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.     

Periodic electroencephalogram discharges in a case of Lafora body disease: An unusual finding

Lafora body disease (LBD) is a form of progressive myoclonic epilepsy, characterized by seizures, myoclonic jerks, cognitive decline, ataxia, and intracellular polyglucosan inclusion bodies (Lafora bodies) in the neurons, heart, skeletal muscle, liver, and sweat gland duct cells. Electroencephalogram (EEG) findings in LBD may include multiple spikes and wave discharges, photosensitivity, multifocal epileptiform discharges, and progressive slowing in background activity. Periodicity in epileptiform discharges has not been frequently depicted in LBD. We herein report an unusual case of LBD who showed generalized periodic epileptiform discharges in EEG.     

Seizure characterization and electroencephalographic features in Glut-1 deficiency syndrome

PURPOSE: To characterize seizure types and electroencephalographic features of glucose transporter type 1 deficiency syndrome (Glut-1 DS). METHODS: Twenty children with clinical and laboratory features of Glut-1 DS were evaluated. Age at seizure diagnosis, seizure classification, and response to treatment were determined by chart review. Thirty-two continuous 24-h EEG monitoring sessions and reports of 42 routine EEG studies were assessed. RESULTS: Age at seizure diagnosis was between 4 weeks and 18 months (mean, 5 months). Seizure types were generalized tonic or clonic (14), absence (10), partial (nine), myoclonic (six), or astatic (four). During 24-h EEGs, background activity showed generalized 2.5- to 4-Hz spike-wave discharges (41%), generalized slowing or attenuation (34%), no abnormalities (34%), focal epileptiform discharges (13%), or focal slowing or attenuation (9%). No seizures were captured during 69% of the studies; the remainder had absence (19%), myoclonic (9%), or partial seizures (3%). On evaluation of routine and 24-h EEG studies, focal epileptiform discharges (24%) and slowing (11%) were more frequent in ages 0-24 months. In older children (2-8 years), generalized epileptiform discharges (37.5%) and slowing (21%) were more common. CONCLUSIONS: In all ages, a normal interictal EEG was the most common EEG finding. When abnormalities occurred, focal slowing or epileptiform discharges were more prevalent in the infant. In older children (2 years or older), a generalized 2.5- to 4-Hz spike-wave pattern emerged. Seizure types observed included, absence, myoclonic, partial, and astatic.     

Cognitive tasks as provocation methods in routine EEG: a multicentre field study

Objective: This study aimed to analyse the effect of neuropsychological activation methods on interictal epileptiform discharges, compared to standard activation methods, for both focal and generalized epilepsies. Methods: This was a multicentre, prospective study including 429 consecutive EEG recordings of individuals with confirmed or suspected diagnosis of epilepsy. Neuropsychological activation included reading aloud in foreign and native language, praxis and a letter cancelation task (each with a duration of three minutes). After counting interictal discharges in three‐minute time windows, activation and inhibition were assessed for each procedure, accounting for spontaneous fluctuations (95% CI) and compared to the baseline condition with eyes closed. Differences between generalized and focal epilepsies were explored. Results: Interictal epileptiform discharges were present in 59.4% of the recordings. Activation was seen during hyperventilation in 31%, in at least one neuropsychological activation method in 15.4%), during intermittent photic simulation in 13.1% and in the resting condition with eyes open in 9.9%. The most frequent single cognitive task eliciting activation was praxis (10.3%). Lasting activation responses were found in 18–25%. Significant inhibition was found in 88/98 patients with baseline interictal epileptiform discharges, and was not task‐specific. Significance: Adding a brief neuropsychological activation protocol to the standard EEG slightly increased its sensitivity in patients with either focal or generalized epilepsy. However, in unselected epilepsy patients, this effect seems only exceptionally to result in ultimate diagnostic gain, compared to standard procedures. From a diagnostic perspective, cognitive tasks should be reserved for patients with a suspicion of cognitive reflex epilepsy/seizures and probably require longer exposure times. Further research is needed to explore potential therapeutic applications of the observed inhibition of interictal epileptiform discharges by cognitive tasks in some patients.     

Initial EEG predicts outcomes in a trial of levetiracetam vs. fosphenytoin for seizure prevention

Continuous electroencephalography (cEEG) is increasingly used to detect both clinical and subclinical seizures in patients with traumatic brain injury (TBI) or subarachnoid hemorrhage (SAH). We assess whether EEG findings predict outcomes in TBI/SAH patients enrolled in a levetiracetam (LEV) vs. fosphenytoin (fos-PHT) seizure prevention trial (NCT00618436). This prospective, single-blinded, comparative trial randomized 52 patients with TBI or SAH to receive prophylactic LEV or fos-PHT. Continuous video EEG monitoring was conducted for the initial 72 h of medication administration. The association between EEG findings (degree of generalized and focal slowing, presence and frequency of epileptiform discharges and seizures) and outcomes (Glasgow Outcomes Scale-Extended (GOS-E) and Disability Rating Scale (DRS)) at discharge, 3 and 6 months was assessed using a generalized linear model. Severity of generalized slowing tended to be associated with outcomes in both treatment groups (discharge DRS, p=0.042; discharge GOS-E, p=0.026; 3 month DRS, p=0.051). The presence of focal slowing, the presence and frequency of epileptiform discharges and the presence of seizures were not predictive of outcome in either treatment group (all p>0.15). While it has been shown that LEV is associated with better outcome than fos-PHT when used as seizure prophylaxis in brain injury, aside from severity of generalized slowing, electrographic findings of focal slowing, epileptiform discharges, and seizures were not themselves associated with outcomes in patients with TBI or SAH enrolled in a randomized clinical trial.     

Acute cognitive effects of nonconvulsive difficult-to-detect epileptic seizures and epileptiform electroencephalographic discharges

This study compares the acute cognitive effects of short nonconvulsive seizures with the effects of interictal epileptiform electroencephalographic (EEG) discharges in children. The study is a prospective, standardized, nonrandomized, and open clinical comparative study. Eligible patients were included when they had (a) unclear seizures and fluctuations in cognitive performance and (b) frequent epileptiform EEG discharges in a recent EEG. All children were assessed with EEG/video (Brainlab) simultaneously with computerized neuropsychologic testing (FePsy) assessing motor speed/alertness, mental speed/attention, and memory function. Eleven patients with short nonconvulsive seizures during cognitive testing were included and compared with 11 matched patients with interictal epileptiform EEG discharges during cognitive testing but without seizures. Patients included in both groups had a reconfirmed diagnosis of epilepsy. Cognitive performance for both groups was compared. Statistical analysis showed significant correlations between the number of seizures (during cognitive testing) and impaired alertness and between the duration of the ictal period and memory impairment. Interictal epileptiform EEG discharges do not have an additional independent effect on cognitive function. The results demonstrate the accumulating cognitive effect of seizures and illustrate that frequent seizures, even when these are short in duration and with subtle symptomatology, can have a substantial impact on daily life and can lead to state-dependent learning impairment. Alertness and short-term memory appeared to be the functions that are most vulnerable for the acute effects of seizures.     

Coexistence of ectopic rhythms and periodic EEG pattern in anoxic encephalopathy

In this paper, we reported unique EEG patterns in two patients with anoxic encephalopathy. In the patient with a longer survival, the early EEG showed: suppression-burst pattern and theta pattern coma during quiet states; and quasi-periodic, generalized, epileptiform discharges associated with alpha-theta pattern coma during periods of arousal. A second EEG showed a disappearance of suppression-burst pattern and alpha coma. A third EEG demonstrated a disappearance of quasi-periodic epileptiform discharges. Such distinct evolution of the electroencephalogram was associated clinically with increased responsiveness despite a fatal course of illness. The second patient who had a more dramatic course, had an EEG immediately preceding death, which showed a combination of periodic pattern and theta pattern coma.     

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.     

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.     

The acute effect of music on interictal epileptiform discharges

This study was a prospective, randomized, single-blinded, crossover, placebo-controlled, pilot clinical trial investigating the effect of Mozart's Sonata for Two Pianos (K448) on the frequency of interictal epileptiform discharges (IEDs) from the EEGs of children with benign childhood epilepsy with centrotemporal spikes, or "rolandic" epilepsy. The goal was to demonstrate decreased frequency of IEDs with exposure to K448. Four subjects were recruited and 4-hour awake EEG recordings performed. IED frequency per minute was averaged over each of three epochs per hour. Mean IED count per epoch, standard deviations, and variance were calculated. Only complete waking epochs were analyzed. Two subjects demonstrated sufficient waking IEDs for statistical analysis, consisting of three epochs of K448-related effects. Significant decreases in IEDs per minute (33.7, 50.6, and 33.9%) were demonstrated comparing baseline with exposure to K448, but not to control music (Beethoven's Für Elise).     

Neuropsychological correlates of subclinical paroxysmal EEG activity in children with epilepsy. 1: Qualitative features (generalized and focal abnormalities)

The cognitive deficit often associated with epilepsy is attributable to the presence and interaction of several factors but whether recurrent subclinical spike-wave discharges interfere with cognitive development is not yet clear. In the present study, the presence of subclinical discharges proved to be significantly associated with lower than average Full-Scale Intelligence Quotient (IQ), Verbal IQ and Performance IQ scores (Wechsler Intelligence Scale for Children) in comparison with patients not presenting EEG abnormalities during test. These findings confirm the adverse effect both of generalized and focal EEG epileptiform abnormalities, even if unaccompanied by overt seizures.     

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.     

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.     

Long term outcomes in patients with preoperative generalized interictal epileptiform abnormalities following amygdalohippocampectomy

We evaluated long term surgical outcomes in 21 patients with temporal lobe epilepsy and presurgical generalized interictal epileptiform discharges (IEDs). Following amygdalohippocampectomy, 12 patients (57.1%) were noted to have favorable outcomes (Engel classification of I-II). Favorable outcomes were significantly associated with a history of auras prior to seizure onset (p=0.021), the absence of generalized IEDs on postoperative EEG (p=0.024), and the presence of focal slowing on postoperative EEG (p=0.045).     

Serial EEG in intractable epilepsy

We compared serial EEGs performed at admission, discharge, and follow-up (mean, 25 months) to clinical outcome in 70 patients with intractable epilepsy. The diagnosis in each case was confirmed by intensive monitoring. EEG features evaluated were background slowing, focal slowing, and focal, bilateral, or generalized epileptiform discharges. Clinical measures were seizure frequency and medication toxicity. No statistically significant correlations were found between improvement in any EEG feature and any clinical measure. EEG did not predict which patients would benefit from intensive monitoring. Serial EEGs may be of little value in assessing the results of treatment in patients with severe epilepsy.     

Epilepsy beyond seizures: Predicting enduring cognitive dysfunction in genetic generalized epilepsies

Reduced cognitive functioning has been documented in the genetic generalized epilepsies (GGE). Among a number of hypothesized causal mechanisms, some evidence from other epilepsy syndromes suggests the impact of epileptiform discharges. This study investigates the relationship between cognitive function in GGE and burden of epileptiform discharges within a 24-hour EEG recording, controlling for variables relevant to cognitive function in epilepsy.As part of a larger prospective cohort study, 69 patients with EEG-confirmed GGE (11–58 years) underwent 24-hour EEG and detailed neuropsychological assessment using the Woodcock Johnson III Tests. Ten-second pages of the EEG were marked manually page-by-page on longitudinal bipolar montage with 0.5 to 70 Hz bandwidth by an experienced EEG reader. Multiple regression analyses were conducted. Epileptiform discharges were detected in 90% of patients. Less than 0.01% of electrophysiological events of two or more seconds were recognized by patients. Regression analysis demonstrated that the cumulative duration of epileptiform discharges over a 24-hour period predicted overall cognitive ability and memory function, accounting for 9.6% and 11.8% of adjusted variance, respectively. None of the epilepsy covariates included in multiple regression analysis added significantly to the model.Duration of epileptiform discharges negatively predicts overall cognitive ability and memory function, even after accounting for other known determinants of cognition. Prolonged epileptiform discharges are common and remain unreported by patients, raising important questions regarding the management of GGE syndromes and their associated comorbidities. Further research is required to investigate causal mechanisms if we are to improve cognitive outcomes in this common group of epilepsies.     

Does Physical Exercise Influence the Occurrence of Epileptiform EEG Discharges in Children?

Summary: Purpose: To determine if, and how, epileptiform EEG discharges in children were influenced by physical exercise.
Methods: Twenty-six children with intractable partial and generalized epilepsy exercised during video-telemetry recording, aiming at exhaustion after ∼10 min.
Results: During the exercise, epileptiform discharges decreased in 20 of 26 children (17 children had at least 25% reduction) and showed a rebound increase after the exercise (17 of 26 children) compared to baseline conditions. This exercise-induced reduction in epileptiform discharges reached statistical significance only in the 16 patients with localization-related epilepsy. Five patients showed an atypical EEG response to exercise with either unchanged or increased epileptiform activity while exercising. As compared to the other patients, these 5 children had experienced frequent clinical seizures during or immediately after exercise in their leisure time.
Conclusions: In the majority of the tested children, epileptiform EEG discharges decreased during exercise. "Exercise-EEG" may be a helpful diagnostic tool to identify patients who are disposed to have exercise-induced seizures.     

Eating Epilepsy: EEG and Clinical Study

We studied a 22-year-old woman with eating epilepsy. During 52 days, her seizures were monitored in an inpatient epilepsy center, and their relation to meals, foods, and other variables was assessed. Of a total of 136 seizures observed, 76 occurred during eating and 60 occurred at noneating times. Observation during 6 h of video monitoring detected a rate of type A seizures (head drop, generalized EEG activity) of 1.0 during eating epochs versus 0.21 during noneating epochs (p less than 0.05). Interictal generalized EEG activity consisting of sharp slow-wave complexes was also markedly increased during eating epochs, with mean 16.6 discharges per epoch versus 2.89 during noneating epochs (p less than 0.02). AED levels remained stable during monitoring. Dietary analysis indicated that many types of food seemed to be implicated and that some specific foods were repeated activators.     

Search for the Structures Initiating Seizures Triggered by Intraventricular Injection of the μ opioid Agonist Dermorphin in Rats

Summary: Free-moving rats received intraventricular (i.c.v.) or intravenous (i.v.) injections of the μ opioid agonist dermorphin (DRM). The EEG activity of the cortex and of several structures near the injected lateral ventricle was recorded. The intravenous injections of DRM did not induce epileptiform activity. The intracerebroventricular injections of DRM triggered several types of electrical seizures and interictal spikes. With the aim of determining which structure gave rise to the epileptiform discharges, we compared the time relationships of epileptiform phenomena occurring in different structures. Epileptiform discharges, at once generalized, appeared first in the CA3 area of the ventral hippocampus, with involvement of the CA1 area of ventral hippocampus, the entorhinal cortex and the amygdala following immediately. We conclude that, after intracerebroventricular in-jection of a p opiate agonist, epileptiform activity originates in the CA3 area of the ventral hippocampus.