Stemming the Tide

Evaporative dry eye (EDE) is a common form of dry eye disease (DED), characterized by tear film lipid layer deficiency which increases tear evaporation, resulting in eye dryness. EDE is more prevalent than aqueous-deficient dry eye, the other form of DED, with more than 80 percent of DED patients presenting with EDE alone or a combination of both (1, 2). The primary cause of EDE is Meibomian gland dysfunction (MGD), a chronic, diffuse abnormality of the Meibomian glands, commonly characterized by terminal duct obstruction and changes in glandular secretion. Alongside EDE, MGD may also cause hyperosmolarity, instability of the tear film, increased bacterial growth on the lid margin; ocular surface inflammation; and damage (3). 

The global prevalence of DED lies between 50–80.4 percent (4, 5), with a large majority of these patients also displaying signs of MGD (6). Looking further, increased rates of DED are found within the older population, in particular, postmenopausal women (4, 7). Conversely, men are more vulnerable to experiencing MGD. Other MGD risk factors include older age and Asian ethnicity. Little is known about the incidence and prevalence of dry eye post-cataract surgery. However, DED is a remarkably frequent consequence of LASIK surgery. Nearly all patients experience DED symptoms immediately after surgery, although these numbers fall after six months to a year (8).

^{Table 1. Causes of EDE.}

India, as an emerging economy with a growing middle class, increasing air pollution and urban migration, and a large aging population, appears to be on the brink of a DED epidemic (9). Inconsistent diagnostic criteria alongside a lack of effective treatment algorithms and limited availability of advanced diagnostic techniques which can only be found at specialized centers are major causes of prevalence of MGD in India that has recently risen (10, 11, 12). Additionally, Indian ophthalmologists have limited treatment options for both EDE and MGD and those available may result in poor outcomes due to the limited effectiveness, drug intolerance, and prolonged therapy (13). Here we want to focus on the challenges faced during EDE diagnosis and management in India and share an overview of emerging therapeutics helping to alleviate the signs and symptoms of MGD.

Major risk factors for evaporative dry eye
 

The Indian population, the majority of whom live with diabetes, dyslipidemia, and other cardiovascular disorders, are at high risk of developing eye diseases. Regular contact lens users, excessive visual display terminal users, and regular smokers are all also highly prevalent for EDE and MGD. Additionally, patients with hypothyroidism, rheumatoid arthritis, and those taking anti-allergic, antihypertensive, anti-depressant, and topical anti-glaucoma drugs are also prone to these ocular syndromes (14, 15, 16). Apart from these risk factors, the increased use of digital screens for work, communication, and entertainment, especially during the pandemic, has resulted in a recent abrupt increase in DED as increases in digital screen usage reduces blink rate leading to EDE (17, 18).

Diagnosis of MGD: the major risk factor 
 

Standardized diagnostic criteria are crucial for the detection of MGD. Additionally, to assist in the preoperative process and ease any postoperative complications, ophthalmologists need to advise patients on EDE diagnoses. More specifically, all patients undergoing ophthalmic surgery should be screened for DED and MGD which can be potential barriers to achieving desired outcomes (19, 20). The standard treatment guidelines for DED management in India, state that diagnosis of DED can be carried out using routine tests (21, See Figure 2).

Specific MGD diagnosis is carried out using common identifiers such as subjective symptoms, lid margin abnormalities, condition of the gland orifices, and meibum grade (22). Morphological analysis of meibomian glands is emerging as a complementary clinical parameter with the diagnostic potential to diagnose early stage MGD (23). Abnormal morphological alterations in the lower eyelid and the shortening of meibomian glands are key markers in EDE patients (24). However, morphological analysis approaches, such as conventional meibography and confocal microscopy, are expensive and are not widely applicable in resource-limited settings of rural India (9).

Current challenges and dilemmas in diagnosing EDE
 

Although disease prevalence is high, clinical diagnosis of EDE, is challenging in terms of differentiating MGD from other causes of dry eye (20, 25). Variability in the clinical presentation of symptoms and a lack of specific diagnostic criteria make EDE diagnosis complex. Although, there are various diagnostic tests available for MGD, there is no uniformity or standardization in test recommendation. Depending on the facilities available, the approach can vary between hospital settings in India. Receiving the appropriate treatment often requires patients to visit a physician many times to learn the underlying cause of their complaints, which can lead to frustration resulting from a perceived lack of clear diagnosis and unsatisfactory improvement during treatment. However, even without using expensive gadgets, a simple slit lamp biomicroscopy can provide indicators of a MGD diagnosis. Clogging of the meibomian ducts, presence of bubbles in the tear film, and vascularization of lid margin as assessed on slit lamp biomicroscope all suggest the presence of MGD. The autorefractometer is another simple device, available to all ophthalmologists, which provides information regarding the meibomian glands and ducts.

Management of EDE: new advancements
 

A recent shift in considering EDE as a multifactorial disorder has led to a plethora of new and more effective medications. Indian ophthalmologists consider patient education and prevention of evaporative stress to the eye by altering the environment as the first step in the management of EDE (26). Accounting for the overlap between aqueous-deficient dry eye and EDE, therapy is tailored to the disease severity alongside patient signs and symptoms. Principally, an early correct diagnosis is crucial for a successful treatment outcome.

The simplest MGD treatment methods used by ophthalmologists across India and elsewhere are warm lid compresses and manual lid massage. Warm lid compresses can be provided either by using warm water and a clean cotton cloth or specialized eye masks that can be heated. These deliver moist heat continuously for approximately 10 minutes – although the heat provided is inconsistent throughout the treatment period.

Other advanced management techniques include: Meibomian gland probing, automated massage, in‑office intense‑pulsed therapy, dietary modification and anti-inflammatory therapy (26). Many AT products are widely available as over-the-counter (OTC), first-line EDE treatments. The active ingredients typically include lubricants and demulcents which offer viscosity, retention time, and adhesion to the ocular surface (27). However, though these agents alleviate the symptoms and reduce DED signs, the underlying causes remain unaffected. There is, therefore, a need for effective therapeutic agents targeting the causative mechanisms of disease, especially for treating MGD, which results in the lipid layer having decreased thickness. Similarly, management of DED post-ocular surgery, requires an examination for components of EDE or MGD. If found, choosing the right AT drop instead of prescribing any readily available product is important.

Pharmaceutical companies are continually improving AT efficacy by adding new excipients in eye formulations such as gelling agents and mineral oil to enhance delivery of the active ingredients. One such example is the unique combination of PEG and PG with HPG that facilitates the development of a viscoelastic gel-matrix, which promotes the retention of the active demulcents for tear film stability, lubrication, and extended protection of the ocular surface. The combinations of CMC and glycerin, formulated with flaxseed and castor oil, are also available in the global market, which protect tears from evaporation and nourishes the lipid layer by providing essential hydration to all the three layers of the tear film. Another emerging innovation is lipid-based ATs using nano emulsion-based technology. A recent product launch is PG/HPG-based biphasic artificial tear formulation, designed for better delivery of anionic lipids and mineral oils to the ocular surface for the improvement of tear film stability in patients with DED.It has an additional advantage of better ocular surface coverage, tear film stabilization, prolonged retention of the lubricant PG, and enhanced moisture retention of the tear film with the unique HPG/borate viscoelastic meshwork (see Figure 4). In addition, in the global market, this recently introduced nano emulsion-based AT is reported to provide long-lasting lubrication and surface protection from evaporation of the tear film (28). However, lipid-enhanced ATs are not widely used for the management of MGD and EDE in India due to limited availability. Launching emerging products in the Indian ophthalmology market may provide more effective treatment options for the management of this widely prevalent and debilitating disease. 

Conclusion
 

Although there are numerous traditional treatment options available, unfortunately, the treatment of EDE remains still challenging. Addition of new treatment options such as lipid-based ATs for EDE may play an important role in alleviating the clinical symptoms and signs of this disease. The increased availability of such formulations and a better understanding of their mechanism of actions may help Indian ophthalmologists to make appropriate treatment decisions. In addition, to tackle the other challenges of high prevalence, patient burden, and underdiagnosis of EDE in Asian countries, there is an utmost need for developing a strategic approach in diagnosis and treating EDE. For that, it is important to educate the eye care practitioners to follow a simple, standardized yet equally effective, accurate, and early diagnostic approach.

Acknowledgment

Medical writing support was provided by Shalini Vasantha, Ph.D  and Shelly Arora, M Pharm Indegene Pvt. Ltd., Bangalore, India.