Anemia and Idiopathic Intracranial Hypertension: A Case-Control Study

Idiopathic intracranial hypertension (IIH) is a condition that mostly affects obese women of childbearing age but has been reported to be temporally related to new diagnoses of anemia. Despite these reports, the association between anemia and IIH remains controversial. The present study aimed to understand the strength of association between anemia and IIH through a case-control design.

Original Contribution Section Editors: Clare Fraser, MD Susan Mollan, MD Anemia and Idiopathic Intracranial Hypertension: A Case–Control Study Irina Sverdlichenko, BHSc, Caberry W. Yu, MD, Edward Margolin, MD, Jonathan A. Micieli, MD Background: Idiopathic intracranial hypertension (IIH) is a condition that mostly affects obese women of childbearing age but has been reported to be temporally related to new diagnoses of anemia. Despite these reports, the association between anemia and IIH remains controversial. The present study aimed to understand the strength of association between anemia and IIH through a case–control design. Methods: Consecutive IIH patients were recruited from neuro-ophthalmology clinics and matched by age and sex to consecutive patients attending neuro-ophthalmology clinics with diagnoses other than IIH. Complete blood counts (CBCs) were reviewed within 6 months of neuroophthalmology presentation, and anemia was diagnosed by hemoglobin of ,120 g/L in women and ,130 g/L in men. Anemia was classified as microcytic (mean corpuscular volume (MCV) , 80 fL), normocytic (MCV 80-100 fL), and macrocytic (MCV . 100 fL) as well as mild (hemoglobin .110 g/L), moderate (hemoglobin 80–109 g/L), and severe (hemoglobin ,80 g/L). Results: One hundred twenty-three IIH patients and 113 controls were included in the study. More IIH patients than controls had anemia (22.8%, 28/123 vs 10.6%, 12/113, P = 0.01) with an odds ratio of 2.48 (95% CI: 1.19, 5.16). There were no differences in severity of anemia or MCV Faculty of Medicine (IS), University of Toronto, Toronto, Canada; Division of Ophthalmology (CWY), Department of Surgery, McMaster University, Hamilton, Canada; Department of Ophthalmology and Vision Sciences (EM), University of Toronto, Toronto, Canada; and Kensington Vision and Research Centre (JAM), Toronto, Canada. This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors. The authors report no conflicts of interest. Patient consent was obtained to publish the data included in this manuscript. All medical interventions have been carried out according to the latest protocols of therapy. The study complies with the guidelines for human studies and was conducted ethically in accordance with the World Health Organization Declaration of Helsinki. This study protocol was reviewed and received approval by the University of Toronto Research Ethics Board Protocol #39135. The data sets generated during and/or analyzed during the current study are not available. Address correspondence to Jonathan A. Micieli, MD, Kensington Vision and Research Centre, 340 College Street, Suite 501, Toronto, ON M5T 3A9, Canada; E-mail: [e-mail] Sverdlichenko et al: J Neuro-Ophthalmol 2023; 43: 63-68 between IIH patients and controls, with anemia most often being mild (57.1%, 16/28 vs 75%, 9/12) and normocytic (50.0%, 14/28 vs 50.0%, 6/12). However, 17.9% (5/28) of IIH patients had severe anemia compared with zero in the control group. IIH patients had a higher mean platelet count than controls (P , 0.001), and there were no differences on leukocyte counts. Conclusion: Idiopathic intracranial hypertension patients have a higher prevalence of anemia compared with non-IIH neuro-ophthalmology patients. The anemia was mostly mild and may be explained by other factors related to worse health status and obesity, including low socioeconomic status, poor nutrition, and polycystic ovary syndrome. However, as a CBC is a widely available test and anemia may influence the IIH disease course, we propose that this test be obtained in all patients with new papilledema. Journal of Neuro-Ophthalmology 2023;43:63–68 doi: 10.1097/WNO.0000000000001664 © 2022 by North American Neuro-Ophthalmology Society I diopathic intracranial hypertension (IIH) is a condition of elevated intracranial pressure (ICP) in the absence of an identifiable cause (1). It primarily affects young women of childbearing age, with an estimated annual worldwide incidence of 12–20 per 100,000 in this population (2). In most patients, IIH causes systemic symptoms, such as headaches and pulsatile tinnitus; permanent vision loss may occur due to papilledema (3). The goal of IIH management is to reduce ICP and preserve visual function while relieving symptoms, with weight loss as the mainstay of treatment (3). Additionally, medical therapy such as acetazolamide is often used, and surgical treatments like optic nerve sheath fenestration or cerebrospinal fluid (CSF) shunting are utilized for more severe cases to prevent irreversible vision loss (3). Previous studies have documented IIH developing in the context of new or chronic anemia diagnoses (4,5). Several large prevalence studies have examined the association between anemia and IIH. An early study by Hanafy et al (6) evaluating the clinical features of infants with IIH and controls identified lower hemoglobin in the IIH group, 63 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. Original Contribution although significance was not reported. A cross-sectional study by Ardissino et al (7) found a statistically higher prevalence of anemia in IIH patients compared with controls. This finding was supported in a meta-analysis carried out by Yu et al. (8) Despite the existing literature supporting the association between anemia and IIH, the relationship remains controversial. Age- and sex-matched case controls by Giuseffi et al (9). and Lin et al (10) failed to find a statistically significant association between anemia and IIH. Moreover, a matched case–control study by Ireland et al (11) found that control patients had a higher anemia prevalence than IIH patients, although they did not report statistical significance. Iron-deficiency anemia is also common among women of childbearing age (12). While the relationship between anemia and IIH has been recognized in the literature, the evidence remains mixed due to the small sample sizes of prevalence studies (9–11,13) and the self-reporting of anemia diagnosis (9). Therefore, the goals of the present study were to evaluate the prevalence of anemia and its strength of association with IIH by comparing consecutive IIH patients with consecutive age- and sex-matched patients seen in neuro-ophthalmology clinics. METHODS Participants We conducted a retrospective chart review of all consecutive IIH patients who presented to tertiary neuroophthalmology clinics affiliated with the University of Toronto between July 2018 and February 2021. IIH patients were matched with respect to age and sex to consecutive controls who attended neuro-ophthalmology clinics but had conditions other than IIH. Inclusion criteria for the IIH group were consecutive patients meeting 2013 revised criteria derived from modified Dandy criteria for IIH diagnosis (14). This includes having papilledema, normal neurologic examination except for cranial nerve abnormalities, normal neuroimaging, normal CSF composition, and elevated lumbar puncture opening pressure of $25.0 cm of water. Additionally, IIH patients had to have complete blood counts (CBC) collected within 6 months of initial neuro-ophthalmology clinic presentation. Inclusion criteria for the control group was consecutive patients having confirmed diagnosis of neuro-ophthalmic conditions other than IIH and CBC values collected within 6 months of initial presentation. The only exclusion criterion for either group was not having CBC values within 6 months of initial presentation. Demographic information, including age and sex, was recorded. Complete Blood Count Medical records for sequential IIH patients and controls were assessed for CBC, which included hemoglobin, mean 64 corpuscular volume (MCV), platelets, and leukocytes. The World Health Organization (WHO) criterion was used for anemia diagnosis (hemoglobin ,120 g/L for women and ,130 g/L for men), and anemia was classified as mild (hemoglobin .110 g/L), moderate (hemoglobin 80–109 g/L), and severe (hemoglobin ,80 g/L) (15). It was also stratified as microcytic (MCV , 80 fL), normocytic (MCV 80–100 fL), and macrocytic (MCV . 100 fL) (16). Statistical Analysis The prevalence of anemia was compared in IIH patients and age- and sex-matched controls with other neuroophthalmic conditions, and the strength of association between anemia and IIH was assessed through odds ratio. Chi-square tests were used for categorical variables, and t-tests were done for continuous variables. A P value of ,0.05 indicated statistical significance. Data collection and analysis were performed using Microsoft Excel Version 16.49. RESULTS Idiopathic Intracranial Hypertension Patients vs Age- and Sex-Matched Neuro-Ophthalmology Controls A total of 123 IIH patients and 113 age- and sex-matched controls were included in the study (Table 1). Neuroophthalmology controls presented with the following conditions: optic neuritis (38.9%, 44/113), pseudopapilledema (25.7%, 29/113), papilledema from other causes (6.2%, 7/ 113), compressive optic neuropathy (5.3%, 6/113), optic disc drusen (4.4%, 5/113), pituitary adenoma (2.7%, 3/ 113), dominant optic atrophy (2.7%, 3/113), monocular diplopia (2.7%, 3/113), physiological anisocoria (1.8%, 2/ 113), concussion (0.9%, 1/113), diplopia due to sixth cranial nerve palsy (0.9%, 1/113), dorsal midbrain syndrome (0.9%, 1/113), hemianopia (0.9%, 1/113), hypertensive retinopathy (0.9%, 1/113), Leber’s hereditary optic neuropathy (0.9%, 1/113), migrainous visual changes (0.9%, 1/ 113), nonarteritic optic neuropathy (0.9%, 1/113), nonorganic vision loss (0.9%, 1/113), strabismus (0.9%, 1/113), and Tolosa–Hunt syndrome (0.9%, 1/113). The IIH group did not differ from the control group by percentage of female participants (P = 0.90) or mean age (P = 0.13). Overall, 22.8% (28/123) of IIH patients met criterion for anemia, with the most common form being mild and normocytic. In comparison, 10.6% (12/113) of controls had anemia, and most had mild anemia, which was normocytic or microcytic. There was no difference in distribution of anemia severity or MCV between IIH patients and controls. In line with these findings, IIH patients had a significantly lower mean hemoglobin than controls (127.6 ± 18.0 vs 133.0 ± 11.8 g/L, P , 0.01). The difference in prevalence of anemia between the groups was also Sverdlichenko et al: J Neuro-Ophthalmol 2023; 43: 63-68 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. Original Contribution TABLE 1. Comparison of clinical characteristics and anemia in IIH patients and neuro-ophthalmology controls Category, Measure IIH Patients (N=123), % (n), Mean ± SD Controls (N=113), % (n), Mean ± SD %Female Age in years Platelets (·109/L) Leukocytes (·109/L) Hemoglobin (g/L) Prevalence of anemia Severity of anemia Mild Moderate Severe MCV (fL) Microcytic Normocytic Macrocytic 94.3% (116) 31.4 ± 9.7 296.6 ± 62.6 8.1 ± 2.2 127.6 ± 18.0 22.8% (28) N = 28 57.1% (16) 25% (7) 17.9% (5) 94.7% (107) 33.2 ± 7.9 263.9 ± 59.9 7.5 ± 3.0 133.0 ± 11.8 10.6% (12) N = 12 75% (9) 25% (3) 0 46.4% (13) 50% (14) 3.6% (1) 50% (6) 50% (6) 0 P 0.90 0.13 ,0.001 0.10 ,0.01 0.01 0.28 0.80 IIH, Idiopathic Intracranial Hypertension; MCV, Mean corpuscular volume. statistically significant (IIH 22.8%, 28/123 vs non-IIH 10.6%, 12/113, P = 0.01). The odds ratio of anemia in IIH patients compared with controls was 2.48 (95% CI: 1.19, 5.16). Additional CBC findings showed no difference between IIH patients and controls on leukocyte count (P = 0.10). However, IIH patients had higher mean platelet count than non-IIH patients (296.6 ± 62.6 ·109/L vs 263.9 ± 59.9 ·109/L, P , 0.001). CONCLUSIONS Anemia has previously been documented as a risk factor for IIH, but findings regarding the association between anemia and IIH remain mixed. Our study demonstrated that IIH patients have a higher prevalence of anemia compared with age- and sex-matched controls with other neuro-ophthalmic conditions. Moreover, while this anemia is most often mild and normocytic, it can be severe, with 17.9% of anemic patients having a hemoglobin of less than 80 g/L. The literature has previously documented variable prevalence of anemia in IIH patients, ranging from 7.5% to 32% (Table 2). A meta-analysis by Yu et al (8) reported a prevalence of 20.1%, which is similar to the 22.8% prevalence in the present study (8). Our finding that IIH patients have a higher likelihood of anemia than age- and sexmatched controls supports the findings of Yu et al (8) (RR 1.44, 95% CI 1.08, 1.92) and Ardissino et al (7) (OR 1.478, P , 0.0001). Our data contrast the results of Giuseffi et al (9), Lin et al (10), and Ireland et al (11), who found no association between anemia diagnosis and/or hemoglobin levels and IIH. It should be noted that these case–control studies had just half our sample size of IIH patients, which may have influenced their ability to detect significant differences. The potential causal relationship of anemia and IIH has been explored in the past, and many convincing case reports Sverdlichenko et al: J Neuro-Ophthalmol 2023; 43: 63-68 and case series have documented a clear onset of IIH with acute anemia. We recently reported 5 cases of severe IIH with acute onset anemia (7). Furthermore, the demographic and clinical characteristics of IIH patients with anemia are different than what is typically seen in the disease. A systematic review and meta-analysis found that more IIH patients with anemia were nonobese (73%) and had a lower proportion of females (68%) as compared with other case series (8). With regards to clinical course, more than half of patients were treated for anemia alone, leading to resolution of disease. Notably, patients treated for anemia alone had a posttreatment lumbar puncture with a reduction in opening pressure of 13.5 cm of water on average. Considering the existing evidence in the literature supporting the potential causal relationship between anemia and IIH; our study findings of the prevalence of anemia in IIH provides further rationale to obtain CBC in all new patients with papilledema and suspected IIH. The exact etiological role of anemia in IIH remains unclear, but several mechanisms have been posited. Irondeficiency anemia (IDA) is considered a hypercoagulable state and has been associated with cerebral venous thrombosis. IDA may contribute to thrombosis due to reduced cell deformability and increased viscosity of microcytic red blood cells (17). Additionally, iron inhibits thrombopoiesis, and thrombocytosis often develops in patients with IDA. Accordingly, 1 retrospective study examining the clinical records of 615 consecutive adults with IDA identified a prevalence of thrombocytosis of 13.3% (18). While IDA may lead to raised ICP in the context of cerebral venous thrombosis, thus mimicking IIH; it is possible that the hyperviscosity present in some patients with IDA increases venous pressure without there being true venous sinus thrombosis (4). Increased venous pressure decreases the rate of CSF resorption at the level of the arachnoid villi, thereby contributing to elevated ICP. In our study, IIH patients had 65 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. Author, Year Study Design Purpose of Study Prevalence of Anemia in Prevalence Anemia in IIH, Controls, n/total (%) n/total (%) Ardissino, Cross 2019 (7) sectional Compare prevalence of conditions including 120/607 31,657/230,792 anemia in IIH patients with control obese (19.8) (13.7) patients Giuseffi, Case-control Compare prevalence of conditions including 16/50 (32.0) 16/100 (16.0) 1991 (9) iron-deficiency anemia in IIH patients with age- and sex-matched controls Case-control Compare prevalence of conditions including 5/40 (8.0) 8/39 (20.5) Ireland, anemia in IIH patients with age- and sex1990 matched controls (11) Lin, 2019 Case-control Compare prevalence of anemia in IIH patients 9/50 (18.0) 6/50 (12.0) (10) to age-, race-, and sex- matched controls, also used complete blood count De gerliyurt, Retrospective Review etiological causes of IIH in children 4/53 (7.5) cohort 2014 (13) Ma, 2020 Retrospective Compare clinical features of IIH patients with 22/153 (19) cohort anemia vs without anemia (14.4) Sverdlichenko et al: J Neuro-Ophthalmol 2023; 43: 63-68 Mollan, 2009 (20) StiebelKalish, 2006 (21) N/A N/A Case series Review cases of IIH with iron-deficiency anemia8/77 (10.4) N/A Case series Review cases of IIH and evaluate its 15/96 (15.6) N/A association with puberty (anemia recorded) Main Study Findings Multivariate analysis showed significant association between anemia and IIH (OR = 1.478, P , 0.0001) Multivariate analysis showed no significant association between anemia and IIH (OR = 1.0, 95% CI 0.4–2.5) Significance of association between anemia and IIH not reported, but controls had higher prevalence of anemia than IIH patients Univariate analysis showed no significant association between anemia and IIH (P=0.401, diagnosis of anemia, P=0.535 hemoglobin female patients, P=0.280 hemoglobin male patients). Prevalence of anemia in IIH patients is 7.5% Anemia patients had higher prevalence of pulsatile tinnitus, worse visual acuity, and worse visual field defects than nonanemia patients at baseline Disease duration was shorter in anemia patients. At follow-up, visual acuity in anemia patients was equal to or better than that of nonanemia patients. There were no differences in visual field findings between anemia and nonanemia patients 7 of 8 cases underwent anemia treatment alone and showed symptom resolution Anemia was not a significant predictor of visual outcome Original Contribution 66 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. TABLE 2. Prevalence studies on anemia and IIH Original Contribution a significantly elevated platelet count compared with controls, suggesting that underlying thrombocytosis may have been a cause of hyperviscosity. Another theory of how IDA leads to raised ICP comes from research, which shows increased cerebral blood flow in the setting of anemia (22). Increased cerebral blood flow may occur through active cerebral vasodilation and is posited to be a compensatory response to maintain optimal cerebral tissue oxygen delivery, potentially leading to raised ICP (23). Although anemia may be causally related to IIH, in those with mild anemia, it may play a lesser role. It is possible that the higher incidence of anemia in IIH patients is a marker for poor overall health in these individuals. The incidence of IIH in the United States is statistically higher among individuals of lower socioeconomic status (SES), which may also be influential in their higher rates of obesity (24). Higher rates of obesity and lower SES are also reported in individuals with anemia. In 1 study of adolescent females in South Korea, girls with anemia were more likely to have lower SES, higher body mass index (BMI), and worse nutritional intake than girls without anemia (25). The association between anemia and IIH may also be explained by obesity and its related factors in female patients, such as polycystic ovarian syndrome (PCOS) (26). Therefore, part of the association of anemia and IIH may come from IIH patients having worse overall health, and anemia may be an indicator of this poor health status. The presentation of IIH patients to neuro-ophthalmology clinics offers an opportunity to address many health-related concerns, including anemia. Our study has several strengths. First, patients were recruited from 3 different centers across Toronto, Canada, which increases the generalizability of our findings. Second, our study examined the strength of association between anemia and IIH by comparing IIH patients with age- and sex-matched controls derived from the same clinical setting. Our study has several limitations: we did not have access to the charts of primary care physicians or hematologists and were therefore limited in our specifications of the type of anemia in IIH patients and controls. Our classification relied mainly on the MCV. Additionally, we did not compare patients and controls on other demographic characteristics that are risk factors for IIH, such as BMI or SES, because these data are not routinely collected for patients seeking care for other neuro-ophthalmic conditions. Finally, because some patients had CBC collected within 6 months of initial presentation, it is difficult to comment on their anemia status at time of diagnosis, only that they occurred in close temporal relationship. While IIH and anemia are both common in young women, anemia is more common in IIH patients compared with non-IIH controls who attended neuro-ophthalmology clinics. However, it is important to keep in mind that the anemia, which is mostly mild, may be explained by other factors related to worse health status and obesity, such as low SES, poor nutrition, and PCOS. Despite this caveat, Sverdlichenko et al: J Neuro-Ophthalmol 2023; 43: 63-68 nearly 18% of anemic IIH patients had severe anemia; there is evidence that this influences not only their disease course but also their overall health. Given that a CBC is a low cost and widely available test, we propose that it be obtained in all patients with papilledema. STATEMENT OF AUTHORSHIP Conception and design: J. Micieli, E. Margolin; acquisition of data: I. Sverdlchenko, J. Micieli, E. Margolin; analysis and interpretation of data: I. Sverdlichenko, C. Yu, E. Margolin, J. Micieli; drafting the manuscript: I. Sverdlichenko, C. Yu, J. 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