Epilepsy and epileptiform EEG: association with autism and language disorders

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

Landau-Kleffner syndrome, electrical status epilepticus in slow wave sleep, and language regression in children

The Landau-Kleffner syndrome (LKS) and electrical status epilepticus in slow wave sleep (ESES) are rare childhood-onset epileptic encephalopathies in which loss of language skills occurs in the context of an epileptiform EEG activated in sleep. Although in LKS the loss of function is limited to language, in ESES there is a wider spectrum of cognitive impairment. The two syndromes are distinct but have some overlap. The relationship between the epileptiform EEG abnormalities and the loss of cognitive function remains controversial, even in LKS which is the most widely accepted as an acquired epileptic aphasia. Language regression also occurs in younger children, frequently in the context of a more global autistic regression. Many of these children have epileptiform EEGs. The term autistic regression with epileptiform EEG has been proposed for these children. Whether these children are part of an extended LKS spectrum is very controversial, because there are differences in age of onset, clinical phenotype, and EEG findings. An understanding of the available data on clinical characteristics, EEG findings, pathology, prognosis, and treatment of these syndromes is essential for further progress in this area.     

Epileptic encephalopathies and their relationship to developmental disorders: do spikes cause autism?

Epileptic encephalopathies are progressive clinical and electroencephalographic syndromes where deterioration is thought to be caused by frequent seizures and abundant EEG epileptiform activity. Seizures occur in approximately 10-15% of children with pervasive developmental disorders (PDD) and 8-10% have epileptiform EEG abnormalities without seizures. Thirty percent of children with PDD have regression of social behavior and language at 2-3 years of age. Some authors speculate that the regression is caused by epileptiform activity even in the absence of overt clinical seizures ("autism with epileptic regression") and suggest that elimination of the epileptiform activity, either medically or surgically, should lead to improvement in behavior. This review examines the data showing that interictal epileptiform discharges are associated with transient clinical dysfunction and discusses the implications of these observations for autistic behavioral abnormalities. The results of resective surgery, vagal nerve stimulation, and multiple subpial transaction on children with autism and epileptiform EEG abnormalities are also discussed. I conclude that there is no evidence that interictal discharges per se cause (or contribute to) the complex behavioral phenotype of autism. There is no justification to support the use of anticonvulsant medication or surgery in children with PDD without seizures; that is, there is no evidence that treatment to eliminate EEG spikes will have a therapeutic effect on the behavioral abnormalities of PDD and autism.     

Acquired aphasia with convulsive disorders in children: a case study with a seven-year follow-up.

In a 7-year follow-up a case of the “syndrome of acquired aphasia with convulsive disorder” is described. In particular, attention is paid to EEG patterns and linguistic analysis. Although seizures have been controlled medically and EEG abnormalities have tended to improve, no close parallel improvement has been observed in the patient's language disorders.     

Genes, language development, and language disorders

Genetic factors are important contributors to language and learning disorders, and discovery of the underlying genes can help delineate the basic neurological pathways that are involved. This information, in turn, can help define disorders and their perceptual and processing deficits. Initial molecular genetic studies of dyslexia, for example, appear to converge on defects in neuronal and axonal migration. Further study of individuals with abnormalities of these genes may lead to the recognition of characteristic cognitive deficits attributable to the neurological dysfunction. Such abnormalities may affect other disorders as well, and studies of co-morbidity of dyslexia with attention deficit disorder and speech sound disorder are helping to define the scope of these genes and show the etiological and cognitive commonalities between these conditions. The genetic contributions to specific language impairment (SLI) are not as well defined at this time, but similar molecular approaches are being applied to identify genes that influence SLI and comorbid disorders. While there is co-morbidity of SLI with dyslexia, it appears that most of the common genetic effects may be with the language characteristics of autism spectrum disorders rather than with dyslexia and related disorders. Identification of these genes and their neurological and cognitive effects should lay out a functional network of interacting genes and pathways that subserve language development. Understanding these processes can form the basis for refined procedures for diagnosis and treatment.     

Genetics of autism spectrum disorders

Characterized by a combination of abnormalities in language, social cognition and mental flexibility, autism is not a single disorder but a neurodevelopmental syndrome commonly referred to as autism spectrum disorder (ASD). Several dozen ASD susceptibility genes have been identified in the past decade, collectively accounting for 10-20% of ASD cases. These findings, although demonstrating that ASD is etiologically heterogeneous, provide important clues about its pathophysiology. Diverse genetic and genomic approaches provide evidence converging on disruption of key biological pathways, many of which are also implicated in other allied neurodevelopmental disorders. Knowing the genes involved in ASD provides us with a crucial tool to probe both the specificity of ASD and the shared neurobiological and cognitive features across what are considered clinically distinct disorders, with the goal of linking gene to brain circuits to cognitive function.     

Functional neuroimaging of autistic disorders

Functional neuroimaging methods hold promise for elucidating the neurobiology of autistic disorders, yet they present difficult practical and scientific challenges when applied to these complex and heterogeneous syndromes. Single-state studies of brain metabolism and blood flow thus far have failed to yield consistent findings, but suggest considerable variability in regional patterns of cerebral synaptic activity. Patients with idiopathic autism are less likely to show abnormalities than are patients with comorbid illness or epilepsy. Activation studies have begun to suggest alterations in brain organization for language and cognition. Neurotransmitter studies using positron emission tomography (PET) suggest abnormalities of serotonergic and dopaminergic function. Studies using magnetic resonance spectroscopy (MRS) have begun to document metabolic deficits in the frontal cortex and cerebellum. A single study using magnetoencephalography suggests a high incidence of epileptiform activity in children with autistic regression. Research needs include well-controlled developmental studies, particularly of young subjects and relatively homogeneous subgroups, which balance scientific rigor with ethical constraints. Investigations of the serotonergic and dopaminergic systems, limbic-based memory and emotional systems, and the role of epileptiform activity in autism represent priorities for future research.     

Fluent versus nonfluent primary progressive aphasia: a comparison of clinical and functional neuroimaging features

To better characterize fluent and nonfluent variants of primary progressive aphasia (PPA). Although investigators have recognized both fluent and nonfluent patients with PPA, the clinical and neuroimaging features of these variants have not been fully defined. We present clinical and neuropsychological data on 47 PPA patients comparing the fluent (n=21) and nonfluent (n=26) subjects. We further compared language features with PET/SPECT data available on 39 of these patients. Compared to the nonfluent PPA patients, those with fluent PPA had greater impairment of confrontational naming and loss of single word comprehension. They also exhibited semantic paraphasic errors and loss of single word comprehension. Patients with nonfluent PPA were more likely to be female, were more often dysarthric, and exhibited phonological speech errors in the absence of semantic errors. No significant differences were seen with regard to left hemisphere abnormalities, suggesting that both variants result from mechanisms that overlap frontal, temporal, and parietal regions. Of the language measures, only semantic paraphasias were strongly localized, in this case to the left temporal lobe. Fluent and nonfluent forms of PPA are clinically distinguishable by letter fluency, single word comprehension, object naming, and types of paraphasic errors. Nevertheless, there is a large amount of overlap between dysfunctional anatomic regions associated with these syndromes.     

Significance of the EEG for the prognosis of therapy in adult epileptic patients

The importance of EEG findings regarding prognosis of therapy and relapses of epilepsies is controversally discussed in the literature. On the basis of 495 patients being in attendance for many years there were some important indications for prognosis, for instance 59 percent of the patients with normal EEG at all times during the cours attained freedom from seizures for at least five years. The best possibilities for differentiation followed from EEG features during medication, especially from degree od disturbances of background activity. Only 13 percent of patients with more than slight disturbances in resting EEG remained seizure free for a long time. Also as a distinctly unfavourable sign proved the combination of generalized and focal epileptiform pattern.     

Language Organization and Reorganization in Epilepsy

The vast majority of healthy individuals are left hemisphere dominant for language; however, individuals with left hemisphere epilepsy have a higher likelihood of atypical language organization. The cerebral organization of language in epilepsy has been studied with invasive procedures such as Wada testing and electrical cortical stimulation mapping (ESM), and more recently, with noninvasive neuroimaging techniques such as functional magnetic resonance imaging (fMRI). Investigators have used these techniques to explore the influence of unique clinical features inherent in epilepsy that might contribute to the reorganization of language, such as location of seizure onset, age of seizure onset, and extent of interictal epileptiform activity. In this paper, we review the contribution of these and other clinical variables to the lateralization and localization of language in epilepsy, and how these patient-related variables affect the results from these three different, yet complementary methodologies. Unlike the abrupt language changes that occur following acute brain injury with disruption of established language circuits, converging evidence suggests that the chronic nature of epileptic activity can result in a developmental shift of language from the left to the right hemisphere or re-routing of language pathways from traditional to non-traditional areas within the dominant left hemisphere. Clinical variables have been shown to contribute to cerebral language reorganization in the setting of chronic seizure disorders, yet such factors have not been reliable predictors of altered language networks in individual patients, underscoring the need for language lateralization and localization procedures when definitive identification of language cortex is necessary for clinical care.     

自闭症谱系障碍的生物基础

自闭症谱系障碍是一组发病于生命早期, 由一系列生理、心理因素引起的神经发育障碍。遗传、脑神经结构、营养素等是自闭症谱系障碍的生物基础的重要来源。个体在孕育早期形成的大脑和机体异常可能是导致自闭症谱系障碍的关键。这种异常在出生后的发育中具体作用于神经活动、脑发育、免疫系统等生理途径。研究者们今后可以尝试横跨不同自闭症谱系障碍亚型、年龄和发育阶段, 开展横向与纵向相结合的大范围研究, 以进一步明确自闭症谱系障碍的生物基础。     

Emotion perception and recognition: An exploration of cultural differences and similarities

The electroencephalogram (EEG) is a powerful method for investigation of different cognitive processes. Recently, EEG analysis became very popular and important, with classification of these signals standing out as one of the mostly used methodologies. Emotion recognition is one of the most challenging tasks in EEG analysis since not much is known about the representation of different emotions in EEG signals. In addition, inducing of desired emotion is by itself difficult, since various individuals react differently to external stimuli (audio, video, etc.). In this article, we explore the task of emotion recognition from EEG signals using distance-based time-series classification techniques, involving different individuals exposed to audio stimuli. Furthermore, since some of the participants in the experiment do not understand the language of the stimuli, we also investigate the impact of language understanding on emotion perception. Using time-series distances as features for the construction of new data representations, applied here for the first time to emotion recognition and related tasks, lead to excellent classification performance, indicating that differences between EEG signals can be used to build successful models for recognition of emotions, individuals, and other related tasks. In the process, we observed that cultural differences between the subjects did not have a significant impact on the recognition tasks and models.     

The cognitive impact of epileptiform EEG-discharges; relationship with type of cognitive task.

In this study we analyzed the effect of differing task dimensions (high vs. low information demand; short vs. long testing duration) on the occurrence of epileptiform EEG-discharges and the cognitive impact of such discharges. We performed this study only in patients with focal discharges as this appears to be the most complicated group to assess any relationship between epileptiform EEG-discharges and cognitive impairment. Seventeen patients with focal discharges in the EEG and an established diagnosis of localization-related (partial) epilepsy were included. The following tasks were used: Low information demand: auditory and visual RT; high information demand: BCRT and CVST. Short testing duration: Arithmetic and Reading; long testing duration: Vocabulary and Block Design. The percentage of patients with epileptiform EEG-discharge and EEG-related cognitive impact were compared using Chi-square testing. The occurrence of epileptiform EEG-discharges was not associated with one of the experimental conditions introduced in our study, that is, high/low information demand or short/long testing period. Also the difference between computerized reaction-time measurement and more traditional 'paper and pencil tasks' such as reading was not statistically significant. The only statistical significant difference was the more frequent occurrence of epileptiform EEG-discharges during tasks that used the visual input mode. In addition, we could identify one test that appeared to be particularly sensitive to direct cognitive effects of epileptiform EEG-discharges. Only for the CVST, the computerized visual searching task, the relationship with epilepsy-related cognitive impact is statistically significant. This test is the most mentally demanding test of the tests presented in our study and measures speed of visual information processing, using complex stimulus patterns and has a long testing duration. Our results do not confirm that any of the investigated task dimensions (high vs. low information demand; short vs. long testing duration) have a dominant effect on the occurrence of epileptiform EEG-discharges and the cognitive impact of such discharges. The effect found for the CVST suggest that three factors combined are necessary to assess the impact of epileptiform EEG-discharges on cognition: visual input mode, longer testing duration and high information processing demand.     

Neurophysiology of Rett syndrome

Neurophysiological evaluations have been widely applied in the study of Rett syndrome (RS) to provide information concerning the developmental aspects of RS; the character and extent of involvement of the central, peripheral, and autonomic nervous system pathways; and evaluation of the clinical symptomatology of RS. The electroencephalogram (EEG) is invariably abnormal and shows characteristic, though not diagnostic, changes: loss of expected developmental features; the appearance of focal, multifocal, and generalized epileptiform abnormalities; and the occurrence of rhythmic slow (theta) activity primarily in the frontal-central regions. Epileptic seizures are reported to occur frequently in RS, and partial and generalized seizures may be experienced by RS girls. However, many events presumed to be seizures have no EEG correlate during video-EEG monitoring, suggesting the possibility of a nonepileptic mechanism. Such monitoring may be necessary to determine appropriate use of antiepileptic drugs. Evoked potentials typically demonstrate intact peripheral auditory and visual pathways and suggest dysfunction of central or "higher" cortical pathways. Somatosensory-evoked potentials may be characterized by "giant" responses, suggesting cortical hyperexcitability. An increased incidence of long QT intervals during electrocardiographic recordings and diminished heart-rate variability, suggesting impairment of the autonomic nervous system, are described in RS. With the discovery of the genetic basis of RS, neurophysiological studies will provide parameters for phenotype-genotype correlations and characterization of animal models.     

Regression in Autistic Spectrum Disorders

A significant proportion of children diagnosed with Autistic Spectrum Disorder experience a developmental regression characterized by a loss of previously-acquired skills. This may involve a loss of speech or social responsitivity, but often entails both. This paper critically reviews the phenomena of regression in autistic spectrum disorders, highlighting the characteristics of regression, age of onset, temporal course, and long-term outcome. Important considerations for diagnosis are discussed and multiple etiological factors currently hypothesized to underlie the phenomenon are reviewed. It is argued that regressive autistic spectrum disorders can be conceptualized on a spectrum with other regressive disorders that may share common pathophysiological features. The implications of this viewpoint are discussed.     

Palilalia and repetitive speech: two case studies.

Palilalia, a disorder of speech characterized by compulsive repetitions of utterances has been found in various neurological and psychiatric disorders. It has commonly been interpreted as a defect of motor speech. This article describes palilalia and other variants of verbal repetitive behavior, such as monosyllabic iterations and conduite d'approche. The clinical features of palilalia, its prevalence in different language tasks, and the individual patterns of verbal repetitive behavior are illustrated in two patients with a long-standing cerebrovascular disease. An attempt is made to locate the origin of different forms of verbal repetitions in a standard model of speech production (Butterworth, 1980a; Garrett, 1980; Levelt, 1989) by analysis of their morphology and correlation with impairments of lexical or phonological processes. From these observations it is suggested that palilalia results from control malfunctions at the level of the Articulator, whereas other variants of pathological verbal iterations result from an impairment of the Formulator or from malfunctions of both the Articulator and the Formulator.     

Language development in Down syndrome: from the prelinguistic period to the acquisition of literacy

Down syndrome (DS) is associated with abnormalities in multiple organ systems and a characteristic phenotype that includes numerous behavioral features. Language, however, is among the most impaired domains of functioning in DS and, perhaps, also the greatest barrier to independent meaningful inclusion in the community. In this article, we review what is known about the extent, nature, and correlates of the language and related problems of individuals with Down syndrome. In doing so, we focus largely on the syndrome-specific features of the language phenotype, although we also consider within-syndrome variation. The review focuses on the prelinguistic foundations of language and the major components of language (i.e., vocabulary, syntax, and pragmatics). We also consider two topics in the treatment and education of individuals with DS: prelinguistic communication intervention and the acquisition of literacy skills.     

Mining event-related brain dynamics

This article provides a new, more comprehensive view of event-related brain dynamics founded on an information-based approach to modeling electroencephalographic (EEG) dynamics. Most EEG research focuses either on peaks 'evoked' in average event-related potentials (ERPs) or on changes 'induced' in the EEG power spectrum by experimental events. Although these measures are nearly complementary, they do not fully model the event-related dynamics in the data, and cannot isolate the signals of the contributing cortical areas. We propose that many ERPs and other EEG features are better viewed as time/frequency perturbations of underlying field potential processes. The new approach combines independent component analysis (ICA), time/frequency analysis, and trial-by-trial visualization that measures EEG source dynamics without requiring an explicit head model.     

Exposure and Response Prevention and Habit Reversal Training: Commonalities, Differential Use, and Combined Applications

Obsessive-compulsive spectrum disorders (OCSDs) have compulsive (i.e., anxiety reductive) and impulsive (i.e., driven by emotional or involuntary impulses) features. The best established psychological treatments for these disorders are behavioral/cognitive-behavioral in nature. More specifically, exposure and response prevention (ERP) (with or without cognitive therapy) and habit reversal training (HRT) are commonly indicated in the treatment of OCSDs. This paper reviews the use of various components of these therapeutic approaches to treat compulsive and impulsive symptomology in individuals with variants of these disorders. Specifically, ERP monotherapy for compulsive (e.g., obsessive-compulsive, body dysmorphic) and impulsive symptoms (e.g., tics, trichotillomania) is discussed as well as a combined treatment approach that integrates elements of ERP and HRT for individuals displaying mixed symptomology. A case example is also provided that illustrates the successful application of various components of ERP and HRT to treat OCSD symptoms. Lastly, other potential OCSD treatments are discussed.