Alternative Therapies for Dry Eye Disease

Rhiya Mittal; Sneh Patel; Anat Galor


Curr Opin Ophthalmol. 2021;32(4):348-361. 

In This Article

Abstract and Introduction


Purpose of Review: Dry eye disease (DED) is a multifactorial disease affecting approximately 5–50% of individuals in various populations. Contributors to DED include, but are not limited to, lacrimal gland hypofunction, meibomian gland dysfunction (MGD), ocular surface inflammation, and corneal nerve dysfunction. Current DED treatments target some facets of the disease, such as ocular surface inflammation, but not all individuals experience adequate symptom relief. As such, this review focuses on alternative and adjunct approaches that are being explored to target underlying contributors to DED.

Recent Findings: Neuromodulation, stem cell treatments, and oral royal jelly have all been studied in individuals with DED and lacrimal gland hypofunction, with promising results. In individuals with MGD, devices that provide eyelid warming or intense pulsed light therapy may reduce DED symptoms and signs, as may topical Manuka honey. For those with ocular surface inflammation, naturally derived anti-inflammatory agents may be helpful, with the compound trehalose being farthest along in the process of investigation. Nerve growth factor, blood-derived products, corneal neurotization, and to a lesser degree, fatty acids have been studied in individuals with DED and neurotrophic keratitis (i.e. corneal nerve hyposensitivity). Various adjuvant therapies have been investigated in individuals with DED with neuropathic pain (i.e. corneal nerve hypersensitivity) including nerve blocks, neurostimulation, botulinum toxin, and acupuncture, although study numbers and design are generally weaker than for the other DED sub-types.

Summary: Several alternatives and adjunct DED therapies are being investigated that target various aspects of disease. For many, more robust studies are required to assess their sustainability and applicability.


Dry eye disease (DED) is 'a multifactorial disease characterized by a loss of homeostasis of the tear film, and accompanied by ocular symptoms, in which tear film instability and hyperosmolarity, ocular surface inflammation and damage, and neurosensory abnormalities play etiological roles.'[1] It presents with variable symptoms (e.g. dryness, pain, poor visual quality) and signs (e.g. low tear production, tear film instability, ocular surface inflammation), and can occur as an isolated disease or co-morbid to systemic diseases such as Sjögren's, graft-versus-host disease, migraine, and fibromyalgia. Its symptoms can be debilitating, limiting the ability to work and negatively affecting mental health.[2] Both intrinsic (e.g. age, gender, genetics) and extrinsic (e.g. prolonged computer use, humidity, air pollution) factors can contribute to symptoms and/or signs of DED.[3,4] With a reported frequency of 5–50% in various populations across studies, DED is a highly prevalent disease and a major source of ocular morbidity in the general population.[4]

DED is often subtyped by the apparent tear film abnormalities noted in a new case. For example, aqueous tear deficiency (ATD) is characterized by decreased tear production/volume, whereas evaporative tear deficiency (ETD) is characterized by an unstable tear film in the setting of adequate tear production.[5] Both subtypes can be accompanied by ocular surface inflammation and/or abnormal tear composition (high or unstable osmolarity).[1] Abnormalities in the organs involved in producing tear products (meibomian glands (MG), goblet cells) can also accompany both DED sub-types, as can anatomic abnormalities of the eyelids and conjunctiva (e.g. ectropion, conjunctivochalasis) and abnormalities in corneal nerves.[6]

A challenge in DED is that its symptoms and signs are often discordant.[7] The variable nerve function may underlie this noted observation. For example, we have shown that corneal sensitivity varies widely in individuals with DED symptoms. In 403 individuals, the mean mechanical detection threshold was 87 mL/min±46 with a wide range of values (10th percentile 40 mL/min vs 90th percentile 145 ml/min). Furthermore, 24% of individuals had corneal sensitivity values that fell at or outside this range, 13% were hypersensitive and 11% were hyposensitive.[8] As such, the symptomatic interpretation of DED signs likely depends on the status of the nerves. In essence, DED may be understood as an umbrella term, characterized by multiple subtypes with different presenting manifestations that occur as a result of distinct underlying tissue injuries. This reality highlights the difficulty in developing a 'gold standard' disease definition and suggests that different treatment algorithms will likely be needed to target different underlying disease contributors in an individual patient.

The clinical work-up of DED involves subtyping individuals based on noted abnormalities.[6] Symptoms of DED can be assessed using various questionnaires (e.g. Dry Eye Questionnaire 5 [DEQ5][9] and Ocular Surface Disease Index [OSDI]).[10] Signs of DED are quantified by examination of the ocular surface. Tear stability can be assessed via tear break up time (TBUT), tear production via Schirmer strips, and corneal and conjunctival epithelial abnormalities via fluorescein and lissamine green staining.[11,12] A slit lamp exam can also detect signs of meibomian gland dysfunction (MGD) or anatomic abnormalities (e.g. conjunctivochalasis). Understanding the symptoms and signs in a patient aids in subtype categorization, which can guide therapeutic decision-making.

Given the complexity of DED, it is not surprising that several therapies are available that target variable aspects of disease. First-line therapies include artificial tears (with and without lipid components) and antiinflammatories (corticosteroids, cyclosporine, lifitegrast).[13] Other common therapies include punctal plugs for individuals with ATD, and eyelid hygiene or oral antibiotics for individuals with MGD.[14] Nevertheless, there is constant demand for novel alternative therapies that target different aspects of disease. The goal of this review is to describe emerging alternative and adjunct therapies in DED (Figure 1), focusing on their underlying mechanisms of action and reviewing available human data.

Figure 1.

Mapping of alternative therapies for DED based on present underlying pathologies. Alternative and adjunct therapies have been developed to treat various underlying causes of DED. Patients with aqueous deficient DED due to lacrimal gland hypofunction may benefit from transcutaneous electrical nerve stimulation (TENS), transcranial magnetic stimulation (TMS), stem cell therapy, or royal jelly therapy. Alternatively, those with evaporative DED due to meibomian gland dysfunction may be treated with office-based eyelid warming and massage devices, intense pulsed light therapy, and topical antibacterial agents, such as Manuka honey. Several therapies are currently available to target DED associated ocular surface inflammation. Trehalose and intense pulsed light therapy are two adjuvant therapies that are also being studied for this purpose. Lastly, nerve dysfunction may also be present in DED. Treatments for neurotrophic keratitis include nerve growth factor (NGF), platelet rich products (PRP), corneal neurotization, and polyunsaturated fatty acids (PUFA). In patients with neuropathic pain, cutaneous nerve blocks, TENS, botulinum toxin, and acupuncture have been used to treat pain of central origin, whereas autologous serum tears (AST) and amniotic membrane transplant (AMT) have been used to treat pain of peripheral origin. DED, dry eye disease.