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I always get so excited when the summer Olympics come around. Being born and raised in Canada and living most of my adult life in the United States, I always find someone to cheer for. I don’t know if it’s just me, but it seems like “eyes” have taken center stage as a theme this year. My social media feed has been filled with photos and articles about Stephen Nedoroscik, the U.S. gymnast who has been affectionately nicknamed “Clark Kent” due to the spectacles he removes right before competing on the pommel horse. It’s exceedingly rare to see an Olympian who wears glasses, never mind one who is so open in discussions about his severe photophobia, strabismus and coloboma. Hopefully he’s inspired a few of our young, bespectacled viewers to continue pursuing their athletic dreams. Then there was Flavia Saraiva, the female gymnast from Brazil whose fall from the uneven bars resulted in a nasty cut above her right eye and severe bruising below it. And who can forget Yusuf Dikec—the Turkish air pistol shooter who went viral for competing (and winning silver!) with no extra vision-enhancing equipment other than his seemingly standard pair of glasses. Add in the clouds of white chalk dust everywhere (my eyes feel gritty and sore just watching it on TV) and the swimmers who aggressively push their swim goggles deep into their eye sockets, and all I can think is eyes, eyes, eyes!

I hope you enjoy the final week of Olympics coverage (hopefully there are no more eye-related injuries) and that you find some time to enjoy this week’s issue which reviews some of the common systemic relationships to eyelid disease. We also take a deeper dive into the ocular surface’s microbiome and the impact that prebiotics and probiotics have on the ocular surface in dry eye disease.

Amber Gaume Giannoni, OD, FAAO
Editor

More Than Just an Eye Exam: Managing Non-Demodex Chronic Lid Disease When You Suspect There May Be a Systemic Impact

When a patient goes to the eye doctor, they often expect to be told about glasses or contact lenses. They may not expect their eye doctor to also bring up their eyelid health and hygiene, or its potential impact and association with other systemic conditions. Until they are educated on the connection between systemic disease and eyelid function and anatomy, patients usually do not realize (or care) that their eyelids contribute to the overall stability of their tear film or symptoms of dryness and intermittent blurry vision.

Educating patients on common systemic conditions and their potential association with chronic ocular surface and eyelid problems (such as blepharitis, meibomian gland dysfunction [MGD] and nocturnal lagophathlmos) is an important consideration in routine exams. By understanding and addressing the multifactorial nature of these conditions, eye care practitioners can provide an integrated approach to care that improves outcomes for patients suffering from chronic eyelid disease.

Common Systemic Connections in Chronic Eyelid Problems

Ocular Rosacea: Rosacea is a chronic inflammatory skin condition that can affect the eyes and periocular area. Signs and symptoms include redness, burning and irritation of the eyes and eyelids, as well as MGD.¹ The inflammatory nature of rosacea can exacerbate eyelid disease, making it essential to manage both the skin and ocular manifestations. If we ignore the latter, patients can experience fluctuation in vision or contact lens instability. They may even postpone needed cataract or refractive surgeries because of their rosacea.¹

Diabetes Mellitus: From the front to the back of the eye, diabetes can affect patients in a variety of ways. With increased susceptibility to infections, neuropathies and chronic eyelid diseases such as blepharitis and MGD, diabetic patients may experience chronic damage to the nerves that innervate the eyelids and meibomian glands.² When not treated quickly, neglect of ocular surface inflammation could lead to altered gland function and impaired secretion of the lipid and aqueous layers of the tear film, resulting in chronic mixed forms (evaporative and aqueous deficient) dry eye.^2-4

Thyroid Eye Disease: Thyroid dysfunction, particularly Graves' disease, can cause thyroid eye disease (TED). TED is an autoimmune orbital inflammatory condition in which antibodies mistakenly attack the tissues around the eyes, leading to inflammation, swelling and chronic ocular and eyelid problems.⁵ This immune response affects the muscles and tissues around the eyes, which results in signs and symptoms such as bulging eyes, dry eyes and eyelid retraction. These effects may contribute to chronic lid inflammation if left untreated.⁵

Sleep Apnea: Obstructive sleep apnea (OSA) is a common sleep disorder associated with several systemic conditions, including cardiovascular disease, hypertension and metabolic syndrome.⁶ Patients with OSA often use continuous positive airway pressure (CPAP) devices to maintain airway patency during sleep, but air leakage from an ill-fitting CPAP mask can dry out the eyes and eyelids. These patients could experience mechanical irritation of the eyelids and ocular surface, potentially leading to or exacerbating chronic eyelid conditions. To make matters worse, patients with OSA may also experience nocturnal lagophthalmos, where the eyelids do not fully close during sleep. This condition can be worsened by concomitant eyelid laxity, which further leads to increased evaporation of the tear film and exposure of the ocular surface, resulting in dryness, irritation and inflammation of the eyelids and conjunctiva.⁶

Diagnostic Methods

Clinically, the Look-Lift-Pull-Push (LLPP) test is a simple and effective way to assess the eyelids, starting with simply looking at the patient. Consideration of meibomian gland function and flow are also necessary components of treating chronic ocular surface disease. Then, lifting and pulling patients’ eyelids can help steer practitioners toward certain ocular and systemic health conditions. For example, clinical findings such as floppy eyelids with poor eyelid apposition and lid laxity, found by simply touching the eyelids during a LLPP test, could point an eye care practitioner toward inquiring further about a potential sleep apnea diagnosis, CPAP use or both. Eyelid seal is also important for these patients because some may have an anatomical or acquired eyelid issue that may be discovered by lifting and pulling the eyelids.

Assessing the quality and quantity of meibomian gland oil expression by pressing on the eyelids is another crucial part of treating dry eye disease. Identifying systemic connections may require a deep dive into a comprehensive patient history and slit lamp examination. Eye care providers should ask about symptoms related to systemic diseases and coordinate with other health care providers for appropriate tests and evaluations.

Effective management of chronic ocular problems involves a combination of eyelid hygiene, topical and systemic treatments, lifestyle adjustments, patient education and regular monitoring. Addressing underlying systemic conditions and using in-office devices to further assist with thermal and mechanical expression can enhance treatment outcomes. A comprehensive, patient-centered approach is essential for improving symptoms and maintaining ocular health. By understanding these associations and integrating systemic health into treatment plans, we can significantly improve patient outcomes and overall well-being.

References:

1. Sobolewska B, Schaller M, Zierhut M. Rosacea and dry eye disease. Ocul Immunol Inflamm. 2022 Apr;30(3):570-579. doi:10.1080/09273948.2021.2025251
2. Naik K, Magdum R, Ahuja A, et al. Ocular surface diseases in patients with diabetes. Cureus. 2022 Mar;14(3):e23401. doi:10.7759/cureus.23401
3. Zhang X, Zhao L, Deng S, Sun X, Wang N. Dry eye syndrome in patients with diabetes mellitus: prevalence, etiology, and clinical characteristics. J Ophthalmol. 2016;2016:8201053. doi:10.1155/2016/8201053
4. Kuo Y-K, Shao S-C, Lin E-T, Pan L-Y, Yeung L, Sun C-C. Tear function in patients with diabetes mellitus: a systematic review and meta-analysis. Front Endocrinol (Lausanne). 2022 Oct 21;13:1036002. doi:10.3389/fendo.2022.1036002.
5. Szelog J, Swanson H, Sniegowski MC, Lyon DB. Thyroid eye disease. Mo Med. 2022 Jul-Aug;119(4):343-350.
6. Karaca I, Yağcı A, Palamar M, Taşbakan MS, Başoğlu ÖK. Evaluation of periorbital tissues in obstructive sleep apnea syndrome. Turk J Ophthalmol. 2020 Dec;50(6):356-361. doi:10.4274/tjo.galenos.2020.35033

The microbiome is the collection of microbes (bacteria, fungi and viruses) that live symbiotically on human skin and the ocular surface, as well as within the digestive system. The microbiome works with other organs to maintain proper homeostasis.¹ Specifically in the eyes, it contributes to the maintenance of a healthy ocular surface.

It is uncertain whether the established ocular surface microbiome has a “core” group of microbes that change in ocular conditions such as dry eye disease (DED), but it has been suggested that the ocular surface has a minimal number of core bacteria with little diversity. Most studies report the presence of Corynebacterium, Cutibacteriumand coagulase-negative Staphylococcus. The purpose of this study, conducted in Norway, was to characterize the ocular microbiome in individuals with either no self-reported symptoms of DED or with varying degrees of DED symptoms and identify the compositional changes that characterize DED.¹

The study included 91 participants (61 with mild and severe DED and 30 controls). To investigate which microbial taxa may be associated with DED, a subgroup (n=20) was chosen based on severe DED characteristics; namely tear break-up time below 5 seconds and Schirmer’s score below 10 mm. Conjunctival samples were cultured on both selective and nonselective agars in different atmospheric conditions to maximize recovery. Antibiotic susceptibility testing and genetic sequencing were carried out on the recovered cultures.¹

Previous studies have reported low or sporadic fungal growth on the ocular surface, but it is uncertain whether fungi are part of the core microbes in the ocular surface microbiome. In this study, no fungal growth was noted from any of the participants. Coagulase-negative staphylococci such as S. epidermidis was found to be the most abundant bacterial type, followed by C. acnes, Corynebacterium, Streptococcus and Micrococcus. S. aureus resistance profiles isolated from DED patients did not differ from controls. All bacteria were sensitive to chloramphenicol and fusidic acid, which are the first-choice antibiotics in Norway for treating staphylococcal conjunctivitis. In the patients with severe DED, Blautia was found to be most associated with DED, followed by several different species of Corynebacterium. The authors note that there is an association between these two bacteria and DED that are not necessarily causative, but do warrant further investigation.¹

References:

1. Naqvi M, Fineide F, Utheim TP, Charnock C. Culture- and non-culture-based approaches reveal unique features of the ocular microbiome in dry eye patients. Ocul Surf. 2024 Apr;32:123-129. doi:10.1016/j.jtos.2024.02.002

Culture- and non-culture-based approaches reveal unique features of the ocular microbiome in dry eye patients

Maria Naqvi, Fredrik Fineide, Tor Paaske Utheim, and Colin Charnock
Ocul Surf. 2024 Apr;32:123-129. doi:10.1016/j.jtos.2024.02.002

PURPOSE: The purpose of this study was to investigate the ocular microbiome in individuals with dry eye disease and to identify features of their ocular microbiome of possible health and diagnostic significance.

METHODS: Conjunctival samples were collected from both eyes in duplicate from 91 individuals (61 dry eye, 30 healthy) and used for both culture-dependent and culture-independent analyses. Samples were either analyzed using next generation sequencing (V3-V4 16S rDNA) or inoculated on a wide range of agar types and grown under a broad range of conditions to maximize recovery. Isolates were identified by partial sequencing of the 16S rDNA and rpoB genes and tested for antibiotic susceptibility. We applied a L2-regularized logistic regression model on the next generation sequencing data to investigate any potential association between severe dry eye disease and the ocular microbiome.

RESULTS: Culture-dependent analysis showed the highest number of colony forming units in healthy individuals. The majority of isolates recovered from the samples were Corynebacterium, Micrococcus sp., Staphylococcus epidermidis, and Cutibacterium acnes. Culture independent analysis revealed 24 phyla, of which Actinobacteria, Firmicutes and Proteobacteria were the most abundant. Over 405 genera were detected, of which Corynebacterium was the most dominant, followed by Staphylococcus and Cutibacterium. The L2-regularized logistic regression model indicated that Blautia and Corynebacterium sp. may be associated with severe DED.

CONCLUSIONS: Our study indicates that the ocular microbiome has characteristic features in severe DED patients. Certain Corynebacterium species and Blautia are of particular interest for future studies.

The Impact of Probiotics and Prebiotics on Dry Eye Disease Signs and Symptoms

Dry eye disease is a multifactorial, highly prevalent anterior segment pathology. Research has viewed dry eye largely as an inflammatory condition that has many features in common with autoimmune diseases,¹ and recent research has explored the relationship between the body’s anti-inflammatory response and microbiomes in the gut and eye.² However, many remaining factors and relationships have yet to be explored.

Prior studies have attempted to measure the concentrations of particular bacteria in the eye or the gut and regulate the amount of these bacteria using pre and probiotic supplements.^1,3-4 However, due to the difficulty in reducing confounds from environmental factors, the relationship between the gut microbiome and the microbiome of the eye have been difficult to study.² Still, researchers have found that gut microbiota does play an important role in regulating low-grade inflammation, extending to the eye and adnexa.¹ The studies aimed to discover whether symptoms of dry eye decrease after supplementation and whether we see clinical improvement subjectively.

By giving prebiotic and probiotic supplements, some studies have found a reduction of dry eye symptoms in as little as four months. Based on the Ocular Surface Disease Index scale, dry eye symptoms significantly improved for patients who took the supplements compared to patients who had placebo.¹ Additionally, observable clinical signs such as tear break-up time and tear meniscus height improved with prebiotic and probiotic use. Other studies have explored the relationships between different vitamins, minerals or dietary habits and dry eye. An exact causal relationship has yet to be determined, but strong correlational relationships have been noted, suggesting that there is a relationship between diet/supplements and dry eye.^4-10

Types of microbiota may also have an impact on the prevalence and severity of dry eye. We now know that several species of bacteria have been found to be associated with dry eye disease.^3,11-15 Further research into the exact concentrations of these bacteria in relation to others may provide more insight to the relationship between bacteria and dry eye.

Research suggests a strong relationship between dysfunction in gut microbiota and Sjögren’s dry eye disease, but the evidence does not appear to be as strong in subjects with mild to moderate dry eye.^11,12,16 Current research trends suggest that prebiotics and probiotics may be effective in helping manage chronic dry eye disease.

References:

1. Tavakoli A, Markoulli M, Papas E, Flanagan J. The impact of probiotics and prebiotics on dry eye disease signs and symptoms. J Clin Med. 2022 Aug;11(16):4889. doi: 10.3390/jcm11164889
2. Shih KC. Tong L. The conjunctival microbiome and dry eye: what we know and controversies. Eye Contact Lens. 2024 May;50(5):208-211. doi:10.1097/ICL.0000000000001077
3. Ma X, Shin Y-J, Yun S-W, Jang SW, Han S-W, Kim D-H. Probiotic LB101 alleviates dry eye in mice by suppressing matrix metalloproteinase-9 expression through the regulation of gut microbiota-involved NF-κB signaling. Plos One. 2024 June. doi:10.1371/journal.pone.0303423
4. Cong Y, Zhang Y, Han Y, Wu Y, Wang D, Zhang B. Recommendations for nutritional supplements for dry eye disease: current advances. Front Pharmacol. 2024 May;15:1388787. doi:10.3389/fphar.2024.1388787
5. Pilkington M, Lloyd D, Guo B, Watson SL, Ooi KG-J. Effects of dietary imbalances of micro- and macronutrients on the ocular microbiome and its implications in dry eye disease. Explor Med. 2024;5:127–147. doi:10.37349/emed.2024.00211
6. Ismail AMA, El-Azeim ASA, Saif HFAEA. Effect of aerobic exercise alone or combined with Mediterranean diet on dry eye in obese hypertensive elderly. Ir J Med Sci. 2023 Dec;192(6):3151-3161. doi:10.1007/s11845-023-03387-6
7. Alanazi SA, El-Hiti GA, Al-Baloud AA, et al. Effects of short-term oral vitamin A supplementation on the ocular tear film in patients with dry eye. Clin Ophthalmol. 2019 Apr;13:599-604. doi:10.2147/OPTH.S198349
8. Galor A, Gardener H, Pouyeh B, Feuer W, Florez H. Effect of a Mediterranean dietary pattern and vitamin D levels on dry eye syndrome. Cornea. 2014 May;33(5):437-441. doi:10.1097/ICO.0000000000000089
9. Bae SH, Shin YJ, Kim HK, Hyon JY, Wee WR, Park SG. Vitamin D supplementation for patients with dry eye syndrome refractory to conventional treatment. Sci Rep. 2016 Oct;6:33083. doi:10.1038/srep33083
10. Kawashima M, Nakamura S, Izuta Y, Inoue S, Tsubota K. Dietary supplementation with a combination of lactoferrin, fish oil, and enterococcus faecium WB2000 for treating dry eye: a rat model and human clinical study. Ocul Surf. 2016 Apr;14(2):255-263. doi:10.1016/j.jtos.2015.12.005
11. Pal S, Vani G, Donthinen PR, Basu S, Arunasri K. Tear film microbiome in Sjogren’s and non-Sjogren’s aqueous deficiency dry eye. Indian J Ophthalmol. 2023 Apr;71(4):1566-1573. doi:10.4103/IJO.IJO_2821_22
12. Goodman CF, Doan T, Mehra D, et al. Case–control study examining the composition of the gut microbiome in individuals with and without immune-mediated dry eye. Cornea. 2023 Nov;42(11):1340-1348. doi:10.1097/ICO.0000000000003195
13. Gupta N, Chhibber-Goel J, Gupta Y, et al. Ocular conjunctival microbiome profiling in dry eye disease: a case control pilot study. Indian J Ophthalmol. 2023 Apr;71(4):1574-1581. doi:10.4103/ijo.IJO_1756_22
14. Song J, Dong H, Wang T, et al. What is the impact of microbiota on dry eye: a literature review of the gut-eye axis. BMC Ophthalmol. 2024 Jun;24(1):262. doi:10.1186/s12886-024-03526-2
15. Chisari G, Chisari EM, Francaviglia A, Chisari CG. The mixture of bifidobacterium associated with fructo-oligosaccharides reduces the damage of the ocular surface. Clin Ter. 2017 May-Jun;168(3):e181-e185. doi:10.7417/T.2017.2002
16. Bai X, Xu Q, Zhang W, Wang C. The gut–eye axis: correlation between the gut microbiota and autoimmune dry eye in individuals with Sjögren syndrome. Eye Contact Lens. 2023 Jan;49(1):1-7. doi:10.1097/ICL.0000000000000953