The effect of GLP-1RA exenatide on idiopathic intracranial hypertension: a randomized clinical trial.

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 >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.

The Impact of Valsalva Manoeuvres and Exercise on Intracranial Pressure and Cerebrovascular Dynamics in Idiopathic Intracranial Hypertension.

Idiopathic intracranial hypertension (IIH) is a disease characterised by elevated intracranial pressure (ICP). The impact of straining and exercise on ICP regulation is poorly understood yet clinically relevant to IIH patient care. We sought to investigate the impact of Valsalva manoeuvres (VMs) and exercise on ICP and cerebrovascular haemodynamics in IIH. People with IIH were prospectively enrolled and had an intraparenchymal telemetric ICP sensor inserted. Three participants (age [mean ± standard deviation]: 40.3 ± 13.9 years) underwent continuous real-time ICP monitoring coupled with cerebrovascular haemodynamic assessments during VMs and moderate exercise. Participants had IIH with supine ICP measuring 15.3 ± 8.7 mmHg (20.8 ± 11.8 cm cerebrospinal fluid (CSF)) and sitting ICP measuring -4.2 ± 7.9 mmHg (-5.7 ± 10.7 cmCSF). During phase I of a VM ICP increased by 29.4 ± 13.5 mmHg (40.0 ± 18.4 cmCSF) but returned to baseline within 16 seconds from VM onset. The pattern of ICP changes during the VM phases was associated to that of changes in blood pressure, the middle cerebral artery blood velocity and prefrontal cortex haemodynamics. Exercise led to minimal effects on ICP. In conclusion, VM-induced changes in ICP were coupled to cerebrovascular haemodynamics and showed no sustained impact on ICP. Exercise did not lead to prolonged elevation of ICP. Those with IIH experiencing VMs (for example, during exercise and labour) may be reassured at the brief nature of the changes. Future research must look to corroborate the findings in a larger IIH cohort.

Dysregulation of Amino Acid, Lipid, and Acylpyruvate Metabolism in Idiopathic Intracranial Hypertension: A Non-targeted Case Control and Longitudinal Metabolomic Study.

Background: Idiopathic intracranial hypertension (IIH) is characterized by increased intracranial pressure occurring predominantly in women with obesity. The pathogenesis is not understood. We have applied untargeted metabolomic analysis using ultrahigh-performance liquid chromatography-mass spectrometry to characterize the cerebrospinal fluid (CSF) and serum in IIH compared to control subjects. Methods and findings: Samples were collected from IIH patients (n = 66) with active disease at baseline and again at 12 months following therapeutic weight loss. Control samples were collected from gender- and weight-matched healthy controls (n = 20). We identified annotated metabolites in CSF, formylpyruvate and maleylpyruvate/fumarylpyruvate, which were present at lower concentrations in IIH compared to control subjects and returned to values observed in controls following weight loss. These metabolites showed the opposite trend in serum at baseline. Multiple amino acid metabolic pathways and lipid classes were perturbed in serum and CSF in IIH alone. Serum lipid metabolite pathways were significantly increased in IIH. Conclusions: We observed a number of differential metabolic pathways related to amino acid, lipid, and acylpyruvate metabolism, in IIH compared to controls. These pathways were associated with clinical measures and normalized with disease remission. Perturbation of these metabolic pathways provides initial understanding of disease dysregulation in IIH.

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

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.

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

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.

Therapeutic lumbar puncture for headache in idiopathic intracranial hypertension: Minimal gain, is it worth the pain?

BACKGROUND: Headache is disabling and prevalent in idiopathic intracranial hypertension. Therapeutic lumbar punctures may be considered to manage headache. This study evaluated the acute effect of lumbar punctures on headache severity. Additionally, the effect of lumbar puncture pressure on post-lumbar puncture headache was evaluated. METHODS: Active idiopathic intracranial hypertension patients were prospectively recruited to a cohort study, lumbar puncture pressure and papilloedema grade were noted. Headache severity was recorded using a numeric rating scale (NRS) 0-10, pre-lumbar puncture and following lumbar puncture at 1, 4 and 6 hours and daily for 7 days. RESULTS: Fifty two patients were recruited (mean lumbar puncture opening pressure 32 (28-37 cmCSF). At any point in the week post-lumbar puncture, headache severity improved in 71% (but a small reduction of -1.1 ± 2.6 numeric rating scale) and exacerbated in 64%, with 30% experiencing a severe exacerbation ≥ 4 numeric rating scale. Therapeutic lumbar punctures are typically considered in idiopathic intracranial hypertension patients with severe headaches (numeric rating scale ≥ 7). In this cohort, the likelihood of improvement was 92% (a modest reduction of headache pain by -3.0 ± 2.8 numeric rating scale, p = 0.012, day 7), while 33% deteriorated. Idiopathic intracranial hypertension patients with mild (numeric rating scale 1-3) or no headache (on the day of lumbar puncture, prior to lumbar puncture) had a high risk of post- lumbar puncture headache exacerbation (81% and 67% respectively). Importantly, there was no relationship between lumbar puncture opening pressure and headache response after lumbar puncture. CONCLUSION: Following lumbar puncture, the majority of idiopathic intracranial hypertension patients experience some improvement, but the benefit is small and post-lumbar puncture headache exacerbation is common, and in some prolonged and severe. Lumbar puncture pressure does not influence the post-lumbar puncture headache.

Topiramate is more effective than acetazolamide at lowering intracranial pressure.

BACKGROUND: The management of idiopathic intracranial hypertension focuses on reducing intracranial pressure to preserve vision and reduce headaches. There is sparse evidence to support the use of some of the drugs commonly used to manage idiopathic intracranial hypertension, therefore we propose to evaluate the efficacy of these drugs at lowering intracranial pressure in healthy rats. METHODS: We measured intracranial pressure in female rats before and after subcutaneous administration of acetazolamide, topiramate, furosemide, amiloride and octreotide at clinical doses (equivalent to a single human dose) and high doses (equivalent to a human daily dose). In addition, we measured intracranial pressure after oral administration of acetazolamide and topiramate. RESULTS: At clinical and high doses, subcutaneous administration of topiramate lowered intracranial pressure by 32% ( p = 0.0009) and 21% ( p = 0.015) respectively. There was no significant reduction in intracranial pressure noted with acetazolamide, furosemide, amiloride or octreotide at any dose. Oral administration of topiramate significantly lowered intracranial pressure by 22% ( p = 0.018), compared to 5% reduction with acetazolamide ( p = >0.999). CONCLUSION: Our in vivo studies demonstrated that both subcutaneous and oral administration of topiramate significantly lowers intracranial pressure. Other drugs tested, including acetazolamide, did not significantly reduce intracranial pressure. Future clinical trials evaluating the efficacy and side effects of topiramate in idiopathic intracranial hypertension patients would be of interest.

Segmentation error in spectral domain optical coherence tomography measures of the retinal nerve fibre layer thickness in idiopathic intracranial hypertension.

BACKGROUND: Optical Coherence Tomography (OCT) imaging is being increasingly used in clinical practice for the monitoring of papilloedema. The aim is to characterise the extent and location of the Retinal Nerve Fibre Layer (RNFL) Thickness automated segmentation error (SegE) by manual refinement, in a cohort of Idiopathic Intracranial Hypertension (IIH) patients with papilloedema and compare this to controls. METHODS: Baseline Spectral Domain OCT (SDOCT) scans from patients with IIH, and controls with no retinal or optic nerve pathology, were examined. The internal limiting membrane and RNFL thickness of the most severely affected eye was examined for SegE and re-segmented. Using ImageJ, the total area of the RNFL thickness was calculated pre and post re-segmentation and the percentage change was determined. The distribution of RNFL thickness error was qualitatively assessed. RESULTS: Significantly greater SegE (p = 0.009) was present in RNFL thickness total area, assessed using ImageJ, in IIH patients (n = 46, 5% ± 0-58%) compared to controls (n = 14, 1% ± 0-6%). This was particularly evident in moderate to severe optic disc swelling (n = 23, 10% ± 0-58%, p < 0.001). RNFL thickness was unable to be quantified using SDOCT in patients with severe papilloedema. CONCLUSIONS: SegE remain a concern for clinicians using SDOCT to monitor papilloedema in IIH, particularly in the assessment of eyes with moderate to severe oedema. Systematic assessment and manual refinement of SegE is therefore important to ensure the accuracy in longitudinal monitoring of patients.

Effect of glucagon like peptide-1 receptor agonist exenatide, used as an intracranial pressure lowering agent, on cognition in Idiopathic Intracranial Hypertension.

BACKGROUND: Cognitive function can be affected in conditions with raised intracranial pressure (ICP) such as idiopathic intracranial hypertension (IIH). Drugs used off label to treat raised ICP also have cognitive side effects, underscoring the unmet need for effective therapeutics which reduce ICP without worsening cognition. The Glucagon Like Peptide-1 (GLP-1) receptor agonist, exenatide, has been shown to significantly reduce ICP in IIH, therefore this study aimed to determine the effects of exenatide on cognition in IIH. METHODS: This was an exploratory study of the IIH:Pressure trial (ISTCRN 12678718). Women with IIH and telemetric ICP monitors (n = 15) were treated with exenatide (n = 7) or placebo (n = 8) for 12 weeks. Cognitive function was tested using the National Institute of Health Toolbox Cognitive Battery at baseline and 12 weeks. RESULTS: Cognitive performance was impaired in fluid intelligence ((T-score of 50 = population mean), mean (SD) 37.20 (9.87)), attention (33.93 (7.15)) and executive function (38.07 (14.61)). After 12-weeks there was no evidence that exenatide compromised cognition (no differences between exenatide and placebo). Cognition improved in exenatide treated patients in fluid intelligence (baseline 38.4 (8.2), 12 weeks 52.9 (6.6), p = 0.0005), processing speed (baseline 43.7 (9.4), 12 weeks 58.4 (10.4), p = 0.0058) and episodic memory (baseline 49.4 (5.3), 12 weeks 62.1 (13.2), p = 0.0315). CONCLUSIONS: In patients with raised ICP due to IIH, exenatide, a drug emerging as an ICP lowering agent, does not adversely impact cognition. This is encouraging and has potential to be relevant when considering prescribing choices to lower ICP.

Idiopathic intracranial hypertension: a step change in understanding the disease mechanisms.

The understanding of idiopathic intracranial hypertension (IIH) has evolved over the past few years. Previously, IIH was considered a disease exclusively affecting the neuro-ophthalmic axis, characterized by raised intracranial pressure, headache and papilloedema, and resulting in the risk of severe and permanent visual loss and life-changing disabling headaches. Recent advances have begun to redefine IIH as a probable metabolic disease involving a range of systemic manifestations. More than 95% of individuals affected by the disease are women of reproductive age with obesity. The incidence is rapidly rising and parallels the escalating worldwide obesity rates. Contemporary insights identify associations with insulin resistance, type 2 diabetes and a twofold increased risk of cardiovascular disease in excess of that driven by obesity alone. Adipose distribution in people with IIH, like that in other metabolic diseases, is preferentially centripetal and is associated with changes in intracranial pressure. Evidence now demonstrates adipose tissue dysfunction in people with IIH, involving transcriptional and metabolic priming for lipogenesis and weight gain. Hormonal perturbations are also observed, including a unique phenotype of androgen excess that promotes cerebrospinal fluid secretion. Knowledge of these additional disease features is driving research into novel therapeutic targets and altering the approach to multidisciplinary care.

The idiopathic intracranial hypertension prospective cohort study: evaluation of prognostic factors and outcomes.

BACKGROUND: There are limited longitudinal data evaluating outcomes in idiopathic intracranial hypertension (IIH). We aimed to evaluate the long-term outcomes in a real-world cohort of patients with IIH and sought to establish the prognostic factors. METHODS: A longitudinal prospective cohort study was conducted over 9 years (2012-2021). Data included demographics and disease status. All consenting patients with IIH were recruited. Visual outcomes included visual acuity, Humphrey visual field and optical coherence tomography (OCT) imaging measurements. Headache frequency, severity, and impact were noted. We analysed the key variables impacting visual and headache outcomes. RESULTS: The cohort contained 490 patients with a confirmed IIH diagnosis. 98% were female with a mean body mass index (BMI) of 38 kg/m2. Those with the highest OCT retinal nerve fibre layer had the worst visual outcomes. We noted a delayed decline, in the visual field and OCT ganglion cell layer after 12 months. In the medically managed cohort (n = 426), we found that disease duration and change in BMI had the greatest influence on visual outcomes. There was a high burden of headache, with a daily headache at presentation and prior migraine history influencing long-term headache prognosis. CONCLUSIONS: There is a delayed decline in visual outcomes in those with the most severe papilloedema. Disease duration and change in BMI were the key visual prognostic factors, therefore those with the more acute disease may require closer monitoring. Improving prognosis in IIH should focus on the potentially modifiable factor of weight management.

Determining the role of novel metabolic pathways in driving intracranial pressure reduction after weight loss.

Idiopathic intracranial hypertension, a disease classically occurring in women with obesity, is characterized by raised intracranial pressure. Weight loss leads to the reduction in intracranial pressure. Additionally, pharmacological glucagon-like peptide-1 agonism reduces cerebrospinal fluid secretion and intracranial pressure. The potential mechanisms by which weight loss reduces intracranial pressure are unknown and were the focus of this study. Meal stimulation tests (fasted plasma sample, then samples at 15, 30, 60, 90 and 120 min following a standardized meal) were conducted pre- and post-bariatric surgery [early (2 weeks) and late (12 months)] in patients with active idiopathic intracranial hypertension. Dynamic changes in gut neuropeptides (glucagon-like peptide-1, gastric inhibitory polypeptide and ghrelin) and metabolites (untargeted ultra-high performance liquid chromatography-mass spectrometry) were evaluated. We determined the relationship between gut neuropeptides, metabolites and intracranial pressure. Eighteen idiopathic intracranial hypertension patients were included [Roux-en-Y gastric bypass (RYGB) n = 7, gastric banding n = 6 or sleeve gastrectomy n = 5]. At 2 weeks post-bariatric surgery, despite similar weight loss, RYGB had a 2-fold (50%) greater reduction in intracranial pressure compared to sleeve. Increased meal-stimulated glucagon-like peptide-1 secretion was observed after RYGB (+600%) compared to sleeve (+319%). There was no change in gastric inhibitory polypeptide and ghrelin. Dynamic changes in meal-stimulated metabolites after bariatric surgery consistently identified changes in lipid metabolites, predominantly ceramides, glycerophospholipids and lysoglycerophospholipids, which correlated with intracranial pressure. A greater number of differential lipid metabolites were observed in the RYGB cohort at 2 weeks, and these also correlated with intracranial pressure. In idiopathic intracranial hypertension, we identified novel changes in lipid metabolites and meal-stimulated glucagon-like peptide-1 levels following bariatric surgery which were associated with changes in intracranial pressure. RYGB was most effective at reducing intracranial pressure despite analogous weight loss to gastric sleeve at 2 weeks post-surgery and was associated with more pronounced changes in these metabolite pathways. We suggest that these novel perturbations in lipid metabolism and glucagon-like peptide-1 secretion are mechanistically important in driving a reduction in intracranial pressure following weight loss in patients with idiopathic intracranial hypertension. Therapeutic targeting of these pathways, for example with glucagon-like peptide-1 agonist infusion, could represent a therapeutic strategy.

Multiple lumbar punctures aiming to relieve headache results in iatrogenic spinal hematoma: a case report.

BACKGROUND: Multiple lumbar punctures have historically been a strategy to relieve headaches associated with idiopathic intracranial hypertension despite limited clinical evidence of long-term efficacy. Lumbar puncture is typically a straightforward procedure with minimal complications reported, however, serious complications can occur. Lumbar-puncture-related spinal hematomas are rare but can lead to irreversible paralysis. CASE PRESENTATION: We report a case of a 28-year-old Caucasian woman who was treated with multiple lumbar punctures to manage headache, thought to be attributed to idiopathic intracranial hypertension. The patient developed a lumbosacral epidural hematoma following a lumbar puncture, which led to incomplete cauda equina syndrome. Multiple lumbar punctures had been the long-term management for the patient's chronic headaches associated with her diagnosis of idiopathic intracranial hypertension. She had no risks of an underlying coagulopathy. Following a lumbar puncture, she re-presented with lower back pain and bilateral paresthesia. Over the subsequent 48 hours, this progressed to urinary incontinence and saddle paresthesia. Imaging revealed an epidural hematoma, which was conservatively managed. She continued to report saddle paresthesia and urinary incontinence 7 months following the lumbar puncture. Between 1974 to 2022, our literature search found 41 case reports detailing lumbar-puncture-related spinal hematomas. It is an established but rare complication of lumbar puncture and there are limited studies looking at the incidence of its occurrence. Whilst coagulopathy has been found to be a risk factor, it is unclear if the gauge of the needle is relevant. Case evidence suggests there may be no significant difference in outcomes between surgical and conservative management of spinal hematomas. This case highlights that lumbar punctures can be invasive, with potentially serious complications. A lumbar puncture should therefore only be performed when clinically justified. CONCLUSIONS: This case highlights a rare complication of lumbar puncture and emphasizes the importance of a risk-benefit discussion for each procedure. Spinal hematoma following lumbar puncture is a rare complication but with potentially devastating consequences. Within the setting of idiopathic intracranial hypertension, the evidence base for the long-term benefit of headache relief by repeat lumbar puncture is low.

Increased systemic and adipose 11ß-HSD1 activity in idiopathic intracranial hypertension.

Context: Idiopathic intracranial hypertension (IIH) is a disease of raised intracranial pressure (ICP) of unknown etiology. Reductions in glucocorticoid metabolism are associated with improvements in IIH disease activity. The basal IIH glucocorticoid metabolism is yet to be assessed. Objective: The objective of this study was to determine the basal glucocorticoid phenotype in IIH and assess the effects of weight loss on the IIH glucocorticoid phenotype. Design: A retrospective case-control study and a separate exploratory analysis of a prospective randomized intervention study were carried out. Methods: The case-control study compared female IIH patients to BMI, age, and sex-matched controls. In the randomized intervention study, different IIH patients were randomized to either a community weight management intervention or bariatric surgery, with patients assessed at baseline and 12 months. Glucocorticoid levels were determined utilizing 24-h urinary steroid profiles alongside the measurement of adipose tissue 11ß-HSD1 activity. Results: Compared to control subjects, patients with active IIH had increased systemic 11ß-hydroxysteroid dehydrogenase (11ß-HSD1) and 5α-reductase activity. The intervention study demonstrated that weight loss following bariatric surgery reduced systemic 11ß-HSD1 and 5α-reductase activity. Reductions in these were associated with reduced ICP. Subcutaneous adipose tissue explants demonstrated elevated 11ß-HSD1 activity compared to samples from matched controls. Conclusion: The study demonstrates that in IIH, there is a phenotype of elevated systemic and adipose 11ß-HSD1 activity in excess to that mediated by obesity. Bariatric surgery to induce weight loss was associated with reductions in 11ß-HSD1 activity and decreased ICP. These data reflect new insights into the IIH phenotype and further point toward metabolic dysregulation as a feature of IIH.

Association of Amount of Weight Lost After Bariatric Surgery With Intracranial Pressure in Women With Idiopathic Intracranial Hypertension.

BACKGROUND AND OBJECTIVES: The idiopathic intracranial hypertension randomized controlled weight trial (IIH:WT) established that weight loss through bariatric surgery significantly reduced intracranial pressure when compared with a community weight management intervention. This substudy aimed to evaluate the amount of weight loss required to reduce intracranial pressure and to explore the effect of different bariatric surgical approaches. METHODS: IIH:WT was a multicenter randomized controlled trial. Adult women with active idiopathic intracranial hypertension and a body mass index ≥35 kg/m2 were randomized to bariatric surgery or a community weight management intervention (1:1). This per-protocol analysis evaluated the relationship between intracranial pressure, weight loss, and the weight loss methods. A linear hierarchical regression model was used to fit the trial outcomes, adjusted for time, treatment arm, and weight. RESULTS: Sixty-six women were included, of whom 23 had received bariatric surgery by 12 months; the mean age was 31 (SD 8.7) years in the bariatric surgery group and 33.2 (SD 7.4) years in the dietary group. Baseline weight and intracranial pressure were similar in both groups with a mean weight of 119.5 (SD 24.1) and 117.9 (SD 19.5) kg and mean lumbar puncture opening pressure of 34.4 (SD 6.3) and 34.9 (SD 5.3) cmCSF in the bariatric surgery and dietary groups, respectively. Weight loss was significantly associated with reduction in intracranial pressure (R2 = 0.4734, p ≤ 0.0001). Twenty-four percentage of weight loss (weight loss of 13.3 kg [SD 1.76]) was associated with disease remission (intracranial pressure [ICP] ≤ 25 cmCSF). Roux-en-Y gastric bypass achieved greater, more rapid, and sustained ICP reduction compared with other methods. DISCUSSION: The greater the weight loss, the greater the reduction in ICP was documented. Twenty four percentage of weight loss was associated with disease remission. Such magnitude of weight loss was unlikely to be achieved without bariatric surgery, and hence, consideration of referral to a bariatric surgery program early for those with active idiopathic intracranial hypertension may be appropriate. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT02124486; ISRCTN registry number ISRCTN40152829; doi.org/10.1186/ISRCTN40152829. CLASSIFICATION OF EVIDENCE: This study provides Class II evidence that weight loss after bariatric surgery results in reduction in intracranial pressure in adult women with idiopathic intracranial hypertension. This study is Class II because of the use of a per-protocol analysis.

Evaluation of diurnal and postural intracranial pressure employing telemetric monitoring in idiopathic intracranial hypertension.

OBJECTIVES: Intracranial pressure (ICP) has been thought to vary diurnally. This study evaluates diurnal ICP measurements and quantifies changes in ICP occurring with changes in body posture in active idiopathic intracranial hypertension (IIH). METHODS: This prospective observational study utilized telemetric ICP monitoring in people with active IIH. Participants had the Raumedic p-Tel ICP intraparenchymal device (Raumedic, Hembrechts, Germany) surgically inserted. Changes in ICP in the supine position were evaluated. Then, the ICP was measured in the standing, sitting, supine, left lateral decubitus positions and with coughing and bending. Ultimately, changes in ICP over the course of 24 h were recorded. ISRCTN registration number 12678718. RESULTS: 15 women were included, mean (standard deviation) age 29.5 (9.5) years, body mass index 38.1 (6.2) kg/m2, and baseline mean ICP of 21.2 (4.8) mmHg (equivalent to 28.8 (6.5) cmCSF). Mean ICP rose with the duration in the supine position 1.2 (3.3) mmHg over 5-minutes (p = 0.175), 3.5 (2.8) mmHg over 30-minutes (p = 0.0002) and by a further 2.1 (2.2) mmHg over 3 h (p = 0.042). Mean ICP decreased by 51% when moving from the supine position to standing (21.2 (4.8) mmHg to 10.3 (3.7) mmHg respectively, p = 0.0001). Mean ICP increased by 13% moving from supine to the left lateral decubitus position (21.2 (4.8) mmHg to 24.0 (3.8) mmHg, p = 0.028). There was no significant difference in ICP measurements at any point during the daytime, or between 5-minute standing or supine recordings and prolonged ambulatory daytime and end of night supine recordings respectively. ICP, following an initial drop, increased progressively in conjunction with lying supine position from 23:00 h to 07:00 h by 34% (5.2 (1.9) mmHg, p = 0.026). CONCLUSION: This analysis demonstrated that ICP does not appear to have a diurnal variation in IIH, but varies by position and duration in the supine position. ICP rose at night whilst the patient was continuously supine. Furthermore, brief standing and supine ICP measures in the day predicted daytime prolonged ambulatory measures and end of night peak ICP respectively. This knowledge gives reassurance that ICP can be accurately measured and compared at any time of day in an ambulant IIH patient. These are useful findings to inform clinical measurements and in the interpretation of ICP analyses in IIH. TRIAL REGISTRATION: ISTCRN (12678718).

Obstructive sleep apnoea in women with idiopathic intracranial hypertension: a sub-study of the idiopathic intracranial hypertension weight randomised controlled trial (IIH: WT).

OBJECTIVE: Obesity is a risk factor for idiopathic intracranial hypertension (IIH) and obstructive sleep apnoea (OSA). We aimed to determine the prevalence of OSA in IIH and evaluate the diagnostic performance of OSA screening tools in IIH. Additionally, we evaluated the relationship between weight loss, OSA and IIH over 12 months. METHODS: A sub-study of a multi-centre, randomised controlled parallel group trial comparing the impact of bariatric surgery vs. community weight management intervention (CWI) on IIH-related outcomes over 12 months (IIH:WT). OSA was assessed using home-based polygraphy (ApneaLink Air, ResMed) at baseline and 12 months. OSA was defined as an apnoea-hypopnoea index (AHI) ≥ 15 or ≥ 5 with excessive daytime sleepiness (Epworth Sleepiness Scale ≥11 ). RESULTS: Of the 66 women in the IIH: WT trial, 46 were included in the OSA sub-study. OSA prevalence was 47% (n = 19). The STOP-BANG had the highest sensitivity (84%) compared to the Epworth Sleepiness Scale (69%) and Berlin (68%) to detect OSA. Bariatric surgery resulted in greater reductions in AHI vs. CWI (median [95%CI] AHI reduction of - 2.8 [ - 11.9, 0.7], p = 0.017). Over 12 months there was a positive association between changes in papilloedema and AHI (r = 0.543, p = 0.045), despite adjustment for changes in the body mass index (R2 = 0.522, p = 0.017). CONCLUSION: OSA is common in IIH and the STOP-BANG questionnaire was the most sensitive screening tool. Bariatric surgery improved OSA in patients with IIH. The improvement in AHI was associated with improvement in papilloedema independent of weight loss. Whether OSA treatment has beneficial impact on papilloedema warrants further evaluation. TRIAL REGISTRATION NUMBER: IIH: WT is registered as ISRCTN40152829 and on ClinicalTrials.gov as NCT02124486 (28/04/2014).

Nuclear Magnetic Resonance Spectroscopy Metabolomics in Idiopathic Intracranial Hypertension to Identify Markers of Disease and Headache.

BACKGROUND AND OBJECTIVE: We evaluated the metabolomic profile in CSF, serum and urine of participants with idiopathic intracranial hypertension (IIH) compared to controls and measured changes in metabolism associated with clinical markers of disease activity and treatment. METHODS: A case-control study compared women aged 18-55 years with active IIH (Friedman diagnostic criteria), to a sex, age and body mass index matched control group. IIH participants were identified from neurology and ophthalmology clinics from National Health Service hospitals and underwent a prospective intervention to induce disease remission through weight loss with re-evaluation at 12 months. Clinical assessments included lumbar puncture, headache, papilledema and visual measurements. Spectra of CSF, serum and urine metabolites were acquired utilizing proton nuclear magnetic resonance spectroscopy. RESULTS: Urea was lower in IIH (CSF; controls median ±IQR 0.196 ±0.008, IIH 0.058 ±0.059, p<0.001, urine; controls 5971.370 ±3021.831, IIH 4691.363 ±1955.774, p=0.009), correlated with ICP (urine p=0.019) and headache severity (CSF p=0.031) and increased by 12 months (CSF 12 months; 0.175 ±0.043, p=0.004, urine; 5210.874 ±1825.302, p=0.043). The lactate:pyruvate ratio was increased compared to controls (CSF; controls 49.739 ±19.523, IIH 113.114 ±117.298, p=0.023, serum; controls 38.187 ±13.392, IIH 54.547 ±18.471, p=0.004) and decreased at 12 months (CSF; 113.114 ±117.298, p<0.001). Baseline acetate was higher in IIH (CSF; controls 0.128 ±0.041, IIH 0.192 ±0.151, p=0.008), correlated with headache severity (p = 0.030) and headache disability (p = 0.003) and was reduced at 12 months (0.160 ±0.060, p = 0.007). Ketones 3-hydroxybutyrate and acetoacetate were altered in CSF at baseline in IIH (3-hydroxybutyrate; controls 0.074 ±0.063, IIH 0.049 ±0.055, p = 0.019, acetoacetate; controls 0.013 ±0.007, IIH 0.017 ±0.010, p = 0.013) and normalized at 12 months (0.112 ±0.114, p = 0.019, 0.029 ±0.017, p = 0.015 respectively). DISCUSSION: We observed metabolic disturbances that are evident in CSF, serum and urine of IIH participants, suggesting global metabolic dysregulation. Altered ketone body metabolites normalized following therapeutic weight loss. CSF:serum urea ratio was altered which may influence ICP dynamics and headache. Elevated CSF acetate, known to stimulate trigeminal sensitization, was associated with headache morbidity. These alterations of metabolic pathways specific to IIH provide biological insight and warrants mechanistic evaluation.

The Health Economic Evaluation of Bariatric Surgery Versus a Community Weight Management Intervention Analysis from the Idiopathic Intracranial Hypertension Weight Trial (IIH:WT).

BACKGROUND: The Idiopathic Intracranial Hypertension Weight Trial (IIH:WT) established the efficacy of bariatric surgery as compared to a community weight management intervention in reducing intracranial pressure in active IIH. The aim of this cost-effectiveness analysis was to evaluate the economic impact of these weight loss treatments for IIH. METHODS: IIH:WT was a five-year randomised, controlled, parallel group, multicentre trial in the United Kingdom, where participants with active IIH and a body mass index ≥35 kg/m2 were randomly assigned (1:1) to receive access to bariatric surgery or a community weight management intervention. All clinical and quality of life data was recorded at baseline, 12 and 24 months. Economic evaluation was performed to assess health-care costs and cost-effectiveness. Evaluations were established on an intention to treat principle, followed by a sensitivity analysis using a per protocol analysis. RESULTS: The mean total health care costs were GBP 1353 for the community weight management arm and GBP 5400 for the bariatric surgery arm over 24 months. The majority of costs for the bariatric surgery arm relate to the surgical procedure itself. The 85% who underwent bariatric surgery achieved a 12.5% reduction in intracranial pressure at 24 months as compared to 39% in the community weight management arm; a mean difference of 45% in favour of bariatric surgery. The cost effectiveness of bariatric surgery improved over time. CONCLUSIONS: The IIH:WT was the first to compare the efficacy and cost-effectiveness of bariatric surgery with community weight management interventions in the setting of a randomised control trial. The cost-effectiveness of bariatric surgery improved over time and therefore the incremental cost of surgery when offset against the incremental reduction of intracranial pressure improved after 24 months, as compared with 12 months follow up.

Cognitive performance in idiopathic intracranial hypertension and relevance of intracranial pressure.

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 11ß 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.