Although once a widely speculated about and largely theoretical topic, spaceflightinduced intracranial hypertension is more accepted as a distinct clinical phenomenon; yet, the underlying physiological mechanisms are still poorly understood. In the past, many terms were used to describe the symptoms of malaise, nausea, vomiting, and vertigo though longer duration spaceflights have increased the prevalence of overlapping symptoms of headache and visual disturbance. Spaceflight-induced visual pathology is thought to be a manifestation of increased intracranial pressure (ICP) because of its similar presentation to cases of known intracranial hypertension on Earth as well as the documentation of increased ICP by lumbar puncture in symptomatic astronauts upon return to gravity. The most likely mechanisms of spaceflight-induced increased ICP include a cephalad shift of body fluids, venous outflow obstruction, blood-brain barrier breakdown, and disruption to CSF flow. The relative contribution of increased ICP to the symptoms experienced during spaceflight is currently unknown though as other factors recently posited to contribute include local effects on ocular structures, individual differences in metabolism, and the vasodilator effects of carbon dioxide. Spaceflight-induced intracranial hypertension must be distinguished from other pathologies with similar symptomatology. The following chapter discusses the proposed physiologic causes and the pathological manifestations of increased ICP in the spaceflight environment and provides considerations for future long-term space travel.
- increased intracranial pressure
- intracranial hypertension
- space adaptation syndrome
- visual impairment
- space flight-associated neuro-ocular syndrome
Since the first manned spaceflight, many terms have been used to describe a collective group of seemingly related neurologic, ophthalmologic, and neurovestibular symptoms. Up to one half of astronauts are incapacitated by malaise, nausea, vomiting, and vertigo within the first few hours or days spent in space . This constellation of symptoms, first described by Titov , was originally referred to as “space motion sickness” (SMS)  because of its similarity to motion sickness in the terrestrial environment. It is hypothesized that two physiologically distinct mechanisms converge to produce the symptoms of SMS [4, 5]: Cephalad fluid shifts are thought to alter the response properties of vestibular receptors while loss of tilt-related otolith signals in microgravity create a conflict between the actual and the anticipated signals collected from the external environment. The breadth of symptoms that astronauts report is likely due to a complex interaction between the neurovestibular system and autonomic nervous system . A separate yet related term, “space adaptation syndrome,” had similarly been used to include not only motion sickness, but also symptoms of head congestion and headaches brought on by a cephalad fluid shift into facial structures .
Most astronauts require only 2–3 days to acclimate to motion sickness in space and few continue to have residual symptoms during short term spaceflight . As more time is spent in space, physiologically distinct yet overlapping symptoms seem to arise including headache and visual disturbance. These findings were noted to be similar to the cases of intracranial hypertension in the terrestrial environment which are caused by an elevation in intracranial pressure (ICP) . Since the launch of the International Space Station (ISS) in 2000, the time that astronauts spend in space has dramatically increased. In addition, a 2015 partnership between the United States and Russia established the concept of 1-year mission onboard the ISS. Long-duration exposure to spaceflight has brought forth concern from the aerospace medicine community because its effects on the central nervous system are unknown.
2. Spaceflight increased intracranial pressure
Post-flight surveys of 300 astronauts from 1989 to 2011 found that approximately 29% reported deficits in distant and near visual acuity following short-duration missions (less than 2 weeks) while 60% reported deficits with long-duration space travel (typically 6 months) . Starting in 2008, more detailed clinical data were collected for seven astronauts following 6 months of continuous orbital flight onboard the ISS. Complete visual and structural eye examinations before and after spaceflight revealed pathologic changes in the eye including optic disk edema, nerve fiber layer thickening, choroidal folds, posterior globe flattening, cotton wool spots, and decreased near vision accompanied by hyperopic shift. Of these seven crewmembers, lumbar punctures performed in the four cases with disk edema revealing opening pressures of 220, 210, 280, and 285 mm H2O at 60, 19, 12, and 57 days post-mission, respectively. It should be noted that no in-flight opening pressure have ever been attempted. With this clinical evidence, the authors hypothesized that the observed findings were due to cerebral venous congestion due to CSF flow disturbance from spaceflight-induced cephalad fluid shifts. A retrospective review of data has since identified eight additional cases of pathologic visual changes  since the original publication.
In a follow-up study, Kramer, Sargsyan  evaluated 27 post-flight crewmembers using T2-weighted orbital and conventional brain sequences. They found various combinations of optic nerve sheath distention, posterior globe flattening, optic disk protrusion, increased optic nerve diameter, and greater concavity of the pituitary gland with posterior stalk displacement. Optic disk protrusion was only found with longer mission duration, indicating that clinical severity is associated with increasing spaceflight exposure. Repeat scans showed that some crewmembers continued to have posterior globe flattening 100 days after spaceflight suggesting that this condition may have a prolonged course or may not entirely return to normal. The authors determined that these findings were representative of intracranial hypertension due to elevated ICP.
Clinically, visual pathology is considered a sensitive measure of increased ICP, as the perineural subarachnoid space of the optic nerve is contiguous with the intracranial subarachnoid space and therefore vulnerable to ICP fluctuations. This contiguity has been verified in a cadaver study which found that the subarachnoid pressures of the optic nerve sheath have a linear relationship to ICP [8, 12]. The National Aeronautics and Space Administration (NASA) has since referred to this spaceflight pathological phenomenon as vision impairment and intracranial pressure (VIIP) [10, 13] and recognized it as a serious threat to long duration spaceflight.
The Space Life Sciences at Johnson Space Center convened a summit in February of 2011 to address the topic of VIIP. At that meeting, a research and clinical advisory panel was created to provide guidance for the future clinical and fundamental research. After further investigation, the visual pathology seen in astronauts seemed to differ from those with intracranial hypertension in the terrestrial environment. Choroidal folds and hyperoptic shifts are sometimes seen in terrestrial intracranial hypertension but seemed to occur disproportionately in astronauts. Retinal cotton-wool spots are not typically seen in terrestrial intracranial hypertension but are prominent features in the visual pathology seen after space flight. Also, astronauts may experience unilateral pathology, which is again uncommon with global increases in intracranial pressure [14, 15]. Because of these discrepancies, visual pathology in astronauts has now been referred to as space flight-associated neuro-ocular syndrome (SANS) . After considering all evidences, the panel concluded that the increase in ICP may not be the sole cause of visual disturbances following spaceflight and chose to examine other possible influences on visual pathology .
2.1. Intraocular pressure
Space flight-induced compartmentalization of cerebrospinal fluid in the subarachnoid space with locally elevated cerebrospinal fluid sheath pressures has been proposed as an additional alternative hypothesis. Local orbital effects may explain ophthalmic structural and functional changes following spaceflight without an accompanying rise in ICP. This hypothesis purports that a local disruption of CSF dynamics surrounding the optic nerve sheath results in an orbital compartment syndrome . A microgravity-induced cephalad fluid shift may lead to choroidal engorgement and subsequent expansion of the choroid against the rigid scleral tissue leading to a sudden increase in intraocular pressure (IOP) [18, 19]. The initial spike in IOP is followed by a decrease over a period of days likely due to a compensatory decrease in aqueous volume . Thus, in-flight, post-flight, and HDT studies suggest the possibility that a lowering of IOP may occur during extended microgravity exposure. Ocular hypotony, generally defined as an IOP of <6.5 mmHg, is well-documented to cause disk edema, posterior globe flattening, choroidal folds, and a hyperopic shift very similar to some of our observed changes .
The lamina cribrosa is a mesh-like structure that acts as a pressure barrier between the intraocular space and cerebrospinal fluid space of the optic nerve sheath . The difference in IOP and CSF pressure across the lamina cribrosa is known as the translaminar pressure difference. Small yet chronically elevated CSF pressure in combination with ocular hypotony would lead to a significant pressure gradient toward the intraocular space and could thereby be responsible for the ophthalmic structural and functional changes seen in astronauts secondary to spaceflight exposure.
3. Factors contributing neuro-ocular symptoms
3.1. Microgravity-induced fluid shifts
Early studies found that exposure to both microgravity and simulated microgravity led to a cephalad shift of plasma fluid into the interstitial spaces of the head and neck [21, 22]. This led researchers to believe that microgravity-induced cephalad fluid shifts caused increased ICP and were a prominent contributor to both space adaptation syndrome  and space motion sickness . The initial support for this mechanism was sought through the use of the head-down tilt (HDT) method which simulates the fluid shifts that occur in the spaceflight environment. In an early study by Murthy et al. , 10 min of 6° HDT was found to significantly increase the ICP of six healthy males as indicated by tympanic membrane displacement. Increasing the angle to 15°, HDT generated a further increase in ICP. Although no long-term monitoring of the HDT method has been attempted in humans, ICP was evaluated for 7-days of 45° HDT using a subarachnoid catheter in rabbits . An immediate increase in ICP was observed which peaked at 12 h of HDT and then decreased gradually toward the pre-HDT baseline value. These findings suggest that rabbits begin to adapt to HDT within the first few days.
Since cephalad fluid shift has been found to increase fluid in the interstitial soft tissue space of the head, it may seem intuitive that the increased filtration of plasma into the intracranial interstitium would lead to increased ICP. However, when autoregulatory mechanisms are intact, they prevent a sustained increase in cerebral blood flow (CBF) in the presence of an elevated cerebral perfusion pressure (CPP) [26, 27]. Kawai et al.  used transcranial Doppler to examine CBF in the middle cerebral artery of humans following 6° HDT. CBF velocity was found to increase immediately upon initiation of HDT, reach a peak at 3 h and then begin to decrease toward baseline after 9 h of HDT. Similarly, no significant differences in CBF velocity were found on transcranial Doppler measurements after up to 2 weeks of spaceflight when compared to pre-flight baseline values [7, 28, 29]. These findings suggested preserved or possibly improved cerebrovascular autoregulation during short-duration spaceflight. When time spent in microgravity is extended, though, there is evidence that autoregulation may become altered.
3.2. Endothelial breakdown
Although autoregulatory mechanisms in the cerebrovasculature have evolved to provide a steady CBF in the face of wide fluctuations of cerebral perfusion pressure, endothelial dysfunction may lower the threshold pressure required to increased deposition of fluid into the intracranial interstitial. Using an
Endothelial cell gap junctions are held closed by the combined pressure of the interstitial fluid in the brain and the intracranial capillary pressure. Lakin et al.  proposed that in a 1-G environment, hydrostatic pressure is transmitted from the brain to the capillaries, thus increasing the pressure needed to close endothelial cell junctions. In spaceflight, the brain is unable to contribute its weight to maintaining the pressure balance, thereby allowing fluid to leak from the intracranial capillaries into the interstitial fluid.
3.3. Venous outflow obstruction and CSF hydrodynamics
Aside from increased CBF, it has also been proposed that cephalad fluid shifts contribute to elevations in ICP by increasing the post-capillary venous pressure  through downstream venous congestion [31, 37]. While supine, a majority of the cerebral outflow occurs through the internal jugular veins. However, internal jugular veins collapse in the standing position and blood is shunted through secondary venous channels (e.g., vertebral plexus and deep cervical veins). This has been confirmed using time of flight MRI techniques in the sitting versus supine positions [38, 39]. Termed “Space obstructive syndrome,” Wiener  proposed that internal jugular vein compression along with loss of gravitational-induced cranial outflow of venous blood in the vertebral veins may lead to venous hypertension. Cerebral outflow may divert through the internal jugular veins when standing if there is a significant increase in CVP (e.g., with a Valsalva maneuver) . This is relevant to spaceflight as the gravitational unloading of the thoracic space causes CVP to paradoxically decrease [42, 43, 44]. Decreased venous flow may lead to a rise in pressure high enough to disturb the gradient between the CSF and cerebral venous sinuses. CSF normally circulates through the subarachnoid space and is absorbed through arachnoid granulations into the cerebral venous sinuses. Similarly, cine phase-contrast MRI examining CSF flow in the upright posture found that a considerably smaller amount of CSF oscillated between the cranium and the spinal canal than in the supine position [38, 39, 41].
3.4. Carbon dioxide
Carbon dioxide (CO2), a natural byproduct of cellular respiration, is known to be a potent vasodilator in the cerebral vasculature. This normal physiologic event occurs to increased CBF to the brain in times of respiratory compromise . Nominal CO2 levels on the ISS are between 2.3 and 5.3 mmHg  and the astronauts presenting with VIIP symptoms were exposed to levels less than 5 mmHg . Although these levels are 20× higher than the normal 0.23 mmHg CO2 on Earth, this CO2 level is still relatively low and not thought to have detrimental physiological effects. However, as there is no natural convection in microgravity, astronauts may be exposed to localized areas of high CO2 when working in a small space, during exercise  and possibly during sleep . In a computational fluid dynamics analysis, Son et al. (2012) determined that without natural convection of gases and ventilation, pCO2 could rise above 9 mmHg around a sleeping astronaut’s mouth within just 10 min. These pockets of CO2 would not be detected by the major constituent analyzers onboard the ISS, and therefore would go unreported. Regular exposure to slightly increased ambient CO2 as well as potential exposure to pockets of high concentrations of CO2 may compromise the integrity of the blood-brain barrier impairing cerebrovascular resistance thus leading to increased CBF and ICP [45, 48]. The response CBF and CVR to CO2 was found to be reduced after long-duration missions on the ISS indicating impaired autoregulation and reduced cerebrovascular CO2 reactivity [27, 49].
3.5. One-carbon metabolism
It has also been shown that variation in an important metabolic pathway, the one-carbon metabolism cycle, is associated with the occurrence of the VIIP syndrome in astronauts . Zwart et al. (2012) found significantly higher serum levels of several one-carbon metabolites in astronauts affected by the VIIP syndrome compared to unaffected astronauts, including serum homocysteine, cystathionine, 2-methylcitric acid, and methylmalonic acid. These findings suggest that polymorphisms in enzymes of the one-carbon pathway may interact with microgravity to cause ophthalmic changes.
It has also been proposed that radiation exposure outside of Earth’s atmosphere may disrupt the integrity of the blood-brain barrier . The two cosmic sources of radiation that are considered to impact mission success are solar particle events and galactic cosmic rays. Sanzari et al.  found that exposure to doses of ionizing radiation similar to that experienced by astronauts during a solar particle event led to significant long-term elevation in ICP in a porcine model. Experiments involving cell phone radiation found that small amounts of radiation may activate endothelial cell proteins causing the endothelial cells to shrink and widen the gap junction [52, 53, 54]. Increased vessel permeability in turn leads to extravasation of albumin into brain parenchyma leading to cerebral edema . There is little evidence, though, that the radiation generated by solar particle events or galactic cosmic rays produce effects similar to that of radiofrequency waves.
There have been several studies showing that resistive exercise during spaceflight may lead to a significant increase in IOP [55, 56]. The effect it has on increased ICP though remains controversial. Heavy loading and resistance exercise are important to prevent musculoskeletal losses, especially bone density . For that reason, resistance exercises have been encouraged aboard the ISS. Inducing a Valsalva maneuver during weight lifting has been shown to increase intrathoracic pressure which may in turn elevate ICP . Aerobic exercise though has not been found to increase ICP likely because it is accomplished without a Valsalva .
3.8. Sodium intake
Prepackaged foods for the International Space Station were originally high in sodium at up to 5300 g per day . High sodium levels create an osmotic shift of body fluid from the interstitial to the intravascular space contributing to increased venous volume, congestion and ultimate jugular venous outflow obstruction. In 1974, a prospective trial of sodium restriction reportedly lead to remission of papilledema in all 9 patients with idiopathic intracranial hypertension that were involved . It is likely that improvement occurs due to concomitant weight loss and not entirely due to sodium and water distribution. However, it is suggested that astronauts consume a lower sodium diet in attempt to prevent long term visual damage. NASA has since reformulated to substantially reduce the intake of sodium in the daily diet of astronauts to less than 3 g per day .
4. Cognitive and structural changes in the brain
Spaceflight imposes a short-term risk to mission operational success by contributing to headaches, malaise, and visual impairment and further may lead to long-term risks that have not yet fully been elicited. The long-term risks of spaceflight-induced intracranial hypertension may be best estimated through observations of chronically increased ICP on earth. Individuals with idiopathic intracranial hypertension (IIH) are plagued with well-documented symptoms of severe headache and vision loss but may also experience pulsatile tinnitus, ataxia, memory disturbances, and cognitive dysfunction [62, 63, 64]. Several small population studies have revealed significant cognitive deficits in patients with IIH especially within verbal and memory tests [65, 66]. In a study by Yri et al. , 31 patients with IIH performed significantly worse on tests of reaction time, processing speed, visuospatial memory, and attention compared to a demographically matched healthy control group. Individuals with IIH continued to exhibit cognitive dysfunction after 3 months of pharmacologic therapy despite improvement in ICP and headache. Further, quality of life measures have been found to be lower compared with population norms .
At this time, there is no evidence for gross structural damage as a cause of cognitive dysfunction in IIH, as brain morphometric and volumetric analysis have also been insignificant compared to healthy controls . Subtle disturbances to white or gray matter substance due to mechanical compression similar to that in normal pressure hydrocephalus has also been proposed .
The evidence to suggest impaired cognition in astronauts related to spaceflight is sparse, but terrestrial data could potentially predict long duration sequela and may influence how we monitor astronauts in the future. In 2017, scientists released the results of a study using MR imaging to compare the brain morphology of astronauts after long and short duration space flight. Astronauts who participated in long-duration flights had significantly more narrowing of the central sulcus, upward shift of the brain, and narrowing of CSF spaces . Another study compared MRIs of the brain before and after spaceflight from 27 astronauts and found decreased volume of the frontotemporal gray matter and an increase in the volume of the medial primary sensorimotor cortexes. This finding was attributed to neuroplasticity during adaptation to microgravity . Long duration spaceflight has also been associated with an increase in periventricular white matter hyperintensities seen on MRI. These hyperdensities are linked to an increase in ventricular CSF volume leading to transependymal CSF flow from the ventricles into the brain parenchyma. It appears it is at least partially reversible on return to normal gravity . Similarly, a significantly increased number of white matter hyperintensities were found in high-altitude U-2 pilots compared to age-matched healthy controls . The presence of these white matter changes were associated with cognitive impairments ranging from slowed though processes to confusion, unresponsiveness, and even permanent cognitive decline [73, 74].
5. Future considerations
Under NASA’s Human Research Roadmap and its Path to Risk Reduction, VIIP/SANS continues to be identified as a top risk that may affect astronauts on long duration missions and remain under intensive investigation by space agencies. Projects are currently planned to characterize fluid distribution and compartmentalization during long-term space travel to determine systemic and ocular factors of individual susceptibility to the development of ICP elevation and to evaluate noninvasive ICP monitoring devices for the clinical evaluation of ICP preflight, in-flight, and post-flight .
On land and in orbit, astronauts are subjected to a multitude of visual examinations including visual acuity tests, amsler grids, tonometry, fundoscopy, and optical coherence tomography. Following long duration space travel, researchers are applying MR imaging, visual field perimetry and cycloplegic refraction. Noninvasive techniques for in-flight ICP, intraocular pressure, and cerebral blood flow measurements are also being investigated including ophthalmodynamometry, tympanic membrane displacement and optic nerve ultrasound. A linear correlation has been found between central retinal vein pressure and ICP due to pressure gradients across the optic nerve sheath . Ophthalmodynamometry is a useful method for determining the central retinal artery pressure and is therefore a useful indirect measure on ICP. Tympanic membrane displacement has been used to detect elevated ICP in hydrocephalus children in the terrestrial environment . Because cerebrospinal fluid and perilymph communicate through the cochlear aqueduct, an increase in ICP is directly transmitted to the footplate of the stapes and resulting in inward displacement. The optic nerve ultrasound also seems to be a reliable non-invasive measure as optic nerve sheath diameter has been found to be highly sensitive and specific for the detection of elevated ICP using . Noninvasive approaches though are correlation based and must be calibrated to each patient based on known ICP baseline measurements. This may lead to a high margin for error. Researchers are currently investigating how to correlate pre-flight to in-flight data across multiple modalities.
As space tourism increases, there will be spaceflight participants that are not as physical fit and have not undergone the rigorous training as that of NASA astronauts. Intracranial hypertension may also pose a risk to future commercial spaceflight. The incidence of intracranial hypertension and visual pathology may rise with the increase in civilian space travelers who are not as physiological adept as their astronaut counterparts. Further, increased ICP in the spaceflight environment may become more concerning in someone who has a predilection, or underlying disease process that, combined with increased ICP, could cause in-flight or post-flight problems .
The ultimate prevention of neuro-ocular dysfunction due to spaceflight would be reproduction of the normal 1G environment. This could theoretically be introduced by the Coriolis force through rotation of the entire space vehicle, part of the vehicle, or using an on-board centrifuge. Reintroduction of gravity is the only single measure than can protect all physiological systems in all individuals against the effects of weightlessness. Until that concept comes to fruition, other countermeasures are actively being researched.
Pharmacological agents are capable of lowering ICP in the terrestrial environment and are being studied as a means of reducing the risk of visual impairment. Acetazolamide acts as a carbonic anhydrase inhibitor leading to decreased production of CSF at the choroid plexus. However, it also increases the risk for renal calculi and would lower intraocular pressure which could worsen choroidal swelling and potentially optic disk swelling. Other diuretics (e.g., furosemide and hydrochlorothiazide) are more potent diuretics and although may theoretically aid in decreasing CSF production would produce undesirable metabolic side effects. Topiramate has been used in the treatment of migraine headaches and has a weak carbonic anhydrase effect which may lower ICP. It too has undesirable side effects such as cognitive slowing .
Many terms have been used to describe the symptoms of head congestion, nausea and vomiting, and visual disturbance in the space-flight environment. Over the years, attempts have been made to connect these seemingly related symptoms to a number of diverse pathophysiological origins. At this time, the contribution of increased ICP to the symptoms experienced during spaceflight is unknown. Although direct measurements of CSF pressure have not been performed in actual spaceflight conditions, the best evidence comes from the presentation of symptoms shared with cases of known intracranial hypertension on Earth as well as the documentation of increase ICP in symptomatic astronauts upon return to gravity. Documentation of CSF opening pressure via a lumbar puncture during spaceflight would provide definitive proof of elevated ICP during spaceflight but carries with it inherent procedural risks of post-lumbar puncture headache, hemorrhage, infection and spinal cord injury . For that reason, noninvasive techniques are being studies though they too have inherent drawbacks.
Spaceflight-induced visual disturbance, first termed by NASA as VIIP, has been identified as a serious risk to astronauts during future long-duration space travel, having already affected over 40% of ISS inhabitants . Although VIIP was originally attributed to spaceflight-induced elevated ICP, further factors now seem to contribute. For that reason, it has more recently been referred to as space flight-associated neuro-ocular syndrome .
Although prior research has provided better insight into the mechanisms of increased ICP in space, the exact pathophysiology is still unclear. It is likely that no entity discussed previously is the sole contributor to the neurological phenomena experienced in long-term spaceflight but a combination of many. Cephalad fluid shift plays a large role along with major contributions from venous outflow obstruction, blood-brain barrier breakdown, alterations in cerebrovascular tone, and disruption of CSF flow. Since not all individuals manifest with symptoms, it is likely that a combination of genetic, anatomical, and lifestyle related factors make some astronauts more susceptive to spaceflight-induced visual pathology as well as intracranial hypertension .
Little is known as to how the spaceflight environment setting will alter the anatomical and physiological integrity of our nervous systems and related structures, but aerospace physicians and astronauts should be educated in the current understanding of how human physiology reacts to this extreme environment. The goal of extending the duration of missions and sending individuals further into space than ever before will challenge the current capabilities of aerospace medicine. It will be critical to develop countermeasures to these known obstacles so that astronauts can participate at their peak in these missions and return safely to earth.