Neuropathic ocular pain: an important yet underevaluated feature of dry eye

Abstract

Dry eye has gained recognition as a public health problem given its prevalence, morbidity, and cost implications. Dry eye can have a variety of symptoms including blurred vision, irritation, and ocular pain. Within dry eye-associated ocular pain, some patients report transient pain whereas others complain of chronic pain. In this review, we will summarize the evidence that chronicity is more likely to occur in patients with dysfunction in their ocular sensory apparatus (ie, neuropathic ocular pain). Clinical evidence of dysfunction includes the presence of spontaneous dysesthesias, allodynia, hyperalgesia, and corneal nerve morphologic and functional abnormalities. Both peripheral and central sensitizations likely play a role in generating the noted clinical characteristics. We will further discuss how evaluating for neuropathic ocular pain may affect the treatment of dry eye-associated chronic pain.

Figure 1

A simplified version of the ocular sensory pathway. First-order neuron (solid line) with nerve ending in the cornea, cell body in the trigeminal ganglion, and synapse in the subnucleus caudalis. In actuality, however, there are multiple synapses for each nociceptor in the trigeminal subnucleus interpolaris/subnucleus caudalis (Vi/Vc) transition zone, and in the subnucleus caudalis/upper cervical transition zone (Vc/C_1-2). Second-order neurons (dashed line) decussate and join the contralateral spinothalamic pathways and synapse in the thalamus. Third-order neurons (dashed line) then relay information to the supraspinal centers, including the somatosensory cortex. Reproduced with permission from Rosenthal and Borsook.

Figure 2

A simplified version of the relationship between environmental insults, inflammation, and nociceptor function. Mechanical, chemical, and thermal insults can damage corneal epithelial cells and nociceptors that results in a cascade of inflammatory mediators including adenosine triphosphate (ATP), prostaglandins (PGs), substance P (SP), matrix metalloproteinases (MMPs), reactive oxygen species (ROS), and nerve growth factor (NGF). In addition, there is an influx of immune cells including T cells, macrophages (Mφ), and neutrophils (Nφ). These cells secrete a variety of cytokines (interleukins and tumor necrosis factor (TNF)) that all alter the function of nociceptors. Other mediators, including resolvins and protectins, are involved in ending the inflammatory cascade and restoring nociceptor function. Persistent environmental stress or inflammatory responses can lead to permanent changes in nociceptor function.

Figure 3

(a) Normal nociceptor response to a noxious stimulus is shown. (b) Neuroplasticity in the first-order neuron (peripheral sensitization). In the absence of a stimulus, the cell body and terminal end of the first-order neuron display spontaneous activity that translates into pain sensation. (c) Neuroplasticity in the second-order neuron (central sensitization). In the absence of a stimulus, the cell body of the second-order neuron displays spontaneous activity that translates into pain sensation.

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.