In the present study, dry eye patients with ocular neuropathic pain features were divided into two groups on the basis of proparacaine challenge test results. Although clinical parameters associated with the tear film and ocular surface, such as TBUT, basal tear secretion, CSS, and MG parameters, were not significantly different between the two groups, the central group complained of more severe ocular pain and non-ocular pain than did the peripheral group. In addition, we noticed that patients in the central group complained of a burning sensation more commonly than did those in the peripheral group.
It is well established that structural and functional changes occur in ocular surface sensory nerves in DED. Reduced tear secretion causes stress on ocular mucosal epithelium, leading to local inflammation and peripheral nerve damage.[19] Long-term inflammation and nerve injury alter trigeminal ganglion and brainstem neurons, changing their excitability, connectivity, and impulse firing causing dysesthesias and neuropathic pain referred to the ocular surface.[19–21]
In vivo confocal microscopy (IVCM) visualizes microstructures, including corneal nerve plexus.[22–24] Some studies have demonstrated the usefulness of the IVCM in evaluating corneal neuropathies by visualizing the decrease in sub-basal corneal nerve density, increase in nerve tortuosity, activation of keratocytes and spindle in corneal stroma, and the presence of microneuromas in the stroma.[11, 23, 24] In many general clinical settings, the IVCM is not available for evaluation.
The 0.5% proparacaine challenge test is a useful method to assess the central sensitization of ocular pain in a general clinical setting which does not provide research equipment such as esthesiometry or confocal microscopy.[10] In previous studies, patients with complete relief of pain after proparacaine administration were classified into the peripheral sensitization group, those with consistent pain without relief were classified into the central sensitization group, and those with partial relief were classified into the mixed sensitization group.[10] Dieckmann et al.[6] reported that most of the patients showed partial improvement in pain, suggesting that central sensitization and peripheral sensitization were mixed, and the rate of contribution to pain depends on the etiology or duration of the disease. Similarly, in our study, 27 out of 33 (81.82%) patients showed mixed sensitization. Therefore, for the analysis, we divided the patients into two groups: central-dominant sensitization group with less than 50% improvement in pain, and peripheral-dominant sensitization group with 50% or more improvement in pain. No significant differences were observed in pain duration between the two groups. Comorbidities such as CPS, neurologic disorders, and psychological disorders were more common in the central group (70.6%) than in the peripheral group (37.5%).
Previous studies have attempted to evaluate patients with ocular pain by using dry eye-related questionnaires, such as the Ocular Surface Disease Index, Dry Eye Questionnaire, and Dry Eye–Related Quality-of-Life Score.[13–15] In many of these questionnaires, ocular pain and dry eye symptoms are queried simultaneously. The Neurobehavioral Rating Scale, which is used as a primary outcome measure for chronic pain, and the Neuropathic Pain Symptom Inventory (NPSI), which is used to evaluate neuropathic pain, have also been used for the evaluation of ocular pain.[25, 26] Recently, the NPSI was appropriately adapted for evaluating ocular pain, and a modified NPSI-Eye was later developed during our study period.[27] Among the available questionnaires, we used the OPAS to evaluate patients with ocular neuropathic pain features, because it provides multi-dimensional information not only on the severity of ocular pain but also on associated and aggravating factors and the QoL; moreover, it is a validated questionnaire for ocular pain.[16]
Kalangara et al.[5] used the term “burning eye syndrome” for a subset of dry eye representing a neuropathic pain of the eye. Burning sensation is often diagnosed as neuropathic pain when primary painful conditions are excluded. Burning mouth syndrome (BMS) shares many features with ocular neuropathic pain.[28–30] BMS is characterized by abnormal burning sensation in the oral cavity, but in the absence of clinical lesions. Patients diagnosed with BMS have been reported to have psychiatric disorders, such as depression and anxiety, or are mentally vulnerable to stress. In addition, loss of small-diameter nerve fibers in the oral mucosa and decreased brain activation to heat stimuli on functional magnetic resonance imaging have been demonstrated in these patients.[30] Our finding that patients with central-dominant sensitization complained more commonly of a burning sensation may support the association between BMS and ocular neuropathic pain. Further investigations focusing on both the oral mucosal and corneal nervous systems could help identify the underlying mechanism of ocular neuropathic pain.
Our study has several limitations. First, the sample size may not be enough to prove the clinical significance of results. Second, because this study is a multicenter study, subtle bias may be present in conducting clinical examinations. Third, corneal esthesiometry or IVCM imaging were not obtained in this study. Fourth, we used a arbitrary 50% cut-off value in the proparacaine challenge test for the analysis and it might not by validated value for determining the types of sensitization. Further studies with larger sample sizes and more precise diagnostic equipment are warranted in the future.