Effects of epileptiform EEG discharges on cognitive function: is the concept of "transient cognitive impairment" still valid?

In this article we review the existing evidence on the cognitive impact of interictal epileptiform EEG discharges. Such cognitive impairment occurs exclusively in direct relation to episodes of epileptiform EEG discharges and must be distinguished from (post) ictal seizure effects and from the nonperiodic long-term "stable" interictal effects caused by the clinical syndrome or the underlying etiology. Especially in patients with short nonconvulsive seizures, characterized often by difficult-to-detect symptoms, the ictal or postictal effects may be overlooked and the resulting cognitive effects may be erroneously related to the epileptiform EEG discharges. The existing epidemiological data show that the prevalence of cognitive impairment during epileptiform EEG discharges is low. In one study 2.2% of the patients referred to a specialized epilepsy center for EEG recording showed a definite relationship between epileptiform EEG discharges and cognitive impairments ("transient cognitive impairment"). Several studies have sought to analyze to what extent cognitive impairment can be attributed to epileptiform EEG discharges among the other epilepsy factors (such as the effect of the clinical syndrome). These studies show that epileptiform EEG discharges have an additional and independent effect, but this effect is mild and limited to transient mechanistic cognitive processes (alertness, mental speed). This finding concurs with clinical studies that also reported only mild effects. In only exceptional cases are epileptiform EEG discharges the dominant factor explaining cognitive impairment. In addition, some studies have indicated that such mild effects may accumulate over time (when frequent epileptiform EEG discharges persist over years) and consequently result in effects on stable aspects of cognitive function such as educational achievement and intelligence. Hence, the clinical relevance is that early detection of cognitive effects of epileptiform EEG discharges and subsequent treatment may prevent a definite impact on cognitive and educational development. The disruptive effects of epileptiform EEG discharges on long-term potentiation, as established in animal experiments, may be one of the neurophysiological mechanisms underlying this accumulation. In conclusion the concept of "transient cognitive impairment" is still valid, but refinement of methodology has shown that a large proportion of presumed transient cognitive impairment can be attributed to subtle seizures, while interictal epileptic activity accounts for a much smaller part of the cognitive effects than previously thought. In particular cryptogenic partial epilepsies are associated with the risk of cognitive impairment. We hope that increased clinical awareness of this need for early detection will stimulate longitudinal and prospective research that eventually also will provide an answer to the questions of when and how epileptiform discharges that are not part of a seizure need to be treated.     

Effect of epilepsy, seizures and epileptiform EEG discharges on cognitive function

Patients with an established diagnosis of epilepsy were included in three groups on the basis of the absence (Group 2) or presence (Group 3) of epileptiform EEG discharges or subtle seizures (Group 4) during the cognitive assessment procedure. A separate age-matched non-epileptic control group (Group 1) was formed. Twenty-five patients were included in each of the four groups. Thus, a total of 100 patients were investigated. The patients were assessed with continuous 21-channel EEG and video-monitoring, combined with cognitive testing. The results show consistently lower performance on cognitive tests for Group 4, the group with subtle seizures. The difference with the control group was significant for the intelligence subtests and for the complex information processing test (p<0.05). No transient cognitive impairment was found. The results are discussed in the light of possible factors that may be responsible for the lower test-scores in the patients of Group 4: both the ictal effects of the seizures themselves, postictal effects and the effects of the epileptiform EEG discharges may have had an impact on cognitive performance. Finally the absence of evidence for transient cognitive impairment in a group with frequent epileptiform EEG discharges is discussed in detail.     

The cognitive effects of interictal epileptiform EEG discharges and short nonconvulsive epileptic seizures

Purpose: Educational difficulties or even severe cognitive deterioration is seen in many childhood epilepsy syndromes. Many of those cognitive deficits are related directly to the brain disorder underlying the epilepsy syndrome. However, in other types of epilepsy, the epileptic seizures and/or epileptiform activity can be the dominant factor. This is especially unknown for the more “subtle” short nonconvulsive seizure types. For this reason, we analyzed a new cohort of children. Methods: A cross‐sectional study of 188 children with epilepsy. Electroencephalography (EEG)–video recordings and cognitive testing were performed simultaneously. The results of children with short nonconvulsive seizures during a 2‐h testing session were compared with all children with epilepsy without seizures during the 2‐h cognitive testing session and with controls without epilepsy. In a second analysis the cognitive effects of frequency of epileptiform EEG discharges were analyzed. Key Findings: The cognitive effects of short nonconvulsive seizures were large, ranging from 0.5 to 1 standard deviation and concerned global cognitive function, speed of central information processing, and memory function. In children without seizures during cognitive testing, the occurrence of frequent epileptiform discharges showed more subtle effects. These effects were independent from the occurrence of short nonconvulsive seizures. Significance: We concluded that although the effect is less pronounced in number of areas involved and magnitude, the type of association between frequent epileptiform activity (>1% of the time) and cognitive function in children with epilepsy is comparable to the association between short nonconvulsive seizures and cognitive function.     

Relative influence of epileptic seizures and of epilepsy syndrome on cognitive function

Cognitive impairment is frequently observed in children with epilepsy. We aimed at addressing to what extent cognitive function is affected by paroxysmal epileptiform activity with or without clinical seizures or by clinical features characteristic of the epilepsy syndrome. To this purpose, combined electroencephalographic (EEG) recording and cognitive testing (IQ and reaction times) were performed in 28 children. Frequent epileptiform EEG discharges significantly reduced reaction time, as did the occurrence of seizures during cognitive testing. Syndrome-related factors tended to affect cognitive functions as well: children with generalized epilepsy and high average seizure frequency obtained lower scores. Linear regression analysis showed that stable aspects of cognitive function, as reflected in intelligence level, are most closely related to the severity of the epilepsy syndrome (average seizure frequency), whereas transient aspects of cognitive function, such as reaction times, are related to the occurrence of epileptiform EEG discharges. This suggests that seizures have a direct effect on transient cognitive aspects, which can accumulate and result in effects on intelligence level.     

Effects of cerebellar stimulation on epilepsy, the EEG and cerebral palsy in man.

Eighteen of the first 29 patients with intractable epilepsy treated by chronic cerebellar stimulation (CCS) demonstrated a marked suppression of seizures. Sixty-eight of 100 patients with cerebral palsy showed clinical improvement after CCS. Electroencephalographic studies in three epileptic patients revealed a significant (P less than 0.001) reduction in number and duration of paroxysmal EEG discharges during epochs when the stimulator was on; prolonged effects were seen at stimulation rates of 200 c/sec and 10 c/sec (monophasic capacitively coupled stimuli). "Rebound" increases in numbers and durations of paroxysmal discharges occurred after cessation of CCS: immediate "rebounds" occurred within the next 5 min; such rebound effects were also seen in the frequency of clinical seizures. CCS at voltages well above threshold for the production of changes in H reflexes, late motor responses (V1 and V2), and evoked potentials resulted in increased "rebound" effects after cessation of stimulation and such effects were seen clinically and neurophysiologically in epileptic and cerebral palsy patients. Variability in the effects of CCS on seizures and the EEG may have been due to technical factors such as positions and impedances of electrodes, output of the stimulator, effects of anticonvulsant medication and patient differences; there was no clinical or physiological evidence of any undesirable neurological effect of CCS. In one patient, onset of CCS was frequently associated with cessation of polyspike and wave discharges; such results raise the possibility of triggering CCS from paroxysmal discharges in the EEG (contingency feedback) but rebound effects may complicate such therapy.     

Primary generalized epilepsy during infancy and early childhood

The present study delineates a benign generalized epileptic disorder during infancy and early childhood similar to the well-defined syndrome of primary generalized epilepsy in adolescence. The inclusion criteria for the study required infants under the age of 4 years mainly presenting with generalized nonfebrile seizures, requiring corroboration with generalized epileptic discharges on electroencephalograms (EEGs); an unremarkable pregnancy, labor, and perinatal course; a favorable response to antiepilepsy drugs, preferably monotherapy; and a normal cognitive outcome. The clinical features of seizures, EEG correlates, response to medications, developmental outcome, and family history were analyzed. Twenty-five infants fulfilled the inclusion criteria, presenting at ages 4 to 36 months (mean 17 months) with recurrent generalized clonic seizures, which were commonly short-lived, lasting up to 5 minutes; two infants also had status epilepticus. Fourteen infants (56%) had accompanying febrile seizures, which preceded the nonfebrile seizures in 10 of them. A positive family history of seizures was found in 8 (32%) patients. Analysis of the EEG showed generalized epileptiform discharges in the form of 3 to 4 Hz spike-wave and normal background activity in 21 patients (84%), with a photosensitive response induced in 3 children. A larger group of 18 infants promptly responded to therapy, mainly valproic acid, which was terminated after 2 years, along with EEG normalization and no recurrence of seizures. A smaller group of 7 patients require prolonged therapy that keeps them seizure free; the EEG remains paroxysmal, and the seizures could recur when treatment is discontinued. All patients are presently seizure free within a follow-up period of 1.5 to 14 years. Their cognition is normal, but 12 patients have short attention and concentration spans, impulsiveness, and learning difficulties. As such, the data presented here delineate an idiopathic generalized epileptic disorder during infancy with a benign course, a rapid response to therapy, and preservation of cognitive skills that may be added to the current classification of the epileptic syndromes.     

Nocturnal epileptiform EEG discharges, nocturnal epileptic seizures, and language impairments in children: review of the literature

This review addresses the effect on language function of nocturnal epileptiform EEG discharges and nocturnal epileptic seizures in children. In clinical practice, language impairment is frequently reported in association with nocturnal epileptiform activity. Vice versa, nocturnal epileptiform EEG abnormalities are a common finding in children with specific language impairment. We suggest a spectrum that is characterized by nocturnal epileptiform activity and language impairment ranging from specific language impairment to rolandic epilepsy, nocturnal frontal lobe epilepsy, electrical status epilepticus of sleep, and Landau-Kleffner syndrome. In this spectrum, children with specific language impairment have the best outcome, and children with electrical status epilepticus of sleep or Landau-Kleffner syndrome, the worst. The exact nature of this relationship and the factors causing this spectrum are unknown. We suggest that nocturnal epileptiform EEG discharges and nocturnal epileptic seizures during development will cause or contribute to diseased neuronal networks involving language. The diseased neuronal networks are less efficient compared with normal neuronal networks. This disorganization may cause language impairments.     

The new approach to classification of focal epilepsies: Epileptic discharge and disconnectivity in relation to cognition

The new classification of epilepsy stratifies the disease into an acute level, based on seizures, and an overarching chronic level of epileptic syndromes (Berg et al., 2010). In this new approach, seizures are considered either to originate and evolve in unilateral networks or to rapidly encompass both hemispheres. This concept extends the former vision of focal and generalized epilepsies to a genuine pathology of underlying networks. These key aspects of the new classification can be linked to the concept of cognitive curtailing in focal epilepsy. The present review will discuss the conceptual implications for acute and chronic cognitive deficits with special emphasis on transient and structural disconnectivity. Acute transient disruption of brain function is the hallmark of focal seizures. Beyond seizures, however, interictal epileptic discharges (IEDs) are increasingly recognized to interfere with physiological brain circuitry. Both concomitant EEG and high-precision neuropsychological testing are necessary to detect these subtle effects, which may concern task-specific or default-mode networks. More recent data suggest that longstanding IEDs may affect brain maturation and eventually be considered as a biomarker of pathological wiring. This brings us to the overarching level of chronic cognitive and behavioral comorbidity. We will discuss alterations in structural connectivity measured with diffusion-weighted imaging and tractography. Among focal epilepsies, much of our current insights are derived from temporal lobe epilepsy and its impact on neuropsychological and psychiatric functioning. Structural disconnectivity is maximal in the temporal lobe but also concerns widespread language circuitry. Eventually, pathological wiring may contribute to the clinical picture of cognitive dysfunction. We conclude with the extrapolation of these concepts to current research topics and to the necessity of establishing individual patient profiles of network pathology with EEG, high-precision neuropsychological testing, and state-of-the-art neuroimaging.This article is part of a Special Issue entitled "The new approach to classification: Rethinking cognition and behavior in epilepsy".     

The Spectrum of Idiopathic Rolandic Epilepsy Syndromes and Idiopathic Occipital Epilepsies: From the Benign to the Disabling

Summary:  Benign childhood epilepsy with centrotemporal spikes (BCECTS) is an idiopathic focal epilepsy syndrome, the benign characteristics of which are debated; in fact, stable or intermittent specific neuropsychological deficits are frequent and may affect scholastic or adaptive abilities. Cognitive dysfunction may be related to a marked increment of the interictal epileptic discharges in NREM sleep: different degrees of neuropsychological deficits depend on the extent of awake and sleep activity and the predominant discharge localization. The age of onset and duration of atypical sleep EEG patterns may correlate with permanent cognitive impairments. These atypical clinical and EEG evolutions have been reported in the literature as different syndromes that constitute the spectrum of idiopathic rolandic epilepsy. Moreover, a clinical link between BCECTS and early-onset benign childhood occipital epilepsy has been demonstrated.
According to the neurobiological approach, the spectrum of Idiopathic Rolandic Epilepsy is based on an age-dependent, idiopathic predisposition to focal seizures and sharp-wave discharges, as an expression of nonlesional cortical excitability. The involvement of a given area of the cerebral cortex may depend on the brain maturational stage.     

Educational underachievement in children with epilepsy: a model to predict the effects of epilepsy on educational achievement

In this study, we evaluated the impact on educational achievement of four characteristics of epilepsy individually and combined: epilepsy syndrome (type of epilepsy), seizure type, the frequency of epileptiform electroencephalographic (EEG) discharges, and the effect of antiepileptic treatment. Simultaneously, the effect on cognitive function and the relationship between educational underachievement and cognitive impairment were evaluated, focusing on memory, attention, speed of information processing, and intelligence level. This study was an open, controlled, parallel-group, nonrandomized clinical investigation. Eligible patients were selected when referred to our center for assessment of relationships between epilepsy and learning impairment in the years 1997 to 2001. Separately, children without neurologic deficit and without educational delay were assessed with the same tests as the children with epilepsy. This latter group is used in this study as a control group. One hundred seventy-six children with epilepsy and 113 controls were included. Gender distribution and age were comparable for the two groups. All children were in regular primary education. The children were assessed with a test battery consisting of tests for educational achievement, cognitive tests and tests for reaction time, and tests for memory and intelligence. Multivariate analysis of variance for tests of educational achievement showed a statistically significant effect for type of epilepsy (F = 4.386; P = .04), caused by the statistically lower scores for patients with localized epilepsy and symptomatic generalized epilepsy. For the reaction-time tests, a statistically significant effect for epileptiform EEG discharges (F = 3.165; P = .01) and treatment (F = 4.472; P = .001) on both vigilance tests was found, caused by patients with frequent epileptiform EEG discharges and polytherapy. Two-way interactions showed an interaction with type of epilepsy, with more patients with symptomatic generalized epilepsy having frequent epileptiform EEG discharges and polytherapy. For memory, none of the analyses showed statistically significant effects. For intelligence only for type of epilepsy, a statistically significant effect was found (F = 10.174; P = < .001). We propose a model with the type of epilepsy (epilepsy syndrome) as the dominant factor explaining educational underachievement in children with epilepsy. Such educational underachievement is most prominent for the localized and symptomatic generalized epilepsies, which suggests a dominant impact of underlying etiology (brain dysfunction or damage). These epilepsies are characterized specifically by a lower intelligence; hence, this could be the primary cognitive factor mediating between the type of epilepsy and educational underachievement. From the other factors, treatment (the use of polytherapy) and frequent epileptiform EEG discharges are associated with impaired vigilance, which could have an additional influence on educational achievement. These factors are, however, not independent of the type of epilepsy.     

Effect of Seizures and Epileptiform Discharges on Cognitive Function

Summary: Several relationships have been obtained between cognitive impairment and epilepsy-related or treatment-related factors. One of these factors is treatment-related: the central cognitive side effects of the antiepileptic drugs (AEDs). The second and third factors are disease-related factors, i.e., the effect of the seizures and underlying epileptiform discharges in the brain and the localization of the epileptogenic focus in specific areas of the brain. Although most cognitive problems have a multifactorial origin and often several factors combined are responsible for the "make-up" of a cognitive problem, we have attempted to isolate one factor: the effect of seizures and epileptiform EEG discharges on cognitive function. Several studies show the impact of ictal activity, but special attention is required for the postictal and interictal effects of epilepsy on cognitive functions. This may explain substantial cognitive impairments in children with subclinical epileptiform discharges or with infrequent subtle seizures.     

Reflex epilepsy in the Papio-papio baboon,particularly photosensitive epilepsy

Papio-papio baboons may present two types of reflex paroxysmal manifestations:

- Myoclonia and generalized seizures are induced by intermittent light stimulation in predisposed animals; this photosensitive epilepsy resembles that observed in some human patients; it involves mainly the cerebral cortex during myoclonia which are accompanied by EEG paroxysmal discharges, and the mesencephalic reticular formation during seizures;

- Myoclonia of a different type, never accompanied by EEG paroxysmal discharged and never evolving into seizures, may occur during movement or agitation of predisposed animals; these myoclonia are considered “non-epileptic” since they do not involve the cerebral cortex but probably the lower brain stem; they resemble that observed in startle disease or in some human degenerative disorders.

The paper demonstrates that these manifestations constitute two different entities with clinical and electrophysiological characteristics as well as pharmacological reactivities completely different one from the other. Their “epileptic” or “non-epileptic” nature is discussed.     

Electroencephalographic cerebral dysrhythmic abnormalities in the trinity of nonepileptic general population, neuropsychiatric, and neurobehavioral disorders

Subclinical electroencephalographic epileptiform discharges in neurobehavioral disorders are not uncommon. The clinical significance and behavioral, diagnostic, and therapeutic implications of this EEG cerebral dysrhythmia have not been fully examined. Currently the only connotation for distinctive epileptiform electroencephalographic patterns is epileptic seizures. Given the prevailing dogma of not treating EEGs, these potential aberrations are either disregarded as irrelevant or are misattributed to indicate epilepsy. This article reappraises the literature on paroxysmal EEG dysrhythmia in normative studies of the "healthy" nonepileptic general populations, neuropsychiatry, and in neurobehavioral disorders. These EEG aberrations may be reflective of underlying morpho-functional brain abnormalities that underpin various neurobehavioral disturbances.     

药物治疗：有希望解决儿童精神认知问题

Subclinical electroencephalogram discharges in children with psycho-cognitive problems are not uncommon. However, the clinical importance and relationship to cognitive deficits, as well as indications for medical treatment, are not well understood. Transient cognitive impairment, which accompanies electroencephalogram discharges, could negatively influence cognitive abilities over time. Studies have suggested that treatment with antiepileptic drugs normalizes electroencephalogram results, thereby preventing electrical paroxysmal discharges that could be harmful to the developing brain. Physicians should attempt to differentiate between corresponding factors, such as subtle seizures, nature of underlying etiology, stable cognitive deficits, seizure-inducing effects, and potential side effects of antiepileptic drugs prior to initiation of medical treatment for definitive diagnosis of transient cognitive impairment and its consequences. Therefore, appropriate criteria for patient selection and proper guidelines for medical therapy, should be addressed in future studies.     

Attention deficit hyperactivity disorder in children with epilepsy

Attention deficit hyperactivity disorder (ADHD) is more frequent in children with epilepsy than in general pediatric population. Several factors may contribute to this comorbidity, including the underlying brain pathology, the chronic effects of seizures and of the epileptiform EEG discharges, and the effects of antiepileptic drugs. Symptoms of ADHD are more common in some specific types of epilepsies, such as frontal lobe epilepsy, childhood absence epilepsy and Rolandic epilepsy, and may antedate seizure onset in a significant proportion of cases. In epileptic children with symptoms of ADHD, treatment might become a challenge for child neurologists, who are forced to prescribe drugs combinations, to improve the long-term cognitive and behavioral prognosis. Treatment with psychotropic drugs can be initiated safely in most children with epilepsy and ADHD symptoms.     

Pearls,perils, and pitfalls in the use of the electroencephalogram

Despite advances in neuroimaging techniques over the past three decades that have helped in identifying structural lesions of the central nervous system, electroencephalography (EEG) continues to provide valuable insight into brain function by demonstrating focal or diffuse background abnormalities and epileptiform abnormalities. It is an extremely valuable test in patients suspected of epilepsy and in patients with altered mental status and coma. Patterns in the EEG make it possible to clarify the seizure type; it is indispensable for the diagnosis of nonconvulsive status epilepticus and for separating epileptic from other paroxysmal (nonepileptic) episodes. There are EEG patterns predictive of the cause of the encephalopathy (i.e., triphasic waves in metabolic encephalopathy) or the location of the lesion (i.e., focal polymorphic delta activity in lesions of the subcortical white matter). The various EEG characteristics of infantile, childhood, and adult epilepsies are described as well as the EEG patterns that are morphologically similar to interictal/ictal epileptiform discharges but unrelated to epilepsy. An EEG is most helpful in determining the severity and, hence, the prognosis of cerebral dysfunction. Lastly, EEG is extremely helpful in assessing normal or abnormal brain functioning in a newborn because of the serious limitation in performing an adequate neurologic examination on the neonate who is intubated or paralyzed for ventilatory control. Under such circumstances, the EEG may be the only available tool to detect an encephalopathic process or the occurrence of epileptic seizures.     

Myoclonic epileptic seizures during clozapine treatment: a report of three cases

Summary Three adult schizophrenic patients without a previous history of epilepsy are reported who, during clozapine treatment, developed paroxysmal EEG patterns and generalized myoclonic jerks without alteration of consciousness. These seizures were phenomenologically identical to those occurring in juvenile myoclonic epilepsy and were classified as generalized epileptic seizures. We tentatively conclude that generalized myoclonic epileptic seizures may be induced by clozapine.     

Prise en charge d’une première crise épileptique de l’adulte : peut-on prévoir l’avenir ?

The new definition of epilepsy recently proposed by an international panel of experts relies on the association of a first clinically certain seizure and of an enduring predisposition of the brain increasing the likelihood of future seizures. In the first part of this review, we will expose and organize into a hierarchical order the risk factors of subsequent recurrence. The major factors are: seizure(s) prior to presentation, paroxysmal abnormalities on early EEG, a remote symptomatic etiology. In the second part of this review, we will address the issue of clinical uncertainty when assessing the epileptic origin of a first clinical paroxysmal event, the reasons of uncertainty and the means to minimize it. We will analyze successively: the accuracy of eyewitness observations of transient loss of consciousness, the reliability and predictive validity of clinical criteria used for seizure assessment, the issue of overlapping clinical features between seizure and other non epileptic paroxysmal events (such as psychogenic non epileptic seizures), and finally the reliability and diagnostic value of early EEG for seizure assessment. To conclude, seizure assessment and diagnosis of epilepsy cannot be dissociated from syndrome and etiology diagnosis, which should be periodically reassessed towards a greater accuracy during the course of the disease.     

Cognitive functions and epileptic activity.

Epilepsy, and its treatment, can affect the development and use of language in a number of different ways. The seizures may be a symptom of a lesion in areas of the brain essential for language function, and the complications of both the seizures and of the drugs can interfere with learning. However, the purpose of this review is to consider the role of epileptic activity as demonstrated by electrical discharges in the electroencephalogram (EEG), whether these are accompanied by overt seizures or not, on cerebral function especially that of language. The Landau-Kleffner, the continuous spike-waves during sleep, and the benign epilepsy of childhood with Rolandic spikes syndromes are considered; as well as the evidence of epileptic discharges affecting language development. If there are doubts that a patient is suffering from epilepsy the diagnosis may be difficult; and anyone involved in the treatment of language disorders should keep this possibility in mind. Particularly during childhood an EEG, awake and asleep, should be an important part of the assessment of both developmental and acquired dysphasia. The control of overt fits may be relatively easy, but drugs are not so effective in controlling the epileptic activity in the EEG. The treatment of such discharges used to be discouraged, but the evidence is now strongly in favour of employing both medical and surgical treatment. The results in restoring language function are sometimes dramatic.     

视频脑电图在小儿癫痫诊断中的应用

目的评价视频脑电图(video-EEG)在小儿癫诊断中的应用价值。方法对126例具有发作性症状的患儿进行连续8h的包括清醒、睡眠、诱发试验及必要的认知测验的视频脑电图监测。结果经发作期视频脑电图证实,39例初诊为癫性发作的患儿中14例(35%)为非癫性发作;15例其他症状发作中13例(86%)为非癫性发作。64例样放电患儿中51例(80%)确定发作类型,22例(34%)确定癫类型。视频脑电图可发现短暂轻微的癫发作及样放电引起的一过性认知损伤。结论视频脑电图在排除非癫性发作、确定癫性发作的类型、评价脑电-临床关系方面可提供准确可靠的证据,进一步提高癫的临床诊断水平。