Idiopathic intracranial hypertension, hormones, and 11?-hydroxysteroid dehydrogenases.
ABSTRACT: Idiopathic intracranial hypertension (IIH) results in raised intracranial pressure (ICP) leading to papilledema, visual dysfunction, and headaches. Obese females of reproductive age are predominantly affected, but the underlying pathological mechanisms behind IIH remain unknown. This review provides an overview of pathogenic factors that could result in IIH with particular focus on hormones and the impact of obesity, including its role in neuroendocrine signaling and driving inflammation. Despite occurring almost exclusively in obese women, there have been a few studies evaluating the mechanisms by which hormones and adipokines exert their effects on ICP regulation in IIH. Research involving 11?-hydroxysteroid dehydrogenase type 1, a modulator of glucocorticoids, suggests a potential role in IIH. Improved understanding of the complex interplay between adipose signaling factors such as adipokines, steroid hormones, and ICP regulation may be key to the understanding and future management of IIH.
Project description:BACKGROUND:Idiopathic intracranial hypertension (IIH) is a condition with few effective management options. So far, there have been no randomized controlled trials evaluating new treatments in IIH. OBJECTIVES:The purpose of this paper is to outline the trial design for the Idiopathic Intracranial Hypertension Drug Trial (IIH:DT), assessing an innovative medical treatment in IIH and the rationale for the chosen trial methodology. METHODS:IIH:DT is a phase II double-blind randomized placebo-controlled trial recruiting 30 female participants with active IIH (intracranial pressure >25cm H2 O and papilledema). Participants are randomized in a 1:1 ratio to 12 weeks of either AZD4017, an 11?-hydroxysteroid dehydrogenase type 1 inhibitor, or a matching placebo. They receive either 400 mg of AZD4017 or placebo twice daily. Participants are followed up at Weeks 1, 2, 3, 4, 6, 8, 10, 12, and 16 postrandomization. The primary outcome is to examine the effect of AZD4017 on intracranial pressure, measured by lumbar puncture, over 12 weeks. Secondary outcome measures include IIH symptoms, visual function, papilledema, headache measures, safety, and tolerability. Cerebrospinal fluid, serum, plasma, urine, and adipose tissue are also taken for exploratory outcomes. RESULTS:All participants were recruited between April 2014 and August 2016. CONCLUSIONS:IIH:DT is the first phase II double-blind randomized placebo-controlled trial assessing the efficacy and safety of the novel pharmacological intervention, AZD4017, for the treatment of IIH. TRIAL REGISTRATION:Clinicaltrials.gov NCT02017444; https://clinicaltrials.gov/ct2/show/NCT02017444 (Archived by WebCite at http://www.webcitation.org/6tVHesN6s).
Project description:Idiopathic intracranial hypertension (IIH) is a disorder characterized by signs and symptoms of increased intracranial pressure without structural cause seen on conventional imaging. Hallmark treatment after failed medical management, has been CSF shunting or optic nerve fenestration with the goal of treatment being preservation of vision. Recently, there have been multiple case reports and case series on dural sinus stenting for this disorder.We aim to review all published cases and case series of dural sinus stenting for IIH, with analysis of patient presenting symptoms, objective findings (CSF pressures, papilledema, pressure gradients across dural sinuses), follow-up of objective findings, and complications.A Medline search was performed to identify studies meeting pre-specified criteria of a case report or case series of patients treated with dural sinus stent placement for IIH. The manuscripts were reviewed and data was extracted.A total of 22 studies were identified, of which 19 studies representing 207 patients met criteria and were included in the analysis. Only 3 major complications related to procedure were identified. Headaches resolved or improved in 81% of patients. Papilledema improved the (172/189) 90%. Sinus pressure decreased from an average of 30.3 to 15 mm Hg. Sinus pressure gradient decreased from 18.5 (n=185) to 3.2 mm Hg (n=172). Stenting had an overall symptom improvement rate of 87%.Although all published case reports and case series are nonrandomized, the low complication and high symptom improvement rate make dural sinus stenting for IIH a potential alternative surgical treatment. Standardized patient selection and randomization trials or registry are warranted.
Project description:INTRODUCTION:Effective treatments are lacking for idiopathic intracranial hypertension (IIH), a condition characterised by raised intracranial pressure (ICP) and papilloedema, and found primarily in obese women. Weight loss and lowering body mass index (BMI) have been shown to lower ICP and improve symptoms in IIH; however, weight loss is typically not maintained, meaning IIH symptoms return. The Idiopathic Intracranial Hypertension Weight Trial (IIH:WT) will assess whether bariatric surgery is an effective long-term treatment for patients with IIH with a BMI over 35?kg/m2. The National Institute for Health and Care Excellence recommends bariatric surgery in people with a BMI over 35?kg/m2 and a qualifying comorbidity; currently IIH does not qualify as a comorbidity. METHODS AND ANALYSIS:IIH:WT is a multicentre, open-label, randomised controlled clinical trial of 64 participants with active IIH and a BMI over 35?kg/m2. Participants will be randomised in a 1:1 ratio to bariatric surgery or a dietary weight loss programme and followed up for 5 years. The primary outcome measure is ICP at 12 months. Secondary outcome measures include ICP at 24 and 60 months, and IIH symptoms, visual function, papilloedema, headache, quality of life and cost-effectiveness at 12, 24 and 60 months. TRIAL REGISTRATION NUMBER:IIH:WT is registered as ISRCTN40152829 and on ClinicalTrials.gov as NCT02124486 and is in the pre-results stage.
Project description:Point-of-care ultrasound (POCUS) has the potential to diagnose papilledema, a sign of increased intracranial pressure, through optic disc elevation as well as optic nerve sheath diameter measurements. Idiopathic intracranial hypertension (IIH) is a syndrome resulting in increased intracranial pressure. We present a case of IIH where the emergency physician diagnosed papilledema by POCUS via presence of both optic disc elevation and a widened optic nerve sheath diameter.
Project description: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.
Project description:Idiopathic intracranial hypertension (IIH, pseudotumor cerebri) is a syndrome of elevated intracranial pressure of unknown cause that occurs predominantly in obese women of childbearing age. It is a diagnosis of exclusion and, therefore, other causes of increased intracranial pressure must be sought with history, imaging, and cerebrospinal fluid examination before the diagnosis can be made. IIH produces symptoms and signs of increased intracranial pressure, including papilledema. If untreated, papilledema can cause progressive irreversible visual loss and optic atrophy. The treatment approach depends on the severity and time course of symptoms and visual loss, as determined by formal visual field testing. The main goals of treatment are alleviation of symptoms, including headache, and preservation of vision. All overweight IIH patients should be encouraged to enter a weight-management program with a goal of 5-10 % weight loss, along with a low-salt diet. When there is mild visual loss, medical treatment with acetazolamide should be initiated. Other medical treatments can be added or substituted when acetazolamide is insufficient as monotherapy or poorly tolerated. When visual loss is more severe or rapidly progressive, surgical interventions, such as optic nerve sheath fenestration or cerebrospinal fluid shunting, may be required to prevent further irreversible visual loss. The choice of intervention depends on the relative severity of symptoms and visual loss, as well as local expertise. At present, the role of transverse venous sinus stenting remains unclear. Although there are no evidence-based data to guide therapy, there is an ongoing randomized double-blind placebo-controlled treatment trial, investigating diet and acetazolamide therapy for IIH.
Project description:Idiopathic intracranial hypertension (IIH) may result in a chronic debilitating disease. Dural venous sinus stenosis with a physiologic venous pressure gradient has been identified as a potential etiology in a number of IIH patients. Intracranial venous stenting has emerged as a potential treatment alternative.A systematic review was carried out to identify studies employing venous stenting for IIH.From 2002 to 2014, 17 studies comprising 185 patients who underwent 221 stenting procedures were reported. Mean prestent pressure gradient was 20.1 mmHg (95% CI 19.4-20.7 mmHg) with a mean poststent gradient of 4.4 mmHg (95% CI 3.5-5.2 mmHg). Complications occurred in 10 patients (5.4%; 95% CI 4.7-5.4%) but were major in only 3 (1.6%). At a mean clinical follow-up of 22 months, clinical improvement was noted in 130 of 166 patients with headaches (78.3%; 95% CI 75.8-80.8%), 84 of 89 patients with papilledema (94.4%; 95% CI 92.1-96.6%), and 64 of 74 patients with visual symptoms (86.5%; 95% CI 83.0-89.9%). In-stent stenosis was noted in six patients (3.4%; 95% CI 2.5-4.3%) and stent-adjacent stenosis occurred in 19 patients (11.4%; 95% CI 10.4-12.4), resulting in restenting in 10 patients.In IIH patients with venous sinus stenosis and a physiologic pressure gradient, venous stenting appears to be a safe and effective therapeutic option. Further studies are necessary to determine the long-term outcomes and the optimal management of medically refractory IIH.
Project description:PURPOSE:To determine the frequency, patterns, associations, and biomechanical implications of retinal and choroidal folds in papilledema due to idiopathic intracranial hypertension (IIH). METHODS:Retinal and choroidal folds were studied in patients enrolled in the IIH Treatment Trial using fundus photography (n = 165 study eyes) and spectral-domain optical coherence tomography (SD-OCT; n = 125). We examined the association between folds and peripapillary shape, retinal nerve fiber layer (RNFL) thickness, disc volume, Frisén grade, acuity, perimetric mean deviation, intraocular pressure, intracranial pressure, and refractive error. RESULTS:We identified three types of folds in IIH patients with papilledema: peripapillary wrinkles (PPW), retinal folds (RF), and choroidal folds (CF). Frequency, with photos, was 26%, 19%, and 1%, respectively; SD-OCT frequency was 46%, 47%, and 10%. At least one type of fold was present in 41% of patients with photos and 73% with SD-OCT. Spectral-domain OCT was more sensitive. Structural parameters related to the severity of papilledema were associated with PPW and RF, whereas anterior deformation of the peripapillary RPE/basement membrane layer was associated with CF and RF. Folds were not associated with vision loss at baseline. CONCLUSIONS:Folds in papilledema are biomechanical signs of stress/strain on the optic nerve head and load-bearing structures induced by intracranial hypertension. Folds are best imaged with SD-OCT. The patterns of retinal and choroidal folds are the products of a complex interplay between the degree of papilledema and anterior deformation of the load-bearing structures (sclera and possibly the lamina cribrosa), both modulated by structural geometry and material properties of the optic nerve head. (ClinicalTrials.gov number, NCT01003639.).
Project description:Idiopathic intracranial hypertension (IIH) is a condition of unknown etiology, characterized by elevated intracranial pressure frequently manifesting with chronic headaches and visual loss. Similar to polycystic ovary syndrome (PCOS), IIH predominantly affects obese women of reproductive age. In this study, we comprehensively examined the systemic and cerebrospinal fluid (CSF) androgen metabolome in women with IIH in comparison with sex-, BMI-, and age-matched control groups with either simple obesity or PCOS (i.e., obesity and androgen excess). Women with IIH showed a pattern of androgen excess distinct to that observed in PCOS and simple obesity, with increased serum testosterone and increased CSF testosterone and androstenedione. Human choroid plexus expressed the androgen receptor, alongside the androgen-activating enzyme aldoketoreductase type 1C3. We show that in a rat choroid plexus cell line, testosterone significantly enhanced the activity of Na+/K+-ATPase, a surrogate of CSF secretion. We demonstrate that IIH patients have a unique signature of androgen excess and provide evidence that androgens can modulate CSF secretion via the choroid plexus. These findings implicate androgen excess as a potential causal driver and therapeutic target in IIH.
Project description:The visual impairment and intracranial pressure (VIIP) syndrome is a neuro-ophthalmologic condition described in astronauts returning from long duration space missions. Idiopathic intracranial hypertension (IIH), also known as pseudotumor cerebri, is characterized by a chronic elevation of intracranial pressure (ICP) in the absence of an intracranial mass lesion. Because VIIP and IIH share some neurologic and ophthalmologic manifestations, the latter might be used as a model to study some of the processes underlying VIIP. This work constitutes a preliminary investigation of the molecular pathways associated with the elevation of ICP in IIH. Gene expression signatures were obtained from exosomes collected from CSF and plasma in patients with possible signs of IIH. The gene expression targets focused on inflammatory genes and miRNAs. The results suggest that inflammatory cytokine-driven processes and immune cell migration are activated when ICP is elevated in IIH patients, either as a cause or effect of the ICP increase. Several miRNAs appear to be involved in this response, among which miR-9 and miR-16 are upregulated in CSF and plasma of higher ICP subjects. This study provides evidence in support of neurophysiological alterations and neuro-immunomodulation in this condition. If similar changes are seen in astronauts manifesting with the VIIP syndrome, an underlying pathophysiological basis may be discovered.