approximately 30% of children with autism and is associated with an epileptiform EEG in approximately 20%. The behavioral phenotypes of CSWS, LKS, and autistic regression overlap. However, the differences in age of regression, degree and type of regression, and frequency of epilepsy and EEG abnormalities suggest that these are distinct phenotypes. CSWS with autistic regression is rare, as is autistic regression associated with ESES. The pathophysiology and as such the treatment implications for children with CSWS and autistic regression are distinct from those with autistic regression without CSWS.