The clinical realm of dry eye disease (DED) management has grown tremendously with the addition of objective point-of-care tests, better understanding of etiologies and new treatment approaches. The headwaters multiply.

Which is good news for a few reasons. DED’s complexity lies in the fact that there can be a disconnect between the presenting signs and symptoms. And it’s complex because DED often involves multiple risk factors and mixed etiologies, and these ultimately all contribute, in varying degrees, to the resultant hyperosmolarity, inflammation and tear instability.^1,2 The headwaters converge. Thus, DED diagnostics should be a universal one to evaluate as a whole.

The driving point is that DED, with its multiple risk factors, is most often a mixed mechanism, where evaporative dry eye, caused by excessive tear loss due to an insufficient lipid or mucin, or meibomian gland dysfunction, most commonly a part of evaporative dry eye, has signs of gland atrophy drop and dropout obstruction.² Purely aqueous tear deficiency, caused by a reduction of lacrimal gland tear secretion, represents the minority of cases.

So diagnosing disease severity and etiology with newer and traditional technologies allows the physician to get a baseline assessment that lets him devise a treatment plan that can: add therapies; subtract any ineffective therapies from the existing regimen; and otherwise change the intervention to improve, or even resolve signs and symptoms.

In this article, we will discuss different diagnostics, via case studies, that can help elucidate the cause of the patient’s dry eye and thus guide targeted therapy.

Case 1 shows why it is important to take a complete patient history; this patient had multiple risk factors for his dry eye.

This patient has moderate DED, with multiple risk factors, including age, use of daily antihistamines, as well as the benzodiazepine and diuretic, and the MMP-9 is elevated, despite his being on chronic cyclosporine 0.05%.

For the allergic rhinitis, the oral antihistamine was discontinued, and he was switched to azelastine nasal antihistamine spray bid, fluticasone nasal spray bid for a short course, and started on lifitegrast 5% bid. The pretreatment topography images demonstrate irregular mires with a steeper keratometry and more astigmatism, while the topography after six weeks of treatment show smoother placido disc imaging, with slightly flatter keratometric values (Figures 1A and B). The post-dry eye treatment K values would have called for a stronger IOL pre-operatively, which may have mitigated the current hyperopic outcome had the DED been treated more aggressively before surgery.

TEST POINTERS

Although tear osmolarity doesn’t differentiate between the dry eye’s two primary diagnoses, aqueous tear deficiency (ATD) or evaporative dry eye (EDE), it gives us an understanding of the stability and health of the tear film. Lemp et. al found that an osmolarity cutoff of 312 mOsm/L had a 73% sensitivity and 92% specificity for diagnosing DED. Fluctuations in measurements either on different days or between eyes can also point to DED.^5,6

Slit lamp examination of the eyelid position, closure and blinking dynamics allows for diagnosis of other causes of patient’s symptoms such as floppy eyelid or ectropion that can result in exposure-related tear dysfunction.

Along with differentiating between EDE and ATD, one important treatment guide is the presence and absence of inflammation. Tear fluid metalloproteinase-9 (MMP-9) serves as an excellent inflammation biomarker.^7,8 Studies with MMP-9 indicate that clinically significant inflammation is present in 40% of dry eye patients, and results correlated well with TBUT, Schirmer testing, conjunctival and corneal staining, number of obstructed meibomian gland ducts and pathologic meibomian gland secretion.⁹ With Inflammadry (Rapid Pathogen Screening, Inc.) researchers found this detector had an 85% sensitivity, 94% specificity for diagnosing DED.¹⁰ Inflammation can show whether anti-inflammatory drugs may be of benefit.

Certain topographers such as the Oculus Keratograph 5M (Oculus), use infrared light to offer noninvasive tear breakup time, tear meniscus height (TMH), and meibography tools — which can aid in diagnosing EDE. Others such as the Tomey (Tomey) also measure parameters such as the surface regularity index (SRI), surface asymmetry index (SAI), and potential visual acuity index to elucidate severity of DED. The device’s placido rings can pick up subtle signs of OSD prior to slit lamp examination.¹¹

Agents such as cyclosporine, lifitegrast, and steroids are excellent anti-inflammatory options regardless of the etiology of the DED and should be used in patients with elevated MMP-9 levels. Topical cyclosporine (0.05%) results in increased tear production, decreased staining, and improved symptoms in patients with ATD secondary to inflammation.^12,13 Topical lifitegrast also results in improvement in ocular symptoms and signs of DED.¹²

New non-contact diagnostic tests can help diagnose EDE disease. Meibomian gland disease (MGD), a common cause of EDE, can occur in the absence of any obvious blepharitis, which is why meibomian gland assessment is vital to DED evaluation,³ as in Case 2.

Although normal tear osmolarity and InflammaDry can be seen in mild to moderate MGD, damage to the glands can be seen early on meibography. This is a patient where focused therapies to treat the MGD is imperative. Doxycycline 20 mg bid was instituted, as well as HydroEye bid, and thermal pulsation was performed two weeks later. The patient experienced significant resolution of discomfort and FBS. The follow-up meibography (Figure 2B) demonstrates a slight improvement in MG architecture with a suggestion of repopulation and lengthening of the individual glands nasally towards the fornix, where there was more disorganization and sparse meibum content in the pre-treatment meibography (Figure 2A).

For EDE especially secondary to MGD many new in-office products provide thermal pulsation and massage, leading to improvements of signs and symptoms of MGD.^12,20 Other new products utilize meibomian gland probing and intense pulse light therapy, which gives symptomatic relief to patients with EDE.¹²

TREATING ATD

The treatment for ATD results in lubrication of the ocular surface and dilution of the hyperosmolar tear film, and improvement in signs and symptoms. For more advanced ATD disease, serum tears (which contain many tear film components such as enzymes, growth factors, and immunoglobulins) amniotic membrane transplantation, and scleral lenses are great treatment options. Daily intake of omega-3 fatty acids delivers improvements in TBUT and Schirmer scores.^12,21

It is also important to rule out conditions that can masquerade as DED such as superior limbic keratoconjunctivitis (SLK), medicamentosa, Thygeson’s, CL toxicity, and conjunctivochalasis since these patients typically don’t respond to standard dry eye therapy.¹² As in this …

DED MASQUERADER

Anterior segment optical coherence tomography is a non-invasive diagnostic method for measuring tear meniscus height (TMH), which is a measure of the tear lake height generally assessed on the lower lid at the junction of the bulbar conjunctiva and the lower eyelid margin.²² ATD patients present with significantly lower TMH (0.13 +/- 0.07 mm) compared to normal eyes (0.25 +/- 0.08 mm).²³ Measuring TMH can also help to diagnose conjunctivochalasis, which is loose redundant conjunctiva between the globe and lower lid that can obstruct the flow of tears and result in tear instability. Conjunctivochalasis is a common cause of ocular symptoms similar to DED.²⁴

CONCLUSION

For those of us who have been researching and treating dry eye disease for some time now, we have come to understand that, to continue this article’s opening metaphor, it is akin to a river with many headwaters with lots of shallows — and who knows how many bends up ahead. OM

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About the Authors

Elizabeth Yeu, MD is assistant professor of ophthalmology at Eastern Virginia Medical School and in private practice at Virginia Eye Consultants in Norfolk, Va. Contact her at 757-622-2200 or eyeu@vec2020.com. Disclosure: Dr. Yeu is a consultant for Alcon, Allergan, AMO, Bausch + Lomb, RPS, Shire, TearScience, and TearLab.

Zaina Al-Mohtaseb, MD is an assistant professor and associate residency director, Department of Ophthalmology, Baylor College of Medicine in Houston, Texas and specializes in cornea, external disease and cataract and refractive surgery. Disclosure: Dr. Al-Mohtaseb is a consultant for Alcon and Allergan.