Persistent Elevation of Opening Pressure Despite Treatment and Symptom Resolution in Pediatric Intracranial Hypertension.

BACKGROUND: Currently no guidelines for repeating a lumbar puncture to guide management in primary intracranial hypertension (PIH) exist. METHODS: An institutional database of patients 18 years and younger followed in the institution's pediatric intracranial hypertension clinic was examined for opening pressure changes in PIH at diagnosis, before medication wean, and following medication wean, as well as to examine whether measurements at the time of diagnosis differed between those with and without disease recurrence. RESULTS: Forty-two patients were included in this study; 36% were male and the mean age at diagnosis was 11.01 years. Treatment duration averaged 9.68 months in those without recurrence and 8.5 months in those with recurrence. Average body mass index percentile of patients with disease recurrence was 83.7 and 72.1 in those without recurrence (P = 0.16). Average opening pressure values of all patients at diagnosis, prewean, and postwean was 36.53 cm H2O, 30.7 cm H2O, and 31.1 cm H2O, respectively. There was no statistically significant difference in opening pressures across these time points (P = 0.14). The change in opening pressure from diagnosis to postwean was statistically significant with a reduction of 5.18 cm H2O (P = 0.04). There was no statistical difference between change in opening pressure at diagnosis versus postwean between those with and without recurrence (P = 0.17). CONCLUSIONS: This clinical observational study suggests that mean opening pressure measurements in patients with PIH remain elevated both before and after medication wean despite papilledema resolution and patient-reported PIH symptoms. Clinically, this suggests that other features such as signs of optic disc edema and symptoms should be used to inform a clinical determination of disease recurrence and treatment course.

Acute management of childhood stroke.

PURPOSE OF REVIEW: The purpose of this paper is to review recent updates in the acute management of childhood arterial ischemic stroke, including reperfusion therapies and neuroprotective measures. RECENT FINDINGS: With the emergence of pediatric stroke centers in recent years, processes facilitating rapid diagnosis and treatment have resulted in improved implementation of early targeted neuroprotective measures as well as the increased use of reperfusion therapies in childhood arterial ischemic stroke. Retrospective data has demonstrated that alteplase is safe in carefully selected children with arterial ischemic stroke in the first 4.5 h from symptom onset, though data regarding its efficacy in children are still lacking. There is also increasing data that suggests that thrombectomy in children with large vessel occlusion improves functional outcomes. Recent adult studies, including the use of Tenecteplase as an alteplase alternative and expansion of late thrombectomy to include patients with large ischemic cores, also are reviewed along with limitations to application of the adult data to pediatric care. SUMMARY: There have been significant advances in the hyperacute care of children with ischemic stroke and early diagnosis and targeted management are of the upmost importance in improving long-term outcomes.

Stroke in the young.

PURPOSE OF REVIEW: The purpose of this review is to review recent findings regarding stroke epidemiology, etiologies, and treatment in children and young adults. RECENT FINDINGS: Incidence in young adults is increasing, and incidence, recurrence, and survival is worse in patients with cryptogenic stroke and in developing countries. Careful consideration of patent foramen ovale closure is now recommended in young adults with cryptogenic stroke. Thrombectomy has recently been extended to carefully selected children with acute ischemic stroke, and two recent publications strongly suggest that it can be beneficial for children. Sickle cell is also an important global contributor to stroke burden, but hydroxyurea can be a cost effective medication for stroke prevention in children. Recent advances in genetic testing and treatments may improve outcomes for patients with monogenic causes of stroke, such as deficiency of adenosine deaminase 2, hemophilia, and Fabry's disease. SUMMARY: Stroke in children and young adults is a morbid disease responsible for enormous indirect societal costs and a high burden of years with disability per affected patient. Recent advances have improved access to care for children with large vessel occlusion and adults with rare causes of stroke. Future research may bring effective treatments for other monogenic causes of stroke as well as increasing access to hyperacute therapies for young stroke patients.

Novel Presentation of Hemiplegic Migraine in a Patient With Cockayne Syndrome.

BACKGROUND: Cockayne syndrome is a rare DNA repair disorder marked by premature aging, poor growth, and intellectual disability. Neurological complications such as seizures, movement disorder, and stroke have been reported. Hemiplegic migraine has not been reported in association with Cockayne syndrome. METHODS: We report a male with Cockayne syndrome due to biallelic heterozygous pathogenic variants in ERCC6 who presented repeatedly with transient focal neurological deficits and headache, which were consistent with hemiplegic migraine. Two siblings also had Cockayne syndrome and presented with similar symptoms. RESULTS: Our patient was originally diagnosed based on clinical suspicion and then confirmed by targeted exome analysis of genes associated with Cockayne syndrome. The family's research exome sequencing data were reanalyzed to identify variants in genes known to cause familial hemiplegic migraine. No variants in the genes known to cause familial hemiplegic migraine were identified. CONCLUSION: This is a novel association of familial hemiplegic migraine in three full siblings with Cockayne syndrome. Hemiplegic migraine has not previously been described as part of the Cockayne syndrome presentation. A separate genetic cause of familial hemiplegic migraines was not identified in an exome-based analysis of genes known to cause this condition. This report may represent an expansion of the Cockayne syndrome phenotype.

Successful thrombectomy in a pediatric patient with large vessel occlusion and COVID-19 related multisystem inflammatory syndrome.

This is a case report of a child with multisystem inflammatory syndrome in children (MIS-C) complicated by an acute ischemic stroke with right M1 occlusion and large penumbra who underwent thrombectomy with TICI 3 recanalization. There were no complications and the patient had improvement in the pediatric NIHSS from 16 to 3 in the subsequent days. This is the first known report of successful mechanical thrombectomy performed in a pediatric patient with MIS-C associated with COVID-19.

Pediatric Moyamoya Biomarkers: Narrowing the Knowledge Gap.

Moyamoya is a progressive cerebrovascular disorder that leads to stenosis of the arteries in the distal internal carotid, proximal middle cerebral and proximal anterior cerebral arteries of the circle of Willis. Typically a network of collaterals form to bypass the stenosis and maintain cerebral blood flow. As moyamoya progresses it affects the anterior circulation more commonly than posterior circulation, and cerebral blood flow becomes increasingly reliant on external carotid supply. Children with moyamoya are at increased risk for ischemic symptoms including stroke and transient ischemic attacks (TIA). In addition, cognitive decline may occur over time, even in the absence of clinical stroke. Standard of care for stroke prevention in children with symptomatic moyamoya is revascularization surgery. Treatment of children with asymptomatic moyamoya with revascularization surgery however remains more controversial. Therefore, biomarkers are needed to assist with not only diagnosis but also with determining ischemic risk and identifying best surgical candidates. In this review we will discuss the current knowledge as well as gaps in research in relation to pediatric moyamoya biomarkers including neurologic presentation, cognitive, neuroimaging, genetic and biologic biomarkers of disease severity and ischemic risk.

Moyamoya syndrome in a child with Legius syndrome: Introducing a cerebral vasculopathy to the SPRED1 phenotype?

Legius syndrome is a disorder of the RAS and mitogen-activated protein kinase (MAPK) pathway first described in 2007 by Eric Legius, et al., that has been considered a milder phenotype than reported in the RASopathy neurofibromatosis type 1 (NF1). However, with approximately 200 cases reported in the literature, the Legius syndrome phenotype remains to be fully characterized. We report a child who presented with moyamoya syndrome and who has Legius syndrome due to a pathogenic variant in SPRED1. Vascular complications such as moyamoya syndrome have been reported in NF1. However, this association has not been reported in Legius syndrome. This child's case may represent an expansion of the clinical phenotype of Legius syndrome, and further study is needed. We emphasize the importance of obtaining neuroimaging studies in patients with Legius syndrome who present with new neurologic deficits.

Early outcomes in youth with psychogenic nonsyncopal collapse.

OBJECTIVE: To evaluate several early outcome measures following diagnosis of psychogenic nonsyncopal collapse (PNSC). METHODS: Over a 34-month period, a prospective cohort study was conducted of patients referred for tilt-table evaluation of fainting and orthostatic intolerance. Clinical histories were obtained and anxiety and depressive symptom questionnaires were completed prior to testing. Among 539 patients referred, 100 (18.6%) were diagnosed with PNSC. Outcome data were collected by telephone or during routine follow-up a median of 572 days postdiagnosis. RESULTS: Eighty-four patients (84%) provided outcome data. Following communication of the diagnosis, 32 patients (38%) had immediate PNSC resolution. Attack resolution occurred in 44% by 1 month, 51% by 6 months, 52% by 12 months, 69% after 12 months, and 31% continued to have PNSC at the time of follow-up. Patients with continued PNSC had higher anxiety scores than patients with immediate resolution (p = 0.047). Following diagnosis, emergency department visits for fainting decreased from 78.6% to 20.2% (p = 0.017), and management by psychology or psychiatry increased from 26.2% to 76.2% (p < 0.001). During the follow-up period, 8 patients (9.5%) were hospitalized for suicidal ideation, a median of 253 (range 33-470) days postdiagnosis; 12 patients (14.3%) developed new (non-PNSC) conversion disorders, a median of 86 (range 9-504) days postdiagnosis. Suicidal ideation was associated with higher anxiety (p = 0.007) but not higher depression scores. CONCLUSIONS: The diagnostic rate of PNSC parallels that of PNES among patients referred for tertiary care evaluations. The improvements in attack frequency following PNSC diagnosis must be tempered by the potential risks of self-harm and the development of new conversion disorders.

Predicting Progression of Intracranial Arteriopathies in Childhood Stroke With Vessel Wall Imaging.

BACKGROUND AND PURPOSE: Childhood arterial ischemic stroke is frequently associated with an intracranial arteriopathy that often progresses in the first 3 to 6 months post stroke. We hypothesized that children with enhancing arteriopathies on vessel wall imaging (VWI) would have a higher risk of arteriopathy progression than those without enhancement. METHODS: Our institutional radiographic database was searched for cases of childhood stroke with VWI. Inclusion criteria consisted of age ranging from 1 month through 20 years, diagnosis of arterial ischemic stroke, available VWI, and follow-up magnetic resonance angiogram. Imaging was reviewed to systematically describe VWI findings, categorize arteriopathies, steroid therapy, and identify progressive arteriopathies using CACADE definitions. RESULTS: Sixteen cases of childhood stroke at Children's Hospital Colorado between January 1, 2010 and July 1, 2016 were reviewed. Strong vessel wall enhancement at presentation was associated with progressive arteriopathy in 83% of cases (10/12), when compared with 0% (0/4) without strong enhancement (P=0.008). CONCLUSIONS: Our case series demonstrates the potential benefit of VWI in children with stroke because it may identify patients who will have progressive arterial disease.

Pyruvate uptake is increased in highly invasive ovarian cancer cells under anoikis conditions for anaplerosis, mitochondrial function, and migration.

Anoikis resistance, or the ability for cells to live detached from the extracellular matrix, is a property of epithelial cancers. The "Warburg effect," or the preference of cancer cells for glycolysis for their energy production even in the presence of oxygen, has been shown to be evident in various tumors. Since a cancer cell's metastatic ability depends on microenvironmental conditions (nutrients, stromal cells, and vascularization) and is highly variable for different organs, their cellular metabolic fluxes and nutrient demand may show considerable differences. Moreover, a cancer cell's metastatic ability, which is dependent on the stage of cancer, may further create metabolic alterations depending on its microenvironment. Although recent studies have aimed to elucidate cancer cell metabolism under detached conditions, the nutrient demand and metabolic activity of cancer cells under nonadherent conditions remain poorly understood. Additionally, less is known about metabolic alterations in ovarian cancer cells with varying invasive capability under anoikis conditions. We hypothesized that the metabolism of highly invasive ovarian cancer cells in detachment would differ from less invasive ovarian cancer cells and that ovarian cancer cells will have altered metabolism in detached vs. attached conditions. To assess these metabolic differences, we integrated a secretomics-based metabolic footprinting (MFP) approach with mitochondrial bioenergetics. Interestingly, MFP revealed higher pyruvate uptake and oxygen consumption in more invasive ovarian cancer cells than their less invasive counterparts. Furthermore, ATP production was higher in more invasive vs. less invasive ovarian cancer cells in detachment. We found that pyruvate has an effect on highly invasive ovarian cancer cells' migration ability. Our results are the first to demonstrate that higher mitochondrial activity is related to higher ovarian cancer invasiveness under detached conditions. Importantly, our results bring insights regarding the metabolism of cancer cells under nonadherent conditions and could lead to the development of therapies for modulating cancer cell invasiveness.

Oncosecretomics coupled to bioenergetics identifies α-amino adipic acid, isoleucine and GABA as potential biomarkers of cancer: Differential expression of c-Myc, Oct1 and KLF4 coordinates metabolic changes.

Bioenergetic profiling of tumors is a new challenge of cancer research and medicine as therapies are currently being developed. Meanwhile, methodological means must be proposed to gather information on tumor metabolism in order to adapt these potential therapies to the bioenergetic specificities of tumors. Studies performed on tumors and cancer cell lines have shown that cancer cells bioenergetics is highly variable. This profile changes with microenvironmental conditions (eg. substrate availability), the oncogenes activated (and the tumor suppressors inactivated) and the interaction with the stroma (i.e. reverse Warburg effect). Here, we assessed the power of metabolic footprinting (MFP) to unravel the bioenergetics and associated anabolic changes induced by three oncogenes, c-Myc, KLF4 and Oct1. The MFP approach provides a quantitative analysis of the metabolites secreted and consumed by cancer cells. We used ultra performance liquid chromatography for quantifying the amino acid uptake and secretion. To investigate the potential oncogene-mediated alterations in mitochondrial metabolism, we measured oxygen consumption rate and ATP production as well as the glucose uptake and lactate release. Our findings show that c-Myc deficiency initiates the Warburg effect along with a reduction of mitochondrial respiration. KLF4 deficiency also stimulated glycolysis, albeit without cellular respiration impairment. In contrast, Oct1 deficiency reduced glycolysis and enhanced oxidative phosphorylation efficiency. MFP revealed that c-Myc, KLF4 and Oct1 altered amino acid metabolism with specific patterns. We identified isoleucine, α-aminoadipic acid and GABA (γ-aminoisobutyric acid) as biomarkers related. Our findings establish the impact of Oct1, KLF4 and c-Myc on cancer bioenergetics and evidence a link between oncosecretomics and cellular bioenergetics profile.