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Over-the-counter or prescription therapies can reduce irritation to a tolerable level in most dry eye patients; however, a small percentage of patients with dry eye (5% or fewer, in my experience) have severe or disabling symptoms, sight-threatening corneal disease that typically is not controlled with conventional therapies or both. These patients require more aggressive therapies, some of which are not widely available.

Effective treatment of these conditions requires a comprehensive evaluation to properly diagnose and classify the dry eye. The workup should include validated symptom questionnaires and diagnostic tests to evaluate tear volume and production, as well as stability and health of the ocular surface epithelium using fluorescein and lissamine green dyes. Commonly used questionnaires include the Ocular Surface Disease Index (OSDI)—which has three components that assess vision-related function, ocular symptoms and environmental triggers—or the Symptom Assessment in Dry Eye (SANDE), which consists of visual analog scales that measure severity and frequency of irritation. I find that the SANDE questionnaire is faster and easier for patients to interpret.

 Severe symptom scores may be due to severe ocular surface disease (e.g., keratoconjunctivitis sicca) or keratoneuralgia; that is, sensitization of the trigeminal nociceptors in the cornea. Patients with this condition have symptoms out of proportion to clinical signs. In fact, the only objective finding may be rapid tear break-up. Patients often complain of sensitivity to wind and air drafts, have allodynia (particularly photo-oculodynia) and often have a history of LASIK surgery.

Treatment should focus on improving dryness and tear stability to reduce nerve signaling. If dry eye treatment is not effective, other therapies, such as topical treatment with autologous blood products (i.e., serum or platelet-rich plasma) have been found to provide relief. Because of its higher growth factor concentration, platelet-rich plasma (PRP) has been reported to have greater efficacy than serum.¹ Scleral lenses can shield the cornea from noxious stimuli, but patients often do not tolerate them because of their heightened corneal sensitivity. Systemic therapies that reduce signaling or pain sensation, such as gabapentin, duloxetine or low-dose naltrexone, can be considered. To minimize side effects, gabapentin can be started at a low dose and gradually increased. Trigeminal nerve stimulation and periocular and trigeminal nerve blocks also have reported efficacy.^2,3

On the other end of the spectrum are patients with severe corneal epithelial disease due to tear dysfunction and inflammation, and, in some cases, mechanical issues (i.e., lid cornification and trichiasis) or exposure. Typically, these patients have aqueous tear deficiency. They may complain of severe irritation or, paradoxically, may have a paucity of symptoms due reduced corneal sensitivity resulting from degeneration of the corneal epithelial nerve plexus. There is probably a neurotrophic component in these corneas.
 
Therapeutic approaches to severe corneal epitheliopathy include frequent lubrication (my preference is artificial tears containing high-molecular-weight hyaluronic acid) and punctal occlusion when tear production or volume is low. Immunomodulatory (cyclosporine) and anti-inflammatory (corticosteroids) agents can often improve symptoms and signs. Cyclosporine has been found to increase conjunctival goblet cell density, which is often reduced in these patients.⁴ Autologous blood products—especially PRP—have also been found to improve symptoms, signs and tear stability. A recent outcome study of patients treated with autologous PRP for at least 6 months at three major eye institutes in the United States reported that 74% had improvement in corneal fluorescein staining with more than a 50-point mean reduction in SANDE questionnaire scores.⁵

Scleral lenses can also dramatically improve eye irritation, visual function and photophobia in patients with severe corneal epithelial disease.^6,7 They are also particularly useful for patients who are unable to produce tears in response to desiccating environmental conditions. Scleral lenses can be used in conjunction with serum or plasma drops, and instillation of PRP drops in the scleral lens reservoir was found to be well tolerated with no adverse effects.⁸

While they are often challenging to manage, patients with severe dry-eye-associated symptoms or signs should have a comprehensive evaluation to identify the underlying problem and often require specialized therapies that have been found to be effective.

References

1. Wang M, Yennam S, Pflugfelder S. Initial experiences using plasma rich in growth factors to treat keratoneuralgia. Front Med (Lausanne). 2022;9:946828. doi:10.3389/fmed.2022.946828
2. Zayan K, Aggarwal S, Felix E, Levitt R, Sarantopoulos C, Galor A. Transcutaneous electrical nerve stimulation for the long term treatment of ocular pain. Neuromodulation. 2020 Aug;23(6):871-877. doi:10.1111/ner.13146
3. Patel S, Mittal R, Felix ER, Sarantopoulos KD, Levitt RC, Galor A. Differential effects of treatment strategies in individuals with chronic ocular surface pain with a neuropathic component. Front Pharmacol. 2021 Dec;12:788524. doi:10.3389/fphar.2021.788524
4. Pflugfelder SC, De Paiva CS, Villarreal AL, Stern ME. Effects of sequential artificial tear and cyclosporine emulsion therapy on conjunctival goblet cell density and transforming growth factor-beta2 production. Cornea. 2008 Jan;27(1):64-69. doi:10.1097/ICO.0b013e318158f6dc
5. Soifer M, Tovar A, Wang M, et al. A multicenter report of the use of plasma rich in growth factors (PRGF) for the treatment of patients with ocular surface diseases in North America. Ocul Surf. 2022 Jul;25:40-48. doi:10.1016/j.jtos.2022.04.007
6. Bavinger JC, DeLoss K, Mian SI. Scleral lens use in dry eye syndrome. Curr Opin Ophthalmol. 2015 Jul;26(4):319-324. doi:10.1097/icu.0000000000000171
7. Basu S, Shanbhag SS, Gokani A, Kedar R, Bahuguna C, Sangwan VS. Chronic ocular sequelae of Stevens-Johnson syndrome in children: long-term impact of appropriate therapy on natural history of disease. Am J Ophthalmol. 2018 May;189:17-28. doi:10.1016/j.ajo.2018.01.028
8. Wang M, Yennam S, McMillin J, et al. Combined therapy of ocular surface disease with plasma rich in growth factors and scleral contact lenses. Ocul Surf. 2022 Jan;23:162-168. doi:10.1016/j.jtos.2021.09.003