European Headache Federation guideline on idiopathic intracranial hypertension

Headache, present in up to 90% of IIH patients, is commonly the primary symptom leading IIH patients to seek medical advice [7, 8]. Headache is also the key factor driving reduced quality of life in IIH [9]. The features of IIH-related headache vary substantially and in the context of a limited amount of clinical studies that aim at characterizing them, the IHS-criteria remain relatively unspecific in their description. Patients commonly describe their headache as pressing, explosive with a frontal, retroorbital localization [3, 10]. Frequently the headache has a migraine phenotype and overuse of analgesic is observed in over a third of IIH patients [11]. Phenotypic similarities may hamper its distinction from migraine and other headaches [7, 8, 12‐17]. In order to establish the diagnosis of IIH it is required that the causality between the clinical symptoms and elevated ICP is demonstrated by a temporal relationship between headache onset and the identification of elevated ICP or an alleviation after a reduction of ICP. However, one study reported that over 20% of patients with other headache disorders also improve after lumbar puncture (LP) [18]. The second edition of the International Headache Classification (ICHD-2) detailed headache alleviation after pressure reduction was a required diagnostic criterion of IIH, however in the recent ICHD-3 criteria this criterion has been removed as headache duration can vary substantially with almost two thirds of IIH-patients complaining of persisting chronic headache despite a normalization of ICP [3, 10, 18, 19]. However, the precise onset of increased ICP and the related headache are difficult to establish, so the preliminary version of the present diagnostic ICHD-3 criteria (ICHD-3 beta) for IIH-headache have been field tested in a recent study and more sensitive and specific criteria have been suggested [18].

Bilateral disc swelling, termed papilloedema when it is caused by raised ICP, is a cardinal feature of IIH and on examination it can be asymmetrical in 4% of cases [7, 20‐25]. Examination of the eye can be challenging and in case of diagnostic uncertainty, papilloedema should be confirmed by an experienced ophthalmologist. Exclusion of pseudopapilloedema is recommended to prevent unnecessary investigations and procedures. These include measurements of intraocular pressure, ruling out hypotony, and critical examination of the optic nerve as small hypermetropic discs, titled myopic discs, vitreous traction and disc drusen can all be mistaken for papilloedema. There is a high frequency (40%) of diagnostic errors in IIH, with the main cause being an incorrect ophthalmic examination [26].

Raised ICP can lead to a number of visual symptoms including transient visual obscurations, visual blurring and double vision. All IIH patients with active papilloedema need close ophthalmological monitoring to evaluate the visual function and assess the risk of visual loss as in some the visual disturbances are progressive and may lead to prolonged ischemia of the optic nerve head resulting in complete and irreversible sight loss secondary to optic atrophy. The tests of visual function are important as no correlation between headache frequency and the degree of papilloedema has been demonstrated [27]. Data from a recent randomized-controlled clinical trial with acetazolamide for the treatment of IIH, the IIH Treatment Trial (IIHTT), revealed that higher-grade papilloedema and a significant loss in visual acuity at presentation are associated with a higher risk of progression to visual field loss despite adequate treatment [28].

Ophthalmic examination should include: visual acuity, a pupil examination, formal visual field assessment and dilated fundal examination to evaluate the papilloedema. The typical visual field findings are that of an enlargement of the blind spot, peripheral constriction and or an inferior nasal step or partial arcuate defect [22, 29] (Fig. 2). To interpret visual fields with confidence a basic understanding of the plots (Table 2), reliability indices (Table 3), and global parameters (Table 3) is required. Visual field testing is a psychophysical test and can be demanding to interpret in any disease including IIH. Besides physical obstacles, cognitive factors including subject attention, motivation, fatigue, and response bias can influence the obtained thresholds. Improvement in reliability has been shown to improve with clear instructions [30]. Despite clear instructions in the IIHTT, performance failures were observed at some point in one fifth of the participants and were likely due to behavioural factors as the fields returned to baseline values on re-testing: therefore not deemed to be disease progression. Retesting is recommended where there is perimetric worsening, in the presence of unreliable indices (Table 3) [31].

The role of imaging the optic nerve head is becoming increasingly important. Qualitative analysis of photographic images remains useful for clinical records. Newer techniques such as wide field imaging using the Optos™ allow high resolution image capture through an undilated pupil, with a magnification tool to examine the optic nerve head (Fig. 3). Optical Coherence Tomography (OCT), in particular spectral domain OCT, offers a non-invasive technique for both qualitative and objective quantification of papilloedema that can support the detection of papilloedema [32‐34]. OCT is found to be a valuable tool for quantification of papilloedema in longitudinal assessment: Fig. 4 demonstrates the clear improvement in papilloedema in a newly diagnosed IIH patient who undertook a low calorie diet for 6 weeks [35]. However, OCT has limitations. In cases of severe papilloedema errors occur in the automated software analysis which can lead to unreliable values, these scans need manual adjustment to ensure reliable results [36]. However as peripapillary retinal nerve fibre layer (RNFL) thickness resolves, most systems do not allow the distinction between reduction in oedema and optic atrophy as both conditions lead to a reduction in RNFL thickness [37]. Software enhancements on certain OCT platforms allow the determination of ganglion cell layer thickness and this may prove to be beneficial to correlate with visual loss. Some OCT platforms have the ability to capture short video footage which is useful to document location and presence of spontaneous venous pulsations (Additional file 1). OCT imaging supports the diagnosis and monitoring of papilloedema as demonstrated in Fig. 5 where there is an increase in the volume at the optic nerve head with recurrence of symptoms of headache and pulsatile tinnitus for one month in a patient previously in ocular remission, but does not mitigate the continued monitoring of all measures of visual function through clinical examination and formal perimetry.

IIH can cause other symptoms, as well as headache and visual disturbances. Recent data however suggests that other systems may also be affected in IIH, presumably as the result of increased ICP, although the exact mechanisms leading to these alterations remain largely unknown. In this context, structural changes in the olfactory nerve [38], which are associated with an olfactory dysfunction in up to 80% of IIH patients, have been demonstrated [39, 40]. Nevertheless, despite an easy determination of olfactory function by the use of extended Sniffin’ Sticks, this observation is not useful for the diagnosis or follow-up examinations in IIH as the effects of a variation in ICP may reflect on olfactory function with a significant delay.

A uni- or bilateral pulsatile tinnitus is commonly observed in IIH [7, 8, 41]. Its underlying cause is not entirely elucidated but it is hypothesized that stenoses in the transverse sinus, which are commonly observed in IIH, may induce audible turbulences in blood flow. Nevertheless further studies are required to confirm this assumption.

Unilateral or bilateral sixth-nerve palsy may occur in IIH causing horizontal diplopia [42, 43]. The reason for this neurological deficit in the context of IIH has not been fully investigated. The pathophysiological mechanism has traditionally been thought to be due to compression against the petrous ligament or the ridge of the petrous temporal bone, or stretching along the intracranial course of the nerve.

Cognitive function has been reported to be affected in IIH. While a number of small uncontrolled studies, which occasionally focused only on single neuropsychological domains, suggested a relationship between IIH and cognitive decline [44‐46], Yri et al. demonstrated in an extensive prospective case-control study that IIH is associated with a global cognitive dysfunction with the most extensive deficit in reaction time and processing speed [47]. Interestingly, the results of this study reveal that despite an improvement of ICP and headache after 3 months of adequate treatment, the cognitive dysfunction appears to persist raising the question if IIH-related cognitive decline is the result of more complex mechanisms rather than the direct effect of mechanical compression. These neuropsychological deficits may hamper significantly a professional reintegration after prolonged absence from work.

Brain imaging is an essential part of the diagnostic algorithm and MRI should be considered the gold standard of care to exclude secondary causes of elevated ICP and to identify structural alterations associated with IIH. These include an empty sella turcica (or at least significant changes in size, shape and volume of the pituitary gland) and a flattening of the posterior optic globe. IIH also leads to an enlargement of the optic nerve sheath and an increased tortuosity of the optic nerve [12, 48‐51]. However, the volume of the optic nerve is not affected [12]. In contrast to early imaging studies based on plain film X-ray imaging that suggested a reduced ventricle size (slit-like ventricles) as indicative for IIH [52], data based on CT and MR imaging techniques demonstrates that size and volume of the lateral ventricles are not altered in IIH [49, 53].

Diagnostic brain imaging in IIH should always include a CT- or MR venography to exclude a venous sinus thrombosis as even clinically inapparent microthromboses may induce a venous outflow obstruction that increases ICP [54]. Furthermore the venography may demonstrate the presence of uni- or bilateral transverse sinus stenoses (TSS) as these are frequently observed in IIH patients with reported prevalence rates of up to 90% [51, 55, 56]. However, if TSS are cause or consequence of elevated ICP remains controversial. Additionally, asymmetry of the transverse sinus can occur in 50% of healthy individuals [57].

Despite the value of neuroimaging in the diagnostic workup of IIH, it does not replace the need for a measurement of lumbar opening pressure as imaging abnormalities show a large interindividual variation and none of the findings are pathognomonic of IIH hence imaging findings only serve as supportive evidence for the diagnosis of IIH.

LP is mandatory in the diagnostic algorithm of IIH. In addition to a normal CSF composition, diagnostic criteria require that opening pressure, which should be measured in the lateral decubitus position with stretched legs and without sedative medications, should not exceed 25 cmH₂O in adults and 28 cmH₂O in children [2, 58, 59]. Increases of ICP may also occur intermittently, in particular in IIH patients without papilloedema [60, 61]. Therefore, if IIH is suspected but opening pressure lies within the normal range during the initial assessment, a second measurement or even continuous monitoring could be considered [61‐63]. Conversely, pressures above 25 cmH₂O can occur in normality [64], with pressures in the range 25–30 cmH₂O constituting a grey area that could be pathological or normal and should be interpreted with caution [43]. Patients with pressures in this “grey zone” should be evaluated cautiously to ensure they meet the other aspects of the IIH diagnostic criteria [43].

Blood tests should be performed for the exclusion of secondary causes of elevated ICP or other medical conditions that may clinically present with similar symptoms. Blood test should be tailored to the individual patient’s presentation. In the absence of typical phenotypic characteristics of IIH (obese female of childbearing age) blood tests to exclude secondary causes of pseudotumor cerebri are key. Excluding conditions that increase the likelihood of a sinus vein thrombosis, which could obstruct venous outflow, may be performed. These could include analysis of coagulation parameters to identify hypercoagulable states as well as a search for diseases that are associated with a higher risk of venous (micro-) thrombosis such as systemic lupus erythematosus and infections of the middle ear or mastoid. Endocrine disorders that may mimic IIH symptoms include Addison’s disease, Cushing’s syndrome, hypoparathyroidism as well as the use of growth hormones and may need to be excluded. Other medical conditions that may induce a secondary increase of ICP and should be identified via serologic examinations include systemic infections, uraemia, renal failure and anaemia [65] (Table 4).

Therapeutic agents currently used in IIH aim to reduce ICP through reduction in CSF secretion. There are few therapeutic options and the recent Cochrane review reported: “the two included randomised controlled trials showed modest benefits for acetazolamide for some outcomes, there is insufficient evidence to recommend or reject the efficacy of this intervention, or any other treatments currently available, for treating people with IIH [85]”. The IIHTT is the largest RCT to date and reports improvement in visual field function in patients with mild visual loss when treated with acetazolamide [86]. Benefits were most marked in those with the most marked papilloedema. However high doses of acetazolamide were used (greater than 40% of patients were treated with 4 g of acetazolamide daily) and this may not be tolerable. Previous studies have demonstrated that 48% of patients discontinue acetazolamide when doses of just 1500 mg are utilised [87]. Side effects include paraesthesia, dysgeusia, vomiting and diarrhoea as well as malaise, fatigue and depression [88, 89]. Acetazolamide is the only therapeutic that has been evaluated in RCT and is regarded as the first line therapy for IIH. However, not all clinicians prescribe acetazolamide for IIH due to the limitations of the evidence base highlighted by the 2015 Cochrane review in conjunction with the potential side effect profile.

In pregnancy the use of acetazolamide is controversial. Data from case series (n = 50 IIH patients using acetazolamide in the first trimester) has not identified an increased risk of foetal malformations although animal data has highlighted teratogenic effects [90, 91].

A number of alternative therapeutic agents are used in IIH, however there is little evidence to support their use.

In animal studies, intravenous and intraventricular high dose furosemide has been shown to reduce CSF secretion by 20–50% [92‐95]. However, clinically relevant routes of delivery and dosing have not been studied. A paediatric case series (n = 8) demonstrated that together acetazolamide and furosemide reduced ICP over 6 weeks, however the absence of a control group limits interpretation [96]. Bumetamide does not reduce CSF secretion in animal studies, and human studies have not been conducted [92].

Amiloride administered into the carotid artery in animal models reduces CSF secretion by up to 50% [97, 98]. But these studies have not used clinically relevant doses or routes of delivery.

Octreotide has been hypothesised to manipulate CSF secretion as there are somatostatin receptors on the choroid plexus [99]. A prospective open-label study of 26 patients reported resolution of papilloedema in 92% of cases however cautious interpretation is needed in the absence of a control group [100].

Topiramate utility in IIH has been suggested by an open label study which randomly assigned 40 patients to acetazolamide or topiramate. They demonstrated treatment equivalence with all patients experiencing improvement in visual fields (ICP was not measured) [101]. Topiramate may have additional advantages in IIH as it can induce weight loss and has efficacy as a migraine preventive therapy [102‐105]. Recently reported in vivo studies demonstrated that both subcutaneous and oral administration of topiramate significantly lowers ICP in rodents whilst other drugs tested, including acetazolamide, furosemide, amiloride and octreotide, did not significantly reduce ICP [106].

Future therapies would ideally control ICP acutely as well as treat the underlying disease process through weight loss. There is growing interest in the role of gut neuro peptides in IIH. The gut peptide glucagon-like peptide-1 (GLP-1) regulates insulin secretion and weight, and currently GLP-1 mimetic drugs are used extensively to treat diabetes (without risk of hypoglycaemia) and obesity [107]. Recent in vitro assays have demonstrated that the GLP-1 receptor agonist exendin-4 reduces CSF secretion [108]. Additionally, clinically relevant doses of exendin-4 dramatically reduced ICP in rodents with raised ICP (44% reduction in ICP within 10 min of dosing with effect maintained for 24 h [108]. A clinical trial is currently underway exploring the physiological effects of exenatide in reducing ICP in IIH.

Therapeutic agents inhibiting the actions of 11Beta hydroxysteroid dehydrogenase type 1 (11β-HSD1) have been proposed in IIH. 11β-HSD1 is an enzyme which converts inactive cortisone to active cortisol and consequently regulates local cortisol availability, a key determinant of fluid secretion [109]. 11β-HSD1 inhibitors have been shown to reduce intraocular pressure through reduction of aqueous humour production by the ocular ciliary body [110]. Akin to this mechanism, 11β-HSD1 is functionally active in the CSF secreting choroid plexus epithelial cells [111]. In patients with IIH, reduction in ICP correlates with reduction in global 11β-HSD1 activity measures [111]. 11β-HSD1 inhibitors have been developed to treat obesity and metabolic syndrome. A phase 2 randomised controlled trial has been conducted in IIH which assesses a specific 11β-HSD1 inhibitor (AZ4017), results are awaited [112].