Autistic Epileptiform Regression Research Articles

Formation of the phenotype “epilepsy–autism” in childhood

The combination of autistic spectrum disorders (ASD) with epilepsy is one of the most common neuropsychiatric comorbidities, which occurs with a frequency of up to 46 %. Such a high frequency is explained by the similarity of the pathophysiological mechanisms of each of the nosologies development. The common basis for both epileptogenesis and the development of ASD is the anomalies of neural communication mediated by the inversion of neurotransmission. In the formation of the epilepsy–autism phenotype the most significant is impairment of the departments responsible for the verbal-mediated social functioning. Such disorders are manifested in the lag of mental functions development, as well as in the epileptiform activity forming and epileptic seizures triggering. The epilepsy – autism comorbid phenotype core is represented by forms with an established genetic defect associated with structural pathology of the CNS. However, other ways of forming such a phenotype are also possible. Thus, in the epileptic or epileptiform encephalopathies picture there are often symptoms of ASD called an acquired epileptic neuropsychological syndrome. On the other hand, ASD (or the pervasive developmental disorder semiotics) may develop against the epileptiform changes background. In such cases, autistic epileptiform (in case of clinical seizures–epileptic) regression is diagnosed. Our concept of the epilepsy–autism phenotype forming is based on a detailed comparison of the etiology and pathogenesis of epilepsy and ASD. It is presented in the original cyclic sequence form. The variability of the epilepsy–autism phenotype is also presented in the form of the diagram explaining the perspective of each of the nosologies relationship.

Controversial issues in comorbidity between epilepsy and autism: subclinical epileptiform activity and autistic epileptiform regression

Early childhood autism, or autism spectrum disorders, is an extremely heterogeneous group of conditions that share similar symptoms of dysontogenesis. The most significant comorbidity in patients with autism is epilepsy, which is still associated with a variety of controversies. The present article covers the most controversial aspects of comorbidity between autism and epilepsy, including the impact of psychopharmacotherapy on the risk of epilepsy, clinical significance of epileptiform activity on the electroencephalogram in patients without epilepsy, and criteria for and prevalence of autistic epileptiform regression syndrome. We found that there is still a lack of reliable evidence for the majority of issues related to the combination of autism and epilepsy. We emphasize the need for further studies. We also provide a detailed description of the history, criteria, prevalence, and clinical examples of autistic epileptiform regression syndrome.

EPILEPTIC ENCEPHALOPATHIES WITH ELECTRICAL STATUS EPILEPTICUS OF SLOW-WAVE SLEEP (ESES): DIAGNOSIS AND PHARMACOTHERAPY

Electrical status epilepticus of slow sleep (ESES) is a sleep EEG pattern with a continuous (85-100%) diffuse epileptiform activity. The morphology of these epileptiform complexes is identical to benign epileptiform discharges of childhood (BEDC). Epilepsy with ESES (or Penelope Syndrome) is a form of age-dependent epileptic encephalopathies with continuous spike-wave activity during slow wave sleep. This group of epilepsies also includes Pseudo-Lennox syndrome, Landau-Kleffner syndrome, autistic epileptiform regression and some others. Usually, the ESES pattern correlates with the severity of cognitive deficit in epileptic children. The list of anti-epileptic drugs (AEDs) used in pharmacotherapy of epileptic encephalopathies includes valproates, levetiracetam, ethosuximide, sulthiame, topiramate, zonisamide and benzodiazepines; those are given in monotherapy or rationalized combined therapy. Levetiracetam was highly effective in 67.6% of patients with ESES (n=23); among them, two cases of clinical and EEG remission during the pre-puberty period, nine cases of clinical remission and 12 cases with a significant decrease in seizures and epileptiform discharges. In 20.6% of patients (n=7), the pharmacotherapy showed low efficacy. In 11.8% of patients (n=4), aggravation of the disease was noted. Combinations of levetiracetam with valproates and levetiracetam with ethosuximide were found the most effective AEDs. In the cases of epileptogenic structural defect that underlines drug-resistant epilepsy with ESES, neurosurgical intervention is recommended.

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

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

EPILEPTIC ENCEPHALOPTHIES WITH ELECTRICAL STATUS EPILEPTICUS SLOW SLEEP (ESES)

Complex of acquired disturbances of cognitive functions in children associated with continuous epileptiform activity on the EEG is a serious problem. Quite often the EEG patterns in epileptic encephalopathies of childhood such as Landau-Kleffner, pseudo-Lennox syndromes, autistic epileptiform regression etc. are represented by the so-called «benign focal epileptiform discharges of childhood» (BEDOC, BFEDC, BEDC). Epileptiform discharges are characterized by high index and diffuse spreading nature, especially during slow-wave sleep, forming the pattern of ESES. In the treatment of epileptic encephalopathies the following AEDs are applied in monotherapy or rational combined therapy: valproates, ethosuximide, levetiracetam, sultiame and benzodiazepines.

Neurodevelopmental disorders in children with epilepsy

Neurodevelopmental disorders, including intellectual disability, autistic-spectrum disorders, speech disorders, attention deficit hyperactivity disorder (ADHD), learning disabilities, are more prevalent in children with epilepsy compared with the general population. Marked developmental delay and regression of acquired skills are characteristic of epileptic encephalopathies. Conditions, in which neurodevelopmental disorders are associated with the marked epileptiform EEG activity, while clinical epileptic seizures are absent, represent a serious problem. The authors consider the features of epilepsy with electrical status epilepticus during slow-wave sleep, pseudo-Lennox syndrome, Landau-Kleffner syndrome, children autistic epileptiform regression, autosomal-dominant rolandic epilepsy with verbal dispraxy and a combination of epilepsy and subclinical epileptiform EEG activity with developmental dysphasia and ADHD. In addition to the optimization of basic treatment with antiepileptic drugs (AEDs), nootropic drugs which do not increase epileptiform activity (hopantenic acid), are recommended.

Epilepsy in autism spectrum disorders

Epilepsy is quite common in autism spectrum disorders, and it is increasingly recognized as an additional clinical problem that must be dealt with. The rate of comorbidity varies, depending upon the age and type of disorder, and currently the conservative estimate of comorbidity cases is 20-25% of the whole spectrum. Major risk factors for seizure occurrence are mental retardation and additional neurological disorders, as well as some specific associated medical conditions. Autism with regression has been reported in one-third of children with previously normal or nearly normal development. In an unknown proportion of these subjects, epileptic disorders are concomitant, leading to so-called autistic epileptiform regression. Furthermore, epileptiform abnormalities without seizures are frequent in this population and their role in the development of the nuclear disturbances of autism is controversial. The therapeutic approaches to epilepsy in autism are conventional treatments, yet when seizures are not evident, there is still controversy. Anticonvulsant medications could also potentially interfere with mood and behavioral disturbances frequently observed in ASD. The current understanding of the association between epilepsy and autism is still limited, but from a clinical point of view this association should not be overlooked, and it should be routinely investigated.

Visual impairment in infancy: impact on neurodevelopmental and neurobiological processes

Visual impairment in infancy: impact on neurodevelopmental and neurobiological processes

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.

Surgical treatment of autistic epileptiform regression

Autistic epileptiform regression (AER), a subtype of epileptic regression syndrome (ERS), is a clinical syndrome characterized by regression of language functions, sociability, and nonverbal communication skills; decline of cognitive skills; the development of stereotyped, repetitive, self-stimulatory behaviors; and, epileptiform brain electrical activity. In this article the authors present the results of a small series of six patients with AER who were surgically treated and have follow-up of at least 15 months. Preoperative diagnostic studies included magnetic resonance imaging (MRI), positron emission tomography (PET) scans, magnetoencephalography (MEG), developmental psychologic evaluations, and video-electroencephalogram (EEG) monitoring with scalp and subdural electrodes. Epileptiform brain electrical activity generator sites were identified in both hemispheres, including in the margin of the Sylvian fissure, in all patients. Multiple cortical subpial transection (MST) was the primary operation for them; it was performed over all areas in which seizure foci were identified. Four patients also underwent minimal cortical resection on MST resistant foci. Follow-up interval is from 15–24 months. There were no complications from surgery. All six patients showed marked improvement in language functions, sociability, repetitive behaviors, and cognitive skills. In addition, of the four patients who had overt clinical seizures, two are seizure-free; one has rare seizures that are much shorter and less complicated than preoperatively; and one has sustained >90% reduction in seizure frequency. The results imply that patients with AER who are medication resistant show marked improvement after the surgical interventions described.

Cognitive and Autistic Epileptiform Regression

Seven children, ages 3 to 8 years, presenting with autism or autistic regression and seizures had occipital spikes, characteristic of benign epilepsies, in a report from New York University Medical Center.

Multiple Subpial Transection for Autistic Epileptiform Regression (AER)

Multiple Subpial Transection for Autistic Epileptiform Regression (AER)

Acquired epileptiform aphasia

The acquired epileptiform aphasias, with Landau-Kleffner's syndrome as the example, represent an important group of syndromes in our quest to understand the relationship between epilepsy, language, and behavior. The controversy that truly frames the literature on the acquired epileptiform aphasias is the role of epileptiform activity on language, behavior, and cognition. This review expands the model of Landau-Kleffner's syndrome to include two other encephalopathies with language and behavioral regression in association with an epileptiform electroencephalogram. Both of these encephalopathies, autistic epileptiform regression and disintegrative epileptiform regression, are associated with an acquired language disorder. The developmental period in which the acquired language disorder begins, the type of language disorder, and the location and type of the epileptiform activity are all important variables that may affect clinical manifestations and prognosis.