Emerging themes in idiopathic intracranial hypertension

IIH is considered a rare condition. Previously, the incidence within the general population was believed to be between 0.5 and 2 per 100,000 [15‐19]. Recent evaluations in the UK, including the largest cohort study to date, reported a 108% increase from 2.26 to 4.69 per 100,000 between 2002 and 2016 [3]. Another large case controlled cohort study found the incidence of IIH in females had tripled from 2.5 to 9.3 per 100,000 between 2005 and 2017 [20]. Secondary to the rising incidence of IIH is the health care cost of the disorder: annual hospital costs in England rose from £9.2 million to £49.9 millon between 2002 and 2014 and was predicted to rise to £462.7 million by 2030 [3]. In 2007 in the US, IIH patients had exceptionally high admission rates of 38% of all those coded with IIH for that year, with costs exceeding $444 million. This estimate also included lost work income [21]. Repeat hospital admissions may reflect that IIH is a disease of social deprivation [20], but also highlights the ineffectiveness of IIH treatment for decades.

Obesity (> 90%), female sex and reproductive age are significant risk factors associated with IIH [1]. An epidemiology study in the US found that women have an eight times likelihood of the disorder compared to men, [17] which is significantly increased when overweight and of reproductive age (20–44 years) with an incidence of 12–20 per 100,000 [15‐17]. Paediatric studies of IIH are not well established; however, one UK study found an incidence of 0.71 per 100,000, which was found to increase with age. For children aged 12–15 years, there is also an association with obesity, whereas the pathophysiology in younger patients remains unclear [22]. IIH in males is uncommon; however, of note males are more likely to develop severe visual loss [23].

Glucagon-like peptide-1 (GLP-1) is a gut peptide secreted in response to food by the distal small intestine and stimulates glucose-dependent insulin secretion [27]. It is also synthesised by neurons in the nucleus tractus solitarius and is involved in satiety and weight loss [28]. In the distal proximal tubule, it interacts with GLP-1 receptors (GLP-1R) to stimulate cAMP-dependent pKA pathways, which result in prevention of Na⁺ absorption into the bloodstream [29]. The ChP also express GLP-1R and interaction with its agonist exendin-4, was demonstrated to reduce Na⁺/K⁺ ATPase, a surrogate measurement of CSF secretion [11]. Single subcutaneous administration of exendin-4 in rat models of raised ICP were able to successfully lower ICP for 24 h, demonstrating the efficacy of this potential drug [11]. GLP-1R agonists are already licensed for the use in diabetes and obesity. The IIH Pressure Trial, ISRCTN12678718, is a randomised controlled trial assessing the effect of repurposing this drug in patients with raised ICP and the results from this trial should be released soon [14].

The predominant risk factors for IIH, including female sex, obesity and reproductive age, suggest a contribution of sex hormones in the pathophysiology of raised ICP. The prevalence of polycystic ovarian syndrome (PCOS) has been found higher in studies of IIH patients than the general population and the phenotypes of both disorders; namely female sex and obesity, are similar [30]. Androgen excess have been associated with IIH, with increased circulating levels of androgens associated with earlier onset in women [31], and female-to-male transgender patients developing IIH after commencing testosterone therapy [32]. Using liquid chromatography–tandem mass spectrometry (LCMS), it has been possible to define a metabolome signature in the serum and CSF of IIH patients, which features excess androgens but is distinct from obesity and PCOS [33]. Until recently, the role of excess testosterone in IIH pathology was unknown. Treatment of rat ChP tissue with testosterone exhibited a marked increase in Na⁺/K⁺ ATPase activity, a surrogate measurement of CSF secretion. This in combination with the finding of androgen receptors on the human ChP, provides evidence for the role of androgen excess in increased CSF secretion [33].

The enzyme 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1) has a key role in regulating CSF secretion by converting cortisone to its active form cortisol, which amplifies glucocorticoid signalling pathways and facilitates the transport of Na⁺ ions. It is expressed and active in the ChP and has demonstrated a role in IIH pathology [34]. 11β-HSD1 offers a link between obesity and raised ICP, as global activity was found to be reduced following therapeutic weight loss in IIH patients, which also correlated with a reduction in ICP [35]. The enzyme has been previously found to be dysregulated in obesity [36], with high levels found in human fat [37] and overexpression mouse models resulting in visceral obesity and a metabolic disorder [38]. Phenotyping studies have begun to elucidate a metabolically distinct profile of adipose tissue of IIH patients. LCMS-based 11β-HSD1 assays in the adipose tissue of IIH patients demonstrated an increased generation of cortisol when treated with cortisone, despite no differences in 11β-HSD1 gene expression [39].

Selective inhibitors of 11β-HSD1 have been used to treat obesity, a metabolic syndrome and diabetes mellitus type 2 [40]; therefore, the potential for these to reduce ICP has also been hypothesised. Recently a double-blind randomized controlled trial in the UK was able to demonstrate that AZD4017, a 11β-HSD1 inhibitor reduced ICP in IIH patients which was correlated to a reduction in serum cortisol:cortisone ratio [12]. This was the first phase II randomized trial of any medicine in IIH and confirmed the safety and tolerability of this 11β-HSD1 inhibitor.

Obesity is a chronic inflammatory condition, in which adipose tissue is capable of functioning as an endocrine organ, secreting a number of pro-inflammatory factors including cytokines, adipokines and chemokines [41]. As cytokine expression profiles are significantly different in IIH patients, could these factors have a role in IIH? [42]. Studies utilising miRNA/mRNA analysis have highlighted abnormalities in pro-inflammatory pathways in the CSF and serum of patients with raised ICP [43]. In particular, compared to controls, chemokine (C–C motif)-ligand 2 (CCL2) has been found to be significantly higher in the CSF of IIH patients, [42] whilst others found IL-2 and IL-17 to be significantly elevated [44]. These suggest a possible inflammatory pathway in IIH pathology and more work is underway to determine the significance of these findings, independent of the metabolic effects of obesity [42]. In one such experiment in the lab, one group of female rats was fed a high fat diet and another group were exposed to IIH-associated inflammatory factors. Both groups of animals exhibited increased CSF secretion with reduced CSF drainage when treated with CCL2 [45]. These studies further highlight a pathogenic link between weight gain and raised ICP. Could this pathway be targeted for a biomarker of altered CSF drainage, or as a therapy?

There are few clinical studies characterising IIH headache [9]. Previously, IIH headaches were considered “high pressure” and, therefore, aggravated by Valsalva manoeuvre, worse when supine and often present on waking or causing the patient to wake from sleep [9, 58]. However, more recent studies indicate that the majority of headaches in IIH meet the International Headache Society criteria for either episodic migraine, chronic migraine or tension-type headache [51, 59, 60]. In the IIHTT, 84% of participants had headache at baseline [60]. Headache is a chronic disabler in IIH and significantly reduces quality of life [8]. The relationship between ICP and headache in IIH remains complicated. Although reduction in ICP was found to alleviate headache in weight loss studies [46], severity, frequency and disability of headache did not correlate with lumbar puncture opening pressure at baseline in the IIHTT [60].

The phenotype of IIH headache appears to mirror that of episodic and chronic migraine [9] and increasingly off-label migraine treatment is used in IIH patients to treat headache without any formal evidence of efficacy [2]. Overuse of simple analgesics, opiates, and non-steroidal anti-inflammatory drugs is common in IIH and may result in medication-overuse headache [61, 62]. Patients who achieve 10–15% weight loss often see an improvement in their headache [46], although sometimes this can only be achieved with bariatric surgery [63]. Although therapeutic LP may reduce headache in the short term, repeated LPs are not recommended as they may result in complications such as intracranial hypotension [64, 65]. Headache generation and pain are thought to be due to peripheral sensitisation of the trigeminovascular system, in which innervation of the dura by nociceptive trigeminal fibers, leads to release of vasoactive neuropeptides including calcitonin gene-related peptide (CGRP) and substance P [66‐68]. In the case of migraine, repeated periods of sensitisation over time is thought to cause a decrease in nociceptive threshold and may result in chronicity [69]. CGRP is thought to play an important role in the pathogenesis of migraine. Plasma CGRP is elevated during migraine attacks and administration of exogenous CGRP may induce migraine without aura in sufferers. Recent trials also demonstrate that monoclonal antibodies against CGRP or the CGRP receptor are effective for the treatment of chronic and episodic migraine [59, 70‐75]. Evidence of CGRP involvement in post-traumatic headache, [76, 77] which also features raised ICP, suggests that these therapeutics would also be effective for IIH headache. Furthermore, the headache phenotype in IIH is typically migraine [60]. At present, there is no trial evidence for the use of CGRP monoclonal antibodies to treat headaches with a migrainous phenotype in IIH.

Visual symptoms of raised intracranial pressure may include: visual blurring, transient visual obscurations (TVOs) and double vision [7]. Often patients can have a mild hyperopic shift due to papilloedema causing visual blurring. TVOs, where there is a short-lived greying or blacking out of the vision in either or both eyes, with return to normal vision, is more common in the acute setting of raised ICP. These often happen on bending or during a Valsalva manoeuvre. Where they increase in frequency at rest is a red flag of progression to fulminant disease requiring urgent assessment. If horizontal binocular diplopia is reported, then a full extra ocular movement examination will likely reveal a unilateral or bilateral sixth-nerve palsy [7]. Rarely other cranial nerve palsies have been reported in IIH [2]. If monocular diplopia is reported, a close examination of the macula with fundoscopy and OCT may reveal either fluid in the acute setting or an epiretinal membrane in the chronic setting.

On examination papilloedema (unilateral or bilateral disc swelling) is one of the essential features required to diagnose IIH [78]. However, examination of the fundus can be challenging [58], and up to 40% of those sent to a tertiary centre had an incorrect diagnosis of IIH made due to diagnostic error in the fundal examination [79]. If there is any clinical uncertainty, papilloedema should be confirmed by an experienced specialist, [2] as optic disc drusen, small hypermetropic discs, titled myopic discs and vitreous traction can all be mistaken for papilloedema [7].

Testing visual function is essential as not only is there no correlation between headache frequency and the degree of papilloedema [80], there is little correlation between papilloedema grade and LP OP. Visual function importantly guides management, particularly in the acute setting of diagnosis or in established IIH with an acute exacerbation of headache [81]. The minimum visual data set recommended is a visual acuity, pupil examination, formal visual field assessment and dilated fundal examination [2, 82]. Where possible ocular imaging is helpful at baseline to document papilloedema and is essential for longitudinal follow-up either by photography or optical coherence tomography (OCT) (Fig. 1). Indeed certain OCT measures show the ability to help distinguish between papilloedema and pseudopapilloedema [83] and other investigators have found associations and correlations with ICP [84]. As with any device, care in interpretation is important due to proprietary software errors in moderate to severe papilloedema (Fig. 2) [85].

Visual fields are typically the first part of the visual function affected by ICP with peripheral constriction, an enlargement of the blind spot and or an inferior nasal step or partial arcuate defect [86, 87]. For the general neurologist, interpretation of the visual fields is essential as in IIH cognitive factors including subject attention, motivation, fatigue, and response bias can influence the results. For example, in the IIH TT, one-fifth of the visual fields had to be repeated due to poor reliability [88]. Understanding of the type of visual field loss and how to interpret the plots presented, reliability indices and global parameters is helpful [82].