Stop me if you heard this one. A 42-year-old woman walks into an ophthalmologist’s office complaining that her eyes are dry and itchy.
Diagnosing and treating ocular surface disease is no joke and often confusing. An in-depth discussion about all of the diagnoses affecting the ocular surface is beyond the scope of this article; however, ocular allergy and dry eye disease (DED) are two of the most common diagnoses seen by the eye-care professional.1-3 Evaluating patients for either condition may be difficult because signs and symptoms are often similar; in fact, they coexist in many cases. But clarifying the diagnosis is critical to initiating the appropriate therapy, and, to make matters worse, the treatments for one (allergy) may exacerbate the other (dry eye).
With this article, I hope to provide a better “algorithm” to diagnose and treat these common, but often complex, ocular surface diseases.
PATHOPHYSIOLOGY OF OCULAR ALLERGY
Beware of false distinctions
Many clinicians separate allergic conjunctivitis into seasonal or perennial before initiating treatment; some treat them the same regardless of their differences. There is a misconception that seasonal is hay fever and perennial is atopic, but it is not that simple. Season allergy is often hay fever conjunctivitis, but vernal keratoconjunctivitis (VKC) may be seasonal as well, occurring mostly in the spring. Also, although atopic keratoconjunctivitis (AKC) is usually perennial, patients may have year-round acute allergies to dust mites, cat dander, and other common allergens. Even more confusing is that patients may have signs and symptoms of both VKC and AKC at the same time. In my fellowship, we were taught that VKC and AKC are on the same spectrum of atopic disease and often referred to them as “vertopic.”
An even better way to approach ocular allergy is to separate these patients into acute allergic conjunctivitis vs. “vertopic” conjunctivitis. Acute allergic conjunctivitis, even if year round, is an immediate Type I, immunoglobulin (IgE)-mediated response to an allergen. The allergen finds the specific IgE on the mast cell that degranulates and releases histamine. This causes an acute response of swelling, vasodilation and inflammation resulting in lid swelling, chemosis, tearing, itching and conjunctival injection. The “vertopic” spectrum (VKC and AKC) is both a Type I, IgE response and a Type IV, delayed hypersensitivity or T-cell mediated response.
It comes down to history
How do we distinguish between acute allergic and vertopic, and why do we need to? The “why” is more obvious, because the treatments differ as do the pathophysiology and hypersensitivity response for each. How we differentiate the two starts by taking a good history. A patient who provides a history of an acute, immediate reaction following an exposure to an allergen (for example, chemosis, itching, tearing and lid swelling after petting a dog or cutting the grass) is an IgE response. Acute allergic conjunctivitis is often rapid.
However, a history of asthma, eczema or a family history of asthma or eczema is suggestive of an atopic conjunctivitis consisting of both a Type I, IgE and Type IV, T-cell response. VKC patients have classic giant papillae of the upper tarsal conjunctiva referred to a “cobblestone papillae” or limbal thickening or bumps (limbal vernal) called “Horner-Trantas dots” composed of eosinophils and epithelial cells. VKC patients also may have sterile ulcers called “shield ulcers” of the superior or central cornea.
AKC patients may have a fine papillary reaction with more of a “milky edema” of the upper tarsal conjunctiva as well as linear scarring with occasional symblepharon. The teaching is that VKC and AKC are different (see Table 1). The truth is AKC and VKC, as mentioned above, are on the same spectrum and patients may have components of each — thus the term “vertopic.”
|Age||Younger patients||Older patients|
|Seasonal vs. Perennial||Seasonal, usually occurring in the spring. May have year-round symptoms.||Frequently perennial but may have seasonal exacerbations.|
|Papillary Reaction||Large “cobblestone” papillae under the upper lid.||Fine papillary reaction with a “milky edema,” upper and lower lid.|
|Conjunctival Findings||Limbal thickening or bumps (Horner-Trantas Dots) seen in limbal vernal KC.||Conjunctival scarring with occasional symblepharon.|
|Corneal Findings||Shield ulcer; stem cell dysfunction possible.||Corneal neovascularization and stem cell dysfunction possible.|
TREATMENT OF OCULAR ALLERGY
Understanding these differences in pathophysiology is important to help treat the allergic patient more effectively. Most clinicians know that acute allergic IgE-mediated conjunctivitis is treated with cold compresses, artificial tears (cold artificial tears work even better), topical antihistamines in combination with or separate from mast cell stabilizers, topical steroids, topical NSAIDs, topical vasoconstrictors (watch for rebound effect) or oral antihistamines.
However, for the atopic response (VKC and AKC), a more effective treatment is to use the above IgE-mediated therapies to treat the Type I response and add a T-cell mediated treatment, such as topical cyclosporine (Restasis, Allergan) or lifitegrast (Xiidra, Shire) — both off-label). I often treat these patients with a topical combination antihistamine and mast cell stabilizer b.i.d. and topical cyclosporine or lifitegrast b.i.d. I add a topical steroid for the more severe cases until the “fire is put out,” then I maintain them on the two b.i.d. drops listed above. With topical steroids, especially with VKC and cobblestone papillae, the use of solutions is preferred to suspensions, as the vehicle of the suspensions may get caught within the papillae and cause more irritation and inflammation.
Other off-label treatments for refractory atopic conjunctivitis are increasing the cyclosporine or lifitegrast to t.i.d. or q.i.d. or compounded topical tacrolimus b.i.d.
PATHOPHYSIOLOGY OF DED
What we know
DED is now well understood to be an inflammatory process.4 Several studies showed a T-cell infiltration in the lacrimal gland and conjunctiva of dry eye patients.5 Inflammation occurs even in those patients where it is not clinically apparent. Ocular surface stress, such as desiccation, leads to inflammatory mediator release and up-regulation of proteins, such as intercellular adhesion molecules (ICAMs). T-cells become activated, migrate into tissue where they bind with antigen presenting cells (APCs) and release cytokines, causing recruitment and activation of more T-cells and, ultimately, damage to the ocular surface.
Hard to (get a) handle
There are many reasons why DED is so difficult to diagnose and treat. The first is that DED is multifactorial with myriad triggers and risk factors. The second is that signs and symptoms may not correlate. Third, and often not realized, is that DED, like glaucoma, often requires a multi-treatment approach. I am frequently asked “What is the main trigger/risk factor of dry eye and how does it affect the treatment approach?” In some respects, it does not matter.
One of the best ways to explain the cycle of inflammation and dry eye is illustrated in Figure 1. Irritation (caused by things like smoking, pollution, contact lenses, topical glaucoma drops and ocular surgery) leads to inflammation, which causes a tear deficiency and instability and more irritation. Inflammation (caused by autoimmune diseases such as Sjogren’s, rheumatoid arthritis and lupus) leads to tear deficiency and instability that cause irritation, which propagates more inflammation, and the cycle continues. Tear deficiency and instability (caused by menopause and decreased androgens, rosacea and posterior blepharitis, systemic meds, etc.) leads to irritation, which leads to inflammation and causes more tear instability.
Ultimately, the cycle is not broken until the inflammation is addressed.
The discussion of dry eye treatments is extensive. To simplify for the purposes of this article, the approach to treatments should be:
- Treat the underlying inflammation, regardless of the trigger. Without breaking the cycle of inflammation, the dry eye may be chronic and progressive.
- Address the trigger if possible. If contacts, smoking or multiple glaucoma drops are causing the irritation, make the necessary changes.
- Use multiple therapies. A partial success in signs or symptoms with cyclosporine or lifitegrast is still a success, not a failure. If a patient is not 100% better, don’t stop the meds — add treatments, such as plugs, as needed. Some patients need two, three or even five different therapies, based upon your algorithm, to improve the condition.
- Look for dry eye co-conspirators if you feel like you are “spinning your wheels.” Dry eye co-conspirators are diseases that masquerade as dry eye or exacerbate it. In addition to ocular allergy, these include superior limbic keratoconjunctivitis (SLK), medicomentosa, mucous fishing syndrome, conjunctivochalasis and contact lens-related inflammation, to name a few.
Many dry eye algorithms follow a severity-based approach (Delphi panel treatment recommendations for DTS6), meaning your treatment plan is different for mild, moderate and severe dry eye. Other algorithms, such as TFOS DEWS II, separate dry eye into aqueous deficiency dry eye (ADDE), evaporative dry eye (EDE) or mixed7.
The Cornea, External Disease, and Refractive Society algorithm, or CEDARS algorithm, uses a diagnostic-based approach by separating dry eye into four basic categories:8
- Aqueous deficiency (diagnosed by low Schirmer’s, decreased tear meniscus or a lissamine green staining pattern consistent with K. Sicca)
- Evaporative, based on goblet cell/mucin deficiency (presumptive diagnosis based upon a rapid tear breakup time with a history suggestive of goblet cell loss, such as the use of chronic glaucoma meds or exposure to chemicals and conjunctival scarring). Goblet cell density may be assessed with impression cytology or biopsy (if available)
- Blepharitis/meibomian gland disease (MGD) (evaporative or non-evaporative), and
- Exposure keratopathy (partial or incomplete blink, lagophthalmos, lower lid ectropian etc.) (Figure 2).
A more targeted treatment
By separating the patient into these four categories, you can approach therapy in a more directed fashion. Remember that many patients fall into one or more of these categories. Determine your treatment based on each category and, in my opinion, get a more effective result. The CEDARS algorithm provides an extensive list of options for each diagnostic category (Figure 3).
For example, if a patient is aqueous deficient, treatment options include cyclosporine, lifitegrast, plugs, tears, ointments, omega-3 fish oils and gel inserts. Other innovative, off-label or compounded options include topical hormones, such as medroxyprogesterone or DHEA (topical androgens), topical albumin, autologous serum drops, amniotic membrane or amniotic cytokine extract drops, scleral lenses and nasal neurostimulation. For the mucin/goblet cell deficient patient, I often start with cyclosporine (based on the phase 3 studies showing a significant increase in goblet cell density compared with the vehicle) or lifitegrast (based upon it’s T-cell suppression).
Other suggestions include vitamin A ointment, either compounded or over-the- counter (outside the United States and available online), which helps to replenish goblet cells,9 moist chamber goggles and scleral lenses. Treatment options for the blepharitis/meibomian gland category include the standard anti-inflammatory treatments such as topical steroids, cyclosporine and lifitegrast (both off-label but excellent options) and omega-3 fish oils, as well as topical (azithromycin) and oral (doxycycline) antibiotics
Additional innovative options include topical compounded metronidazole ointment (same medicine as topical metrogel for facial rosacea but compounded in an ophthalmic preparation), topical compounded doxycycline drops (for those who cannot tolerate oral doxycycline) and topical clindamycin ointment (compounded). As well as the warm compresses, lid cleansers and pharmaceutical options, procedural therapies include thermal pulsation (LipiFlow, J&J Vision), pulsed light therapy (Lumenis) and meibomian gland probing (Maskin, Rhein Medical), to name a few.
Addressing the final category, exposure keratopathy, starts by identification — it is often missed as a cause for evaporative dry eye. I am not an oculoplastics specialist and therefore refer these poor lid closure patients to my colleagues. Having said that, I may suggest ointments at night for nocturnal lagophthalmos or moist chamber goggles during the day.
BETTER APPROACH FOR BETTER OUTCOMES
Ocular allergy and DED may be similar in presentation and occur concurrently, but often differ in therapeutic approach. Treatments based upon pathophysiology and diagnosis may provide for a happier and healthier patient. OM
- Gomes, PJ. Trends in prevalence and treatment of ocular allergy. Curr Opin Allergy Clin Immunol. 2014;14:451-456.
- The Gallup Organization, Inc. The 2009 Gallup Study of Dry Eye Sufferers. Princeton, NJ: Multi Sponsor Surveys, Inc: 2009.
- Stapleton F, Alves M, Bunya VY, et al. TFOS, DEWS II Epidemiology Report, Ocu Surf, 2017;15:334-365.
- Bron AJ, de Paiva CS, Chauhan SK, et al. TFOS, DEWS II Pathophysiology Report. Ocu Surf. 2017;15:438-510.
- Stern ME, Gao J, Schwalb TA, et al. Conjunctival T-cell subpopulations in Sjögren's and non-Sjögren's patients with dry eye. Invest Oph Vis Sci. 2002;43:2609-2614.
- Behrens A, Doyle JJ, Stern L, et al. Dysfunctional Tear Syndrome Study Group. Dysfunctional tear syndrome: A Delphi approach to treatment recommendations. Cornea. 2006;25:900-907.
- Tear Film and Ocular Surface Society (TFOS) Dry Eye Workshop (DEWS) TFOS DEWS II Report and Algorithm. The Ocular Surface. 2017;15:264-649.
- Milner MS, Beckman KA, Luchs JI, et al. Dysfunctional tear syndrome: Dry eye disease and associated tear film disorders — new strategies for diagnosis and treatment. Curr Opin Ophthalmol. 2017;28(suppl 1):3-47.
- Kim EC, Choi JS, Joo CK. A comparison of vitamin A and cyclosporine A 0.05% eye drops for treatment of dry eye syndrome. AJO. 2009;147:206-213. e3.