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Purpose: To conduct a genome-wide association study (GWAS) of individuals with neuropathic ocular pain (NOP) symptoms to identify genomic variants that may predispose to NOP development. Design: Prospective study of individuals with NOP. Participants: Three hundred twenty-nine patients recruited from the Miami Veterans Affairs eye clinic. Methods: The Neuropathic Pain Symptom Inventory modified for the eye (NPSI-Eye) was completed to calculate a NPSI-Eye-Sub-Score (summed ratings of burning and wind sensitivity) as an indicator of NOP severity. A GWAS was performed for the NPSI-Eye-Sub-Score with a significance threshold of P < 5 × 10-8. A gene-based analysis was performed using the multimarker analysis of genomic annotation software (in the functional mapping and annotation of GWAS online platform). The 13 865 778 single nucleotide polymorphisms (SNPs) from our GWAS analysis were mapped to 10 834 protein coding genes, and significant genes were run through gene set enrichment analysis. Main Outcome Measures: Identification of SNPs and protein products that may be associated with the development of NOP. Results: One hundred seventy-one SNPs reached a threshold of P < 10-5, of which 10 SNPs reached the suggestive level of significance of P < 5 × 10-7 and 1 SNP met our genome-wide significance threshold of P < 5 × 10-8. This lead SNP, rs140293404 (P = 1.23 × 10-8), is an intronic variant found within gene ENSG00000287251 coding for transcript ENST00000662732.1. Rs140293404 is in linkage disequilibrium with exon variant rs7926353 (r2 > 0.8) within ENSG00000279046 coding for transcript ENST00000624288.1. The most significant genes from gene-based tests were matrix metalloproteinase-19 (MMP19) (P = 1.12 × 10-5), zinc finger RNA-binding motif and serine/arginine rich-1 (ZRSR1) (P = 1.48 × 10-4), CTC-487M23.8 (P = 1.79 × 10-4), receptor expression-enhancing protein-5 (REEP5) (P = 2.36 × 10-4), and signal recognition particle-19 (SRP19) (P = 2.56 × 10-4). From gene set enrichment analysis, the sensory perception (false discovery rate = 6.57 × 10-3) and olfactory signaling (false discovery rate = 1.63 × 10-2) pathways were enriched with the most significant genes. Conclusions: Our GWAS revealed genes with protein products that may impact sensory perception, lending biological plausibility to a role for SNPs identified by our GWAS in the development of NOP. A better understanding of the biological relevance of these genes and pathways in the pathophysiology associated with NOP may facilitate future novel mechanism-based treatments. Financial Disclosures: Proprietary or commercial disclosure may be found in the Footnotes and Disclosures at the end of this article.

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Chronic ocular surface pain (COSP) may be defined as a feeling of pain, perceived as originating from the ocular surface, that persists for >3 months. COSP is a complex multifactorial condition associated with several risk factors that may significantly interfere with an individual's daily activities, resulting in poor quality of life (QoL). COSP is also likely to have a high burden on patients with substantial implications on global healthcare costs. While patients may use varied terminology to describe symptoms of COSP, any ocular surface damage in the ocular sensory apparatus (nociceptive, neuropathic, inflammatory, or combination thereof) resulting in low tear production, chronic inflammation, or nerve abnormalities (functional and/or morphological), is typically associated with COSP. Considering the heterogeneity of this condition, it is highly recommended that advanced multimodal diagnostic tools are utilized to help discern the nociceptive and neuropathic pain pathways in order to provide targeted treatment and effective clinical management. The current article provides an overview of COSP, including its multifactorial pathophysiology, etiology, prevalence, clinical presentation, impact on QoL, diagnosis, current management, and unmet medical needs.

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In the homeostasis of the ocular surface, vitamins play a critical role in regulating inflammatory responses and promoting cell differentiation, development and correct function. Systemic vitamin supplementation has been available for many decades; in recent years, thanks to pharmacological advancements, topical vitamin delivery has also become available in an attempt to better treat ocular surface disease (OSD) and dry eye disease (DED). In this paper, we reviewed the current evidence on the role of vitamin supplementation in OSD and DED. We originally searched the PubMed archive, inspected the references and restricted the search to pertinent papers. The body of evidence was evaluated using the amelioration of both signs and symptoms as the outcome, when available. We found that in patients with vitamin deficiency, systemic supplementation of Vitamin A is effective in treating OSD, reducing both DED signs and symptoms. Additionally, systemic supplementation of vitamin D is useful in reducing DED symptoms and increasing tear volume. Vitamin A is also effective in reducing DED signs and symptoms when administered locally. The efficacy of supplementation with other vitamins is still not fully proven. In conclusion, the inclusion of vitamins into the treatment strategies for OSD and DED allows for better treatment customization and better outcomes in these patients.

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Neuropathic ocular pain is a frequent occurrence in medium to severe dry eye disease (DED). Only palliative treatments, such as lubricants and anti-inflammatory drugs, are available to alleviate patients' discomfort. Anesthetic drugs are not indicated, because they may interfere with the neural feedback between the cornea and the lacrimal gland, impairing tear production and lacrimation. Gabapentin (GBT) is a structural analog of gamma-amino butyric acid that has been used by systemic administration to provide pain relief in glaucomatous patients. We have already shown in a rabbit model system that its topic administration as eye drops has anti-inflammatory properties. We now present data on rabbits' eyes showing that indeed GBT given topically as eye drops has analgesic but not anesthetic effects. Therefore, opposite to an anesthetic drug such as oxybuprocaine, GBT does not decrease lacrimation, but-unexpectedly-even stimulates it, apparently through the upregulation of acetylcholine and norepinephrine, and by induction of aquaporin 5 (AQP5) expression in the lacrimal gland. Moreover, data obtained in vitro on a primary human corneal epithelial cell line also show direct induction of AQP5 by GBT. This suggests that corneal cells might also contribute to the lacrimal stimulation promoted by GBT and participate with lacrimal glands in the restoration of the tear film, thus reducing friction on the ocular surface, which is a known trigger of ocular pain. In conclusion, GBT is endowed with analgesic, anti-inflammatory and secretagogue properties, all useful to treat neuropathic pain of the ocular surface, especially in case of DED.

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Purpose of Review: Corneal neuropathic pain can be difficult to treat, particularly due to its lack of response to standard dry eye therapies. We describe a variety of topical therapeutic options that are available to treat corneal neuropathic pain with a significant or primary peripheral component. We also describe possible mechanisms of action for such topical therapies. Recent Findings: Topical corticosteroids and blood-derived tear preparations can be helpful. Newer therapies, including topical lacosamide and low-dose naltrexone are emerging therapeutic options that may also be considered. Summary: Corneal neuropathic pain with a significant peripheral component may be managed with a variety of topical therapeutic options.

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PURPOSE: Differences in pain processing and autonomic function among patients have been implicated in the development of chronic pain after surgery. This study was designed to evaluate whether pain and autonomic metrics predict severity of chronic dry eye (DE) symptoms after LASIK, as there is increasing evidence that DE symptoms may be manifestations of persistent post-operative ocular pain. METHODS: Secondary analysis of prospective randomized clinical trial. Patients were treated with either pregabalin or placebo. As no significant differences in DE symptoms were detected by treatment allocation at six months, all participants were grouped together for the present analyses. Subjects were evaluated pre-LASIK with regard to evoked pain sensitivity (utilizing quantitative sensory testing), autonomic metrics and DE and ocular pain symptoms (via validated questionnaires). Measures of DE and ocular pain were assessed post-LASIK, and the Dry Eye Questionnaire 5 (DEQ5) score 6-months after surgery was the primary outcome of interest. RESULTS: 43 individuals were randomized to pregabalin (n = 21) or placebo (n = 22). 42 completed the 6-month visit. Several baseline autonomic metrics correlated with 6-month post-operative DEQ5 scores, including lower systolic (r -0.37, p = 0.02) and diastolic blood pressure (r -0.32, p = 0.04). Ocular pain at 6 months was also negatively correlated with blood pressure (r -0.31, p = 0.047). The presence of painful aftersensations was a significant predictor of chronic DE symptoms at 6 months (mean DEQ5 scores: 8.0 ± 1.9 versus 5.0 ± 5.0, p = 0.009). CONCLUSIONS: Heightened parasympathetic tone and prolonged pain sensitivity measured prior to surgery predicted greater DE symptom severity 6 months after LASIK. TRIAL REGISTRATION: NCT02701764.

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This study aims to evaluate the efficacy of gabapentin treatment in dry eye disease (DED) and neuropathic ocular pain. Our study was performed with 72 patients. The painDETECT questionnaire was used for neuropathic pain screening. Patients who were thought to have severe DED according to ocular surface disease index (OSDI) questionnaire, Schirmer's test type 1 and tear break up time test results were treated with artificial tear and cyclosporine drops. Gabapentin treatment was also initiated in addition to artificial tear and cyclosporine drops treatments to the patients with neuropathic component and DED findings. We divided the patients into two groups: group 1 (n: 36), patients treated with artificial tear and cyclosporine drops and group 2 (n: 36), patients treated with artificial tear, cyclosporine drops and gabapentin. In the first evaluation, no significant differences were found between groups in terms of OSDI score, Schirmer's test result and TBUT. After the 6 weeks of treatment, in both groups OSDI score, Schirmer's test result and TBUT statistically significantly improved. OSDI score, Schirmer's test result and TBUT significantly improved after the 6 weeks of gabapentin treatment than artificial tear and cyclosporine treatment group (p < 0.001). Dry eye patients should be screened for neuropathic ocular pain symptoms and individualized treatment has to be applied. Our study showed that the use of gabapentin is effective in severe dry eye patients with neuropathic ocular pain.

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BACKGROUND: To compare the clinical characteristics of dry eye patients with ocular neuropathic pain features according to the types of sensitization based on the Ocular Pain Assessment Survey (OPAS). METHODS: Cross-sectional study of 33 patients with dry eye and ocular neuropathic pain features. All patients had a comprehensive ophthalmic assessment including detailed history, the intensity and duration of ocular pain, the tear film, ocular surface, and Meibomian gland examination, and OPAS. Patients with < 50% improvement in pain intensity after proparacaine challenge test were assigned to the central-dominant sensitization group (central group) and those with ≥50% improvement were assigned to the peripheral-dominant sensitization group (peripheral group). All variables were compared between the two groups. RESULTS: No significant differences were observed in age, sex, underlying diseases, history of ocular surgery, duration of ocular pain, tear film, ocular surface and Meibomian gland parameters (all p > 0.05). Ocular pain and non-ocular pain severity and the percentage of time spent thinking about non-ocular pain were significantly higher in the central group than in the peripheral group (all p < 0.05). Central group complained more commonly of a burning sensation than did the peripheral group (p = 0.01). CONCLUSIONS: Patients with central-dominant sensitization may experience more intense ocular and non-ocular pain than the others and burning sensation may be a key symptom in those patients.

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PURPOSE: To report a case of chronic neuropathic ocular pain in a patient without visual complaints. OBSERVATIONS: A 37-year-old male with a history of bilateral laser-assisted in situ keratomileusis (LASIK) presented with pain symptoms of 8 months duration in the left eye. The prior LASIK surgery was complicated by corneal ectasia in the left eye requiring penetrating keratoplasty and subsequent placement of a glaucoma drainage implant for uncontrolled, elevated intraocular pressure. The patient was evaluated with a complete clinical examination, including Goldmann applanation tonometry, dilated fundus examination, fluorescein angiography, optical coherence tomography, and magnetic resonance imaging. After 3 weeks of treatment with gabapentin 300 mg BID, the patient reported complete resolution of the ocular pain. CONCLUSIONS AND IMPORTANCE: The pathophysiology of neuropathic ocular pain remains poorly understood. Clinical evaluation often reveals minimal ophthalmic exam findings, leading to an underdiagnosis of the condition by ophthalmologists. Gabapentin may be an underutilized medication in the treatment of chronic ocular pain.

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PURPOSE: Individuals receiving botulinum toxin A (BoNT-A) injections in the head and neck for migraine treatment have reported decreases in photophobia and sensations of dryness, independent of ocular surface parameters. We hypothesized that patients without migraine but with similar ocular neuropathic-like symptoms would also experience symptomatic improvement with periocular BoNT-A injections, independent of ocular surface changes. OBSERVATIONS: We identified four individuals without a history of migraine but with neuropathic ocular pain (symptoms of dryness, burning, and photophobia that were out of proportion to ocular surface findings and unresponsive to ongoing dry eye (DE) therapies). Individuals underwent 1 session of periocular BoNT-A injections. Validated questionnaires (Visual Light Sensitivity Questionnaire-8, Dry Eye Questionnaire-5) assessed photophobia and DE symptoms pre- and 1-month post-injections. All four reported improvements in frequency and severity of photophobia and eye discomfort following BoNT-A injections. Tear film parameters (phenol red thread test, tear break-up time, corneal staining, and Schirmer test) and eyelid (palpebral fissure height and levator palpebrae superioris function) and eyebrow (position) anatomy were also evaluated before and after injections. Despite a unanimous improvement in symptoms, there were no consistent changes in ocular surface parameters with BoNT-A injections across individuals. CONCLUSIONS: Periocular BoNT-A shows promise in reducing photophobia and sensations of dryness in individuals with neuropathic-like DE symptoms without a history of migraine, independent of tear film, eyelid, or eyebrow parameters.

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PURPOSE: To evaluate the relationship between the severity of ocular and systemic pain. METHODS: A cross-sectional study was conducted in patients with ocular pain symptoms who were observed in Keio University Hospital between April 2017 and September 2018. Evaluations consisted of the Dry Eye-Related Quality of Life Score (DEQS), Short-Form McGill Pain Questionnaire (SF-MPQ), visual analog scale (VAS), and ophthalmologic examination, including tear breakup time measurement and Schirmer I test. The revised Asia Dry Eye Society Dry Eye Disease (DED) diagnostic criteria were used. RESULTS: The present study involved 41 participants (31 women; mean age, 57.6 ±â€¯17.5 years). Thirteen participants had aqueous-deficient DED, 18 participants had short tear break-up time DED, and 10 participants had no DED. Multivariate regression analysis revealed that the DEQS was significantly associated with both the SF-MPQ total (Coefficient score ß = 0.92, p < 0.01) and the VAS (ß = 0.25, p = 0.01). In addition, correlation analysis revealed that the DEQS had a significant positive linear correlation with both the SF-MPQ total (Spearman correlation score rs = 0.70, p < 0.01) and the VAS (rs = 0.66, p < 0.01). CONCLUSIONS: The findings of the present study suggested that the ocular pain score was significantly associated with systemic pain score. Participants with higher systemic pain scores have an increased risk of having ocular pain.

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PURPOSE: We report a case of a male patient with chronic ocular pain that resolved completely following peripheral nerve blocks. OBSERVATIONS: A 66-year-old male presented with a seven-year history of severe left eye pain and photophobia. The pain began after retinal detachment repair with scleral buckle placement. Previous treatments included topical (autologous serum tears, corticosteroids, diclofenac, cyclosporine) and oral (gabapentin, diclofenac) therapies with no pain relief. The patient's pain was so severe that he requested enucleation. After discussion, the decision was made to perform periocular nerve blocks. Prior to the procedure, the patient reported an average pain intensity of 8 out of 10 and photophobia daily. Following left supraorbital, supratrochlear, infraorbital and infratrochlear injections with bupivacaine and methylprednisolone, pain intensity and photophobia improved to 1-2 out of 10. One week later, repeat infraorbital and infratrochlear nerve blocks were given, after which time the patient reported complete resolution of symptoms that lasted for 7 months. Repeat nerve blocks were administered with repeat resolution of pain. There were no complications associated with the procedures. CONCLUSIONS AND IMPORTANCE: Chronic ocular pain can be a debilitating condition. Periorbital nerve blocks can provide pain relief and should be considered as a potential treatment option after medical management has failed.

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PURPOSE: This study aims to understand the effect of vitamin B12 deficiency on neuropathic ocular pain (NOP) and symptoms in patients with dry eye disease (DED). METHODS: Patients with severe DED (without receiving topical artificial tears treatment) and ocular pain were enrolled (n = 90). Patients with severe DED and vitamin B12 deficiency (group 1, n = 45) received parenteral vitamin B12 supplement + topical treatment (artificial tears treatment + cyclosporine), and patients with severe DED and normal serum vitamin B12 level (group 2, n = 45) received only topical treatment (artificial tears treatment + cyclosporine). Patients were evaluated by the ocular surface disease index (OSDI) questionnaire, 3rd question (have you experienced painful or sore eyes during last week?) score of OSDI as a pain determiner and pain frequency measure), tear break up time (TBUT), and Schirmer's type 1 test. We compared the groups' OSDI, TBUT, and Schirmer's test recordings at the first visit and after 12 weeks retrospectively. RESULTS: The OSDI score, 3rd OSDI question score, TBUT, and Schirmer's test results improved after 12 weeks (p < 0.001 for each group). The mean vitamin B12 level at enrollment was 144.24 ±43.36 pg/ml in group 1 and 417.53 ±87.22 pg/ml in group 2. The mean vitamin B12 level in group 1 reached to 450 ±60.563 pg/ml after 12 weeks of treatment. The mean score changes between the groups were not statistically significant; however, the decrease in the OSDI questionnaire score (-30.80 ±5.24) and 3rd OSDI question score (-2.82 ±0.53) were remarkable in group 1 (Table 2). The mean TBUT increase was +7.98 ±2.90 s and Schirmer's test result increase was +12.16 ±2.01 mm in group 1. The mean TBUT increase was +6.18 ±1.49 s and Schirmer's test result increase was +6.71 ±1.47 mm in group 2. CONCLUSIONS: These findings indicate that vitamin B12 deficiency is related with NOP. It may be important to consider measuring the serum vitamin B12 level in patients with severe DED presenting with resistant ocular pain despite taking topical treatment.

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PURPOSE: Conjunctival microvascular responses may be a surrogate metric of efferent neural pathway function innervating the ocular surface as changes in blood flow occur within seconds after a stimulus. As somatosensory dysfunction may partially underlie dry eye (DE), in this study we evaluate whether bulbar conjunctival microvascular alterations correlate with various aspects of DE. METHODS: Fifty-six DE patients were prospectively recruited from a Veterans Affairs ophthalmology clinic over an 11-month period. DE symptoms and ocular pain were assessed along with DE signs. A novel functional slit lamp biomicroscope (FSLB) was used to image the temporal bulbar conjunctiva from the right eye before and after central corneal stimulation with an air puff. Blood flow velocities were measured and noninvasive microvascular perfusion maps (nMPMs) were created. RESULTS: The bulbar blood flow velocity was 0.50 ± 0.15 mm/s at baseline and increased to 0.55 ± 0.17 mm/s after stimulation (P < 0.001); the average change in velocity was 0.05 ± 0.09. nMPMs values and venule diameter, on the other hand, did not significantly increase after stimulation (1.64 ± 0.004 at baseline, 1.65 ± 0.04 after stimulation, P = 0.22 and 22.13 ± 1.84 µm at baseline, 22.21 ± 2.04 µm after stimulation, P = 0.73, respectively). Baseline blood flow velocity positively associated with Schirmer scores (r = 0.40, P = 0.002). Those with higher self-rated wind hyperalgesia demonstrated less change in blood flow velocity (r = -0.268, P = 0.046) after air stimulation on the central cornea. CONCLUSION: Conjunctival blood flow velocity, but not vessel diameter or complexity, increases after wind stimuli. Baseline flow positively correlated with Schirmer scores while change in flow negatively correlated with self-reported wind hyperalgesia.

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INTRODUCTION: Recent evidence suggests that dry eye (DE) may be comorbid with other chronic pain conditions. OBJECTIVES: To evaluate DE as a comorbid condition in the U.S. veteran population. METHODS: Retrospective review of veterans seen in the Veterans Administration Healthcare System (Veteran Affairs) between January 1, 2010, and December 31, 2014. Dry eye and nonocular pain disorders were ascertained by International Classification of Diseases, Ninth Revision (ICD-9) codes. Dry eye was further separated into ICD-9 codes representing tear film dysfunction or ocular pain. χ2 and logistic regression analyses were used to examine frequency and risk of DE, ocular pain, and tear film dysfunction by pain disorders. RESULTS: Of 3,265,894 veterans, 959,881 had a DE diagnosis (29.4%). Dry eye frequency increased with the number of pain conditions reported (P < 0.0005). Ocular pain was most strongly associated with headache (odds ratio [OR] 2.98; 95% confidence interval [CI] 2.95-3.01), tension headache (OR 2.64; 95% CI 2.58-2.71), migraine (OR 2.58; 95% CI 2.54-2.61), temporomandibular joint dysfunction (OR 2.39; 95% CI 2.34-2.44), pelvic pain (OR 2.30; 95% CI 2.24-2.37), central pain syndrome (OR 2.24; 95% CI 1.94-2.60), and fibromyalgia/muscle pain (OR 2.23; 95% CI 2.20-2.26), all P < 0.0005. Tear film dysfunction was most closely associated with osteoarthritis (OR 1.97; 95% CI 1.96-1.98) and postherpetic neuralgia (OR 1.95; 95% CI 1.90-2.00), both P < 0.0005. CONCLUSIONS: Dry eye, including both ocular pain and tear film dysfunction, is comorbid with pain conditions in this nationwide population, implying common mechanisms.

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UNLABELLED: Recent data show that dry eye (DE) susceptibility and other chronic pain syndromes (CPS) such as chronic widespread pain, irritable bowel syndrome, and pelvic pain, might share common heritable factors. Previously, we showed that DE patients described more severe symptoms and tended to report features of neuropathic ocular pain (NOP). We hypothesized that patients with a greater number of CPS would have a different DE phenotype compared with those with fewer CPS. We recruited a cohort of 154 DE patients from the Miami Veterans Affairs Hospital and defined high and low CPS groups using cluster analysis. In addition to worse nonocular pain complaints and higher post-traumatic stress disorder and depression scores (P < .01), we found that the high CPS group reported more severe neuropathic type DE symptoms compared with the low CPS group, including worse ocular pain assessed via 3 different pain scales (P < .05), with similar objective corneal DE signs. To our knowledge, this was the first study to show that DE patients who manifest a greater number of comorbid CPS reported more severe DE symptoms and features of NOP. These findings provided further evidence that NOP might represent a central pain disorder, and that shared mechanistic factors might underlie vulnerability to some forms of DE and other comorbid CPS. PERSPECTIVE: DE patients reported more frequent CPS (high CPS group) and reported worse DE symptoms and ocular and nonocular pain scores. The high CPS group reported symptoms of NOP that share causal genetic factors with comorbid CPS. These results imply that an NOP evaluation and treatment should be considered for DE patients.

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The term "dry eye" has evolved over the past 2 decades to include both symptoms (visual complaints and dysesthesias) and signs (aqueous and evaporative deficiency) of disease. Dry eye is common in older individuals and a source of morbidity. Confusion arises, however, on what combination of symptoms and signs constitute "dry eye" and how to best individualize treatment in patients. This editorial will discuss the evolution of dry eye, discuss potential sub-categorizations for the disease, and discuss their potential implications on treatment.