Fig. 1.1
Preflight and postflight optic nerve photos exhibiting optic nerve head edema in an astronaut following long-duration spaceflight (Reprinted with permission from Mader et al. [18])
Fig. 1.2
Postflight choroidal folds (indicated by arrows) in both eyes of an astronaut following long-duration spaceflight (Reprinted with permission from Mader et al. [18])
Lumbar puncture was performed in four astronauts of this ISS cohort several days to weeks after their return to Earth. The opening pressures were 22, 21, 28, and 28.5 cm H2O at 66, 19, 12, and 57 days after mission, respectively. Although these are borderline elevated pressures [1], it is unclear if these ICP readings represent normal variation or the residua of higher ICP while in flight. Beyond this, ICP varies throughout the day much like IOP, so these snapshots may not be representative of the true mean ICP.
The assortment of neuro-ophthalmologic findings associated with spaceflight bears some similarity to the well-characterized condition of idiopathic intracranial hypertension (IIH ). Optic disk edema, choroidal folds, increased CSF signal in optic nerve sheaths, and globe flattening with hyperopic refractive shifts are common to both conditions. There are, however, several distinguishing features to suggest that high ICP alone may not be responsible for the observed changes. Astronauts exhibit more impressive choroidal folds and larger hyperopic shift s than those seen in IIH. Further, the imaging used (OCT, MRI, CT, and ultrasound) after long-duration spaceflight demonstrates larger and more persistent shift of CSF into the optic nerve subarachnoid space and more dramatic globe flattening than seen in IIH. Another distinguishing feature is the presence of cotton wool spots, which are not typically associated with IIH. Beyond imaging and examination, the demographics of these two populations are distinctly different, from gender and body habitus to the absence of medications linked to IIH in the astronaut cohort. Finally, the astronauts did not report the associated symptoms that characterize terrestrial IIH, namely, pulsatile tinnitus, diplopia, or chronic severe headaches. In fact, headaches reported by this long-duration spaceflight group were mild and did not interfere with in-flight activities [18]. This is distinct, however, from the more severe headache experience early in flight as mentioned above.
A follow-up study, in which the postflight MRIs for 27 astronauts after exposure to microgravity were reviewed, found that several exhibited radiologic similarities to those seen in IIH [14]. Posterior globe flattening and optic nerve protrusion were seen in a small subset of these subjects, and moderate concavity of the pituitary dome (partially empty sella) with posterior stalk deviation was also seen in multiple subjects. Increased optic nerve sheath diameter and intrinsic optic nerve enlargement was noted in a small group of subjects. The majority of the subjects demonstrated a central area of T2 hyperintensity within the optic nerve and kinking of the optic nerve sheath as well (Fig. 1.3). A study of MRI images pre- and post-HDT bed rest showed positional and structural changes to the brain, including a shift of the center of mass upward with posterior rotation of the brain and changes in ventricular volume [29]. These changes suggest alterations in CSF homeostasis associated with tissue redistribution.
Fig. 1.3
T2 MRI demonstrating optic nerve kinking (long arrows) and posterior globe flattening (short arrows) (Reprinted with permission, Kramer et al. [14])
Given the known relationship between the ophthalmologic findings of disk swelling and retinal nerve fiber layer thickening and increased ICP, as well as the radiologic evidence correlating CNS changes and finally the mild elevation of ICP postflight, NASA has named this syndrome as vision impairment and intracranial pressure (VIIP ) [20] .The pathogenesis of optic nerve edema in increased ICP is a mechanical phenomenon in which the pressure along optic nerve sheath becomes elevated. The persistence of optic nerve sheath expansion as well as optic disk swelling for months or years postflight (Mader et al. in press) has led researchers to conclude that CSF dynamics in microgravity may result in permanent changes in optic nerve sheath anatomy. The subarachnoid spaces surrounding the optic nerve are widest at the lamina cribrosa and narrowest in the optic canal. Cisternography with contrast injected directly into the spinal CSF has demonstrated reduced signal beyond the canalicular optic nerve, giving rise to the concept of CSF compartmentalization [13]. This finding challenges the assumption that CSF flow is continuous and equivalent throughout the subarachnoid spaces, cisterns, and ventricles. The relative stasis and trapping of the CSF around the nerve could be further exacerbated by CSF flow changes and positional changes of the brain. Optic disk swelling such as that seen in astronauts may indeed be due to elevated ICP or alternatively by venous engorgement, inflammation, toxicity, metabolic imbalances, or local ischemia. The choroidal folds and hyperopic shift are suggestive of an increase in choroidal thickness as occurs with venous engorgement. This association also provides a possible link between the cephalad fluid shifts and observed ophthalmologic changes.
Vision changes in astronauts create a major safety concern that must be addressed before a planned long-duration spaceflight to Mars (lasting approximately 3 years each way), as these changes could endanger mission success in addition to impacting short- and long-term visual function for individual astronauts. Hyperopic shift is easily correctable by “space anticipation” glasses and has not had a long-term effect on visual potential and function. The crystalline lens is among the most radiosensitive body tissues, and increased terrestrial exposure to ionizing radiation is known to increase the rate of cataract formation. Deep space radiation exposure, which would occur during a flight to Mars, is likely to be even more intense than the exposure received in low-earth orbit (e.g., aboard the ISS), and the potential for accelerated cataract formation exists [7, 8]. While cataract surgery on Earth is one of the most common medical procedures in the developed world, its performance in space or on an alien planet would present formidable challenges. Finally, because we do not understand the etiology of spaceflight-induced optic disk swelling and its persistence in some cases for months after return to the terrestrial environment, the trajectory of this condition (relentless progression vs possible stabilization or even remission as autoregulation occurs) hampers the development of countermeasures that might reduce risk. As a result of the observed changes, NASA is collecting pre-, post-, and inf-light data on the structure and function of ocular and orbital tissues using visual acuity testing, fundus photography, and optical coherence tomography, as well as orbital echography to allow scientists to study changes in a sequential manner and to permit physicians to recognize potentially vision-threatening changes and implement appropriate treatment. To date, no changes have been seen in-flight that would have necessitated medical treatment or other interventions such as early return to 1G, which would have devastating consequences for mission accomplishment.
Study of ICP Changes in Microgravity
Although it is postulated that the visual changes are due to intracranial hypertension, the putative changes in ICP, both short and longer term, have been studied under very limited circumstances. ICP elevation, as noted above, is believed to be occur at least in part because of cephalad fluid shifts. In rabbit studies monitoring ICP by subarachnoid catheter, ICP was immediately elevated from a mean of 4.3 to 8.0 mmHg in 45° HDT reaching a peak of 15.8 mmHg at 11 h but then trended back toward baseline over 7 days [34], suggesting adaptation after the initial spike. Similarly, CBF as measured by transcranial Doppler in humans demonstrated a sudden rise with HDT that decreased toward baseline after 3–6 h in the HDT position [12]. A study of healthy human subjects demonstrated increased ICP after 10 min of HDT as estimated by tympanic membrane displacement [21]; however, similar ICP data are not available from long-duration spaceflight missions. The rapid compensation for the initial ICP rise with HDT implies that autoregulation occurs in the terrestrial environment during HDT; because similar autoregulation may not occur in microgravity as noted above, HDT may not be an adequate model for studying the phenomenon. Furthermore, rodents and rabbits have optic nerve anatomy differences from humans, such as the absence of a lamina cribrosa, that may cause their eyes to respond differently to any changes in CBF and/or ICP.
Because of the concern that ICP might be elevated in space, NASA’s Space and Clinical Operations Division as well as affiliated research programs have prioritized efforts to measure ICP either directly or indirectly. A number of methods, some long-standing and others more novel, are being studied as potential methods to be deployed aboard the ISS. Potential strategies include measurement of tympanic membrane displacement, waveform analysis of transcranial Doppler, analysis of otoacoustic emissions, and flow detection within the ophthalmic artery under orbital compression [2, 27]. Many of these methods provide only qualitative data or lack technologic readiness for application in spaceflight at this time. Furthermore, results of noninvasive ICP tests in flight might not be comparable to post- and preflight opening pressures determined by LP. Sampling bias also hampers data analysis, since ICP, like blood pressure and IOP, varies both short term and diurnally. Nonetheless, NASA is committed to measuring ICP in flight and continues to pursue efforts to allow for accurate and meaningful data to be obtained, while protecting astronaut health in flight and minimizing risk to them that could arise during any procedures.
The gold standard for ICP measurement at 1G remains manometric recording of CSF pressure during lumbar puncture in the lateral decubitus position. Equilibration in the manometer can take several minutes if a small bore (less than 23 ga) needle is selected, and the use of a 20 ga needle is recommended [16]. As noted above, postflight LP has been done, but generally days or weeks after return from microgravity. More timely measurement of opening pressure upon return to 1G would be ideal and might be a better indicator of ICP during the final days of the mission, but performing LP immediately on landing is logistically complicated. Not only are there many competing demands on the astronauts’ time, but also all returns from the International Space Station presently occur in Kazakhstan (Mader 2016). A standard LP in space would present numerous procedural challenges and risks. There are anatomic changes such as lengthening of the vertebral column and shifting of the nerve roots against the meningeal walls in weightlessness that could increase the risk of procedure complication or failure. Ultrasound assisted LP could mitigate some of these risks but makes the procedure more difficult, possibly requiring a second proceduralist. The aforementioned venous congestion could increase risk of bleeding. Bacterial growth rates and virulence appear to be higher in spaceflight, and the immune system becomes depressed, raising a theoretical increased risk of the microgravity environment. It is unclear if CSF production is normal in space which could inhibit recovery. There are also practical aspects of the procedure such as anchoring of equipment, the patient, and the proceduralist. Classic manometry would not yield useful information as the manometry column is based on Earth’s gravitational pull, so digital closed system devices would need to be employed [2]. Given the lack of suitable noninvasive alternatives however, it has been suggested that astronauts be sent into space with a spinal catheter in place. While valuable information might be obtained in this way, a complication such as infection or CSF leak and resultant intracranial hypotension could have devastating consequences in an environment where immediate treatment would not be available. Physicians and scientists continue to struggle with this difficult problem.
Additional contributors to ICP elevation aside from fluid shifts alone must be considered. The blood-brain barrier (BBB) potentially could be compromised, leading to changes in ICP and CBF. The BBB is mediated by specialized endothelial cells lining the cerebral vasculature which are selectively permeable and allow for passive and active transport from the blood into the CSF. Hydrostatic forces, osmotic forces, increased pCO2, radiation, illness, and a myriad of other factors may influence permeability [20]. Lakin and colleagues created a mathematical model which simulated the intracranial system and cerebrovascular changes of microgravity and demonstrated a hypothetical breakdown in BBB would cause ICP to increase [15]. There is currently no evidence for or against the idea that changes in the BBB are part of the pathogenic process leading to ophthalmic change s in microgravity.
Intraocular Pressure
Abrupt change in body posture from vertical to horizontal or even inverted may cause an acute rise in intraocular pressure (IOP ) [26]. This may be due to choroidal vascular engorgement and increased episcleral venous pressure. However, a gradual decrease in IOP during prolonged (7–30 days) HDT has been observed [33]. This IOP reduction may be related to a decline in plasma volume that occurs as well during prolonged HDT [6]. A subsequent study of IOP in subjects measured pre- and post-HDT (14 or 70 days) did not find a difference in IOP outcome between the 14- and 70-day groups [32]. In addition, IOP measurements in flight aboard the ISS demonstrate a trend toward stable or lower ICP during longer missions without findings of hypotony or visual dysfunction [18]. Homeostasis between ICP and IOP has been proposed to be important for normal optic nerve function and axonal health, as these two opposing forces act on opposite sides of the eye wall at the lamina cribrosa (Fig. 1.4). This translaminar pressure gradient (TLPD ) might result in laminar deformation and glaucomatous cupping when IOP-ICP is excessive, while papilledema may occur when ICP-IOP rises. The combination of reduced IOP with stable or potentially elevated ICP in microgravity could increase the TLPD and subject optic nerve axons to injury [4].
