Alternative Therapies for Dry Eye Disease

Rhiya Mittal; Sneh Patel; Anat Galor


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

In This Article

Therapies for Lacrimal Gland Hypofunction

Lacrimal gland hypofunction, or low production and secretion of tears, is a common cause of ATD, and can occur in isolation or co-morbid with a systemic disease (Sjögren's, graft-versus-host disease).[15] Lacrimal gland hypofunction can manifest secondary to glandular inflammation, destruction, or denervation, among other causes.[16] Mainstay treatments for ATD include artificial tears and antiinflammatories,[15] however several alternative therapies are being explored that have been shown to be effective in improving gland output. Some of these therapies include neurostimulation, stem cell therapies, and topical royal jelly (RJ).

Peripheral Neurostimulation

Neurostimulation has been previously applied to a host of neurological disorders, including bladder dysfunction, Parkinson's disease, and neuropathic pain (NP).[17] More recently, it has been applied to lacrimal gland hypofunction.[18] Neurostimulation can be applied to peripheral (e.g. transcutaneous electrical nerve stimulation [TENS]) or central (e.g. transcranial magnetic stimulation [TMS]) nerves to stimulate innervated tissues.[18] Commercially available TENS devices induce lacrimation by stimulating anterior ethmoidal nerve afferents (branches of the trigeminal nerve), sending signals to the superior salivatory nucleus as an intermediate, and subsequently activating lacrimal glands, MG, and goblet cells, aiding in release of their tear film components.[18] TMS instead applies a coil externally to the scalp and directly stimulates neurons within targeted regions of the brain.[19]

The first peripheral nerve stimulator approved for DED was TrueTear (Allergan, Dublin, Ireland), a previously available handheld device that delivered microcurrents to the anterior ethmoidal nerves via prongs inserted into the nasal cavity.[20] Several studies demonstrated the use of TrueTear in improving symptoms and signs of ATD. In a randomized study of 48 individuals with ATD (OSDI≥13, Schirmer≤ 10 mm, stimulated Schirmer≥7 mm higher than basal), all subjects were treated with active and sham treatment one hour apart. The single three-minute active treatment acutely increased tear production (via Schirmer) to a greater degree than sham (active: 5.5 ± 3.0 mm to 25.3 ± 1.5 mm vs sham: 5.5 ± 3.0 mm to 9.2 ± 1.1 mm; P < 0.0001).[20] TrueTear's effect on tear production was also maintained over time. In a randomized study of 58 individuals with ATD (OSDI≥23, Schirmer≤10 mm, stimulated Schirmer≥7 mm higher than basal), subjects who received active treatment (n = 31) for 30 s 4–8 times/day over at least 30 days showed greater stimulated change in Schirmer directly after treatment at 0, 7, 14, 30, and 90 days compared to a sham-treated group (n = 27) (Δactive: +17.3 ± 2.1 mm, +10.4 ± 1.6 mm, +7.6 ± 1.5 mm, +7.1 ± 1.7 mm, +9.0 ± 2.0 mm, respectively vs Δsham: +1.3 ± 1.4 mm, -2.0 ± 1.0 mm, −5.0 ± 1.3 mm, −0.4 ± 0.7 mm, +0.4 ± 0.6 mm, respectively; P < 0.001 for all timepoints). In addition, the active treatment group demonstrated greater improvement in symptoms, TBUT, and corneal staining vs the sham group, but these improvements did not reach statistical significance.[21] Interestingly, intranasal stimulation has also been shown to improve aspects of DED beyond tear production. In a prospective, interventional study of 15 individuals with ATD (OSDI≥13, Schirmer≤10 mm, stimulated Schirmer≥7 mm higher than basal) a single 3-min treatment improved MG function in all subjects. Prestimulation, MG area was measured at 2,187.6 ± 635.9 μm2 via infrared meibography while poststimulation, the area was 1,933.2 ± 538.5 μm2, (11.6% decrease; P = 0.001), suggesting contraction of the glands due to stimulation.[22] In all studies, the most frequently reported adverse events included nasal pain or discomfort and epistaxis. Despite these early promising studies, TrueTear was removed from the market in 2020.

iTEAR (Olympic Ophthalmics, Inc., Issaquah, WA) is another TENS device that is currently available on the market. This device mechanically stimulates the external branch of the anterior ethmoidal nerve via an oscillating tip placed against the lateral aspect of the nose.[23] In an open-label study, 101 individuals with ATD (Schirmer≤10 mm, stimulated Schirmer≥7 mm higher than basal) used the device at home bilaterally at least 2×/day for 30 s for at least 30 days. At 30 days, OSDI was found to have decreased (40.3 ± 22.9 to 25.4 ± 18.6; P = 0.05). Schirmer also changed significantly directly after stimulation at 0, 14, and 30 days (+22 ± 7.8 mm, +11.1 ± 8.4 mm, +9.4 ± 9.3 mm, respectively; P < 0.05 for all). Noted side effects were minimal but included slight headache, sneezing, and intermittent nasal soreness.[23]

Peripheral neurostimulation is also possible through use of pharmacologic agents. OC-01 (Oyster Point Pharma, Princeton, NJ), a nasal spray containing the nicotinic acetylcholine receptor agonist varenicline, activates the trigeminal parasympathetic pathway to stimulate tear production.[24] Demonstrating this, in a study of 123 subjects with ATD (Schirmer≤10 mm), subjects were assigned 1:1:1 (n = 41 each) to receive a single nasal spray (1.2 mg/mL OC-01, 0.6 mg/mL OC-01, or placebo) to each nostril 2×/day for 84 days. At day 84, the OC-01 groups showed significantly greater improvements in Schirmer scores in comparison to placebo (0.6 mg/mL: 5.5–16.1 mm; P < 0.05 vs 1.2 mg/mL: 5.4–16.4 mm; P < 0.05 vs placebo: 5.3–11.5 mm; P value not provided). The most frequently reported adverse reactions in this study included sneezing, blurry vision, and headache.[24]

TMS has traditionally been used in the treatment of depression and pain,[18] but one company (EpiTech, Kefar Sava, Israel) is currently examining the use of TMS-like technology in stimulating peripheral nerves in DED. Demonstrating this potential use, in an open-label study, 29 individuals with DED of mixed etiologies [Sjogren's (n = 13), MGD (n = 12), ATD (n = 5)] all received a single 11-min treatment with the device in-office. At week 12 posttreatment, corneal staining was decreased compared to baseline (Δ-1.7; P < 0.001), and overall symptoms also decreased (via Patient-Reported Outcomes with LASIK-2 score, range: 0–100: Δ-15.3; P < 0.001), with no reported adverse effects.[25] Given small numbers and the lack of controlled studies, more data are needed to explore the safety and efficacy of TMS in DED.

Overall, these studies demonstrate that devices and compounds that can either electrically or pharmacologically stimulate peripheral or central nerves involved in lacrimal gland function may improve symptoms and signs of DED. Because these modalities target tear production, these studies have mostly focused on individuals with ATD, although future studies may show potential use for these therapies outside the scope of lacrimal hypofunction.

Stem Cell Therapies

Due to their multipotent differentiation capacity, stem cells have been studied as a regenerative strategy in various diseases (e.g. cardiovascular, autoimmune, neurodegenerative, oncologic).[26] Their use in lacrimal gland hyposecretion is more recent. A canine model first documented the therapeutic benefits of mesenchymal stem cell injection into the lacrimal gland as a treatment for ATD.[27] The efficacy of stem cell therapy in ATD was also documented in a Sjögren's murine model (thrombospondin-1−/− mice),[28] where restoration of lacrimal gland structure, decreased ocular inflammation, and increased tear production were noted after treatment.[29] More recently, human studies have begun to explore this strategy. In an open-label study, 7 subjects with ATD (OSDI>30, TBUT<10 s, Schirmer≤5 mm) received a transconjunctival injection of adipose-derived stem cells. After 16 weeks, all DE parameters improved from baseline, including OSDI (58.9 ± 20.6 to 34.1 ± 21.6; P<0.002), TBUT (3.7 ± 1.5 s to 7.1 ± 1.9 s; P < 0.002), Schirmer (4.6 ± 0.7 mm to 8.1 ± 3.1 mm; P < 0.03), and staining (Oxford grade; 2.4 ± 0.7 to 1.3 ± 1; P < 0.10). Minor adverse reactions were reported, including pain at the site, periorbital edema, ocular discomfort, and blurred vision.[30] Further human studies are needed, however, as the majority of studies have thus far been confined to preclinical models.

Royal Jelly

RJ (made by bees) is another compound shown to promote lacrimal gland activity. Bees release it through hypopharyngeal and mandibular glands into larvae honeycomb chambers, from where beekeepers harvest it.[31] RJ has been noted to have antibacterial, anti-inflammatory, antifungal, and hypotensive properties and has been used in humans to treat a variety of disorders outside the eye including menopause,[32] sarcopenia,[33] cancer, diabetes, and Alzheimer's disease.[34] Though its exact mechanisms are not fully understood, RJ has been found to promote mobilization of Ca2+ ions through muscarinic signal transduction pathways within lacrimal glands, allowing for phosphorylation of adenosine monophosphate kinase and preservation of local adenosine triphosphate. As such, preserving intraglandular energy status is a potential mechanism by which RJ improves tear secretion.[35] Demonstrating the use of RJ in ocular disorders, a randomized controlled study divided 43 individuals with ATD (symptoms on DEQ5, TBUT≤5 s, Schirmer≤5) into treatment (n = 21; 400 mg RJ tablet 6 times/day orally) and placebo (n = 22) groups. At 8 weeks, the treatment vs placebo group had greater improvements in tear stability via TBUT (treatment: 4.5 ± 3.2 s to 6.2 ± 2.9 s; P = 0.04; placebo: 3.8 ± 2.5 s to 5.3 ± 2.5 s; P = 0.3; between groups: P = 0.8) and tear production via Schirmer (treatment: 13.6 ± 10.6 mm to 19.5 ± 11.7 mm; P = <0.001; placebo: 13.8 ± 13.8 mm to 14.3 ± 13.4 mm; P = 1.0; between groups: P = 0.8), however, the in between group differences did not reach statistical significance. None of the subjects reported any adverse events or side effects.[36] Beneficial effects of RJ were seen in a rat model of ATD (low room temperature and humidity, constant airflow, and placement of rats on a swing to decrease blinking). Rats were treated with 1 mL of distilled water (vehicle) or RJ, honey, pollen, larva, or propolis orally once daily for 11 days. After 11 days, rats treated with RJ had the greatest increase in lacrimal protein secretion (ΔRJ:+175% vs Δvehicle: +60%; P<0.001) and tear secretion (RJ: +1.2× vs vehicle: +0.5×; P < 0.001) compared to all other compounds.[35] The findings from these studies suggest that RJ may impact lacrimal gland activity, potentially via increasing lacrimal gland energy content.

In summary, neurostimulation, stem cell therapy, and topical RJ are all potential adjuvant/alternative therapies that have been shown to improve lacrimal gland output in individuals with ATD.