Don’t forget to flip the lids in keratoconus

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

Characterization

Keratoconus is characterized by noninflammatory progressive thinning of the cornea. Symptoms include blurred and distorted vision. Although 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 saying keratoconus is more common in females than in males, whereas other publications note the opposite.^1-3 Keratoconus usually emerges around puberty, evolves fastest during the teens and 20s, and generally stops progressing by the fourth decade of life.⁴

A manifest refraction may reveal irregular astigmatism or decreased best-corrected visual acuity (BCVA), whereas 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 (OCT) 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 patients with keratoconus. 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 (see Figure 1).^5,6

This is best appreciated by lower and upper eyelid eversion.

Clinical evidence

Results from one study discovered a statistically significant association between participants with keratoconus and those with complete atopy, which was defined as having a history of itchy skin, asthma/hay fever, generally dry skin in the past year, visible eczema, and onset of these symptoms under the age of 2 years.⁶

Interestingly, the authors of the same study conducted a multivariate analysis revealing that those with complete atopy were 3.67 times more likely to develop keratoconus, although the data were not statistically significant (P = .08).⁶

The authors determined that the most significant risk factor for keratoconus was eye rubbing, reporting that study participants who did so, regardless of their degree of atopy, were 5 to 7 times more likely to develop keratoconus (P = .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

Because of 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 OTC topical allergy eye drops, with 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 patients with keratoconus had increased times for their lids to return to the original position, as compared with 1 in 15 patients in the control group.9

Therefore, during routine evaluation of patients with keratoconus, the upper and lower eyelids should be gently manipulated and everted to determine the extent of eyelid laxity (See Figure 2).

Finding causation

When floppy eyelids are detected in patients with keratoconus, clinicians should always question eye rubbing habits as well as sleeping position preferences.

If patients report sleeping facedown, it is likely that their eyelids are being everted by their pillow, which could lead to unintended eye exposure and rubbing during sleep. Patients may complain of severe dryness, irritation, redness, and mucus buildup 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% to 100%.^9,10

Although the exact etiology of floppy eyelid syndrome and its relationship to obstructive sleep apnea are unknown, 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 But there are no studies providing a clear explanation for 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 MMP, causing degradation of the basement membrane. This would lead to cytokine diffusion from the damaged epithelium to the stroma and promote 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 reached 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 and 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, it can lead to pulmonary and arterial hypertension, increasing stroke and cardiac events risk.

Furthermore, because of the strong association between keratoconus and floppy eyelid syndrome, it is vital that practitioners screen patients with keratoconus, especially those having a body mass index greater than 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. Atopic dermatitis, allergic conjunctivitis, floppy eyelid syndrome, and obstructive sleep apnea are conditions that should not be 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. 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;18(2):91-97.
doi:10.3109/09286586.2011.560747

3. Krachmer JH, Feder RS, Belin MW. Keratoconus and related noninflammatory corneal thinning disorders. Surv Ophthalmol. 1984;28(4):293-322. doi:10.1016/0039-6257(84)90094-8

4. Romero-Jiménez M, Santodomingo-Rubido J, Wolffsohn JS. Keratoconus: a review. Cont Lens Anterior Eye. 2010;33(4):157-166; quiz 205. doi:10.1016/j.clae.2010.04.006

5. Sharma N, Rao K, Maharana PK, Vajpayee RB. Ocular allergy and keratoconus. Indian J Ophthalmol. 2013;61(8):407-409. doi:10.4103/0301-4738.116063

6. Bawazeer AM, Hodge WG, Lorimer B. Atopy and keratoconus: a multivariate analysis. Br J Ophthalmol. 2000;84(8):834-836. doi:10.1136/bjo.84.8.834

7. Ahuja P, Dadachanji Z, Shetty R, et al. Relevance of IgE, allergy and eye rubbing in the pathogenesis and management of keratoconus. Indian J Ophthalmol. 2020;68(10):2067-2074. doi:10.4103/ijo.IJO_1191_19

8. Tran I, Harquel J, Sauer A, et al. Atopy, floppy eyelid syndrome, obstructive sleep apnea syndrome, eye rubbing and keratoconus. Invest Ophthalmol Vis Sci. 2012;53(14):6818.

9. Pihlblad MS, Schaefer DP. Eyelid laxity, obesity, and obstructive sleep apnea in keratoconus. Cornea. 2013;32(9):1232-1236. doi:10.1097/ICO.0b013e318281e755

10. McNab AA. Floppy eyelid syndrome and obstructive sleep apnea. Ophthalmic Plast Reconstr Surg. 1997;13(2):98-114. doi:10.1097/00002341-199706000-00005

11. Gupta PK, Stinnett SS, Carlson AN. Prevalence of sleep apnea in patients with keratoconus. Cornea. 2012;31(6):595-599. doi:10.1097/ICO.0b013e31823f8acd

12. Collier SA. Is the corneal degradation in keratoconus caused by matrix-metalloproteinases? Clin Exp Ophthalmol. 2001;29(6):340-344. doi:10.1046/j.1442-9071.2001.d01-17.x

13. Tazaki T, Minoguchi K, Yokoe T, et al. Increased levels and activity of matrix metalloproteinase-9 in obstructive sleep apnea syndrome. Am J Respir Crit Care Med. 2004;170(12):1354-1359. doi:10.1164/rccm.200402-193OC