Long-term characterization of cognitive phenotypes in children with seizures over 36 months.

RATIONALE: Children with new-onset epilepsies often exhibit co-morbidities including cognitive dysfunction, which adversely affects academic performance. Application of unsupervised machine learning techniques has demonstrated the presence of discrete cognitive phenotypes at or near the time of diagnosis, but there is limited knowledge of their longitudinal trajectories. Here we investigate longitudinally the presence and progression of cognitive phenotypes and academic status in youth with new-onset seizures as sibling controls. METHODS: 282 subjects (6-16 years) were recruited within 6 weeks of their first recognized seizure along with 167 unaffected siblings. Each child underwent a comprehensive neuropsychological assessment at baseline, 18 and 36 months later. Factor analysis of the neuropsychological tests revealed four underlying domains - language, processing speed, executive function, and verbal memory. Latent trajectory analysis of the mean factor scores over 36 months identified clusters with prototypical cognitive trajectories. RESULTS: Three unique phenotypic groups with distinct cognitive trajectories over the 36-month period were identified: Resilient, Average, and Impaired phenotypes. The Resilient phenotype exhibited the highest neuropsychological factor scores and academic performance that were all similar to controls; while the Impaired phenotype showed the polar opposite with the worst performances across all test metrics. These findings remained significant and stable over 36 months. Multivariate logistic regression indicated that age of onset, EEG, neurological examination, and sociodemographic disadvantage were associated with phenotype classification. CONCLUSIONS: This study demonstrates the presence of diverse latent cognitive trajectory phenotypes over 36 months in youth with new-onset seizures that are associated with a stable neuropsychological and academic performance longitudinally.

Visual-spatial memory may be enhanced with theta burst deep brain stimulation of the fornix: a preliminary investigation with four cases.

Memory loss after brain injury can be a source of considerable morbidity, but there are presently few therapeutic options for restoring memory function. We have previously demonstrated that burst stimulation of the fornix is able to significantly improve memory in a rodent model of traumatic brain injury. The present study is a preliminary investigation with a small group of cases to explore whether theta burst stimulation of the fornix might improve memory in humans. Four individuals undergoing stereo-electroencephalography evaluation for drug-resistant epilepsy were enrolled. All participants were implanted with an electrode into the proximal fornix and dorsal hippocampal commissure on the language dominant (n = 3) or language non-dominant (n = 1) side, and stimulation of this electrode reliably produced a diffuse evoked potential in the head and body of the ipsilateral hippocampus. Each participant underwent testing of verbal memory (Rey Auditory-Verbal Learning Test), visual-spatial memory (Medical College of Georgia Complex Figure Test), and visual confrontational naming (Boston Naming Test Short Form) once per day over at least two consecutive days using novel test forms each day. For 50% of the trials, the fornix electrode was continuously stimulated using a burst pattern (200 Hz in 100 ms trains, five trains per second, 100 µs, 7 mA) and was compared with sham stimulation. Participants and examiners were blinded to whether stimulation was active or not, and the order of stimulation was randomized. The small sample size precluded use of inferential statistics; therefore, data were analysed using descriptive statistics and graphic analysis. Burst stimulation of the fornix was not perceived by any of the participants but was associated with a robust reversible improvement in immediate and delayed performance on the Medical College of Georgia Complex Figure Test. There were no apparent differences on either Rey Auditory-Verbal Learning Test or Boston Naming Test. There was no apparent relationship between performance and side of stimulation (language dominant or non-dominant). There were no complications. Preliminary evidence in this small sample of patients with drug-resistant epilepsy suggests that theta burst stimulation of the fornix may be associated with improvement in visual-spatial memory.

Multiple hippocampal transections for intractable hippocampal epilepsy: Seizure outcome.

PURPOSE: The purpose of this study was to evaluate the seizure outcomes after transverse multiple hippocampal transections (MHTs) in 13 patients with intractable TLE. METHODS: Thirteen patients with normal memory scores, including 8 with nonlesional hippocampi on MRI, had temporal lobe epilepsy (TLE) necessitating depth electrode implantation. After confirming hippocampal seizure onset, they underwent MHT. Intraoperative monitoring was done with 5-6 hippocampal electrodes spaced at approximately 1-cm intervals and spike counting for 5-8min before each cut. The number of transections ranged between 4 and 7. Neuropsychological assessment was completed preoperatively and postoperatively for all patients and will be reported separately. RESULTS: Duration of epilepsy ranged between 5 and 55years. There were no complications. Intraoperatively, MHT resulted in marked spike reduction (p=0.003, paired t-test). Ten patients (77%) are seizure-free (average follow-up was 33months, range 20-65months) without medication changes. One of the 3 patients with persistent seizures had an MRI revealing incomplete transections, another had an additional neocortical seizure focus (as suggested by pure aphasic seizures), and the third had only 2 seizures in 4years, one of which occurred during antiseizure medication withdrawal. Verbal and visual memory outcomes will be reported separately. Right and left hippocampal volumes were not different preoperatively (n=12, p=0.64, Wilcoxon signed-rank test), but the transected hippocampal volume decreased postoperatively (p=0.0173). CONCLUSIONS: Multiple hippocampal transections provide an effective intervention and a safe alternative to temporal lobectomy in patients with hippocampal epilepsy.

Proposal: different types of alteration and loss of consciousness in epilepsy.

There are at least five types of alterations of consciousness that occur during epileptic seizures: auras with illusions or hallucinations, dyscognitive seizures, epileptic delirium, dialeptic seizures, and epileptic coma. Each of these types of alterations of consciousness has a specific semiology and a distinct pathophysiologic mechanism. In this proposal we emphasize the need to clearly define each of these alterations/loss of consciousness and to apply this terminology in semiologic descriptions and classifications of epileptic seizures. The proposal is a consensus opinion of experienced epileptologists, and it is hoped that it will lead to systematic studies that will allow a scientific characterization of the different types of alterations/loss of consciousness described in this article.

Language and social functioning in children and adolescents with epilepsy.

Individuals with epilepsy have difficulties with social function that are not adequately accounted for by seizure severity or frequency. This study examined the relationship between language ability and social functioning in 193 children with epilepsy over a period of 36months following their first recognized seizure. The findings show that children with persistent seizures have poorer language function, even at the onset of their seizures, than do their healthy siblings, children with no recurrent seizures, and children with recurrent but not persistent seizures. They continue to demonstrate poorer language function 36months later. This poor language function is associated with declining social competence. Intervention aimed at improving social competence should include consideration of potential language deficits that accompany epilepsy and social difficulty.

The Impact of Sociodemographic Disadvantage on Cognitive Outcomes in Children With Newly Diagnosed Seizures and Their Unaffected Siblings Over 36 Months.

BACKGROUND: Accumulating evidence indicates that children with newly diagnosed epilepsy have comorbidities including cognitive challenges. Research investigating comorbidities has focused on clinical epilepsy characteristics and neurobiological/genetic correlates. The role that sociodemographic disadvantage (SD) may play has received less attention. We investigated the role of SD in cognitive status in youth with newly diagnosed epilepsy over a follow-up of 36 months to determine the degree, extent, and duration of the role of disadvantage. METHODS: A total of 289 children (six to 16 years) within six weeks of their first seizure along with 167 siblings underwent comprehensive neuropsychological assessments (intelligence, language, memory, executive function, processing speed, and academic achievement) at baseline, 18 months later, and at 36 months from baseline. Baseline demographic information (race, caregivers education, household income, and parental marital status), clinical epilepsy characteristics (e.g., age of onset), and magnetic resonance imaging (MRI) and electroencephalographic (EEG) information was collected. RESULTS: An SD index was computed for each family and categorized into four groups by level of disadvantage. In children and siblings, the least disadvantaged group exhibited the highest Full-Scale IQ, neuropsychological factor scores, and academic performances, whereas the most disadvantaged showed the polar opposite with the worst performances across all tests. Findings remained stable and significant over 36 months. Linear regression analyses indicated that disadvantage was a more constant and stable predictor of cognitive and academic performance over time compared with clinical epilepsy characteristics and MRI/EEG abnormalities. CONCLUSIONS: This study indicates the strong association between SD and cognitive/academic performance in children with newly diagnosed epilepsy and their siblings is significant and predictive of three-year cognitive outcomes.

SCAT5 Sex Differences: Normative Data, Clinical Thresholds, and Relevance for Identification of Concussion.

OBJECTIVE: This study evaluated sex differences in performance on the Sport Concussion Assessment Tool-5 (SCAT5) Standardized Assessment of Concussion (SAC) and in baseline SCAT5 symptom reporting. It established clinically relevant cut points for low performance on the SAC based on both reliable chance indices (RCIs) and normative performance. This study also evaluated the diagnostic utility of the sex-adjusted SCAT5 SAC for identification of suspected concussion in collegiate athletes. METHOD: In total, 671 uninjured collegiate athletes were administered the SCAT5 and 264 of these athletes also completed SCAT5 testing ~1 year later. Fifty-four athletes were administered the SCAT5 after being removed from play due to suspected concussion. Sex differences in cognitive performance and symptom reporting at baseline were evaluated and sex-specific clinically relevant cut points were provided. Chi square and logistic regression models were used to evaluate if SAC performance was a significant predictor of concussion status. RESULTS: Female athletes outperformed male athletes on the SCAT 5 SAC and showed minimally higher symptom endorsement. Use of sex-corrected normative data improved performance of the SAC in identification of suspected concussion when a low score cut point was used. Logistic regression models showed that sex-corrected SAC change from baseline (RCI) improved the predictive value of the model after first accounting for other elements of the SCAT5. CONCLUSIONS: Present results support the use of sex-specific normative data for the SCAT5 SAC, particularly if using low performance without comparison to a baseline; however, reliable change from a pre-injury baseline may have somewhat higher diagnostic utility.

Cognition/Psychological Burden and Resilience in Cutaneous T-Cell Lymphoma and Psoriasis Patients: Real-Life Data and Implications for the Treatment.

Background: Psoriasis and cutaneous T-cell lymphoma (CTCL) expose patients to chronic inflammation as well as physical and psychological disabilities, but the impact of such alterations on cognitive function is unknown. Objective: This study is aimed at determining if CTCL and psoriasis impact cognitive functioning in relation to psychological and health-related quality of life (HR-QOL) status. Methods: A cross-sectional study was performed in an outpatient dermatology clinic of a university teaching hospital. Thirty-nine subjects with CTCL (N = 20) or psoriasis (N = 19) who met eligibility criteria were included. The cognitive domains of memory, attention and processing speed, and executive function were assessed with standard neuropsychological tests. Subjects were assessed for depression, anxiety, and HR-QOL (using the SKINDEX-29 questionnaire). Results: Study participants were CTCL and psoriasis subjects; cognitive impairment was found in the domain of memory in 17.9% subjects with CTCL or psoriasis. Lower scores on executive function tests were predicted by higher (worse HR-QOL) SKINDEX-29 functioning scores (p = 0.01). A higher estimated baseline intellectual functioning predicted lower scores (better HR-QOL) on the symptoms and functioning domains of SKINDEX-29 (p = 0.01 and 0.02, respectively) and a statistical trend (p = 0.07) for the emotion domain. Memory and acute anxiety were adversely impacted by shorter disease duration (p = 0.01 for both). Conclusions: Memory impairment may be associated comorbidity in CTCL and psoriasis. Subjects with stronger cognitive resources appear to cope better with health-related quality of life (HR-QOL) challenges.

Stereotactic-EEG-guided radiofrequency multiple hippocampal transection (SEEG-guided-RF-MHT) for the treatment of mesial temporal lobe epilepsy: a minimally invasive method for diagnosis and treatment.

For the treatment of mesial temporal lobe epilepsy on the language-dominant side in patients at high risk of memory decline, we propose a minimally invasive diagnostic and treatment technique, adopting the principles of multiple hippocampal transections (MHT) using stereo-electroencephalography-guided radiofrequency (SEEG-guided-RF-MHT). This new technique allows targeting of the longitudinal fibers in the hippocampus critical for seizure spreading, while sparing the transverse circuits which are considered important for memory processing and avoiding discomfort and longer post-operatory recovery time associated with craniotomies. We report the efficacy and safety of this procedure in a preliminary observational study of cases. Five patients at high risk of memory decline, including three with non-lesional hippocampi on MRI, had temporal lobe epilepsy (TLE) necessitating depth electrode implantation. A new strategy of SEEG electrode placement was used to mimic MHT. After confirming hippocampal seizure onset, all the patients had three linear ablations perpendicular to the amigdalohippocampal complex. The procedure was performed at the patient's bedside with the patient awake during the full length of the procedure. Four out of five patients were seizure-free (average follow up: 14-18 months). There were no associated complications. Visual inspection of brain MRI of patients at six months following SEEG-guided RF-MHT showed significant hippocampal volume preservation. Subjects who received the procedure in the dominant side reported no subjective memory complaints in the follow-up clinic assessments at six months. Our preliminary seizure outcome seems very promising since the majority of our patients (four out of five patients) were seizure-free. Since no lesions are made outside the amygdalo-hippocampal complex using this technique and the temporal stem remains intact, more favorable memory and language outcome is expected in patients at high risk of memory decline.

Self-esteem and symptoms of depression in children with seizures: relationships with neuropsychological functioning and family variables over time.

PURPOSE: To test over time the relationships of neuropsychological functioning to mental health in children following a first recognized seizure and, of primary importance, to determine if the strength of these relationships differs based on risk and protective factors. METHODS: In a larger prospective study, 135 children with a first seizure (ages 8-14 years) and 73 healthy sibling controls completed neuropsychological testing at baseline and 36 months. Structured telephone interviews were used to obtain data from children on mental health and family environment; major caregiving parents provided data on demographic and family variables. Data analyses included correlation coefficients and linear regression models. RESULTS: Children with seizures showed an overall trend for improvement in mental health. More children with seizures than siblings had declines in processing speed. Declines in neuropsychological functioning were correlated with worse mental health. With regard to risk and protective factors, higher parent education protected against decline in self-esteem related to decline in processing speed. Better family functioning and greater parental support protected against decline in self-esteem related to decrease in verbal memory and learning. Older child age protected against increase in depressive symptoms related to decline in processing speed. DISCUSSION: Seizure onset had a negative impact on mental health in children with declines in cognitive functioning except for older children and those with more family resources. Children should be assessed for declines in processing speed and, if found, those subgroups of children with less educated or more anxious parents and those in less supportive families should be targeted for interventions.

The relationship of neuropsychological functioning to adaptation outcome in adolescents with spina bifida.

Adolescents with spina bifida (SB) vary in their ability to adapt to the disease, and it is likely that numerous risk and protective factors affect adaptation outcomes. The primary aim was to test neuropsychological impairment, exemplified herein by executive dysfunction, as a risk factor in the Ecological Model of Adaptation for Adolescents with SB. Specific hypotheses were that: (1) executive functioning predicts the adaptation outcome of functional independence in adolescents with SB; (2) executive functioning mediates the impact of neurological severity on functional independence; and (3) family and adolescent protective factors are related to functional independence and moderate the relationship between executive functioning and functional independence. Forty-three adolescents aged 12-21 years completed neuropsychological measures and an interview that assessed risk, adolescent and family protective factors, and functional independence. Age, level of lesion, executive functioning, and the protective factor adolescent activities were significantly correlated with the functional independence outcome. In hierarchical regression analysis, the model accounted for 61% of the variance in functional independence outcomes. Executive functioning mediated the impact of neurological severity on functional independence.

The relationship between sleep problems and neuropsychological functioning in children with first recognized seizures.

Epilepsy is associated with sleep disturbance, but little is known about how early this relationship develops and how it affects neuropsychological functioning. This study documented the frequency and types of sleep problems and examined how sleep problems are associated with seizures and neuropsychological functioning in 332 children following their first recognized seizure (ages 6-14) and in 225 sibling controls. Formal neuropsychological batteries were administered to all subjects. Sleep was measured using the Sleep Behavior Questionnaire and the Child Behavior Checklist. Sleep problems were more frequent in the seizure sample relative to siblings and previously published norms; bedtime difficulties, daytime somnolence, and parasomnias were the most frequently occurring sleep problems. In the seizure group, sleep problems were related to seizure parameters and to neuropsychological functioning. Seizure patients with significant sleep problems had worse neuropsychological functioning on all measures. Findings demonstrate the significant impact of sleep disturbance on children with newly recognized seizures.

Magnetic resonance imaging findings in children with a first recognized seizure.

This study characterized structural abnormalities associated with onset of seizures in children, using magnetic resonance imaging and a standardized classification system in a large prospective cohort. Two hundred eighty-one children aged 6-14 years completed magnetic resonance imaging within 6 months of their first recognized seizure. Most examinations were performed with a standardized, dedicated seizure protocol; all were scored using a standard scoring system. At least one magnetic resonance imaging abnormality was identified in 87 of 281 (31%) children with a first recognized seizure. Two or more abnormalities were identified in 34 (12%). The commonest abnormalities were ventricular enlargement (51%), leukomalacia/gliosis (23%), gray-matter lesions such as heterotopias and cortical dysplasia (12%), volume loss (12%), other white-matter lesions (9%), and encephalomalacia (6%). Abnormalities defined as significant, or potentially related to seizures, occurred in 40 (14%). Temporal lobe and hippocampal abnormalities were detected at a higher frequency than in previous studies (13/87). Magnetic resonance imaging and a standardized, reliable, valid scoring system demonstrated a higher rate of abnormal findings than previously reported, including findings formerly considered incidental. Practice parameters may need revision, to expand the definition of significant abnormalities and support wider use of magnetic resonance imaging in children with newly diagnosed seizures.

Academic underachievement among children with epilepsy: proportion exceeding psychometric criteria for learning disability and associated risk factors.

This study assessed rates of learning disabilities (LD) by several psychometric definitions in children with epilepsy and identified risk factors. Participants (N = 173, ages 8-15 years) completed IQ screening, academic achievement testing, and structured interviews. Children with significant head injury, chronic physical conditions, or mental retardation were excluded. Using an IQ-achievement discrepancy definition, 48% exceeded the cutoff for LD in at least one academic area; using low-achievement definitions, 41% to 62% exceeded cutoffs in at least one academic area. Younger children with generalized nonabsence seizures were at increased risk for math LD using the IQ-achievement discrepancy definition; age of seizure onset and attention-deficit/hyperactivity disorder (ADHD) were risk factors for reading and math LD using low-achievement definitions. Writing was the most common domain affected, but neither ADHD nor seizure variables reliably identified children at risk for writing LD. Although children with earlier seizure onset, generalized nonabsence seizures, and comorbid ADHD appear to be at increased risk for some types of LD by some definitions, these findings largely suggest that all children with epilepsy should be considered vulnerable to LD. A diagnosis of epilepsy (even with controlled seizures and less severe seizure types) should provide sufficient cause to screen school-age children for LD and comorbid ADHD.

Resection of Temporal Neocortex During Multiple Hippocampal Transections for Mesial Temporal Lobe Epilepsy Does not Affect Seizure or Memory Outcome.

BACKGROUND: Multiple hippocampal transection (MHT) is a surgical treatment for mesial temporal lobe epilepsy associated with improved postoperative neuropsychological outcomes compared with lobectomy. OBJECTIVE: To determine whether resection of the amygdala and anterior temporal neocortex during MHT affects postoperative seizure/memory outcome. METHODS: Seventeen patients with normal magnetic resonance imaging and stereo-electroencephalogram-proven drug-resistant dominant mesial temporal lobe epilepsy were treated with MHT. Nine patients underwent MHT alone (MHT-) and 8 patients underwent MHT plus removal of the amygdala and anterior 4.5 cm of temporal neocortex lateral to the fusiform gyrus (MHT+). Verbal and visual-spatial memory were assessed in all patients preoperatively and in 14 patients postoperatively using the Wechsler Memory Scale. Postoperative seizure control was assessed at 12 months for all patients. RESULTS: Overall, 11 of 17 patients (64.7%) were Engel class 1 at 1 year (6/9 MHT-, 5/8 MHT+, P = .38), and 10 of 14 patients (71.4%) had no significant postoperative decline in either verbal or visual memory (6/8 MHT-, 4/6 MHT+, P = .42). Verbal memory declined in 2 of 8 MHT- and 1 of 6 MHT+ patients, and visual memory declined in 1 of 8 MHT- and 2 of 6 MHT+ patients. Two patients had improved visual memory postoperatively, both in the MHT+ group. CONCLUSION: MHT on the dominant side is associated with high rates of seizure freedom and favorable memory preservation outcomes regardless of the extent of neocortical resection. Preservation of the temporal neocortex and amygdala during MHT does not appear to decrease the risk of postoperative memory decline, nor does it alter seizure outcome.

Neuropsychological correlates of electroencephalograms in children with epilepsy.

INTRODUCTION: This study examined the degree to which neurophysiological activity on routine clinical EEG is associated with neuropsychological deficiencies in children with epilepsy. METHODS: Ninety-five children with epilepsy (58 chronic, 37 recent-onset; mean age = 10.41 years, S.D. = 2.87 years; mean age at onset = 5.86 years, S.D. = 3.46 years) completed a neuropsychological battery. Neurophysiological data were collected from the most recent EEG. RESULTS: In the recent-onset sample, no neuropsychological scores were related to any EEG variable. In the chronic sample, however, presence of slow-wave activity was related to memory impairment (p < 0.01). Post-hoc analyses on other neuropsychological measures showed localization of epileptiform activity (EA) might be related to verbal learning. DISCUSSION: Children with slow-wave activity on EEG might be at increased risk for developing neuropsychological deficits. When these abnormalities are observed on a child's EEG, closer monitoring of cognitive and academic functioning seems warranted. Differences between these findings and past research suggest that conclusions drawn from adult surgical studies cannot be generalized to pediatric patients, especially recent-onset samples, without qualification. Differences between the recent-onset and chronic samples in this cross-sectional study raise the possibility that neurophysiological abnormalities have a cumulative effect on cognitive development.

Test-retest reliability of the Extended Complex Figure Test--Motor Independent administration (ECFT-MI).

The Extended Complex Figure Test (ECFT; Fastenau, 1996b, 2003a), adds recognition and matching trials to the Rey-Osterrieth Complex Figure Test (ROCFT). An alternate administration of the ECFT, the ECFT-Motor Independent version (ECFT-MI; Fastenau, 2003a) measures visuospatial memory without the motoric demands of the ROCFT. ECFT-MI test-retest reliabilities were examined in 55 healthy adults tested two times separated by one week. The Recognition Trial showed strong reliability for the Total Score (r = .80, p < .0001). Reliabilities for Recognition Detail Scale and Subscales (r = .62-.74, p < .0001) and for the Global Scale (r = .51, p < or = .005) were attenuated by fewer items per subscale but were comparable to other memory tests. Matching Trial reliability coefficients were attenuated by extreme ceiling effects and restriction of range, but scores were very consistent between the two administrations. This study supports the temporal stability of the ECFT-MI.