Pathogenic Mechanism of Dry Eye-Induced Chronic Ocular Pain and a Mechanism-Based Therapeutic Approach.

Purpose: Dry eye-induced chronic ocular pain is also called ocular neuropathic pain. However, details of the pathogenic mechanism remain unknown. The purpose of this study was to elucidate the pathogenic mechanism of dry eye-induced chronic pain in the anterior eye area and develop a pathophysiology-based therapeutic strategy. Methods: We used a rat dry eye model with lacrimal gland excision (LGE) to elucidate the pathogenic mechanism of ocular neuropathic pain. Corneal epithelial damage, hypersensitivity, and hyperalgesia were evaluated on the LGE side and compared with the sham surgery side. We analyzed neuronal activity, microglial and astrocytic activity, α2δ-1 subunit expression, and inhibitory interneurons in the trigeminal nucleus. We also evaluated the therapeutic effects of ophthalmic treatment and chronic pregabalin administration on dry eye-induced ocular neuropathic pain. Results: Dry eye caused hypersensitivity and hyperalgesia on the LGE side. In the trigeminal nucleus of the LGE side, neuronal hyperactivation, transient activation of microglia, persistent activation of astrocytes, α2δ-1 subunit upregulation, and reduced numbers of inhibitory interneurons were observed. Ophthalmic treatment alone did not improve hyperalgesia. In contrast, continuous treatment with pregabalin effectively ameliorated hypersensitivity and hyperalgesia and normalized neural activity, α2δ-1 subunit upregulation, and astrocyte activation. Conclusions: These results suggest that dry eye-induced hypersensitivity and hyperalgesia are caused by central sensitization in the trigeminal nucleus with upregulation of the α2δ-1 subunit. Here, we showed that pregabalin is effective for treating dry eye-induced ocular neuropathic pain even after chronic pain has been established.

Optogenetic Inhibition of Nav1.8 Expressing Corneal Afferents Reduces Persistent Dry Eye Pain.

Purpose: The aim of the present study was to investigate the contribution of Nav1.8 expressing corneal afferent neurons to the presence of ongoing pain in lacrimal gland excision (LGE)-induced dry eye. Methods: The proton pump archaerhodopsin-3/eGFP (ArchT/eGFP) was conditionally expressed in corneal afferents using Nav1.8-cre mice. Dry eye was produced by unilateral LGE. Real time place preference was assessed using a three-chamber apparatus. A neutral, unlit center chamber was flanked by one illuminated with a control light and one illuminated with an ArchT activating light. For real-time preference, animals were placed in the neutral chamber and tracked over five 10-minute sessions, with the lights turned on during the second and fourth sessions. In other studies, movement was tracked over three 10-minute sessions (the lights turned on only during the second session), with animals tested once per day over the course of 4 days. A local anesthetic was used to examine the role of ongoing corneal afferent activity in producing place preference. Results: The corneal afferent nerves and trigeminal ganglion cell bodies showed a robust eGFP signal in Nav1.8-cre;ArchT/eGFP mice. After LGE, Nav1.8-cre;ArchT/eGFP mice demonstrated a preference for the ArchT activating light paired chamber. Preference was prevented with pre-application to the cornea of a local anesthetic. Nav1.8-cre;ArchT/eGFP mice with sham surgery and LGE wild-type control mice did not develop preference. Conclusions: Results indicate LGE-induced persistent, ongoing pain, driven by Nav1.8 expressing corneal afferents. Inhibition of these neurons represents a potential strategy for treating ongoing dry eye-induced pain.

Brain Functional Connectivity Changes in Patients with Acute Eye Pain: A Resting-State Functional Magnetic Resonance Imaging (fMRI) Study.

BACKGROUND By using functional magnetic resonance imaging (fMRI), we aimed to study the changes in potential brain function network activity in patients with acute eye pain. Also, by using the voxel-wise degree centrality (DC) method, we aimed to explore the relationship between spontaneous brain activity and the clinical features of patients with acute eye pain. MATERIAL AND METHODS A total of 15 patients with acute eye pain (5 women and 10 men; EP group) and 15 healthy controls (5 women and 10 men; HC group), were scanned by fMRI. The DC method was used to evaluate changes in spontaneous brain activity. Receiver operating characteristic (ROC) curves were analyzed, and Pearson correlation analysis was used to study the relationship between DC values and clinical manifestations in different regions of brain. RESULTS The area of the left limbic lobe showed a reduction in DC value in patients in the EP group. DC values were elevated in the left cerebellum posterior lobe, left inferior parietal lobule, left inferior temporal gyrus, left precuneus, and right cerebellum posterior lobe in the EP group. The visual analog scale value of the eyes in the EP group was negatively correlated with the left limbic lobe signal value and positively correlated with the left inferior parietal lobule signal value. Further, the scores of the hospital anxiety and depression scale and DC value of the left limbic lobe were negatively correlated. CONCLUSIONS Compared with the HC group, patients with acute eye pain had abnormal patterns of intrinsic brain activity in different brain regions, which may help reveal the potential neural mechanisms involved in eye pain.

Role of Choline in Ocular Diseases.

Choline is essential for maintaining the structure and function of cells in humans. Choline plays an important role in eye health and disease. It is a precursor of acetylcholine, a neurotransmitter of the parasympathetic nervous system, and it is involved in the production and secretion of tears by the lacrimal glands. It also contributes to the stability of the cells and tears on the ocular surface and is involved in retinal development and differentiation. Choline deficiency is associated with retinal hemorrhage, glaucoma, and dry eye syndrome. Choline supplementation may be effective for treating these diseases.

Spontaneous subperiosteal orbital hematoma in a patient with chronic sinusitis.

Periorbital swelling is a common presentation to the emergency department (ED), and its etiology can range from benign to acutely vision-threatening. Orbital subperiosteal hematoma is a rare ED diagnosis that is typically associated with trauma, though can infrequently occur spontaneously in the setting of sudden elevations in cranial venous pressure, bleeding diathesis, and sinusitis. We present a case of a 55-year-old female with a history of chronic sinusitis who presented to the ED with a three-day history of left-sided periorbital swelling along with painful extraocular movements and markedly decreased visual acuity following a cross-country road trip through elevation. Contrast computed tomography scan of the orbits revealed a large extraconal collection in the subperiosteal space causing significant mass effect on the left globe, along with findings of diffuse sinonasal disease bilaterally. Intravenous antibiotics were started immediately and the patient underwent surgical incision and drainage of the subperiosteal space, where she was diagnosed with a spontaneous subperiosteal orbital hematoma secondary to chronic sinusitis. Within the literature, there are fewer than 20 case reports of orbital subperiosteal hematoma secondary to sinusitis. The purpose of this case report is to assist emergency physicians in considering the rare but potentially vision-threatening condition of spontaneous subperiosteal orbital hematoma within their differential diagnosis of patients with periorbital swelling and proptosis, as well as to provide an approach to management within the ED.

A web-based survey on various symptoms of computer vision syndrome and the genetic understanding based on a multi-trait genome-wide association study.

A variety of eye-related symptoms due to the overuse of digital devices is collectively referred to as computer vision syndrome (CVS). In this study, a web-based survey about mind and body functions, including eye strain, was conducted on 1998 Japanese volunteers. To investigate the biological mechanisms behind CVS, a multi-trait genome-wide association study (GWAS), a multivariate analysis on individual-level multivariate data, was performed based on the structural equation modeling methodology assuming a causal pathway for a genetic variant to influence each symptom via a single common latent variable. Twelve loci containing lead variants with a suggestive level of significance were identified. Two loci showed relatively strong signals and were associated with TRABD2B relative to the Wnt signaling pathway and SDK1 having neuronal adhesion and immune functions, respectively. By utilizing publicly available eQTL data, colocalization between GWAS and eQTL signals for four loci was detected, and a locus on 2p25.3 showed a strong colocalization (PPH4 > 0.9) on retinal MYT1L, known to play an important role in neuronal differentiation. This study suggested that the use of multivariate questionnaire data and multi-trait GWAS can lead to biologically reasonable findings and enhance our genetic understanding of complex relationships among symptoms related to CVS.

Efficacy and safety of tripterygium glycosides for active moderate to severe Graves' ophthalmopathy: a randomised, observer-masked, single-centre trial.

BACKGROUND: Tripterygium glycosides (TG) has been used to treat a spectrum of inflammatory and autoimmune diseases. Our preliminary studies have shown that TG is effective in the treatment of active Graves' ophthalmopathy (GO). OBJECTIVE: We aimed to compare the efficacy and tolerability of TG with intravenous methylprednisolone (iv.MP) in patients with active moderate-to-severe GO. METHODS: This study was an observer-masked, single-centre, block-randomised trial. Patients with active moderate-to-severe GO were randomly assigned to receive iv.MP (500 mg once per week for 6 weeks followed by 250 mg per week for 6 weeks) or with TG (20 mg tablet three times per day for 24 weeks). The primary endpoints were the overall response rate and the patients' quality of life at 12 and 24 weeks. RESULTS: In this study, 161 patients were enrolled and randomised from 2015 to 2019. A total of 79 were randomly assigned to receive iv.MP and 82 to receive TG. A greater overall response rate was found in the TG group compared with the iv.MP group at week 24 (90.2% vs 68.4%, P = 0.000). Similarly, the patients' quality of life of the TG group showed a significantly higher response than the iv.MP group at week 24 (89.02% vs 72.15%, P = 0.001). The TG therapy showed a better CAS response than the iv.MP (91.5% vs 70.9% improved, P < 0.05), and up to 91.2% of patients were inactive. Also, the TG group showed a significantly higher improved rate of diplopia, proptosis, visual acuity, soft tissue involved and the decrease of eye muscle motility than the iv.MP group at week 24. Significantly more patients in the iv.MP group than the TG group experienced adverse events. CONCLUSION: Compared with iv.MP treatment, TG therapy is more effective and safer for patients with active moderate to severe GO.

Trochleaectomy: An Effective Treatment of Trochlear Pain in Monocular Patients.

BACKGROUND: Conventional treatment options for trochlear pain arising from trochleitis or primary trochlear headache include oral anti-inflammatory medications and/or local injection of corticosteroids and local anesthetic. Trochleaectomy is an additional option to consider for monocular patients with intractable trochlear pain. METHODS: We report 3 patients undergoing trochleaectomy for refractory trochlear pain syndromes. RESULTS: Trochleaectomy resulted in resolution of their periocular discomfort. CONCLUSIONS: Trochleaectomy is an effective procedure to treat trochlear pain syndrome in functionally monocular patients.

Cool Crosslinking: Riboflavin at 4°C for Pain Management After Crosslinking for Keratoconus Patients, A Randomized Clinical Trial.

PURPOSE: To explore corneal cooling as a method of pain management in corneal-accelerated collagen cross-linking. METHODS: This was a prospective and interventional randomized clinical trial registered in the National Institutes of Health Clinical Trials through the identifier NCT030760770. The research was conducted at the Institute of Ophthalmology "Conde de Valenciana." A total of 98 patients were randomly assigned to one of the following 2 groups: cold riboflavin (4°C) group or control group (riboflavin at room temperature). The inclusion criteria were patients of any sex, older than 18 years of age with keratoconus diagnosis who needed management with cross-linking in both eyes because of the evidence of progression. The exclusion criteria were patients who had cross-linking without epithelial debridement, unilateral cross-linking, or any other ocular pathologies besides keratoconus and any cognitive incapacity that would make the understanding of the pain test difficult. The main outcome measures were pain, tearing, photophobia, foreign body sensation, and irritation. RESULTS: At 2 hours post-op, pain in the case and control groups was 3.80 ± 3.00 and 8.08 ± 2.21 (P < 0.05), tearing was 1.56 ± 1.96 and 8.29 ± 2.42 (P < 0.05), photophobia was 5.44 ± 3.57 and 7.83 ± 2.64 (P < 0.05), foreign body sensation was 2.20 ± 2.78 and 6.54 ± 2.73 (P < 0.05), and irritation was 3.48 ± 2.98 and 6.79 ± 3.00 (P < 0.05), respectively. A statistical significant difference was maintained in pain values on day 1 (2.79 ± 3.09 and 4.91 ± 3.27 [P < 0.05]), 2 (2.54 ± 2.41 and 4.00 ± 2.43 [P < 0.05]), and 4 (0.45 ± 0.76 and 1.22 ± 1.67 [P < 0.05]). CONCLUSIONS: This study demonstrated that pain and associated symptoms decreased significantly in the riboflavin 4°C group.

Intraoperative Pain Sensation During Cataract Surgery: Why Does Timing Matter?

Purpose: To investigate whether timing influences pain perception during cataract surgery and to investigate the possible mechanisms.Methods: Patients scheduled for cataract surgery both in the morning and afternoon were consecutively enrolled. Questionnaires to evaluate anxiety, including the Simplified State-Trait Anxiety Inventory, Amsterdam Preoperative Anxiety and Information Scale, and a visual analogue scale (VAS) for anxiety, were completed preoperatively, whereas a VAS for pain and the Wong-Baker FACES® Pain Rating Scale questionnaire were completed after surgery. Preoperative blood pressure and heart rate were recorded. Blood samples were acquired before surgery, and plasma cortisol, adrenocorticotropic hormone, adrenalin, and noradrenalin were tested.Results: Fifty-five patients underwent uneverntful cataract surgery (28 in the morning and 27 in the afternoon) were included in the final analysis. Greater intraoperative pain perception during cataract surgery was reported in the afternoon than in the morning. Overall anxiety levels were significantly higher in the afternoon. Plasma adrenalin levels were significantly higher in the afternoon. Cortisol levels were higher in the afternoon. Preoperative anxiety levels were closely related to intraoperative pain perception. Both adrenalin and cortisol correlated positively with preoperative anxiety, but only adrenalin correlated significantly with the pain scores.Conclusions: Patients undergoing cataract surgery in the afternoon showed more preoperative anxiety, which may have increased their relevant stress hormones. Both the patient's emotional state and hormone levels may together aggravate his/her perceived pain in the afternoon. Monitoring preoperative anxiety levels, blood pressure, and heart rate should help to identify patients at higher risk of perceived intraoperative pain.Clinical trial registration:Trial registration number: NCT02182921Registration site: clinicaltrials.gov.

Eye pain in the white and quiet eye.

PURPOSE OF REVIEW: Eye pain is one of the most common presenting symptoms in ophthalmology. It can range from bothersome to debilitating for patients, and it can be vexing for clinicians, especially in the white and quiet eye. The purpose of this review is to provide updates of recent literature regarding eye pain and to communicate our current understanding regarding the evaluation and management of conditions that cause eye pain with a relatively normal examination. RECENT FINDINGS: This review concerns recent literature regarding eye pain in the white and quiet eye. It is arranged by cause of pain and discusses dry eye syndrome, recurrent corneal erosion, postrefractive surgical pain, eye strain, intermittent angle closure, benign essential blepharospasm, trochleodynia, trochleitis and trochlear headache, and posterior scleritis. SUMMARY: Eye pain in the white and quiet eye remains a difficult-to-navigate topic for practitioners. However, a careful history and focused physical examination can elucidate the diagnosis in many cases. Recent updates to the literature have advanced our knowledge of how to identify and treat the underlying causes of eye pain.

Randomized Control Trial on the Effectiveness of Collagen Cross-linking on Bullous Keratopathy.

PURPOSE: To investigate the long-term effect and safety of collagen cross-linking (CXL) on patients with bullous keratopathy (BK) in a randomized control manner. It is, to our knowledge, the first randomized control study on the effect of CXL on BK. METHODS: Subjects were randomized to receive CXL as in the standard protocol for treating keratoconus or a placebo treatment. Subjects were assessed at baseline and up to 12 months after treatment. Primary outcomes were central corneal thickness (CCT) and pain scores. RESULTS: Forty-two patients with BK participated in the study treatment, 26 subjects were randomized to the CXL group and 16 subjects to the control group. The reduction of CCT in the CXL group was 37.6 and 63.8 µm at 2 and 4 weeks, respectively, which were significantly higher than that in the control group. However, there was no statistical difference in CCT reduction between the 2 groups at 12 weeks and after. There were no consistent advantages in pain score, corneal clarity, and visual acuity over the controls throughout the 1-year follow-up. However, CXL was associated with more recurrent epithelial defect (12%), and 2 of the 3 subjects with epithelial defect required amniotic membrane transplant. CONCLUSIONS: CXL reduced corneal thickness in the patients with BK, at least for the initial period. However, there were no improvement in pain, corneal clarity, and vision that were of more clinical relevance to the patients. Its short-term benefit was unlikely to outweigh its potential risk of recurrent epithelial defect.

Prospective 3-arm study on pain and epithelial healing after corneal crosslinking.

PURPOSE: To investigate the effect of 3 regimes on pain and wound healing after corneal crosslinking (CXL). SETTING: Tertiary academic referral center, Utrecht, the Netherlands. DESIGN: Prospective cohort study. METHODS: Consecutive progressive keratoconus patients who underwent 9 mW/cm epithelium-off CXL were included. Patients received a bandage contact lens (n = 20), occlusive patch (n = 20), or antibiotic ointment (n = 20) after treatment. Pain scores and quality of life, measured by the McGill Pain Questionnaire and Visual Analogue Scale (VAS), were analyzed. Epithelial healing after 2 days, correlations between pain and psychological factors that influence pain perception (depression anxiety stress score and pain catastrophizing score), and oral pain medication were evaluated. RESULTS: Sixty eyes of 52 patients were analyzed. On average, patients experienced considerable pain after CXL (median VAS score 6.2, range 0 to 10). The postoperative regimen did not significantly affect pain scores, although the antibiotic ointment group reported a higher VAS score (median VAS score 7.2 vs 6.7 and 6.0; P = .57). Occlusive patching showed a trend to quicker resolution of epithelial defects (85% completely healed vs 65% with lenses and 70% with antibiotic ointment; P = .43). Correlations with pain-modulating psychological factors were weak (R < 0.3) and not significant. The use of pain medication corresponded poorly to the prescribed use. CONCLUSION: This study demonstrated clinical equivalence of 3 regimes in combating postoperative pain after routine CXL. Wound healing appeared quicker in the occlusive patch group and therefore might be the best standard of care after CXL. The clinical tradition of using bandage contact lenses should be reevaluated.

Effect of non-invasive intranasal neurostimulation on tear volume, dryness and ocular pain.

PURPOSE: To evaluate the effect of one TrueTear session on change in tear volume and symptoms of dryness and ocular pain. METHODS: Retrospective interventional case series of patients seen in a dry eye clinic. Seventy-five individuals underwent an ocular surface examination and one session of neurostimulation. Outcome measures included objective change in tear volume measured via phenol red test, and subjective change in sensations of dryness and ocular pain measured on a 0-10 Numerical Rating Scale. RESULTS: The mean age of the 75 individuals was 59±13 years, and the majority were male (73%). Intranasal neurostimulation increased tear volume (mean 13.40±8.00 mm, p<0.0005) and reduced intensities of dryness (mean -2.85±2.79, p<0.0005) and ocular pain (mean -1.48±2.41, p<0.0005 for both). However, these effects were independent of one another as change in symptom report did not correlate with change in tear volume (r=-0.13, p=0.25 for dryness; r=0.07, p=0.56 for pain). In a multivariable model, the strongest predictors for increased tear volume were lower baseline tear volume (standardised beta (ß)=-0.50, p<0.0005) and absence of an autoimmune disease (ß=-0.36, p=0.001) (R2=0.30). The strongest predictors for reduced dryness and pain scores were lower baseline dryness and ocular pain scores. No complications related to neurostimulation were noted. CONCLUSION: Intranasal neurostimulation increased tear volume and reduced intensities of dryness and ocular pain, independently of one another.

Blue light activates pulvinar nuclei in longstanding idiopathic photophobia: A case report.

Numerous pathologies can contribute to photophobia. When considering light transduction alone, photophobia may be triggered through melanopsin pathways (non-image forming), rod and cone pathways (image-forming), or some combination of the two. We evaluated a 39 year old female patient with longstanding idiopathic photophobia that was exacerbated by blue light, and tested her by presenting visual stimuli in an event-related fMRI experiment. Analysis showed significantly greater activation in bilateral pulvinar nuclei, associated with the melanopsin intrinsically photosensitive retinal ganglion cell (ipRGC) visual pathway, and their activation is consistent with the patient's report that blue light differentially evoked photophobia. This appears to be the first demonstration of functional activation of the ipRGC pathway during photophobia in a patient.

Corneal Inlay Damage After Cosmetic Laser Treatment of the Eyelid With Long-Pulsed Nd:YAG Laser.

Importance: Protective eyewear or corneal shields are recommended during cosmetic facial laser treatment. Objective: To describe the occurrence of corneal inlay damage following treatment to the eyelids and face with an Nd:YAG laser. Design, Setting, and Participants: This observational case report includes a single incident case cared for at a tertiary care center. A 58-year-old man who had undergone bilateral uncomplicated myopic laser in situ keratomileusis surgery in 2003 and corneal inlay implant in the nondominant left eye in 2013 experienced decreased visual acuity (VA) and pain in the left eye after the application of 2 passes of the Nd:YAG laser to his face and both eyelids for facial tightening. At presentation, the uncorrected VA was counting fingers OS and 20/20 OD. Slitlamp biomicroscopy showed a corneal epithelial defect overlying a deformed corneal inlay, peripheral scattered pigmentary deposits, corneal haze, and brown discoloration of the lamellar pocket of the inlay. He underwent explant of the inlay and debridement 48 hours later because of deteriorating VA and increasing corneal haze. Exposure: Application of long-pulsed Nd:YAG laser at 1064 nm to the middle one-third of both upper eyelids and the periorbital region in a man with a corneal inlay implant. Corneal shields were not worn during the procedure. The peak penetration depth of this laser system is approximately 4 mm. The mean (SD) thickness of the upper eyelid in Asian eyes is 1.127 (0.238) mm. Main Outcomes and Measures: Improvement of corneal inlay damage. Results: In this 58-year-old man, 3 months after the inlay explant, the intrastromal discoloration had resolved. There was still residual corneal haze, but the patient was able to achieve a best-corrected VA of 20/25 OS for distance and J3 (Snellen equivalent, 20/30) OS for near. Conclusions and Relevance: Although the exact cause and effect cannot be determined from a single case, our findings suggest that a history of corneal inlay implant should be asked about prior to any long-pulsed Nd:YAG laser treatment to the periorbital skin and eyelids. Furthermore, these findings suggest that laser treatment to the eyelids should be avoided and that protective eyewear or corneal shields are recommended during cosmetic facial laser treatment in all patients.

Reduced Visual Quality of Life Associated with Migraine is Most Closely Correlated with Symptoms of Dry Eye.

BACKGROUND AND OBJECTIVE: Patients with migraine frequently report ocular or visual symptoms including aura, photophobia, and eye pain. Using validated instruments, our group previously reported that due to these symptoms, patients have marked reductions in visual quality of life. In chronic migraine, these reductions can be as substantial as those reported for other neuro-ophthalmic diseases such as multiple sclerosis with optic neuritis and idiopathic intracranial hypertension. Because the instruments take several different dimensions into account, we were unable to determine which ocular symptom(s) contributed to reduced visual quality of life. The purpose of this investigation was to attempt to determine which ocular symptom(s) were driving the observed reduction in visual quality of life. METHODS: We designed a cross-sectional survey-based study to assess visual quality of life, headache impact, aura, dry eye, and photophobia in migraine patients. Subjects were recruited from the Headache Clinic and General Neurology Clinic at a tertiary teaching hospital. Subjects completed validated questionnaires including: The visual functioning questionnaire-25 (VFQ-25), the headache impact test (HIT-6), the visual aura rating scale (VARS), the ocular surface disease index (OSDI), and the Utah photophobia score (UPSIS-17). Associations between VFQ-25 and OSDI, VFQ-25 and VARS, VFQ-25 and UPSIS-17, HIT-6 and OSDI, HIT-6 and VARS, and HIT-6 and UPSIS-17 were calculated. RESULTS: Of the 62 patients who completed all questionnaires, 17 had episodic migraine and 45 had chronic migraine. Twenty-three patients experienced aura and 39 did not report aura. The most striking correlations were observed between the VFQ-25 and the OSDI (-0.678; P < .001), between the HIT-6 and UPSIS-17 (0.489; P < .001), and between the HIT-6 and OSDI (0.453; P < .001). CONCLUSIONS: Dry eye seems to be the most important symptom that reduces visual quality of life and worsens headache impact. This symptom may be a form of allodynia, a well-known feature of chronic migraine. Photophobia appears to have modest effects on headache impact. In the future, we hope to determine whether treatment of dry eye symptoms can improve visual quality of life and reduce headache impact.