Standard measurements for papilloedema include peripapillary retinal nerve fibre layer (pRNFL) and ONH volume. These are reliably increased in active IIH compared with controls, are significantly associated with CSF opening pressure and improve following treatment . OCT has revealed dynamic deformation of the peripapillary retinal pigment epithelium and Bruch's membrane (pRPE/BM) regressing towards the normal shape with reduction of ICP [24,25]. Deformation in pRPE/BM may be of particular value in evaluating atrophic papilloedema with minimal RNFL swelling, as deflection of pRPE/BM may correlate with disease activity. Macular RNFL thickness has been shown to be significantly reduced compared with controls, reduces over time and is associated with ONH volume measurements at baseline and visual function [26,27].
OCT angiography (OCTA) is a relatively new, noninvasive investigative modality, allowing visualization of ONH vasculature. OCTA is based on detecting differences in amplitude, intensity or phase variance between sequential B-scans taken at the same location of the retina. Early use has been directed at papilloedema is with small cohorts, reported on multiple OCT platforms, with differing methodology. The advantage of OCTA is the ability to segment layers and view below retinal haemorrhage, but despite the small field of view, there is high resolution [28▪]. Early findings include dilated tortuous OHN capillaries with no vascular dropout in comparison to ischaemic OHN oedema where there is vascular dropout . OCTA may provide useful biomarkers and aide diagnosis as fundus fluorescence angiography, its predecessor, remains an invasive test [30▪].
OCT technology is limited by penetration particularly in severe OHN swelling. Measurement of the pRPE/BM deflection is semi-automated and accurately placing landmarks is challenging . Proprietary automated algorithms commonly fail to correctly segment the layers, and manual re-segmentation is recommended [15,31]. Overall, as the different parameters of OCT are investigated, the outstanding advantage of OCT is the provision of reliable quantitative method for the longitudinal monitoring of IIH patients (Fig. 2).
The most common method of ICP measurement in IIH remains lumbar puncture, with several well documented negative aspects . Direct measurement of ICP is either noninvasive (yet to be used routinely) or invasive. Invasive ICP measurement can be performed at various anatomical sites namely intraventricular, intraparenchymal, subarachnoid, subdural, epidural; where there is CSF communication ICP can be measured by lumbar puncture . Basic ICP measurement by external ventricular, lumbar drains or lumbar puncture is made by fluid column; more recently a variety of microsensors have become available that locate in the target tissue. These have been limited by drift phenomena and the requirement for external wiring, thus the risk of infection with use in excess of 72 h.
Telemetric ICP monitors are now available commercially. There are two main systems, Neurovent p-Tel, Raumedic, Helmbrechts, Germany and Sensor Reservoir, Miethke, Potsdam, Germany. The wiring issue is resolved with wireless power and reading utilizing induction technology. The drift issue is solved in both systems by way of an external monitor reading atmospheric pressure and solid-state sensor technology. The two systems differ with Neurovent p-Tel siting a pressure sensor in the brain parenchyma; meanwhile the Miethke system is based on a sensor within a reservoir attached to a ventricular drain. Both devices are readable by external hand-held equipment, both devices are passive in the sense that they have no power or memory integral to the device and so pressure is only recorded with the external equipment in situ.
The major initial application for the Miethke system is in refining valve settings in challenging patients, a recent case series highlights this application, of note the highest frequency of valve adjustments was seen in the IIH cohort .
More data is available for the Raumedic p-Tel as it has been available for longer. It sites a solid-state pressure sensor approximately 20 mm into the brain parenchyma, usually within the right frontal lobe. From the largest published series, there is a low complication rate, approximately 6% overall, with seizures affecting 3% and infection in 1.5% [35▪▪]; however, this was in a series of patients with significant structural brain abnormality (for example, hydrocephalus) and the rate of such complications is likely lower in IIH patients. Of note, the UK driving regulations allow resumption of driving 1 week after insertion in patients without complications. The device provides a high degree of accuracy with low drift . Many have been kept in situ beyond the licensed 3-month period [35▪▪,37]; where they have been shown to retain their accuracy with low drift of 2.5 mmHg over a median 241-day implantation period. The device samples at 5 Hz, considerably lower than the wired and Miethke systems, although this is sufficient for waveform analysis [36,38]. The device is capable of long-term recordings for up to 1 week with the present hardware and can be worn by an ambulant patient out with the hospital environment (Fig. 3) .
Telemetric ICP monitors have an evolving role in diagnosis and monitoring of several conditions. In IIH, particular roles could include evaluating whether neurosurgical shunt placement is advised in a deteriorating patient developing fulminant disease. Furthermore, it is useful in evaluating whether pressure is pathologically elevated in those with minimal ocular features and in shunted patients. Monitors can inform the setting of CSF shunt valves aiming to abrogate low pressure headaches, at present seen in 23% . ICP telemetry may also facilitate the differentiation between raised pressure headaches and migrainous headaches .
Acetazolamide is the longest established treatment for IIH. In 2015, following the publication of the first two randomized control trials for medical treatment in IIH [8▪,40], an updated Cochrane review highlighted that there was insufficient evidence to recommend or reject the efficacy of acetazolamide for treating IIH and insufficient evidence for other drugs used in IIH . Of note, there was no effect of acetazolamide on headache seen in the IIHTT . The common existing drugs used in IIH have been evaluated acutely in vivo at clinically relevant doses, and were not found to significantly reduce ICP, with the exception of topiramate [42▪]. There is, therefore, an unmet need for novel therapeutic strategies in IIH (Fig. 4).
Disordered CSF dynamics have been suspected to underlie the raised ICP seen in IIH. There are currently no novel drugs targeting the underlying pathogenesis driving IIH, which remains elusive. Novel therapies are currently focussed on reducing ICP through reducing CSF secretion. Ideally novel therapies would also reduce weight as this approach is disease modifying in IIH [43▪▪].
The choroid plexus is the principle site of CSF production; this is driven by the net movement of sodium ions (Na+) from the blood to the cerebral ventricles, creating an osmotic gradient down, which water moves. Although several channels are involved in this process, the principle channel is the Na+ and K+-dependent adenosine triphosphatase (Na+/K+/ATPase) that actively transports Na+ into the cerebral ventricle and is the rate-limiting step [44,45].
11ß-hydroxysteroid dehydrogenase type 1 (11ß-HSD1) is an intracellular enzyme that converts inactive cortisone to the active cortisol. This amplifies local glucocorticoid activity independent of systemic cortisol. 11ß-HSD1 expression and activity has been demonstrated in choroid plexus epithelial cells, along with other key elements of the glucocorticoid signalling pathway [46,47]. Inhibitors have been developed, including AZD4017, originally as potential therapies for diabetes mellitus type 2 and the metabolic syndrome. Glucocorticoid metabolism has been characterized in IIH in relation to therapeutic weight reduction; global 11ß-HSD1 activity decreased with weight loss as measured by urinary glucocorticoid metabolites by gas chromatography/mass spectroscopy [43▪▪]. Importantly it was noted that the reduction in ICP significantly correlated with reduction in 11ß-HSD1 activity . Of interest, is that 11ß-HSD1 inhibition reduced intraocular pressure and it has been shown that secretory mechanisms of the ocular ciliary body are akin to that of choroid plexus epithelium [46–48].
The incretin glucagon-like peptide 1 (GLP-1) is a gut peptide secreted by the distal small intestine in response to food intake . GLP-1 stimulates glucose-dependant insulin secretion and inhibits glucagon release, lowering blood glucose only in the presence of insulin and not resulting in hypoglycaemia . GLP-1 is also synthesized in neurons of the nucleus tractus solaris that project to the hypothalamus  and promotes satiety and weight loss . GLP-1 analogues have a clinical role in the management of type 2 diabetes mellitus, as well as for weight loss in obesity. Several GLP-1 agonists have been developed and are now licensed drugs . These include exenatide twice daily, exenatide once weekly, liraglutide, lixisenatide, albiglutide, dulaglutide and most recently semaglutide. Currently, only liraglutide is licensed for weight loss in obesity. They vary in structure and pharmacology, ability to penetrate the blood–brain barrier (BBB) as evidenced by CNS effects. Importantly, the choroid plexus epithelium lies outside the BBB .
There are also developments with surgical management of IIH, two trials are currently ongoing, the IIH Weight Trial  (ClinicalTrials.gov Identifier: NCT02124486) is a randomized controlled trial of Bariatric Surgery Versus a Community Weight Loss Programme and opened to recruitment in 2014. The SIGHT trial (ClinicalTrials.gov Identifier: NCT03501966) opened in 2018 and is a triple-arm randomized controlled trial of medical therapy (acetazolamide) vs. medical therapy with Optic Nerve Sheath Fenestration vs. medical therapy with ventriculoperitoneal shunting.
The incidence of IIH is increasing along with global rates of obesity, a key pathological factor, making IIH research and management increasingly important. The first consensus guidelines for the management of IIH have now been published guiding the clinical management of this condition. Looking to the future, there are several new avenues of clinical therapeutics based on reducing CSF secretion, with GLP-1 receptor agonists appearing promising as they also significantly reduce weight. Advances in OCT technology will continue to improve our diagnosis and monitoring of papilloedema, and may provide unique biomarkers. Early indications show that telemetric ICP monitoring may provide insight into CSF dynamics in IIH and facilitate management decisions.
Papers of particular interest, published within the annual period of review, have been highlighted as:
1▪▪. Mollan SP, Davies B, Silver NC, et al. Idiopathic intracranial hypertension
: consensus guidelines on management. J Neurol Neurosurg Psychiatry 2018; 89:1088–1100.
Over 20 common questions answered for clinicians on all aspects of IIH and IIH WOP. Consensus-based statements founded by a specialist interest group that included patients, allied health professionals, neurologists, neuroophthalmologists, neurosurgeons, neuroradiologists, and informed by multiple surveys of practice. It was reviewed by four professional bodies in the United Kingdom (UK), an international panel and by IIH UK, a UK-based patient charity for IIH.
2. Markey KA, Mollan SP, Jensen RH, Sinclair AJ. Understanding idiopathic intracranial hypertension
: mechanisms, management, and future directions. Lancet Neurol 2016; 15:78–91.
3. Mollan SP, Aguiar M, Evison F, et al. The expanding burden of idiopathic intracranial hypertension
. Eye (Lond) 2018; 81:1159.
4. McCluskey G, Doherty-Allan R, McCarron P, et al. Meta-analysis and systematic review of population-based epidemiological studies in idiopathic intracranial hypertension
. Eur J Neurol 2018; 25:1218–1227.
5. Mollan SP, Spitzer D, Nicholl DJ. Raised intracranial pressure
in those presenting with headache. BMJ 2018; 363:k3252.
6. Friedman DI, Quiros PA, Subramanian PS, et al. Headache in idiopathic intracranial hypertension
: findings from the idiopathic intracranial hypertension
treatment trial. Headache 2017; 57:1195–1205.
7▪. Mollan SP, Hoffmann J, Sinclair AJ. Advances in the understanding of headache in idiopathic intracranial hypertension
. Curr Opin Neurol 2019; 32:92–98.
Up-to-date review of our understanding of headache in IIH. Presents the latest literature phenotyping the IIH headache as migraine, and highlighting the issue of medication of overuse headache in the IIH cohort.
8▪. Wall M, Kupersmith MJ, Kieburtz KD, et al. The idiopathic intracranial hypertension
treatment trial: clinical profile at baseline. JAMA Neurol Am Med Assoc 2014; 71:693–701.
The Idiopathic Intracranial Hypertension Treatment Trial (IIH TT) represents the largest randomized, prospectively analyzed cohort of untreated patients with IIH to date. It reported the use of acetazolamide with a low-sodium weight-reduction diet compared with diet alone resulted in modest improvement in visual field function in patients with mild visual loss. The IIHTT also reported improved quality-of-life outcomes at 6 months with acetazolamide and diet group compared with diet alone.
9. Mollan SP, Ali F, Hassan-Smith G, et al. Evolving evidence in adult idiopathic intracranial hypertension
: pathophysiology and management. J Neurol Neurosurg Psychiatry 2016; 87:982–992.
10. Yri HM, Jensen RH. Idiopathic intracranial hypertension
: clinical nosography and field-testing of the ICHD diagnostic criteria. A case-control study. Cephalalgia 2014; 35:553–562.
11. Mulla Y, Markey KA, Woolley RL, et al. Headache determines quality of life in idiopathic intracranial hypertension
. J Headache Pain 2015; 16:521.
12. Mollan SP, Hemmings K, Herd C, et al. What are the research priorities for idiopathic intracranial hypertension
? A priority setting partnership between patients and healthcare professionals. BMJ Open 2019; (in press).
13. Friedman DI, Liu GT, Digre KB. Revised diagnostic criteria for the pseudotumor cerebri syndrome in adults and children. Neurology 2013; 81:1159–1165.
14. Sinclair AJ, Kuruvath S, Sen D, et al. Is cerebrospinal fluid shunting in idiopathic intracranial hypertension
worthwhile? A 10-year review. Cephalalgia 2011; 31:1627–1633.
15. Hoffmann J, Mollan SP, Paemeleire K, et al. European Headache Federation guideline on idiopathic intracranial hypertension
. J Headache Pain 2018; 19:93.
16. Scott CJ, Kardon RH, Lee AG, et al. Diagnosis and grading of papilledema in patients with raised intracranial pressure
using optical coherence tomography
vs clinical expert assessment using a Clinical Staging Scale. Arch Ophthalmol Am Med Assoc 2010; 128:705–711.
17. Auinger P, Durbin M, Feldon S, et al. OCT Sub-Study Committee for NORDIC Idiopathic Intracranial Hypertension
Study Group, Baseline OCT measurements in the idiopathic intracranial hypertension
treatment trial, part II: correlations and relationship to clinical features. Invest Ophthalmol Vis Sci 2014; 55:8173–8179.
18. Scotton WJ, Mollan SP, Walters T, et al. Characterising the patient experience of diagnostic lumbar puncture in idiopathic intracranial hypertension
: a cross-sectional online survey. BMJ Open 2018; 8: e020445-7.
19. Fisayo A, Bruce BB, Newman NJ, Biousse V. Overdiagnosis of idiopathic intracranial hypertension
. Neurology 2016; 86:341–350.
20. Rebolleda G, Kawasaki A, de Juan V, et al. Optical coherence tomography
to differentiate papilledema from pseudopapilledema. Curr Neurol Neurosci Rep 2017; 17:74.
21. Malmqvist L, Bursztyn L, Costello F, et al. The Optic Disc Drusen Studies Consortium Recommendations for Diagnosis of Optic Disc Drusen Using Optical Coherence Tomography
. J Neuroophthalmol 2018; 38:299–307.
22. Traber GL, Weber KP, Sabah M, et al. Enhanced depth imaging optical coherence tomography
of optic nerve head drusen a comparison of cases with and without visual field loss. Ophthalmology 2016; 124:1–8.
23. Kattah JC, Pula JH, Mejico LJ, et al. CSF pressure, papilledema grade, and response to acetazolamide in the Idiopathic Intracranial Hypertension
Treatment Trial. J Neurol 2015; 262:2271–2274.
24. Sibony P, Kupersmith MJ, Honkanen R, et al. Effects of lowering cerebrospinal fluid pressure on the shape of the peripapillary retina in intracranial hypertension. Invest Ophthalmol Vis Sci 2014; 55:8223–8231.
25. Wang J-K, Kardon RH, Ledolter J, et al. OCT Sub-Study Committee and the NORDIC Idiopathic Intracranial Hypertension
Study Group. Peripapillary retinal pigment epithelium layer shape changes from acetazolamide treatment in the Idiopathic Intracranial Hypertension
Treatment Trial. Invest Ophthalmol Vis Sci 2017; 58:2554–2565.
26. Albrecht P, Blasberg C, Ringelstein M, et al. Optical coherence tomography
for the diagnosis and monitoring of idiopathic intracranial hypertension
. J Neurol 2017; 264:1370–1380.
27. Monteiro MLR, Afonso CL. Macular thickness measurements with frequency domain-OCT for quantification of axonal loss in chronic papilledema from pseudotumor cerebri syndrome. Eye (Lond) 2014; 28:390–398.
28▪. Tan ACS, Tan GS, Denniston AK, et al. An overview of the clinical applications of optical coherence tomography
angiography. Eye 2018; 32:262–286.
A narrative review of the technology and methods in OCT angiography. Key advantages over Fundus Fluorescein Angiography are highlighted.
29. Rougier M-B, Le Goff M, Korobelnik J-F. Optical coherence tomography
angiography at the acute phase of optic disc edema. Eye Vis (Lond) 2018; 5:15.
30▪. Revelle B, Pepper I, Mollan SP, Hickman S. The utility of fundus fluorescein angiography in neuroophthalmology. Neuroophthalmology 2019; (in press).
A comprehensive review of the utility of Fundus Fluorescein Angiography (FFA) relating to neuroophthalmic disorders. It gives a practical guide to performing and reporting FFAs, highlighting key features that distinguish retinal lesions.
31. Aojula A, Mollan SP, Horsburgh J, et al. Segmentation error in spectral domain optical coherence tomography
measures of the retinal nerve fibre layer thickness in idiopathic intracranial hypertension
. BMC Ophthalmol 2018; 17:257.
32. Scotton WJ, Mollan SP, Walters T, et al. Characterising the patient experience of diagnostic lumbar puncture in idiopathic intracranial hypertension
: a cross-sectional online survey. BMJ Open 2018; 8:e020445.
33. Zhang X, Medow JE, Iskandar BJ, et al. Invasive and noninvasive means of measuring intracranial pressure: a review. Physiol Meas 2017; 38:R143–R182.
34. Antes S, Stadie A, Müller S, et al. Intracranial pressure-guided shunt valve adjustments with the miethke sensor reservoir. World Neurosurg 2018; 109:e642–e650.
35▪▪. Antes S, Tschan CA, Kunze G, et al. Clinical and radiological findings in long-term intracranial pressure monitoring. Acta Neurochir (Wien) 2014; 156:1009–1019.
Outlines early clinical experience with novel telemetric ICP monitors.
36. Antes S, Tschan CA, Heckelmann M, et al. Telemetric intracranial pressure monitoring with the raumedic neurovent P-tel. World Neurosurg 2016; 91:133–148.
37. Norager NH, Lilja-Cyron A, Bjarkam CR, et al. Telemetry in intracranial pressure monitoring: sensor survival and drift. Acta Neurochir (Wien) 2018; 121:2137–2144.
38. Lilja A, Andresen M, Hadi A, et al. Clinical experience with telemetric intracranial pressure monitoring in a Danish neurosurgical center. Clin Neurol Neurosurg 2014; 120:36–40.
40. Ball AK, Howman A, Wheatley K, et al. A randomised controlled trial of treatment for idiopathic intracranial hypertension
. J Neurol 2010; 258:874–881.
41. Piper RJ, Kalyvas AV, Young AMH, et al. Interventions for idiopathic intracranial hypertension
. Cochrane Database Syst Rev 2015; Art. No.: CD003434. DOI: 10.1002/14651858.CD003434.pub3.
42▪. Scotton W, Botfield H, Uldall M, et al. 1545 Topiramate is as effective as acetazolamide at lowering intracranial pressure in healthy rodents. J Neurol Neurosurg Psychiatry 2017; 88 (Suppl 1):A8.3–A8.3-A9.
Key article defining the evidence of existing drugs used in IIH and their mechanisms of action with subsequent evaluation at clinically relevant doses in vivo.
43▪▪. Sinclair AJ, Burdon MA, Nightingale PG, et al. Low energy diet and intracranial pressure in women with idiopathic intracranial hypertension
: prospective cohort study. BMJ 2010; 341:c2701.
Prospective cross over trial in IIH who followed a low-energy (calorie) diet for 3 months had significantly reduced LP OP, headache improved by greater than 50%, in headache severity, headache frequency and weekly use of analgesics.
44. Brown PD, Davies SL, Speake T, Millar ID. Molecular mechanisms of cerebrospinal fluid production. Neuroscience 2004; 129:955–968.
45. Speake T, Whitwell C, Kajita H, et al. Mechanisms of CSF secretion by the choroid plexus. Microsc Res Tech 2001; 52:49–59.
46. Sinclair AJ, Onyimba CU, Khosla P, et al. Corticosteroids, 11beta-hydroxysteroid dehydrogenase isozymes and the rabbit choroid plexus. J Neuroendocrinol 2007; 19:614–620.
47. Sinclair AJ, Walker EA, Burdon MA, et al. Cerebrospinal fluid corticosteroid levels and cortisol metabolism in patients with idiopathic intracranial hypertension
: a link between 11β-HSD1 and intracranial pressure regulation? J Clin Endocrinol Metab 2010; 95:5348–5356.
48. Aleci C, Mannone C, Rebaudengo N. On the relationship between ocular and ventricular fluid dynamics. Advancing a joint classification and a pilot study in patients suffering from nonocclusive hydrocephalus. Neuroophthalmol Visual Neurosci 2015; 1:27–36.
49. Rosenstock J, Banarer S, Fonseca VA, et al. INCB13739-202 Principal Investigators. The 11-beta-hydroxysteroid dehydrogenase type 1 inhibitor INCB13739 improves hyperglycemia in patients with type 2 diabetes inadequately controlled by metformin monotherapy. Diabetes Care 2010; 33:1516–1522.
50. Newton M, Cooper BT. Benign intracranial hypertension during prednisolone treatment for inflammatory bowel disease. Gut 1994; 35:423–425.
51▪. Markey KA, Ottridge R, Mitchell JL, et al. Assessing the efficacy and safety of an 11β-hydroxysteroid dehydrogenase type 1 inhibitor (AZD4017) in the Idiopathic Intracranial Hypertension
Drug Trial, IIH:DT: clinical methods and design for a phase ii randomized controlled trial. JMIR Res Protoc 2017; 6:e181.
First double-blind RCT of a novel therapeutic agent in IIH.
52. Baggio LL, Drucker DJ. Biology of Incretins: GLP-1 and GIP. Gastroenterology 2007; 132:2131–2157.
53. Campbell JE, Drucker DJ. Pharmacology, physiology, and mechanisms of incretin hormone action. Cell Metab 2013; 25:819–837.
54. Larsen PJ, Tang-Christensen M, Holst JJ, Orskov C. Distribution of glucagon-like peptide-1 and other preproglucagon-derived peptides in the rat hypothalamus and brainstem. Neuroscience 1997; 77:257–270.
55. Astrup A, Rössner S, Van Gaal L, et al. Effects of liraglutide in the treatment of obesity: a randomised, double-blind, placebo-controlled study. Lancet Elsevier 2009; 374:1606–1616.
56. Aroda VR. A review of GLP-1 receptor agonists: evolution and advancement, through the lens of randomised controlled trials. Diabetes Obes Metab 2018; 20 (Suppl 2):22–33.
57. Eftekhari S, Salvatore CA, Johansson S, et al. Localization of CGRP, CGRP receptor, PACAP and glutamate in trigeminal ganglion. Relation to the blood-brain barrier. Brain Res 2015; 1600:93–109.
58. Carraro-Lacroix LR, Malnic G, Girardi ACC. Regulation of Na+/H+ exchanger NHE3 by glucagon-like peptide 1 receptor agonist exendin-4 in renal proximal tubule cells. Am J Physiol Renal Physiol 2009; 297:F1647–F1655.
59. Damkier HH, Brown PD, Praetorius J. Cerebrospinal fluid secretion by the choroid plexus. Physiol Rev Am Physiol Soc 2013; 93:1847–1892.
60▪▪. Botfield H F, Uldall M S, Westgate C S J, et al. A glucagon-like peptide-1 receptor agonist reduces intracranial pressure in a rat model of hydrocephalus. Sci Transl Med Am Assoc Adv Sci 2017; 9: pii: eaan0972.
Article outlining the mechanistic basis for a potential new class of ICP-modulating therapy.
61. Ottridge R, Mollan SP, Botfield H, et al. Randomised controlled trial of bariatric surgery versus a community weight loss programme for the sustained treatment of idiopathic intracranial hypertension
: the Idiopathic Intracranial Hypertension
Weight Trial (IIH:WT) protocol. BMJ Open 2017; 7:1–9.