Idiopathic intracranial hypertension in Sweden : epidemiological studies focused on incidence and risk factors

Idiopathic intracranial hypertension (IIH) is a disorder which is not that unusual for neurologists and ophthalmologists to meet in clinical practice even though it only affects around 1 per 100,000 individuals. It gives rise to symptoms of headache and visual disturbances caused by high intracranial pressure (ICP). The first recorded patient with this disorder was described by Quicke in 1893, followed by 22 cases reported by Dandy in 1937, who later summarized the common diagnostic characteristics of the disorder (1). Even though we have known about this disorder for far more than 100 years and several studies have been performed to investigate its origin, we still don’t know what causes the increased pressure. We know that it more commonly affects females of reproductive age, in particular those who are obese. But why this is the case is not known. Several hypotheses have been suggested and studied over the years. Additionally, several risk factors that could be involved in the development of high intracranial pressure have been proposed. However, since the disorder and some of its risk factors are rare, there have been conflicting findings as to the strength of some of the proposed associations between such risk factors and IIH development.

The intension of this thesis was to conduct studies investigating the incidence of IIH in Sweden as well as describing a Swedish cohort to shed light onto potential different risk factors. We used Swedish large national registers to investigate if risk factors were more common in IIH cases compared to controls prior to diagnosis. Study I is a descriptive study of all patients with a diagnosis code for IIH in Stockholm County during 2006-2013.We included 207 individuals ≥18 years of age with the diagnosis code G93.2 registered in the national patient register during these years. We validated the diagnosis coding by review of medical records and found that only 65% fulfilled the modified Dandy diagnostic criteria for IIH. The incidence was 0.65 per 100,000 individuals, in the lower range of most reported incidence studies on IIH. Among those fulfilling IIH diagnosis criteria, as reported in other studies, most patients were females (F/M ratio of 6:1) and females were slightly younger than men at time of diagnosis (mean age women 31 (CI 29-33) compared to 43 (CI 36-50) in men). These results provided the motivation to improve finding correctly diagnosed IIH patients to include in register studies. In study II we therefore developed algorithms, that included parameters thought to improve prediction by using data which are possible to extract from registers, to better predict which patients to include as “true” IIH cases. We developed the algorithms by testing these parameters using a stepwise logistic regression model on a randomized one half of study I individuals and then tested how well they predicted on the other half. By using parameters age, receiving 3 or more registrations of the diagnosis code G93.2, and in the second algorithm also adding acetazolamide treatment (needing use of drug register data) prediction of true cases improved to 86% and 88%, respectively.

With use of the developed algorithms we continued to do the national case-control register studies looking at exposure to risk factors in the year prior to the first IIH diagnosis to undertake study III and IV. We looked at the whole population over 18 years during 2000-2016. In study III and IV 902 IIH cases and 4510 matched general population (GP) controls and 4510 obese controls were included. Matching factors were age, sex, and region of residence at the time the IIH patient in the matched group was diagnosed. When analyzing drug dispensations, we had 654 IIH cases and 3270 corresponding GP and obese controls, respectively included. In study I, we found that conditions causing an inflammatory response were common. In study III we therefore wanted to analyze this in a larger population. The results from study III showed increased OR for both infectious (OR = 4.3; 95% CI 3.3-5.6) and inflammatory disorders (OR = 3.2; 95% CI 2.4-4.3) the year prior to the first IIH diagnosis compared to GP controls. Similarly, OR were significantly increased though of slightly lower magnitude compared to the obese controls. In Study IV we investigated the incidence of IIH in Sweden and evaluated risk factors previously proposed in the literature. The mean incidence in the adult population over the study period was similar to study I; 0.71 per 100,000 individuals. The incidence showed however a steady increase which we believe is related to increasing obesity worldwide, as well as in Sweden. Regarding risk factors we could conclude that we saw a significant increased risk of exposure to several disorders, especially kidney failure, SLE, PCOS, tetracyclines, and lithium and systemic corticosteroid treatments. We also found surprisingly high OR for arterial hypertension which in recent years has not been considered a risk factor although it has been described. Equally important, our results confirm that hormonal contraceptives and pregnancy are not likely to be risk factors for IIH. In this study and this thesis, we discuss common denominators regarding risk factors for IIH and proposed three main hypotheses; an inflammation theory, an androgen theory and an ICP regulatory mechanism theory to be of interest for further research.

List of scientific papers

I. Population-based incidence and clinical characteristics of idiopathic intracranial hypertension. Anna Sundholm, Sarah Burkill, Olafur Sveinsson, Fredrik Piehl, Shahram Bahmanyar, A Ingela M Nilsson Remahl. Acta Neurol Scand. 2017 Nov;136(5):427-433.
https://doi.org/10.1111/ane.12742

II. Improving identification of idiopathic intracranial hypertension patients in Swedish patient register. Anna Sundholm, Sarah Burkill, Shahram Bahmanyar, A Ingela M Nilsson Remahl. Acta Neurol Scand. 2018 Mar;137(3):341-346.
https://doi.org/10.1111/ane.12876

III. Infectious and inflammatory disorders might increase the risk of developing idiopathic intracranial hypertension – a national case-control study. Anna Sundholm, Sarah Burkill, Elisabet Waldenlind, Shahram Bahmanyar, A Ingela M Nilsson Remahl. Cephalalgia. [Accepted]
https://doi.org/10.1177/0333102420928079

IV. Idiopathic intracranial hypertension, a national Swedish study of incidence and risk factors. Anna Sundholm, Sarah Burkill, Elisabet Waldenlind, Shahram Bahmanyar, A Ingela M Nilsson Remahl. [Submitted]