Neuropathic Ocular Pain: An Important Yet Underevaluated Feature of Dry Eye

A Galor; RC Levitt; ER Felix; ER Martin; CD Sarantopoulos


Eye. 2015;29(3):301-312. 

In This Article

Central Sensitization and Chronic Dry Eye Symptoms

If ocular surface damage persists, or if the inflammatory cascade is not dampened, changes may occur in the central nervous system (CNS) and produce central sensitization (Figure 3). This is defined as pain hypersensitivity that may arise from reduced activation thresholds and abnormal signaling amplification within the CNS.[28] The hallmark of central sensitization is pain that is disconnected from ongoing peripheral pathology. This is commonly seen in dry eye as patient symptoms often do not mirror ocular surface findings.[73] The process of central sensitization may also initially be reversible, but it often becomes permanent (Figure 4).

Figure 4.

A simplified model of chronic dry eye development. Dry eye symptoms arise after an environmental insult, inflammation, and hyperosmolarity activate nociceptors (nociceptive pain). Typically, as in scenario a, the insult and inflammation resolve along with the dry eye symptoms. In susceptible patients, however, or in patients with ongoing insults, chronic changes can occur in the peripheral and central nervous system and lead to chronic dry eye symptoms (scenario b). Although the approach to patients in each category should differ, current dry eye measures do not incorporate ocular sensory apparatus function in their diagnosis or treatment algorithms.

Although the mechanisms are not fully understood, central sensitization in nonocular pain conditions is frequently associated with the comorbidities depression and anxiety.[74] A similar correlate has been described in dry eye as patients with depression and posttraumatic stress disorder (PTSD) were found to have a twofold increased risk of a dry eye diagnosis compared with patients without these diagnoses.[75,76] Furthermore, evidence for a discordance between dry eye symptoms and peripheral pathology comes from findings that patients with PTSD and depression complained of more symptoms but had similar tear film parameters compared with patients without depression or PTSD.[77] Others studies in Asian populations have described similar relationships between depression and dry eye.[78–80]

Hypersensitivity to other stimuli and the development of diffuse pain states can also be seen with central sensitization,[74] and again these features have been described in dry eye. Data from the national VA database demonstrated that patients with chronic pain diagnoses (ICD-9 codes 338.29, 724.2, 724.5, 338.4, and 338.28) were 1.9 times more likely to carry a dry eye diagnosis compared with their counterparts without chronic pain (odds ratio (OR) 1.89, 95% confidence interval (CI) 1.88–1.90). In addition, fibromyalgia (ICD-9 code 729.1) imparted a twofold increased risk for dry eye (OR 1.96, 95% CI 1.94–1.98) whereas migraine (ICD-9 code 346) imparted a 1.4-fold increased risk (OR 1.37, 95% CI 1.35–1.38) (A Galor et al, unpublished data). Additional support for the presence of central sensitization in some dry eye patients comes from a study of 1635 female twin volunteers in the United Kingdom. Patients with dry eye had higher pain sensitivity at a remote site (forearm) than those without the disease.[81] These clinical data demonstrating abnormal functional responses to nonocular stimuli suggest heightened systemic pain sensitivity, consistent with central sensitization.

Similar to peripheral sensitization, changes in ion channel expression and function, levels of mediators, cytosolic signaling, and other factors underlie these phenotypic changes.[62,82,83] As above, the anatomy of the ocular sensory apparatus lends biologic plausibility to the idea of central sensitization in dry eye. The first synapse of the ocular sensory apparatus occurs in the Vi/Vc zone, and specific dry-responsive projection neurons have been identified in this area. A subset of these neurons receive additional converging input from corneal primary afferents sensitive to protons, heat, and chemicals.[37] Therefore, projection neurons in the transition zone integrate innocuous as well as noxious sensory information from the eye, and may constitute the neurophysiological substrate of central sensitization. In fact, the Vi/Vc transition zone is a well-recognized area involved in the generation and maintenance of hyperexcitability and central sensitization.[84]