BY: ANTIGONE KORDAS
COVID-19, caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has significantly challenged the medical community, with diagnosis and therapeusis mainly focusing on the respiratory-related signs and symptoms. While uncommon, ophthalmic complications can occur and affect ~6-12% of COVID-19 patients with ocular symptoms preceding systemic symptoms by 3 hours to 5 days in 13% of patients.
With COVID-19 on the rise throughout the community, it may become commonplace to see patients with viral ocular symptoms or even long-term ocular complications, either as a direct or indirect result of the pandemic. The following article is a guide of what the most common ocular conditions to expect are.
In systemic reviews, the most common ocular manifestation of COVID-19 is conjunctivitis (86%), ocular pain (31–34%), dry eyes (33%), discharge (19%), and redness (11%) .
Since genetic material of the virus (RNA) has been reported to be present within the tears of infected patients, extra care must be taken to not allow the eyes to serve as a transmission route. The first case of reported conjunctivitis and COVID-19 involved a doctor in China who performed a medical inspection at the Wuhan Fever Clinic without wearing any eye protection, therefore highlighting the importance of such procedures, especially within our field. It is also important to note that systemic infection is possible as infected tears can transport the virus through the nasolacrimal duct and towards the nasopharynx.
While the pathogenesis of conjunctivitis caused by COVID-19 is not entirely understood, several theories exist involving transmission via air-borne droplets or hand-eye contact .
Signs: Predominantly bilateral conjunctival hyperemia, chemosis, follicles on palpebral conjunctiva, epiphora, watery discharge, mild eyelid oedema, enlarged pre-auricular or submaxillary lymph nodes. At present, there have been no sight-threatening cases reported and eye involvement was more likely in patients with severe COVID-19. At this stage, conjunctivitis related to COVID-19 is self-limiting and conservative management such as use of lubricating drops and formulations for comfort is recommended.
Kawasaki Disease (KD) is a type of vasculitis of the medium-sized vasculature with an acute presentation and mostly affecting young children under the age of 5. Towards the beginning of the pandemic in 2020, a strong connection had been observed between KD and COVID-19 within a province of Italy, with a particular study reporting that up to 80% of paediatric patients positive for COVID-19 presented with an increased incidence of more severe KD. More recently however, it has been found that children exposed to COVID-19 develop Kawasaki-like illness, termed Multisystem Inflammatory Syndrome (MIS-C), rather than KD itself. The main difference between MIS-C and typical KD is that MIS-C patients suffer from gastrointestinal issues (diarrhoea, abdominal pain and nausea), shock and coagulopathy more frequently. MIS-C is also more common in older children over the age of 5, with several studies reporting an age range of 7.5-10 years.
Signs of Typical KD: Fever, oropharyngeal and extremity swelling, polymorphous rash (different types of rashes occurring all over the body), mucous membrane changes, strawberry tongue appearance and unilateral cervical lymphadenopathy. More specific ocular manifestations of the condition include iridocyclitis, keratitis, vitreous opacities, papilloedema, subconjunctival haemorrhage and conjunctival injection (specifically bilateral, painless, non-purulent and with limbal sparing).
Image (Courtesy of Robert Sundel, MD): Conjunctivitis in KD with limbal sparing.
Given that COVID-19 targets vascular pericytes expressing ACE-2 and these receptors are found in the ciliary body, retina and RPE, it follows that viral infection can potentially lead to damage of the microvasculature and blood-retina barrier and therefore cause ocular circulation issues. A study examining histological specimens of retinas from deceased COVID-19 patients found particles of the virus in the ganglion cell layer (GCL), inner plexiform, inner nuclear layer (INL), outer plexiform, outer nuclear layer (ONL), retinal pigment epithelium, and choroid..
With the potential for coagulopathy, ischaemia and inflammation with COVID-19, certain conditions may arise during infection include retinopathy. An 8.86-fold increased risk of retinal microvascular pathology has been found in infected patients, including retinal haemorrhages, cotton wool spots, retinal infarcts and thinning of the GCL and INL. A lower vascular density on OCTA has also been found in patients with more severe COVID-19 presentations.
Image: Retinal findings in four patients with COVID-19
A: Shows a cotton wool spot at the superior retinal arcade with subtle microhaemorrhage.
B-D: Shows hyper-reflective lesions of the inner plexiform and ganglion cell layers, a feature observed in all patients.
Acute macular neuroretinopathy (AMN) and paracentral acute middle maculopathy (PAMM) (involve ischaemia to the deep retinal capillary plexus) have also been found in patients with COVID-19 and are marked by hyperreflective changes of the OPL and INL.
Image: Retinal findings in AMN
A, B: Near-infrared imaging of the right eye (A) and left eye (B) shows multiple hyporeflective lesions in the paracentral macula. The small lesions imaged have a petaloid shape, but most are large and confluent, and almost form a ring around the fovea.
C, D: OCT of the right eye (C) and left eye (D) at the level of the green line in A, B, shows interruption of the ellipsoid zone and the interdigitation zone (black arrows).
Other potential retinal findings include hyperreflective lesions in the inner and outer retina, MEWDS, CRVO and Multifocal Choroiditis with Adie’s pupil.
OCULAR SURFACE DISORDERS
Ocular surface disorders such as exposure keratitis and corneal abrasions have been reported in patients in ICU who are on ventilators and respiratory masks.
Neurological complications of COVID-19 include Meningitis, Encephalomyelitis, Polyneuritis, Encephalopathy and Guillain-Barre Syndrome. Patients who have had COVID-19 may potentially present with diplopia secondary to oculomotor nerve palsy due to direct viral infection of the nerve or subsequent inflammation.
A study found that up to 21% of patients with COVID-19 may have systemic neurological problems and ~0.4% have cranial nerve impairment to some extent, including CNIII, CNIV and CNVI. A systemic review also found an increased prevalence of Guillain-Barre Syndrome (a condition where the person’s immune system attacks nerves) in COVID-19 patients compared to the general population (0.15% compared to 0.02%).
Signs: Ophthalmoparesis, abnormal cranial nerve MRI and findings.
1. Ocular and Systemic Complications of COVID-19: Impact on Patients and Healthcare . Leung, E. H., Fan, J., Flynn Jr, H. W., & Albini, T. A. 2022, Clinical Ophthalmology, Vol. 16, pp. 1-13.
2. Clinical and prodromal ocular symptoms in Coronavirus disease: a systematic review and meta-analysis. . Inomata T, Kitazawa K, Kuno T, et al. 10, 2020, Investigative Ophthalmology & Visual Science, Vol. 61, p. 29.
3. Ocular surface manifestations of coronavirus disease 2019 (COVID-19): a systematic review and meta-analysis. Aggarwal K, Agarwal A, Jaiswal N, et al. 11, 2020, PLoS One, Vol. 15, p. e0241661.
4. Detection of severe acute respiratory syndrome Coronavirus-2 in the tears of patients with Coronavirus disease 2019. Karimi, Saeed, et al. 7, 2020, Eye, Vol. 34, pp. 1220–1223.
5. Assessing Viral Shedding and Infectivity of Tears in Coronavirus Disease 2019 (COVID-19) Patients. Jun Seah, Ivan Yu, et al. 7, 2020, Ophthalmology, Vol. 127, pp. 977-979.
6. 2019-nCoV transmission through the ocular surface must not be ignored. Lu, Cheng-Wei, Liu, Xiu-Fen and Jia, Zhi-fang. 10224, 2020, The Lancet, Vol. 395, p. E39.
7. Ocular Findings in COVID-19 Patients: A Review of Direct Manifestations and Indirect Effects on the Eye. Bertoli, Federica, et al. 2020, Journal of Ophthalmology, Vol. 2020.
8. Characteristics of Ocular Findings of Patients With Coronavirus Disease 2019 (COVID-19) in Hubei Province, China. Ping, Wu, et al. 5, 2020, JAMA Ophthalmology, Vol. 138, pp. 575-578.
9. Conjunctivitis and COVID‐19: A meta‐analysis. Loffredo, Lorenzo, et al. 9, 2020, Journal of Medical Virology, Vol. 92, pp. 1413-1414.
10. Ocular manifestations of Kawasaki disease (mucocutaneous lymph node syndrome). Jacob, J L, et al. 5, 1982, Canadian Journal of Ophthalmology, Vol. 17, pp. 199-202.
11. An outbreak of severe Kawasaki- like disease at the Italian epicentre of the SARS-CoV-2 epi- demic: an observational cohort study. Verdoni, L and Mazza, A. 10239, 2020, The Lancet, Vol. 395, pp. 1771-1778.
12. Paediatric multisystem inflammatory syndrome temporally associated with SARS-CoV-2 mimicking Kawasaki disease (Kawa-COVID-19): a multicentre cohort. Pouletty, M, et al. 8, 2020, Annals of the Rheumatic Diseases, Vol. 79, pp. 999-1006.
13. Multisystem inflammatory syndrome in US Children and adolescents. Feldstein LR, Rose EB, Horwitz SM, Collins JP, Newhams MM, Son MBF et al. 4, 2020, The New England Journal of Medicine, Vol. 383, pp. 334-336.
14. Severe COVID-19 infection and thrombotic microangiopathy: success does not come easily. Gavriilaki, E and Brodsky, R A. 6, 2020, British Journal of Haematology, Vol. 189.
15. Presumed SARS-CoV-2 viral particles in the human retina of patients with COVID-19. Araujo-Silva, C A, et al. 2021, JAMA Ophthalmology, Vol. 139, p. 1015.
16. COVID-19 related retinal micro-vasculopathy - a review of current evidence: COVID-19 related retinal micro-vasculopathy. Teo, K Y, et al. 21, 2021, American Journal of Ophthalmology, Vols. S0002-9394, pp. 00476–1.
17. Retinal microvascular abnormalities in patients after COVID-19 depending on diseas.e severity. Zapata, M A, et al. 2020, British Journal of Ophthalmology, Vol. 0, pp. 1-5.
18. Retinal findings in patients with COVID-19. Marinho, P M, et al. 10237, 2020, The Lancet, Vol. 395, p. P1610.
19. Bilateral acute macular neuroretinopathy following COVID-19 infection . Giacuzzo, C, Eandi, C M and Kawasaki, A. 2021, Acta Ophthalmologica.
20. An uncommon cold of the retina. De Salvo, G, et al. 21, 2021, Survey of Ophthalmology, Vols. S0039-6257, pp. 00178-8.
21. Central Retinal Vein Occlusion in patients with COVID-19 infection: a systematic review. Ullah, I, et al. 2021, Annals of Medicine and Surgery, Vol. 71, p. 102898.
22. Ophthalmic and neuro-ophthalmic manifestations of Coronavirus disease 2019 (COVID-19). Ortiz-Seller, A, et al. 8, 2020, Ocular Immunology and Inflammation, Vol. 28, pp. 1285–1289.
23. Neuro-ophthalmic manifestations of coronavirus disease 19. Tisdale, A K and Chwalisz, B K. 6, 2021, Current Opinion in Ophthalmology, Vol. 31, pp. 489–494.
24. Neurological manifestations of patients infected with the SARS-CoV-2: a systematic review of the literature. Cagnazzo, F, et al. 8, 2021, Journal of Neurology, Vol. 268, pp. 2656–2665.
25. Prevalence, clinical characteristics and outcomes of Guillain-Barré syndrome spectrum associated with COVID-19: a systematic review and meta-analysis. . Palaiodimou, L, et al. 10, 2021, European Journal of Neurology, Vol. 28, pp. 3517–3529.
26. COVID-19 presenting with ophthalmoparesis from cranial nerve palsy. Dinkin, M, et al. 9, 2020, Neurology, Vol. 95, pp. 221-223.
Associate Professor Matthew Simunovic is a Sydney-based ophthalmologist who specialises in medical retina and vitreoretinal surgery and is also involved in research.
He graduated from medical school at the University of Cambridge, where he also obtained his PhD and aspired to become an ophthalmologist. Prior to this, he studied optometry at UNSW with his love for eyes stemming from a young age by his uncle who was an optometrist in Brisbane. He completed his fellowship training at The University of British Columbia in Vancouver, Moorfield’s Eye Hospital in London and at the John Radcliffe Hospital/Nuffield Laboratory of Ophthalmology at the University of Oxford.
A/Prof. Simunovic is currently working in the retinal unit at Sydney Eye Hospital and the Sydney Children’s Hospital network. He works in private practice at Retina Associates Bondi Junction and Chatswood as well as Sutherland Eye Surgeons and operates privately at Bondi Junction Private Hospital. He is an Associate Professor at the Save Sight Institute at the University of Sydney and his research group conducts clinical research and laboratory research into developing treatments for retinal disease, improving visual function as well as experimental vitreoretinal surgery. His research is currently being supported by the Macular Diseases Foundation Australia and the NHMRC.
To see a list of the research projects and publications A/Prof. Simunovic is involved in, click here.
If any YO members are interested in being involved with research with A/Prof. Simunovic, send us an email to get in contact!
Read the interview with A/Prof. Simunovic below for a detailed description on his recent clinical research and the life-changing impact that Luxturna is having on patients with Leber’s Congenital Amaurosis 2.
Luxturna (voretigene neparvovec) is the first ever ocular gene therapy recently approved here in Australia by the Therapeutics Goods Administration (TGA) for use in patients with Leber’s Congenital Amaurosis 2 (LCA2). LCA2 is a retinal dystrophy caused by biallelic mutations to the RPE65 gene, which is essential in recycling the chromophore (the modified version of Vitamin A bound to rhodopsin and the cone opsins). In patients with LCA2 where there is no functional RPE65 in the eye but the RPE and photoreceptors are still intact, the introduction of the RPE65 gene results in the production of the RPE65 protein, establishing the visual cycle and improving vision.
The research which led to the development of Luxturna was mainly conducted in the USA, initially developed in the laboratory of Prof. Jean Bennett at the University of Pennsylvania.
The research team involved in delivering the treatment here in Australia commenced with identification and genotyping patients, which was performed by my colleagues Prof. Robyn Jamieson and Prof. John Grigg. Preparation of the medication according to the regulations surrounding genetically modified organisms (GMOs) was led by Peter Barclay in the pharmacy at Children’s Hospital Westmead. A theatre nursing team, anaesthetists and recovery teams were involved, as well as the surgical team which included myself and Dr Gaurav Bhardwaj.
Novartis supply and distribute Luxturna and were primarily responsible for regulatory approval in Australia.
The surgery initially involves a small gauge pars plana vitrectomy, where three small, valved ports are inserted through the sclera anteriorly to the retina via the pars plana. Once inserted, an infusion line is run into one of the ports. This provides a steady flow of balanced salt solution (designed to mimic aqueous humour) to prevent the eye from collapsing when the vitreous is cut and aspirated. The vitreous is removed using a vitrector through another port (a miniscule instrument with 0.5mm diameter that has a guillotine cutter and aspiration line). The final port allows for a light pipe into the eye so that the fundus is viewed via an indirection viewing system at a surgical microscope. In many patients, a posterior vitreous detachment needs to be induced surgically, which can be quite tricky in younger patients and children with firmer vitreoretinal adhesions.
Once the bulk of the core and peripheral vitreous has been removed, the sub-retinal injection is performed using a 38-guage Teflon tipped cannula (0.125mm diameter) placed in the subretinal space. Once in the correct surgical plane, the injection commences, however most surgeons prefer to create a bleb first using a balanced salt solution before the injection so that they can use the on-table OCT to confirm they are in the correct plane. Inadvertently injecting Luxturna into the choroid or the vitreous can potentially lead to lack of efficacy and/or inflammation. Once in the correct surgical plane, a total of 0.3mL Luxturna is injected via the same puncture site into the bleb and the surgeon will then check for peripheral retinal holes or tears using 360-degree scleral indentation (treated with cryopexy or laser if they do arise). The fluid is then exchanged in the vitreous cavity for filtered air to encourage migration of subretinal fluid to the desired treatment area during post-operative positioning. It also assists in the closure of the scleral incision sites/assessing the patency of closure as well as helps prevent retinal detachment if any retinal holes or tears are found.
Image: The Luxturna sub-retinal injection in action.
Image: A/Prof. Simunovic operating on the first patient to be treated with Luxturna
Once the surgery is complete, the patient is positioned in a way that allows for gravity to move the Luxturna to the position of the residual island of viable retina. This area is usually the macula. For example, if the injection is performed superior to the macula, the patient may be positioned upright or face up.
Image: The Research Team (from left to right): Prof. John Grigg (paediatric ophthalmologist), Prof. Robyn Jamieson (clinical geneticist), Dr Gaurav Bhardwaj (vitreoretinal surgeon), A/Prof. Matthew Simunovic, Nicole Johnston (Novartis), Ajit Viswalingam (Novartis), Sonja Nikolic (Novartis)
While it is well-known that pars plana vitrectomy accelerates nuclear sclerosis and cataract formation, there are some patients that are resilient to its effects. This includes younger patients and diabetics. To date, some of the older patients have had pre-existing cataract, which is anticipated to progress more rapidly following surgery. However, cataract extraction is not performed concurrently for Luxturna patients.
Improvements in key functional tests have been seen in treated patients which mirror those of the Phase III/pivotal trials. The latter demonstrated a 2.1 log unit improvement (21dB) in retinal sensitivity, which has translated to significant real-world improvements. For example, the first patient treated saw me recently and mentioned that they’d seen stars for the first time. There have also been subjective improvements in colour vision, form discrimination and near vision, with one patient now about to crochet and thread larger needles. Treatment takes about 2 weeks to work, with one patient no longer using a mobility cane to navigate under street lighting about 2 weeks following their surgery.
I did my PhD at a time when there was a whirlwind of activity in the area of molecular biology for inherited retinal disease and the vague hope that gene therapy was on the horizon. Of course, even back then, there were important things that clinicians could do to help patients, but it was exciting to know that a common (1 in 2,000-3,000 and the commonest cause of blindness in children and those of working age) group of conditions might one day be “treatable”. Likewise, it has been exciting to be involved in gene therapy and other emerging treatments, not least because they offer hope of meaningful improvements in vision and quality of life for patients and their families.
We have more patients coming for Luxturna surgery in the New Year. On the clinical research front, my team and I are involved in clinical trials of therapeutics for retinal detachment, age-related macular degeneration and macular telangiectasia type II. We are also conducting an investigator-initiated trial looking at the fate of subretinally injected drugs using a fluorophotometry protocol we have developed. My group is also conducting clinical projects exploring visual function and structure in retinal disease (including inherited retinal disease and surgical retinal disease) which draws on machine-learning (in collaboration with colleagues in Computer Science at USyd). In addition, we are in the throes of completing an inherited retinal disease registry, which the Save Sight Registries host. This has been a significant undertaking with input from clinicians in Australia, New Zealand, the USA, Germany, Switzerland, Belgium, Portugal and the UK. Finally, in the lab, we are developing causative mechanism independent approaches to treat retinal degeneration using different optogenetic approaches – one approach is targeted at addressing vision loss from dry ARMD (funded by the Macular Disease Foundation Australia), and the other addresses inherited retinal degeneration of differing severity (supported by the NHMRC).
Optometrists see patients with inherited retinal degeneration both at initial presentation and for ongoing care. Therefore, they are well-placed to keep patients informed about developments in the area and provide appropriate referrals. Many patients with these conditions have been told that “nothing can be done”. Even before the advent of gene therapy, this was not true. This group of patients benefit from refractive management and often from low vision aids and active management of associated problems like cataract, cystoid maculopathy, epiretinal membrane, etc. It’s crucial that patients are offered the chance to be assessed by clinicians with an interest in inherited retinal disease and by a genetics service, whether the patient wishes to undergo “genetic testing” or not.