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.

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.

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.

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.

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.

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.

Landau-Kleffner syndrome in Norway: long-term prognosis and experiences with the health services and educational systems.

We have conducted a retrospective study based on the medical records of 19 children with Landau-Kleffner syndrome and semistructured interviews of their parents. There was considerable heterogeneity in the children's symptoms. Eleven children were followed for more than 10 years (mean=14.4 years); four have normal language, four have moderate language problems, and three have no functional verbal language today. Late-onset language decline, short duration of the initial aphasic period, and marked fluctuations in speech abilities appeared to be associated with a positive outcome with respect to future language skills. The parents reported having to argue strongly with the health authorities and educational system to obtain a correct diagnosis and receive adequate help. Their main concern was not being taken seriously when they expressed their worries, and they expressed a strong wish for someone who could ensure that appropriate support measures were implemented and who could coordinate assistance.

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.

Scalp-recorded high-frequency oscillations in childhood sleep-induced electrical status epilepticus.

Because high-frequency oscillations (HFOs) may affect normal brain functions, we examined them using electroencephalography (EEG) in epilepsy with continuous spike-waves during slow-wave sleep (CSWS), a condition that can cause neuropsychological regression. In 10 children between 6 and 9 years of age with epilepsy with CSWS or related disorders, we investigated HFOs in scalp EEG spikes during slow-wave sleep through temporal expansion of the EEG traces with a low-cut frequency filter at 70 Hz as well as through time-frequency power spectral analysis. HFOs (ripples) concurrent with spikes were detected in the temporally expanded traces, and the frequency of the high-frequency peak with the greatest power in each patient's spectra ranged from 97.7 to 140.6 Hz. This is the first report on the detection of HFOs from scalp EEG recordings in epileptic patients. We speculate that epileptic HFOs may interfere with higher brain functions in epilepsy with CSWS.

Long-term outcome of 32 children with encephalopathy with status epilepticus during sleep, or ESES syndrome.

PURPOSE: To prospectively evaluate the efficacy of drug treatment and long-term cognitive outcome in children with encephalopathy with status epilepticus during sleep (ESESS). METHODS: Thirty-two children were diagnosed and prospectively followed up for at least 3 years at our unit between 1991 and 2007. Twenty-seven children were included in the prospective treatment study with valproate (VPA) and 17 with VPA combined with ethosuximide (ESM). Treatment response of disappearance of electrical status epilepticus during sleep (SES) was documented with overnight EEG recordings. Neuropsychological follow up for at least 5 years was available in 18 patients. RESULTS: Six children had atypical rolandic (AR) epilepsy, nine Landau-Kleffner syndrome (LKS), and 17 symptomatic epilepsy. Before ESESS, 20 children were cognitively normal. Prospective treatment with VPA and ESM was effective in 3 of the 17 children (18%) treated. Abolition of SES with drug treatment was observed in 16 patients. In all, 10 children (31%), 4 with AR (67%), 3 with LKS (33%), and 3 with symptomatic etiology (19%), including 9 with treatment response regained the pre-ESESS cognitive level. Unfavorable cognitive outcome was predicted by younger age at ESESS diagnosis, lower IQ at the time of the diagnosis, and no response to drug treatment when compared with those with favorable cognitive outcome. Eight of the 16 nonresponders underwent epilepsy surgery. DISCUSSION: Treatment response with VPA combined with ESM was observed more often than with other drug combinations. Most children with ESESS experienced permanent cognitive impairment. Cognitive outcome depends on treatment response on electroencephalography (EEG) and seizures, and on underlying etiology.

Levetiracetam as add-on therapy in different subgroups of "benign" idiopathic focal epilepsies in childhood.

Several recent studies have shown that levetiracetam (LEV) can be beneficial in the treatment of children with typical rolandic epilepsy (RE). Reports about the effectiveness of LEV in the treatment of children with the less benign variants in the spectrum of "benign" idiopathic focal epilepsies are still rare. Little is known about the effect of LEV on interictal epileptiform discharges in these syndromes. We report on LEV therapy in 32 children (mean age: 10.6 years, range: 4-14) with RE or variants like atypical benign idiopathic partial epilepsy of childhood (ABIPEC), Landau-Kleffner syndrome (LKS), and continuous spikes and waves during sleep (CSWS) and in children with benign idiopathic focal epileptiform discharges of childhood (BIFEDC). Cognitive and behavioral problems, not seizures, may be related to the pathological EEG. Patients with a reduction in seizure frequency >50% and/or reduction in BIFEDC >90% 3 months after having started LEV therapy were defined as responders. The average dose of LEV was 39 mg/kg body wt per day; LEV was given in monotherapy to 31.3% of the patients. Overall, 20 of 32 patients (62.5%) did benefit: 12 of 24 patients had a >50% reduction in seizure frequency; 2 of 24 patients (8.3%) were completely seizure free; 18 of 32 patients (56.3%) had a >90% reduction in BIFEDC (including CSWS); 6 of 32 (18.8%) had an EEG completely free of epileptiform discharges; and 17 of 32 (53.1%) showed improvement in cognition and/or language functions and/or behavior. Surprisingly, LEV tended to be more helpful in atypical rolandic epilepsies and other variants.

Some facts about sleep relevant for Landau-Kleffner syndrome.

Our understanding of the neural mechanisms of non-rapid eye movement sleep (NREM) is steadily increasing. Given the intriguing activation of paroxysmal activity during NREM sleep in patients with Landau-Kleffner syndrome (LKS), a thorough characterization of commonalities and differences between the neural correlates of LKS paroxysms and normal sleep oscillations might provide useful information on the neural underpinning of this disorder. Especially, given the suspected role of sleep in brain plasticity, this type of information is needed to assess the link between cognitive deterioration and electroencephalography (EEG) paroxysms during sleep.

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.

Encephalopathy with status epilepticus during slow sleep: "the Penelope syndrome".

ESES (encephalopathy with status epilepticus during sleep) is an epileptic encephalopathy with heterogeneous clinical manifestations (cognitive, motor, and behavioral disturbances in different associations, and various seizure types) related to a peculiar electroencephalography (EEG) pattern characterized by paroxysmal activity significantly activated during slow sleep-that is, a condition of continuous spikes and waves, or status epilepticus, during sleep. The pathophysiologic mechanisms underlying this condition are still incompletely understood; recent data suggest that the abnormal epileptic EEG activity occurring during sleep might cause the typical clinical symptoms by interfering with sleep-related physiologic functions, and possibly neuroplasticity processes mediating higher cortical functions such as learning and memory consolidation. As in the myth of Penelope, the wife of Odysseus, what is weaved during the day will be unraveled during the night.

Atypical rolandic epilepsy.

Typical benign rolandic epilepsy (BRE) is a frequent and well-delineated epileptic syndrome in childhood. Mild cognitive and behavioral difficulties are increasingly recognized in the course of BRE and should not be considered as atypical features. Atypical features are recognized on electroclinical grounds. These features, particularly early age at onset and frequent spikes or spike-wave discharges, seem to be risk factors for neuropsychological deficits but also for an atypical evolution of BRE. Atypical evolutions of BRE are defined by the appearance of severe neuropsychological impairments and continuous spike-and-waves during slow sleep (CSWSS). The clinical expressions of these situations correspond to the syndromes known as atypical benign focal epilepsy of childhood (ABFEC), status of BRE, Landau-Kleffner syndrome (LKS), and CSWSS syndrome, which may be part of a continuum related to BRE.

Specific language impairment versus Landau-Kleffner syndrome.

The occurrence of sleep electroencephalography (EEG) abnormalities in some children with specific language impairment (SLI), the various forms of language dysfunction patterns seen in children with benign childhood epilepsy with centrotemporal spikes (BECTS), and finally the acquired aphasia in Landau-Kleffner syndrome (LKS) indicate a large spectrum of interactions between language and epilepsy. As such, the question is whether SLI and LKS should rather be considered along a continuum or as two entirely distinct entities. In addition, the rationale for using antiepileptic medications in rare forms of SLI is discussed.