A.J.A. de Louw

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.

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

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.

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.

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

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.

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. GLIA 37:89–91, 2002.

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.

Aetiology of cognitive impairment in children with frontal lobe epilepsy

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.

Cognitive deterioration in adult epilepsy: clinical characteristics of “Accelerated Cognitive Ageing”

“Epileptic dementia” is reported in adults with childhood‐onset refractory epilepsy. Cognitive deterioration can also occur in a “second‐hit model”.

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.