The Neurobiology of Dry Eye

Dry eye disease (DED) is one of the most common yet elusive conditions encountered in eye care. Some patients report debilitating burning, stinging, and light sensitivity, despite a relatively normal-appearing ocular surface, while others exhibit significant punctate keratitis, tear film instability, and eyelid inflammation but feel fine. This disconnect between symptoms and signs has puzzled clinicians for decades and often leads to unintentional misdiagnosis or mismanagement. Untreated or poorly managed DED can result in severe consequences including chronic neuropathic pain, neurotrophic ulceration, and permanent vision loss. Successful management depends on understanding the neurobiology of pain and its role in maintaining ocular surface homeostasis.

CORNEAL NERVE ANATOMY AND PHYSIOLOGY

The tear film is an extremely complex, multilayered, neuronally regulated structure that serves to physically protect the ocular surface by washing away environmental irritants and preventing infection, maintaining optical clarity as the first refractive surface of the eye, delivering oxygen and nutrients to the avascular cornea, and distributing growth and immune factors across the surface to support epithelial renewal.¹

To achieve homeostasis, the body relies on the peripheral afferent sensory nerves to gather information about the internal and external environment, communicate that information to the central nervous system (CNS) for integration and processing, and appropriately respond by sending signals back to the target tissue through efferent peripheral nerves to stimulate motor responses such as muscle contraction and gland secretion (Figure 1).

For how important vision is for survival, and how crucial the tear film and ocular surface are to vision, it is not surprising that the cornea is the most densely innervated tissue in the body.² Corneal nerves enable exquisite sensitivity to internal and environmental stimuli, allowing the CNS to regulate blink rate and harmoniously coordinate basal and reflexive gland secretions and tear production. The CNS controls tear film stability and osmolarity through the lacrimal functional unit and the corneal blink reflex.

NOCICEPTORS AND TRP CHANNELS

The corneal sensory nerves are branches of the nasociliary nerve (a branch of the ophthalmic division, V1, of the trigeminal nerve). Along with afferent sensory nerves in the conjunctiva and eyelid, the corneal sensory nerves terminate in nociceptors, specialized nerve endings that detect mechanical, chemical, and thermal changes. To distinguish among different stimuli, the trigeminal system contains several nociceptor subtypes: mechanoreceptors, which sense tactile pressure or distortion of the epithelium; polymodal nociceptors, which respond to chemical irritants, bacterial toxins, pH changes, and noxious thermal stimuli; and cold thermoreceptors, which indirectly monitor tear film evaporation to promulgate basal tear homeostasis. Each nociceptor subtype expresses distinct transient receptor potential (TRP) channels that transduce stimuli into electrical neural signals, including TRPV1 (noxious heat, capsaicin), TRPM8 (cool, menthol), TRPA1 (chemical irritants, inflammatory mediators), and osmosensitive channels (cell stretch/swelling, hyperosmolarity).³

NEURAL REFLEXES AND CORNEAL HEALING

Corneal nerves continuously monitor the ocular surface for changes in tear temperature (indirectly measuring tear volume), inflammation, and osmotic stress. They send afferent signals via the trigeminal pathway to the brainstem, which adjusts blink rate and tearing reflexes accordingly. Reflex arcs engage the efferent facial nerve (VII) to contract the orbicularis oculi (blinking) and parasympathetic fibers to stimulate lacrimal and meibomian gland secretion (tearing).

In addition to their sensory role, corneal nerves also release neuromodulators and neuropeptides that promote corneal epithelial growth, proliferation, and cell differentiation, playing a crucial role in the corneal healing response. The corneal epithelium reciprocates by releasing nerve growth factors that support neuronal survival, creating a symbiotic neuroepithelial relationship that is essential to maintaining ocular surface health.³

PATHOPHYSIOLOGY OF NOCICEPTIVE PAIN IN DED

Under normal circumstances, this cycle of afferent monitoring, CNS processing, and efferent modulation preserves ocular surface integrity (Figure 2). In DED, however, the neurosensory system becomes maladaptive. Chronic ocular surface damage, inflammation, and aberrant neural activity establish a vicious cycle of discomfort, photophobia, and pain.

Pain, in its simplest form, is the nervous system’s warning of actual or potential tissue damage.⁴ Acute nociceptive pain is protective; it engages brainstem reflexes and conscious somatosensory awareness. Normally, nociceptive pain resolves when the stimulus is removed and inflammation has subsided. Acute flares of DED that resolve quickly reflect the nociceptive pain component of the disease.

However, DED is multifactorial, with the ocular surface being continually challenged by factors such as poor eyelid hygiene, infection, contact lens overwear, environmental pollutants, and lagophthalmos. These stressors disrupt the tear film, induce chronic hyperosmolarity, and activate corneal nociceptors. When undertreated, this ongoing insult drives chronic epithelial and nerve damage, inflammation, and a self-perpetuating cycle of neuroinflammation. Damaged nociceptors develop lower pain activation thresholds and increased excitability responses to stimuli, a process known as peripheral sensitization.⁵ Clinically, these changes explain symptoms such as hyperalgesia (exaggerated pain from a mildly irritating stimulus) and allodynia (pain from stimuli that should not be painful, such as wind or light). This is why many patients describe severe ocular discomfort disproportionate to slit-lamp findings. Alternatively, progressive nerve injury further impairs corneal healing, reducing neurotrophic support and risking neurotrophic keratopathy, where patients present asymptomatically with significant objective clinical findings, as they have lost the neural ability to feel the surface of their eye.

PATHOPHYSIOLOGY OF NEUROPATHIC PAIN IN DED

If peripheral sensitization persists, chronic peripheral nerve input can lead to central sensitization, where the second- and third-order neurons in the somatosensory trigeminal afferent pathways become hyper-responsive and amplify pain signals, even in the absence of nociceptive stimuli. Central neuropathic eye pain can result secondary to maladaptive plasticity from undertreated and chronic DED or may be caused by conditions that causes direct damage to the CNS (eg, traumatic brain injury, fibromyalgia, diabetes, and systemic medications).

Unlike nociceptive pain that may be described as discomfort, dryness, or itching, neuropathic pain is often described as hot, burning, shooting, stabbing, or electric-like pain. Clues that the patient may have neuropathic pain include symptoms severely disproportionate to ocular signs, persistence of pain after instilling topical anesthesia (proparacaine challenge), and persistence of symptoms despite aggressive DED therapy and objective ocular surface improvement.

THERAPEUTIC OPPORTUNITIES IN DED

Understanding the neurobiology of pain allows clinicians to more accurately phenotype DED and develop targeted, patient-centered treatment approaches. Not all symptoms are driven by ocular surface inflammation. Patients may have neuropathic mechanisms (eg, trigeminal neuralgia, neurodegenerative disease), systemic factors (eg, medications that affect neurosensory pathways; systemic inflammation from chronic stress, poor diet, not sleeping), or local structural abnormalities (eg, eyelid malposition, blepharitis) that contribute to and perpetuate DED unless properly ameliorated.

While inflammation generates symptoms, it is ultimately a response to underlying insults. Effective treatment requires addressing both the inflammation and its root causes. Over-the-counter lubricants may provide temporary relief but do not address chronic disease drivers such as poor eyelid hygiene, meibomian gland dysfunction, or environmental stressors. Alternatively, heat-based treatments for meibomian gland dysfunction will not address neurosensory abnormalities on the cornea and may actually worsen nociceptive and neuropathic pain. Given the complicated nature of DED, many patients likely need a combination of complementary treatment strategies for proper disease management (Table).

MORE THAN MEETS THE EYE

DED is more than just an ocular surface disorder; it is a neurosensory condition where corneal and central pain pathways play central roles. Appreciating the contributions of peripheral and central sensitization helps explain why symptoms and signs may not always align and why some patients remain refractory to traditional therapies. As our understanding of the neurobiology of ocular pain advances, so too does the opportunity for more precise, personalized therapy, improving outcomes and quality of life for patients living with this complex disease.