Women with idiopathic intracranial hypertension (IIH) are at twice the risk of heart conditions and stroke


Female patients who suffer from a disabling neurological disorder known as idiopathic intracranial hypertension (IIH) are at twice the risk of heart conditions and stroke, a study led by the University of Birmingham has shown for the first time.

IIH is a debilitating condition in which the pressure around the brain is severely raised, causing disabling chronic headaches.

It can also compress the optic nerve, causing permanent vision loss in 25 percent of those affected.

The condition is most common in women with obesity in their twenties and thirties.

A study, published today in JAMA Neurology, compared the GP patient records of 2,760 women with IIH with a control group of 27,125 women who do not have IIH.

The women in the two groups were of a similar weight and age, with an average age of 32.

The researchers found that women with IIH were twice as likely to be at risk of cardiovascular disease, including heart failure and stroke, as women of the same weight and age without IIH.

The research, supported by the National Institute for Health Research (NIHR) and the Medical Research Council, also showed the increasing prevalence and incidence of IIH in women, which has more than tripled between 2005 and 2017. Incidence has increased from 2.5 to 9.3 per 100,000 person years.

The research was carried out by experts within Birmingham Health Partners, a strategic alliance between the University of Birmingham and two NHS Foundation Trusts -Birmingham Women’s & Children’s, and University Hospitals Birmingham (UHB), where members collaborate to bring healthcare innovations through to clinical application.

Professor Sinclair, of the University of Birmingham’s Institute of Metabolism and Systems Research, said: “With both prevalence and incidence of IIH on the rise, in line with a global increase in obesity, it is really important that we have this information so we can plan healthcare delivery and services to care for these patients who often feel they are overlooked.”

Professor Sinclair is also a consultant neurologist at UHB, leading one of the world’s largest IIH clinical services based at Queen Elizabeth Hospital Birmingham.

By combining clinical neurology with translational research, Professor Sinclair and her team are now world leading experts in brain pressure.

Professor Sinclair added:

“The study findings support broadening the care for IIH patients to include assessing and modifying cardiovascular risk as this may reduce long term complications from cardiovascular disease.

“IIH patients are typically identified at a young age, which could provide the opportunity for early assessment for modifiable cardiovascular risk factors, followed by appropriate management to minimise or mitigate these risk factors.”

Dr. Nicola Adderley, Lecturer in Health Informatics and Epidemiology at the University of Birmingham’s Institute of Applied Health Research, said: “Individuals with a high body mass index are at an increased risk of cardiovascular disease.

We therefore wanted to compare women with and without IIH who had the same age and weight to establish if there was a difference in risk between women with and without IIH independent of weight.

“The increased risk of cardiovascular disease observed in women with IIH compared with those without IIH was over and above what we would expect due to obesity alone, and appears to be related to IIH itself.

“We hope we will now see further evaluation of this important observation to determine if a change to healthcare policy with early intervention in patients with IIH will improve their long-term health outcomes.”

Shelly Williamson, Chair of charity IIH UK which provides support for patients with the condition, said: “Whilst many women with IIH will be shocked by this important research, I am pleased that it is now known that IIH is a risk factor for cardiovascular disease.

“IIH is a debilitating condition and, in the future, widening of care for IIH patients to include assessing cardiovascular risk and ensuring they are monitored and treated accordingly may be an important step in patient care.”

Idiopathic intracranial hypertension (IIH), or pseudotumor cerebri, formerly called benign intracranial hypertension, is a challenging condition with raised intracranial pressure (ICP) in the absence of identifiable cause [Friedman et al. 2013Mollan et al. 2014Friedman, 2014].

In the literature, IIH primarily affects young obese women and the estimated incidence in this population is 20 per 100,000 which is 20-fold higher than in normal-weight individuals [Durcan et al. 1988Radhakrishnan et al. 1993].

Due to the close relationship with obesity, which has been reported to have increased three-fold over just 15 years in Western countries [WHO, 2013], the incidence of IIH is expected to increase rapidly.

As obesity affects children and males to a similar degree as in females, and as the reports of IIH in these groups are accumulating [Bruce et al. 2009Standridge, 2010] it can be hypothesized that obesity is the main underlying causative factor, and not gender or age.

Still, case-control studies with male and female patients matched by weight are needed to clarify the role of gender.

At time of diagnosis various degrees of visual impairment are present in up to 90% of patients with IIH [Craig et al. 2001] and in prior studies an estimated rate of 10–24% progressed to severe and permanent visual impairment [Carta et al. 2004Durcan et al. 1988].

Visual loss can occur anytime along the course of the disease but is often insidious and as central vision is spared until late in the course of the illness the visual loss is often asymptomatic until profound.

In addition, diagnosis is often delayed as the general knowledge of IIH is limited and multiple doctors from various specialties have been consulted before patients are identified.

In a new series from our group the visual prognosis after one year was good, probably due to earlier diagnosis, more awareness, a dedicated team effort or a close follow-up [Yri et al. 2012].

Clinical presentation and diagnosis

In most patients IIH manifests with severe headache, visual disturbances and bilateral papilledema [Carta et al. 2004Mollan et al. 2014Yri and Jensen, 2015Yri et al. 2012]. The symptoms are clearly summarized [Wall et al. 2014a] (Figure 1) and were confirmed in the recent field testing of diagnostic criteria [Yri and Jensen, 2015].

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Figure 1.
Percentage of patients and their presenting symptoms in Idiopathic Intracranial Hypertension, modified from Wall and colleagues [Wall et al. 2014a].

Headache is present in around 93% of patients at the time of diagnosis, usually being constant or occurring daily or nearly daily [Craig et al. 2001Yri et al. 2012].

It lacks specific features and may mimic chronic migraine, chronic tension-type headaches or both.

Headache related to IIH is more likely to be focal than holocranial, and often with pulsating elements. Aggravation by coughing, straining and physical activity is reported by the majority of patients [Yri and Jensen, 2015Yri et al. 2014b].

The current diagnostic criteria for headache attributed to IIH given by the International Classification of Headache Disorders (ICHD-III beta) [Headache Classification Subcommittee of the International Headache Society, 2013] are presented in Table 1. Recently, these criteria have been field tested and new validated criteria have been proposed [Yri and Jensen, 2015].

Still, the headache attributed to IIH is scarcely studied and none of the existing trials elucidated the effects of current headache treatments. The headaches may also determine the impaired quality of life reported in a study of IIH patients from the Birmingham group [Mulla et al. 2015].

Table 1.

International Classification of Headache Disorders, third edition beta (ICHD-3-beta) criteria for headache attributed to IIH [Headache Classification Subcommittee of the International Headache Society, 2013].

A Any headache fulfilling criterion CB Idiopathic intracranial hypertension (IIH) has been diagnosed, with cerebrospinal fluid (CSF) pressure >250 mmCSF (measured by lumbar puncture performed in the lateral decubitus position, withoutsedative medications, or by epidural or intraventricular monitoring)C Evidence of causation demonstrated by at least two of the followingHeadache has developed in temporal relation to IIH, or has led to its discoveryHeadache is relieved by reducing intracranial hypertensionHeadache is aggravated in temporal relation to increase in intracranial pressureD Not better accounted for by another ICHD-3 beta diagnosis

IIH, idiopathic intracranial hypertension; CSF, cerebrospinal fluid.

Characteristic for the condition is the presence of a pulsatile tinnitus that is believed to arise from intensified vascular pulsation occurring with high ICP. Although very common, it is often not reported by the patients unless specifically queried about it.

Patients with papilledema often present with transitory visual obscurations which can be a manifestation of increased bulb pressure, retinal ischemia or transient ischemia at the optic nerve caused by papilledema.

Increased ICP without papilledema has been reported in unresponsive chronic migraine patients suggesting a diagnosis of IIH without papilledema [De Simone et al.2014Mathew et al. 1996Wang et al. 1998].

However, such a diagnosis is challenging and requires caution with additional clinical or neuroradiological confirmation as suggested in the revised diagnostic criteria for pseudotumor cerebri syndrome (Table 2) [Friedman et al. 2013].

Other symptoms and clinical signs include dizziness, nausea, reduced memory and concentration and horizontal diplopia due to sixth nerve palsy [Carta et al. 2004Mollan et al. 2014Yri and Jensen, 2015Yri et al. 2012].

Recent studies demonstrated a marked cognitive dysfunction [Kharkar et al. 2011Yri et al. 2014aZur et al. 2015] and indicated that impaired executive function, working memory, processing speed and reaction time remained after normalization of ICP and alleviation of the headache and the visual symptoms [Yri et al. 2014a].

It is likely that such cognitive dysfunction could contribute to the substantial loss of work capacity and life quality in patients with IIH and increased focus of the underlying pathophysiology and of their rehabilitation are highly relevant.

able 2.

Diagnostic criteria for pseudotumor cerebri syndrome [Friedman et al.2013].

Required for diagnosis of pseudotumor cerebri syndrome

a) Papilloedema
b) Normal neurologic examination except for cranial nerve abnormalities
c) Neuroimaging: Normal brain parenchyma without evidence of hydrocephalus, mass, or structural lesion and no abnormal meningeal enhancement on MRI, with and without gadolinium, for typical patients (female and obese), and MRI, with and without gadolinium, and magnetic resonance venography for others; if MRI is unavailable or contraindicated, contrast-enhanced CT may be used
d) Normal CSF composition
e) Elevated lumbar puncture opening pressure (⩾250 mm CSF in adults and ⩾280 mm CSF in children [250 mm CSF if the child is not sedated and not obese]) in a properly performed lumbar puncture

Diagnosis of pseudotumor cerebri syndrome without papilloedema

In the absence of papilloedema, a diagnosis of pseudotumor cerebri syndrome can be made if B–E from above are satisfied, and in addition the patient has a unilateral or bilateral abducens nerve palsy.In the absence of papilloedema or sixth nerve palsy, a diagnosis of pseudotumor cerebri syndrome can be suggested but not made if B–E from above are satisfied, and in addition at least three of the following neuroimaging criteria are satisfied:
1) Empty sella
2) Flattening of the posterior aspect of the globe
3) Distention of the perioptic subarachnoid space with or without a tortuous optic nerve
4)Transverse venous sinus stenosis

A diagnosis of pseudotumor cerebri syndrome is definite if the patient fulfills criteria A–E. The diagnosis is considered probable if criteria A–D are met but the measured CSF pressure is lower than specified for a definite diagnosis.

CSF, cerebrospinal fluid; CT, computerized tomography; MRI, magnetic resonance imaging.

More information: Nicola J. Adderley et al. Association Between Idiopathic Intracranial Hypertension and Risk of Cardiovascular Diseases in Women in the United Kingdom, JAMA Neurology (2019). DOI: 10.1001/jamaneurol.2019.1812

Journal information: Archives of Neurology
Provided by University of Birmingham


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