Maria Dahlin

The Circulating Metabolic Regulator FGF21 Is Induced by Prolonged Fasting and PPARα Activation in Man

FGF21 is a critical metabolic regulator, pivotal for fasting adaptation and directly regulated by PPARalpha in rodents. However, the physiological role of FGF21 in man is not yet defined and was investigated in our study. Serum FGF21 varied 250-fold among 76 healthy individuals and did not relate to age, gender, body mass index (BMI), serum lipids, or plasma glucose. FGF21 levels had no diurnal variation and were unrelated to bile acid or cholesterol synthesis. Ketosis induced by a 2 day fast or feeding a ketogenic diet (KD) did not influence FGF21 levels, whereas a 74% increase occurred after 7 days of fasting. Hypertriglyceridemic nondiabetic patients had 2-fold elevated FGF21 levels, which were further increased by 28% during fenofibrate treatment. FGF21 circulates in human plasma and increases by extreme fasting and PPARalpha activation. The wide interindividual variation and the induction of ketogenesis independent of FGF21 levels indicate that the physiological role of FGF21 in humans may differ from that in mice.

Plasma phospholipid fatty acids are influenced by a ketogenic diet enriched with n-3 fatty acids in children with epilepsy

The ketogenic diet (KD) is used to treat medically refractory epilepsy in children. Alterations of fatty acid (FA) levels may reflect one mechanism of action. We examined the influence of the KD on FA levels and seizure control. The levels of 17 FAs in plasma phospholipids were determined before and 1, 3, 6, and 12 months after initiation of the KD in 25 children (mean age 6.3 years) with intractable epilepsy. Fluid omega-3 FA was supplemented in the diet after one month. Highly significant changes of the levels of several FAs were found. Linoleic acid (LA) and eicosapentaenoic acid (EPA) increased, whereas arachidonic acid (AA) and Mead acid (20:3 n-9) decreased. Docosahexaenoic acid (DHA) increased insignificantly. However, no correlation of changes in FA levels with seizure response was found. The ratio of omega-6 to omega-3 gradually decreased from 7.0 before to 4.9 at 12 months after starting the diet, presumably a cardiovascular benefit. The composition of the KD differs as to FA content and type between different treating centers but, still, the efficacy reports are very similar. This study demonstrates the possibility of composing the KD in such a way that the FA profile is kept within a normal range, which may reduce cardiovascular risks.

Age and Comedications Influence Levetiracetam Pharmacokinetics in Children

The pharmacokinetics of many antiepileptic drugs differs between adults and children. The influence of age and concomitant medications on the dose/concentration ratio of levetiracetam was examined in 103 children with epilepsy. Dosing and plasma levels of levetiracetam and concomitant antiepileptic drugs were reviewed retrospectively. The dose/concentration ratio was calculated as the weight-normalized dose (mg/kg/day) divided by the steady-state trough plasma drug level, which was used as a measure of apparent oral clearance of levetiracetam. Children were classified into age groups and treatment groups: levetiracetam given with enzyme inducers (n = 24) or nonenzyme inducers (n = 69), or as monotherapy (n = 10). Levetiracetam clearance differed significantly between age groups (0-4, 5-11, and 12-17 years), i.e., the younger the child, the higher the clearance. The increase was 1.7-fold between the youngest and oldest age groups. Children on enzyme inducers exhibited significantly higher clearance (1.3-fold), compared with those on nonenzyme inducers and monotherapy. Levetiracetam did not influence the clearance of lamotrigine, valproate, topiramate, or clonazepam. In conclusion, younger age and comedication with an enzyme inducer increased levetiracetam clearance. This finding should be taken into account when treating individual patients.

Growth dependence on insulin-like growth factor-1 during the ketogenic diet.

Purpose:  To examine the influence of the ketogenic diet (KD) on linear growth and insulin‐like growth factor I (IGF‐I) levels in children with pharmacotherapy‐resistant epilepsy.

Rufinamide in Children with Refractory Epilepsy: Pharmacokinetics, Efficacy, and Safety

We examined the influence of age and type of concomitant antiepileptic drugs (AEDs) on the pharmacokinetics of rufinamide (RUF) as well as its efficacy and safety in 51 children with refractory epilepsy. In a retrospective noninterventional survey, dose-to-concentration ratios of RUF and concomitant AEDs were calculated: the weight-normalized dose (mg/kg/d) divided by the steady-state trough plasma drug level, which was used as a measure of clearance. During treatment with RUF concomitantly with valproic acid (VPA) young children, aged 0 to 4.9 years, had a low clearance of RUF, which did not differ from older children. If not on VPA but on enzyme inducers, young children had a threefold higher clearance of RUF than the older ones. In young children not on VPA, those on enzyme inducers had 1.7-fold higher clearance than those on nonenzyme inducers. In children neither on VPA nor on enzyme inducers, RUF clearance was age-dependent with higher clearance in younger children. Adding RUF did not change the pharmacokinetics of concomitantly used AEDs. Seizure response after 2 to 3 months on RUF treatment was found in 12 of 51 children (23.5%), at mean plasma level of 36.9 ± 22.0 µmol/L. Adverse events were reported in 41% of the patients of which fatigue was most frequent (24%).

Zonisamide: pharmacokinetics, efficacy, and adverse events in children with epilepsy.

BACKGROUND Zonisamide is a new generation antiepileptic drug (AED) widely used in children with refractory epilepsy, although until recently, it was used to a large extent as off-label or unlicensed medication due to the lack of evidence-based studies. Children have a different pharmacokinetic profile than adults and an adult dose regimen cannot be directly translated into pediatric use. Patients and METHODS In this retrospective noninterventional study of the medical records of 75 children with pharmacoresistant epilepsy, the pharmacokinetics, efficacy and safety of zonisamide were examined. The dose-to-concentration ratio, the daily weight-normalized dose of zonisamide divided by its plasma concentration, was used as a measure of clearance. In addition, data on the efficacy of zonisamide to reduce seizures and reported adverse events were extracted from the medical records and analyzed. RESULTS Young children (range, 0-4 years) had a significantly increased zonisamide clearance compared with older ones (range, 5-17 years) and those with enzyme-inducing comedication (carbamazepine, phenobarbital, or phenytoin) had increased clearance compared with those on nonenzyme inducers; the increases were 1.7-fold and 1.8-fold, respectively. No significant difference in clearance was found between female and male subjects. The clearances of concomitant AEDs were not affected by zonisamide administration. The overall efficacy of zonisamide for reducing seizure frequency ≥ 50% was 35% and the most frequent adverse event was fatigue, reported in 23% of the patients. CONCLUSION Patients with enzyme-inducing comedication or of young age (range, 0-4 years) might need higher weight-normalized doses to achieve the same plasma levels as in patients with no enzyme-inducing comedication or patients of older age. Zonisamide was not found to influence the pharmacokinetics of concomitant AEDs. The shortage of pharmacokinetic studies of zonisamide in children highlights the need for research of this kind.

Renal angiomyolipoma in patients with tuberous sclerosis complex: findings from the TuberOus SClerosis registry to increase disease Awareness

Abstract Background Renal angiomyolipoma occurs at a high frequency in patients with tuberous sclerosis complex (TSC) and is associated with potentially life-threatening complications. Despite this frequency and severity, there are no large population-based cohort studies. Here we present baseline and follow-up data of the international TuberOus SClerosis registry to increase disease Awareness (TOSCA) with an aim to provide detailed clinical characteristics of renal angiomyolipoma among patients with TSC. Methods Patients of any age with a documented clinic visit for TSC within 12 months or who were newly diagnosed with TSC before participation in the registry were eligible. Data specific to renal angiomyolipoma included physical tumour characteristics (multiple, bilateral, lesion size and growing lesions), clinical signs and symptoms, and management. The effects of age, gender and genotype on the prevalence of renal angiomyolipoma were also evaluated. Results Renal angiomyolipoma was reported in 51.8% of patients at baseline, with higher frequency in female patients (57.8% versus 42.2%). The median age at diagnosis was 12 years. Prevalence of angiomyolipoma was higher in patients with TSC2 compared with TSC1 mutations (59.2% versus 33.3%, P < 0.01). Of the 1031 patients with angiomyolipoma at baseline, multiple lesions were reported in 88.4% and bilateral in 83.9% of patients, while the size of angiomyolipoma was >3 cm in 34.3% of patients. Most patients were asymptomatic (82%). Frequently reported angiomyolipoma-related symptoms included bleeding, pain, elevated blood pressure and impaired renal function. Embolization and mammalian target of rapamycin inhibitors were the two most common treatment modalities. Conclusions The TOSCA registry highlights the burden of renal angiomyolipoma in patients with TSC and shows that renal manifestations are initially asymptomatic and are influenced by gender and genotype. Furthermore, the occurrence of significant problems from angiomyolipoma in a minority of younger patients suggests that surveillance should begin in infancy or at initial diagnosis.

TSC-associated neuropsychiatric disorders (TAND): findings from the TOSCA natural history study

BackgroundMost evidence for TSC-associated neuropsychiatric disorders (TAND) to date have come from small studies and case reports, and very little is known about TAND in adults. We explored baseline TAND data from the large-scale international TOSCA natural history study to compare childhood and adult patterns, describe age-based patterns, and explore genotype-TAND correlations.ResultsThe study enrolled 2216 eligible participants with TSC from 170 sites across 31 countries at the data cut-off for the third interim analysis (data cut-off date: September 30, 2015). The most common behavioural problems (reported in > 10% of participants) were overactivity, sleep difficulties, impulsivity, anxiety, mood swings, severe aggression, depressed mood, self-injury, and obsessions. Psychiatric disorders included autism spectrum disorder (ASD, 21.1%), attention deficit hyperactivity disorder (ADHD, 19.1%), anxiety disorder (9.7%), and depressive disorder (6.1%). Intelligence quotient (IQ) scores were available for 885 participants. Of these, 44.4% had normal IQ, while mild, moderate, severe, and profound degrees of intellectual disability (ID) were observed in 28.1, 15.1, 9.3, and 3.1%, respectively. Academic difficulties were identified in 58.6% of participants, and neuropsychological deficits (performance <5th percentile) in 55.7%. Significantly higher rates of overactivity and impulsivity were observed in children and higher rates of anxiety, depressed mood, mood swings, obsessions, psychosis and hallucinations were observed in adults. Genotype-TAND correlations showed a higher frequency of self-injury, ASD, academic difficulties and neuropsychological deficits in TSC2. Those with no mutations identified (NMI) showed a mixed pattern of TAND manifestations. Children and those with TSC2 had significantly higher rates of intellectual disability, suggesting that age and genotype comparisons should be interpreted with caution.ConclusionsThese results emphasize the magnitude of TAND in TSC and the importance of evaluating for neuropsychiatric comorbidity in all children and adults with TSC, across TSC1 and TSC2 genotypes, as well as in those with no mutations identified. However, the high rates of unreported or missing TAND data in this study underline the fact that, even in expert centres, TAND remains underdiagnosed and potentially undertreated.