Obese individuals are at greater risk for more frequent migraine

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As worldwide obesity rates continue to soar, new research shows that growing numbers of people are developing a potentially blinding type of weight-linked headache that was once considered rare.

Though the study was conducted in Wales, one U.S. expert said the same surge in these headaches is likely happening in this country and elsewhere, but he cautioned that just because someone is obese and has headaches doesn’t mean he or she have this rare headache, known as idiopathic intracranial hypertension (IIH).

Obese individuals are at greater risk for more frequent migraine, too,” noted Dr. Brian Grosberg, director of the Hartford HealthCare Headache Center in Connecticut.

In the study, IIH rates increased sixfold in Wales between 2003 and 2017 – from 12 per 100,000 people to 76 per 100,000 people. During the same 15-year span, obesity rates in Wales rose from 29% of the population to 40%.

“The considerable increase in IIH incidence” has several causes, but is likely “predominately due to rising obesity rates,” said study author William Owen Pickrell, a consultant neurologist at Swansea University.

“The worldwide prevalence of obesity nearly tripled between 1975 and 2016, and therefore, these results also have global relevance.”

His findings were published in the Jan. 20 issue of Neurology.

IIH is a type of headache that occurs when the fluid around your brain and spinal cord builds up in your skull. This places extra pressure on your brain and the optic nerve in the back of your eye, causing symptoms that can mimic a brain tumor such as debilitating head pain, blind spots and possibly vision loss, according to the National Eye Institute.

The cause is not fully understood, but weight loss is the main treatment. Some people may need medication and/or surgery to drain the fluid and relieve the pressure. “There is some evidence that weight loss can improve headache symptoms,” Pickrell said.

During the review, researchers found 1,765 cases of IIH, 85% in women. They looked at patients’ body mass index (BMI), a measure of body fat based on height and weight, as well as their economic status based on their address. They compared this information to that of individuals without IIH.

Overall, the risk of developing IIH was higher in those who were obese.

Economic status only affected women’s risk, and this finding was independent of their weight, according to the study. Obese women of child-bearing age were at highest risk of IIH.

People with IIH were also more likely to require emergency hospital admissions than their counterparts without these headaches, with 9% requiring brain surgery to prevent blindness, the study found.

Pickrell did say there could be explanations other than obesity for the surge in IIH.

“The increase may also be attributable to increased IIH diagnosis rates due to raised awareness of the condition and greater use of [digital] technology at routine optometry appointments,” he said. Eye doctors often diagnose IIH during routine exams that look at the back of the eye.

The biggest concern with these headaches is the potential for vision loss, which likely explains the increased rates of emergency hospital admissions seen in the new study among people with IIH.


Idiopathic intracranial hypertension (IIH), also known as primary pseudotumour cerebri syndrome, is a neurological disorder characterised by raised intracranial pressure (ICP) that can cause papilloedema with no identifiable cause found [1, 2]. There is a rising incidence of this disease, which is most common in females of working age [3, 4], and appears to be related to the prevalence of obesity [4, 5], the major known risk factor for the disease [1, 6].

IIH is associated with headache, which impacts quality of life [7]; over half of those with IIH report ongoing headaches at 12 months following initial diagnosis [8]. IIH can cause visual loss, even to the level of severe visual impairment or legal blindness [9]. Current medical treatments are often poorly tolerated [10], and the overarching research aspirations of both patients and clinicians are to understand the aetiology and management of IIH, with particular focus on headache [11].

The recent guidance in IIH acknowledges uncertainties in many aspects of the disease [1]. Novel targets are now being identified, and insights into monitoring disease activity are improving [12]. This article is based on previously conducted studies and does not contain any studies with human participants or animals performed by any of the authors.

Epidemiology of IIH
IIH is considered a rare disease; however, increasing numbers of patients are being reported. Previously, the incidence in the general population was reported to be between 0.5 and 1.0 per 100,000 [5]. Comparing rates within the United Kingdom (UK) between the years 2007 and 2008, Raoof et al. found the incidence of IIH was 1.56 per 100,000 for men and 2.86 per 100,000 for women [12, 13].

Recent evidence indicates a greater than 100% increase in the incidence of IIH in England between 2002 and 2016, which rose from 2.3 to 4.7 per 100,000 in the general population [3]. In females, the incidence of IIH more than tripled between 2005 and 2017, from 2.5 to 9.3 per 100,000 person-years, and increased markedly in those with a body mass index (BMI) higher than 30 kg/m2 [4].

Adult women are more likely to develop IIH than men, with a peak incidence in females aged 25 years of 15.2 per 100,000 [3]. Worldwide, IIH is more common in countries such as the UK [3, 13], Italy [14], Israel [15] and the USA [16], while incidence is lower in Asia [17, 18]. A recent systematic review identified a positive correlation between a country-specific prevalence of obesity and incidence of IIH [6].

The incidence of IIH in childhood is estimated to be around 0.5 per 100,000 [19, 20]. Paediatric IIH has been classified by anthropometric features, with three identifiable subgroups of paediatric IIH: a young cohort that is not overweight, an early adolescent group that is either overweight or obese, and a late adolescent group that is mostly obese. This indicates that the underlying pathological mechanisms for IIH may differ depending on age and BMI [21].

Pathophysiology
The pathological processes underlying elevated ICP in IIH patients are unknown. Current research is focused on understanding the respective roles of obesity, increased cerebrospinal fluid (CSF) production and hormonal dysregulation. Additional theoretical mechanisms, such as venous hypertension and reduced CSF absorption, may also play a role in the pathophysiology of IIH [2, 22, 23].

There is however an emerging theme that IIH is a neurometabolic disease [23]. Adderley et al. found a twofold increase in cardiovascular disease risk in women with IIH compared to age-, sex- and, most importantly, BMI-matched controls [4]. This suggests that multiple factors may be driving the disease.

Obesity
There is a well-established link between IIH and obesity [6, 24]; the prevalence of IIH in populations with a higher BMI is greater than in the general population [5]. The dramatic rise in obesity rates globally [25] is mirrored in the rising incidence of IIH [3, 5, 26]. Daniels et al. found that, compared to controls, patients with IIH reported higher weight gain in the 1-year period prior to the onset of the disease.

Higher BMI and weight gain percentage were also associated with higher (dose-dependent) risk of IIH. Interestingly, weight gain of just 5–15% can lead to an increased risk of IIH [27]. Ko et al. found that patients who experienced a recurrence of IIH following symptom resolution showed weight gain of just 6% of total body weight [24].

Records were analysed over a 16-year period at two hospitals, and the authors found that 26 out of the 50 patients analysed had IIH recurrence (increase in an average BMI of 1.3 per year), and the 24 who had no recurrence did not gain weight (average decrease in BMI of 0.96 per year) [24].

This shows the exquisite sensitivity between even modest weight gain and recurrence of IIH. Adderley et al. reported that the incidence of IIH increased rapidly above a BMI of 30 kg/m2 [4]. This evidence reinforces the close link between obesity and IIH.

Lifestyle interventions such as diet and exercise have long been known to be an effective treatment for IIH; the first study to demonstrate the effectiveness of a lifestyle intervention for improvement of IIH symptoms was carried out in 1974 [28]. In the mid-1990s, the first cases of bariatric surgery for IIH were reported [29]. Previous literature shows that between 3 and 15% loss in body weight is required to put the disease into remission.

An objective evaluation of weight loss in IIH was performed as a prospective crossover cohort trial using a very low-calorie meal replacement to induce significant weight loss, defined as a loss of 15% or greater of total body weight. Such weight loss resulted in significantly lowered ICP and improved papilloedema, visual function (perimetry and acuity) and headache outcomes (50% improvement in headache frequency, severity and frequency of analgesic use) [30].

In the Idiopathic Intracranial Hypertension Treatment Trial (IIHTT), a randomised controlled trial (RCT) investigating the use of acetazolamide in IIH patients with mild visual loss, the treatment group used acetazolamide, and both groups (placebo and treatment) were provided a low-sodium diet with behavioural weight management support. The treatment group experienced an average 6% weight loss compared to 3% weight loss in the controls [31]. The IIHTT used a psychological statistical method to report that weight loss did not mediate the treatment effect of acetazolamide.

Distribution of body fat in IIH has been investigated, and it was demonstrated that truncal fat mass was the only parameter that correlated with lumbar puncture pressure, as compared with limb fat mass, BMI, waist circumference and total fat mass [32]. A relationship has been established between truncal weight loss in patients with IIH and a reduction in disease activity [30].

The relationship between obesity and IIH in men is less clear, although men appear to be at risk of greater vision loss and obstructive sleep apnoea if they have IIH [33].

CSF Dysregulation
CSF is secreted by the choroid plexus, which consists of epithelial cells lining the ventricles in the brain. CSF secretion 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 and rate-limiting step is the Na+- and K+-dependent adenosine triphosphatase (Na+/K+/ATPase) that actively transports Na+ into the cerebral ventricle [34, 35]. CSF flows through the ventricles and into the subarachnoid space, before being returned to the bloodstream via arachnoid granulations.

Specific inhibition of Na+/K+/ATPase with ouabain has been shown to reduce CSF secretion by 70–80% [36].

Aquaporins (AQPs), membrane-bound water transport channels, are thought to be involved in the osmotic homeostasis of the brain. Research has not demonstrated a pathogenic role for AQP4 in the genesis of IIH [37]. AQP1, another channel, appears to be important in drug-induced elevation of ICP, and animal studies show a link between obesity, AQP1 expression and raised ICP [38]. However, no investigations of the role of AQP1 in IIH in humans have yet been reported.

Impaired drainage of CSF into the subarachnoid space is another potential source of IIH. The turnover of CSF was found to be reduced in patients with papilloedema [39]. Patients with IIH have been shown to have abnormalities in blood clotting [40], and it has been suggested that microthrombi could cause impaired CSF drainage in IIH [41]. However, no direct evidence of microthrombi causing raised ICP has been shown to date.

Glucagon-Like Peptide 1
Glucagon-like peptide-1 (GLP-1) is an incretin with weight-modifying properties, and has been shown to have a natriuretic effect in the kidney through inhibition of the Na+/H+ exchanger in proximal tubule cells. CSF secretion, as discussed above, is controlled by Na+/K+/ATPase channels and pumps fluid into the ventricles akin to an inverted renal proximal tubule. Exploratory work showed that the choroid plexus expresses GLP-1 receptor [42].

Botfield et al. thus hypothesised that GLP-1 could modulate CSF secretion at the choroid plexus, thereby mediating ICP [42]. Following from this, it was demonstrated that exendin-4, a GLP-1 receptor agonist, significantly reduced the activity of Na+/K+/ATPase. In a rodent study, Botfield et al. showed that exendin-4 led to a 65% reduction in ICP within 30 min of administration, and that its effect on ICP was cumulative.

This finding is now being translated into the IIH Pressure Clinical Study (IIHPCS; ISRCTN12678718). The IIH pressure study is a double-blinded, placebo-controlled physiology study assessing the effects of exenatide on ICP in patients with active IIH, and is expected to report soon.

Glucocorticoid Metabolism
Glucocorticoid metabolism has previously been characterised in IIH subjects before and after therapeutic weight reduction. 11β-Hydroxysteroid dehydrogenase type 1 (11β-HSD1) is an intracellular enzyme that converts inactive cortisone into the active cortisol. This amplifies local glucocorticoid activity independent of systemic cortisol [43].

Global 11β-HSD1 activity was found to decrease with weight loss, and a significant correlation was found between the reduction in ICP and the decrease in global 11β-HSD1 activity [44]. It is now known that 11β-HSD1 is expressed and has activity in the choroid plexus epithelial cells, along with other key elements of the glucocorticoid signalling pathway.

Inhibitors of 11β-HSD1, such as oral AZD4017, have been developed for type 2 diabetes mellitus, obesity and metabolic syndrome. The IIH Drug Trial hypothesised that specific inhibition of 11β-HSD1 using such drugs may decrease ICP in individuals with IIH, which could open an entirely novel therapeutic avenue for targeting the disease [45]. The results of this trial are presented later in this article.

Hormonal Dysregulation
Hormonal dysregulation has been shown to play an important role in the pathogenesis of IIH [2, 22, 23]. Androgens have been identified as potential key players in IIH pathophysiology. Serum testosterone, and the enzyme 5α-reductase involved in its metabolism, has been shown to be higher in those with IIH compared to age- and BMI-matched controls [46].

In a recent study that comprehensively compared the systemic and CSF androgen metabolome in women with IIH to sex-, BMI- and age-matched control groups with either simple obesity or polycystic ovary syndrome (PCOS), IIH women showed a pattern of androgen excess with increased serum testosterone and increased CSF testosterone and androstenedione [47]. This was found to be distinct from that observed in PCOS and simple obesity.

The authors went on to show that human choroid plexus expressed the androgen receptor, alongside the androgen-activating enzyme aldo-keto reductase type 1C3, and in a rodent model testosterone significantly enhanced the activity of Na+/K+ ATPase, a surrogate of CSF secretion. In summary, androgens can modulate CSF secretion via the choroid plexus, and these findings implicate androgen excess as a potential causal driver for IIH and therefore a potential therapeutic target [47].

The hormone leptin plays an important role in the regulation of fat storage. Leptin is secreted by adipocytes, and its concentration in the body correlates with total body fat [48]. Higher serum leptin has been demonstrated in IIH patients, controlling for age and BMI, indicating that leptin dysregulation may be important in IIH [49].

Another study showed that leptin was elevated in the CSF of IIH patients, though there was no correlation with leptin CSF levels and BMI [50]. However, leptin is secreted disproportionately from subcutaneous fat compared to visceral fat [51], and since neither of these studies accounted for fat distribution, elevation of leptin in IIH patients may be a secondary effect of non-central body adiposity. These studies indicate that the role of leptin in IIH warrants further investigation.

Venous Hypertension
Increased dural venous sinus pressure has been proposed as a potential mechanism underlying IIH. Neuroimaging studies have established that venous sinus stenosis is a common finding among patients with IIH [52, 53], yet the extent of stenosis and the clinical course of IIH are still to be fully correlated [52]. Reducing the ICP by removal or diversion of CSF has been shown to reduce dural venous stenosis [54], and these findings may indicate that the stenosis may be a consequence, rather than a cause, of IIH [55].

Despite good evidence of the effect of stenting on the venous sinus pressure gradient, the effect on CSF pressure is less clearly understood. There are many uncontrolled institutional case-based series reporting resolution of papilloedema and improvement in headache following venous sinus stenting, which is discussed below in management of IIH.

Clinical Presentation
Headache is present in over 90% of people diagnosed with IIH. The phenotype of increased ICP headache is no longer thought of as an early morning headache [56], and migraine is now reported to be the predominant phenotype [57]. The International Headache Society criteria have been modified to reflect that improvement in headache with ICP reduction is no longer a requirement as a diagnostic criterion of headache attributable to IIH [58].

Pulsatile tinnitus, either unilateral or bilateral, is commonly reported in IIH. Transient visual obscurations are common in IIH and are described by patients as ‘greying’ or ‘blacking out’ of vision in one or both eyes and lasting seconds. Transient visual obscurations are usually associated with changes in posture. Unilateral or bilateral sixth-nerve palsy may occur secondary to raised ICP and cause horizontal diplopia [22]. Cognitive function has been reported to be affected in IIH [59].

To confirm a diagnosis of IIH, papilloedema needs to be present, and care must be taken in the examination of the optic nerve, as papilloedema can be misdiagnosed. This has led to unnecessary investigations, procedures and therapy, with the leading reason being the incorrect interpretation of the optic nerve appearance during clinical examination [60]. Examination of the eye can be challenging, and where diagnostic uncertainty exists, the guidelines recommend that papilloedema be confirmed by an experienced specialist [1, 61].

The detection of papilloedema by fundus photography is extremely sensitive, even among non-specialists such as emergency medicine doctors. However, it is of note that none of the cases presented in a recent study by Blanch et al. had subtle papilloedema (Frisén grade 1), which can present the diagnostic dilemma of papilloedema versus pseudopapilloedema [62].

Other imaging tools such as optical coherence tomography (OCT) and fundus fluorescence angiography (FFA) are helpful [1, 61]. More evidence of the utility of OCT and OCT angiography in defining papilloedema from pseudopapilloedema is emerging [63, 64]. These findings need to be validated across the different OCT device platforms and larger data sets to enable clinicians to implement their findings in routine clinical care.

reference link :https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7708542/


More information: Learn more about IHH and how it is diagnosed and treated at the National Eye Institute.

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