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Preclinical update on regulation of intracranial pressure in relation to idiopathic intracranial hypertension.

ABSTRACT: BACKGROUND:Elevated intracranial pressure (ICP) is observed in association with a range of brain disorders. One of these challenging disorders is idiopathic intracranial hypertension (IIH), characterized by raised ICP of unknown cause with significant morbidity and limited therapeutic options. In this review, special focus is put on the preclinical research performed in order to understand the pathophysiology behind ICP regulation and IIH. This includes cerebrospinal fluid dynamics, molecular mechanisms underlying disturbances in brain fluids leading to elevated ICP, role of obesity in IIH, development of an IIH model and ICP measurements in rodents. The review also discusses existing and new drug targets for IIH that have been evaluated in vivo. CONCLUSIONS:ICP monitoring in rodents is challenging and different methods have been applied. Some of these methods are invasive, depend on use of anesthesia and only allow short-term monitoring. Long-term ICP recordings are needed to study IIH but existing methods are hampered by several limitations. As obesity is one of the most common risk factors for IIH, a rodent obese model has been developed that mimics some key aspects of IIH. The most commonly used drugs for IIH have been evaluated in vivo for their efficacy at lowering ICP in the existing animal models. These studies suggest these drugs, including acetazolamide, might have limited or no reducing effect on ICP. Two drug targets that can impact ICP in healthy rodents are topiramate and a glucagon-like peptide-1 receptor (GLP-1R) agonist. However, it remains to evaluate their effect in an IIH model with more precise and valid ICP monitoring system. Therefore, continued evaluation in the preclinical research with refined tools is of great importance to further understand the pathophysiology behind disorders with raised ICP and to explore new drug targets.

SUBMITTER: Eftekhari S

PROVIDER: S-EPMC6878629 | biostudies-literature | 2019 Nov

REPOSITORIES: biostudies-literature

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Preclinical update on regulation of intracranial pressure in relation to idiopathic intracranial hypertension.

Eftekhari Sajedeh S Westgate Connar Stanley James CSJ Uldall Maria Schmidt MS Jensen Rigmor Hoejland RH

Fluids and barriers of the CNS 20191126 1

<h4>Background</h4>Elevated intracranial pressure (ICP) is observed in association with a range of brain disorders. One of these challenging disorders is idiopathic intracranial hypertension (IIH), characterized by raised ICP of unknown cause with significant morbidity and limited therapeutic options. In this review, special focus is put on the preclinical research performed in order to understand the pathophysiology behind ICP regulation and IIH. This includes cerebrospinal fluid dynamics, mole ...[more]

PMID: 31767019

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Project description:Cognitive impairments have been reported in idiopathic intracranial hypertension; however, evidence supporting these deficits is scarce and contributing factors have not been defined. Using a case-control prospective study, we identified multiple domains of deficiency in a cohort of 66 female adult idiopathic intracranial hypertension patients. We identified significantly impaired attention networks (executive function) and sustained attention compared to a body mass index and age matched control group of 25 healthy female participants. We aimed to investigate how cognitive function changed over time and demonstrated that deficits were not permanent. Participants exhibited improvement in several domains including executive function, sustained attention and verbal short-term memory over 12-month follow-up. Improved cognition over time was associated with reduction in intracranial pressure but not body weight. We then evaluated cognition before and after a lumbar puncture with acute reduction in intracranial pressure and noted significant improvement in sustained attention to response task performance. The impact of comorbidities (headache, depression, adiposity and obstructive sleep apnoea) was also explored. We observed that body mass index and the obesity associated cytokine interleukin-6 (serum and cerebrospinal fluid) were not associated with cognitive performance. Headache severity during cognitive testing, co-morbid depression and markers of obstructive sleep apnoea were adversely associated with cognitive performance. Dysregulation of the cortisol generating enzyme 11β hydroxysteroid dehydrogenase type 1 has been observed in idiopathic intracranial hypertension. Elevated cortisol has been associated with impaired cognition. Here, we utilized liquid chromatography-tandem mass spectrometry for multi-steroid profiling in serum and cerebrospinal fluid in idiopathic intracranial hypertension patients. We noted that reduction in the serum cortisol:cortisone ratio in those undergoing bariatric surgery at 12 months was associated with improving verbal working memory. The clinical relevance of cognitive deficits was noted in their significant association with impaired reliability to perform visual field tests, the cornerstone of monitoring vision in idiopathic intracranial hypertension. Our findings propose that cognitive impairment should be accepted as a clinical manifestation of idiopathic intracranial hypertension and impairs the ability to perform visual field testing reliably. Importantly, cognitive deficits can improve over time and with reduction of intracranial pressure. Treating comorbid depression, obstructive sleep apnoea and headache could improve cognitive performance in idiopathic intracranial hypertension.

Project description:PurposeTo evaluate the alteration of pressure characteristics in the cerebral venous sinuses before and after venous sinus stenting (VSS) using mean sinus pressures (MSPs), sinus pressure gradient (SPG), and sinus pressure pulsatility (SPP) parameters among the idiopathic intracranial hypertension (IIH) patients.Materials and methodsProspective evaluation of 45 consecutive IIH patients who underwent VSS at our institution. A written informed consent approved by the Weill Cornell Institutional Review Board was signed by the study participants. All patients (n = 45) were evaluated for MSPs and SPG. In a subgroup of 12 (n = 12) consecutive patients, SPP was measured. MSP was measured using microcatheter at superior sagittal sinus (SSS), transverse sinus (TS), and sigmoid sinus (SS). SPG was measured as trans-stenotic gradient and trans-torcular gradient. SPP was recorded in the dominant TS with a six French intermediate catheter. Statistical analysis was performed using paired student t-test and two sample t-tests tested for both equal and unequal variances. P values below 0.05 were considered significant.ResultsThe mean age of the study population was 30.6 ± 10 years (7-59 years) and 43 out of 45 are female patients. The mean weight and BMI of the study population were 96 ± 24.7 kg (30.8-144 kg) and 35.6 ± 8.3 kg/M2 (16.4-51.4 kg/M2), respectively. VSS in IIH patients resulted in immediate reduction of MSP in the SSS {Δ Mean: -8.1 mm Hg [95% confidence interval (CI): -5.0-11.7 mm Hg], p < 0.001} and TS [Δ Mean: -11.8 mm Hg (95% CI: -7.5 to 13.4 mm Hg), p < 0.001] and increase of MSP in SS [Δ Mean: 7.5 mm Hg (95% CI: 6-10.1 mm Hg), p < 0.001]. Significant reduction of trans-stenotic SPG reduction [Δ Mean: -15.7 mm Hg (95% CI: -13.6-17.8 mm Hg), p < 0.001] and SPP [Δ Mean: -8 mm Hg (95% CI: -2.5-13.4 mm Hg), p < 0.05] was observed following VSS.ConclusionVSS resulted in immediate alteration of the cerebral venous sinus pressure measurements in patients with IIH.

Project description:ObjectiveTo characterize the phenotype, headache-related disability, medical co-morbidities, use of symptomatic headache medications, and headache response to study interventions in the Idiopathic Intracranial Hypertension Treatment Trial (IIHTT).MethodsPatients with untreated IIH and mild vision loss enrolled in the IIHTT and randomized to acetazolamide (ACZ) and weight loss or placebo (PLB) and weight loss had prospective assessment of headache disability using the Headache Impact Test-6 (HIT-6) questionnaire. Subjects with headache at the baseline visit were assigned a headache phenotype using the International Classification for Headache Disorders version 3 beta (ICHD-3b). Medication overuse was determined using the participants' reported medication use for the preceding month and ICHD-3b thresholds for diagnosing medication overuse headache. We investigated relationships between headache disability and various other clinical characteristics at baseline and at 6 months.ResultsHeadache was present in 139 (84%) of the 165 enrollees at baseline. The most common headache phenotypes were migraine (52%), tension-type headache (22%), probable migraine (16%), and probable tension-type headache (4%). Fifty-one (37%) participants overused symptomatic medications at baseline, most frequently simple analgesics. A similar amount of improvement in the adjusted mean (± standard error) HIT-6 score occurred in the ACZ (-9.56 ± 1.05) and PLB groups (-9.11 ± 1.14) at 6 months (group difference -0.45, 95% CI -3.50 to 2.60, P = .77). Headache disability did not correlate with any of the studies, variables of interest, which included: the lumbar puncture opening pressure at baseline or at 6 months, body mass index, the amount of weight lost, papilledema grade, perimetric mean deviation, or the use of hormonal contraception. Headache disability was significantly associated with patient-reported quality of life in the physical, mental, and visual domains.ConclusionsHeadache was common, of varied character, disabling, and associated with poorer quality of life in our cohort of patients with mild visual impairment. The lack of correlation between headache disability and cerebrospinal fluid (CSF) pressure at baseline and at the end of the randomized phase of the study implies that headache in IIH may be related to factors other than intracranial hypertension, and that specific headache treatment is needed in addition to therapies directed at lowering CSF pressure.

Project description:ObjectiveTo observe intracranial pressure in women with idiopathic intracranial hypertension who follow a low energy diet.DesignProspective cohort study.SettingOutpatient department and the clinical research facility based at two separate hospitals within the United Kingdom.Participants25 women with body mass index (BMI) >25, with active (papilloedema and intracranial pressure >25 cm H(2)O), chronic (over three months) idiopathic intracranial hypertension. Women who had undergone surgery to treat idiopathic intracranial hypertension were excluded.InterventionStage 1: no new intervention; stage 2: nutritionally complete low energy (calorie) diet (1777 kJ/day (425 kcal/day)); stage 3: follow-up period after the diet. Each stage lasted three months.Main outcome measureThe primary outcome was reduction in intracranial pressure after the diet. Secondary measures included score on headache impact test-6, papilloedema (as measured by ultrasonography of the elevation of the optic disc and diameter of the nerve sheath, together with thickness of the peripapillary retina measured by optical coherence tomography), mean deviation of Humphrey visual field, LogMAR visual acuity, and symptoms. Outcome measures were assessed at baseline and three, six, and nine months. Lumbar puncture, to quantify intracranial pressure, was measured at baseline and three and six months.ResultsAll variables remained stable over stage 1. During stage 2, there were significant reductions in weight (mean 15.7 (SD 8.0) kg, P<0.001), intracranial pressure (mean 8.0 (SD 4.2) cm H(2)O, P<0.001), score on headache impact test (7.6 (SD 10.1), P=0.004), and papilloedema (optic disc elevation (mean 0.15 (SD 0.23) mm, P=0.002), diameter of the nerve sheath (mean 0.7 (SD 0.8) mm, P=0.004), and thickness of the peripapillary retina (mean 25.7 (SD 36.1) micro, P=0.001)). Mean deviation of the Humphrey visual field remained stable, and in only five patients, the LogMAR visual acuity improved by one line. Fewer women reported symptoms including tinnitus, diplopia, and obscurations (10 v 4, P=0.004; 7 v 0, P=0.008; and 4 v 0, P=0.025, respectively). Re-evaluation at three months after the diet showed no significant change in weight (0.21 (SD 6.8) kg), and all outcome measures were maintained.ConclusionWomen with idiopathic intracranial hypertension who followed a low energy diet for three months had significantly reduced intracranial pressure compared with pressure measured in the three months before the diet, as well as improved symptoms and reduced papilloedema. These reductions persisted for three months after they stopped the diet.

Project description:ImportanceThere is an unmet need for noninvasive biomarkers of intracranial pressure (ICP), which manifests as papilledema that can be quantified by optical coherence tomography (OCT) imaging.ObjectiveTo determine whether OCT of the optic nerve head in papilledema could act as a surrogate measure of ICP.Design, setting, and participantsThis longitudinal cohort study used data collected from 3 randomized clinical trials that were conducted between April 1, 2014, and August 1, 2019. Participants who were female and had active idiopathic intracranial hypertension were enrolled from 5 National Health Service hospitals in the UK. Automated perimetry and OCT imaging were followed immediately by ICP measurement on the same day. Cohort 1 used continuous sitting telemetric ICP monitoring (Raumedic Neurovent P-tel device) on 1 visit. Cohort 2 was evaluated at baseline and after 3, 12, and 24 months and underwent lumbar puncture assessment of ICP.Main outcomes and measuresOptical coherence tomography measures of the optic nerve head and macula were correlated with ICP levels, Frisén grading, and perimetric mean deviation. The OCT protocol included peripapillary retinal nerve fiber layer, optic nerve head, and macular volume scans (Spectralis [Heidelberg Engineering]). All scans were validated for quality and resegmented manually when required.ResultsA total of 104 women were recruited. Among cohort 1 (n = 15; mean [SD] age, 28.2 [9.4] years), the range of OCT protocols was evaluated, and optic nerve head central thickness was found to be most closely associated with ICP (right eye: r = 0.60; P = .02; left eye: r = 0.73; P = .002). Subsequently, findings from cohort 2 (n = 89; mean [SD] age, 31.8 [7.5] years) confirmed the correlation between central thickness and ICP longitudinally (12 and 24 months). Finally, bootstrap surrogacy analysis noted a positive association between central thickness and change in ICP at all points (eg, at 12 months, a decrease in central thickness of 50 μm was associated with a decrease in ICP of 5 cm H2O).Conclusions and relevanceIn this study, optic nerve head volume measures on OCT (particularly central thickness) reproducibly correlated with ICP and surrogacy analysis demonstrated its ability to inform ICP changes. These data suggest that OCT has the utility to not only monitor papilledema but also noninvasively prognosticate ICP levels in idiopathic intracranial hypertension.

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Preclinical update on regulation of intracranial pressure in relation to idiopathic intracranial hypertension.

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Preclinical update on regulation of intracranial pressure in relation to idiopathic intracranial hypertension.

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