Introduction

Anemia has recently been observed in astronauts, the process being termed “Space Anemia.” ^{Reference Trudel, Shahin, Ramsay, Laneuville and Louati1} Analyzing blood levels in 14 astronauts after six months during spaceflight, Trudel, et al observed a unique phenomenon that observed that the mechanism of space anemia is contributed by a hemolytic process. ^{Reference Trudel, Shahin, Ramsay, Laneuville and Louati1} Astronauts that undergo long-duration spaceflight can develop a set of distinct findings characterized as spaceflight associated neuro-ocular syndrome (SANS). ^{Reference Lee, Mader and Gibson2} Currently, SANS serves as one of the largest physiological barriers to future spaceflight, however, the pathophysiology behind this neuro-ophthalmic phenomenon is not well-defined. ^{Reference Waisberg, Ong, Masalkhi and Lee3} It was once thought to be due solely to elevated intracranial hypertension, previously named “Vision Impairment and Intracranial Hypertension” (VIIP). Further research has suggested that elevated intracranial pressure (ICP) may not be the sole reason for SANS, however, its role in SANS is still being investigated. In this manuscript, we describe the potential mechanisms linking anemia and SANS. While much is still unknown, the role of anemia/space anemia may be critical in further understanding of these severe diseases.

Space anemia is a phenomenon characterized by a decrease in the number of circulating red blood cells and plasma volume that astronauts encounter while in space. ^{Reference Smith4} Neocytolysis is a form of selective hemolysis, the process that causes the decrease in red blood cell mass. ^{Reference Santo, Cirillo and Kirsch5} The investigation of anemia in space is constrained by the scarcity of participants and the harsh environmental circumstances. ^{Reference Trudel, Shahin, Ramsay, Laneuville and Louati1,Reference Waisberg, Ong, Zaman, Kamran, Lee and Tavakkoli6} In one investigation, 17,336 measures of hemoglobin concentration were collected from 721 space missions and controls to examine the acute and long-term consequences of space exposure on hemoglobin decrement. The study revealed that space anemia is marked by a gradual decrease in hemoglobin concentration over time. ^{Reference Trudel, Shahin, Ramsay, Laneuville and Louati7}

The inclusion of space anemia in the screening and surveillance protocols of astronauts is crucial, given its potential to negatively impact physical performance and overall health outcomes during and post-space missions. ^{Reference Trudel, Shahin, Ramsay, Laneuville and Louati7} Nevertheless, further investigation is required to comprehensively comprehend the mechanisms that underlie this phenomenon and to develop efficacious interventions that minimize its impact.

The SANS phenomenon is something some astronauts have experienced after spending extended durations in microgravity conditions. ^{Reference Lee, Mader, Gibson, Brunstetter and Tarver8} Optic disc edema, globe flattening, choroidal folds, and hyperopic shifts are some of the main clinical signs of the disease. ^{Reference Lee, Mader and Gibson2,Reference Waisberg, Ong and Lee9} Although the underlying causes of SANS are not fully understood, it is thought that they are associated with the redistribution of blood flow and bodily fluids that occurs in microgravity, which affects ICP. ^{Reference Lee, Mader, Gibson, Brunstetter and Tarver8} Whereas the etiology of idiopathic intracranial hypertension (IIH) is believed to be linked to decreased absorption of cerebrospinal fluid. ^{Reference Wall10} Increased ICP in an alert and oriented patient without a recognized origin is a hallmark of IIH. ^{Reference Wall10} Headache, visual loss, and pulsatile tinnitus are some of its main symptoms. ^{Reference Wang, Bhatti and Danesh-Meyer11} Impaired cerebrospinal fluid absorption syndrome is assumed to be the condition’s underlying cause. ^{Reference Wall10}

Increased ICP is another theory that has been put out to explain the emergence of SANS. It has been hypothesized that some of these ocular alterations may be significantly influenced by the considerable displacement of bodily fluid toward the head that occurs in microgravity through biomechanical processes. ¹² Increased posterior globe flattening has been a SANS finding that has been replicated in head-down tilt bed-rest studies. ^{Reference Sater, Conley Natividad and Seiner13,Reference Waisberg, Ong and Kamran14}

In recent research, Ferguson, et al compared results in patients with increased ICP from IIH with observations in astronauts following long-duration spaceflight to determine the frequency and location of choroidal and retinal folds. The scientists concluded that there are parallels between the choroidal and retinal fold patterns in SANS and IIH, indicating that elevated ICP might play a role in the onset of SANS. ^{Reference Ferguson, Pardon and Laurie15}

Idiopathic intracranial hypertension is an elevation of ICP without an identifiable cause (negative neuroimaging and normal cerebrospinal fluid contents); IIH generally affects obese, young women. If left untreated, IIH can cause significant morbidity. The pathophysiology of IIH is not yet fully elucidated, but possible theories include increased cerebrospinal outflow resistance and cerebral venous outflow abnormalities. ^{Reference Mollan, Ali, Hassan-Smith, Botfield, Friedman and Sinclair16} The relationship between anemia and IIH remains particularly controversial because in young women of childbearing age, iron deficiency anemia is also very common. Many of the factors that have been implicated in the development of IIH are closely related, and it is difficult to isolate a particular risk factor to determine a causal relationship. The rarity of IIH further exacerbates this issue by decreasing the size of available patient cohorts that can be analyzed.

The mechanisms linking anemia and IIH remain ill-defined. The elevated ICP could be related to anemia inducing a hypercoagulable state and increased venous pressure. ^{Reference Biousse, Rucker, Vignal, Crassard, Katz and Newman17} Another competing hypothesis suggests that decreased hemoglobin levels may cause hypoxia in the brain, resulting in increased ICP because of edema and increased permeability of capillaries. ^{Reference Reid and Harris18} A third theory suggests that a lower hemoglobin level increases the circulating blood volume in the cerebrum, resulting in an increased ICP. ^{Reference Biousse, Rucker, Vignal, Crassard, Katz and Newman17}

Many cross-sectional studies and case reports suggest a possible causal role of anemia in IIH. Case reports are useful while describing rare relationships, however it is important to acknowledge the potential risks of reporting bias. In this section, we discuss key studies, case reports, and systematic reviews that analyze the relationship of anemia and IIH.

Mollan, et al ^{Reference Mollan, Ball and Sinclair19} reported that an association of iron-deficiency anemia and IIH in a neuro-ophthalmology unit with an incidence of 10.3%. This study also included a case series of eight patients with anemia and IIH, with seven of these patients having complete reversal of signs and symptoms after the treatment of anemia alone. Based on these findings, a recommendation for a complete blood count (CBC) was made for patients with signs of raised ICP. ^{Reference Mollan, Ball and Sinclair19}

Lin, et al ^{Reference Lin, Berry, Nakawah, Sadaka and Lee20} however performed a matched case-control study that found no significant association between anemia and IIH when comparing standardized CBC values, and suggested that the increased prevalence of anemia was due to the demographic overlap with younger women.

Ardissino, et al ^{Reference Ardissino, Moussa, Tang, Muttoni, Ziprin and Purkayastha21} used multivariate analysis with adjustment of confounders on the records of 231,399 patients, with 667 having a clinical diagnosis of IIH, in the retrospective Clinical Practice Research Datalink which showed that anemia (P = .033) was independently associated with IIH.

Waisberg, et al ^{Reference Waisberg, Yu, Sverdlichenko and Micieli22} reported on five consecutive cases of fulminant IIH and new onset severe anemia (Hb<80g/L). This case series concluded that a CBC should be performed on all new cases of papilledema since severe anemia is temporally associated with fulminant IIH cases and that the treatment of anemia can be enough to normalize the ICP.

Yu, et al ^{Reference Yu, Waisberg, Kwok and Micieli23} performed a systematic review of the literature on anemia and IIH and found 74 cases of IIH associated with anemia, and of these, only 16 of these patients were obese (body mass index>30kg/m ^{Reference Lee, Mader and Gibson2} ). Iron deficiency anemia was the most common cause of anemia. In over 50% of cases with anemia and IIH, the treatment of the anemia alone was sufficient to resolve symptoms, without additional medications or surgery. Future comparative studies are needed to fully elucidate the relationship between anemia and IIH.