More to keratoconus than meets the cornea: Be sure to flip the lids

In addition to evaluating vision and the cornea, the eyelids must also be closely examined in keratoconus patients.

When examining patients with keratoconus, it is a given that clinicians need to evaluate the cornea. However, we must remember that there are several common conditions associated with keratoconus, and taking a careful look at the eyelids may help to improve our overall management of these patients.

Keratoconus is characterized by noninflammatory progressive thinning of the cornea. Symptoms of keratoconus include blurred and distorted vision. While the precise etiology of keratoconus is unclear, it is suspected to occur from a combination of genetic, environmental, and hormonal influences.

Additionally, the gender distribution of keratoconus is variable, with some studies citing keratoconus is more common in females than males, while other publications note the opposite.^1,2,3 Keratoconus usually emerges around puberty and evolves fastest during the teens and twenties. Keratoconus generally stops progressing by the fourth decade of life.⁴

A manifest refraction may reveal irregular astigmatism or decreased best corrected visual acuity, while a slit lamp examination may reveal corneal thinning, central striae, Fleischer’s ring and/or corneal scarring. Corneal topography or tomography and ocular coherence tomography are noninvasive imaging modalities that can be used to monitor corneal curvature and thickness in detail.

However, in addition to evaluating vision and the cornea, the eyelids must also be closely examined in keratoconus patients. It is well known that keratoconus is associated with atopic conditions, such as asthma, eczema, and allergic conjunctivitis, which may present with diffuse papillae on the palpebral conjunctiva.^5,6 This is best appreciated by lower and upper eyelid eversion.

Results from one study discovered a statistically significant association between study participants with keratoconus and those with complete atopy, which was defined as having a history of itchy skin, asthma/hay fever, general dry skin in the past year, visible eczema, and onset of these symptoms under the age of two.6 Interestingly, the authors of the same study conducted a multivariate analysis that revealed that those with complete atopy were at a 3.67 times higher risk of developing keratoconus, although the data was not statistically significant (p=0.08).⁶ The authors determined that the most significant risk factor for keratoconus was eye rubbing, reporting that study participants with eye rubbing, regardless of their degree of atopy, were at a 5-7 times higher risk of developing keratoconus (p=0.001).⁶

Thus, the most likely mechanism by which atopy might contribute to keratoconus is through the eye rubbing tendency of atopic patients.⁶ These individuals have higher circulating Immunoglobulin E (IgE) levels; these antibodies bind to mast cells and cause histamine release. This cascade induces “itchy eyes” associated with allergic conjunctivitis. The act of eye rubbing then releases inflammatory cytokines, which have been associated with the progression of keratoconus.⁷

Due to the correlation between eye rubbing and keratoconus, it is essential that patients diagnosed with keratoconus are evaluated and treated for any underlying atopy, which could be contributing to eye rubbing and subsequent progression of keratoconus. In addition, it is important that any symptoms of ocular allergies are addressed to reduce the frequency of eye rubbing. Today, there are many good over-the-counter topical allergy eye drops, even some in preservative-free formulation. Refrigerated, cold artificial tears may also help suppress ocular itching and rubbing.

Additionally, there is an association between keratoconus and floppy eyelid syndrome, likely due to the increased rubbing of the eye associated with atopy.⁸ In a prospective case-controlled study, investigators determined that the incidence of floppy eyelid syndrome among patients with keratoconus was far greater than in the general population. In a vertical pull test (where the lower lid is pulled away and down from the globe and the amount of time it takes for the lid to return to its original position is measured), results revealed that 14 out of 15 keratoconus patients had increased times for their lids to return to the original position, as compared to 1 in 15 patients in the control group.⁹ Therefore, during routine evaluation of keratoconus patients, the upper and lower eyelids should be gently manipulated and also everted to determine the extent of eyelid laxity.

When floppy eyelids are detected in keratoconus patients, one should always question eye rubbing habits, as well as sleeping position preferences. If patients report sleeping face down, it is likely that their eyelids are being everted by their pillow and this may lead to unintended eye exposure and rubbing during sleep. Patients may complain of severe dryness, irritation, redness, and mucus build-up upon awakening. Education to alter sleeping position, increase ocular lubrication before sleeping, and use protective eye masks or goggles at night may be helpful.

Interestingly, there is also a correlation between floppy eyelid syndrome and obstructive sleep apnea. Some studies cite the rate of sleep apnea among those with floppy eyelid syndrome being as high as 90-100%.^9,10 The exact etiology of floppy eyelid syndrome and its relationship to obstructive sleep apnea is unknown, but the assumed mechanism involves an underlying inflammatory process present in both conditions.9 Studies have investigated the role of matrix metalloproteinases (MMPs) that link floppy eyelid syndrome and obstructive sleep apnea.¹¹ However, there have been no studies that provide a clear mechanistic explanation for the observed increased levels of specific MMPs in keratoconus, floppy eyelid syndrome, and obstructive sleep apnea.

In keratoconus, one study proposed the mechanism that damaged epithelial cells could activate MMP-2 via induced (Membrane type 1) MT1-MMP, causing degradation of the basement membrane; this would lead to cytokine diffusion from the damaged epithelium to the stroma and promote (Interleukin-1) IL-1-mediated inflammation.¹² In obstructive sleep apnea, the authors of a study hypothesized that the elevated levels of MMP-9 observed in patients with obstructive sleep apnea were due to apnea-related hypoxia during sleep. The authors came to that conclusion based on findings that serum levels and activity of MMP-9 were correlated with the duration of hypoxia during sleep (percentage of time with SaO2 < 90%), which demonstrates that hypoxia could increase MMP-9 production in patients with obstructive sleep apnea.¹³

Regardless of the underlying mechanism, patients diagnosed with floppy eyelid syndrome, who confirm symptoms of snoring, waking with a dry mouth, or sleeping on their stomach, should be referred to their primary care physician for sleep studies. Untreated sleep apnea can lead to pulmonary and arterial hypertension, increasing the risk of stroke and cardiac events. Furthermore, due to the strong association between keratoconus and floppy eyelid syndrome, it is vital that practitioners screen keratoconus patients, especially those having a BMI >30 or who are obese, for obstructive sleep apnea.

Ultimately, optometrists are uniquely positioned not only to detect and manage keratoconus, but also to care for the patient’s general well-being. By looking beyond the thinned cornea and focusing on distinctive aspects of the eyelid tissue and structure, we can gain insight into various atopic conditions that could be affecting the patient’s quality of life and general health. Atopic dermatitis, allergic conjunctivitis, floppy eyelid syndrome, and obstructive sleep apnea are conditions that we should not overlook in our keratoconic population.

References

1. Coco G, Kheirkhah A, Foulsham W, Dana R, Ciolino JB. Keratoconus progression associated with hormone replacement therapy. Am J Ophthalmol Case Rep. 2019;15:100519. Published 2019 Jul 16. doi:10.1016/j.ajoc.2019.100519

2. Millodot M, Shneor E, Albou S, Atlani E, Gordon-Shaag A. Prevalence and associated factors of keratoconus in Jerusalem: a cross-sectional study. Ophthalmic Epidemiol. 2011 Apr;18(2):91-7. doi: 10.3109/09286586.2011.560747. PMID: 21401417.

3. ​​Krachmer JH, Feder RS, Belin MW. Keratoconus and related non-inflammatory corneal thinning disorders. Surv Ophthalmol. 1984;28:293–322.

4. Romero-Jiménez M, Santodomingo-Rubido J, Wolffsohn JS. Keratoconus: a review. Cont Lens Anterior Eye. 2010;33(4):157-166. doi:10.1016/j.clae.2010.04.006

5. Sharma, N., Rao, K., Maharana, P. K., & Vajpayee, R. B. (2013). Ocular allergy and keratoconus. Indian journal of ophthalmology, 61(8), 407–409. https://doi.org/10.4103/0301-4738.116063

6. Bawazeer AM, Hodge WG, Lorimer B. Atopy and keratoconus: a multivariate analysis. Br J Ophthalmol. 2000;84:834–836.

7. Ahuja P, Dadachanji Z, Shetty R, Nagarajan SA, Khamar P, Sethu S, D'Souza S. Relevance of IgE, allergy and eye rubbing in the pathogenesis and management of Keratoconus. Indian J Ophthalmol. 2020 Oct;68(10):2067-2074. doi: 10.4103/ijo.IJO_1191_19. PMID: 32971611; PMCID: PMC7727983.

8. Ines Tran, J. Harquel, A. Sauer, D. Gaucher, C. Speeg-Schatz, P. Bourgin, T. Bourcier; Atopy, Floppy Eyelid Syndrome, Obstructive Sleep Apnea Syndrome, Eye Rubbing And Keratoconus. Invest Ophthalmol Vis Sci. 2012;53(14):6818.

9. Pihlblad, M. S., & Schaefer, D. P. (2013). Eyelid Laxity, Obesity, and Obstructive Sleep Apnea in Keratoconus. Cornea. 32(9), 1232–1236. doi:10.1097/ico.0b013e318281e755

10. McNab AA. Floppy eyelid syndrome and obstructive sleep apnea. Ophthal Plast Reconstr Surg. 1997; 13:98– 114.

11. Gupta PK, Stinnett SS, Carlson AN. Prevalence of sleep apnea in patients with keratoconus. Cornea. 2012;31:595–599

12. Collier SA. Is the corneal degradation in keratoconus caused by matrix-metalloproteinases? Clin Exp Ophthalmol. 2001 Dec;29(6):340-4. doi: 10.1046/j.1442-9071.2001.d01-17.x. PMID: 11778801.

13. Tazaki T, Minoguchi K, Yokoe T, Samson KT, Minoguchi H, Tanaka A, Watanabe Y, Adachi M. Increased levels and activity of matrix metalloproteinase-9 in obstructive sleep apnea syndrome. Am J Respir Crit Care Med. 2004 Dec 15;170(12):1354-9. doi: 10.1164/rccm.200402-193OC. Epub 2004 Sep 10. PMID: 15361365.