Cognitive and developmental outcomes in patients with epileptic encephalopathy are hypothesized to result from an interplay between the underlying epileptic pathologic substrate and the acquired consequences of frequent and repetitive seizures and epileptiform discharges that often straddle the interictal and ictal boundaries. This article briefly reviews the evidence related to this assumption, presents critical questions that need to be answered to clarify this relationship, and advances a set of concrete steps that may help improve developmental patient outcomes.
In epileptic encephalopathy, the seizures and interictal epileptiform activity create additional neurocognitive dysfunction beyond that due to the underlying etiology. Treatment leading to a reduction in seizures or interictal abnormalities may help improve neurocognitive function in these situations. The focus of our discussion is reviewing data that support the concept that treatment can impact outcome independent of the etiology in some cases.
Epileptic activity is a surrogate for an underlying etiology and stopping the activity has a limited impact on developmental outcome
The concept of epileptic encephalopathy is important in clinical practice, but its relevance to an individual must be assessed in the appropriate context. Except in rare situations, epileptic activity is a surrogate for an underlying etiology, and stopping the activity has a limited impact on developmental outcome. Labeling a group of epilepsies as “the epileptic encephalopathies,” risks minimizing the impact of epileptic activity on cognition and behavior more widely in epilepsy. Similarly, describing the encephalopathy associated with many infantile onset epilepsies as “epileptic” may be misleading. Finally, concentrating on the epileptic activity alone and not considering the wider consequences of the underlying etiology on cognitive and behavioral development, may focus research efforts and the search for improved therapies on too narrow a target. Therefore, epileptic encephalopathies should not be considered as a specific group of epilepsies but, rather, the concept of epileptic encephalopathy should be applicable to all types of epilepsies and epilepsy syndromes, whenever it is relevant in the clinical course of a particular individual, at any age.
The baboon provides a natural model of genetic generalized epilepsy (GGE). This study compares the intrinsic connectivity networks of epileptic and healthy control baboons using resting-state functional magnetic resonance imaging (rs-fMRI) and data-driven functional connectivity mapping.Methods
Twenty baboons, matched for gender, age, and weight, were classified into two groups (10 epileptic [EPI], 10 control [CTL]) on the basis of scalp electroencephalography (EEG) findings. Each animal underwent one MRI session that acquired one 5-min resting state fMRI scan and one anatomic MRI scan—used for registration and spatial normalization. Using independent component analysis, we identified 14 unique components/networks, which were then used to characterize each group's functional connectivity maps of each brain network.Results
The epileptic group demonstrated network-specific differences in functional connectivity when compared to the control animals. The sensitivity and specificity of the two groups' functional connectivity maps differed significantly in the visual, motor, amygdala, insular, and default mode networks. Significant increases were found in the occipital gyri of the epileptic group's functional connectivity map for the default mode, cingulate, intraparietal, motor, visual, amygdala, and thalamic regions.Significance
This is the first study using resting-state fMRI to demonstrate intrinsic functional connectivity differences between epileptic and control nonhuman primates. These results are consistent with seed-based GGE studies in humans; however, our use of a data-driven approach expands the scope of functional connectivity mapping to include brain regions/networks comprising the whole brain.
Research in other disorders suggests that genetic causal attribution of epilepsy might be associated with increased stigma. We investigated this hypothesis in a unique sample of families containing multiple individuals with epilepsy.Methods
One hundred eighty-one people with epilepsy and 178 biologic relatives without epilepsy completed a self-administered survey. In people with epilepsy, felt stigma was assessed through the Epilepsy Stigma Scale (ESS), scored 1–7, with higher scores indicating more stigma and >4 indicating some felt stigma. Felt stigma related to having epilepsy in the family was assessed through the Family Epilepsy Stigma Scale (FESS), created by replacing “epilepsy” with “epilepsy in my family” in each ESS item. Genetic attribution was assessed through participants' perceptions of the (1) role of genetics in causing epilepsy in the family, (2) chance they had an epilepsy-related mutation, and (3) (in people with epilepsy) influence of genetics in causing their epilepsy.Results
Among people with epilepsy, 22% met criteria for felt stigma (ESS score >4). Scores were increased among individuals who were aged ≥60 years, were unemployed, reported epilepsy-related discrimination, or had seizures within the last year or >100 seizures in their lifetime. Adjusting for other variables, ESS scores in people with epilepsy were significantly higher among those who perceived genetics played a “medium” or “big” role in causing epilepsy in the family than in others (3.4 vs. 2.7, p = 0.025). Only 4% of relatives without epilepsy had felt stigma. Scores in relatives were unrelated to genetic attribution.Significance
In these unusual families, predictors of felt stigma in individuals with epilepsy are similar to those in other studies, and stigma levels are low in relatives without epilepsy. Felt stigma may be increased in people with epilepsy who believe epilepsy in the family has a genetic cause, emphasizing the need for sensitive communication about genetics.
Children with epilepsy have elevated rates of behavior problems. Research findings on the impact of epilepsy surgery on children's behavior have been mixed, with some studies showing improvements in behavior 3 to 18 months after surgery and other studies finding no change within this time interval. We examined behavior in a large surgical sample and in a nonsurgical comparison group. We also examined for potential effects of epilepsy-related and cognitive/linguistic variables.Methods
Behavior was assessed by parent report in 147 children who underwent epilepsy surgery and 40 children who did not, using the Child Behavior Checklist (CBCL). For the surgical group, the CBCL was completed prior to surgery (baseline) and approximately 1 year after surgery (follow-up); ratings of the nonsurgical group were also conducted twice, at comparable intervals.Results
At baseline, the groups did not differ on age, sex, age at seizure onset, antiepileptic drugs (AEDs), or intelligence quotient (IQ). Baseline Social and Attention Problems were higher in the nonsurgical group. At follow-up, 65% of the surgical group and 20% of the nonsurgical group were seizure-free. Behavioral change was not related to surgical status or seizure outcome. Children with temporal lobe seizure focus had more Externalizing Behaviors compared to those with frontal or multilobar foci. Attention was poorer in children who underwent frontal lobe excisions relative to temporal or multilobar excisions. Baseline IQ did not predict behavioral change.Significance
Our results suggest that surgery and seizure outcome do not affect behavior in the first year following surgery; it may be the abnormal neural substrate and not seizure control that influences behavior in children with epilepsy. If changes are to occur due to seizure freedom, they may require a longer time to emerge. Some behaviors may be resistant to change in children with epilepsy or may require even longer intervals for improvement.
Latencies from intracranial seizure onset to ictal tachycardia: A comparison to surface EEG patterns and other clinical signs
Information on the relative timing of electroencephalography (EEG) seizure onset, ictal tachycardia (ITC), and first other clinical seizure manifestations is crucial for an understanding of the potential benefit of ITC-detection based closed-loop intervention systems for epilepsy treatment. This study analyzes the temporal relation of ITC, other clinical signs, and seizure onset in relation to intracranial and surface EEG.Methods
Seventy-eight seizures with ITC from 13 patients undergoing invasive EEG recordings with simultaneous recordings of electrocardiography (ECG), intracranial EEG (iEEG) and surface EEG, and video recordings to determine clinical onset were analyzed. Latencies for ITC were calculated for thresholds of 100 bpm and for a 20% heart rate increase above baseline obtained 60 s prior to seizure onset on iEEG. Patient-based, seizure-based, and seizure origin–based analyses were performed.Results
Mean latencies between seizure onset in invasive EEG and the following onset of ITC in the seizure- and patient-based analysis for both thresholds varied between 21.6 and 23.7 s, showing that ITC is an ictal rather a preictal phenomenon. In 10 of 13 patients and in 56 of 78 seizures, at least one of the thresholds for ITC was crossed before any other clinical sign. In the majority of cases, ITC also preceded ictal onset as determined in surface EEG. Latencies to ictal tachycardia were shorter for hippocampal than for extrahippocampal temporal seizure onset. ITC occurred earlier in right than in left temporal seizures.Significance
iEEG preceded other seizure manifestations, but ictal tachycardia was an early sign particularly in mesial temporal and in right temporal seizure onset and often preceded not only other clinical manifestations but also first visible patterns in surface EEG. Detection of ictal tachycardia was thus the best noninvasively assessed marker for closed-loop interventions in this multimodally assessed patient group.
The HLA-A*2402/Cw*0102 haplotype is associated with lamotrigine-induced maculopapular eruption in the Korean population
The use of lamotrigine (LTG) can be limited by the occurrence of cutaneous adverse drug reactions (cADRs) that range from maculopapular eruption (MPE) to the more severe Steven-Johnson syndrome and toxic epidermal necrolysis. A few human leukocyte antigen (HLA)–related genetic risk factors for carbamazepine-induced cADR have been identified. However, the HLA-related genetic risk factors associated with LTG-induced cADR are not yet well known. We performed HLA genotyping in 50 Korean patients with epilepsy, including 21 patients presenting LTG-induced MPE and 29 LTG-tolerant patients. A significant association between the HLA-A*2402 allele and LTG-induced MPE was identified, in comparison with the LTG-tolerant group (odds ratio [OR] 4.09, p = 0.025) and the general Korean population (OR 3.949, p = 0.005). The frequencies of the Cw*0102 or Cw*0702 alleles were significantly higher in the LTG-MPE group than in the Korean population, whereas the frequency of the A*3303 allele was lower. The coexistence of the A*2402 and Cw*0102 alleles was significantly associated with the LTG-MPE group when compared to the LTG-tolerant group (OR 7.88, p = 0.007). In addition, the Cw*0701 allele was more frequent in the LTG-tolerant group than in the Korean population. These findings suggest the presence of HLA-related genetic risk factors for LTG-induced MPE in the Korean population.