Pediatric intracranial hypertension: Experience from 2 Tertiary Centers

Objectives:To review the experience of 2 tertiary centers in Saudi Arabia with intracranial hypertension (IH) in the pediatric population.Methods:We retrospectively reviewed and analyzed pediatric patients diagnosed with IH from June 2002 to May 2017 in 2 institutes.Results:We identified 53 patients (30 females and 23 males) with a mean age of 7 years at the time of presentation. Among them, 41 patients were younger than 12 years, and 12 were older. Obese and overweight patients constituted 27.00% (n = 14) of all cases, 8 (66.7%) of whom were older than 12 years. The most common presenting feature was papilledema followed by headache. Vitamin D deficiency, which constituted the most common associated condition, was identified in 12 (22.6%) patients. Acetazolamide was the treatment option in 98.11% of patients, and only 5.7% underwent surgical interventions. The length of follow-up ranged from 6 months to 8 years.Conclusion:Intracranial hypertension is rare in children and commonly seen in overweight females older than 12 years similar to adults. Patients younger than 12 years tend to develop secondary IH. More studies are needed to characterize the clinical presentation and guide the management plan.

Intracranial hypertension (IH) is rarely reported in children. It is characterized by increased intracranial pressure (ICP) without any evidence of underlying brain pathology, structural abnormalities, hydrocephalus, or any abnormal meningeal enhancement.1 The incidence of IH differs from region to region due to variations in the prevalence of obesity and other secondary causes. The annual incidence of IH in children is 0.9 per 100,000 in the United States,2 0.5 per 100,000 in Germany,3 0.6 per 100,000 in Nova Scotia and Prince Edward Island in Eastern Canada,4 and 1.2 per 100,000 in Croatia.5 A study carried out in Oman estimated the incidence of IH to be 1.9 per 100,000 in children below 15 years of age; with it being higher in female children.6 The present study aimed to review the clinical presentation, possible aetiological factors, diagnosis, management, and outcomes in children with IH in 2 tertiary institutes in Saudi Arabia.     

Activation of apoptotic caspase cascade during the transition to pressure overload-induced heart failure.

OBJECTIVES: A pressure overload model was developed to simulate aortic stenosis and assess caspase activity during the transition to heart failure. BACKGROUND: Cardiomyocyte apoptosis is implicated in the pathogenesis of heart failure, and caspase activation is central to this pathophysiological process. METHODS: A total of 10 sheep were banded with variable aortic constriction devices, progressively inflated to increase left ventricular (LV) afterload. Serial LV endomyocardial biopsy samples were obtained to measure caspase activity and presence of apoptosis. RESULTS: Over the first 3 to 4 weeks, hypertrophy developed in the sheep (LV mass index 90.8 +/- 4.9 g/m2 vs. 44.0 +/- 3.0 g/m2, p < 0.01), followed by gradual dilatation of the left ventricle (diastolic LV internal diameter 4.23 +/- 0.08 cm vs. 3.39 +/- 0.07 cm, p < 0.01). Ventricular function remained stable until 7 to 8 weeks after banding, when there was significant deterioration (fractional shortening 18.3 +/- 2.4% vs. 46.9 +/- 2.6%, p < 0.01), associated with clinical heart failure. Serial LV endomyocardial biopsy samples were obtained at each echocardiographically defined stage (LV hypertrophy, LV dilation, and LV failure). Activity of caspases-3, -8, and -9 (measured by specific fluorogenic peptide substrates and immunohistochemistry) increased progressively, particularly with the onset of myocardial dysfunction (caspase-3 7.92 +/- 1.19 vs. 1.00 +/- 0.15, caspase-8 1.94 +/- 0.21 vs. 1.00 +/- 0.04, caspase-9 5.87 +/- 0.97 vs. 1.00 +/- 0.18 relative fluorescent units, p < 0.05). No evidence of deoxyribonucleic acid (DNA) fragmentation, however, was identified by immunohistochemical assays. CONCLUSIONS: Activation of cardiomyocyte caspase enzymes occurs during the transition to heart failure, without completion of apoptotic DNA fragmentation. Increased activity of caspase-8 and -9 suggests both mitochondrial and death-receptor mediated pathways are involved in this pathological process. Further knowledge of these pathways may stimulate development of apoptosis-based strategies for slowing progression of heart failure in aortic stenosis patients.     

Multifocal Visual Evoked Potential (mfVEP) and Pattern-Reversal Visual Evoked Potential Changes in Patients with Visual Pathway Disorders: A Case Series

The purpose of this study was to evaluate multifocal visual evoked potential (mfVEP) and pattern-reversal visual evoked potential (PVEP) changes in patients with pathology at various levels of the visual pathway determined by other methods. Six patients with different visual pathway disorders, including vascular ischaemic events and compressive optic neuropathy, were reviewed. All patients were tested with both mfVEP and full-field and half-field PVEPs. Results were assessed in relation to other diagnostic tests such as magnetic resonance imaging, Humphrey visual field test, and optical coherence topography. The cases in this study demonstrate a potential higher sensitivity of mfVEP compared with conventional PVEPs in detecting lesions affecting the peripheral field, horizontal hemifields, and lesions of the post-chiasmal pathway. The limitation of the PVEP in this setting is probably due to phase cancellation and overrepresentation of the macular region. mfVEP provides a more accurate assessment of visual defects when compared with conventional PVEP. The independent assessment of different areas of the visual field improves the detection and localization of lesions and provides an objective topographical map that can be used in clinical practice as an adjunct to other diagnostic tests and to assess disease progression.     

X‐linked duplication copy number variation in a familial overgrowth condition

We describe an overgrowth condition associated with X‐linked copy number variation. Three brothers displayed an overgrowth pattern at birth that continued postnatally. Clinical findings included macrocephaly, distinctive facial features, developmental delay and variable clubfoot. Normal fetal growth was noted until the third trimester by Hadlock standards, revealing a late gestational overgrowth pattern. Microarray analysis in the family showed a maternally inherited 680 kb copy number duplication at Xq26.1‐q26.2 in all three brothers. Molecular sequencing for known overgrowth conditions including GPC3, Sotos 1 (NSD1), Malan (NFIX), Perlman (DIS3L2), Weaver (EZH2), Opitz–Kaveggia (MED12) loci were negative. BWS IC1 and IC2 methylation and CDKN1C testing was also negative. Normal IGF1 levels excluded X‐linked acrogiantism. The duplicated region Xq26.1‐q26.2 contained IGSF1 and at least part of the lncRNA FIRRE. IGSF1, a highly expressed pituitary immunoglobulin superfamily gene, was recently implicated in a genome‐wide association study of canine size. IGSF1 variants were associated with large canine breeds compared to smaller breeds. Our findings support the hypothesis that an X‐linked variant encompassing the IGSF1 region may be associated with body size. Although IGSF1 loss has been noted in human hypothyroidism, this is the first reported phenotype in a family with copy number duplication in the region. Our findings suggest that prenatal evaluation, cross‐species evaluation, Mendelian, and GWAS studies may describe a distinctive familial condition and its corresponding phenotypic features.     

Initial Assessment of the Pathogenic Mechanisms of the Recently Identified Alzheimer Risk Loci

Recent genome wide association studies have identified CLU, CR1, ABCA7 BIN1, PICALM and MS4A6A/MS4A6E in addition to the long established APOE, as loci for Alzheimer's disease. We have systematically examined each of these loci to assess whether common coding variability contributes to the risk of disease. We have also assessed the regional expression of all the genes in the brain and whether there is evidence of an eQTL explaining the risk. In agreement with other studies we find that coding variability may explain the ABCA7 association, but common coding variability does not explain any of the other loci. We were not able to show that any of the loci had eQTLs within the power of this study. Furthermore the regional expression of each of the loci did not match the pattern of brain regional distribution in Alzheimer pathology. Although these results are mainly negative, they allow us to start defining more realistic alternative approaches to determine the role of all the genetic loci involved in Alzheimer's disease.