How Nerves Unite the Complex System Behind Every Healthy Tear
Cory J. Lappin, OD, MS, FAAO, and Matthew Shulman, MD
This content was developed and is sponsored by Viatris, Inc
Understanding the Interconnected Mechanisms of Dry Eye Disease (DED)
Dry eye disease (DED) is a common condition encountered in clinical practice, yet its underlying pathophysiology remains complex and multifactorial. The ocular surface comprises various structures that work in harmony to maintain homeostasis. Disruption of any one of these components can lead to a breakdown in this balance, resulting in the vicious cycle of DED.
To better understand DED, it’s essential to understand how the structures of the ocular surface and their functions are interconnected. The eyelids, cornea, conjunctiva, goblet cells, lacrimal glands and accessory glands, meibomian glands, and the sensory and motor nerves make up the lacrimal functional unit (LFU). This intricate system is closely integrated with the trigeminal nerve and its parasympathetic pathways, which regulate tear production. Understanding this neural network is crucial for comprehending the multifactorial nature of DED and developing effective management strategies.
Nerve Regulation of Healthy Tear Production and Ocular Surface Homeostasis
The LFU is innervated by the ophthalmic branch of the trigeminal nerve, which transmits sensory information from the eyes to the brain.1,2 The corneal nerves, which arise from this branch, continuously collect sensory input and translate this feedback into physiological responses such as blinking and tear secretion, which is essential for maintaining a stable tear film. Through these actions, the trigeminal nerve plays a vital role in preserving ocular surface homeostasis.1,2
Tear production can be triggered reflexively through the trigeminal parasympathetic pathway, such as when an eyelash enters the eye. However, the same pathway is also sensitive to low-level, continuous stimuli, like normal tear film evaporation, which stimulates the production of basal tears that nourish and protect the ocular surface.3
The cornea is one of the most densely innervated tissues in the body, receiving an abundance of sensory feedback through the nerves of the LFU. These highly sensitive receptors detect even subtle changes in temperature, pressure, and potentially harmful stimuli, triggering the secretion of aqueous, lipid, and mucin components of the tear film to protect the ocular surface. This reflex is continuously active in healthy eyes, but it can be disrupted in conditions like neurotrophic keratitis, in which nerve sensitivity is impaired.
In addition, one-third of basal tear secretion is stimulated when branches of the trigeminal nerve passing through the nasal mucosa are activated during normal breathing, transmitting this information to the brain, and thus the LFU, to trigger tear secretion.3
The Interconnected Nature of Dry Eye Disease
Recognizing the role of nerves in connecting the structures of the LFU helps us understand how DED manifests and progresses. The disease process often begins when a reduction in basal tear production destabilizes the tear film. This instability triggers sensory nerves in the ocular surface, which activate a series of responses throughout the LFU. Over time, inflammation and cellular damage impair nerve sensitivity, diminishing their ability to communicate effectively and causing the eyes to compensate through mechanisms like increased blinking and tear production. As DED advances, this may lead to further damage, including inflammation and meibomian gland dysfunction (MGD).
The interconnectedness of the LFU underscores the multifactorial nature of DED. For instance, while MGD and premature tear evaporation are common in DED, up to 50% of DED patients also experience insufficient tear production,4 blurring the lines between evaporative and aqueous-deficient DED. Dysfunction of the lacrimal and meibomian glands does not occur in isolation, as these glands are linked through the neuronal network of the LFU, meaning dysfunction in one area often exacerbates problems in others.
Implications for Clinical Management
Understanding the LFU as a complex, interconnected system designed to maintain homeostasis offers insights into more effective treatment approaches for DED. Whether managing chronic DED in the clinic or preparing a patient for ocular surgery, the goal should always be to restore ocular surface health, stabilize the tear film, and ensure proper basal tear production. By supporting the LFU’s natural function, treatment strategies can help maintain a healthier ocular surface and more effectively address the symptoms of DED.
In clinical practice, managing DED requires a comprehensive approach that targets both the causes and symptoms. Therapeutic strategies should focus on restoring balance within the LFU, whether through therapies that promote tear production, address meibomian gland dysfunction, or reduce inflammation. Ultimately, understanding the neural regulation of the LFU allows for a more holistic approach to DED treatment, improving patient outcomes over the long term.
References
- Bron AJ, de Paiva CS, Chauhan SK, et al. TFOS DEWS II pathophysiology report. Ocul Surf. 2017;15(3):438-510.
- Jones L, Downie LE, Korb D, et al. TFOS DEWS II management and therapy report. Ocul Surf. 2017;15(3):575-628.
- Gupta A, Heigle T, Pflugfelder SC. Nasolacrimal stimulation of aqueous tear production. 1997;16(6):645-648.
- Matossian C, Crowley M, Periman L, Sorkin S. Personalized management of dry eye disease: beyond artificial tears. Clin Ophthalmol. 2022;16:3911-3918.
Cory J. Lappin, OD, MS, FAAO, practices at Phoenix Eye Care and the Dry Eye Center of Arizona.
Disclosures: Alcon, Barti, Bausch + Lomb, Bruder Healthcare and M&S Technologies (Hilco Vision), CSI Dry Eye Software, Dompé, Lumenis, Myze, NuLids, PRN Vision Group, Rinsada, Tarsus Pharmaceuticals, Viatris, Vital Tears. Dr. Lappin was compensated by Viatris for his work on this article.
Matthew Shulman, MD, specializes in cataract and refractive surgery and cornea and external disease at the Center for Excellence in Eye Care, Miami, Florida.
Disclosures: Dr. Shulman was compensated by Viatris for his work on this article.
USA-NON-2024-00039, 02/25
