IMPORTANCE Idiopathic intracranial hypertension (IIH) causes headaches, vision loss, and reduced quality of life. Sustained weight loss among patients with IIH is necessary to modify the disease and prevent relapse.OBJECTIVE To compare the effectiveness of bariatric surgery with that of a community weight management (CWM) intervention for the treatment of patients with active IIH. DESIGN, SETTING, AND PARTICIPANTSThis 5-year randomized clinical trial (Idiopathic Intracranial Hypertension Weight Trial) enrolled women with active IIH and a body mass index (calculated as weight in kilograms divided by height in meters squared) of 35 or higher at 5 National Health Service hospitals in the UK between March 1, 2014, and May 25, 2017. Of 74 women assessed for eligibility, 6 did not meet study criteria and 2 declined to participate; 66 women were randomized. Data were analyzed from November 1, 2018, to May 14, 2020.INTERVENTIONS Bariatric surgery (n = 33) or CWM intervention (Weight Watchers) (n = 33). MAIN OUTCOMES AND MEASURESThe primary outcome was change in intracranial pressure measured by lumbar puncture opening pressure at 12 months, as assessed in an intention-to-treat analysis. Secondary outcomes included lumbar puncture opening pressure at 24 months as well as visual acuity, contrast sensitivity, perimetric mean deviation, and quality of life (measured by the 36-item Short Form Health Survey) at 12 and 24 months. Because the difference in continuous outcomes between groups is presented, the null effect was at 0. RESULTSOf the 66 female participants (mean [SD] age, 32.0 [7.8] years), 64 (97.0%) remained in the clinical trial at 12 months and 54 women (81.8%) were included in the primary outcome analysis. Intracranial pressure was significantly lower in the bariatric surgery arm at 12 months (adjusted mean [SE] difference, −6.0 [1.8] cm cerebrospinal fluid [CSF]; 95% CI, −9.5 to −2.4 cm CSF; P = .001) and at 24 months (adjusted mean [SE] difference, −8.2 [2.0] cm CSF; 95% CI, −12.2 to −4.2 cm CSF; P < .001) compared with the CWM arm. In the per protocol analysis, intracranial pressure was significantly lower in the bariatric surgery arm at 12 months (adjusted mean [SE] difference, −7.2 [1.8] cm CSF; 95% CI, −10.6 to −3.7 cm CSF; P < .001) and at 24 months (adjusted mean [SE] difference, −8.7 [2.0] cm CSF; 95% CI, −12.7 to −4.8 cm CSF; P < .001). Weight was significantly lower in the bariatric surgery arm at 12 months (adjusted mean [SE] difference, kg; 95% CI, −32.1 to −10.7 kg; P < .001) and at 24 months (adjusted mean [SE] difference, kg; 95% CI, −37.5 to −15.7 kg; P < .001). Quality of life was significantly improved at 12 months (adjusted mean [SE] difference, 7.3 [3.6]; 95% CI, 0.2-14.4; P = .04) and 24 months (adjusted mean [SE] difference, 10.4 [3.8]; 95% CI, 3.0-17.9; P = .006) in the bariatric surgery arm. CONCLUSIONS AND RELEVANCEIn this randomized clinical trial, bariatric surgery was superior to a CWM intervention in lowering intracranial pressure. The continued improvement over the course of 2 year...

Background: Idiopathic intracranial hypertension (IIH) is a condition predominantly affecting obese women of reproductive age. Recent evidence suggests that IIH is a disease of metabolic dysregulation, androgen excess and an increased risk of cardiovascular morbidity.Here we evaluate systemic and adipose specific metabolic determinants of the IIH phenotype.Methods: In fasted, matched IIH (N=97) and control (N=43) patients, we assessed: glucose and insulin homeostasis and leptin levels. Body composition was assessed along with an interrogation of adipose tissue function via nuclear magnetic resonance metabolomics and RNA sequencing in paired omental and subcutaneous biopsies in a case control study. Results:We demonstrate an insulin and leptin resistant phenotype in IIH in excess to that driven by obesity. Adiposity in IIH is preferentially centripetal and is associated with increased disease activity and insulin resistance. IIH adipocytes appear transcriptionally and metabolically primed towards depot-specific lipogenesis.Conclusions: These data show that IIH is a metabolic disorder in which adipose tissue dysfunction is a feature of the disease. Managing IIH as a metabolic disease could reduce disease morbidity and improving cardiovascular outcomes.

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Objective Headache is a near‐universal sequela of idiopathic intracranial hypertension (IIH). The aim of this paper is to report current knowledge of headache in IIH and to identify therapeutic options. Background Disability in IIH is predominantly driven by headache; thus, headache management is an urgent and unmet clinical need. At present, there is currently no scientific evidence for the directed use of abortive or preventative headache therapy. Methods A detailed search of the scientific literature and narrative review was performed. Results Headache in IIH is driven by raised intracranial pressure (ICP) and reduction of ICP has been reported in some studies to reduce headache. Despite resolution of papilledema and normalization of raised ICP, a majority suffer persistent post‐IIH headache. The lack of evidence‐based management approaches leaves many untreated. Where clinicians attempt to manage IIH headache, they use off‐label therapies to target the prevailing headache phenotype. A recent prospective open‐label study demonstrated the effective use of a calcitonin gene‐related peptide monoclonal antibody therapy in IIH for persistent post‐IIH headache. Conclusions There is overwhelming evidence of the headache burden in IIH. Studies are required to investigate the biological foundations of headache related to ICP and to develop treatments specifically directed to manage headache in IIH.

Objective Headache is the predominant disabler in idiopathic intracranial hypertension (IIH). The aim was to characterise headache and investigate the association with intracranial pressure. Methods IIH:WT was a randomised controlled parallel group multicentre trial in the United Kingdom investigating weight management methods in IIH. Participants with active IIH (evidenced by papilloedema) and a body mass index (BMI) ≥35 kg/m2 were recruited. At baseline, 12 months and 24 months headache characteristics and quality of life outcome measures were collected and lumbar puncture measurements were performed. Results Sixty-six women with active IIH were included with a mean age of 32.0 years (SD ± 7.8), and mean body mass index of 43.9 ± 7.0 kg/m2. The headache phenotype was migraine-like in 90%. Headache severity correlated with ICP at baseline (r = 0.285; p = 0.024); change in headache severity and monthly headache days correlated with change in ICP at 12 months (r = 0.454, p = 0.001 and r = 0.419, p = 0.002 respectively). Cutaneous allodynia was significantly correlated with ICP at 12 months. (r = 0.479, p < 0.001). Boot strap analysis noted a positive association between ICP at 12 and 24 months and enabled prediction of both change in headache severity and monthly headache days. ICP was associated with significant improvements in quality of life (SF-36). Conclusions We demonstrate a positive relationship between ICP and headache and cutaneous allodynia, which has not been previously reported in IIH. Those with the greatest reduction in ICP over 12 months had the greatest reduction in headache frequency and severity; this was associated with improvement of quality of life measures. Trial registration This work provides Class IIa evidence of the association of raised intracranial pressure and headache. ClinicalTrials.gov number, NCT02124486.

Introduction Idiopathic intracranial hypertension (IIH) is becoming a recognized condition due to the increasing incidence linked to a global obesity epidemic. Sources of data All English papers on PubMed, Cochrane and Scholar between inception until 1 March 2020 were considered. Areas of agreement Studies suggest central adiposity has a pathogenic role. Recent weight gain is a risk factor and weight loss has a key role in management. Areas of controversy Interpretation of abnormal lumbar puncture opening pressure is debated. There is an increasing recognition of obesity stigma and how this should be approached. Growing points Further evidence is required for the choice of surgical intervention for fulminant IIH. Education regarding IIH should be evidence based. Areas timely for developing research Novel research of the pathology of IIH is influencing development of therapies such as glucagon-like peptide-1 receptor agonists and targeting unique androgen signatures. The newly discovered cardiovascular risk requires further attention.

Therapeutics to reduce intracranial pressure are an unmet need. Preclinical data have demonstrated a novel strategy to lower intracranial pressure using glucagon-like peptide-1 (GLP-1) receptor signalling. Here, we translate these findings into patients by conducting a randomized, placebo-controlled, double-blind trial to assess the effect of exenatide, a GLP-1 receptor agonist, on intracranial pressure in idiopathic intracranial hypertension. Telemetric intracranial pressure catheters enabled long-term intracranial pressure monitoring. The trial enrolled adult women with active idiopathic intracranial hypertension (intracranial pressure &gt;25 cmCSF and papilloedema) who receive subcutaneous exenatide or placebo. The three primary outcome measures were intracranial pressure at 2.5 h, 24 h and 12 weeks and alpha set a priori at less than 0.1. Among the 16 women recruited, 15 completed the study (mean age 28 ± 9, body mass index 38.1 ± 6.2 kg/m2, intracranial pressure 30.6 ± 5.1 cmCSF). Exenatide significantly and meaningfully lowered intracranial pressure at 2.5 h −5.7 ± 2.9 cmCSF (P = 0.048); 24 h −6.4 ± 2.9 cmCSF (P = 0.030); and 12 weeks −5.6 ± 3.0 cmCSF (P = 0.058). No serious safety signals were noted. These data provide confidence to proceed to a phase 3 trial in idiopathic intracranial hypertension and highlight the potential to utilize GLP-1 receptor agonist in other conditions characterized by raised intracranial pressure.

Cognitive impairments have been reported in Idiopathic Intracranial Hypertension (IIH), however evidence supporting these deficits are 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 IIH 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 months 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 CSF) 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 IIH. Elevated cortisol has been associated with impaired cognition. Here we utilised liquid chromatography-tandem mass spectrometry for multi-steroid profiling in serum and CSF in IIH 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 IIH. Our findings propose that cognitive impairment should be accepted as a clinical manifestation of IIH and impairs the ability to reliably perform visual field testing. 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 IIH.