Publications by authors named "Alexandra Sinclair"

74 Publications

Diagnosis and management of migraine in ten steps.

Nat Rev Neurol 2021 Jun 18. Epub 2021 Jun 18.

Danish Headache Center, Department of Neurology, Rigshospitalet Glostrup, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark.

Migraine is a disabling primary headache disorder that directly affects more than one billion people worldwide. Despite its widespread prevalence, migraine remains under-diagnosed and under-treated. To support clinical decision-making, we convened a European panel of experts to develop a ten-step approach to the diagnosis and management of migraine. Each step was established by expert consensus and supported by a review of current literature, and the Consensus Statement is endorsed by the European Headache Federation and the European Academy of Neurology. In this Consensus Statement, we introduce typical clinical features, diagnostic criteria and differential diagnoses of migraine. We then emphasize the value of patient centricity and patient education to ensure treatment adherence and satisfaction with care provision. Further, we outline best practices for acute and preventive treatment of migraine in various patient populations, including adults, children and adolescents, pregnant and breastfeeding women, and older people. In addition, we provide recommendations for evaluating treatment response and managing treatment failure. Lastly, we discuss the management of complications and comorbidities as well as the importance of planning long-term follow-up.
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http://dx.doi.org/10.1038/s41582-021-00509-5DOI Listing
June 2021

Headache attributed to idiopathic intracranial hypertension and persistent post-idiopathic intracranial hypertension headache: A narrative review.

Headache 2021 Jun 9;61(6):808-816. Epub 2021 Jun 9.

Birmingham Neuro-Ophthalmology, Queen Elizabeth Hospital, Birmingham, UK.

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.
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http://dx.doi.org/10.1111/head.14125DOI Listing
June 2021

The Role of Metabolism in Migraine Pathophysiology and Susceptibility.

Life (Basel) 2021 May 1;11(5). Epub 2021 May 1.

Metabolic Neurology, Institute of Metabolism and Systems Research, College of Medical and Dental Sciences, University of Birmingham, Birmingham B15 2TT, UK.

Migraine is a highly prevalent and disabling primary headache disorder, however its pathophysiology remains unclear, hindering successful treatment. A number of key secondary headache disorders have headaches that mimic migraine. Evidence has suggested a role of mitochondrial dysfunction and an imbalance between energetic supply and demand that may contribute towards migraine susceptibility. Targeting these deficits with nutraceutical supplementation may provide an additional adjunctive therapy. Neuroimaging techniques have demonstrated a metabolic phenotype in migraine similar to mitochondrial cytopathies, featuring reduced free energy availability and increased metabolic rate. This is reciprocated in vivo when modelling a fundamental mechanism of migraine aura, cortical spreading depression. Trials assessing nutraceuticals successful in the treatment of mitochondrial cytopathies including magnesium, coenzyme q10 and riboflavin have also been conducted in migraine. Although promising results have emerged from nutraceutical trials in patients with levels of minerals or vitamins below a critical threshold, they are confounded by lacking control groups or cohorts that are not large enough to be representative. Energetic imbalance in migraine may be relevant in driving the tissue towards maximum metabolic capacity, leaving the brain lacking in free energy. Personalised medicine considering an individual's deficiencies may provide an approach to ameliorate migraine.
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http://dx.doi.org/10.3390/life11050415DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8147354PMC
May 2021

Outcomes measures in idiopathic intracranial hypertension.

Expert Rev Neurother 2021 Jun 7;21(6):687-700. Epub 2021 Jun 7.

Birmingham Neuro-Ophthalmology, Queen Elizabeth Hospital, Birmingham, United Kingdom (UK).

: Idiopathic intracranial hypertension is a condition characterized by raised intracranial pressure, papilledema, and normal neuroimaging (aside from radiological signs of raised intracranial pressure). Symptoms of idiopathic intracranial hypertension include chronic headaches and for some, visual loss. New treatments are unmet clinical needs.: The aim of this review is to present the evidence base and considered opinion on outcome measures to determine successful management of idiopathic intracranial hypertension.: Less invasive measures of disease activity such as optical coherence tomography will continue to grow in this field, both as a measure of papilledema, and potentially as a surrogate for intracranial pressure and visual function. As a highly disabling aspect of the disease is headache, treatment outcomes for headache morbidity need to be appropriately chosen and standardized to allow comparison between trials.
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http://dx.doi.org/10.1080/14737175.2021.1931127DOI Listing
June 2021

Post-traumatic headache attributed to traumatic brain injury: classification, clinical characteristics, and treatment.

Lancet Neurol 2021 06;20(6):460-469

Danish Headache Center, Department of Neurology, Rigshospitalet Glostrup, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark; Danish Knowledge Center on Headache Disorders, Glostrup, Denmark; Department of Nervous Diseases of the Institute of Professional Education, IM Sechenov First Moscow State Medical University, Moscow, Russia; Department of Neurology, Azerbaijan Medical University, Baku, Azerbaijan. Electronic address:

Post-traumatic headache is a common sequela of traumatic brain injury and is classified as a secondary headache disorder. In the past 10 years, considerable progress has been made to better understand the clinical features of this disorder, generating momentum to identify effective therapies. Post-traumatic headache is increasingly being recognised as a heterogeneous headache disorder, with patients often classified into subphenotypes that might be more responsive to specific therapies. Such considerations are not accounted for in three iterations of diagnostic criteria published by the International Headache Society. The scarcity of evidence-based approaches has left clinicians to choose therapies on the basis of the primary headache phenotype (eg, migraine and tension-type headache) and that are most compatible with the clinical picture. A concerted effort is needed to address these shortcomings and should include large prospective cohort studies as well as randomised controlled trials. This approach, in turn, will result in better disease characterisation and availability of evidence-based treatment options.
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http://dx.doi.org/10.1016/S1474-4422(21)00094-6DOI Listing
June 2021

Burden and attitude to resistant and refractory migraine: a survey from the European Headache Federation with the endorsement of the European Migraine & Headache Alliance.

J Headache Pain 2021 May 18;22(1):39. Epub 2021 May 18.

Christian Hospital, Unna, Germany.

Background: New treatments are currently offering new opportunities and challenges in clinical management and research in the migraine field. There is the need of homogenous criteria to identify candidates for treatment escalation as well as of reliable criteria to identify refractoriness to treatment. To overcome those issues, the European Headache Federation (EHF) issued a Consensus document to propose criteria to approach difficult-to-treat migraine patients in a standardized way. The Consensus proposed well-defined criteria for resistant migraine (i.e., patients who do not respond to some treatment but who have residual therapeutic opportunities) and refractory migraine (i.e., patients who still have debilitating migraine despite maximal treatment efforts). The aim of this study was to better understand the perceived impact of resistant and refractory migraine and the attitude of physicians involved in migraine care toward those conditions.

Methods: We conducted a web-questionnaire-based cross-sectional international study involving physicians with interest in headache care.

Results: There were 277 questionnaires available for analysis. A relevant proportion of participants reported that patients with resistant and refractory migraine were frequently seen in their clinical practice (49.5% for resistant and 28.9% for refractory migraine); percentages were higher when considering only those working in specialized headache centers (75% and 46% respectively). However, many physicians reported low or moderate confidence in managing resistant (8.1% and 43.3%, respectively) and refractory (20.7% and 48.4%, respectively) migraine patients; confidence in treating resistant and refractory migraine patients was different according to the level of care and to the number of patients visited per week. Patients with resistant and refractory migraine were infrequently referred to more specialized centers (12% and 19%, respectively); also in this case, figures were different according to the level of care.

Conclusions: This report highlights the clinical relevance of difficult-to-treat migraine and the presence of unmet needs in this field. There is the need of more evidence regarding the management of those patients and clear guidance referring to the organization of care and available opportunities.
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http://dx.doi.org/10.1186/s10194-021-01252-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8130435PMC
May 2021

Cost-effectiveness of bariatric surgery versus community weight management to treat obesity-related idiopathic intracranial hypertension: evidence from a single-payer healthcare system.

Surg Obes Relat Dis 2021 Jul 30;17(7):1310-1316. Epub 2021 Mar 30.

Collaboration for Outcomes Research and Evaluation, Faculty of Pharmaceutical Sciences, University of British Columbia, Vancouver, Canada.

Background: Idiopathic intracranial hypertension (IIH) is associated with significant morbidity, predominantly affecting women of childbearing age living with obesity. Weight loss has demonstrated successful disease-modifying effects; however, the long-term cost-effectiveness of weight loss interventions for the treatment of IIH has not yet been established.

Objectives: To estimate the cost-effectiveness of weight-loss treatments for IIH.

Setting: Single-payer healthcare system (National Health Service, England).

Methods: A Markov model was developed comparing bariatric surgery with a community weight management intervention over 5-, 10-, and 20-year time horizons. Transition probabilities, utilities, and resource use were informed by the IIH Weight Trial (IIH:WT), alongside the published literature. A probabilistic sensitivity analysis was conducted to characterize uncertainty within the model.

Results: In the base case analysis, over a 20-year time horizon, bariatric surgery was "dominant," led to cost savings of £49,500, and generated an additional 1.16 quality-adjusted life years in comparison to the community weight management intervention. The probabilistic sensitivity analysis indicated a probability of 98% that bariatric surgery is the dominant option in terms of cost-effectiveness.

Conclusion: This economic modeling study has shown that when compared to community weight management, bariatric surgery is a highly cost-effective treatment option for IIH in women living with obesity. The model shows that surgery leads to long-term cost savings and health benefits, but that these do not occur until after 5 years post surgery, and then gradually increase over time.
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http://dx.doi.org/10.1016/j.soard.2021.03.020DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8241428PMC
July 2021

Effectiveness of Bariatric Surgery vs Community Weight Management Intervention for the Treatment of Idiopathic Intracranial Hypertension: A Randomized Clinical Trial.

JAMA Neurol 2021 06;78(6):678-686

Department of Metabolic Neurology, Institute of Metabolism and Systems Research, College of Medical and Dental Sciences, University of Birmingham, Birmingham, United Kingdom.

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 Participants: This 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 Measures: The 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.

Results: Of 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, -21.4 [5.4] kg; 95% CI, -32.1 to -10.7 kg; P < .001) and at 24 months (adjusted mean [SE] difference, -26.6 [5.6] 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 Relevance: In this randomized clinical trial, bariatric surgery was superior to a CWM intervention in lowering intracranial pressure. The continued improvement over the course of 2 years shows the impact of this intervention with regard to sustained disease remission.

Trial Registration: ClinicalTrials.gov Identifier: NCT02124486.
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http://dx.doi.org/10.1001/jamaneurol.2021.0659DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8077040PMC
June 2021

Systemic and adipocyte transcriptional and metabolic dysregulation in idiopathic intracranial hypertension.

JCI Insight 2021 May 24;6(10). Epub 2021 May 24.

Institute of Metabolism and Systems Research, College of Medical and Dental Sciences, University of Birmingham, Birmingham, United Kingdom.

BACKGROUNDIdiopathic 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.METHODSIn 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.RESULTSWe demonstrate an insulin- and leptin-resistant phenotype in IIH in excess of 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 toward depot-specific lipogenesis.CONCLUSIONThese 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 improve cardiovascular outcomes.FUNDINGThis study was supported by the UK NIHR (NIHR-CS-011-028), the UK Medical Research Council (MR/K015184/1), Diabetes UK, Wellcome Trust (104612/Z/14/Z), the Sir Jules Thorn Award, and the Midlands Neuroscience Teaching and Research Fund.
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http://dx.doi.org/10.1172/jci.insight.145346DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8262372PMC
May 2021

Migraine: disease characterisation, biomarkers, and precision medicine.

Lancet 2021 04 25;397(10283):1496-1504. Epub 2021 Mar 25.

Institute of Psychiatry, Psychology and Neuroscience, King's College London, UK.

Migraine is a disabling neurological disorder, diagnosis of which is based on clinical criteria. A shortcoming of these criteria is that they do not fully capture the heterogeneity of migraine, including the underlying genetic and neurobiological factors. This complexity has generated momentum for biomarker research to improve disease characterisation and identify novel drug targets. In this Series paper, we present the progress that has been made in the search for biomarkers of migraine within genetics, provocation modelling, biochemistry, and neuroimaging research. Additionally, we outline challenges and future directions for each biomarker modality. We also discuss the advances made in combining and integrating data from multiple biomarker modalities. These efforts contribute to developing precision medicine that can be applied to future patients with migraine.
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http://dx.doi.org/10.1016/S0140-6736(20)32162-0DOI Listing
April 2021

Headache for ophthalmologists: current advances in headache understanding and management.

Eye (Lond) 2021 Jun 12;35(6):1574-1586. Epub 2021 Feb 12.

Department of Neurology, University Hospitals Birmingham NHS Foundation Trust, B15 2TH, Birmingham, UK.

Patients with headache and head pain are often referred to ophthalmologists. These symptoms can either be associated with underlying ophthalmic conditions, or more often are headache disorders unrelated to the eyes. Understanding the phenotype of the headache is critical for advice, safe discharge or onward referral. This review will provide an update on the criteria for common headache disorders that are often seen by ophthalmology and embrace disorders associated with ophthalmic diseases. It will also describe the changing management of migraine and outline recent therapies that are currently available.
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http://dx.doi.org/10.1038/s41433-021-01421-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8169696PMC
June 2021

Green Flags and headache: A concept study using the Delphi method.

Headache 2021 02 6;61(2):300-309. Epub 2021 Jan 6.

Department of Neurology, University Hospital Zurich, Zurich, Switzerland.

Objective: The aim of this study was to collect and rate Green Flags, that is, symptoms or pieces of information indicating that a patient is more likely to suffer from a primary than from a secondary headache.

Background: When assessing headaches, a central question to be answered is whether the pain is primary or secondary to another disorder. To maximize the likelihood of a correct diagnosis, relevant signs and symptoms must be sought, identified, and weighed against each other.

Methods: The project was designed as a Delphi study. In the first round, an expert panel proposed green flags that were rated anonymously in two subsequent rounds. Proposals with an average rating of 4.0 and higher on a scale from 0 to 5 reached consensus.

Results: Five Green Flags reached consensus: (i) "The current headache has already been present during childhood"; (ii) "The headache occurs in temporal relationship with the menstrual cycle"; (iii) "The patient has headache-free days"; (iv) "Close family members have the same headache phenotype"; and (v) "Headache occurred or stopped more than one week ago."

Conclusions: We propose five Green Flags for primary headache disorders. None being a pathognomonic sign, we recommend searching for both Green Flags and Red Flags. If both are present, a secondary headache should be suspected. Overall, the application of the Green Flag concept in clinical practice is likely to increase diagnostic accuracy and improve diagnostic resource allocation. Prospective studies in clinical populations should be conducted to validate these Green Flags.
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http://dx.doi.org/10.1111/head.14054DOI Listing
February 2021

Negative impact of COVID-19 lockdown on papilloedema and idiopathic intracranial hypertension.

J Neurol Neurosurg Psychiatry 2021 07 24;92(7):795-797. Epub 2020 Dec 24.

Metabolic Neurology, Institute of Metabolism and Systems Research, University of Birmingham, Birmingham, UK

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http://dx.doi.org/10.1136/jnnp-2020-325519DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8223635PMC
July 2021

Erenumab for headaches in idiopathic intracranial hypertension: A prospective open-label evaluation.

Headache 2021 Jan 14;61(1):157-169. Epub 2020 Dec 14.

Metabolic Neurology, Institute of Metabolism and Systems Research, College of Medical and Dental Sciences, University of Birmingham, Birmingham, UK.

Objective: To determine the effectiveness of erenumab in treating headaches in idiopathic intracranial hypertension (IIH) in whom papilledema had resolved.

Background: Disability in IIH is predominantly driven by debilitating headaches with no evidence for the use of preventative therapies. Headache therapy in IIH is an urgent unmet need.

Methods: A prospective, open-label study in the United Kingdom was conducted. Adult females with confirmed diagnosis of IIH now in ocular remission (papilledema resolved) with chronic headaches (≥15 days a month) and failure of ≥3 preventative medications received erenumab 4-weekly (assessments were 3-monthly). The primary end point was change in monthly moderate/severe headache days (MmsHD) from baseline (30-day pretreatment period) compared to 12 months.

Results: Fifty-five patients, mean (SD) age 35.3 (9) years and mean duration of headaches 10.4 (8.4) years with 3.7 (0.9) preventative treatment failures, were enrolled. Mean baseline MmsHD was 16.1 (4.7) and total monthly headache days (MHD) was (29) 2.3. MmsHD reduced substantially at 12 months by mean (SD) [95% CI] 10.8 (4.0) [9.5, 11.9], p < 0.001 and MHD reduced by 13.0 (9.5) [10.2, 15.7], p < 0.001. Crystal clear days (days without any head pain) increased by 13.1 (9.5) [9.6, 15.3], p < 0.001, headache severity (scale 0-10) fell by 1.3 (1.7) [0.9, 1.9], p < 0.001, and monthly analgesic days reduced by 4.3 (9.2) [1.6, 6.9], p = 0.002. All these measures had improved significantly by 3 months, with a consistent significant response to 12 months. Headache impact test-6 score and quality of life Short Form-36 Health Survey significantly improved at 12 months. Sensitivity analysis revealed similar results for patients with and without a prior migraine diagnosis (28/55 (52%) patients) or those with or without medication overuse (27/55 (48%) patients).

Conclusions: This study provides evidence for the effectiveness of erenumab to treat headaches in IIH patients with resolution of papilledema. It provides mechanistic insights suggesting that calcitonin gene-related peptide is likely a modulator driving headache and a useful therapeutic target.
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http://dx.doi.org/10.1111/head.14026DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7898289PMC
January 2021

New horizons for idiopathic intracranial hypertension: advances and challenges.

Br Med Bull 2020 12;136(1):118-126

Metabolic Neurology, Institute of Metabolism and Systems Research, College of Medical and Dental Sciences, University of Birmingham, Birmingham B15 2TT, UK.

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.
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http://dx.doi.org/10.1093/bmb/ldaa034DOI Listing
December 2020

11βHSD1 Inhibition with AZD4017 Improves Lipid Profiles and Lean Muscle Mass in Idiopathic Intracranial Hypertension.

J Clin Endocrinol Metab 2021 Jan;106(1):174-187

Institute of Metabolism and Systems Research, College of Medical and Dental Sciences, University of Birmingham, Birmingham, UK.

Background: The enzyme 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1) determines prereceptor metabolism and activation of glucocorticoids within peripheral tissues. Its dysregulation has been implicated in a wide array of metabolic diseases, leading to the development of selective 11β-HSD1 inhibitors. We examined the impact of the reversible competitive 11β-HSD1 inhibitor, AZD4017, on the metabolic profile in an overweight female cohort with idiopathic intracranial hypertension (IIH).

Methods: We conducted a UK multicenter phase II randomized, double-blind, placebo-controlled trial of 12-week treatment with AZD4017. Serum markers of glucose homeostasis, lipid metabolism, renal and hepatic function, inflammation and androgen profiles were determined and examined in relation to changes in fat and lean mass by dual-energy X-ray absorptiometry.

Results: Patients receiving AZD4017 showed significant improvements in lipid profiles (decreased cholesterol, increased high-density lipoprotein [HDL] and cholesterol/HDL ratio), markers of hepatic function (decreased alkaline phosphatase and gamma-glutamyl transferase), and increased lean muscle mass (1.8%, P < .001). No changes in body mass index, fat mass, and markers of glucose metabolism or inflammation were observed. Patients receiving AZD4017 demonstrated increased levels of circulating androgens, positively correlated with changes in total lean muscle mass.

Conclusions: These beneficial metabolic changes represent a reduction in risk factors associated with raised intracranial pressure and represent further beneficial therapeutic outcomes of 11β-HSD1 inhibition by AZD4017 in this overweight IIH cohort. In particular, beneficial changes in lean muscle mass associated with AZD4017 may reflect new applications for this nature of inhibitor in the management of conditions such as sarcopenia.
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http://dx.doi.org/10.1210/clinem/dgaa766DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7765633PMC
January 2021

Using Optical Coherence Tomography as a Surrogate of Measurements of Intracranial Pressure in Idiopathic Intracranial Hypertension.

JAMA Ophthalmol 2020 12;138(12):1264-1271

Metabolic Neurology, Institute of Metabolism and Systems Research, College of Medical and Dental Sciences, University of Birmingham, Birmingham, United Kingdom.

Importance: There 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.

Objective: To determine whether OCT of the optic nerve head in papilledema could act as a surrogate measure of ICP.

Design, Setting, And Participants: This 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 Measures: Optical 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.

Results: A 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 Relevance: In 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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http://dx.doi.org/10.1001/jamaophthalmol.2020.4242DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7582233PMC
December 2020

Calcitonin gene related peptide monoclonal antibody treats headache in patients with active idiopathic intracranial hypertension.

J Headache Pain 2020 Sep 25;21(1):116. Epub 2020 Sep 25.

Metabolic Neurology, Institute of Metabolism and Systems Research, College of Medical and Dental Sciences, University of Birmingham, Birmingham, B15 2TT, UK.

Background: Headache is the dominant factor for quality of life related disability in idiopathic intracranial hypertension (IIH) and typically has migraine-like characteristics. There are currently no evidence-based therapeutics for headache in IIH, and consequently this is an important unmet clinical need.

Case Series: We report a series of seven patients in whom headaches were the presenting feature of IIH and the headaches had migraine-like characteristics, as is typical in many IIH patients. Papilloedema settled (ocular remission) but headaches continued. These headaches responded markedly to erenumab, a monoclonal antibody targeted against the calcitonin gene related peptide (CGRP) receptor. Of note, there was a recurrence of raised ICP, as evidenced by a return of the papilloedema, however the headaches did not recur whilst treated with erenumab.

Conclusions: Those with prior IIH who have their headaches successfully treated with CGRP therapy, should remain under close ocular surveillance (particularly when weight gain is evident) as papilloedema can re-occur in the absence of headache. These cases may suggest that CGRP could be a mechanistic driver for headache in patients with active IIH.
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http://dx.doi.org/10.1186/s10194-020-01182-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7523364PMC
September 2020

11β-Hydroxysteroid dehydrogenase type 1 inhibition in idiopathic intracranial hypertension: a double-blind randomized controlled trial.

Brain Commun 2020 10;2(1):fcz050. Epub 2020 Jan 10.

Institute of Metabolism and Systems Research, College of Medical and Dental Sciences, University of Birmingham, Birmingham B15 2TT, UK.

Treatment options for idiopathic intracranial hypertension are limited. The enzyme 11β-hydroxysteroid dehydrogenase type 1 has been implicated in regulating cerebrospinal fluid secretion, and its activity is associated with alterations in intracranial pressure in idiopathic intracranial hypertension. We assessed therapeutic efficacy, safety and tolerability and investigated indicators of efficacy of the 11β-hydroxysteroid dehydrogenase type 1 inhibitor AZD4017 compared with placebo in idiopathic intracranial hypertension. A multicenter, UK, 16-week phase II randomized, double-blind, placebo-controlled trial of 12-week treatment with AZD4017 or placebo was conducted. Women aged 18-55 years with active idiopathic intracranial hypertension (>25 cmHO lumbar puncture opening pressure and active papilledema) were included. Participants received 400 mg of oral AZD4017 twice daily compared with matching placebo over 12 weeks. The outcome measures were initial efficacy, safety and tolerability. The primary clinical outcome was lumbar puncture opening pressure at 12 weeks analysed by intention-to-treat. Secondary clinical outcomes were symptoms, visual function, papilledema, headache and anthropometric measures. efficacy was evaluated in the central nervous system and systemically. A total of 31 subjects [mean age 31.2 (SD = 6.9) years and body mass index 39.2 (SD = 12.6) kg/m] were randomized to AZD4017 ( = 17) or placebo ( = 14). At 12 weeks, lumbar puncture pressure was lower in the AZD4017 group (29.7 cmHO) compared with placebo (31.3 cmHO), but the difference between groups was not statistically significant (mean difference: -2.8, 95% confidence interval: -7.1 to 1.5; =0.2). An exploratory analysis assessing mean change in lumbar puncture pressure within each group found a significant decrease in the AZD4017 group [mean change: -4.3 cmHO (SD = 5.7); =0.009] but not in the placebo group [mean change: -0.3 cmHO (SD = 5.9); =0.8]. AZD4017 was safe, with no withdrawals related to adverse effects. Nine transient drug-related adverse events were reported. One serious adverse event occurred in the placebo group (deterioration requiring shunt surgery). biomarkers of 11β-hydroxysteroid dehydrogenase type 1 activity (urinary glucocorticoid metabolites, hepatic prednisolone generation, serum and cerebrospinal fluid cortisol:cortisone ratios) demonstrated significant enzyme inhibition with the reduction in serum cortisol:cortisone ratio correlating significantly with reduction in lumbar puncture pressure ( = 0.005,  = 0.70). This is the first phase II randomized controlled trial in idiopathic intracranial hypertension evaluating a novel therapeutic target. AZD4017 was safe and well tolerated and inhibited 11β-hydroxysteroid dehydrogenase type 1 activity . Reduction in serum cortisol:cortisone correlated with decreased intracranial pressure. Possible clinical benefits were noted in this small cohort. A longer, larger study would now be of interest.
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http://dx.doi.org/10.1093/braincomms/fcz050DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7425517PMC
January 2020

Emerging themes in idiopathic intracranial hypertension.

J Neurol 2020 Dec 22;267(12):3776-3784. Epub 2020 Jul 22.

Metabolic Neurology, Institute of Metabolism and Systems Research, College of Medical and Dental Sciences, University of Birmingham, Birmingham, B15 2TT, UK.

Purpose: Idiopathic intracranial hypertension (IIH) is a rare disorder characterised by raised intracranial pressure. The underlying pathophysiology is mostly unknown and effective treatment is an unmet clinical need in this disease. This review evaluates key emerging themes regarding disease characteristics, mechanisms contributing to raised intracranial pressure and advances in potential therapeutic targets.

Findings: IIH is becoming more common, with the incidence rising in parallel with the global obesity epidemic. Current medical management remains centred around weight management, which is challenging. Metabolic investigations of patients have identified specific androgen profiles in cerebrospinal fluid (CSF), which suggest an endocrine dysfunction impacting CSF secretion in IIH. Glucagon-like peptide-1 (GLP-1) and 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1) have been found to play a role in CSF dynamics in IIH and have formed the basis of the first clinical trials looking at new treatments.

Conclusions: Identification of novel molecular targets thought to underlie IIH pathology is now being translated to clinical trials.
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http://dx.doi.org/10.1007/s00415-020-10090-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7674362PMC
December 2020

Idiopathic intracranial hypertension: Update on diagnosis and management.

Clin Med (Lond) 2020 07;20(4):384-388

University Hospitals Birmingham NHS Foundation Trust, Birmingham, UK and University of Birmingham, Edgbaston, UK

Idiopathic intracranial hypertension is a condition of raised intracranial pressure of unknown cause. Features include new onset headache, which is frequently non-specific; papilloedema is present, visual disturbances are common; and there may be sixth nerve palsy. Diagnosis includes brain imaging with venography to exclude structural causes and venous sinus thrombosis. Lumbar puncture reveals pressure greater than 250 mmCSF with normal constituents. Treatments aim to modify the disease, prevent permanent visual loss and manage headaches. These include weight loss. For those with rapid visual decline, urgent surgical intervention is essential. For most, this is a chronic condition characterised by significantly disabling headaches.
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http://dx.doi.org/10.7861/clinmed.2020-0232DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7385768PMC
July 2020

European headache federation consensus on the definition of resistant and refractory migraine : Developed with the endorsement of the European Migraine & Headache Alliance (EMHA).

J Headache Pain 2020 Jun 16;21(1):76. Epub 2020 Jun 16.

Department of Clinical and Molecular Medicine, Sapienza University of Rome, Rome, Italy.

Introduction: Despite advances in the management of headache disorders, some patients with migraine do not experience adequate pain relief with acute and preventive treatments. It is the aim of the present document to provide a definition of those migraines which are difficult-to-treat, to create awareness of existence of this group of patients, to help Healthcare Authorities in understanding the implications, and to create a basis to develop a better pathophysiological understanding and to support further therapeutic advances.

Main Body: Definitions were established with a consensus process using the Delphi method. Patients with migraine with or without aura or with chronic migraine can be defined as having resistant migraine and refractory migraine according to previous preventative failures. Resistant migraine is defined by having failed at least 3 classes of migraine preventatives and suffer from at least 8 debilitating headache days per month for at least 3 consecutive months without improvement; definition can be based on review of medical charts. Refractory migraine is defined by having failed all of the available preventatives and suffer from at least 8 debilitating headache days per month for at least 6 consecutive months. Drug failure may include lack of efficacy or lack of tolerability. Debilitating headache is defined as headache causing serious impairment to conduct activities of daily living despite the use of pain-relief drugs with established efficacy at the recommended dose and taken early during the attack; failure of at least two different triptans is required.

Conclusions: We hope, that the updated EHF definition will be able to solve the conflicts that have limited the use of definitions which have been put forward in the past. Only with a widely accepted definition, progresses in difficult-to-treat migraine can be achieved. This new definition has also the aim to increase the understanding of the impact of the migraine as a disease with all of its social, legal and healthcare implications. It is the hope of the EHF Expert Consensus Group that the proposed criteria will stimulate further clinical, scientific and social attention to patients who suffer from migraine which is difficult-to-treat.
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http://dx.doi.org/10.1186/s10194-020-01130-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7296705PMC
June 2020

Guide to preclinical models used to study the pathophysiology of idiopathic intracranial hypertension.

Eye (Lond) 2020 08 2;34(8):1321-1333. Epub 2020 Jan 2.

Metabolic Neurology, Institute of Metabolism and Systems Research, College of Medical and Dental Sciences, University of Birmingham, Birmingham, B15 2TT, UK.

Idiopathic intracranial hypertension (IIH) is characterised by raised intracranial pressure (ICP) and papilloedema in the absence of an identifiable secondary cause typically occurring in young women with obesity. The impact is considerable with the potential for blindness, chronic disabling headaches, future risk of cardiovascular disease and marked healthcare utilisation. There have been marked advances in our understanding the pathophysiology of IIH including the role of androgen excess. Insight into pathophysiological underpinnings has arisen from astute clinical observations, studies, and an array of preclinical models. This article summarises the current literature pertaining to the pathophysiology of IIH. The current preclinical models relevant to gaining mechanistic insights into IIH are then discussed. In vitro and in vivo models which study CSF secretion and the effect of potentially pathogenic molecules have started to glean important mechanistic insights. These models are also useful to evaluate novel therapeutic targets to abrogate CSF secretion. Importantly, in vitro CSF secretion assays translate into relevant changes in ICP in vivo. Models of CSF absorption pertinent to IIH, are less well established but highly relevant and of future interest. There is no fully developed in vivo model of IIH but this remains an area of importance. Progress is being made to improve our understanding of the underlying aetiology in IIH including the characterisation of disease biomarkers and their mechanistic role in driving disease pathology. Preclinical models, used to evaluate IIH mechanisms are yielding important mechanistic insights. Further work to refine these techniques will provide translatable insights into disease aetiology.
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http://dx.doi.org/10.1038/s41433-019-0751-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7376028PMC
August 2020

Non-invasive vagus nerve stimulation (nVNS) for the preventive treatment of episodic migraine: The multicentre, double-blind, randomised, sham-controlled PREMIUM trial.

Cephalalgia 2019 Oct 15;39(12):1475-1487. Epub 2019 Sep 15.

Leiden University Medical Center, Leiden, The Netherlands.

Introduction: Non-invasive vagus nerve stimulation (nVNS; gammaCore®) has the potential to prevent migraine days in patients with migraine on the basis of mechanistic rationale and pilot clinical data.

Methods: This multicentre study included a 4-week run-in period, a 12-week double-blind period of randomised treatment with nVNS or sham, and a 24-week open-label period of nVNS. Patients were to administer two 120-second stimulations bilaterally to the neck three times daily (6-8 hours apart).

Results: Of 477 enrolled patients, 332 comprised the intent-to-treat (ITT) population. Mean reductions in migraine days per month (primary outcome) were 2.26 for nVNS (n = 165; baseline, 7.9 days) and 1.80 for sham (n = 167; baseline, 8.1 days) ( = 0.15). Results were similar across other outcomes. Upon observation of suboptimal adherence rates, post hoc analysis of patients with ≥ 67% adherence per month demonstrated significant differences between nVNS (n = 138) and sham (n = 140) for outcomes including reduction in migraine days (2.27 vs. 1.53;  = 0.043); therapeutic gains were greater in patients with aura than in those without aura. Most nVNS device-related adverse events were mild and transient, with application site discomfort being the most common.

Conclusions: Preventive nVNS treatment in episodic migraine was not superior to sham stimulation in the ITT population. The "sham" device inadvertently provided a level of active vagus nerve stimulation. Post hoc analysis showed significant effects of nVNS in treatment-adherent patients. PREMIUM; NCT02378844; https://clinicaltrials.gov/ct2/show/NCT02378844.
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http://dx.doi.org/10.1177/0333102419876920DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6791025PMC
October 2019

United Kingdom CSF Disorders Day 2018.

Neuroophthalmology 2019 Apr 8;43(2):131-134. Epub 2019 Feb 8.

Birmingham Neuro-ophthalmology Unit, University Hospital Birmingham, Birmingham, UK.

The multi-specialty approach to managing patients with cerebrospinal fluid (CSF) disorders requires neurology, neurosurgery, neuroradiology and neuro-ophthalmology. The annual United Kingdom CSF disorders meeting presented the first guidelines for idiopathic intracranial hypertension focusing on protecting the vision, managing the underlying disease and reducing headache morbidity. The most recent scientific concepts in CSF disorders were presented, as was the applied understanding of shunt and valve technology.
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http://dx.doi.org/10.1080/01658107.2018.1561722DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6619955PMC
April 2019

Association Between Idiopathic Intracranial Hypertension and Risk of Cardiovascular Diseases in Women in the United Kingdom.

JAMA Neurol 2019 Sep;76(9):1088-1098

Metabolic Neurology, Institute of Metabolism and Systems Research, University of Birmingham, Birmingham, United Kingdom.

Importance: Cardiovascular disease (CVD) risk has not been previously evaluated in a large matched cohort study in idiopathic intracranial hypertension (IIH).

Objectives: To estimate the risk of composite cardiovascular events, heart failure, ischemic heart disease, stroke/transient ischemic attack (TIA), type 2 diabetes, and hypertension in women with idiopathic intracranial hypertension and compare it with the risk in women, matched on body mass index (BMI) and age, without the condition; and to evaluate the prevalence and incidence of IIH.

Design, Setting, And Participants: This population-based matched controlled cohort study used 28 years of data, from January 1, 1990, to January 17, 2018, from The Health Improvement Network (THIN), an anonymized, nationally representative electronic medical records database in the United Kingdom. All female patients aged 16 years or older were eligible for inclusion. Female patients with IIH (n = 2760) were included and randomly matched with up to 10 control patients (n = 27 125) by BMI and age.

Main Outcomes And Measures: Adjusted hazard ratios (aHRs) of cardiovascular outcomes were calculated using Cox regression models. The primary outcome was a composite of any CVD (heart failure, ischemic heart disease, and stroke/TIA), and the secondary outcomes were each CVD outcome, type 2 diabetes, and hypertension.

Results: In total, 2760 women with IIH and 27 125 women without IIH were included. Age and BMI were similar between the 2 groups, with a median (interquartile range) age of 32.1 (25.6-42.0) years in the exposed group and 32.1 (25.7-42.1) years in the control group; in the exposed group 1728 women (62.6%) were obese, and in the control group 16514 women (60.9%) were obese. Higher absolute risks for all cardiovascular outcomes were observed in women with IIH compared with control patients. The aHRs were as follows: composite cardiovascular events, 2.10 (95% CI, 1.61-2.74; P < .001); heart failure, 1.97 (95% CI, 1.16-3.37; P = .01); ischemic heart disease, 1.94 (95% CI, 1.27-2.94; P = .002); stroke/TIA, 2.27 (95% CI, 1.61-3.21; P < .001); type 2 diabetes, 1.30 (95% CI, 1.07-1.57; P = .009); and hypertension, 1.55 (95% CI, 1.30-1.84; P < .001). The incidence of IIH in female patients more than tripled between 2005 and 2017, from 2.5 to 9.3 per 100 000 person-years. Similarly, IIH prevalence increased in the same period, from 26 to 79 per 100 000 women. Incidence increased markedly with BMI higher than 30.

Conclusions And Relevance: Idiopathic intracranial hypertension in women appeared to be associated with a 2-fold increase in CVD risk; change in patient care to modify risk factors for CVD may reduce long-term morbidity for women with IIH and warrants further evaluation.
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http://dx.doi.org/10.1001/jamaneurol.2019.1812DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6618853PMC
September 2019

What are the research priorities for idiopathic intracranial hypertension? A priority setting partnership between patients and healthcare professionals.

BMJ Open 2019 03 15;9(3):e026573. Epub 2019 Mar 15.

Department of Metabolic Neurology, University of Birmingham, Birmingham, UK.

Objective: Idiopathic intracranial hypertension (IIH) is under-researched and the aim was to determine the top 10 research priorities for this disease.

Design: A modified nominal group technique was used to engage participants who had experience of IIH.

Setting: This James Lind Alliance Priority Setting Partnership was commissioned by IIH UK, a charity.

Participants: People with IIH, carers, family and friends, and healthcare professionals participated in two rounds of surveys to identify unique research questions unanswered by current evidence. The most popular 26 uncertainties were presented to stakeholders who then agreed the top 10 topics.

Results: The top 10 research priorities for IIH included aetiology of IIH, the pathological mechanisms of headache in IIH, new treatments in IIH, the difference between acute and gradual visual loss, the best ways to monitor visual function, biomarkers of the disease, hormonal causes of IIH, drug therapies for the treatment of headache, weight loss and its role in IIH and finally, the best intervention to treat IIH and when should surgery be performed.

Conclusions: This priority setting encouraged people with direct experience of IIH to collectively identify critical gaps in the existing evidence. The overarching research aspiration was to understand the aetiology and management of IIH.
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http://dx.doi.org/10.1136/bmjopen-2018-026573DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6429891PMC
March 2019

Tip of the iceberg in idiopathic intracranial hypertension.

Pract Neurol 2019 04;19(2):178-179

Metabolic Neurology, Institute of Metabolism and Systems Research, University of Birmingham, Birmingham, UK

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http://dx.doi.org/10.1136/practneurol-2019-002198DOI Listing
April 2019

Novel advances in monitoring and therapeutic approaches in idiopathic intracranial hypertension.

Curr Opin Neurol 2019 06;32(3):422-431

Metabolic Neurology, Institute of Metabolism and Systems Research, University of Birmingham.

Purpose Of Review: The current article appraises the recent developments in idiopathic intracranial hypertension (IIH), with particular attention to novel therapeutic avenues and advanced clinical assessment and monitoring with optical coherence tomography and telemetric intracranial pressure devices.

Recent Findings: The incidence of IIH is increasing. The first consensus guidelines for IIH have been published detailing investigation and management algorithms for adult IIH. Improved understanding, clinical assessment and monitoring are emerging with the use of optical coherence tomography. Intracranial pressure telemetry is providing unique insights into the physiology of raised intracranial pressure in IIH. There are now an increasing number of ongoing clinical trials evaluating weight loss methods and novel targeted therapies, such as 11ß-HSD1 inhibition and Glucagon-like peptide 1 (GLP-1) receptor agonists.

Summary: Several studies are evaluating new therapies for IIH. Monitoring techniques are advancing, aiding diagnosis and allowing the clinician to accurately evaluate changes in papilloedema and intracranial pressure.
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http://dx.doi.org/10.1097/WCO.0000000000000690DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6522204PMC
June 2019

A unique androgen excess signature in idiopathic intracranial hypertension is linked to cerebrospinal fluid dynamics.

JCI Insight 2019 03 21;4(6). Epub 2019 Mar 21.

Institute of Metabolism and Systems Research, University of Birmingham, Edgbaston, Birmingham, United Kingdom.

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.
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http://dx.doi.org/10.1172/jci.insight.125348DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6483000PMC
March 2019
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