Freckle in the wrong place

Juan Ding, OD, PhD

Choroidal nevus is a collection of pigmented cells in the choroid, a thin layer of tissue just underneath retina. In layman’s term we often refer nevus to a ‘freckle’. Traditionally choroidal nevus is considered a benign condition. True, only about 1 in 8000 of nevi will turn into a melanoma. So the vast majority of choroidal nevus is benign. But does that mean that they don’t cause a problem? The answer is it depends. For some unfortunate people, it does cost their vision.

I recently had the pleasure of meeting a gentleman in his 60s who had vision loss in his right eye for 20+ years. The cause? A choroidal nevus that happened to be in the worst location, under the fovea. This is where our central vision is, so as a result of a nevus growing there his visual acuity was 20/400. He used to see a renowned ocular oncologist for many years and it remained stable for years, meaning it’s not turning into a melanoma. However, due to the unfortunate location of this freckle, his right eye cannot see details at all.

So given that this is chronic and stable, he was in the clinic actually complaining about something else. He has developed double vision and had to pull over while driving because of seeing two roads. Important to note, even though the nevus took away his central vision, his peripheral vision was quite normal and he relied on peripheral vision of both eyes to drive. I measured and found that he had a mild esophoric deviation, this means that his eyes are converging a little bit too much towards each other. But normally this is a small misalignment and most people compensate for this well. In his situation though, because his right eye does not see too well, it is not able to send a clear signal to the brain which then in turn is not able to feed back to both eyes to fuse the images into single vision. 

Solution to this double vision issue? A small amount of prism made it go away.

So how does this freckle that has such a big impact on his vision look? Figure 1 below is a color photo of this freckle, which was in the center of the eye.

Figure 1. Fundus image of a choroidal nevus at fovea. The arrow points to a black blob which is the nevus.

Figure 2 below shows the cross section showing how thick this freckle is.

Figure 2. Cross section view of the fovea with nevus under the retina.

So are choroidal nevi good or bad? It appears that they may not be as benign as we often believe. A retrospective medical review looked at more than 3000 eyes with stable choroidal nevi and found that of those that had nevi under the fovea, 26% developed vision loss over 15 years [1]. And it is not even that rare to have nevi under fovea, about 6% of choroidal nevus patients in this review series had their nevi right under the fovea [1]. So what is the mechanism for reduced vision if the nevi are stable? It appears that even though the size and thickness of the nevi may not change over time, they may cause edema of the retina, detachment of the RPE and thinning of the photoreceptors. If these changes occur at the fovea, then you get reduced central vision; if in the periphery as in most cases, there may be a peripheral visual field defect. It is not rare to have visual field defects from choroidal nevi; in fact, it is quite common to have field defects, ranging from 38% to 85% depending on the population analyzed [2, 3]. 

In my patient’s case, you can see that it is not even a large or thick nevus. However, it is right in the fovea and there is a thin layer of fluid between RPE and the retina, and the foveal region looks significantly thinned out (Figure 2).

It is easy to overlook choroidal nevus, because it is so commonly seen in an eye doctor’s office, and it rarely converts to melanoma. However, it is important to realize that even though it is not a cancer, it is a tumor all the same. It is not just an inert growth under the retina, but rather can often slowly but actively cause changes to the retina, affecting its function. If it happens to be under the fovea, significant vision loss can happen to patients. 

References

[1] Shields CL, Furuta M, Mashayekhi A, et al. Visual Acuity in 3422 Consecutive Eyes With Choroidal Nevus. Arch Ophthalmol. 2007;125(11):1501–1507. doi:10.1001/archopht.125.11.1501

[2] Tamler  EMaumenee  AE A clinical study of choroidal nevi.  AMA Arch Ophthalmol 1959;62 (2) 196- 202

[3] Flindall  RJDrance  SM Visual field studies of benign choroidal melanomata.  Arch Ophthalmol 1969;81 (1) 41- 44

My eye is a mess

It was the end of the clinic day. I finished my last patient’s chart and was ready to go, before noticing that a procedure result just popped out. I clicked into it, it’s a visual field testing result of a 60 year old gentleman I saw a few days ago. He complained that after ceiling plaster dropped into his right eye, his right eye could not see in the periphery. 

This is a regular patient of mine. When the plaster incident happened 2 weeks ago I was on vacation so he saw another doctor in the practice. He initially went to the emergency room, received plenty of eye washing and antibiotic eye drops. He then saw my colleague two more times and according to the notes, his eye was recovering well. When I saw him his right eye was white and quiet, cornea completely healed, no defect, scar or edema. Internal structures of the eye were also normal. His visual acuity was 20/20. He did have trouble seeing fingers on the right side in his right eye. But his optic nerve appeared healthy. He’s a glaucoma suspect at baseline and I have been monitoring this over 2 years. The RNFL OCT that measures nerve thickness was stable to before. So the question is, why would he have a new visual field defect? 

Dr. House says, patients always lie. He insisted that this problem came about after the plaster accident. ‘My eye is a mess’, he said. ‘First it hurt like hell for three whole days, then I cannot see out of my right eye’.

For a chemical injury to hurt the optic nerve, there had to be other signs, like inflammation in the anterior chamber, vitreous and retina. But there was none. 

Also it made no sense that he’s losing vision from glaucoma progression, which is typically slow. 

It happened suddenly so it’s not a tumor pressing onto his optic nerve either.

Could he be exaggerating because he was frustrated about the whole thing? After all, he waited in the ED for 4 hours, and he was on hold for scheduling to see eye doctors for a long time and did not get call backs. 

Of course a formal visual field testing is in order. And that result just arrived in my inbox.

One peek at it, I knew I would not be going home any time soon (Figure 1). 

Figure 1. Visual field testing result of the right eye (top image) and the left eye (bottom image). The dark color indicates that the patient was not able to see in that part of the visual field.

The right eye was not seeing the right side of things, just as he complained. Problem is, his left eye was also missing quite a few things on the right side. The left eye was much less severe and it was not picked up in the confrontational visual field test we did in the exam room. 

This is what we call a hemianopsia (Figure 1), and it’s an emergency because a stroke was on the differential list. 

I called him immediately. I advised him to go to ED immediately, even though he did not have any other stroke symptoms. He does have a history of heart attack and has a pacemaker.

I then called his primary care doctor and she was going to follow up with him. 

Hemianopsia happens when one side of the brain that is in charge of vision becomes defective. This can happen with a stroke, a tumor or inflammation. In fact, according to the Cleveland Clinic, 70% of hemianopsia is due to stroke, 15% from brain tumors and 5% from bleeding in the brain [1].  Patients’ eyes can be completely normal, because the problem happens in the brain. It can happen as the only abnormal finding, without other telltale signs of a stroke. The dangerous part is that it is easily missed and over-looked, because the visual acuity can be 20/20, and you don’t find anything wrong with the eyes. Further, patients often describe this in a non-specific manner. Over the years I have heard ‘floaters in the left eye’, ‘my right eye is blurry’, or ‘my eye is a mess’. It is vitally important to always do a confrontational visual field and if suspicious, a formal visual field to clarify and confirm. Otherwise a critical, potentially life-threatening condition may be missed.

Hemianopsia from a stroke may improve over time though may not return to baseline completely, depending on the severity of the damage. Most start recovery within months of the stroke, but it may take up to 18 months for maximum recovery to occur [1]. I will see my patient in 3 months to check his visual field again. To help with vision deficit, certain prism may be used to expand the visual field, but that would the subject of another article.

References: 

[1] https://my.clevelandclinic.org/health/diseases/15766-homonymous-hemianopsia-

Scary- my eye is popping out!

Can your eye really pop out of your head? You see that in cartoons but can it happen to real people?

A group of our optometrist friends were chatting yesterday about this. One said that one of her patients told her about this history, and that she heard about this three times now from different sources. She did not see it herself but she was curious about it. 

I remember such an incident of one of my patients. It was an African American lady in her 30s in good health. I was holding her upper eyelid up in order to examine the lower part of her retina, when she suddenly screamed and screamed, ‘Oh my god, my eye pops out!’ she screamed repeatedly. I almost panicked by her screaming. But I looked at her and saw that her eyelid was retracted and got stuck behind the eyeball and the eyeball was fine. So I gently massaged her upper lid and asked her to blink. A few seconds later her eyelid came down and all was normal. At this time, my technician who was working in the next room came knocking on the door and asked if everything was OK. I told her that all was good. My patient was a little embarrassed about her reaction and calmed down. The rest of the exam was uneventful and the patient left with an essentially normal eye exam.

Having that experience made me cautious about manipulating patients’ eyelids thereafter. Some people’s eyelids are loose and you can easily flip them. If they also happen to have protruding eyeballs, then the lids can get stuck behind the eyeball, which further limits the eyeball from moving.

I thought that eyeball popping out was a misnomer, it’s rather the eyelid going behind. If you think about it, the eyeball is secured by 6 external eye muscles to the eye socket, and the optic nerve which is like a cable also connects the eyeball to the brain. How can you easily get the eyeball out of the socket? If you could, I imagine there would be a lot of damage, potentially to the optic nerve and can cause vision loss. Sure with strong force such as in trauma, eyeballs can fly out of the socket, even the brain can burst out of the skull. But for a person to have spontaneous eyeball popping out, that would require a very high pressure behind the eye, and it just does not happen that easily.

However, it turns out that I did not know this subject well enough. It truely can happen in a condition called globe subluxation. Yes the eyelid could be stuck behind, but the eyeball is really out of (maybe partially) the eye socket. This can be caused by trauma, but it can also happen from triggers such as eyelid rubbing or straining badly. 

Here is a photo from a real patient who suffered from globe subluxation. This is from a recent publication of a case report and all copyright belongs to the original authors and journal [1].

Figure 1. Spontaneous globe subluxation in a middle-aged woman [1]. Copyright in reference [1]

Quite a scene right? No doubt this is very unnerving to the patient as well as to the doctor!

According to this article, the most common risk factor associated with spontaneous globe luxation (SGL) is proptosis (that just means the eyeball is bulging) from having shallow orbits (eye sockets) or things growing in the back of the eyeball. The most common stuff growing behind the eyeball is actually from a condition called thyroid eye disease, in which excess fat and fibroblasts accumulate in the eye socket. Interestingly people with African descent tend to have shallow eye sockets and their eyes generally appear a little more bulging due to this reason. Other factors include loose tissues and muscles supporting the eye, loose eyelid, or having too much fat in the eye socket due to obesity. 

So what harm does globe subluxation do? Seems obvious that an eyeball hanging out is an eyeball not working well for its function, which is seeing. Indeed, if this is severe or goes on for a long time, the optic nerve may be damaged, resulting in vision loss, sometimes permanent. On the other hand, when the eyeball is out, it’s not covered by the lids, and the surface drys out quickly, which can cause pain, light sensitivity and blurry vision immediately. If you think about it, our eyelids really do a good job protecting the eyeball, you can simply close your eyes. With eye protruding out like in the photo above, the eyeball is left there to dry up and exposed to the outside world should something hit or scratch on it.

So how do you pop the eyeball back in? First, relax. Then ask the patient to lay down with face up (or recline on your exam chair). Ask the patient to look down while you gently apply pressure on the globe downward and inward. You can use a cotton swab to roll the eyelids back while applying pressure to the globe [2]. 

Lastly, after the eye goes back to normal, we should probably do some investigation as to why it’s out in the first place. As mentioned above, thyroid eye disease, floppy eyelid syndrome, or maybe even a tumor behind the eye can make a patient prone to developing globe subluxation. So these need to be ruled out.

When I think back about my patient, I wonder if that’s actually not the first time this happened to her. She could not see her eyes, how would she know her eye popped out if she had no prior experience? To me, that was not a true globe subluxation, but rather an eyelid retraction. But her eyelid being so loose and retracting easily should also raise some suspicion on my part to work up further for thyroid eye disease and floppy eyelid syndrome.

According to literature, this is a very rare condition. However it can happen when maneuvering eyelids including when rubbing or inserting/removing contact lenses. I feel lucky that so far I have not encountered this with numerous patients that I have worked with for contact lens I/R training. But the moral of the story is that don’t touch your eyes, cause they can pop out (just exaggerating). 

References

[1] Yadete, T., Isby, I., Patel, K. et al. Spontaneous globe subluxation: a case report and review of the literature. Int J Emerg Med 14, 74 (2021). https://doi.org/10.1186/s12245-021-00398-x

https://intjem.biomedcentral.com/articles/10.1186/s12245-021-00398-x

[2] https://www.reviewofoptometry.com/article/how-to-handle-globe-subluxation

An unusual case of presbyopia

This well-dressed, well-groomed 42 year old woman came to my office complaining about blurry near vision for the past week. Her vision was 20/20 in each eye without any correction for distance. At near she did have difficulty and required a +1.75 add to read 20/20. Her eyes were healthy otherwise. I came to the only diagnosis that is presbyopia and educated her on this subject. 

She never wore glasses before and had always had good vision. She was quite depressed about the prospect of aging and could not believe that this happened to her.

To me it’s such a normal diagnosis, I did not think twice about it. Too bad this happened to her, but won’t this happen to everyone eventually?

I gave her a prescription of progressive lenses and asked to see her again in 1 year.

4 days later, she came to my office again. The appointment note said to re-evaluate vision. I was surprised and annoyed – why wouldn’t people accept the fact that they are getting older?

She sat down and started with “ Doctor, I have some good news that will change the prescription you gave me last time.” 

“What kind of good news will that be?” I thought to myself.

“My husband found this patch behind my ear that I forgot to take off after our vacation…”

“Oh my god” I said to myself silently. Of course it’s the scopolamine patch that everyone forgets about, which then gets absorbed by the skin and works to knock out the accommodation of the eyes, leading to the blurry near vision.

So the mystery is solved. This is not a usual case of presbyopia after all. My patient is a victim of drug-induced cycloplegia. 

She does have some eye strain after using computers for a long time. So I gave her a prescription of +1.00 add for near work as needed. I did tell her about the OTC readers, but she preferred prescription glasses.

Reflecting back on her case, her symptoms were newly onset, almost sudden onset, this is kind of a red flag, because presbyopia comes up gradually. Further, she’s not a latent hyperope, so +1.75 add was too high for her age. It’s her age that fooled me. If she were 20 years old, I would have investigated further.

Lesson learned: if accommodation is not what it should be, always ask about scopolamine patch. 

Should you take antibiotics with that bump on your eyelid?


Eyelid bumps, sometimes called styes, are very common. They are usually red, sometimes painful, and sometimes will stay there for months. Sometimes these bumps keep coming back. There are two major types of eyelid bumps, one called hordeolum and the other chalazion. Both are caused by blocked oil glands in the eyelid, called meibomian glands. This gland secretes oil through an opening on the eyelid margin (that’s the thin edge at the base of the eye lashes). This oil is really important to keep our tears in good quality (refer to some of my previous posts on meibomian gland and dry eye). When the opening is blocked, the oil backs up inside the gland, and forms a bump. In terms of the hordeolum, this oil content is infected by our normal skin bacterial flora, so this is technically an infection, but it’s often self-limited. In terms of the chalazion, this content undergoes an inflammatory process but not infection. This is one of the reasons that the hordeolum is often painful and chalazion is not.

Regardless, given similar etiology, the treatment is to open up the blocked gland and let the oil flow again. And one effective way to do this is to apply a warm compress on the bump, this allows the content to soften and drain more easily.

However, doctors sometimes prescribe antibiotics, be it an oral pill, or an eye drop or ointment. So the question is: is it necessary to take antibiotics for hordeolum or chalazion?

There is a recent research [1] that retrospectively looked at more than 2,712 cases of these two conditions, some of these were treated with warm compress alone, some with antibiotics alone, and some with warm compress as well as antibiotics. The final outcome shows that all 3 treatments led to a similar rate of resolution, over 70% for chalazion and over 90% for hordeolum. This shows that additional topic antibiotic drops/ointment or oral antibiotics do not really give additional benefit. Warm compress alone works just as well. It’s interesting that antibiotics alone also have a good success rate, though only 1% of patients were treated by this method. 

The limitation is that this is a retrospective study. There is a randomized controlled trial looking at chalazion and found similar outcome: antibiotics do not give additional benefit in addition to warm compress [2].

Given the rampant antibiotic resistance these days, I think it’s reasonable to apply just warm compress and not start antibiotics automatically for every eyelid bump.

References: 

[1] Alsoudi, Amer F. B.S.; Ton, Lauren B.S.; Ashraf, Davin C. M.D.; Idowu, Oluwatobi O. M.D.; Kong, Alan W. B.S.; Wang, Linyan M.D.; Kersten, Robert C. M.D.; Winn, Bryan J. M.D.; Grob, Seanna R. M.D.; Vagefi, M. Reza M.D. Efficacy of Care and Antibiotic Use for Chalazia and Hordeola, Eye & Contact Lens: Science & Clinical Practice: November 8, 2021 – Volume – Issue – doi: 10.1097/ICL.0000000000000859

[2] Wu AY, Gervasio KA, Gergoudis KN, Wei C, Oestreicher JH, Harvey JT. Conservative therapy for chalazia: is it really effective? Acta Ophthalmol. 2018 Jun;96(4):e503-e509. doi: 10.1111/aos.13675. Epub 2018 Jan 16. PMID: 29338124; PMCID: PMC6047938.

Myopia progression in young adults

It is very common to see children develop myopia and get worse over time. We know that adults typically don’t have myopia progression because their eyes have fully developed and stopped growing, just like their height. However, in real life, some young people do have increased prescription numbers year after year. Researchers observed that college students continue to have increased myopia previously in Europe and the US. Now a new study [1] from Australia followed young people for 8 years (20 to 28 years of age) and confirmed this finding.

Among 516 subjects with no myopia, 14% were found to have developed myopia after 8 years. Among 698 subjects with myopia less than 6 diopters, 0.7% were found to have developed high myopia (more than 6 diopters) after 8 years. Among 691 subjects who were included in the progression analysis, 37.8% had myopic shift of 0.50 D or more. On average, the myopic progression was -0.04 D (ranging -0.03 to -0.06) per year, and axial length increase was 0.02 mm (0.014 to 0.025) per year. 

We can see that this is a small myopic shift, but it is a true shift and statistically significant.

So what kind of people are more prone to develop this myopic shift as adults? They found that East Asians were more likely than whites, females were more likely than males, those with myopic parents were more likely than those without myopic parents, and those who spend less time outdoors were more likely to develop more myopia as adults. Interestingly, they used an objective way to evaluate outdoor activities, conjunctival ultraviolet autofluorescence area, as the larger the area, the longer exposure to the sun.

These are also the risk factors of myopia progression in kids. So having myopic parents, being a female, being an East Asian, and spending less time outdoors are just not good in terms of myopia, kids or adults alike. You will notice that no one can change the first 3 risk factors, but the last one is highly modifiable. 

The take home message is that myopia progression can continue into adulthood, though at a much slower rate. And spending more time outside is always a good thing if you don’t want your glasses to get thicker.

Reference: 

[1] Lee SS, Lingham G, Sanfilippo PG, et al. Incidence and Progression of Myopia in Early Adulthood. JAMA Ophthalmol. Published online January 06, 2022. doi:10.1001/jamaophthalmol.2021.5067

Normative database of axial length in children

This article is for eye doctors who use axial length routinely in their myopia control clinic, and certain parents who are curious and/or obsessed with the numbers of their children’s eyes (trust me, I do encounter these parents weekly).

Briefly, axial length is the length of the eyeball, which grows throughout the first 18 years of a person’s life. It is normal for the eyes to grow longer over time until it stabilizes at adulthood. But the growth can be accelerated resulting in long axial length in myopia. Therefore in many eye doctors’ offices, this value is measured to monitor myopia development and record whether myopia control is successful with a given intervention.

Understandably, it is important to have a normative database to evaluate whether a given child’s axial length is normal. Basically, there have been quite a few published articles on typical axial lengths of children of various ages. I have put together data from two recent studies that encompass ages from 3 months to 18 years below. The mean values for a given age are listed, as well as standard deviation. Table 1 is from Florida, USA, on 165 American children (Miami study) [1] and table 2 is from Shanghai, China, on 14,127 Chinese children (Shanghai study) [2]. Obviously the 2nd study is a much larger scale, and I really am very excited about this very new data. The first study, though with much fewer subjects, is quite remarkable as well in my opinion, as it examined kids as early as 3 months, understandably not easy to do and not many other studies were able to look at this age group. So I am keeping these two tables as a reference for my own patients. 

For those who are more visual, Figure 1 and Figure 2 are these numbers plotted in graphs.

Table 1. Axial length of 3 month to 7 years old children (Miami study)

Table 2. Axial length of 4 to 18 years old children (Shanghai study)

Figure 1. Axial length mean (solid line) and 95% confidence interval (dotted lines) in 3 month to 7 years old children (Miami study).

Figure 2. Axial length ranges in 4 to 18 years old children (Shanghai study).

A few things to keep in mind from these data. 

First, these are from two distinct populations. The 3 month to 7 years old study group (Miami study) were children from Miami, FL. No ethnic background information was given in the paper, but one can assume it could be typical from that area. The 4 to 18 years old study group (2nd Shanghai study) were Chinese children. It is well known that Chinese children have longer axial lengths than Caucasions and African descents (and more prevalent myopia rates unfortunately), so we certainly cannot assume that this is inclusive of all possible scenarios. 

Second, you can see that for any given age, there is a wide range of axial lengths in both studies. This tells us that normal is a range, NOT a single number. Do NOT compare the number of your child to your neighbor’s kids. This is not a competition. Also, it has been demonstrated again and again that it is the rate of axial length growth, rather than the absolute number, that better predicts myopia progression. Do not get anxious over one measurement. Monitor the axial length over time to find the trend. 

Lastly, I would still stress that while it is great that we have a normative database for axial length, it is still the gold standard to perform cycloplegic refraction to accurately assess a child’s true refractive error. Axial length measurement is a powerful tool, but it does not and cannot replace cycloplegic refraction.

References:

[1] Miami study: Bach A, Villegas VM, Gold AS, Shi W, Murray TG. Axial length development in children. Int J Ophthalmol. 2019;12(5):815-819. Published 2019 May 18. doi:10.18240/ijo.2019.05.18

[2] Shanghai study: He X, Sankaridurg P, Naduvilath T, Wang J, Xiong S, Weng R, Du L, Chen J, Zou H, Xu X. Normative data and percentile curves for axial length and axial length/corneal curvature in Chinese children and adolescents aged 4-18 years. Br J Ophthalmol. 2021 Sep 16:bjophthalmol-2021-319431. doi: 10.1136/bjophthalmol-2021-319431. Epub ahead of print. PMID: 34531198.

Low dose atropine drops and ortho K combo work better than ortho K alone in myopia control

Many parents ask whether their children should be on both atropine and ortho K to control myopia. There were small studies, some showing better result with the combo treatment. There was also a small scale study that I talked about that showed when ortho k failed to control myopia progression, additional atropine did not help.

Now a new research that analyzed 5 clinical studies involving 341 children revealed that ortho K + low dose atropine worked better than ortho K alone in controlling myopia progression [1]. On average, using the combo treatment results in 0.25 mm axial length elongation compared to about 0.35 mm in ortho K alone after 12 months of treatment. This is a small, but statistically significant finding.  

I think having this data is helpful. When a child has sub-optimal control with ortho K alone, I can recommend adding atropine. If a child has fast progressing myopia and parents are anxious, I can recommend starting with both treatments to maximize the control.

Would you be interested in seeking both treatments together right from the beginning?

Reference:

[1]https://journals.lww.com/claojournal/Fulltext/2021/02000/The_Efficacy_of_Atropine_Combined_With.7.aspx

Cancer chemo drug to treat retinitis pigmentosa?

Recently US FDA granted orphan drug designation of ADX-2191(methotrexate for intravitreal injection) by Aldeyra Therapeutics, Inc for the treatment of retinitis pigmentosa (RP) [1]. RP is a serious genetic condition that leads to retinal cell death and vision loss. It is a rare condition, which is defined as affecting fewer than 200,000 people in the United States. It has no cure, and limited treatment options, and is one of those eye conditions that doctors cannot do much about. So it is great to hear that now a drug is being developed to improve RP. 

What is also surprising is that methotrexate is not a new drug. In fact, it has been around for quite some time now, and primarily used to treat cancer of the blood, bone, lung, breast, head, and neck. It can also treat rheumatoid arthritis and psoriasis. It works by inhibiting cancer cells and certain immune cells to replicate, thereby can be used to treat cancer and certain autoimmune conditions. Now that it is injected into the eyeball for RP, does it mean it inhibits cells to grow and divide in the retina? In RP, retinal cells die, so it does not appear to be helpful to have a drug that further reduces cell duplication. Plus, the retinal cells are already terminally differentiated and do not divide anyways. So how does methotrexate work to help RP?

I am very curious now about this and looked into literature. It turns out it is a brand new mechanism of action of this old drug that renders it effective against RP. Scientists from University of Pittsburgh, University of Cincinnati and National Institute of Health discovered that methotrexate can reduce the misfolding of a protein called rhodopsin that is frequently mutated in RP, without affecting the healthy version of this protein. Rhodopsin is THE molecule to mediate vision in the retina. When it is mutated such as in RP, it folds in the wrong shape, leading to loss of function and death of retinal cells. Methotrexate could help the body’s natural garbage disposal system to work better to clear these wrongly formed proteins, and improved vision in a mouse model of RP [2].

Note this study using mice was published in 2020, and the FDA designation of orphan drug in 2021. The company moved fast!

Of course, orphan drug designation does not mean it’s already approved or will be approved by the FDA eventually for the treatment of RP. Phase 1 clinical trial was being planned and investigated at Mass Eye and Ear/ Harvard Medical School [3]. Hopefully data in humans will give some hope to those with this condition.

References: 

[1] Aldeyra Therapeutics receives Orphan Drug designation from the U.S. Food and Drug Administration for ADX-2191 to treat retinitis pigmentosa. News release. Aldeyra Therapeutics, Inc. Accessed August 4, 2021. https://www.businesswire.com/news/home/20210804005122/en/Aldeyra-Therapeutics-Receives-Orphan-Drug-Designation-from-the-U.S.-Food-and-Drug-Administration-for-ADX-2191-to-Treat-Retinitis-Pigmentosa

[2] Liu X, Feng B, Vats A, Tang H, Seibel W, Swaroop M, Tawa G, Zheng W, Byrne L, Schurdak M, Chen Y. Pharmacological clearance of misfolded rhodopsin for the treatment of RHO-associated retinitis pigmentosa. FASEB J. 2020 Aug;34(8):10146-10167. doi: 10.1096/fj.202000282R. Epub 2020 Jun 14. PMID: 32536017; PMCID: PMC7688577.

[3] https://adisinsight.springer.com/drugs/800053948

10 year use of low dose atropine for myopia control

We know that low dose atropine has been used to control myopia progression for a number of years now. It is still not approved by the US or Chinese FDA partially because long-term safety data are lacking. Previous studies demonstrated 2 years of using to be safe and effective. But myopia control is a long-term thing, maybe up to 10 years if a child starts to develop myopia from an early age (6- 8 years of age). 

Well now there is a study in Taiwan following children using low dose atropine for 10 years. This is a cohort study, no controls, and with only 23 subjects. Every child (that had myopia) was on low dose atropine for the entire 10 years and monitored every 2-4 months to check their refraction and axial length. It is certainly not a controlled or randomised study, and with a low sample size. However, I think it gives us a lot of information in a clinical setting on what to expect once a child is on low dose atropine for myopia control long term.

They also adopted a commonly used clinical approach, stepwise increase in treatment dosage if the treatment effect is not enough. For example, every myopic child started with 0.05% atropine. If a child did well on this, they continued this dosage throughout the 10 year period. If however their myopia continued to progress more than 0.50 D every 6 months, then they were switched to higher concentrations of 0.1%, 0.25%, and until 0.5%. A high concentration of 1% was not used.

In my clinic (and perhaps many others), I usually start with even lower concentration, 0.01%, which has been clinically proven to be effective in myopia control and with the least side effects including pupil dilation, light sensitivity and blurry near vision. I would go up to 0.02% and 0.05% if myopia control is not achieved, and I seldom go higher than 0.05% because at this point the side effect is noticeable and may interfere with normal study and life of a child. Eye doctors in Taiwan are more aggressive in myopia control in terms of using atropine and I thank them for the study. I always wonder whether I should ramp it up, and if higher concentrations are effective, then maybe it’s worth the side effects (and potentially risks of using this for 10 years).

This study answered my question to some degree. First of all, 65% patients were only using 0.05% atropine throughout the study, which means 35% patients did not respond well to the initial low dose. This is a high number. Remember 0.05% is already a higher concentration than the most commonly prescribed 0.01%, and still ⅓ of children do poorly on it. When we encounter children like this (and we will), do we further increase the dosage? In their study they did, and what they discovered was that for those who did not do well in the initial low concentration of atropine, despite the stepwise increase in the atropine concentration, their myopia control was still worse than the kids who responded to the initial low dose atropine. There were vast inter-individual differences, but the mean numbers look like this: the responding kids started with -1.5 D and progressed to -4.7 D after 10 years, whereas the poorly responding kids started with -0.9 D and progressed to -6.6 D. Their study did not have a control, but based on natural history of myopia progression in their population, they predicted about -7.7 D if no myopia control was done at all. So for those that respond to atropine, a reduction of 3 D of myopia over 10 years is quite good, especially it prevents these kids from developing high myopia (more than -6.0 D), which is associated with more retinal related complications. On the other hand, 10 years of high dose atropine in children who were poor responders resulted in only 1 D of myopia reduction, it seemed less worthwhile, considering the burden of using drops daily for 10 years and the side effects associated with dilation. Of course, this is purely based on a mean value, and individuals can be quite different, and for some, maybe 1 D reduction is still something that helps. 

But the lesson here is that if a child responds poorly to low dose atropine, merely increasing the concentration may not be the answer. They may be better off with additional or alternative control methods, such as ortho K lenses or multifocal soft contact lenses. 

Another outcome is that they did not find significant side effects with 10 year use of low dose atropine drops. The study also claimed that the children were not prescribed PALs. That is interesting, considering that atropine at concentration of 0.1% or above will have significant dilation and cycloplegic effects. Given that they used higher concentrations, it can be assumed that 0.01% atropine can also be used without significant side effects for up to 10 years.

So the take home message is that long term use of low dose atropine (10 years) may be safe and effective, but if a child responds poorly to low dose atropine, then they may benefit more from other methods of control. But keep in mind that this is a limited study with small number of patients. We still wait for larger scale and better controlled study.

The study cited in this article:

Chuang, MN., Fang, PC. & Wu, PC. Stepwise low concentration atropine for myopic control: a 10-year cohort study. Sci Rep 11, 17344 (2021). https://doi.org/10.1038/s41598-021-96698-6