Hyperosmolar Tears Enhance Cooling Sensitivity of the Corneal Nerves in Rats: Possible Neural Basis for Cold-Induced Dry Eye Pain

Harumitsu Hirata; Mark I. Rosenblatt

doi:10.1167/iovs.14-14642

How Should Corneal Nerves Be Incorporated Into the Diagnosis and Management of Dry Eye?

Current Ophthalmology Reports ◽

10.1007/s40135-021-00268-y ◽

2021 ◽

Author(s):

Sneh Patel ◽

Divy Mehra ◽

Kimberly Cabrera ◽

Anat Galor

Keyword(s):

Dry Eye ◽

Diagnosis And Management ◽

Corneal Nerves

Topical TRPM8 Agonist for Relieving Neuropathic Ocular Pain in Patients with Dry Eye: A Pilot Study

Journal of Clinical Medicine ◽

10.3390/jcm10020250 ◽

2021 ◽

Vol 10 (2) ◽

pp. 250

Author(s):

Hyeon Jeong Yoon ◽

Jonghwa Kim ◽

Jee Myung Yang ◽

Edward T. Wei ◽

Seong Jin Kim ◽

...

Keyword(s):

Quality Of Life ◽

Pilot Study ◽

Pain Intensity ◽

Dry Eye ◽

Associated Factors ◽

Treatment Result ◽

Ocular Pain ◽

Eye Pain ◽

Validated Questionnaire

Background: Activation of TRPM8, a cold-sensing receptor located on the cornea and eyelid, has the potential to relieve the neuropathic ocular pain (NOP) in dry eye (DE) by inhibiting other aberrant nociceptive inputs. We aimed to investigate the effect of a topical TRPM8 agonist, cryosim-3 (C3), on relieving DE-associated NOP. Methods: We conducted a prospective pilot study of 15 patients with DE-associated NOP. These patients applied topical C3 to their eyelid, 4 times/day for 1 month. The patients underwent clinical examinations. They also completed the Ocular Pain Assessment Survey (OPAS), which is a validated questionnaire for NOP, at baseline, 1 week, and 1 month after treatment. Result: At 1 week, the OPAS scores of eye pain intensity, quality of life (driving/watching TV, general activity, sleep, and enjoying life/relations with other people), and associated factors (burning sensation, light sensitivity, and tearing) improved. The total OPAS scores of eye pain intensity, quality of life, and associated factors remained improved at 1 month. The Schirmer test scores also improved at 1 month. Conclusion: TRPM8 agonist (C3) could be a novel agent for treating patients with DE-associated NOP who are unresponsive to conventional treatments.

Changes in Murine Subbasal Corneal Nerves After Scopolamine-Induced Dry Eye Stress Exposure

Investigative Opthalmology & Visual Science ◽

10.1167/iovs.18-26318 ◽

2019 ◽

Vol 60 (2) ◽

pp. 615 ◽

Cited By ~ 9

Author(s):

Cem Simsek ◽

Takashi Kojima ◽

Taeko Nagata ◽

Murat Dogru ◽

Kazuo Tsubota

Keyword(s):

Dry Eye ◽

Stress Exposure ◽

Corneal Nerves

Thrombospondin-1 Is Necessary for the Development and Repair of Corneal Nerves

International Journal of Molecular Sciences ◽

10.3390/ijms19103191 ◽

2018 ◽

Vol 19 (10) ◽

pp. 3191 ◽

Cited By ~ 5

Author(s):

Yukako Tatematsu ◽

Qalbi Khan ◽

Tomas Blanco ◽

Jeffrey Bair ◽

Robin Hodges ◽

...

Keyword(s):

Confocal Microscopy ◽

Sjögren’S Syndrome ◽

Dry Eye ◽

Ocular Surface ◽

Sjögren's Syndrome ◽

Sjogren’S Syndrome ◽

Sjogren's Syndrome ◽

Corneal Nerves ◽

Thrombospondin 1 ◽

Sjögren‘S Syndrome

Thrombospondin-1-deficient (TSP-1−/−) mice are used as an animal model of Sjögren’s Syndrome because they exhibit many of the symptoms associated with the autoimmune type of dry eye found in primary Sjögren’s Syndrome. This type of dry eye is linked to the inflammation of the lacrimal gland, conjunctiva, and cornea, and is thought to involve dysfunction of the complex neuronal reflex arc that mediates tear production in response to noxious stimuli on the ocular surface. This study characterizes the structural and functional changes to the corneal nerves that are the afferent arm of this arc in young and older TSP-1−/− and wild type (WT) mice. The structure and subtype of nerves were characterized by immunohistochemistry, in vivo confocal microscopy, and confocal microscopy. Cytokine expression analysis was determined by Q-PCR and the number of monocytes was measured by immunohistochemistry. We found that only the pro-inflammatory cytokine MIP-2 increased in young corneas of TSP-1−/− compared to WT mice, but tumor necrosis factor-α (TNF-α), monocyte chemoattractant protein-1 (MCP-1), and macrophage inflammatory protein-2 (MIP-2) all increased in older TSP-1−/− mouse corneas. In contrast, CD11b+ pro-inflammatory monocytes did not increase even in older mouse corneas. Calcitonin gene-related peptide (CGRP)-, but not Substance P (SubP)-containing corneal nerves decreased in older, but not younger TSP-1−/− compared to WT mouse corneas. We conclude that CGRP-containing corneal sensory nerves exhibit distinct structural deficiencies as disease progresses in TSP-1−/− mice, suggesting that: (1) TSP-1 is needed for the development or repair of these nerves and (2) impaired afferent corneal nerve structure and hence function may contribute to ocular surface dysfunction that develops as TSP-1−/− mice age.

Neurotrophic keratitis in autoimmune polyglandular syndrome type 1: a case report

BMC Ophthalmology ◽

10.1186/s12886-020-01770-w ◽

2021 ◽

Vol 21 (1) ◽

Author(s):

Po-Ying Wu ◽

Huai-Wen Chang ◽

Wei-Li Chen

Keyword(s):

Dry Eye ◽

Ocular Surface ◽

Hypogonadotropic Hypogonadism ◽

Ocular Surface Disease ◽

Syndrome Type ◽

Autoimmune Polyglandular Syndrome ◽

Corneal Nerves ◽

Neurotrophic Keratitis ◽

Autoimmune Polyglandular Syndrome Type

Abstract Background Autoimmune polyglandular syndrome type 1 (APS-1) is a rare autosomal recessive disease. In patients with APS-1, the most frequently reported ocular manifestations are keratoconjunctivitis with dry eye and retinal degeneration. However, to our knowledge, no research studies have reported the relationship between APS-1 and neurotrophic keratitis (NK). Possible explanations such as limbus cell deficiency being the primary cause of APS-1 keratopathy are not applicable to our unusual case of the patient with APS-1 presenting as ocular surface disease with NK. Our case findings suggest a new explanation for the observed corneal pathology and a potential treatment for these patients. Case presentation A 27-year-old woman was referred to our hospital because of intermittent blurred vision and recalcitrant ocular surface problems in both eyes for many years. She has a history of autoimmune polyglandular syndrome type 1 (APS-1), which includes hypothyroidism, hypoparathyroidism, hypoadrenalism, and hypogonadotropic hypogonadism. In vivo confocal microscopy clearly demonstrated significant degeneration of the sub-basal nerve plexus and stromal nerve bundles in her corneas bilaterally. She was diagnosed with severe NK and ocular surface disease caused by dry eye. Treatment included the application of therapeutic soft contact lenses and punctual occlusion; however, both treatments had a limited effect. Conclusion Patients with APS-1 may have ocular surface disease and severe damage to corneal nerves. Regular follow-up and treatment focusing on the regeneration of corneal nerves is particularly important in these patients.

Omega-3 supplementation is neuroprotective to corneal nerves in dry eye disease: a pilot study

Ophthalmic and Physiological Optics ◽

10.1111/opo.12365 ◽

2017 ◽

Vol 37 (4) ◽

pp. 473-481 ◽

Cited By ~ 26

Author(s):

Holly R. Chinnery ◽

Cecilia Naranjo Golborne ◽

Laura E. Downie

Keyword(s):

Pilot Study ◽

Dry Eye ◽

Dry Eye Disease ◽

Eye Disease ◽

Omega 3 ◽

Corneal Nerves

Evaluation of objective visual quality in dry eye disease and corneal nerve changes

International Ophthalmology ◽

10.1007/s10792-020-01483-5 ◽

2020 ◽

Vol 40 (11) ◽

pp. 2995-3004

Author(s):

Jiahui Ma ◽

Shanshan Wei ◽

Xiaodan Jiang ◽

Yilin Chou ◽

Yuexin Wang ◽

...

Keyword(s):

Dry Eye ◽

Clinical Symptoms ◽

Visual Quality ◽

Strehl Ratio ◽

Modulation Transfer ◽

Ocular Surface Disease Index ◽

Eyelid Margin ◽

Cutoff Value ◽

Corneal Nerves ◽

Corneal Nerve

Abstract Purpose To explore objective visual quality in dry eye diseases (DED) and the correlation between corneal nerves and objective visual quality. Methods Ninety-eight eyes of 49 patients with DED were included. Each patient was evaluated with the ocular surface disease index (OSDI), eyelid margin signs and meibomian gland assessments; corneal staining; tear film breakup time (TBUT); tear meniscus height (TMH); in vivo confocal microscopic (IVCM); objective visual quality including the objective scatter index (OSI), mean objective scattering index (mOSI), modulation transfer function (MTF) cutoff value and Strehl ratio. Results A significant correlation was found between the OSDI and mOSI (r = 0.422, p = 0.005), MTF cutoff value (r = − 0.355, p = 0.020), and Strehl ratio (r = − 0.446, p = 0.003). The OSI was significantly correlated with TBUTf (r = − 0.213, p = 0.042). The mOSI, MTF cutoff value, Strehl ratio were correlated with eyelid margin signs and meibomian assessments. Additionally, there was a statistically significant correlation between corneal nerve length and the mOSI (r = − 0.239, p = 0.037), OSI (r = − 0.294, p = 0.028), MTF cutoff value(r = 0.282, p = 0.012), and Strehl ratio (r = 0.299, p = 0.008). Conclusions Our study explored that objective visual quality was correlated with clinical symptoms and signs in DED patients. Furthermore, for the first time, our study explored the relationship between corneal nerves and objective visual quality and discovered that longer and wider corneal nerves were associated with better objective visual quality, which suggested that nerve changes may be a factor that related to poor visual quality in DED patients.

The Role of Neuropeptides in Pathogenesis of Dry Dye

Journal of Clinical Medicine ◽

10.3390/jcm10184248 ◽

2021 ◽

Vol 10 (18) ◽

pp. 4248

Author(s):

Daniel Duck-Jin Hwang ◽

Seok-Jae Lee ◽

Jeong-Hun Kim ◽

Sang-Mok Lee

Keyword(s):

Dry Eye ◽

Dry Eye Disease ◽

Eye Disease ◽

Future Research ◽

Immune Systems ◽

Pathogenic Mechanisms ◽

Corneal Nerves ◽

Ocular Surface Diseases ◽

Corneal Nerve

Neuropeptides are known as important mediators between the nervous and immune systems. Recently, the role of the corneal nerve in the pathogenesis of various ocular surface diseases, including dry eye disease, has been highlighted. Neuropeptides are thought to be important factors in the pathogenesis of dry eye disease, as suggested by the well-known role between the nervous and immune systems, and several recently published studies have elucidated the previously unknown pathogenic mechanisms involved in the role of the neuropeptides secreted from the corneal nerves in dry eye disease. Here, we reviewed the emerging concept of neurogenic inflammation as one of the pathogenic mechanisms of dry eye disease, the recent results of related studies, and the direction of future research.

Incidence and Risk Factors of Dry Eye in Children and Adolescents With Diabetes Mellitus: A 3-Year Follow-Up Study

Frontiers in Medicine ◽

10.3389/fmed.2021.760006 ◽

2021 ◽

Vol 8 ◽

Author(s):

Zhangling Chen ◽

Ying Xiao ◽

Yu Qian ◽

Qiurong Lin ◽

Zhaoyu Xiang ◽

...

Keyword(s):

Diabetes Mellitus ◽

Risk Factors ◽

Children And Adolescents ◽

Incidence Rate ◽

Dry Eye ◽

Study Cohort ◽

Children And Adolescent ◽

Eye Pain ◽

Long Course

Purpose: To investigate the incidence and risk factors of dry eye in children with diabetes mellitus (DM) over a period of 3 years.Methods: Children and adolescents with DM (age: 3–14 years) from the Shanghai Children and Adolescent Diabetes Eye (SCADE) study cohort who did not have dry eye in January 2018 were followed-up for 3 years and re-examined in January 2021, and the incidence rate and risk factors for dry eye were calculated.Results: Forty children and adolescents with DM came for follow-up in 2021. Nine of them were diagnosed with dry eye, resulting in a 3-year incidence rate of 22.5% and an annual mean incidence rate of 7.5% for dry eye. Univariate regression analysis confirmed that decreased corneal sensation (OR [Odds Ratio] = 25.60; 95%CI [Confidence Interval] = 1.31~501.69; P = 0.03) was the risk factor for dry eye incidence. Long course of DM (OR = 1.80; 95%CI = 0.96~3.38; P = 0.07), eye pain (OR = 12.27; 95%CI = 0.65~231.48; P = 0.09), and dry eye in parents (OR = 15.99; 95%CI = 0.76~337.75; P = 0.08) may interfere with the incidence of dry eye in them.Conclusions: The incidence of dry eye in children and adolescents with DM is high.

The Effects of Rebamipide 2% Ophthalmic Solution Application on Murine Subbasal Corneal Nerves After Environmental Dry Eye Stress

International Journal of Molecular Sciences ◽

10.3390/ijms20164031 ◽

2019 ◽

Vol 20 (16) ◽

pp. 4031

Author(s):

Cem Simsek ◽

Takashi Kojima ◽

Shigeru Nakamura ◽

Murat Dogru ◽

Kazuo Tsubota

Keyword(s):

Dry Eye ◽

Ophthalmic Solution ◽

Inflammatory Cells ◽

Office Workers ◽

Therapeutic Effects ◽

Fiber Density ◽

Neuroprotective Effects ◽

Staining Score ◽

Corneal Nerves

Rebamipide ophthalmic solution is a mucin secretagogue which is an important therapeutic agent in the treatment of dry eye. It has been noted that dry eye in office workers is associated with a decrease in secretory mucin. This study aimed to evaluate the effects of 2% rebamipide ophthalmic solution in mice subjected to environmental dry eye stress (EDES), which mimics the conditions of office workers. Thirty eyes from thirty BALB/c mice (eight-week-old males) were divided into three treatment groups: artificial tear (vehicle), 2% rebamipide ophthalmic solution, and 0.1% hyaluronic acid (HA) ophthalmic solution. After four days of pretreatment, mice were exposed to EDES for three days. The corneal subbasal nerve and inflammatory cells were then examined using in vivo confocal microscopy. Following EDES exposure, the lissamine green staining score was significantly lower and corneal sensitivity was more preserved in the 2% rebamipide group than in the HA group. In addition, the subbasal nerve fiber density was significantly higher and the DC density was significantly lower in the 2% rebamipide group than in the HA group. Overall, the topical rebamipide ophthalmic solution showed more favorable therapeutic effects when compared to the HA ophthalmic solution in a mouse model of EDES, likely owing to its anti-inflammatory and neuroprotective effects.