Accelerated Cognitive Ageing in epilepsy: exploring the effective connectivity between resting-state networks and its relation to cognitive decline.

OBJECTIVE: This study aims at understanding the dynamic functional brain organization in Accelerated Cognitive Ageing (ACA) in epilepsy. We also assess to which extend the (abnormal) effective connectivity between brain networks correlates with the (estimated) decline in IQ scores observed in the ACA patients. MATERIAL AND METHODS: Two multi-echo resting-state fMRI scans of 10 ACA patients and 14 age- and education-matched healthy controls were acquired. A task-based fMRI was acquired in-between those two scans, for possible cognitive fatigue effects on reserve capacity. Granger causality (GC), a measure of effective connectivity between brain regions, was applied on 7 major cognitive networks, and group-wise compared, using permutation testing statistics. This was performed on each of the resting-state sessions independently. We assessed the correlation between the cognitive deterioration scores (representing cognitive decline), and the paired-networks granger causality values. RESULTS: The cingulate cortex appeared to be more engaged in ACA patients. Its dynamics towards the right fronto-parietal cortex, salience network, and the dorsal attention networks (DAN) was stronger than in controls, only in the first resting-state scan session. The Granger causality from the DAN to the default mode network (DMN) and from the ventral attention network (VAN) to the left fronto-parietal network (FPL) was also stronger in ACA patients and again only in the first scans. In the second resting-state scans, only the DMN was more strongly connected with the cingulate cortex in ACA patients. A weaker GC from DMN to FPL, and stronger GC from the salience network to cingulate cortex were associated with more decline in the Full-scale IQ and more GC from DMN to VAN would lead to more decline in the Perceptual Reasoning Index in ACA. CONCLUSION: The results are in line with the hypothesis of over-recruitment at low cognitive load, and exhaustion at higher cognitive load, as shown by the compensation-related utilization of neural circuits hypothesis (CRUNCH) model for ageing. Moreover, the DMN to VAN directed connectivity strongly correlates with the (estimated) decline in the Perceptual Reasoning Index, which is also in line with a recent study on ageing with mild cognitive impairment in elderly, and the posterior-anterior shift in aging (PASA) model. This study therefore supports the idea that the cognitive decline in our patients resembles the decline observed in healthy ageing, but in an accelerated mode. This study also sheds light on the directions of the impaired connectivity between the main networks involved in the deterioration process, which can be helpful for future development of treatment solutions.

Failed transition to independence in young adults with epilepsy: The role of loneliness.

PURPOSE: Many young adults with epilepsy are still living with their parents ('failed transition to independence') despite reaching the adult age. This study evaluated patient-related variables and measures of loneliness correlated to 'failed transition to independence' in adults, 25-30 years of age, with (childhood-onset) epilepsy. METHODS: Patients with (childhood-onset) epilepsy and 25-30 years of age were recruited from Epilepsy Center Kempenhaeghe. Inclusion criteria were: diagnosis of (childhood-onset) epilepsy, and an (estimated) IQ > 70. Patients were sent one questionnaire and informed consent was obtained from all participants. Questions included the patient's level of functioning and satisfaction on three transitional domains (medical status, educational/vocational status, independence/separation from their parents), satisfaction with their friendships, and the validated De Jong-Gierveld Loneliness Scale. 'Transition to independence' was defined and categorized in a continuum with scores ranging from 0 ('Failed transition') to 4 for all patients. A Bivariate Correlation analysis was used to compute correlations between patient characteristics and failed transition to independence. RESULTS: 59 patients were included in the analysis, of which 19 (32.2%) had a failed transition to independence. A statistically significant correlation was found between transition to independence and the social loneliness scale (p =  0.047) and the total loneliness scale (p =  0.04), and for the patients self-reported satisfaction with their independence/separation from parents (p =  0.01) and friendships (p =  0.04). CONCLUSIONS: Adults with epilepsy with a failed transition to independence experience loneliness and are not satisfied with their current developmental and social situation.

A randomized controlled trial of the ketogenic diet in refractory childhood epilepsy.

OBJECTIVE: To evaluate the efficacy and tolerability of the ketogenic diet (KD) during the first 4 months of a randomized controlled trial (RCT) in refractory epilepsy patients aged 1-18 years. METHODS: Children and adolescents with refractory epilepsy, not eligible for epilepsy surgery, were included. Following 1 month at baseline, patients were randomized to either the KD or to care as usual (CAU).Primary outcome is the proportion of patients with at least 50% reduction in seizure frequency at 4 months. Secondary outcomes are mean percentage of baseline seizures, seizure severity, and side effects. RESULTS: Fifty-seven patients were randomized; nine dropped out, leaving 48 for analysis (i.e., 26 KD, 22 CAU). In an intention-to-treat analysis, 13 patients (50%) treated with the KD and four patients (18.2%) of the CAU group were responders.Mean seizure frequency at 4 months compared to baseline, after removal of two outliers in the KD group, was significantly lower (P = 0.024) in the KD group (56%) (95% CI: 36-76) than in the CAU group (99%) (95% CI: 65-133%).Twice as many patients in the KD group had a relevant decrease in seizure severity score (P = 0.070).Patients treated with the KD had a significantly higher score for gastrointestinal symptoms (P = 0.021) without an increase in the total score of side effects. CONCLUSIONS: This trial provides class I evidence that the KD is an effective therapy in children and adolescents with refractory epilepsy compared with CAU. Most often reported side effects are gastrointestinal symptoms.The study has been registered with the Netherlands Trial Registry (NTR2498).

Cognitive deterioration in adult epilepsy: clinical characteristics of "Accelerated Cognitive Ageing".

OBJECTIVES: "Epileptic dementia" is reported in adults with childhood-onset refractory epilepsy. Cognitive deterioration can also occur in a "second-hit model". MATERIALS AND METHODS: We studied the clinical and neuropsychological characteristics of patients with cognitive deterioration (≥1 SD discrepancy between current IQ and premorbid IQ). Memory function, reaction time and processing speed were also evaluated. Analyses were performed to investigate which clinical characteristics correlated with cognitive deterioration. RESULTS: Twenty-seven patients were included with a mean age of 55.7 years old, an average age at epilepsy onset of 33.9 years and a mean duration of 21.8 years. Over 40% had experienced at least one status epilepticus. About 77.8% had at least one comorbid disease (most of (cardio)vascular origin). Cognitive deterioration scores were significant for both Performance IQ and Full Scale IQ, but not for Verbal IQ. Impairments in fluid functions primarily affected the IQ-scores. Memory was not impaired. Epilepsy factors explained 7% of the variance in deterioration, whereas 38% was explained by relatively low premorbid IQ and educational level, high age at seizure onset and older age. CONCLUSIONS: A subgroup of patients with localization-related epilepsy exhibits cognitive decline characterized by deterioration in PIQ and FSIQ, but with preserved higher order functions (VIQ and memory). Patients typically have epilepsia tarda, comorbid pathology, relatively low educational level and older age. These are factors known to increase the vulnerability of the brain by diminishing cognitive reserve. Cognitive deterioration may develop according to a stepwise "second-hit model", affecting and accelerating the cognitive ageing process.

Long-term effects of a multidisciplinary transition intervention from paediatric to adult care in patients with epilepsy.

PURPOSE: To evaluate the long-term effects of a multidisciplinary transition intervention compared to the impact of patient-related intrinsic factors on the improvement in medical and psychosocial outcome. METHODS: All patients who visited our multidisciplinary Epilepsy Transition Clinic between March 2012 and September 2014 were invited to participate (n=114). Patients were sent one questionnaire and informed consent was obtained. Questions included the patient's level of functioning on three transitional domains and a list with medical health care workers. Previously defined scores on three transitional domains and the risk profile score were re-evaluated. Past and current patient characteristics were compared using descriptive statistics. Discriminant analyses were used to determine the influence of patient-related intrinsic factors (defined as the risk factors from our previous study) and a multidisciplinary transition intervention on the improvement of medical and psychosocial outcome. RESULTS: Sixty-six out of 114 invited participants (57.9%) completed the questionnaire. Discriminant analyses showed that the patient-related intrinsic factors combined proved a strong predictor for improvement in medical outcome (72.7%) and relatively strong for educational/vocational outcome (51.5%). The transition interventions are a relative strong predictor of improvement in medical outcome (56.1%), educational/vocational outcome (53.0%) and improvement in the overall risk score (54.5%). CONCLUSION: Based on the overall improvement of psychosocial outcome in most patients, and the influence of a transition intervention on medical, educational/vocational outcome and the overall risk score, it is likely that adolescents with epilepsy benefit from visiting a multidisciplinary epilepsy transition clinic.

Technical aspects of neurostimulation: Focus on equipment, electric field modeling, and stimulation protocols.

Neuromodulation is a field of science, medicine, and bioengineering that encompasses implantable and non-implantable technologies for the purpose of improving quality of life and functioning of humans. Brain neuromodulation involves different neurostimulation techniques: transcranial magnetic stimulation (TMS), transcranial direct current stimulation (tDCS), vagus nerve stimulation (VNS), and deep brain stimulation (DBS), which are being used both to study their effects on cognitive brain functions and to treat neuropsychiatric disorders. The mechanisms of action of neurostimulation remain incompletely understood. Insight into the technical basis of neurostimulation might be a first step towards a more profound understanding of these mechanisms, which might lead to improved clinical outcome and therapeutic potential. This review provides an overview of the technical basis of neurostimulation focusing on the equipment, the present understanding of induced electric fields, and the stimulation protocols. The review is written from a technical perspective aimed at supporting the use of neurostimulation in clinical practice.

Cognitive deterioration in adult epilepsy: Does accelerated cognitive ageing exist?

A long-standing concern has been whether epilepsy contributes to cognitive decline or so-called 'epileptic dementia'. Although global cognitive decline is generally reported in the context of chronic refractory epilepsy, it is largely unknown what percentage of patients is at risk for decline. This review is focused on the identification of risk factors and characterization of aberrant cognitive trajectories in epilepsy. Evidence is found that the cognitive trajectory of patients with epilepsy over time differs from processes of cognitive ageing in healthy people, especially in adulthood-onset epilepsy. Cognitive deterioration in these patients seems to develop in a 'second hit model' and occurs when epilepsy hits on a brain that is already vulnerable or vice versa when comorbid problems develop in a person with epilepsy. Processes of ageing may be accelerated due to loss of brain plasticity and cognitive reserve capacity for which we coin the term 'accelerated cognitive ageing'. We believe that the concept of accelerated cognitive ageing can be helpful in providing a framework understanding global cognitive deterioration in epilepsy.

Evaluation of a multidisciplinary epilepsy transition clinic for adolescents.

INTRODUCTION: The main goal of the transition clinic is to explore and optimize medical issues during transition from adolescence to adulthood, and to ease the transition into adult care. However, only limited data on the process and outcomes of transitional care in clinical practice are available. OBJECTIVE: To describe the process and outcomes of an Epilepsy Transition Clinic in a tertiary referral center in The Netherlands. METHODS: Data were collected from patients with epilepsy (aged 15-25 years), who visited the transition clinic between March 2012 and September 2014. RESULTS: The Epilepsy Transition Clinic is staffed with a multidisciplinary team including a neurologist/epileptologist, clinical neuropsychologist, a social worker and an educationalist/occupational counselor, all with knowledge of paediatric and adult medical and developmental issues. In total, 117 patients with epilepsy were included in the analysis. After consultation, 89 patients received a diagnostic work-up (76.1%), change in AED prescription (n = 64, 54.7%), or consultation/tailored advice (n = 73, 62.4%). In fourteen patients (12.0%) the epilepsy diagnosis was changed. Nineteen patients (16.2%) had complete epilepsy remission for over one year. Forty-three patients (36.8%) were referred to adult care. CONCLUSION: This study describes a multidisciplinary epilepsy transition clinic staffed by a neurologist/epileptologist, neuropsychologist, a social worker and an educationalist/occupational counselor. Diagnostic work-up and evaluation of psychosocial and educational/vocational status during adolescence are strongly recommended.

Developing from child to adult: Risk factors for poor psychosocial outcome in adolescents and young adults with epilepsy.

INTRODUCTION: Childhood-onset epilepsy during the years of transition to adulthood may affect normal social, physical, and mental development, frequently leading to psychosocial and health-related problems in the long term. OBJECTIVE: This study aimed to describe the main characteristics of patients in transition and to identify risk factors for poor psychosocial outcome in adolescents and young adults with epilepsy. METHODS: Patients with epilepsy, 15-25years of age, who visited the Kempenhaeghe Epilepsy Transition Clinic from March 2012 to December 2014 were included (n=138). Predefined risk scores for medical, educational/occupational status, and independence/separation/identity were obtained, along with individual risk profile scores for poor psychosocial outcome. Multivariate linear regression analysis and discriminant analysis were used to identify variables associated with an increased risk of poor long-term psychosocial outcome. RESULTS: Demographic, epilepsy-related, and psychosocial variables associated with a high risk of poor long-term outcome were lower intelligence, higher seizure frequency, ongoing seizures, and an unsupportive and unstable family environment. Using the aforementioned factors in combination, we were able to correctly classify the majority (55.1%) of the patients regarding their risk of poor psychosocial outcome. CONCLUSION: Our analysis may allow early identification of patients at high risk of prevention, preferably at pretransition age. The combination of a chronic refractory epilepsy and an unstable family environment constitutes a higher risk of transition problems and poor outcome in adulthood. As a consequence, early interventions should be put into place to protect youth at risk of poor transition outcome.

Carbamazepine and oxcarbazepine in adult patients with Dravet syndrome: Friend or foe?

PURPOSE: In newly diagnosed patients with Dravet syndrome sodium channel blockers are usually avoided. However, in many adult patients the diagnosis was made long after the initiation of therapy. The purpose of our study was to acquire information concerning the potential risks and benefits of (ox)carba(ma)zepine withdrawal in adult patients with genetically confirmed Dravet syndrome. METHOD: We identified 16 adults with Dravet syndrome, living in a tertiary care facility for people with epilepsy and an intellectual disability. We reviewed clinical history, genetic findings, the type and duration of sodium channels blockers that were used, seizure types and frequency, and the effect of a change in these medications. RESULTS: The study population consisted of 9 men and 7 women. Median age was 35 years (range 20-61 years). An attempt to withdraw carbamazepine (CBZ) was made in 9 patients. In 3 of these patients an increase in tonic-clonic seizures was observed. An attempt to withdraw oxcarbazepine (OXC) was made in 3 patients, leading to a complete stop in 2 patients. 3 of the 4 deaths in the withdrawal-group were related to epilepsy. CONCLUSION: In adult patients with Dravet syndrome withdrawal of CBZ or OXC is not without risks. We suggest that (ox)carba(ma)zepine withdrawal should be considered in these patients but only if there is a good reason to do so and only if they are closely monitored.

Effect of "Touch Rugby" Training on the Cardiovascular Autonomic Control In Sedentary Subjects.

This study aimed to explore the effects of "touch-rugby" training on the cardiovascular autonomic control in sedentary subjects. 22 adults (30-64 years old) were included in this study. Before (pre-test) and after (post-test) the period of training, cardio-respiratory recordings were achieved at rest and during a graded maximal exercise on a treadmill. The Smoothed-Pseudo-Wigner-Ville Distribution provided instantaneous time frequency components of RR intervals and systolic blood pressure variability in low- and high-frequency bands. The baroreflex sensitivity was assessed in low-frequency and high-frequency bands. Between pre-test and post-test, resting heart rate (74±10 vs. 69±12 beats.min(-1), p<0.05) and systolic blood pressure (118±19 vs. 103±22 mm Hg, p<0.01) decreased. Root mean square of successive differences (34.6±30.1 vs. 47.6±34.8 ms, p<0.001), high-frequency RR variability (590±288 vs. 1262±767 ms², p<0.001) increased whereas low-frequency/high-frequency ratio decreased (3.5±3.4 vs. 1.5±0.9, p<0.05). The high-frequency baroreflex sensitivity increased (13.4±10.1 vs. 26.0±20.9 ms.mmHg(-1), p<0.05). Playing touch rugby with one session weekly over 3 months modified the cardiovascular autonomic control of sedentary subjects. A decrease in the sympathetic tone combined with both an increase in the vagal tone and a decrease in systolic blood pressure at rest were observed. Therefore, such training appears to be beneficial to cardiac health.

Transition to adult medical care for adolescents with epilepsy.

INTRODUCTION: During transition to adult medical care, the adolescent with epilepsy is especially prone to emotional, mental, physical, and social developmental difficulties, leading to stigma and poor psychosocial and socioeconomic outcome in the long term. OBJECTIVES: The aim of this review is twofold: to describe the psychosocial and medical transition from adolescence to adulthood and to evaluate the most effective model for transitional services in adolescents with epilepsy. METHODS: We searched PubMed for quantitative and qualitative data about transition from adolescence to adulthood in patients with epilepsy. RESULTS: A total of 49 articles were retrieved. We reviewed personal, psychosocial, and medical issues during transition and their long-term individual and societal consequences. Identifying risk factors for poor transition can lead to appropriate interventions for patients and their family. Although the concept of multidisciplinary transition care for adolescents with epilepsy is widely recognized, only a few transition clinics have been established. There is lack of evidence for their quality and cost-effectiveness. CONCLUSION: In addition to medical problems, more attention should be paid to the risk of psychosocial problems during transition from pediatric to adult care. The implementation of transition care for adolescents with epilepsy is considered beneficial; however, its effectiveness should be further investigated.

Cognitive effects of lacosamide as adjunctive therapy in refractory epilepsy.

BACKGROUND: Lacosamide (LCM) is a novel antiepileptic drug (AED) with potential benefit as adjunctive treatment in patients with partial-onset seizures. As yet, limited information on cognitive effects of LCM is available, especially in real-life settings. AIMS: In this open clinical prospective study, the cognitive effects of LCM were evaluated when used as adjunctive antiepileptic therapy in patients with refractory epilepsy. METHODS: We included 33 patients aged between 16 and 74 years (mean: 37 years). All patients had a localization-related epilepsy. Patients were assessed at baseline before starting LCM treatment and during follow-up when the optimal clinical dose was achieved. MATERIALS: Subjective complaints were evaluated using the SIDAED; effects on cognition were evaluated using the computerized visual searching task (CVST). RESULTS: The CVST showed significant faster information processing reaction times at the second evaluation (P = 0.013), which was not correlated with seizure control, type of epilepsy, age, gender, drug load, number of concomitant drugs, dose or duration of LCM treatment. On the SIDAED, patients complained more about their cognitive function at the second evaluation (P = 0.005). For the SIDAED, a positive correlation at follow-up was found between the total severity score and higher age (r = 0.375, P = 0.031), but not with epilepsy factors or treatment characteristics. DISCUSSION/CONLUSION: Screening of the cognitive effects of LCM showed that LCM does not have negative effects on information processing speed. As this is the most sensitive function for cognitive side effects of AEDs, LCM does not seem to induce the common negative cognitive effects. Remarkably, patients complained more, especially about their cognitive function, which is possible the 'doing better, feeling worse phenomenon'.

Aetiology of cognitive impairment in children with frontal lobe epilepsy.

OBJECTIVES: Cognitive impairment is frequent in children with frontal lobe epilepsy (FLE), but its aetiology is unknown. MRI scans often reveal no structural brain abnormalities that could explain the cognitive impairment. This does not exclude more subtle morphological abnormalities that can only be detected by automated morphometric techniques. AIMS: With these techniques, we investigate the relationship between cortical brain morphology and cognitive functioning in a cohort of children with FLE and healthy controls. MATERIALS AND METHODS: Thirty-four children aged 8-13 years with FLE of unknown cause and 41 healthy age-matched controls underwent neuropsychological assessment and structural brain MRI. Patients were grouped as cognitively impaired or unimpaired. Intracranial volume, white matter volume, lobular cortical volume, cortical thickness and volumes of cortex structures were compared between patients and controls, and potential correlations with cognitive status were determined. RESULTS: The group of cognitively impaired children with FLE had significantly smaller left temporal cortex volumes, specifically middle temporal grey matter volume and entorhinal cortex thickness. In addition, cognitively impaired children with FLE had smaller volumes of structures in the left and right frontal cortex, right temporal cortex and the left subcortical area. CONCLUSION: Cognitively impaired children with FLE have smaller volumes of various cortex structures within the frontal lobes and in extra-frontal regions, most notably temporal cortex volumes. These findings might well explain the broad scale of cognitive domains affected in children with FLE complicated by cognitive impairment and highlight that FLE impacts on areas beyond the frontal lobe.

Early intensive care unit-acquired hypernatremia in severe sepsis patients receiving 0.9% saline fluid resuscitation.

BACKGROUND: Intensive care unit (ICU)-acquired hypernatremia is associated with increased mortality and ascribed to excessive sodium/insufficient free water intakes. We aimed to determine whether the volume of intravenous 0.9% saline fluid resuscitation was associated with hypernatremia in severe sepsis. METHODS: We retrospectively reviewed the charts of patients admitted to our medical ICU over 1 year with severe sepsis, and recorded all fluid intakes and plasma sodium levels (Nap ) for 5 days along with clinical data. ΔNap was defined as the difference between maximal Nap reached and initial Nap . Hypernatremia was defined as Nap > 145 mmoles/l. RESULTS: Among 95 patients with severe sepsis, 29 developed hypernatremia within 5 days (31%), reaching a maximum Nap of 149.1 ± 2.5 mmoles/l on average 3.8 ± 1.5 days after admission. For every 50-ml/kg increase in 0.9% saline intake for the first 48 h, the odds of hypernatremia were 1.61 times larger [confidence interval (CI): 0.98-2.62; P = 0.06] and the mean of ΔNap increased by 1.86 mmoles/l (CI: 0.86-2.86; P < 0.001). Compared with non-hypernatremic patients, hypernatremic patients received more 0.9% saline within the first 48 h (111 ± 50 ml/kg vs. 92 ± 42 ml/kg, P < 0.05) and more other fluids from 48 to 96 h (64 ± 38 ml/kg vs. 42 ± 24 ml/kg, P < 0.05). Patients developing hypernatremia had increased length of mechanical ventilation (12.0 ± 12.6 vs. 9.1 ± 7.2 days, P < 0.05) and ICU mortality (38.5% vs. 13%, P < 0.01). CONCLUSIONS: Early acquired hypernatremia is a frequent complication in severe sepsis patients and is associated with the volume of 0.9% saline received during the first 48 h of admission.

Pediatric frontal lobe epilepsy: white matter abnormalities and cognitive impairment.

OBJECTIVES: Cognitive impairment is frequent in children with frontal lobe epilepsy (FLE). Its etiology remains unknown. With diffusion tensor imaging, we have studied cerebral white matter properties and associations with cognitive functioning in children with FLE and healthy controls. METHODS: Thirty children aged 8-13 years with FLE of unknown cause and 39 healthy age-matched controls underwent neuropsychological assessment, structural and diffusion-weighted brain MRI. Patients were grouped as cognitively impaired or unimpaired, and their white matter diffusion properties were compared with the controls. RESULTS: Children with FLE had reduced apparent diffusion coefficients in various posteriorly located tract bundles, a reduced fractional anisotropy (FA) of the white matter tract between the right frontal and right occipital lobe, and smaller volumes of several collections of interlobar bundle tracts, compared with controls. The cognitively impaired patient group demonstrated significant increases in FA of the white matter of both occipital lobes, a reduced FA of white matter tract bundles between the right frontal and both left occipital lobe and subcortical white matter area, and smaller volumes of two collections of tract bundles connecting the frontal lobe with the temporal and parietal lobes, compared with controls. CONCLUSIONS: Children with FLE had white matter abnormalities mainly in posterior brain regions, not confined to the area of the seizure focus. Cognitively impaired children with FLE showed the most pronounced white matter abnormalities. These possibly reflect disturbed maturation and might be part of the etiology of the cognitive impairment.

Hypocapnia-dependent facilitation of augmented breaths: observations in awake vs. anesthetized rats.

We investigated whether commonly used injectable laboratory anesthetics alter the regulation of augmented breaths (ABs) in different respiratory backgrounds. Male rats were studied on three separate experimental days, receiving one of three injections in randomized order: ethyl carbamate ('urethane'; 1.2mgkg(-1)), ketamine/xylazine (ket/xyl; 80/10mgkg(-1)), or normal saline. Following each of the three interventions, breathing was monitored during 15min exposures to normoxia (room air), hypoxia (10% O(2)) and hypoxia+CO(2) (10% O(2), 5% CO(2)). Urethane anesthesia completely eliminated ABs from the breathing rhythm in room air conditions (p<0.001), and decreased the hypocapnia-dependent component of this response (p<0.001). ket/xyl left the normal incidence of ABs in room air breathing intact but significantly suppressed the hypoxia-induced facilitation of ABs (p=0.0015). These results provide the first clear evidence that laboratory anesthesia can profoundly alter the regulation of ABs including the hypocapnia-dependent component of their facilitation.