A novel space ocular syndrome is driving technology advances on and off the planet

Dorit B. Donoviel*a, Cheryl N. Zimmerb, Richard Claytonb, aCenter for Space Medicine, Baylor College of Medicine, 6500 Main Street, Suite 910, Houston, TX

77030; bAnnidis Corporation, 100 Maple Grove Rd., Ottawa, ON, Canada, K2V 1B8

ABSTRACT Astronauts are experiencing ophthalmological changes including optic disc edema, globe flattening, choroidal folds, and significant hyperopic shifts. In a handful of cases in which it was measured, intracranial pressure as measured by lumbar punctures was elevated post-flight. The severity of symptoms is highly variable and the underlying etiology is unknown, but a spaceflight associated cephalad-fluid shift is thought to play a role. NASA requires portable, non-invasive, clinically-validated approaches to assessing the ocular and the cerebral physiological, anatomical, and functional changes. Multispectral Imaging (MSI) that enables instruments installed on satellites in space to observe Earth was applied in an ophthalmic medical device that is clinically being used on Earth and now being evaluated for use on humans in space. The Annidis RHA™ (Ottawa, Canada) uses narrow band light emitting diodes (LEDs) to create discrete slices of anatomical structures of the posterior pole of the eye. The LEDs cover a frequency range from 520 to 940 nm, which allow for specific visualization of the different features of the posterior segment of the eye including retina, choroid and optic nerve head. Interestingly, infrared illumination at 940 nm reflects from the posterior sclera, retro-illuminating the choroidal vasculature without the need for invasive contrast agents. Abnormalities in retinal, choroidal or cerebral venous drainage and/or arterial flow may contribute to the microgravity ocular syndrome (MOS) in astronauts; hence this space technology may prove to be invaluable for diagnosing not only the health of our planet but also of the humans living on it and above it.

Keywords: Multispectral imaging, MSI, astronaut, papilledema, ocular, ophthalmology, eye, space, medical, retina, choroid.

1. INTRODUCTION Astronauts undergo a multitude of adaptations to living in microgravity for extended periods of time, including a cephalad fluid shift which has been implicated in ocular changes that affect visual acuity. Astronauts living in low-Earth orbit (LEO) require several corrective lenses of different prescriptions to mitigate the transitory vision alterations. Other ophthalmological anatomical features of MOS that affect largely male astronauts include a swelling of the optic nerve, or papilledema, of mild to moderate severity, choroidal folds, cotton wool spots and flattening of the globe suggesting an elevation in intracranial pressure (ICP). These findings are commonly unilateral, affecting the right eye to a greater extent and for the most part resolve after spaceflight. Several astronauts who had their cerebral spinal fluid (CSF) opening pressure measured by lumbar puncture (LP), demonstrated mildly to moderately elevated ICP upon return1,2. On Earth, patients that exhibit papilledema generally also present with elevated ICP and require CSF drainage and close monitoring. Without intervention, these patients are at a high risk for visual neuron loss and permanent decrements in peripheral vision3. Hence, NASA’s Human Research Program (HRP) classified MOS as a high priority for research, clinical monitoring, and mitigation for both LEO and planetary exploration missions4. Administering healthcare in space presents many challenges. First, the astronauts often are not clinicians. Second, medical capabilities are extremely limited due to constraints of mass, volume, power, and the time and resources it takes to integrate the equipment in the space environment. Medical devices must be miniaturized, easy to set up, stow, and use. Components must be radiation hardy, robust or at least easily replaceable. Finally, due to limited stowage aboard an exploration class vehicle, the technology must be absolutely essential for either diagnosis or mitigation of a high likelihood, high consequence medical condition. Thus, the bar is set very high for flying healthcare technologies.

* donoviel@bcm.edu; phone: 1 713 210-9280; fax: 1 713 798 7413; bcm.edu/centers/space-medicine

For decades, high resolution multispectral imaging (MSI) has been instrumental in studying planetary surfaces and their atmospheres composition, texture, structure and dynamics. An approach of planetary and engineering sciences blended to maximize scientific capabilities and operational feasibility with spaceflight-qualified instrumental solutions has been highly successful. Similarly, MSI has also been widely used in biomedical imaging, finding applications in molecule-specific identification, single cell microscopy, and whole animal in-vivo imaging in basic research and in clinically used systems5. This paper focuses on a clinically available ocular MSI imaging system. The Annidis RHATM (Ottawa, Canada) system is clinically useful to identify astronauts at risk and early anatomical changes that could help elucidate the etiology and eventually an effective mitigation strategy to address this spaceflight condition.

2. MULTISPECTRAL IMAGING: APPLYING TERRESTRIAL MEDICAL RESULTS TO

SPACE EXPLORATION 3.

The instrument: The Annidis RHATM multi-spectral retinal imaging system (Figure 1) is a semi-automated non-mydriatic commercial instrument specifically designed to produce images and data sets which enable early detection, diagnosis, and monitoring of eye and systemic diseases in routine clinical use. Drawing on knowledge from the use of multi-spectral imaging in other fields of remote sensing it was originally conceived to provide detailed quantitative analysis of the pixel spectra, similar to standard remote sensing analysis, to determine functional health of the visible anatomy (vascular, neural and photosensory). Difficulty in correcting for the many physiological variations in the semitransparent multi-layer structure of the retina across the range of patients has resulted in slow progress in quantitative spectral analysis; however many practical uses of the MSI image sets have been demonstrated beyond chemical analysis. Eye care providers find that heuristic evaluation of the multi-plane RHA image sets has significant clinical value for detection and interpretation of gross and subtle retinal features and anomalies, enabling early detection and rapid evaluation of retinal changes. To validate the utility of the Annidis RHATM in identifying the early stages of papilledema, the National Space Biomedical Research Institute (NSBRI) sponsored a diagnostic comparison study in a terrestrial MOS analog population of patients with papilledema due to a condition termed idiopathic intracranial hypertension (IIH). The Annidis RHATM is being compared side by side with standard of care Optical Coherence Tomography (OCT). The study is not yet complete; hence this paper will focus on the technical features of the RHATM device. While useful for terrestrial applications and likely for pre and post flight surveillance of astronauts, the configuration of the current commercial RHA is not appropriate for space flight. A new version will be required for a space capable system and we discuss some of its desirable features. Image sets and image production: The MSI image sets consist of 10 full aperture retinal reflectivity images from specific spectral slices (from 500 nm to 850 nm, each chosen for their utility across a wide demographic range), a fundus auto-fluorescence (FAF) image (with 600 nm stimulus and ~ 690 nm detection), and a reduced aperture stereo pair (Figure 2). A variant also provides a novel choroidal image, using trans-scleral choroidal illumination (TCI) (Figure 3), at 940 nm. In addition, the RHA produces composite images using combinations of the images to create pseudo-color, red-cyan stereo anaglyph, and inner and outer retina oxyhemoglobin contrasted images.

Figure 1: RHA Multi-spectral retinal imager Figure 2: Example of MSI image set

MSI-940 image

Inverted MSI-940* Image generation method

Figure 3: Trans-scleral Choroidal Imaging (TCI) *Inverted contrast is used for similarity with ICG angiograms (as shown in Figure 7 below) Unlike optical coherence tomography (OCT) images, which are constructed from axial scans of the variations in refractive index within the depth of the retina, MSI images rely on the absorption and refection spectra of retinal structures and chromophores (Figure 4), as is typical in most forms of spectral analysis6. The multiple semi-transparent layers of the retina and choroid, and the sclera, in combination with the absorption spectra of the various pigments within them, provide a rich source of image data for analysis (Figure 5).

Figure 4: Absorbing species in the eye

While conventional fundus color imaging does make use of retinal absorption and reflection characteristics to produce the images, color image sensors provide only 3 broad spectral bands (red, green, and blue: RGB), each of which averages any spectrally dependent intensity variations which do exist within each of those bands. In masked side-by-side comparisons using images from 812 eyes collected from 5 clinics, RHA images identified approximately 17% more retinal anomalies than a combination of images obtained using color fundus camera and wide field SLO images (Annidis, unpublished). Table 1 lists key factors responsible for the enhanced differential visibility, compared to conventional fundus imaging, of retinal features in the MSI image sets produced by the RHA. Table 1: Key features affecting differential visibility • Individual narrow band MSI images can be optimally contrasted to bring out retinal features more clearly for each

tailored spectral band. • The unique annular optical imaging system, combined with pupil centered illumination, results in reduced depth

of field, enhancing both the visibility of the target structures, and the sensitivity to angular variations in the reflection or scattering.

• Multiple wavelengths combined with wavelength dependent choroidal absorption allows control of the degree of back-lighting from scleral reflection (controlled “red-eye”) (Figure 5).

• Multiple closely spaced wavelengths in key spectral regions ensure images with maximum feature discernibility for the targeted structures across a wide range of patient pigmentation levels (Figure 6).

• Long wavelength bands probe through dense pigment to provide images of the deep retina and choroid. • The longer wavelength bands experience less scattering when penetrating diffusive media (such as cataracts). • Annular imaging allows internal angular filtering for optical processing, such as creation of stereo pairs. • Multiple wavelengths with differential penetration provide the ability to “see though” an overlapping structure to

another beneath it (Figures 7, 8 and 9). • Trans-scleral choroidal illumination produces detailed, non-invasive, views of the choroid, comparable to those of

ICG (indocyanine green) angiography (Figures 3 and 7). • Multi-image processing can synthesize additional information, such as oxyhemoglobin/deoxyhemoglobin based

contrast, not visible in the sources (Figure 10 & Figure 11)

Figure 5: Elements of retinal structure, and impact on MSI wavelength penetration and emission

Figure 6: Spectral coverage of various technologies, equalization options, and MSI image sets

TCI based MSI-940 images

ICG Angiography

Non-invasive MSI-940

Figure 7: Choroidal imaging for central serous choroiretinopathy (CSCR) Images taken on either side of the isosbestic points (where the oxygenated and deoxygenated curves cross: Figure 8 and Figure 9) are useful for generating vascular maps using the degree of oxyhemoglobin saturation as the contrast agent. For the inner retina, images near the 587 nm isosbestic are used, while the choroid images are above and below 790 nm7.

Specific absorption of oxygenated (red) and deoxygenated (blue) hemoglobin

Figure 8: For inner retina (spectral range: 470-700 nm) Figure 9: For deep choroid (spectral range: 650-1040 nm)

CSCR CSCR

Examples of OHContrast maps for inner retina (OHContrast1) and deep choroid (OHContrast2)

Figure 10: OHContrast1 map Figure 11: MSI-760&MSI-810 produce OHContrast2 map Retinal vasculature and Healthy choroidal vasculature choroidal neovascular membrane (CNV) Utility of RHA image sets from terrestrial clinics: An example of enhanced differential visibility of retinal features is shown in Figure 12 which presents three examples comparing the optimum MSI slice to the corresponding conventional color image. Many of the structures which are clearly visible in the MSI images are poorly resolved or missing from the color images.

Figure 12: Example comparison of conventional fundus camera images and single slices from an MSI image set. (Top) Color standard fundus camera images. (Bottom) Single MSI wavelength images of the same eyes. Terrestrially, RHA retinal image sets have provided utility in detecting specific retinal issues (Table 2). Table 2: Some retinal pathology detected using RHA MSI • epiretinal membranes, vitreo-macular traction • choroidal melanoma • macular holes, cysts, retinal folds • lacquer cracks • choroidal folds • drusen, exudates • geographic atrophy, window defects • cotton wool spots

CNV

• retinal and sub-retinal neo-vascularization • retinal edema • hemorrhages and other bleeds • papilledema • micro-aneurysms • vascular occlusion • changes in melanin distribution with the RPE

(aggregation, CHRPE, micro-window defects, etc.) • nevi

4. APPLICATION TO MOS AND EXAMPLES OF RELEVANT CASES FROM COMMERCIAL CLINICS

Based on features listed in Table 2, the RHA is well placed to address NASA’s MOS concerns regarding long duration space flight in micro-gravity, as well as other relevant indicators of retinal and systemic health (Table 3). Table 3: Key characteristics of MOS MOS feature1,2

RHA utility

RHA process

Hyperopic shift moderate Small depth of field objectively tracks retinal focus Globe flattening possible Stereo imaging shows topography variations in posterior region (Figure 15(d)) Choroidal folds high FAF, MSI stack (Figure 13), MSI-940 Cotton wool spots high MSI-580 (Figure 15) Optic disc edema high On-going study using terrestrial IIH cohort (Figure 15(a)-(f)) Optic nerve sheath distension

none Not amenable to optical imaging. Ultrasound or MRI preferred.

The NSBRI-funded study with IIH patients is evaluating the RHATM MSI technology side by side with the standard of care OCT imaging in the identification of clinically relevant features in patients pre and post treatment for IIH. The study will complete later in 2017 and results cannot be presented here. Instead, typical terrestrial cases are presented to indicate the potential utility, on which the formal NSBRI study is based. The following image sets show examples of some of the key MOS features from other terrestrial clinics. Figure 13 and Figure 14 show images of choroidal folds (parallel light grey linear features) and cotton wool spots (CWS) (a), respectively - two of the listed characteristics of MOS. Note that Figure 14 also clearly shows hemorrhagic (b) and exudative (c) co-morbidity throughout the retina.

Figure 13: Choroidal folds and macular micro-aneurysms Figure 14: Cotton wool spots and hemorrhages (MSI-580) (MSI-580)

Folds

(a) (b)

(c)

The images in Figure 15 show some of the spectral images available for analysis, from within a full multi-spectral set, for a case of papilledema, similar to those seen in the IIH cohort study and expected to be similar to MOS.

MSI spectral slices from a papilledema case

(a) MSI-580

(b) MSI-850

(c) OHContrast1

(d) Stereo anaglyph

(e) FAF-600

(f) Color-RG

Figure 15: Selected papilledema images

a)

b)

c)

d)

e)

(a)

(b)

Legend to Figure 15. Image Feature (a) MSI-580 Vessel distortion (a), distended optic nerve (b), and multiple hemorrhages (c), micro

aneurysms (d), and hyaloid membrane remnants (e) (b) MSI-850 Normal deep retina/choroid beyond the optic nerve region (c) OHContrast1 Nominal retinal and optic nerve perfusion (d) Stereo anaglyph (a) elevation and structure of the optic nerve

(b) topography of the distorted retina (dashed line is elevated contour, dotted lines indicate receding slope)

(e) FAF-600 Normal retinal function through lack of hyper or hypo reflective regions (f) Color-RG Reference images for standard in office optometric and ophthalmic exams Other uses for the RHA technology, not currently discussed in the context of MOS are listed in Table 4. Of particular interest is the OHContrast1 map (Figure 16), which has the potential to identify optic nerve ischemia. Table 4: Additional, potentially useful, RHA capabilities

Retinal effect RHA process RPE disruption/melanin aggregation MSI-660 … MSI-740 (Figure 12)

Terrestrial IIH cases have shown this co-morbidity in the macula Vascular changes OH1 and OH2 oxyhemoglobin maps

Retinal and sub-retinal neovascularization (Figure 10) Ischemic Optic Neuropathy (Figure 16 (right))

Aneurysms (macro and micro) MSI-580 (Figure 15(a)) Hemorrhages MSI-550 … MSI-660 (depending on severity) (Figure 14 & Figure 15(a))

.

Optic nerve perfusion using OHContast1

Figure 16: Optic nerve ischemia (Left): Normal perfusion (Right): Hypoperfusion Given the capability of the RHA MSI imaging system and the overlap with the requirements for investigation of MOS, the next avenue of collaboration involves optimizing a multi-spectral imaging system for space applications. While the space market is not large and does not directly justify such development, many of the attributes desired for a space

capable system will confer commercial advantages in smaller, portable systems for general ocular health management in smaller clinics, remote locations, under-developed countries and extreme environments.

5. REQUIREMENTS FOR A SPACE CAPABLE MSI SYSTEM The current RHA is both a response to the system requirements for the original target commercial market and a reflection of the state of technology and available knowledge at the time of development. Technological advances and increased understanding of retinal MSI optimization have enabled new views on the preferred implementation of the next generation of the RHA. Beyond the direct requirements for terrestrial systems, NSBRI has identified key requirements for a space capable system. These attributes are directly in line with, or consistent with, the research direction for a new generation of RHA. Table 4: Technical requirements for space applications of medical technologies: • Multi-functional devices to save space • No radiation emitted • Radiation sensitive components (LED sources,

camera sensor, controller & code) must be easily replaceable

• Compatible with mission IT infrastructure and telemedicine based image evaluation

• Volume, mass minimized • Easy to use for a non-expert operator. • No sharp edges • no off-gassing • Easy stowage • no crew mission impact (e.g. short test, non-mydriatic) • Simple data management. Easy for operator to tag

the subject and time/date stamp when the examination occurred

• Easy for ground electronic medical records (EMR) and subject matter experts to manage incoming data and subsequent data analysis

Table 5: MSI imaging subsystems targeted for redesign for commercial, remote, and space applications

Subsystem Major goals Annidis design status Multi-spectral source No mechanical switching

Rapid flash sequence Reduced mass & volume Replaceable components

Concept investigation

Retinal camera Reduced volume On-board image store Replaceable components

Concept investigation

Eye tracking system Internal actuation Conceptual Internal fixation Wide field for peripheral imaging Concept investigation Self imaging Controlled physical contact positioning

Self imaging feedback Conceptual

Mechanical partitioning Partition imaging and data management Tethered or standalone handheld image capture Wireless and/or socket data transfer

Conceptual

An artist’s concept of a space-compatible portable RHATM MSI imaging system is shown in Figure 17.

Figure 17: Artist concept of spaceflight version of the RHA MSI device

6. CONCLUSION Multispectral imaging has provided us with important insights about our planet and others in the solar system, as well as fundamental information about cellular anatomy and chemistry. Such powerful technology platforms find use in medical applications and stand to elucidate early signs of an interesting and possibly debilitating new medical syndrome related to time spent in space. There is much to learn about ophthalmological physiology and the development of MOS and IIH through the use of the MSI device. It is likely that unless we identify what specifically is causing MOS and prevent it, we will need a miniaturized RHA to take on long-duration space missions in order to carefully monitor the astronauts. Through public-private partnerships, both parties stand to gain new medical capabilities and new understanding of human adaptation to living on and off planet Earth.

7. ADDITONAL IMAGES:

Figure 1: Stereo pair for Figure 15 (d): cross eye viewing (dashed lines provide a planar reference for depth perception)

MSI-550

MSI-580

MSI-595

MSI-620

MSI-660

MSI-680

MSI-740

MSI-760

MSI-810

MSI-850

FAF-600

MSI-ColorRG

OHContrast1

OHContrast2

Stereo-660

Pupil image

Figure 2: High resolution images for Figure 2, demonstrating differential view of retina with wavelength

ACKNOWLEDGEMENTS AND AFFILIATIONS DBD is Deputy Chief Scientist and Industry Forum Lead of the NSBRI. The NSBRI is supported by NASA NCC 9-58. The Baylor College of Medicine Center for Space Medicine is supported by internal college funds. CNZ and RC are employees of Annidis Corporation and have a conflict of interest to declare with respect to the RHATM device described here.

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