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).

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.

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.

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'.

Impact of perinatal asphyxia on the GABAergic and locomotor system.

Perinatal asphyxia can cause neuronal loss and depletion of neurotransmitters within the striatum. The striatum plays an important role in motor control, sensorimotor integration and learning. In the present study we investigated whether perinatal asphyxia leads to motor deficits related to striatal damage, and in particular to the loss of GABAergic neurons. Perinatal asphyxia was induced in time-pregnant Wistar rats on the day of delivery by placing the uterus horns, containing the pups, in a 37 degrees C water bath for 20 min. Three motor performance tasks (open field, grip test and walking pattern) were performed at 3 and 6 weeks of age. Antibodies against calbindin and parvalbumin were used to stain GABAergic striatal projection neurons and interneurons, respectively. The motor tests revealed subtle effects of perinatal asphyxia, i.e. small decrease in motor activity. Analysis of the walking pattern revealed an increase in stride width at 6 weeks of age after perinatal asphyxia. Furthermore, a substantial loss of calbindin-immunoreactive (-22%) and parvalbumin-immunoreactive (-43%) cells was found in the striatum following perinatal asphyxia at two months of age. GABA(A) receptor autoradiography revealed no changes in GABA binding activity within the striatum, globus pallidus or substantia nigra. We conclude that perinatal asphyxia resulted in a loss of GABAergic projection neurons and interneurons in the striatum without alteration of GABA(A) receptor affinity. Despite a considerable loss of striatal neurons, only minor deficits in motor performance were found after perinatal asphyxia.

Apoptosis in the rat spinal cord during postnatal development; the effect of perinatal asphyxia on programmed cell death.

The aim of our study was to investigate the effect of perinatal asphyxia on developmental apoptosis in the cervical and lumbar spinal cord in the neonatal rat. Perinatal asphyxia was induced by keeping pups at term in utero in a water bath at 37 degrees C for 20 min, followed by resuscitation. Effects of this treatment on developmental apoptosis were studied on postnatal days 2, 5 and 8 using terminal deoxynucleotidyl transferase (TdT)-dUTP-biotin nick end labelling (TUNEL) and caspase-3 staining. TUNEL positive cells were identified using double immunostaining. On postnatal day 2 an increase of 215% in TUNEL positive cells was detected (P=0.005) in laminae IV-VII of the lumbar spinal cord of rats which underwent perinatal asphyxia compared to controls. An increase of 55% compared to controls (P=0.03) was seen in laminae I-III of the lumbar spinal cord at postnatal day 8. TUNEL positive cells could be partly identified as microglia cells (ED1 positive) and oligodendrocytes (O4 positive). The effect of perinatal asphyxia on programmed cell death in the neonatal rat spinal cord was mainly observed in the intermediate zone and dorsal horn of the lumbar spinal cord. We conclude that perinatal asphyxia has a pronounced effect on the survival of cells in a specific region of the spinal cord and thus may have a profound effect on the development of motor networks.

Baclofen inhibits ANP-mediated cyclic GMP synthesis in the rat cervical spinal cord.

The neurotransmitter gamma-aminobuteric acid (GABA) is believed to have a controlling action on spinal locomotor networks. In spasticity, spinal locomotor networks are thought to play a role. A well known drug in the treatment of spasticity is the GABA(B) agonist Baclofen. We report an inhibitory effect of Baclofen on the ANP-mediated cGMP synthesis in the superficial dorsal horn (laminae I-III) of the rat cervical spinal cord. This inhibitory effect of Baclofen could not be detected after incubation with the NO donor SNP. The clinical effect of Baclofen on the reduction of spasticity might be explained by an enhancement of GABAergic inhibition of ANP mediated cGMP concentration in the spinal cord dorsal horn, thus reducing afferent input.

Percutaneous radiofrequency lesion adjacent to the dorsal root ganglion in the treatment of spasticity and pain in children with cerebral palsy.

The use of percutaneous radiofrequency (RF) lesion adjacent to the dorsal root ganglion (RF-DRG) in the treatment of pain has been established for years. A relatively novel indication for RF-DRG treatment is spasticity in children with cerebral palsy. In this article the pathophysiology and management of spasticity is discussed with an emphasis on the role of RF-DRG. In the management of spasticity, RF-DRG could prove to be a little invasive treatment option with little adverse effects.

Developmental apoptosis in the spinal cord white matter in neonatal rats.

We investigated developmental apoptosis in the white matter of the cervical spinal cord at postnatal days 2, 5, and 8. Apoptotic cells were labeled using TUNEL and caspase-3 immunostaining. Apoptotic cells were diffusely distributed throughout the white matter of the spinal cord. The total amount of apoptotic cells in the cervical spinal cord white matter was related to postnatal age, with the lowest at P2 (mean 7.9, SD 5.6) and the highest at P8 (mean 109, SD 21.4). Using double immunostaining for ED-1 and O4, apoptotic cells were identified as microglia and oligodendrocytes.