the blind MENACE
and why we invested in EARLYSIGHT
SEPTEMBER 2020
by Ferran Martí, Marta Gaia Zanchi
There is about one out of three chances that you are reading this post through either glasses or lenses. If you live in Asia, I could guess you are wearing either, and get it right 50% of the times. A lot has been said about the drawbacks of spending most of our day in front of a screen, but few realize the scale of the incoming “visual” pandemic. It is estimated that by 2050, more than half of the global population will suffer some kind of visual impairment: myopia, hyperopia, or presbyopia.
Myopia is especially concerning in many East Asian countries, where the incidence is exceptionally high in the youngest generation. A recent study (2018) found that the prevalence of myopia among 20 years old in South Korea is of 97%, followed closely by Hong Kong (80%) and Singapore (74%). Although it doesn't sound alarming to have myopia — especially if you can afford LASIK surgery — it is one of the biggest risk factors for having a more serious eye disease later in life.
High myopia (prevalence 0.9%–3.1%) is particularly worrisome. It comes with an increased risk of cataract development, retinal detachment, glaucoma, and macular degeneration. Most of the advanced eye diseases can result in blindness and even though the current prevalence of high myopia is not very high, soon 0.45%-1.5% of the global population may be affected. Unfortunately, this growth will persist and even accentuate in the future; the prevalence of high myopia in high school graduates of some East Asian countries is already reaching 10%-20%.
There are of course correlating trends that contribute to this forecast. We should not only blame video games and TikTok: an aging population and comorbidities like diabetes are also sponsoring this change. Diabetes has its own proprietary eye disease, diabetic retinopathy (which can also cause complete vision loss). Most are aware that diabetes is trending upwards; less known is that almost a third of diabetics will suffer vision-threatening diabetic retinopathy at some point in their life.
Now that we can see this tidal wave coming, we should question ourselves how we can prepare for it. Let’s take a deeper look:
Diabetic retinopathy
Diabetic retinopathy (DR) is growing along with the increasing prevalence of diabetes, where microvascular changes resulting from poorly controlled blood sugar may damage blood vessels in the retina and lead to severe vision loss or blindness. It remains a leading cause of visual loss in working-age populations. The diagnosis of DR is made by clinical manifestations of vascular abnormalities in the retina.
The most common cause of vision loss in patients with DR is diabetic macular edema (DME). DME is characterized by swelling or thickening of the macula due to sub- and intra-retinal accumulation of fluid in the macula triggered by the breakdown of the blood-retinal barrier. DME can occur at any stage of DR and cause distortion of visual images and a decrease in visual acuity.
Preventing diabetic retinopathy from developing into visual impairment and blindness is possible. In the diabetic retina, cellular changes in the retinal pigment epithelium (RPE) and neurons occur before vision loss or diabetic retinopathy can be identified clinically.
If detected at an early stage, lifestyle adjustments and other preventive methods can significantly change the progression of the disease. Intravitreal administration (eye injection) of anti-VEGF agents is currently the mainstay of therapy for both early and advanced stages of DR.
Glaucoma
Glaucoma is caused by raised intraocular pressure. It is this raised pressure that compresses and damages the optic nerve. Once the optic nerve is damaged, it fails to carry visual information to the brain and this results in loss of vision. The exact pathophysiology contributing to this is not fully understood. It is believed that the raised pressure on the retina causes the ganglion cell axons in the sensitive retina to die off (retinal ganglion apoptosis) and in addition the small blood vessels of the retina are also compressed depriving it of nutrients. Ultimately, this leads to irreversible blindness if left untreated.
Glaucoma is a disabling disease that mostly targets the elderly. With increasing population sizes, ageing populations, extended life expectancy, and increased incidence of myopia, glaucoma is assuming greater proportions in the burden of disease. It is estimated that currently 76M people worldwide have glaucoma in 2020, and this number is expected to increase to 112M by 2040.
The current gold standard for glaucoma treatment is regularly using Glucomite, which is an eye drop solution that decreases eye pressure and stabilizes disease progression. Glaucoma is generally asymptomatic until late in the disease, at which point permanent visual problems arise. Therefore, early detection and appropriate treatment is essential.
Age-related macular degeneration
Age-related macular degeneration (AMD) is a disease that affects the retina, a layer at the back of the eyeball. This layer contains light-sensitive cells. Although the etiology and pathogenesis of AMD remain largely unclear, a complex interaction of genetic and environmental factors is thought to exist. Visual impairment in AMD is caused by the loss of a cell type called retinal pigmented epithelium (RPE) cell, which supports and nourishes the light-sensitive photoreceptor cells in the retina of the eye.
AMD affects, by definition, older individuals. Early stages of this disease are mostly asymptomatic until they (slowly) progress to late stages of the disease, which can cause severe visual loss. One in four Europeans over the age of 60 is affected by AMD. AMD is also responsible for approximately 40% of visual impairments and 45% of blindness cases in the United States today. Worldwide, almost 200 million people are affected by AMD today, and this number is anticipated to increase to 288 million by 2040.
Late stage AMD can either present itself as dry or wet AMD, while dry AMD accounts for almost 90% of the cases, wet AMD is responsible for most vision impairment cases. There is currently no effective treatment for the most common form of this disease in its late form (dry AMD). The gold standard for wet AMD is the application of intravitreal (IVT) anti-vascular endothelial growth factor (VEGF) drugs via periodic intravitreal injection, which relies on early diagnosis as is focused on halting or slowing down the diseases. A new approach to treating AMD involves the transplantation of RPE cells derived from either human embryonic or induced pluripotent stem cells. For early stage AMD, the treatment options are related to tackling risk factors such as smoking or vitamin deficiency. The early identification of AMD in patients is crucial in delivering early treatment.
What do these conditions have in common?
- they are rising in prevalence in all countries
- they have no effective, simple treatment options when diagnosed at an advanced stage
- if detected early, their progression can be effectively halted with preventive strategies
- in all three affections, retinal cellular changes occur before the diseases can be identified clinically (changes in the RPE layer for DR and AMD and in the NFL’s for glaucoma)
In diabetic retinopathy, glaucoma, and age-related macular degeneration, retinal cellular changes occur before the diseases can be identified clinically.
Why is it so difficult to diagnose early?
Early detection of DR, glaucoma, and AMD hinges on the possibility to directly observe or indirectly measure early changes happening at the cellular level in the retina, in-vivo. Direct observation aided by imaging biomarkers to detect lesions before irreversible visual loss occurs is, in principle, the holy grail. It is also complex. The retina is an intricate tissue composed of many layers. Individual cell imaging is very challenging for many reasons, including ocular aberration reducing the lateral resolution, as well as eye-motion artifacts and a lack of contrast of transparent cells. Another limitation is that most of the light entering the pupil is either absorbed or reflected at the interface of photoreceptor segments, overwhelming the weak signal backscattered from the neuronal or RPE cells. The photoreceptor signal is maximum for an illumination beam entering the center of the eye pupil and decreases sharply when entering at its edge.
This forces doctors to subjectively “interpret” the images due to a lack of quantitative data and having to use different imaging modalities in order to obtain a single final diagnosis. The lack of data is a consequence of the absence of quantitative measurements that could be linked to clinical endpoints (i.e. structural changes of the RPE layer of a certain form will lead to AMD). This problem is exacerbated by the need to use different imaging modalities (fundus photography examination, OCT, tonometry, etc) in order to get a final diagnosis, the reason being that none of these tools has enough sensitivity and specificity for making a diagnosis when used alone.
For example, fundus photography (FP) is one of the most common imaging modalities that can be utilized to detect retinal changes. It requires a fundus camera, a specialized low power microscope with an attached camera. It is frequently performed by ophthalmologists and optometrists as part of a dilated eye examination. However, due to all the limitations and complexities mentioned above, FP by itself has a low diagnostic sensitivity and is generally effective only when the disease has progressed to a stage when the patient is already reporting vision loss, to the point that some US insurers consider FP experimental and investigational for screening in asymptomatic persons without signs or symptoms of disease (which is another way to say, FP of a normal retina is considered not medically necessary).
The current gold standard for diagnosis is based on combining different imaging modalities like FP, Optical Coherence Tomography (OCT) and Scanning Laser Ophthalmoscopy (SLO). However, these can image only small areas of the retina at a time (with a higher sensitivity), and have important drawbacks limiting the clinical adoption. For example, the method of stabilizing the patient (elders), who are required to bite a bar for up to 15 minutes, while being scanned in order to reach the high stability required.
Overall, these factors make the end diagnosis very dependent on doctors experience, and complicates building a collective database of endpoints for early detection
The imaging challenge remains unsolved today and in-vivo early diagnosis of diabetic retinopathy, glaucoma, and AMD, remains a largely unaddressed need. In principle, imaging of the neuronal or RPE cells could allow cell quantification in the clinical setting and bring clinical diagnosis of eye diseases to a new level. Cracking the challenge would mean not only early diagnosis, but also, the possibility to follow the time course of retinal diseases, understand their pathophysiology, and evaluate treatment response and disease progression.
What we can do as investors?
Besides the obvious move of investing in LASIK centers in developing Asian countries, we have been looking for solutions that will cushion the impact of the significant increase in eye diseases our society will have in the coming decades.
It would be a mistake to reduce the solution of this problem to meeting certain technological thresholds in terms of illumination, sensitivity (signal-to-noise ratio), and imaging areas. The right technology needs to meet patients at the right time and in the right setting in order to become a solution. Today, despite recommendations for routine eye examinations every one or two years, patients wait until they lose the vision in one eye before they come for a check-up of the other eye. Solving the problem requires the development of imaging biomarkers that are accepted and adopted in routine eye health screenings, and, patients who are educated enough about the risks of blindness associated with diabetes and old age to attend those screenings.
For us, the right solution is: EARLYSIGHT
a new way to detect changes in the retina at the cellular level in patients who do not yet present with vision loss symptoms during routinary ophthalmic examinations.
