Journal of Neuroimmunology 201202 (2008) 212 220 www.elsevier.

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Exploring the pathogenesis of IIH: An inflammatory perspective

Alexandra J. Sinclair a,c,, Alexandra K. Ball b , Michael A. Burdon a , Carl E. Clarke b , Paul M. Stewart c , S. John Curnow a , Saaeha Rauz a
Academic Unit of Ophthalmology, School of Immunology, Infection and Inflammation, College of Medical and Dental Sciences, University of Birmingham, Birmingham, B15 2TT, United Kingdom b Neurology, School of Experimental Medicine, College of Medical and Dental Sciences, University of Birmingham, Birmingham, B15 2TT, United Kingdom Endocrinology, School of Experimental Medicine, College of Medical and Dental Sciences, University of Birmingham, Birmingham, B15 2TT, United Kingdom Received 31 March 2008; received in revised form 12 June 2008; accepted 12 June 2008
a

Abstract Idiopathic intracranial hypertension (IIH) is a common blinding condition amongst the young obese female population (20 per 100,000) characterised by elevated intracranial pressure (ICP). The aetiology of IIH is not known. In this review we explore the literature investigating the pathogenesis of IIH and suggest additional hypotheses. Chronic inflammation is emerging as an aetiological factor in the pathogenesis of obesity and we propose that this may be a feature of IIH. Obesity is also related to dysregulation of cortisol production by the pre-receptor enzyme, 11hydroxysteroid dehydrogenase, and we speculate that this may have a role in the pathogenesis of obesity and raised ICP seen in IIH. 2008 Elsevier B.V. All rights reserved.
Keywords: Idiopathic intracranial hypertension; Obesity; Chronic inflammation; 11-hydroxysteroid dehydrogenase

1. Introduction Idiopathic intracranial hypertension (IIH) is a disabling condition characterised by elevated intracranial pressure (ICP) and disordered cerebrospinal fluid (CSF) dynamics. Affected individuals typically suffer with chronic disabling headaches together with significant visual loss, which can be severe and permanent in up to 25% of affected patients (Corbett et al., 1982). The diagnosis of IIH is based on the modified Dandy Criteria (Friedman and Jacobson, 2002) which specifies that patients must have elevated ICP in the absence of an intracranial mass. A range of aetiologies which constitute secondary intracranial hypertension must also be excluded (Table 1). Effective therapeutic strategies in IIH have not been established and a recent Cochrane review concluded that there was
Corresponding author. Academic Unit of Ophthalmology, School of Immunology, Infection and Inflammation, Institute for Biomedical Research, University of Birmingham, Wolfson Drive, Edgbaston, Birmingham, B15 2TT, United Kingdom. Tel.: +44 121 414 2764; fax: +44 121 415 8712. E-mail address: a.b.sinclair@bham.ac.uk (A.J. Sinclair). 0165-5728/$ - see front matter 2008 Elsevier B.V. All rights reserved. doi:10.1016/j.jneuroim.2008.06.029

insufficient evidence to determine which treatments were potentially beneficial and which were potentially harmful (Lueck and McIlwaine, 2002). Medical treatments such as carbonic anhydrase inhibitors aim to reduce CSF secretion, whereas in severe cases neurosurgical intervention such as CSF shunting is required. The reported incidence of IIH is 0.9 to 2.2 per 100,000 in the general population (Durcan et al., 1988; Radhakrishnan et al., 1993), rising to above 19 per 100,000 in studies confined to young, overweight women. This background incidence is likely to increase further in developed countries with the epidemic of obesity. It is also interesting to note that the condition occurs almost exclusively, over 92%, in females (Galvin and Van Stavern, 2004; Radhakrishnan et al., 1993; Wall and George, 1991). 2. What is known about the pathogenesis of IIH? Although the hallmark of IIH is raised ICP, the underlying aetiology of IIH is not known. Elevated ICP is likely to relate to abnormalities in the balance between production, by the choroid

A.J. Sinclair et al. / Journal of Neuroimmunology 201202 (2008) 212220 Table 1 Secondary causes of elevated intracranial pressure Venous sinus thrombosis Anaemia Obsrtuctive sleep apnoea Drug related (antibiotics, non-steroidal anti-inflammatory drugs, vitamin A, lithium, cimetidine) Guillain Barr syndrome CSF hyperprotinaemia or hypercullularity (spinal cord tumour, malignant meningitis) Karahalios et al., (1996) Biousse et al., (2003) Asensio Sanchez et al., (2004) Ball and Clarke, (2006)

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Ropper and Marmarou, (1984) Cremer et al., (1997), Feldmann et al., (1986), Ridsdale and Moseley, (1978)

plexus (CP) and drainage, primarily at the arachnoid granulation tissue (AGT) of CSF. Several possible mechanisms for the raised ICP have been postulated: increased CSF secretion, increased cerebral volume, increased CSF outflow resistance and increased cerebral venous pressure. 2.1. CSF hypersecretion The first suggestion that CSF hypersecretion resulted in IIH was made over a century ago (Quincke et al., 1897) when alcohol, stress or changes in the weather were thought to lead to CSF hypersecretion and subsequent raised ICP. In 1979 ventricular infusion studies (which monitor CSF dilution and calculate the rate of CSF production) demonstrated elevated CSF secretion in five patients with IIH (Donaldson, 1979). These findings were supported by velocity sensitive magnetic resonance imaging (MRI), a calculation of CSF flow, which also showed hypersecretion in IIH (Gideon et al., 1994). These studies, however, were confounded by small numbers and assumptions made in the mathematical modelling. Nevertheless the observation that CSF protein levels are reduced in IIH supports the theory of CSF hypersecretion (Chandra et al., 1986) although low protein in IIH is not a universal finding (Johnston et al., 1991). In other conditions in which there is CSF hypersecretion, such as choroid plexus papilloma, hydrocephalus is a feature. The absence of hydrocephalus in IIH suggests that increased CSF secretion may not be a feature. Increased brain water content has been postulated as the cause of IIH but evidence, based on histology of brain biopsies and diffusion weighted MRI scanning, is sparse (Gideon et al., 1995; Wall et al., 1995). In summary, the limited studies investigating CSF hypersecretion in IIH have been inconclusive but continues to be debated in the literature (Ball and Clarke, 2006). 2.2. Increased CSF outflow resistance Impaired CSF drainage is increasingly recognised as a probable cause of IIH. The majority of evidence to support this has come from CSF infusion studies which demonstrated reduced CSF drainage in IIH (Malm et al., 1992). Studies scrutinising the transit time of a radio-labelled tracer injected into the CSF (cisternography) have demonstrated delayed uptake into the circulation in patients with IIH, implicating compromised CSF drainage (Orefice et al., 1992). These findings have not been universally replicated (Janny et al., 1981). The importance of CSF drainage in CSF dynamics is highlighted by observations of secondary intracranial hyperten-

sion in conditions such as Guillain Barr syndrome (Ropper and Marmarou, 1984), spinal cord tumour (Feldmann et al., 1986), malignant/infective meningitis (Cremer et al., 1997) and subarachnoid haemorrhage (Kida et al., 1988). These conditions are characterised by CSF hypercellularity or hyperproteinaemia which is believed to block the AGT, thereby restricting drainage and elevating CSF pressure. This has been shown histologically in cases of subarachnoid haemorrhage which demonstrate red blood cells obstructing the AGT core (Kida et al., 1988). Elevated ICP is also noted in patients with AGT agenesis (Gilles and Davidson, 1971; Gutierrez et al., 1975). These observations emphasises the importance of AGT in CSF drainage and ICP homeostasis. 2.3. Increased cerebral venous pressure There is considerable evidence from venography and manometry studies that venous sinus pressure is raised in IIH, particularly in the transverse and superior sagittal sinus (Karahalios et al., 1996) (King et al., 1995). In addition, focal cerebral venous stenoses have been reported in IIH patients (Higgins et al., 2004), and stenting the stenosed veins has been shown to improve symptoms in a few cases of IIH (Rajpal et al., 2005). The underlying cause for the stenoses remains controversial and may represent either small venous sinus thromboses, congenital variations (Johnston et al., 2002), intraluminal septa (Subramaniam et al., 2004) or indentations from giant arachnoid granulations swollen by raised ICP (Kollar et al., 2001). It is most likely, however, that the stenoses are a consequence of raised pressure originating from brain parenchyma or the CSF compartment on the venous system (Farb et al., 2003). This is substantiated in an elegant study by King et al. (2002) in which patients with IIH underwent cerebral venous manometry before and after a lumbar puncture (LP) (King et al., 2002). The pressure in the superior sagittal and transverse sinus, which was initially elevated, significantly reduced following LP with subsequent reduction of CSF pressure and disappearance of the apparent venous stenoses. This study, and others, conclude that the cerebral venous stenoses and elevated venous pressure in IIH results from collapse of the venous sinus walls due to raised intracranial pressure i.e. the stenoses occur as a secondary phenomenon and are not the primary cause of IIH (Goodwin, 2003; McGonigal et al., 2004). It is also possible that the cerebral venous stenoses play an important role in aggravating IIH by further decreasing CSF drainage across the AGT and thus further increasing the CSF pressure.

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2.4. Other A number of other studies have highlighted possible aetiological factors in IIH. Elevated retinol has been identified in the CSF of patients with IIH (Warner et al., 2007). In addition, elevated ICP has been noted in individuals taking vitamin A containing drugs and following ingestion of vitamin A rich foods, such as polar bear liver (Rodahl and Moore, 1943). Vitamin A has therefore been implicated in the pathogenesis of IIH, although the mechanism remains unclear. Elevated plasma leptin levels have also been documented in patients with IIH, but the role of leptin in ICP regulation is not known (Lampl et al., 2002). Microthrombi obstructing the AGT have been postulated as a cause of IIH with thrombophilic defects being reported in between 14 and 68% of patients with IIH (Glueck et al., 2005; Sussman et al., 1997), although a number of patients in these studies had underlying venous sinus thrombosis. In summary although raised ICP in IIH suggests disordered CSF dynamics, there is no consensus regarding the mechanism. We therefore conceptualise two new theories: dysregulation of inflammation and dysregulation of glucocorticoid metabolism, and how these could be fundamental in our understanding of the underlying pathophysiological processes of IIH. 3. Obesity 3.1. Obesity and IIH One of the most striking features of IIH is its association with obesity, with over 94% of patients being clinically obese (Galvin and Van Stavern, 2004). The incidence of IIH increases to 19.3 to 21 per 100,000 in the obese population compared with 0.9 to 2.2 per 100,000 in the general population (Durcan et al., 1988; Ireland et al., 1990; Radhakrishnan et al., 1993). Although evidence for current treatment protocols in IIH is lacking, weight loss is almost universally advised, despite little proof of efficacy (Johnson et al., 1998; Kupersmith et al., 1998; Newborg, 1974). The mechanism by which obesity is related to IIH is debated. Obstructive sleep apnoea, a condition associated with obesity, leads to nocturnal hypercapnia, right heart failure and surges in intrathoracic pressure which can elevate ICP; (Jennum and Borgesen, 1989). It has also been suggested that pressure effects of centrally distributed adiposity elevate intra-abdominal pressure which subsequently elevates intra-thoracic pressure and cerebral venous pressure and finally ICP (Sugerman et al., 1995). This theory does not explain why despite ubiquitous elevation of intra-abdominal pressure in obese patients (Sugerman et al., 1997; Whiteley et al., 2006), only a small proportion of patients develop IIH. The current literature does not establish whether obesity in IIH represents cause or effect. We therefore hypothesise that the relationship of IIH to obese female patients strongly suggests that neuroendocrine dysfunction plays an important aetiological role in these patients. 3.2. Obesity, adipokines and chronic inflammation Over the last decade the epidemic of obesity has escalated rapidly in the western world. Obesity is defined as a body mass

index greater than 30 kg/m2 (Alberti and Zimmet, 1998) and is frequently associated with hyperlipidaemia, hypertension, glucose intolerance and fatty liver. Collectively these features are known as the Metabolic syndrome, a state of impaired insulin sensitivity predisposing to type 2 diabetes and atherosclerotic vascular disease (Ginsberg, 2000). Obesity is characterised by an enlarged white adipose tissue mass which not only provides an energy store but additionally represents an important endocrine organ that has the ability to secrete over a hundred factors, including proteins, cytokines, fatty acids and prostaglandins (Fain, 2006; Mercer et al., 1996). The endocrine properties of adipose tissue enable communication with numerous other organs facilitating appetite regulation, energy homeostasis, insulin sensitivity, reproductive function, bone metabolism and immune modulation (Fantuzzi, 2005). The link between inflammation and obesity may have evolutionary roots. Individuals able to effectively store fat as an energy source for use during periods of rationed nutrition and those able to mount an inflammatory response and fight infection during times of endemic disease, have survival advantages (Hotamisligil, 2006). In the developed world, the threat of starvation and untreated infection has now declined, but efficiency in maintaining energy stores in conjunction with a heightened inflammatory response remains and possibly explains the coexistence of chronic, low grade inflammation with obesity. The role of inflammation in many obesity associated complications, such as vascular disease and insulin resistance (Wellen and Hotamisligil, 2005) highlights the pathological importance of this pathway. Chronic inflammation was first recognised in obesity over 10 years ago when elevated TNF expression was demonstrated in adipose tissue from obese mice and humans (Hotamisligil et al., 1995; Hotamisligil et al., 1993; Kern et al., 1995). Since then, numerous in vivo and in vitro studies have demonstrated an association between obesity and a range of inflammatory cytokines such as interleukin-1 beta (IL-1) (Maedler et al., 2002), interleukin-6 (IL-6) (Fain, 2006; Vozarova et al., 2001), interleukin-8 (IL-8) (Fain, 2006; Gerhardt et al., 2001; Straczkowski et al., 2002), monocyte chemoattractant protein-1 (MCP1, also known as CC-chemokine ligand-2, (CCL2)) (Gerhardt et al., 2001; Sartipy and Loskutoff, 2003), hepatocyte growth factor (HGF) (Bell et al., 2006), nerve growth factor (NGF) (Nisoli et al., 1996) and plasminogen-activator inhibitor type 1 (PAI-1) (De Pergola and Pannacciulli, 2002; McGill et al., 1994) (Table 2). The mechanism by which inflammatory cytokines regulate or are regulated by obesity remains an area of debate. A number of adipokines, cytokines and growth factors predominantly secreted from and synthesised by adipocytes (Trayhurn and Wood, 2004), have also been linked to obesity (Arita et al., 1999; Ouchi et al., 2003); (Fukuhara et al., 2005; Steppan et al., 2001; Steppan and Lazar, 2004) (Table 2). One of the principle adipokines, leptin, encoded by the ob gene (Zhang et al., 1994), has numerous functions but principally regulates appetite (Klok et al., 2007) via neurotransmitters including neuropeptide Y (Mercer et al., 1996) in the arcuate, ventromedial, paraventricular and dorsomedial nuclei of the hypothalamus. Leptin resistance is implicated in obesity and serum leptin

A.J. Sinclair et al. / Journal of Neuroimmunology 201202 (2008) 212220 Table 2 Inflammatory mediators secreted from adipose tissue Inflammatory mediator TNF IL-1 IL-6 IL-8 MCP-1 PAI-1 MIP-1 NGF IL-18 HGF Leptin Adiopnectin Resistin Visfatin Study Increased expression in adipose of obese mice and humans. In vitro inhibition of islet cells. Increased circulating levels in obese humans. Increased expression in adipose of obese humans. Increased circulating levels in obese humans. Increased expression in adipose of obese humans. Secreted by preadipocytes Secreted by preadipocytes. Increased expression in obese mice adipose tissue. Increased circulating levels in obese humans. Secreted by preadipocytes. Increased secretion from adipose tissue in obese compared to lean mice. Increased expression in obese human adipose tissue. Increased circulating levels in obese humans. Increased circulating levels in obese humans. Increased circulating levels in obese humans. Decreased circulating levels in obese humans. Secreted by adipose tissue and contributes to insulin resistance. Increased circulating levels in obese humans. Reference

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Hotamisligil et al., (1995), Hotamisligil et al., (1993), Kern et al., (1995) Maedler et al., (2002) Fain, (2006), Vozarova et al., (2001) Fain, (2006), Gerhardt et al., (2001), Straczkowski et al., (2002) Gerhardt et al., (2001), Sartipy and Loskutoff, (2003) De Pergola and Pannacciulli, (2002), McGill et al., (1994) Gerhardt et al., (2001) Nisoli et al., (1996) Bruun et al., (2007), Evans et al., (2007) Bell et al., (2006) Ostlund et al., (1996), Schwartz et al., (1996) Ouchi et al., (2003), Arita et al., (1999) Steppan et al., (2001) Fukuhara et al., (2005)

levels have been noted to rise in association with increasing BMI (Ostlund et al., 1996; Schwartz et al., 1996). Leptin resistance may result from diminished transport of leptin across the blood brain barrier. CSF:serum leptin ratios decrease with increasing BMI (Caro et al., 1996) and additionally, central infusion of leptin into obese leptin deficient mice corrects obesity (Van Heek et al., 1997). Alternatively, leptin resistance may represent impaired hypothalamic signalling (Howard and Flier, 2006). Macrophage accumulation in adipose tissue, particularly visceral adipose, increases in obesity (Weisberg et al., 2003; Xu et al., 2003). Expression of almost all of the TNF, as well as modest levels of other inflammatory cytokines, in adipose tissue is accounted for by adipose resident macrophages (Weisberg et al., 2003), highlighting the sizable contribution of macrophages to chronic inflammatory response seen in obesity. 3.3. Do adipokines and inflammation contribute to the pathogenesis of IIH? IIH is phenotypically characterised by obesity and as such, may also demonstrate an inflammatory profile. Inflammatory

cytokines have not been previously evaluated in IIH. We suggest, however, that inflammation and subsequent regulation of central nervous system glucocorticoid availability may be pivotal in ICP homeostasis. This will be discussed in more detail in Section 4. Serum leptin levels have been demonstrated to be significantly elevated in patients with IIH compared to both lean and obese controls (Lampl et al., 2002; Subramanian et al., 2004). CSF leptin levels are also noted to be higher in IIH compared to age, gender and BMI matched controls (Ball et al., 2007). These studies indicate that leptin may have a role in ICP regulation. 4. Endocrine dysfunction in IIH IIH is almost exclusively a disease of women (female:male ratios ranging from 4:1 to 15:1) (Durcan et al., 1988; Radhakrishnan et al., 1993). The condition typically occurs between puberty and menopause, with a mean age of onset being documented as 2835 years (Galvin and Van Stavern, 2004; Glueck et al., 2005). Although IIH is associated with the endocrinopathies (Table 3), numerous case reports have linked IIH to glucocorticoid therapy (Table 4).

Table 3 Case reports of endocrinopathies associated with idiopathic intracranial hypertension Disorder Cushing's disease/syndrome Adrenal hyperplasia Primary aldosteronism Addisons Hypothyroidism Growth hormone Hypoparathyroidism ACTH deficiency Oral contraception Pregnancy Number of cases 2 1 2 1 1 6 1 1 2 2 Reference Britton et al., (1980), Newman et al., (1980) De Campo et al., (1988) Weber et al., (2002) Condulis et al., (1997) Serratrice et al., (2002) Clayton and Cowell, (2000), Crock et al., (1998), Reeves and Doyle, (2002) Madan Mohan et al., (1993) Aanderud and Jorde, (1988) Ivancic and Pfadenhauer, (2004), Janzik, (1973) Elian et al., (1968), Gumma, (2004)

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Table 4 Case reports of idiopathic intracranial hypertension attributed to corticosteroid therapy Treatment Corticosteroid therapy Number of cases 1 1 1 1 4 1 1 1 1 1 2 1 1 5 1 4 1 Reference Valentine, (1959) Dees and Mc, (1959) Dees and Mc, (1959) Lorenzo and Avellanal, (1961) Walker and Adamkiewicz, (1964) Ivey and Denssesten, (1969) Jewell, (1972) Vyas et al., (1981) Pampapathi and Kabuubi, (1987) Lucas et al., (1991) Newton and Cooper, (1994) Lorrot et al., (1999) Chebli et al., (2004) Greer, (1963) Hosking and Elliston, (1978) Liu et al., (1994) Saigusa et al., (2002)

Chronic corticosteroid withdrawal

The effects of glucocorticoids on BMI have long been recognised and are illustrated in Cushing's syndrome, a condition characterised by central obesity and elevated plasma cortisol levels. Although elevated plasma cortisol is not a typical feature in obese individuals, there is growing evidence that dysfunctions of 11-hydroxysteroid dehydrogenase type 1 (11-HSD1) may be pathological. 11-HSD, which resides in the lumen of the endoplasmic reticulum (Odermatt et al., 1999), is a bidirectional enzyme regulating pre-receptor corticosteroid hormone availability. 11-HSD has two isoforms: 11-HSD1, which acts predominantly as an oxoreductase in vivo, activating cortisol from cortisone and a dehydrogenase, 11-HSD2, which inactivates cortisol to cortisone. 11-HSD1 is expressed in a wide variety of tissues but its principle role in humans is mediating local cortisol availability, a potent anti-inflammatory mediator, driving hepatic gluconeogenesis and regulating adipocyte differentiation (Tomlinson et al., 2004). In obesity, aberrant hepatic 11-HSD1 activity has been demonstrated using cortisol generation curves (administration of cortisone acetate following an overnight dexamethasone suppression test) (Rask et al., 2001; Stewart et al., 1999). Global 11-HSD1 activity, determined from urinary tetrahydrocortisols (THF + allo-THF)/tetrahydrocortisone (THE) ratios, are also disrupted in the obese (Andrew et al., 1998; Rask et al., 2001; Reynolds et al., 2001). Additionally, aberrant 11-HSD1 expression has also been documented in subcutaneous fat from obese individuals (Li et al., 2007; Paulmyer-Lacroix et al., 2002; Tomlinson et al., 2002). These studies suggest that 11HSD1 is dysregulated in obesity and it is possible that aberrant 11-HSD1 activity may contribute to IIH. We can further speculate that anomalous 11-HSD1 activity is driving the obesity in IIH or conversely that the obesity itself alters 11HSD1 activity in IIH. 11-HSD1 activity is regulated by multiple factors including sex steroids (Arcuri et al., 1997; Gomez-Sanchez et al., 2003;

Ho et al., 1999; Nwe et al., 2000) which manifests as reduced enzyme activity in women compared to men (Dimitriou et al., 2003; Low et al., 1994). Aberrant sex hormone metabolism is suggested in IIH as patients are almost universally female and of reproductive age (Galvin and Van Stavern, 2004). It is possible that the suppression of 11-HSD1 activity normally seen in women may be lost in IIH as a result of abnormal sex hormone metabolism. 11-HSD1 may also have a direct affect on ICP regulation. In the CP epithelium, CSF production is dependent on an osmotic gradient created by the Na + K + ATPase pump and intracellular carbonic anhydrase activity, driving water into the ventricles (Ernst et al., 1986; Speake et al., 2001). This is analogous to the ion transporting mechanisms involved in aqueous humour production by the embryogically-related ocular ciliary epithelium. In this tissue, 11-HSD1 activation of cortisol is thought to mediate aqueous humour production and intraocular pressure homeostasis through induction of corticosteroid regulated target genes both in the ocular ciliary epithelium and trabecular meshwork (predominant site of aqueous humour drainage) (Rauz et al., 2003a,b; Rauz et al., 2001). We propose that a similar 11-HSD1 dependant mechanism may exist in the CP contributing to CSF production and ICP. In support of this, 11-HSD1 has been localised to the CP epithelium and has demonstrated oxo-reductase activity in both rabbits and humans (Sinclair et al., 2007a,b). In contrast to the CP, the mechanisms underlying CSF drainage by the AGT are less well defined, but are likely to be related to active or passive ion transporting channels in the arachnoid core, that open into the dural venous sinus. In the eye, exogenous glucocorticoids alter the microconfiguration of the drainage structures within the trabecular meshwork resulting in induction of glucocorticoid responsive proteins such as myocilin (Ishibashi et al., 2002; Polansky et al., 1997). These changes in the trabecular meshwork lead to increased resistance to aqueous humour drainage thereby raising intraocular pressure (Clark et al., 2001; Ishibashi et al., 2002). A comparable mechanism may exist at the AGT, the site of CSF outflow, raising ICP in at risk populations such as patients with IIH. It is interesting to note that intraocular pressure, in addition to being regulated by 11-HSD1 and glucocorticoids, is positively associated with obesity (Akinci et al., 2007; Mori et al., 2000). This further emphasises the potential relationship of obesity to pressure regulation (intracranial and intraocular) and 11-HSD1. Importantly, it is established that 11-HSD1 activity is regulated by inflammatory cytokines (TNF, IL-1, IL-6) and adipokines (leptin) (Tomlinson et al., 2001; Tomlinson et al., 2004). Hence obesity induced dysregulation of inflammatory cytokines and adipokines may drive 11-HSD1 activity and aberrant glucocorticoid metabolism in IIH. 5. Conclusion The association of obesity with chronic low grade inflammation, adipokines and 11-HSD1 activity have been discussed. We suggest that in IIH, a condition characterised by

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Fig. 1. Schematic diagram illustrating the potential role of obesity and inflammation in the pathogenesis of idiopathic intracranial hypertension. Dysregulation of the cortisol generating enzyme 11-hydroxysteroid dehydrogenase type 1 (11-HSD1) is implicated in obesity. Additionally chronic inflammation, a feature of obesity, may manipulate 11-HSD1 activity through the generation of inflammatory cytokines. Aberrant 11-HSD1 activity and glucocorticoid metabolism may have a critical role in intracranial pressure regulation via actions at either the choroid plexus or arachnoid granulation tissue. The following abbreviation have been used, increase (+), decrease (), cerebral spinal fluid (CSF). References: 1) Wellen and Hotamisligil, 2005; 2) Fain, 2006; 3) Tomlinson et al., 2001; 4) Li et al., 2007.

obesity, aberrant inflammatory and adiposity related cytokine profiles may drive 11-HSD1 activity. Consequently increased 11-HSD1 levels in patients with IIH may enhance cortisol levels at the CP and AGT leading to altered CSF dynamics thereby contributing to the raised ICP seen in these patients (Fig. 1). We speculate that IIH is likely to have a multifactorial pathogenesis with 11-HSD1, glucocorticoid dysregulation and inflammation contributing to the aetiology. Acknowledgement Alexandra Sinclair is a Medical Research Council Clinical Research Training Fellow (London, UK). References
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