Week in Review: Number 2

Technique for Uniform Integration of Retinal Cells
Regenerating the retina and the optic nerve is one of the holy grails in ophthalmology, an endeavor that is still in the nascent phases of study and investigation at this point. The current study by Johns Hopkins Medicine researchers, using mouse retinas in vitro, illustrates an important obstacle to that goal: how to integrate the stem cells (retinal ganglion cells derived from human embryonic stem cells in this case) uniformly. In most cases, the many layers of the retina present a challenge, resulting in clumping of the cells. You can think of them as teeny, tiny tumors. The research team found, however, that areas of their in vitro retina model that were breached by incision showed more uniform integration of the retinal ganglion cells. They hypothesized that the internal limiting membrane (ILM), the innermost layer of the retina composed of footplates of Müller cells, could be the limiting factor. After loosening the ILM with an enzyme and removing it, the researchers found more normal integration of the retinal ganglion cells and establishment of new connections to the rest of the retina. This is one of those studies that seems obvious in hindsight. It makes sense that the ILM would present a barrier. So what was interesting was to see the process unfold of what would happen once the ILM was removed.

Toward Reliable Algorithms
Using artificial intelligence to screen retinal diseases is a promising line of research, with many software algorithms currently in development. The utility of this technology lies in its ability to accurately and reliably detect early disease states, a goal that is constantly improving. The current study examined the effectiveness of seven artificial intelligence (AI) algorithms in the detection of diabetic retinopathy, a common ocular complication of diabetes that could lead to vision loss. The algorithms were compared with human screeners in a teleretinal screening system, and both of these were compared to the standard of diagnostic expertise of retina specialists. A strength of the study is its sample size of nearly 24,000 images, from two VA health systems in this case. The researchers found much inconsistency between what is advertised of the algorithms and their performance in real-world clinical settings, with only one of the seven algorithms studied performing as well as the human screeners. This study is especially interesting for two reasons: (1) It highlights the importance of developing consistent methods in the diagnostic tool kit; conclusions can only be reliable if the methods are reliable. (2) Because this study is a kind of meta-analysis of several algorithms, it demonstrates the value of examining a broad range of information sources to arrive at the most robust method available. Note that through the examination of seven different algorithms, one was discovered to be as reliable as the human screeners, for the particular populations under study.

Air Pollution Risk in AMD
This observational study from the U.K. investigated the correlation between air pollution and increased risk of age-related macular degeneration (AMD), using both subjective and objective measures. The sample size is exceptionally large, comprising 115,954 UK Biobank study participants, who completed self-reported surveys of their AMD diagnosis, as formally diagnosed by a doctor. Among these participants, 52,602 were also assessed of retinal changes via optical coherence tomography (OCT). Estimates of ambient air pollution were from the BioSHaRE-EU Environmental Determinants of Health Project, and matched with official geographic data. In short, this is a robust observational study. The researchers found that people in the most polluted areas were at least 8% more likely to report having AMD. While observational studies cannot confirm cause, the results are not particularly surprising. Previous research, for example, identified smoking as a risk factor for AMD. Air pollution can be thought of as widespread ambient-level "smoking." Again, while the research team caution that observational studies cannot investigate mechanism, they suggest that ambient air pollution could be associated with AMD through oxidative stress and inflammation. Though the results are not unexpected, nor preventable given the ubiquitous challenge of air pollution, this study is a good example of a robust observational study, and highlights the benefit, perhaps even the need, to work toward better air quality for better health.

Ciliary Body as "Niche" for Eye Tissues
This study is interesting for two reasons. Firstly, the ciliary body is not as commonly talked about, unless you specialize in glaucoma, in which case it is talked about a lot. The ciliary body produces aqueous humor, a filtrate of blood, that nourishes the tissues of the eye. Glaucoma is a very complex disease with many contributing factors and consequences, but where the ciliary body is concerned, if too much aqueous is produced, it can lead to elevated intraocular pressure and damage to the optic nerve and other tissues (i.e., glaucoma). This study doesn't take the perspective of the ciliary body's connection to glaucoma though. Rather, it examines the ciliary body as a potential "niche" for eye tissues. The researchers themselves hesitate to call it a reserve for "stem cells," since previous research had disproved that hypothesis. However, they promote the hypothesis of a more indirect role of the ciliary body in maintaining eye tissues by means of the Notch signaling pathway. The details of the involved proteins are described in the article, but the synoposis is that the Notch pathway provides signals that affect the cellular morphogenesis and function of other eye tissues. In other words, the ciliary body doesn't provide the stem cells themselves, but rather regulates development of eye tissues through a signaling pathway. Finally, the research also explored how these proteins are involved in the functioning of the ciliary body itself.

Vision Testing for Early Detection of Parkinson's
The eye is the window to the soul, and also to neurological and systemic health, sometimes quite literally. Earlier in my training, I used to be amazed that funduscopy could detect cardiovascular disease, and then I was amazed that OCT could detect neurological diseases like Alzheimer's. Then the list grew and grew of what this window and this most valued function could allow us to see. The current studies, for example, correlate vision testing with new MRI scanning techniques in the early detection of Parkinson's-related cognitive decline. The connection is very indirect, but the research team found that Parkinson’s patients with visual dysfunction had more decoupling (for our purposes, an MRI-related measure) in memory-related regions in the temporal lobe. Both studies have small sample sizes, of 77 and 88 people with Parkinson's disease. And the connection is very indirect and limited at this point. That being said, with further development, early detection of Parkinson's disease via vision testing is encouraging.

Air Pollution Risk in AMD

Article: Air pollution linked to higher risk of sight loss from AMD
Source: University College London (U.K.), via ScienceDaily
Published: January 26, 2021
Article: Air pollution linked to heightened risk of progressive and irreversible sight loss (AMD)
Source: BMJ Newsroom
Published: January 25, 2021

This observational study from the U.K. investigated the correlation between air pollution and increased risk of age-related macular degeneration (AMD), using both subjective and objective measures. The sample size is exceptionally large, comprising 115,954 UK Biobank study participants, who completed self-reported surveys of their AMD diagnosis, as formally diagnosed by a doctor. Among these participants, 52,602 were also assessed of retinal changes via optical coherence tomography (OCT). Estimates of ambient air pollution were from the BioSHaRE-EU Environmental Determinants of Health Project, and matched with official geographic data. In short, this is a robust observational study. The researchers found that people in the most polluted areas were at least 8% more likely to report having AMD. While observational studies cannot confirm cause, the results are not particularly surprising. Previous research, for example, identified smoking as a risk factor for AMD. Air pollution can be thought of as widespread ambient-level "smoking." Again, while the research team caution that observational studies cannot investigate mechanism, they suggest that ambient air pollution could be associated with AMD through oxidative stress and inflammation. Though the results are not unexpected, nor preventable given the ubiquitous challenge of air pollution, this study is a good example of a robust observational study, and highlights the benefit, perhaps even the need, to work toward better air quality for better health.

My rating of this study: ⭐⭐⭐

Chua SYL, Warwick A, Peto T, et al. "Association of ambient air pollution with age-related macular degeneration and retinal thickness in UK Biobank." British Journal of Ophthalmology.  Published online 25 January 2021. https://doi.org/10.1136/bjophthalmol-2020-316218

Vision Testing for Early Detection of Parkinson's

Article: Eye tests predict Parkinson's-linked cognitive decline 18 months ahead
Source: University College London (U.K.), via ScienceDaily  and Technology Networks
Published: January 19, 2021

Macrostructural white matter changes in Parkinson's
disease patients and low visual performance over time

The eye is the window to the soul, and also to neurological and systemic health, sometimes quite literally. Earlier in my training, I used to be amazed that funduscopy could detect cardiovascular disease, and then I was amazed that OCT could detect neurological diseases like Alzheimer's. Then the list grew and grew of what this window and this most valued function could allow us to see. The current studies, for example, correlate vision testing with new MRI scanning techniques in the early detection of Parkinson's-related cognitive decline. The connection is very indirect, but the research team found that Parkinson’s patients with visual dysfunction had more decoupling (for our purposes, an MRI-related measure) in memory-related regions in the temporal lobe. Both studies have small sample sizes, of 77 and 88 people with Parkinson's disease. And the connection is very indirect and limited at this point. That being said, with further development, early detection of Parkinson's disease via vision testing is encouraging.

My rating of this study: ⭐

Zarkali A, McColgan P, Leyland L, et al. "Visual Dysfunction Predicts Cognitive Impairment and White Matter Degeneration in Parkinson's Disease." Movement Disorders.  Published online 9 January 2021. https://doi.org/10.1002/mds.28477

Zarkali A, McColgan P, Leyland L, et al. "Organisational and neuromodulatory underpinnings of structural-functional connectivity decoupling in patients with Parkinson’s disease." Communications Biology.  4(86). 19 January 2021. https://doi.org/10.1038/s42003-020-01622-9

Toward Reliable Algorithms

Article: AI algorithms detect diabetic eye disease inconsistently
Source: University of Washington Medicine, via NEI
Published: January 5, 2021

Relative performance of human grader compared with AI algorithms

Using artificial intelligence to screen retinal diseases is a promising line of research, with many software algorithms currently in development. The utility of this technology lies in its ability to accurately and reliably detect early disease states, a goal that is constantly improving. The current study examined the effectiveness of seven artificial intelligence (AI) algorithms in the detection of diabetic retinopathy, a common ocular complication of diabetes that could lead to vision loss. The algorithms were compared with human screeners in a teleretinal screening system, and both of these were compared to the standard of diagnostic expertise of retina specialists. A strength of the study is its sample size of nearly 24,000 images, from two VA health systems in this case. The researchers found much inconsistency between what is advertised of the algorithms and their performance in real-world clinical settings, with only one of the seven algorithms studied performing as well as the human screeners. This study is especially interesting for two reasons: (1) It highlights the importance of developing consistent methods in the diagnostic tool kit; conclusions can only be reliable if the methods are reliable. (2) Because this study is a kind of meta-analysis of several algorithms, it demonstrates the value of examining a broad range of information sources to arrive at the most robust method available. Note that through the examination of seven different algorithms, one was discovered to be as reliable as the human screeners, for the particular populations under study. 

My rating of this study: ⭐⭐⭐

Lee AY, Yanagihara RT, Lee CS, et al. "Multicenter, Head-to-Head, Real-World Validation Study of Seven Automated Artificial Intelligence Diabetic Retinopathy Screening Systems." Diabetes Care.  44(5): 1168-1175. Published online 5 January 2021. https://doi.org/10.2337/dc20-1877

Technique for Uniform Integration of Retinal Cells

Article: A rift in the retina may help repair the optic nerve
Source: Johns Hopkins Medicine, via ScienceDaily,  EyeNet,  and Ophthalmology Times
Published: January 14, 2021

Greater cell density dispersal with enzyme pre-treatment

Regenerating the retina and the optic nerve is one of the holy grails in ophthalmology, an endeavor that is still in the nascent phases of study and investigation at this point. The current study by Johns Hopkins Medicine researchers, using mouse retinas in vitro, illustrates an important obstacle to that goal: how to integrate the stem cells (retinal ganglion cells derived from human embryonic stem cells in this case) uniformly. In most cases, the many layers of the retina present a challenge, resulting in clumping of the cells. You can think of them as teeny, tiny tumors. The research team found, however, that areas of their in vitro retina model that were breached by incision showed more uniform integration of the retinal ganglion cells. They hypothesized that the internal limiting membrane (ILM), the innermost layer of the retina composed of footplates of Müller cells, could be the limiting factor. After loosening the ILM with an enzyme and removing it, the researchers found more normal integration of the retinal ganglion cells and establishment of new connections to the rest of the retina. This is one of those studies that seems obvious in hindsight. It makes sense that the ILM would present a barrier. So what was interesting was to see the process unfold of what would happen once the ILM was removed.

My rating of this study: ⭐⭐⭐

Zhang KY, Tuffy C, Mertz JL, et al. "Role of the Internal Limiting Membrane in Structural Engraftment and Topographic Spacing of Transplanted Human Stem Cell-Derived Retinal Ganglion Cells." Stem Cell Reports.  16(1):149-167. 12 January 2021. https://doi.org/10.1016/j.stemcr.2020.12.001

Ciliary Body as "Niche" for Eye Tissues

Article: A Niche for the Eye
Source: Stowers Institute for Medical Research, via Neuroscience News and Research  and NEI
Published: January 1, 2021

Wild type mouse eye morphology

This study is interesting for two reasons. Firstly, the ciliary body is not as commonly talked about, unless you specialize in glaucoma, in which case it is talked about a lot. The ciliary body produces aqueous humor, a filtrate of blood, that nourishes the tissues of the eye. Glaucoma is a very complex disease with many contributing factors and consequences, but where the ciliary body is concerned, if too much aqueous is produced, it can lead to elevated intraocular pressure and damage to the optic nerve and other tissues (i.e., glaucoma). This study doesn't take the perspective of the ciliary body's connection to glaucoma though. Rather, it examines the ciliary body as a potential "niche" for eye tissues. The researchers themselves hesitate to call it a reserve for "stem cells," since previous research had disproved that hypothesis. However, they promote the hypothesis of a more indirect role of the ciliary body in maintaining eye tissues by means of the Notch signaling pathway. The details of the involved proteins are described in the article, but the synoposis is that the Notch pathway provides signals that affect the cellular morphogenesis and function of other eye tissues. In other words, the ciliary body doesn't provide the stem cells themselves, but rather regulates development of eye tissues through a signaling pathway. Finally, the research explored how these proteins are involved in the functioning of the ciliary body itself.

My rating of this study: ⭐⭐

Pang J, Le L, Zhou Y, et al. "NOTCH Signaling Controls Ciliary Body Morphogenesis and Secretion by Directly Regulating Nectin Protein Expression." Cell Reports.  34(2):108603. 12 January 2021. https://doi.org/10.1016/j.celrep.2020.108603

Week in Review: Number 1

Neurological Basis of Charles Bonnet Syndrome
This is a very interesting study both for scientific and clinical reasons. The idea to investigate spontaneous "resting-state" fluctuations in the brain via patients with Charles Bonnet syndrome is excellent. These are patients who experience visual hallucinations, "phantom vision" if you will, after losing sight. Their eyes no longer send input to their brain, but these patients can still "see" with their intact visual cortex. Of note is the finding that brain wave activity reminiscent of slow spontaneous fluctuations emerged just before onset of the hallucination, indicating that the hallucinations were evoked internally and not from external stimuli. Limitations of the study include its small sample size of only five patients with Charles Bonnet syndrome. However, the news coverage of Charles Bonnet syndrome is an excellent opportunity to call attention to this condition. As you can imagine, hallucinations can be a frightening and isolating experience. So awareness of Charles Bonnet syndrome for both trainees and the public increases assurance if they encounter the situation.

Anti-fibrotic Therapy for Glaucoma
In this study, researchers at the University of Burmingham in the U.K. investigated the use of anti-fibrotic low molecular weight dextran-sulphate (ILB) as a potential therapeutic for open-angle glaucoma (OAG) in preclinical rodent models. The researchers state, "[W]e demonstrated that ILB acts, in part, by downregulating transforming growth factor (TGF) β signaling genes and by altering gene expression relating to extracellular matrix dynamics, leading to tissue remodeling, reduced fibrosis and functional tissue regeneration. These observations indicate the potential of ILB^® to alleviate fibrotic diseases." To my knowledge, that would be a novel mechanism to treat OAG by reducing fibrosis of the trabecular meshwork. A major limitation of the approach, however, is that ILB as currently formulated is delivered by daily subcutaneous injection. The researchers are planning to work on a topical "shear thinning fluid gel" as a delivery method.

Early Detection of Cognitive Decline in Type 1 Diabetics
Ocular Coherence Tomography (OCT) and its most recent additional function of angiography (OCTA) have been explored in recent years as a means of early detection of neurodegenerative diseases such as Alzheimer's. The retina, being an extension of the brain (specifically the diencephalon), allows for a unique, noninvasive, and comparatively inexpensive view into conditions that affect the central nervous system. What was new to me, i.e., what this article introduced me to, is the potential connection between diabetes and Alzheimer's disease. The researchers found associations between proliferative diabetic retinopathy (PDR) and certain memory and psychomotor tasks. The small and somewhat cloistered study, comprising 129 participants, investigated the link for people with Type 1 diabetes, but the researchers plan on future studies for the larger population of people who are affected by Type 2 diabetes.

Ultra-Thin Sensor for Smart Contact Lenses
Smart contact lenses "could soon become" mainstream for a long time now. I don't think there is actually anything exciting about this paper. Their contact lens is a prototype design, from an engineering approach, that has not progressed to testing in animal (rabbit) models yet. I suppose thin electrical components would indeed be very important for a device that would sit against a very sensitive ocular surface, but let's say that this design is still in a very early phase at this point.

In the News
An interesting read. A more experienced version of my own thoughts generally, except for the following: “I sometimes tell a patient with complex disease, ‘I’ll teach you something about your disease at every visit, and eventually you’ll have a PhD in glaucoma.’ I’ve even been known to assign homework.” This is a great joke! And I think it’s a great example to show the devaluing of doctoral degrees across the board. Just as it is a rigorous process to earn an MD, it is a rigorous process to earn a PhD. For one, a PhD requires generating new knowledge, not merely disseminating existing knowledge that (prior) PhDs have produced. I don’t want to go as far as to say that it is ironic, but this is something to be mindful of as well.

In Other News
1) Aphantasia
2) Optical illusions and dogs
3) Magnetic sense in birds

Anti-fibrotic Therapy for Glaucoma

Article: Birmingham research paves the way for new anti-fibrotic therapy for glaucoma
Source: University of Birmingham (U.K.)
Published: January 7, 2021
Article: Novel Anti-fibrotic Therapy for Glaucoma
Source: Genetic Engineering and Biotechnology News
Published: January 8, 2021

In this study, researchers at the University of Burmingham in the U.K. investigated the use of anti-fibrotic low molecular weight dextran-sulphate (ILB) as a potential therapeutic for open-angle glaucoma (OAG) in preclinical rodent models. The researchers state, "[W]e demonstrated that ILB acts, in part, by downregulating transforming growth factor (TGF) β signaling genes and by altering gene expression relating to extracellular matrix dynamics, leading to tissue remodeling, reduced fibrosis and functional tissue regeneration. These observations indicate the potential of ILB^® to alleviate fibrotic diseases." To my knowledge, that would be a novel mechanism to treat OAG by reducing fibrosis of the trabecular meshwork. A major limitation of the approach, however, is that ILB as currently formulated is delivered by daily subcutaneous injection. The researchers are planning to work on a topical "shear thinning fluid gel" as a delivery method.


Edit: Another potential drawback of using anti-fibrotic agents is the possibility of causing tissue damage. For example, use of mitomycin C (MMC) after pterygium excision can sometimes result in corneoscleral melt. At the same time, subconjunctival MMC has been explored in trabeculectomy.

My rating of this study: ⭐⭐

Hill LJ, Botfield HF, Begum G, et al. "ILB® resolves inflammatory scarring and promotes functional tissue repair." npj Regenerative Medicine.  6(3). 7 January 2021. https://doi.org/10.1038/s41536-020-00110-2

Neurological Basis of Charles Bonnet Syndrome

Article: A Brain Mechanism for 'Vision' in the Blind is Revealed
Source: Weizmann Institute of Science, via ScienceDaily  and Technology Networks
Published: January 7, 2021

The visual centers in those seeing a film or imagining as instructed had similar timing in their brain activity,
while those experiencing spontaneous hallucinations showed a gradual increase in slow fluctuations.

This is a very interesting study both for scientific and clinical reasons. The idea to investigate spontaneous "resting-state" fluctuations in the brain via patients with Charles Bonnet syndrome is excellent. These are patients who experience visual hallucinations, "phantom vision" if you will, after losing sight. Their eyes no longer send input to their brain, but these patients can still "see" with their intact visual cortex. Of note is the finding that brain wave activity reminiscent of slow spontaneous fluctuations emerged just before onset of the hallucination, indicating that the hallucinations were evoked internally and not from external stimuli. Limitations of the study include its small sample size of only five patients with Charles Bonnet syndrome. However, the news coverage of Charles Bonnet syndrome is an excellent opportunity to call attention to this condition. As you can imagine, hallucinations can be a frightening and isolating experience. So awareness of Charles Bonnet syndrome for both trainees and the public increases assurance if they encounter the situation.

My rating of this study: ⭐⭐

Hahamy A, Wilf M, Rosinl B, et al. "How do the blind ‘see’? The role of spontaneous brain activity in self-generated perception." Brain. 144(1):340–353. January 2021. https://doi.org/10.1093/brain/awaa384

Ultra-Thin Sensor for Smart Contact Lenses

Article: Manufacturing process of ultra-thin sensor for smart contact lenses
Source: University of Surrey (U.K.), via ScienceDaily
Published: January 6, 2021

Optical transmittance test and in vitro cytotoxicity test of the smart contact lens

Smart contact lenses "could soon become" mainstream for a long time now. I don't think there is actually anything exciting about this paper. Their contact lens is a prototype design, from an engineering approach, that has not progressed to testing in animal (rabbit) models yet. I suppose thin electrical components would indeed be very important for a device that would sit against a very sensitive ocular surface, but let's say that this design is still in a very early phase at this point.

My rating of this study: ⭐

Guo S, Wu K, Li C, et al. "Integrated contact lens sensor system based on multifunctional ultrathin MoS2 transistors." Matter.  4(3):969-985. 3 March 2021. https://doi.org/10.1016/j.matt.2020.12.002

Early Detection of Cognitive Decline in Type 1 Diabetics

Article: Routine eye scans may give clues to cognitive decline in diabetes
Source: Joslin Diabetes Center at Harvard Medical School, via ScienceDaily
Published: January 4, 2021

Ocular Coherence Tomography (OCT) and its most recent additional function of angiography (OCTA) have been explored in recent years as a means of early detection of neurodegenerative diseases such as Alzheimer's. The retina, being an extension of the brain (specifically the diencephalon), allows for a unique, noninvasive, and comparatively inexpensive view into conditions that affect the central nervous system. What was new to me, i.e., what this article introduced me to, is the potential connection between diabetes and Alzheimer's disease. The researchers found associations between proliferative diabetic retinopathy (PDR) and certain memory and psychomotor tasks. The small and somewhat cloistered study, comprising 129 participants, investigated the link for people with Type 1 diabetes, but the researchers plan on future studies for the larger population of people who are affected by Type 2 diabetes.

My rating of this study: ⭐

Fickweiler W, Wolfson EA, Paniagua SM, et al. "Association of Cognitive Function and Retinal Neural and Vascular Structure in Type 1 Diabetes." The Journal of Clinical Endocrinology & Metabolism.  Published online 30 December 2020. https://doi.org/10.1210/clinem/dgaa921

In the News

Article: Dr. TikTok, Dr. Google, and You
Publication: EyeNet (American Academy of Ophthalmology)
Published: c. January 6, 2021

This blog is specialized in commentary about more exoteric interest in eye care, that is, developments that reach media attention and subsequently the public. Publications by magazines and journals in ophthalmology and optometry are of great interest to a trainee, but the magnitude and the beauty of such information should not be the purview of this review. That being said, I realized retroactively that my first commentary about an article related to eye care published this year was an opinion piece in EyeNet, a publication of the American Academy of Ophthalmology. As this is an archive of my thoughts, my journey, as much as it is a repository of news articles, I wanted to record those words here as well. It marked a very personally meaningful topic and discussion.

An interesting read. A more experienced version of my own thoughts generally, except for the following: “I sometimes tell a patient with complex disease, ‘I’ll teach you something about your disease at every visit, and eventually you’ll have a PhD in glaucoma.’ I’ve even been known to assign homework.” This is a great joke! And I think it’s a great example to show the devaluing of doctoral degrees across the board. Just as it is a rigorous process to earn an MD, it is a rigorous process to earn a PhD. For one, a PhD requires generating new knowledge, not merely disseminating existing knowledge that (prior) PhDs have produced. I don’t want to go as far as to say that it is ironic, but this is something to be mindful of as well.

Dear Reader

Welcome to Review of Optology

In the interest of supplementing eye care presence, unarguably a source of optimism during challenging times, I have started this personal blog. There are more established magazines in ophthalmology and optometry for a more esoteric audience of eye care providers. This blog serves as an archive of research progress in eye care that reaches media attention, the public, in 2021. As an aspiring clinician/physician-scientist, I think it is beneficial to be informed about the kind of eye care exposure that reaches patients, in order to answer their questions in a more quotidian way. And as with any endeavor that contains a personal touch, this blog also documents my growing familiarity with the field, and my thoughts about it during an early point in my career. I take care to convey information accurately and with citations where appropriate, but take these words with a grain of salt as coming from a student who is still training and not yet licensed. If you do find errors, please leave a comment so that they may be revised accordingly. Happy reading.