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Aortic aneurysms are rare manifestations in children with tuberous sclerosis complex (TSC) with life threating implications. Although an association between TSC, aortic and other aneurysms has been recognized, mechanistic insights explaining the pathophysiology behind aneurysm development and genetic aberrations in TSC have so far been lacking. Here, we summarize existing knowledge on aneurysms in TSC and present a case of a 2-year-old boy with an infrarenal aortic aneurysm, successfully treated with open aortic reconstruction. Histologic examination of the excised aneurysm wall showed distortion of vessel wall structure with loss of elastin and a pathologic accumulation of smooth muscle cells. Until now, these pathologic features have puzzled researchers as proliferating smooth muscle cells would rather be expected to preserve vessel wall integrity. Recent reports exploring the biological consequences of the dysregulated intracellular signaling pathways in patients with TSC provide plausible explanations to this paradox, which may support the development of future therapeutic strategies.

The vast clinical and radiological spectrum of pyruvate dehydrogenase complex (PDHc) deficiency continues to pose challenges both in diagnostics and disease monitoring. Prompt diagnosis is important to enable early initiation of ketogenic diet. The patients were recruited from an ongoing population-based study in Sweden. All patients with a genetically confirmed diagnosis who had been investigated with an MRI of the brain were included. Repeated investigations were assessed to study the evolution of the MRI changes. Sixty-two MRI investigations had been performed in 34 patients (23 females). The genetic cause was mutations in PDHA1 in 29, PDHX and DLAT in 2 each, and PDHB in 1. The lesions were prenatal developmental in 16, prenatal clastic in 18, and postnatal clastic in 15 individuals. Leigh-like lesions with predominant involvement of globus pallidus were present in 12, while leukoencephalopathy was present in 6 and stroke-like lesions in 3 individuals. A combination of prenatal developmental and clastic lesions was present in 15 individuals. In addition, one male with PDHA1 also had postnatal clastic lesions. The most common lesions found in our study were agenesis or hypoplasia of corpus callosum, ventriculomegaly, or Leigh-like lesions. Furthermore, we describe a broad spectrum of other MRI changes that include leukoencephalopathy and stroke-like lesions. We argue that a novel important clue, suggesting the possibility of PDHc deficiency on MRI scans, is the simultaneous presence of multiple lesions on MRI that have occurred during different phases of brain development.

Background The low carbohydrate, high fat ketogenic diet can be an effective anticonvulsant treatment in some pediatric patients with pharmacoresistant epilepsy. Its mechanism(s) of action, however, remain uncertain. Direct sampling of cerebrospinal fluid before and during metabolic therapy may reveal key changes associated with differential clinical outcomes. We characterized the relationship between seizure responsiveness and changes in lipid and carbohydrate metabolites. Methods We performed metabolomic analysis of cerebrospinal fluid samples taken before and during ketogenic diet treatment in patients with optimal response (100% seizure remission) and patients with no response (no seizure improvement) to search for differential diet effects in hallmark metabolic compounds in these two groups. Optimal responders and non-responders were similar in age range and included males and females. Seizure types and the etiologies or syndromes of epilepsy varied but did not appear to differ systematically between responders and non-responders. Results Analysis showed a strong effect of ketogenic diet treatment on the cerebrospinal fluid metabolome. Longitudinal and between-subjects analyses revealed that many lipids and carbohydrates were changed significantly by ketogenic diet, with changes typically being of larger magnitude in responders. Notably, responders had more robust changes in glucose and the ketone bodies β-hydroxybutyrate and acetoacetate than non-responders; conversely, non-responders had significant increases in fructose and sorbose, which did not occur in responders. Conclusions The data suggest that a differential and stronger metabolic response to the ketogenic diet may predict a better anticonvulsant response, and such variability is likely due to inherent biological factors of individual patients. Strategies to boost the metabolic response may be beneficial.

ObjectivesTo describe the process and results of the updated Swedish practice guidelines for monotherapy in epilepsy.Materials and MethodsThe Swedish Medical Products Agency led the process together with medical experts. Evidence rating in accordance with the International League Against Epilepsy (ILAE) template was linked to the Cochrane group's GRADE system. Evidence from recently published trials and meta‐analyses was added. A national expert panel participated in the project and contributed their clinical experience.ResultsIn seizures with focal onset, carbamazepine, lamotrigine, or levetiracetam is recommended for children and adults (ILAE level A‐C for adults/Cochrane level strong for children and adults). Oxcarbazepine is an alternative for children, although its level A evidence, in a single class I trial, could relate to poor phenytoin tolerability. Eslicarbazepine acetate, lacosamide, and zonisamide are alternatives for adults and gabapentin for the elderly (ILAE level A). Carbamazepine is not a first choice for the elderly due to its high potential for interactions. In generalized epilepsy with tonic‐clonic seizures (GTC), lamotrigine, levetiracetam, and sodium valproate are recommended for children and adults (ILAE level C‐D/Cochrane level moderate‐strong) although sodium valproate is contraindicated in girls and women of childbearing age unless special considerations are met. Ethosuximide is the first choice in absence epilepsy without GTC (ILAE level A).ConclusionsLamotrigine and levetiracetam can be used as first choice for focal seizures and generalized epilepsy with GTC, suitable in all age‐groups and for both men and women. Recommendations for GTC seizures have lower evidence than those for focal seizures. (Less)

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 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.

Background: Knowledge is increasing about TSC-Associated Neuropsychiatric Disorders (TAND), but little is known about the potentially confounding effects of intellectual ability (IA) on the rates of TAND across age, sex, and genotype. We evaluated TAND in (a) children vs. adults, (b) males vs. females, and (c) TSC1 vs. TSC2 mutations, after stratification for levels of IA, in a large, international cohort. Methods: Individuals of any age with a documented visit for TSC in the 12 months prior to enrolment were included. Frequency and percentages of baseline TAND manifestations were presented by categories of IA (no intellectual disability [ID, intelligence quotient (IQ)>70]; mild ID [IQ 50–70]; moderate-to-profound ID [IQ

The gut microbiota has been linked to various neurological disorders via the gut–brain axis. Diet influences the composition of the gut microbiota. The ketogenic diet (KD) is a high-fat, adequate-protein, low-carbohydrate diet established for treatment of therapy-resistant epilepsy in children. Its efficacy in reducing seizures has been confirmed, but the mechanisms remain elusive. The diet has also shown positive effects in a wide range of other diseases, including Alzheimer’s, depression, autism, cancer, and type 2 diabetes. We collected fecal samples from 12 children with therapy-resistant epilepsy before starting KD and after 3 months on the diet. Parents did not start KD and served as diet controls. Applying shotgun metagenomic DNA sequencing, both taxonomic and functional profiles were established. Here we report that alpha diversity is not changed significantly during the diet, but differences in both taxonomic and functional composition are detected. Relative abundance of bifidobacteria as well as E. rectale and Dialister is significantly diminished during the intervention. An increase in relative abundance of E. coli is observed on KD. Functional analysis revealed changes in 29 SEED subsystems including the reduction of seven pathways involved in carbohydrate metabolism. Decomposition of these shifts indicates that bifidobacteria and Escherichia are important contributors to the observed functional shifts. As relative abundance of health-promoting, fiber-consuming bacteria becomes less abundant during KD, we raise concern about the effects of the diet on the gut microbiota and overall health. Further studies need to investigate whether these changes are necessary for the therapeutic effect of KD., Gut–brain axis: The ketogenic diet alters functional gut microbiota The ketogenic diet changes both the relative abundance of gut microbiota and their metabolic activities. The diet forces a shift from carbohydrates to ketones as a primary energy source and has demonstrated efficacy in reducing epileptic seizures in children. After animal models implicated gut microbiota in this amelioration, Stefanie Prast-Nielsen, of Sweden’s Karolinska Institutet, and her team sequenced microbiotic DNA of fecal samples from 12 children with epilepsy before and after 3 months on a ketogenic diet. Changes included reductions in the numbers of Bifidobacterium and an increase in Escherichia coli. Carbohydrate metabolism significantly changed after 3 months on the diet. Some reductions raise questions about the diet’s potential impact on gut and overall health. More studies are also needed to discern the mechanistic impact of these changes on seizure activity.

For some people with medically refractory epilepsy adjunct treatment with neurostimulation and ketogenic diet can be an option. Vagal nerve stimulation, VNS, consists of chronic intermittent electrical stimulation of the vagus nerve. VNS is effective and well tolerated in adolescents and adults. There is insufficient evidence on the efficacy of deep brain stimulation, DBS, and brain-responsive neurostimulation, RNS. Ketogenic diet is an established treatment in epilepsy with an increased number of indications, especially in neurometabolic diseases, where dietary therapy can completely eliminate epilepsy and improve cognitive and motor development. Ketogenic diet is a calculated diet consisting of a high amount of fat, the daily need of protein and a minimum of carbohydrates. The fat is converted to ketone bodies and transported across the blood-brain barrier to be used as an alternative energy source in the brain. Strictly calculated menus, regular monitoring and support from a team of dietician, nurse and physician are required.

Purpose: To examine the influence of the ketogenicdiet (KD) on linear growth and insulin-likegrowth factor I (IGF-I) levels in children withpharmacotherapy-resistantepilepsy.Methods: A prospective study was designed toevaluate growth, serum IGF-I levels, bloodb-hydroxybutyric acid (b-OHB), and seizurefrequency before and during KD in 22 children(median age 5.5 years). Growth was assessed bymeasurements of weight, height, body mass index(BMI), and height velocity. Standard deviationscores (SDS) were calculated for all measuredparameters as well as for serum IGF-I to eliminatethe influence of age- and sex-related differencesamongpatients.Results: Fourteen of the 22 patients responded tothe KD. Weight, height, BMI, and height velocitydecreased significantly during the KD. We foundthat the KD had profound influence on growth andIGF-I levels. No correlation was found betweenseizure response and growth alterations. Heightvelocity correlated negatively with b-OHB duringthe KD. The slope of the regression of heightvelocity against IGF-I decreased significantly dur-ingtheKD.Conclusions: Height velocity was most affected inthose with pronounced ketosis, which impliesthat, in clinical practice, the level of ketosisshould be related to outcomes in seizure responseand growth. Our data indicate that growth dis-turbances and the decreased sensitivity of growthto similar IGF-I levels during KD are indepen-dent of seizure reduction. The metabolic statusinduced by KD may be the mechanism underlyingboth alterations of linear growth and seizurereduction.KEY WORDS: Growth, IGF-I, Ketogenic diet,Pharmacoresistantepilepsy.Theketogenicdiet(KD),introducedbyWilderin1921,isusedinthetreatmentofchildrenwithpharmacotherapy-resistant epilepsy (Wilder, 1921). Despite its long historyof clinical use, it is still not clear how the diet affects thebrain and what the mechanisms are that underlie itsseizure-suppressive action (Cheng et al., 2003a; Bough R Liuet al., 2003). Since an increasing number of patients aretreated with the KD, it is important to evaluate its effectsongrowthandnutritionalstatus.

The ketogenic diet (KD) is an established, effective nonpharmacologic treatment for intractable childhood epilepsy. The KD is provided differently throughout the world, with occasionally significant variations in its administration. There exists a need for more standardized protocols and management recommendations for clinical and research use. In December 2006, The Charlie Foundation commissioned a panel comprised of 26 pediatric epileptologists and dietitians from nine countries with particular expertise using the KD. This group was created in order to create a consensus statement regarding the clinical management of the KD. Subsequently endorsed by the Practice Committee of the Child Neurology Society, this resultant manuscript addresses issues such as patient selection, pre-KD counseling and evaluation, specific dietary therapy selection, implementation, supplementation, follow-up management, adverse event monitoring, and eventual KD discontinuation. This paper highlights recommendations based on best evidence, including areas of agreement and controversy, unanswered questions, and future research.

The brain aspartate-glutamate carrier (AGC1) is specifically expressed in neurons, where it transports aspartate from the mitochondria to the cytosol, and plays a role in transfer of nicotinamide adenine dinucleotide (NADH)-reducing equivalents into the mitochondria as a part of the malate-aspartate shuttle. Deficient function of AGC1 underlies an inborn error of metabolism that presents with severe hypotonia, arrested psychomotor development, and seizures from a few months of age. In AGC1 deficiency, there is secondary hypomyelination due to lack of N-acetylaspartate (NAA), which is normally generated by acetylation of aspartate in the neuron and required for fatty acid synthesis by the adjacent oligodendrocyte. Based on experiences from AGC2 deficiency, we predicted that reduced glycolysis should compensate for the metabolic defect and allow resumed myelination in AGC1 deficiency. Carbohydrate restriction was therefore initiated in a patient with AGC1 deficiency at 6 years of age by introducing a ketogenic diet. The response was dramatic, clinically as well as radiologically. Psychomotor development showed clear improvement, and magnetic resonance imaging (MRI) indicated resumed myelination. This is the first successful treatment of secondary hypomyelination reported. Because AGC1 is driven by the proton gradient generated by the neuronal mitochondrial respiratory chain, the results have potential relevance for secondary hypomyelination in general.

Background Tuberous sclerosis complex (TSC) is a rare, multisystem, genetic disorder with an estimated prevalence between 1/6800 and 1/15000. Although recent years have seen huge progress in understanding the pathophysiology and in the management of TSC, several questions remain unanswered. A disease registry could be an effective tool to gain more insights into TSC and thus help in the development of improved management strategies. Methods TuberOus SClerosis registry to increase disease Awareness (TOSCA) is a multicentre, international disease registry to assess manifestations, interventions, and outcomes in patients with TSC. Patients of any age diagnosed with TSC, having a documented visit for TSC within the preceding 12 months, or newly diagnosed individuals are eligible. Objectives include mapping the course of TSC manifestations and their effects on prognosis, identifying patients with rare symptoms and co-morbidities, recording interventions and their outcomes, contributing to creation of an evidence-base for disease assessment and therapy, informing further research on TSC, and evaluating the quality of life of patients with TSC. The registry includes a ‘core’ section and subsections or ‘petals’. The ‘core’ section is designed to record general information on patients’ background collected at baseline and updated annually. Subsections will be developed over time to record additional data related to specific disease manifestations and will be updated annually. The registry aimed to enrol approximately 2000 patients from about 250 sites in 31 countries. The initial enrolment period was of 24 months. A follow-up observation period of up to 5 years is planned. Results A pre-planned administrative analysis of ‘core’ data from the first 100 patients was performed to evaluate the feasibility of the registry. Results showed a high degree of accuracy of the data collection procedure. Annual interim analyses are scheduled. Results of first interim analysis will be presented subsequent to data availability in 2014. Implications The results of TOSCA will assist in filling the gaps in understanding the natural history of TSC and help in planning better management and surveillance strategies. This large-scale international registry to study TSC could serve as a model to encourage planning of similar registries for other rare diseases.

The aim of this study was to investigate the levels of [(3)H]dopamine in blood, the cerebrospinal fluid (CSF) and brain tissue samples in rats and to find out whether the drug is transferred along the olfactory pathway to the central nervous system following nasal administration. [(3)H]Dopamine (50 microCi) was given to male Sprague-Dawley rats either intravenously or nasally to the right nostril. For the absorption study, blood samples were withdrawn from the carotid artery. The CSF samples were taken by cisternal puncture and then brain tissue samples were excised. The presence of unchanged dopamine in the samples was ascertained using thin layer chromatography (TLC). The radioactivity in the samples was measured using liquid scintillation. The greatest amount of the total radioactivity absorbed from the nasal mucosa into the systemic circulation was observed at the first sampling point 15 min after administration. The bioavailability of the total radioactivity was 68+/-30%. The uptake of [(3)H]dopamine in the brain was significantly higher 30 min after nasal administration than after intravenous administration (P

Summary: Purpose: To evaluate the effect of low-dose clonazepam (CZP) on the amount of epileptiform activity in children with focal and generalized epilepsy. Methods: In a single-blind pilot study, followed by a double-blind, placebo-controlled, randomized, crossover study, 15 children with epilepsy were evaluated by using 24-h long-term EEG recordings during baseline days and days after injections of placebo and CZP. The drug was given as a single i.m. injection of 0.02 mg/kg BW. Blood samples were obtained regularly for analysis of plasma concentrations of CZP. The number of epileptiform discharges was determined during corresponding periods with the individual child in the same state of alertness, the same real time of day, and with concomitant antiepileptic drugs (AEDs) unchanged. Results: In the double-blind study, low-dose CZP produced a highly significant (p = 0.0015) decrease in the amount of epileptiform activity (mean, -69% vs. placebo, -2%) obtained during periods when median plasma concentrations ranged from 18 to

Objective— To gain insight into the function of proprotein convertase subtilisin kexin type 9 (PCSK9) in humans by establishing whether circulating levels are influenced by diurnal, dietary, and hormonal changes. Methods and Results— We monitored circulating PCSK9 in a set of dynamic human experiments and could show that serum PCSK9 levels display a diurnal rhythm that closely parallels that of cholesterol synthesis, measured as serum lathosterol. In contrast to these marked diurnal changes in cholesterol metabolism, serum low-density lipoprotein (LDL) cholesterol levels remained stable during the diurnal cycle. Depletion of liver cholesterol by treatment with the bile acid–binding resin, cholestyramine, abolished the diurnal rhythms of both PCSK9 and lathosterol. Fasting (>18 hours) strongly reduced circulating PCSK9 and lathosterol levels, whereas serum LDL levels remained unchanged. Growth hormone, known to be increased during fasting in humans, reduced circulating PCSK9 in parallel to LDL cholesterol levels. Conclusion— Throughout the day, and in response to fasting and cholesterol depletion, circulating PCSK9 displays marked variation, presumably related to oscillations in hepatic cholesterol that modify its activity in parallel with cholesterol synthesis. In addition to this sterol-mediated regulation, additional effects on LDL receptors may be mediated by hormones directly influencing PCSK9.

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.A prospective study was designed to evaluate growth, serum IGF-I levels, blood beta-hydroxybutyric acid (beta-OHB), and seizure frequency before and during KD in 22 children (median age 5.5 years). Growth was assessed by measurements of weight, height, body mass index (BMI), and height velocity. Standard deviation scores (SDS) were calculated for all measured parameters as well as for serum IGF-I to eliminate the influence of age- and sex-related differences among patients.Fourteen of the 22 patients responded to the KD. Weight, height, BMI, and height velocity decreased significantly during the KD. We found that the KD had profound influence on growth and IGF-I levels. No correlation was found between seizure response and growth alterations. Height velocity correlated negatively with beta-OHB during the KD. The slope of the regression of height velocity against IGF-I decreased significantly during the KD.Height velocity was most affected in those with pronounced ketosis, which implies that, in clinical practice, the level of ketosis should be related to outcomes in seizure response and growth. Our data indicate that growth disturbances and the decreased sensitivity of growth to similar IGF-I levels during KD are independent of seizure reduction. The metabolic status induced by KD may be the mechanism underlying both alterations of linear growth and seizure reduction.

Summary FGF21 is a critical metabolic regulator, pivotal for fasting adaptation and directly regulated by PPARα 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 PPARα 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.

The aim of this study was to investigate whether morphine can be transferred along the olfactory pathway to the CNS, thereby circumventing the blood-brain barrier, after nasal administration to rodents. Radiolabelled and unlabelled morphine were administered via the right nostril to mice and rats. Olfactory bulbs, brain tissue and blood samples were collected. Morphine-derived radioactivity was measured using liquid scintillation (LS) and the concentrations of morphine and its metabolite morphine-3-glucuronide (M3G) were also assessed with high-performance liquid chromatography. The location of morphine-derived radioactivity in the rat brain was visualised by autoradiography. Overall, the levels of morphine in the right olfactory bulbs (ROBs) significantly exceeded those in the left olfactory bulbs (LOBs) and brain tissue samples 15, 60 and 240 min after right-sided nasal administration. Fifteen minutes after intravenous administration, there were no significant differences between olfactory bulbs and the other brain areas. Five minutes after nasal administration, autoradiography revealed radioactivity surrounding the ROB and reaching one of the ventricles in the brain. After 60 min, radioactivity had reached the peripheral parts of the ROB. All the techniques used in this study demonstrate that morphine was transferred along the olfactory pathway to the CNS after nasal administration to rodents.

Objectives Our aime was to study the short- and long-term effects of ketogenic diet on the disease course and disease-related outcomes in patients with pyruvate dehydrogenase complex deficiency, the metabolic factors implicated in treatment outcomes, and potential safety and compliance issues. Methods Pediatric patients diagnosed with pyruvate dehydrogenase complex deficiency in Sweden and treated with ketogenic diet were evaluated. Study assessments at specific time points included developmental and neurocognitive testing, patient log books, and investigator and parental questionnaires. A systematic literature review was also performed. Results Nineteen patients were assessed, the majority having prenatal disease onset. Patients were treated with ketogenic diet for a median of 2.9 years. All patients alive at the time of data registration at a median age of 6 years. The treatment had a positive effect mainly in the areas of epilepsy, ataxia, sleep disturbance, speech/language development, social functioning, and frequency of hospitalizations. It was also safe—except in one patient who discontinued because of acute pancreatitis. The median plasma concentration of ketone bodies (3-hydroxybutyric acid) was 3.3 mmol/l. Poor dietary compliance was associated with relapsing ataxia and stagnation of motor and neurocognitive development. Results of neurocognitive testing are reported for 12 of 19 patients. Conclusion Ketogenic diet was an effective and safe treatment for the majority of patients. Treatment effect was mainly determined by disease phenotype and attainment and maintenance of ketosis. Electronic supplementary material The online version of this article (doi:10.1007/s10545-016-0011-5) contains supplementary material, which is available to authorized users.