Rapid improvements in sequencing and array-based platforms are resulting in a flood of diverse genome-wide data, including data from exome and whole-genome sequencing, epigenetic surveys, expression profiling of coding and noncoding RNAs, single nucleotide polymorphism (SNP) and copy number profiling, and functional assays. Analysis of these large, diverse data sets holds the promise of a more comprehensive understanding of the genome and its relation to human disease. Experienced and knowledgeable human review is an essential component of this process, complementing computational approaches. This calls for efficient and intuitive visualization tools able to scale to very large data sets and to flexibly integrate multiple data types, including clinical data. However, the sheer volume and scope of data pose a significant challenge to the development of such tools.

Integrative Genomics Viewer

https://www.thelancet.com/pdfs/journals/lancet/PIIS0140-6736(06)68175-0.pdf

Guillain-Barré syndrome

Celiac disease is an immune-mediated enteropathy caused by a permanent sensitivity to gluten in genetically susceptible individuals. It occurs in children and adolescents with gastrointestinal symptoms, dermatitis herpetiformis, dental enamel defects, osteoporosis, short stature, delayed puberty and persistent iron deficiency anemia and in asymptomatic individuals with type 1 diabetes, Down syndrome, Turner syndrome, Williams syndrome, selective immunoglobulin (Ig)A deficiency and first degree relatives of individuals with celiac disease. The Celiac Disease Guideline Committee of the North American Society for Pediatric Gastroenterology, Hepatology and Nutrition has formulated a clinical practice guideline for the diagnosis and treatment of pediatric celiac disease based on an integration of a systematic review of the medical literature combined with expert opinion. The Committee examined the indications for testing, the value of serological tests, human leukocyte antigen (HLA) typing and histopathology and the treatment and monitoring of children with celiac disease. It is recommended that children and adolescents with symptoms of celiac disease or an increased risk for celiac disease have a blood test for antibody to tissue transglutaminase (TTG), that those with an elevated TTG be referred to a pediatric gastroenterologist for an intestinal biopsy and that those with the characteristics of celiac disease on intestinal histopathology be treated with a strict gluten-free diet. This document represents the official recommendations of the North American Society for Pediatric Gastroenterology, Hepatology and Nutrition on the diagnosis and treatment of celiac disease in children and adolescents.

Guideline for the diagnosis and treatment of celiac disease in children: recommendations of the North American Society for Pediatric Gastroenterology, Hepatology and Nutrition.

Summary Background The ketogenic diet has been widely and successfully used to treat children with drug-resistant epilepsy since the 1920s. The aim of this study was to test the efficacy of the ketogenic diet in a randomised controlled trial. Methods 145 children aged between 2 and 16 years who had at least daily seizures (or more than seven seizures per week), had failed to respond to at least two antiepileptic drugs, and had not been treated previously with the ketogenic diet participated in a randomised controlled trial of its efficacy to control seizures. Enrolment for the trial ran between December, 2001, and July, 2006. Children were seen at one of two hospital centres or a residential centre for young people with epilepsy. Children were randomly assigned to receive a ketogenic diet, either immediately or after a 3-month delay, with no other changes to treatment (control group). Neither the family nor investigators were blinded to the group assignment. Early withdrawals were recorded, and seizure frequency on the diet was assessed after 3 months and compared with that of the controls. The primary endpoint was a reduction in seizures; analysis was intention to treat. Tolerability of the diet was assessed by questionnaire at 3 months. The trial is registered with ClinicalTrials.gov, number NCT00564915. Findings 73 children were assigned to the ketogenic diet and 72 children to the control group. Data from 103 children were available for analysis: 54 on the ketogenic diet and 49 controls. Of those who did not complete the trial, 16 children did not receive their intervention, 16 did not provide adequate data, and ten withdrew from the treatment before the 3-month review, six because of intolerance. After 3 months, the mean percentage of baseline seizures was significantly lower in the diet group than in the controls (62·0% vs 136·9%, 75% decrease, 95% CI 42.4–107.4%; p Interpretation The results from this trial of the ketogenic diet support its use in children with treatment-intractable epilepsy. Funding HSA Charitable Trust; Smiths Charity; Scientific Hospital Supplies; Milk Development Council.

https://www.gutbrainaxis.org/pdf/cross%20paper%20KD%20vs%20AEDs.pdf

The ketogenic diet for the treatment of childhood epilepsy: a randomised controlled trial

Inflammatory reactions occur in the brain in various CNS diseases, including autoimmune, neurodegenerative, and epileptic disorders. Proinflammatory and antiinflammatory cytokines and related molecules have been described in CNS and plasma, in experimental models of seizures and in clinical cases of epilepsy. Inflammation involves both the innate and the adaptive immune systems and shares molecules and pathways also activated by systemic infection. Experimental studies in rodents show that inflammatory reactions in the brain can enhance neuronal excitability, impair cell survival, and increase the permeability of the blood-brain barrier to blood-borne molecules and cells. Moreover, some antiinflammatory treatments reduce seizures in experimental models and, in some instances, in clinical cases of epilepsy. However, inflammatory reactions in brain also can be beneficial, depending on the tissue microenvironment, the inflammatory mediators produced in injured tissue, the functional status of the target cells, and the length of time the tissue is exposed to inflammation. We provide an overview of the current knowledge in this field and attempt to bridge experimental and clinical evidence to discuss critically the possibility that inflammation may be a common factor contributing, or predisposing, to the occurrence of seizures and cell death, in various forms of epilepsy of different etiologies. The elucidation of this aspect may open new perspectives for the pharmacologic treatment of seizures.

https://onlinelibrary.wiley.com/doi/pdf/10.1111/j.1528-1167.2005.00298.x

Brain inflammation in epilepsy: experimental and clinical evidence.

Objective An important number of epileptic patients who began with epileptic seizures during the first year of life have not just been well classified. The objective is to identify the different types of epilepsies and epileptic seizures which begin during the first year of life, according to the last classification of epilepsy and epileptic syndromes of 1989. Material and methods We have studied 471 patients who consulted to our service in the last 5 years, with epileptic seizures during the first year of life. We excluded neonatal seizures and febrile convulsions. Results 1. Partial epilepsy: a) idiopathic: 12 (2.5%); b) symptomatic: 130 (28%); c) cryptogenic: 25 (5%). 2. Generalized epilepsy: a) idiopathic: benign myoclonic epilepsy in infancy, 6 (1%); b) cryptogenic-symptomatic: symptomatic West syndrome, 155 (33%); cryptogenic West syndrome, 65 (14%); cryptogenic myoclonic epilepsy, 6 (1%); early infantile epileptic encephalopathy, 8 (1.6%); early myoclonic encephalopathy, 4 (0.8%); other symptomatic generalized epilepsies without specific aetiology, 14 (3%). 3. Epilepsies and syndromes undetermined as to whether they are focal or generalized: a) severe myoclonic epilepsy in infancy, 15 (3%); symptomatic epilepsy with multifocal and independent spikes, 3 (0.6%); other undetermined epilepsies not defined above, 3 (0.6%). 4. Special syndromes: occasional convulsions, 15 (3%). Conclusions West syndrome is the commonest type of epilepsy during the first year of life, particularly symptomatic West syndrome. Symptomatic partial epilepsies are in the second place in frequency. We identified 12 patients with idiopathic partial epilepsy, who full-filled clinical and EEG characteristics of a recently described epilepsy: benign infantile familial convulsions. The study showed the predominance of symptomatic epilepsy, generalized (represented by West syndrome) and partials. Finally 6% of the patients have a generalized epilepsy, cryptogenic or symptomatic, not defined in the classification.

Epilepsies during the first year of life

Introduction Prospective study to evaluate efficacy of ketogenic diet (KD) in the treatment of children with intractable epilepsies (IE). Tolerability of the KD was also considered. Material and methods Criteria for inclusion were: 1. Epilepsy refractary to treatments with antiepileptic drugs (AED) in monotherapy and combining two or three AED. 2. Acknowledgment of blood levels of these drugs in therapeutic range. 3. Absence of liver or kidney disease, metabolic abnormalities, inborn errors of metabolism or other progressive encephalopathies. 4. Family supposedly in economic and psychologic conditions to accept the difficulties of strictly maintaining KD. We used a classic KD following the criteria suggested by the John Hopkins Pediatrics Epilepsy Center. Baseline neurological and physical examination, EEG, blood chemistry including lipid profile were obtained prior to initiative and during the KD. KD efficacy was measured as percent reduction of baseline seizures frequency, considering positive results as reductions of 50% or over. Acceptance of the diet and quality of life were specially considered. Eighteen patients with ages from 2 to 11 years were admitted. Ten of them were males. Diagnosis followed the last Classification of Epileptic Syndromes of the ILAE, and distribution was: Symptomatic partial epilepsies, 8 cases (one had West syndrome at age 5 months); cryptogenic partial epilepsies, 1 case; Lennox-Gastaut syndrome, 2 cases; severe myoclonic epilepsy of infancy, 6 cases and epilepsy with myoclonic astatic seizures 1 case. Results Four patients were not able to achieve persistent ketosis either due to patient's rejection of KD or to parents non compliance. KD was kept for at least two months before considering failures. Five patients did not show significant improvement and KD was stopped. At present nine patients have been on KD from 6 to 24 months (average 16 months). Four of them showed a 75-100% reduction in seizures frequency and in three the reduction was of 50-75%. Conclusions KD was fairly well tolerated by 14 of 18 children and their families. Fifty percent of the 14 patients complying KD showed significant improvement in seizure frequency and in quality of life. Due to the small number of patients and short follow-up, we can not speculate about results in relation to each epileptic syndrome, neither the risk of late complications.

[Ketogenic diet: efficacy and tolerability in childhood intractable epilepsy].

OBJECTIVE To evaluate the therapeutic response of West's syndrome (WS) associated with cerebral paralysis (CP) secondary to periventricular leucomalacia (PVL). MATERIAL AND METHODS We made a retrospective analysis of the clinical histories of 10 patients with SW and CP secondary to periventricular leucomalacia. We studied 10 patients, 9 boys and 1 girl with a current age of between 3 and 11 years, 8 premature newborn babies and two full term new born babies. RESULTS The infantile spasms (IS) started between the ages of 4-10 months (average age 8.3 months). In 100% of cases they came in runs. In one patient alone they were associated with partial motor crises. EEG showed typical hypsarrhythmia in 8 cases, asymmetrical hypsarrhythmia in 1 case and modified hypsarrhythmia in another case. Seven patients were given ACTH, associated with valproic acid in 4 cases and benzodiazepines in 2 cases. The remaining 3 patients were treated with valproate as the only drug. The IS disappeared and the EEG became normal within 14 days of the start of treatment in 9 patients who remain symptom-free after between 2 and 11.9 years follow-up. In one patient there was partial control of the spasms, and the clinical picture cleared up 10 months after starting treatment with vigabatrine. All 10 patients had spastic quadriplegia. All had mental retardation of between slight and serious degree. The cerebral CT and MR showed signs compatible with PVL and in 3 cases there was associated diffuse cerebral atrophy. CONCLUSIONS We have found a good electro-clinical response in 10 patients with WS, CP and PVL. The results are in agreement with those of other authors.

[West's syndrome in patients with cerebral paralysis and periventricular leukomalacia: a good response to treatment].

INTRODUCTION Partial benign epilepsy of childhood with occipital paroxysms (EPBI-O) described by Gastaut in 1982, has been recognized in the latest Classification of Epilepsy and Epileptic Syndromes as being a form of idiopathic partial epilepsy. In 1989 Panayiotopoulos described a different form of idiopathic occipital epilepsy. OBJECTIVE We analyzed the electro-clinical characteristics of EPBI-O in order to identify the different forms of idiopathic occipital epilepsy. MATERIAL AND METHODS This prospective study included 74 patients who fulfilled the diagnostic criteria of EPBI-O. The patients were evaluated between January 1990 and June 1996 by means of clinical and electro-encephalic examinations during a follow-up period of between 6 months and 6.5 years. RESULTS We identified two groups. Group I: eighteen patients with visual crises and post-ictal migrainous episodes, with or without motor crises, predominantly when awake and with the onset of these crises at 8.7 years old. On EEG there were P-O occipital paroxysms which reacted to eyelid opening and group II: fifty-six patients with crises of vomiting followed by oculo-encephalic version, predominantly during sleep and with an average age of 4.9 years when these crises started to occur. On EEG there were occipital spikes with identical morphology to that of the benign epilepsy of childhood with spikes of Roland (EPBI-R). Two patients had associated crises of EPBI-O of Group II and EPBI-R with independent occipital and Roland spikes. These formed a third group. CONCLUSIONS This study confirms the existence of two variantes of EPBI-O; the 'Gastaut' type and the 'Panayiotopoulos' type with a more benign and more frequent course.

Natalio Fejerman

Papers

Epilepsies during the first year of life

[Ketogenic diet: efficacy and tolerability in childhood intractable epilepsy].

[West's syndrome in patients with cerebral paralysis and periventricular leukomalacia: a good response to treatment].

Idiopathic partial epilepsy with occipital paroxysms

Neuropsychologic and neurolinguistic aspects in acquired epileptic aphasia (AEA) or Landau-Klefener syndrome