Since the pandemic, the multi-system effects of Long-COVID – from its clinical manifestations to its pathophysiology – have been documented extensively throughout medical literature. However, the long-term ocular symptoms in previous COVID patients have been somewhat less examined than the enduring cardiovascular, respiratory, and neurological effects associated with the virus.

Now, a recent Nature communications study conducted in Sweden has looked at a small cohort of non-hospitalized patients reporting lasting, sometimes severe, eye issues as a result of contracting mild COVID-19 anywhere from three months to up to three years beforehand.

The Ophthalmologist reached out to corresponding author, Neil Lagali, a scientist and ophthalmology researcher based at the Division of Ophthalmology in Linköping University, Sweden, to learn more about how the study came to be developed and what specialist tests the researchers used to accurately diagnose the varying ocular symptoms patients were presenting with.

What first prompted you to investigate persistent eye symptoms after COVID-19?

This was quite a different study than what we're used to doing, because usually we have an idea and a study protocol and then we try to recruit patients. But this was the complete reverse of that: patients started to come into the eye clinic with these complaints and we didn't really know what it was. But they were all saying that it started after initially having COVID. We looked at a few people and then more started to contact us, and so then we decided, okay, let's do a formal study on this.

Were you surprised by the amount of people that were coming to you with these symptoms months after their initial infection?

Yes, because we didn't realize how big a problem it actually was. In the end, we recruited 100 people for the study, but we stopped after that because that's what was in our protocol. But still more and more patients kept coming in with these same symptoms.

I believe many of these participants had already had routine eye examinations that hadn’t revealed any significant abnormalities?

Yes, that’s correct. And that was part of the reason they started to come to us, because we're a larger academic hospital and we have some specialized testing resources.

Early on, the media found out that we were doing this study and they published stories detailing what we were looking at. We hadn’t even started the study then, but news spread throughout Sweden and then many people started to contact us. One of the things all these people had in common was that they had already been to eye clinics or optometrists and didn't get the help they needed – nobody could figure out what was wrong because everything looked normal in the routine exams.

Can you explain a little about why you think these changes were missed in standard clinical practice?

In our study we performed these same standard eye tests, and we confirmed that everything did appear to be normal. We then broadened our study to use a number of advanced techniques to look at the eye in ways that you wouldn't typically do if you didn't have reason to do so in a normal ophthalmology examination. 

Can you describe the types of specialized tests you performed?

One test was for eye coordination. Binocular vision should be synchronous and so both eyes should focus on an object together, and that's of course controlled by the brain. Using tests an optometrist usually has for binocular and near vision, we found that a lot of these patients had strabismus.

We then did dynamic pupillometry and looked at how the pupil changed in response to light. What we saw with this test is that these patients have a weakened pupillary response, and so they're letting in more light than they should.

We also used a special in vivo confocal microscope that you affix to the eye, allowing you to identify nerve damage and inflammatory cells in the cornea, and that’s actually what we saw in these patients – heightened T cells in the cornea and nerve damage. That is a technique that some of the larger academic centers have as well, but it’s also not that common.

Additionally, one of the hot topics right now in ophthalmology is looking at the tear film, and so that was another specialized test we performed for our study. 

We took tear film samples from all the patients and the controls, and conducted a proteomics analysis on those tears. What was interesting is that we found that the pattern of proteins indicated T cell dysregulation that correlated with elevated ANGPTL2, SKAP2, and DAPP1 levels. Interestingly, this same pattern has been found in the blood of patients with severe COVID. So even though the patients we studied only had mild COVID, they still had this pattern in their tear proteins that was indicative of a very severe COVID infection. And when we added a few of these specific proteins to our diagnostic model, it really increased the sensitivity and specificity of our model in being able to diagnose this problem. These diagnostics don't exist today, but it's something that the field is moving towards: trying to find effective ways to use tear film biomarkers.

Are there particular symptoms that should prompt referral for specialized testing?

An extreme sensitivity to light is one, and this is often coupled with eye pain and headaches. Also, difficulties in reading text, and dizziness related to trying to focus on objects. Clinicians should also be looking at a patient’s timeline in relation to when the symptoms started versus when they had COVID. Because the typical pattern is that they have COVID, they recover, and then anywhere from a few weeks to a few months after recovery, they start to develop these ocular symptoms.

What do you think is the single most important message clinicians should take away from your findings?

I think the most important message is that this is a real condition and it can be objectively measured and diagnosed.

What are your next steps for this research?

The logical question now that we can accurately detect this issue is: what is the treatment? We have a couple of ongoing studies looking into this. One is an eye training program in collaboration with optometrists that have special programs where the person can perform at-home eye focus training exercises several times a day. In combination with that, treatment could involve getting special eyeglasses with prisms, or colored eyeglasses that can filter and block out certain wavelengths of light that trigger the sort of pain response these patients are experiencing.

We have already been studying these treatments with a lot of patients and are seeing some good results, which we will be publishing shortly. We are also looking at ways in which to deal with the more severe eye pain a lot of these patients are experiencing. So we are doing another study on cranial stimulation – stimulating the nerves in the brain to try to change their threshold for activation. So far, we have seen some good initial results in reducing this pain and light sensitivity, which may lead to clinical trials in the near future.