Anemia and Idiopathic Intracranial Hypertension: A Systematic Review and Meta-analysis

Idiopathic intracranial hypertension (IIH) is a condition typically affecting young, obese women. Although anemia is recognized as a risk factor of IIH from case reports, their relationship remains controversial as several comparative studies showed no significant association. This study aimed to examine the relationship between anemia and IIH.

Original Contribution Section Editors: Clare Fraser, MD Susan Mollan, MD Anemia and Idiopathic Intracranial Hypertension: A Systematic Review and Meta-analysis Caberry W. Yu, MD, Ethan Waisberg, MB BcH, Jason M. Kwok, MD, Jonathan A. Micieli, MD Background: Idiopathic intracranial hypertension (IIH) is a condition typically affecting young, obese women. Although anemia is recognized as a risk factor of IIH from case reports, their relationship remains controversial as several comparative studies showed no significant association. This study aimed to examine the relationship between anemia and IIH. Methods: MEDLINE, Embase, Cochrane Library, and grey literature were searched to September 2020. Primary studies on patients with diagnoses of anemia of any kind and IIH were included. Primary outcomes included the total number of cases of anemia and IIH. A meta-analysis on the prevalence of anemia in IIH compared with control patients was conducted. Grading of Recommendations, Assessment, Development and Evaluations (GRADE) was used to rate the quality of evidence. Results: Overall, 62 cases and 5 observational or case–control studies were included. Pooled incidence of anemia in patients with IIH was 195/1,073 (18.2%). Patients with IIH (n = 774) had a significantly higher prevalence of anemia compared with controls (n = 230,981) (RR 1.44 [95% confidence interval 1.08–1.92]). Patients were 67.7% females and had a mean age of 22.4 years. The mean opening pressure was 37.9 cmH2O. Anemia was most commonly caused by iron deficiency (51.6%) and aplastic anemia (19.4%). Most patients (59.7%) showed improvement or resolution with anemia treatment only without intracranial pressure-lowering therapy. Evidence was limited because of high risk of reporting bias from the large number of case reports and case–control studies. Conclusions: Anemia is significantly more common in IIH compared with control patients, and case reports suggest a direct relationship. Complete blood counts should be considered in all patients with papilledema, particularly in atypical presentations (male, nonobese, nonperipapillary Department of Surgery (CWY), McMaster University, Hamilton, Canada; UCD School of Medicine (EWH), University College Dublin, Belfield, Dublin, Ireland; Department of Ophthalmology and Vision Sciences (JMK, JAM), Faculty of Medicine, University of Toronto, 1 King’s College Circle, Toronto, Canada; and Kensington Vision and Research Centre (JAM), Toronto, Canada. The authors report no conflicts of interest. Supplemental digital content is available for this article. Direct URL citations appear in the printed text and are provided in the HTML and PDF versions of this article on the journal’s Web site (www. jneuro-ophthalmology.com). Address correspondence to Jonathan A. Micieli, MD, Kensington Vision and Research Centre, 340 College Street, Suite 501, Toronto, ON, Canada, M5T 3A9; E-mail: [e-mail] e78 retinal hemorrhages, prominent risk factor for anemia) or in treatment-refractory IIH. Journal of Neuro-Ophthalmology 2022;42:e78–e86 doi: 10.1097/WNO.0000000000001408 © 2021 by North American Neuro-Ophthalmology Society I diopathic intracranial hypertension (IIH) is a condition characterized by elevated intracranial pressure (ICP) in the absence of an identifiable cause. It primarily affects women of childbearing age and has an incidence of 1–2 per 100,000 among the general population (1,2). With rising rates of obesity in many countries in the world, the incidence and prevalence of IIH are also expected to rise (3). Patients with IIH may present with incidentally discovered papilledema or may seek medical attention because of new or changing headache, pulsatile tinnitus, transient visual obscurations, and/or vision loss (4). Permanent vision loss is the most feared complication and treatment involves weight loss, acetazolamide, and surgery for severe cases (5). The pathophysiology of IIH remains unknown but proposed theories include cerebral venous outflow abnormalities and increased cerebrospinal outflow resistance at the level of the arachnoid granulations or CSF lymphatic drainage sites (5). Anemia is commonly described as a risk factor for IIH due to early reports of bilateral optic disc swelling with iron deficiency anemia (6,7). There are numerous convincing case reports of nonobese individuals who developed IIH in close temporal relationship to new-onset anemia of various causes (8–10). However, the relationship between anemia and IIH remains controversial as iron deficiency anemia is also common in young women of childbearing age. In addition, larger controlled studies have failed to reveal an association between anemia and IIH despite numerous case reports supporting their causal relationship (4,11). No prior systematic review has been conducted to elucidate the role of anemia in IIH. Thus, the aim of this study is to summarize the evidence implicating anemia as a potential risk factor in IIH and investigate the prevalence of anemia among patients with IIH. Yu et al: J Neuro-Ophthalmol 2022; 42: e78-e86 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. Original Contribution METHODS We performed this review in accordance with the Cochrane Handbook for Systematic Reviews of Interventions (12) and reported findings following the Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) guidelines (13). Eligibility Criteria All published articles on anemia and IIH in English were considered for inclusion. Anemia was defined as hemoglobin less than 12.0 g/dL. The 2013 revised IIH criteria derived from the modified Dandy criteria were used for diagnosis of IIH, which include symptoms of increased ICP (e.g., headaches and papilledema); normal neurologic examination except for cranial nerve palsies; awake and alert patient; normal neuroimaging (computed tomography or MRI) including normal brain parenchyma without evidence of hydrocephalus, mass, structural lesion, or abnormal meningeal enhancement; normal CSF composition and elevated lumbar puncture opening pressure above 25.0 cm of water (cmH2O) in adults (14). Post hoc adjustment was made to include patients diagnosed with anemia without a documented hemoglobin level and those without a documented opening pressure (or opening pressure 20.0 to 25.0 cmH2O with convincing story for intracranial hypertension) to capture early published cases on IIH. Articles were excluded if patients had intracranial hypertension caused by other abnormalities aside from anemia such as intracranial masses or cerebral venous sinus thrombosis. The primary outcomes of the review were the number of cases of IIH related to anemia and prevalence of any anemia in IIH patients. Search Methods and Study Selection We searched the MEDLINE, EMBASE, and Cochrane Library databases from inception to September 13, 2020 (see Supplemental Digital Content 1, search strategies available in Online Supplement, eTable 1, http://links.lww.com/ WNO/A514). Grey literature search was conducted on ProQuest, OpenGrey, and Web of Science databases. Articles were limited to the English language with no year restrictions. A manual search of references in original studies and relevant reviews and editorials was also conducted. After deduplication, each record was reviewed by 2 reviewers (C.W.Y. and E.W.) independently by title and abstract, then by full text. All discrepancies were resolved by a third reviewer (J.A.M.). Data Collection and Risk of Bias Assessment Two reviewers extracted data for each study with preconstructed abstraction forms in accordance with PRISMA. Conflicts were resolved by consultation of a third reviewer (J.A.M.). Extracted data included study characteristics (e.g., author, publication year, and design), patient demographics (e.g., age and sex), presentation (e.g., symptoms and signs), Yu et al: J Neuro-Ophthalmol 2022; 42: e78-e86 investigations for anemia (e.g., hemoglobin, mean corpuscular volume, and serum ferritin/B12/iron as appropriate) and for IIH (e.g., neuroimaging, lumbar puncture), and outcome (e.g., treatment and final outcome). All hemoglobin levels were converted to g/dL, and all opening pressures were converted to cmH2O. Risk of bias was assessed for meta-analyzed studies using the NIH quality assessment of case–control studies, which consists of 12 questions to assess selection bias, information bias, measurement bias, or confounding (15). Risk of bias was not assessed for case reports or series. The quality of evidence for the estimate derived from the meta-analysis was assessed using the Grading of Recommendations, Assessment, Development and Evaluation (GRADE) (16,17). Outcomes started at “low quality” evidence as observational studies were included and were downgraded by one level for serious concerns (or by 2 levels for very serious concerns) on risk of bias, inconsistency, indirectness, imprecision, or publication bias. Assessments were conducted by 2 reviewers with disagreements resolved by consensus. Data Synthesis and Analysis Throughout, continuous data were collected with means and ranges, whereas categorical parameters were collected using percentages of the total sample. In the reporting of the pooled prevalence Pof anemia in IIH, weighted mean was n w i xi defined as x ¼ Pi¼1 , with the number of participants n i¼1 wi representing the weighting factor. Pooled estimates were provided only if 2 or more studies were included for the same comparator outcome. For associations between anemia and IIH, a meta-analysis was performed using the Mantel–Haenszel method and random-effects models (18). The outcome was compared using the risk ratio (RR) and 95% confidence interval (95% CI). We assessed statistical heterogeneity using the I2 statistic, with I2 .50% considered as a meaningful level of heterogeneity (12). Subgroup analyses based on diagnostic criteria of anemia (hemoglobin reported vs not) and IIH (2013 revised IIH criteria vs others) were performed. Publication bias was assessed using funnel plots when 10 or more studies were included in a meta-analysis (19). RESULTS Study Characteristics Full texts were reviewed for 66 articles. Overall, 48 citations (43 case reports/series, 5 observational or case–control studies) were included (see Supplemental Digital Content 1, eFigure 1, http://links.lww.com/WNO/A514). We present a literature review of the cases of both IIH and anemia, followed by a meta-analysis of observational or case–control studies to assess the pooled prevalence of anemia among patients with IIH compared with controls. e79 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. Original Contribution Literature Review of Case Reports Overall, 62 cases of anemia associated with IIH were included from the literature review (Table 1). Reports were published between 1941 and 2020. There were 36 cases that had anemia and IIH diagnosed in accordance with the 2013 revised IIH criteria (eTable 2), whereas 26 additional cases were identified to have anemia with presumed IIH (consistent presentation but missing lumbar puncture) (eTable 3). Overall, patients were 67.7% female and had a mean age of 22.4 years (range 15 months–53 years old). Patients were obese in 16 cases (26.6%). The mean duration of vision loss before presentation was 32.8 days (range 1 day to 3 months). Almost all cases (60/62) presented with bilateral optic disc edema, whereas 2 patients presented with unilateral optic disc edema. On dilated fundus examination, 14 of 62 patients had peripapillary hemorrhages and 7 had cotton wool spots. Fourteen patients had additional findings of retinal hemorrhages outside the peripapillary area, including 4 with subhyaloid or preretinal hemorrhages. Forty-nine patients had a documented lumbar puncture, with a mean opening pressure of 37.9 cmH2O (range 25.0–60.0 cmH2O). The mean (range) hemoglobin was 6.6 g/dL (range 3.0– 10.7 g/dL). The most common cause was iron deficiency (32/ 62, 51.6%), followed by aplastic anemia (12/62, 19.4%), megaloblastic anemia (5/62, 8.1%), sickle cell disease (5/62, 8.1%), and hemolytic anemia (4/62, 6.5%). Patients were treated for anemia without any ICP-lowering therapy in 54.8% of all cases (34/62), most commonly using iron replacement (22/34) and/ or blood transfusion (17/34). Only 12 patients were treated with ICP-lowering therapy without anemia treatment using acetazolamide (11/12) or serial lumbar punctures (2/12). A combination of anemia and ICP-lowering therapy was used in 15 cases, including 2 patients who required ventriculoperitoneal or lumboperitoneal shunt. Follow-up was reported with a mean time of 5 months. Outcome was not reported or unknown in 5 patients. Of the reported patients, 34/57 (59.7%) showed improvement or resolution with anemia treatment alone, 7/57 (12.3%) on ICP-lowering therapy alone, and 14/57 (24.6%) on both anemia and ICP-lowering therapy. Only one case of worsening was reported at the final followup, occurring in a patient with iron deficiency anemia who was treated with both anemia and ICP-lowering therapy. In the 15 patients treated with anemia treatment alone and had a lumbar puncture after treatment, there was a reduction in CSF opening pressure of mean 13.5 cmH2O (range 0–42.4) at a mean follow-up of 2.5 months (range 1 week–6 months). Results of Larger Prevalence Studies Two larger case series (n = 173 patients with IIH) and 5 observational or case–control studies (n = 900 patients with IIH) were reviewed. Only one retrospective observational study existed to compare patients with IIH with and without anemia. It found that those with anemia (n = 22) had a shorter e80 disease course and tended to present with pulsatile tinnitus, more severe visual field defects, and transverse sinus stenosis than those without anemia (n = 131) (20). It also found that those with anemia had faster resolution of symptoms and better prognosis after treatment. Table 2 summarizes the studies that investigated prevalence of anemia among patients with IIH (4,11,20–23). The weighted incidence of anemia in patients with IIH among 7 studies was 195/1,073 (18.2%). Meta-Analysis on the Prevalence of Anemia in IIH and Control Patients Four studies had reported the prevalence of anemia in patients with IIH as compared with a control group. Three of 4 studies used age-matched and sex-matched controls, while one did not (Table 2). Anemia had a prevalence of 150/747 (20.1%) in patients with IIH and 31,687/230,981 (13.7%) in control patients. There was a significantly higher prevalence of anemia among patients with IIH compared with controls (RR 1.44 [95% CI 1.08, 1.92], Figure 1). There was no significant heterogeneity (I (2) = 22%). Supplemental Digital Content 1 (see eFigure 2, http://links. lww.com/WNO/A514) shows no significant difference between subgroups as defined by the diagnostic criteria for anemia (hemoglobin reported vs not, P = 0.91) and IIH (2013 revised IIH criteria vs other, P = 0.28). Risk of Bias Assessment and GRADE Certainty of Evidence Overall, the studies included in the meta-analysis had high internal validity but were limited by their case–control or crosssectional design (see Supplemental Digital Content 1, eTable 4, http://links.lww.com/WNO/A514). All studies had clear research objectives and had defined the study population with uniformly applied inclusion/exclusion criteria. Cases and controls were defined uniformly, with 3 studies using all components of the 2013 revised IIH criteria, whereas the fourth had used most components (including elevated ICP and neuroimaging). Main biases arose from unreliable exposure assessment, whereby 3 of 4 studies used survey to identify anemia, whereas only 1 study had used hemoglobin levels for confirmation. In addition, 2 studies did not control for confounding variables in statistical analysis. Publication bias was not assessed, as less than 10 studies were included in each meta-analysis (19). It was mitigated by thorough searches of the grey literature. Overall, the GRADE certainty of evidence summary is provided in Table 3. Despite low concerns for inconsistency, indirectness, and imprecision, evidence was mainly downgraded as the largest study included was cross-sectional and restricted to population with BMI .30 kg/m2, whereas all other studies were case–control in design, resulting in inherent selection and detection biases. Thus, GRADE certainty of evidence was low. Yu et al: J Neuro-Ophthalmol 2022; 42: e78-e86 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. Original Contribution TABLE 1. Summary of 62 cases on anemia and idiopathic intracranial hypertension Category Sex, female/total (%) Mean age (range) Obesity (BMI .30 kg/m2 if reported) Mean duration of symptom onset (range) Mean duration of visual symptoms (range) Initial presentation Bilateral disc edema Unilateral disc edema Peripapillary hemorrhages Cotton wool spots Retinal hemorrhages outside the peripapillary area Subhyaloid/preretinal hemorrhages Neuroimaging Any neuroimaging (MRI or MRV or CT or CTV) Brain MRI or MRV Brain CT or CTV Brain venous imaging (CTV or MRV) Lumbar puncture Documented elevated opening pressure Mean (range) opening pressure, cmH2O Mean (range) hemoglobin, g/dL Etiology Iron deficiency Aplastic anemia Fanconi aplastic anemia Megaloblastic anemia Pernicious anemia Sickle cell disease Hemolytic anemia Beta-thalassemia Transient erythroblastopenia of childhood Drug adverse effect Cause unknown Treatment Number only treated for anemia (e.g. blood transfusion and iron) Iron replacement Blood transfusion B12 replacement Dietary changes Others (e.g. surgical resection of polyps and immunosuppression) Number only treated with ICP-lower therapy (e.g. acetazolamide and surgical treatment) Acetazolamide Therapeutic LPs Number treated with both anemia and ICP-lowering therapy Surgical treatment (ventriculoperitoneal or lumboperitoneal shunt) No treatment Outcome Mean follow-up time (range) Overall Improvement or resolution Worsening or no improvement Unknown Among those with known outcomes (n=57) Anemia treatment only Improvement or resolution Yu et al: J Neuro-Ophthalmol 2022; 42: e78-e86 Result 42/62 (67.7%) 22.4 years (15 months–53 years) 16/60 (26.6%) 42.4 days (1 day–6 months) 32.8 days (1 day–3 months) 60/62 (96.8%) 2/62 (3.2%) 14/62 (22.6%) 7/62 (11.3%) 14/62 (22.6%) 4/62 (6.5%) 62/62 (100.0%) 42/62 (67.8%) 23/62 (37.1%) 26/62 (41.9%) 49/62 (79.0%) 37.9 (25.0–60.0) 6.6 (3.0–10.7) 32/62 12/62 2/62 5/62 1/62 5/62 4/62 1/62 1/62 1/62 1/62 (51.6%) (19.4%) (3.2%) (8.1%) (1.6%) (8.1%) (6.5%) (1.6%) (1.6%) (1.6%) (1.6%) 34/62 22/34 17/34 3/34 2/34 2/34 12/62 (54.8%) (64.7%) (50.0%) (8.8%) (5.9%) (5.9%) (19.4%) 11/62 2/62 15/62 2/62 1/62 (17.7%) (3.2%) (24.2%) (3.2%) (1.6%) 5.1 months (range 72 hours-36 months) 56/62 (90.3%) 1/62 (1.6%) 5/62 (8.1%) 34/57 (59.7%) 0/57 (0%) e81 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. Original Contribution (Continued ) Category Result Worsening or no improvement ICP-lowering therapy only Improvement or resolution Worsening or no improvement Both Improvement or resolution Worsening or no improvement Mean change of opening pressure (range), cmH2O Anemia treatment only (n = 15) at mean 2.5 months (range 1 week–6 months) ICP-lowering therapy only (n = 0) Both (n = 2) at mean 2 (range 1–3) months 7/57 (12.3%) 0/57 (0%) 14/57 (24.6%) 1/57 (1.8%) 213.5 (0 to 242.4) N/A 213.0 (212.0 to 214.0) F, female; M, male; MRV, magnetic resonance venography; CT, computed tomography; cmH2O, centimeters of water; ICP, intracranial pressure; LP, lumbar puncture; N/A, not applicable. DISCUSSION The potential relationship between anemia and intracranial hypertension has been recognized for decades, yet the nature of this relationship remains debated. Our study suggests that the presence of anemia may be causally related to the development of intracranial hypertension. However, the evidence is mainly limited to case reports and crosssectional studies with high potential for reporting bias. The large proportion of nonobese individuals (73%), lower proportion of female patients (68%), very young or older patient age, and resolution of disease with the treatment of anemia alone further supports this notion. In comparison, other larger case series such as the IIH Treatment Trial found the IIH cohort to be 90% women and 88% obese, with mean (SD) age of 29.0 (6.4) years (24–26). We also found that patients treated for anemia alone with posttreatment lumbar puncture had a reduction of opening pressure by mean 13.5 cmH2O. Although iron deficiency is the most common cause of anemia and includes causes of blood loss and poor absorption of iron, other types of anemia have been reported. This suggests that it is the low hemoglobin that plays a role rather than iron deficiency itself. Patients with IIH also have a higher prevalence of anemia compared with those without anemia, and our pooled data indicate that the prevalence of anemia among patients with IIH is 18.2%. The presentation of patients with intracranial hypertension and anemia was similar to that seen in typical patients with IIH. However, those with anemia were found to present with a shorter duration of visual symptoms compared with those without anemia (20). This may be related to the underlying disease process causing the anemia, which can be acute. There was a wide range in age at presentation, and IIH associated with anemia may occur at almost any stage of life. Papilledema occurring in very young or older individuals should e82 include a complete blood count as they are not in the typical demographic for IIH. Retinal abnormalities associated with anemia include hemorrhages and cotton wool spots, but cotton wool spots were only found in a minority of patients with anemia and IIH, indicating that the optic nerve appearance cannot be used to differentiate those with anemia and those without (27). Moreover, many patients with IIH without anemia present with peripapillary hemorrhages, dilated venules, and cotton wool spots (28). Our study included both case report data and those from larger studies. Although considered low level of evidence because of high risk of reporting bias, case reports have the advantage of describing rare occurrences and relationships. The most convincing evidence for a direct relationship between IIH and anemia comes from our finding that more than half of all cases were successfully treated only by addressing the underlying anemia. Many of these cases were in nonobese individuals, which are uncommonly seen in patients with IIH. Moreover, studies have found that some patients with anemia and IIH did not respond to ICP-lowering therapy, further supporting the notion that a direct relationship exists (9). Although spontaneous resolution of IIH because of undocumented weight and diet changes is possible, these are rare and less likely in our cohort because of the high proportion of nonoverweight patients (29). Data from retrospective and comparative studies suggests that anemia is more common in patients with IIH compared with controls, but this included various degrees of anemia. The clinical significance of the severity of anemia on IIH development and vision loss still remains unknown. Only one retrospective study comparing anemic patients with IIH to patients with IIH without anemia exists, and further research is needed on this topic (20). The mechanisms underlying the association between anemia and increased intracranial pressure remain Yu et al: J Neuro-Ophthalmol 2022; 42: e78-e86 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. Original Contribution TABLE 2. Summary of prevalence studies Prevalence of Anemia Diagnosis of Diagnosis of in IIH, n/ total (%) Anemia IIH Prevalence Association of Anemia in Control, Between Anemia and IIH n/total (%) Ardissino 2019 (21) Crosssectional study 31,657/ Multivariate 230,792 analysis (13.7) showed significant association (OR = 1.478, P , 0.0001) Giuseffi 199 (14) Medical Medical 120/607 Compare records records (19.8) prevalence of (criteria (criteria NR) conditions NR) including anemia in patients with IIH with control obese patients Survey (self- Modified 16/50 Case-control Compare reported) Dandy (32.0) study prevalence of criteria conditions including iron deficiency anemia in IIH patients to agematched and sex-matched controls Survey (self- Papilledema, 5/40 (8.0) Case-control Compare reported) increased study prevalence of opening conditions pressure including (.250 anemia in IIH mmH2O) patients to agewith normal matched and CSF sex-matched content, controls normal CT 9/50 Survey (self- Modified Case-control Compare (18.0) Dandy reported) study prevalence of and hemo criteria anemia in IIH patients to age- globin levels matched, racematched, and sex-matched controls, also used complete blood count 16/100 (16.0) Multivariate analysis showed no significant association (OR 1.0, 95% CI 0.4–2.5) 8/39 (20.5) NR 6/50 (12.0) Univariate analysis showed no significant association (P=0.401, diagnosis of anemia, P=0.535, hemoglobin female patients, P=0.280 hemoglobin male patients) N/A Author Year Ireland 1990 (22) Lin 2019 (11) Ma 2020 (20) Study Design Purpose Retrospective Compare clinical Hemoglobin Modified levels Dandy cohort features of IIH criteria patients with anemia vs without anemia Yu et al: J Neuro-Ophthalmol 2022; 42: e78-e86 22/153 (14.4) N/A e83 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. Original Contribution (Continued ) Author Year Study Design Mollan 2009 (5) Case series Stiebel-Kalish 2006 (23) Case series Purpose Prevalence of Anemia Diagnosis of Diagnosis of in IIH, n/ total (%) Anemia IIH 8/77 Review cases of Hemoglobin Modified (10.4) levels Dandy IIH with iron criteria deficiency anemia 15/96 Review cases of Hemoglobin Medical (15.6) records IIH and evaluate levels (criteria NR) its association with puberty (anemia recorded) Prevalence Association of Anemia in Control, Between Anemia and IIH n/total (%) N/A N/A N/A N/A CT, computed tomography; IIH, idiopathic intracranial hypertension; NR, not reported; N/A, not applicable; OR, odds ratio; 95% CI, 95% confidence interval. unknown. Several hypotheses have been proposed in the literature. Anemia, in particular iron deficiency anemia, is considered a hypercoagulable state and is proposed to increase viscosity and pressure in the venous system (9). Hyperviscosity has been previously proposed to cause an IIH phenotype through intracranial elevation associated with prothrombotic conditions such as polycythemia vera (30). In addition, iron deficiency anemia has been associated with cerebral venous and arterial thrombosis in prior case reports (31–33), and hypercoagulability has been reported in hemolytic anemia and sickle cell disease (34). The increase in venous pressure in the absence of a clear thrombosis can decrease the rate of cerebrospinal fluid resorption at the arachnoid villi, leading to increased ICP (35,36). Another hypothesis is that low hemoglobin levels may lead to local hypoxia in the brain, resulting in increased ICP because of capillary permeability and brain edema (7,37,38). Others have proposed that decreased hemoglobin levels may increase cerebral circulating blood volume, leading to increased ICP (9,39). Further studies are required to examine the pathophysiology of anemia in IIH. The strengths of this study include the comprehensive and objective search strategy used to obtain studies examining a relationship between IIH and anemia. We included all types of studies including case reports and comparative studies. The findings of this study should be interpreted in light of the following limitations. First, a lumbar puncture of confirmed raised opening pressure and normal neuroimaging was only found in 36 cases. The remaining 26 cases did not have a lumbar puncture, thus did not meet the 2013 revised IIH criteria. However, the clinical presentations were highly likely IIH related to anemia. As anemia is a risk factor for cerebral venous sinus thrombosis, a condition also more commonly found in young women, the lack of imaging to exclude this etiology is a major source of bias that future studies should address. Second, the meta-analysis results were largely driven by a cross-sectional study of 231,399 obese patients using medical records. The study was subject to observer bias, undocumented loss to follow-up, and differences in IIH and anemia definition between patients. The 3 remaining trials included in the meta-analysis individually failed to find an association between anemia and IIH, likely because of small sample sizes of 50 or less patients with IIH, selfreporting of anemia, and lack of confounding variable FIG. 1. Forest plot of the prevalence of anemia in idiopathic intracranial hypertension compared with control patients. IIH, idiopathic intracranial hypertension. e84 Yu et al: J Neuro-Ophthalmol 2022; 42: e78-e86 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. Original Contribution TABLE 3. GRADE certainty of evidence summary table for meta-analysis Certainty Assessment No of Studies (Study Design) Prevalence of DR, studies reporting baseline DR only (follow-up: median 8 years) 4 (1 cross-sectional, 3 case–control) Risk of Bias Inconsistency Indirectness Imprecision Not serious* Not serious† Not serious‡ Not serious§ Certainty Assessment No of Studies (Study Design) Prevalence of DR, studies reporting baseline DR only (follow-up: median 8 years) 4 (1 cross-sectional, 3 case–control) Other Considerations Overall Certainty of Evidence LOW None Summary of Findings IIH Patients, Anemia/Total (%) Control Patients, Anemia/Total (%) Relative Pooled Effect Size (95% CI) 150/747 (20.1%) 31,687/230,981 (13.8%) RR 1.44 (1.08, 1.92) Absolute Pooled Effect Size (95% CI) 60 more per 1,000 (from 11 more to 126 more) *Although the observational studies were not randomized, they had clear aims, included consecutive patients, appropriate inclusion/exclusion criteria, reliable IIH definitions, and masking of outcome assessors to the anemia status. The main risk of bias arose from the exposure assessment, whereby survey results of anemia may be subject to recall bias. † All included studies directly compared anemia in IIH with control patients and report common outcomes of interest. ‡ Low heterogeneity (I2 , 50%) with similar point estimates and overlapping confidence intervals. § The total number of cases of anemia was more than 300. CI, confidence interval; RR, risk ratio; IIH, idiopathic intracranial hypertension. adjustment in statistical analysis of 2 studies. Third, no large-scale prospective study of anemia and IIH has been performed to date; thus, it is possible that the relationship between anemia and IIH is due to chance alone. Fourth, the inclusion of case reports has high concern for reporting bias; cases should be interpreted with caution. CONCLUSION Although IIH and anemia are both common in young women, anemia was 44% more common in patients with IIH compared with control patients. Evidence limited to case reports suggests a direct relationship between anemia and IIH, with symptoms resolving in over 50% of cases with anemia treatment alone without acetazolamide or surgery. A complete blood count should be obtained in all cases of papilledema, particularly in atypical presentations (male, nonobese, nonperipapillary retinal hemorrhages, prominent risk factor for anemia) in the absence of an identifiable cause or risk factors for IIH, and in treatment-refractory IIH. Owing to high risk for selection and reporting biases in existing reports, future comparative studies with proper imaging Yu et al: J Neuro-Ophthalmol 2022; 42: e78-e86 evaluation should be conducted to elucidate the pathophysiology and relationship between anemia and IIH. STATEMENT OF AUTHORSHIP Category 1: a. Conception and design: C. W. Yu, E. Waisberg, J. M. Kwok, and J. A. Micieli; b. Acquisition of data: C. W. Yu and Ethan Waisberg; c. Analysis and interpretation of data: C. W. Yu, E. 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