Constantine D. Sarantopoulos

Dry eye symptoms align more closely to non-ocular conditions than to tear film parameters

Objective To evaluate the relationship between dry eye symptoms, non-ocular conditions and tear film parameters. Methods Design: Cross-sectional study. Participants/setting: The study population consisted of patients who were seen in the Miami Veterans Affairs eye clinic. Patients filled out standardised questionnaires assessing dry eye symptoms (dry eye questionnaire 5 (DEQ5) and ocular surface disease index (OSDI)), non-ocular pain, depression and post-traumatic stress disorder (PTSD), and also underwent measurement of tear film parameters. Main outcome measures: Correlations between dry eye symptoms and non-ocular conditions as compared with tear film parameters. Results 136 patients with a mean age of 65 (SD 11) years participated in the study. All correlations between the dry eye questionnaire scores (DEQ5 and OSDI) and (A) self-reported non-ocular pain measures (numerical rating scale and pain history), (B) depression and (C) PTSD were significant and moderate in strength (Pearsons coefficient 0.24 to 0.60, p<0.01 for all). All correlations between the dry eye questionnaires and tear film measures were weak (Pearsons coefficient −0.10 to 0.18) and most were not significant. Multivariable linear regression analyses revealed that PTSD and non-ocular pain more closely associated with dry eye symptoms than did tear film parameters. Specifically, non-ocular pain and PTSD accounted for approximately 36% of the variability in DEQ5 scores (R=0.60) and approximately 40% of variability in OSDI scores (R=0.64). Of note, none of the tear parameters remained significantly associated with dry eye symptoms in either model. Conclusions Dry eye symptoms more closely align to non-ocular pain, depression and PTSD than to tear film parameters.

Corneal Mechanical Thresholds Negatively Associate With Dry Eye and Ocular Pain Symptoms.

Purpose To examine associations between corneal mechanical thresholds and metrics of dry eye. Methods This was a cross-sectional study of individuals seen in the Miami Veterans Affairs eye clinic. The evaluation consisted of questionnaires regarding dry eye symptoms and ocular pain, corneal mechanical detection and pain thresholds, and a comprehensive ocular surface examination. The main outcome measures were correlations between corneal thresholds and signs and symptoms of dry eye and ocular pain. Results A total of 129 subjects participated in the study (mean age 64 ± 10 years). Mechanical detection and pain thresholds on the cornea correlated with age (Spearmans ρ = 0.26, 0.23, respectively; both P < 0.05), implying decreased corneal sensitivity with age. Dry eye symptom severity scores and Neuropathic Pain Symptom Inventory (modified for the eye) scores negatively correlated with corneal detection and pain thresholds (range, r = −0.13 to −0.27, P < 0.05 for values between −0.18 and −0.27), suggesting increased corneal sensitivity in those with more severe ocular complaints. Ocular signs, on the other hand, correlated poorly and nonsignificantly with mechanical detection and pain thresholds on the cornea. A multivariable linear regression model found that both posttraumatic stress disorder (PTSD) score (β = 0.21, SE = 0.03) and corneal pain threshold (β = −0.03, SE = 0.01) were significantly associated with self-reported evoked eye pain (pain to wind, light, temperature) and explained approximately 32% of measurement variability (R = 0.57). Conclusions Mechanical detection and pain thresholds measured on the cornea are correlated with dry eye symptoms and ocular pain. This suggests hypersensitivity within the corneal somatosensory pathways in patients with greater dry eye and ocular pain complaints.

Assessment of Somatosensory Function in Patients With Idiopathic Dry Eye Symptoms

Importance Somatosensory dysfunction likely underlies dry eye (DE) symptoms in many individuals yet remains an understudied component of the disease. Its presence has important diagnostic and therapeutic implications. Objective To assess the integrity of nociceptive system processes in persons with DE and ocular pain using quantitative sensory testing (QST) techniques applied at a site remote from the eye. Design, Setting, and Participants A cross-sectional study conducted at Miami Veterans Affairs Hospital included 118 individuals with a wide variety of DE symptoms and signs. The study was conducted from October 31, 2013, to January 28, 2016. Interventions Individuals completed questionnaires regarding ocular symptoms (5-Item Dry Eye Questionnaire [DEQ5], Ocular Surface Disease Index [OSDI], and Neuropathic Pain Symptom Inventory modified for the eye [NPSI-E]), psychological status, and medication use and underwent an ocular surface examination. The QST metrics included measures of vibratory and thermal thresholds and cold and hot pain temporal summation (surrogate measures of central sensitization) on the forearm. Main Outcomes and Measures Correlations among DE and ocular pain symptom severity with QST metrics measured on the forearm. The OSDI score ranges from 0 to 100, with 100 indicating the most severe DE symptoms. The DEQ5 score ranges from 0 to 22, with the highest score indicating the most severe symptoms, and the NPSI-E score ranges from 0 to 100, with the highest score indicating the most severe symptoms. Psychological state was measured with the 9-item Patient Health Questionnaire, the PTSD Checklist-Military Version for PTSD, and the Symptom Checklist-90 for anxiety. Results Of the 118 patients who participated in the study, 105 (88.9%) were men (mean [SD] age, 60 [10] years), and a mean of 41% had PTSD, 10% depression, and 0.93% anxiety. Using stepwise linear regression analyses, significant associations were identified between overall DE symptom severity and posttraumatic stress disorder scores and tear breakup time (DEQ5 model: R = 0.54; OSDI model: R = 0.61, P < .001). All other variables (ie, demographics, comorbidities, medications, tear film factors, and QST metrics) dropped out of these models. When specifically considering neuropathic-like qualities of DE pain, however, anxiety and hot pain temporal summation at the forearm explained 17% of the variability in ocular burning (R = 0.41; P < .001), and PTSD score, tear breakup time, and hot pain temporal summation at the forearm explained 25% of the variability in sensitivity to wind (R = 0.50; P < .001) and 30% of the variability in total NPSI-E scores (R = 0.55; P < .001). Conclusions and Relevance Our findings demonstrate that neuropathic-like DE pain symptom severity correlates with quantitative measures of pain sensitivity at a site remote from the eye. This result provides additional evidence that DE symptoms are not only manifestations of a local disorder but also involve somatosensory dysfunction beyond the trigeminal system.

Characteristics of Ocular Pain Complaints in Patients With Idiopathic Dry Eye Symptoms

Objective: The purpose of this study was to examine the severity and quality of ocular pain complaints in patients with dry eye symptoms. Methods: Subjects with clinically relevant dry eye symptoms (dryness, discomfort, tearing) of unknown origin seen in the Miami Veterans Affairs eye clinic were administered questionnaires for dry eye symptoms and ocular pain and underwent a standardized ocular examination. Qualities and severity ratings of ocular pain in subjects with idiopathic dry eye were compared with similar measures from published data in other chronic pain populations. Results: The study sample consisted of 154 subjects, of which 91% were men and ranged in age from 27 to 89 (mean age=61). Fifty-three percent of participants reported an average ocular pain of at least moderate intensity (numerical rating scale≥4), with specific characteristics (i.e., “burning” spontaneous pain) reported at frequencies comparable to prevalent chronic neuropathic pain syndromes as reported in the literature. Significant correlations were found between ocular pain metrics and dry eye symptom severity scores (r=0.57–0.66). Dry eye signs, however, did not generally correlate with ocular pain severity. Conclusions: A significant proportion of subjects with idiopathic dry eye symptoms reported moderate or greater ocular pain intensity, with most endorsing descriptors commonly used by patients with nonocular neuropathic pain conditions. Identifying subgroups of dry eye patients based on the presence and characteristics of ocular pain complaints may improve dry eye subclassification and better individualize treatment strategies.

Human Tear Serotonin Levels Correlate with Symptoms and Signs of Dry Eye

PURPOSE Serotonin, a neurotransmitter known to be involved in nociceptor sensitization, is present in human tears. The purpose of this study was to correlate tear serotonin levels, as a marker of nociceptor sensitization, to facets of dry eye (DE), including symptoms and signs. DESIGN Cross-sectional study. PARTICIPANTS A total of 62 patients with normal eyelid and corneal anatomy were prospectively recruited from a Veterans Administration Ophthalmology Clinic over 11 months. METHODS Dry eye symptoms (Ocular Surface Disease Index [OSDI]), signs (tear break-up time [TBUT], corneal staining, and Schirmers score), and clinical descriptors of neuropathic ocular pain (NOP) (sensitivity to light or sensitivity to wind) were assessed. For tear analysis, each patients tears were collected after instilling 50 μl of sterile saline to the lower cul-de-sac of each eye and using capillary action microcaps to collect the ocular wash. Tear serotonin levels were measured using enzyme-linked immunosorbent assay. MAIN OUTCOME MEASURES Correlations between tear serotonin concentrations and DE symptoms and signs. RESULTS The mean age of the population was 61±14 years, and 84% (n = 52) of the patients were male. Serotonin concentrations negatively correlated with Schirmers scores (r = -0.28; P = 0.02) but did not correlate with other DE parameters, such as OSDI scores, sensitivity to light or wind, TBUT, and staining. According to our hypothesis, we divided patients into groups based on both DE symptoms and aqueous tear production; serotonin concentrations were significantly higher in DE group 1 (OSDI ≥6 and Schirmers <8) compared with both DE group 2 (OSDI ≥6 and Schirmers ≥8) and controls (OSDI <6 and Schirmers ≥8). Patients in DE group 2 more frequently reported sensitivity to light (64%) and wind (67%) compared with DE group 1 (40% and 60%, respectively) and controls (8% and 17%, respectively). CONCLUSIONS Patients with DE symptoms and aqueous tear deficiency had higher tear serotonin levels compared with those with DE symptoms but normal tear production and those without DE symptoms.

The Association of Dry Eye Symptom Severity and Comorbid Insomnia in US Veterans.

Purpose: To investigate the association between dry eye (DE) and insomnia symptom severity. Methods: Cross-sectional study of 187 individuals seen in the Miami Veterans Affairs eye clinic. An evaluation was performed consisting of questionnaires regarding insomnia (insomnia severity index [ISI]) and DE symptoms, including ocular pain, followed by a comprehensive ocular surface examination. Using a two-step cluster analysis based on intensity ratings of ocular pain, the patient population was divided into two groups (high and low ocular pain groups: HOP and LOP). A control group was ascertained at the same time from the same clinic as defined by no symptoms of DE (Dry Eye Questionnaire 5 [DEQ5], <6). The main outcome measure was the frequency of moderate or greater insomnia in the DE groups. Results: The mean age of the study sample was 63 years, and 93% were male. All insomnia complaints were rated higher in the HOP group compared with the LOP and control groups (P<0.0005). Most (61%) individuals in the HOP group experienced insomnia of at least moderate severity (ISI≥15) compared with the LOP (41%) and control groups (18%) (P<0.0005). Black race (odds ratio [OR], 2.7; 95% confidence interval [CI], 1.2–6.0; P=0.02), depression severity (OR, 1.2; 95% CI, 1.1–1.3; P<0.0005), and DE symptom severity (DEQ5; OR, 1.1; 95% CI, 1.01–1.2; P=0.03) were significantly associated with clinical insomnia (ISI≥15) after controlling for potential confounders. Conclusions: After adjusting for demographics and medical comorbidities, we show that DE symptom severity is positively associated with insomnia severity.

Longitudinal Examination of Frequency of and Risk Factors for Severe Dry Eye Symptoms in US Veterans

Importance Dry eye syndrome is a common condition that affects millions of individuals. Many cross-sectional studies have evaluated risk factors for dry eye severity, but few have assessed risk factors or symptom progression over time. Objectives To assess symptom progression in dry eye syndrome and determine risk factors associated with severe symptoms at 1 year. Design, Setting, and Participants A longitudinal study was conducted from October 1, 2013, to April 30, 2015, among patients at the Miami Veterans Affairs Hospital with a wide variety of dry eye symptoms and signs (ranging from none to severe). Main Outcomes and Measures Change in dry eye symptom severity during 1 year, as assessed by responses to dry eye symptom questionnaires administered at the initial visit and 1 year later, as well as baseline risk factor analysis for severe dry eye symptoms at 1 year, defined as a Dry Eye Questionnaire 5 score of 12 or more. Results Of the 120 patients (mean [SD] age, 64 [11] years; 109 male and 11 female), 26 of 58 (44.8%) with either no symptoms or mild or moderate symptoms at baseline progressed to more severe symptoms at 1 year, while 46 of 62 patients (74.2%) with severe symptoms at baseline reported that severe symptoms persisted at 1 year. Baseline ocular risk factors for severe dry eye symptoms at 1 year included more severe dry eye symptoms, ocular pain, and neuropathic pain–like ocular symptoms. Nonocular risk factors included sleep disturbances (eg, sleep apnea and insomnia), mental health status (eg, posttraumatic stress disorder and depression), nonocular pain, and medications (eg, anxiolytics and analgesics). In a multivariable analysis, the most significant risk factors were sleep apnea (odds ratio [OR], 3.80; 95% CI, 1.00-14.49; P = .05), Dry Eye Questionnaire 5 score (OR, 1.15; 95% CI, 1.02-1.30; P = .02), and posttraumatic stress disorder score (OR, 1.04; 95% CI, 1.01-1.08; P = .02). Conclusions and Relevance Patients with severe dry eye symptoms and ocular pain at baseline were more likely to have persistent severe dry eye symptoms on 1-year follow-up. Furthermore, nonocular risk factors that have been associated with dry eye cross-sectionally, such as psychiatric comorbidities and nonocular pain, were also associated with severe dry eye symptoms at 1 year. Although this cohort was limited to US veterans, which may not be generalizable to other populations, our results suggest that pain perception and severity are important when evaluating and managing dry eye.

Epidemiology of discordance between symptoms and signs of dry eye

Background/aims The frequent lack of association between dry eye (DE) symptoms and signs leads to challenges in diagnosing and assessing the disease. Methods Participants underwent ocular surface examinations to evaluate signs of disease and completed questionnaires to assess ocular symptoms, psychological status and medication use. To assess nociceptive system integrity, quantitative sensory testing (QST), including vibratory and thermal threshold measures and temporal summation of pain were obtained at the forearm and forehead. Correlations between DE discordance score (degree of discrepancy between symptom severity and DE signs) and patient characteristics were determined. Higher discordance scores indicated more symptoms than signs. Results 326 patients participated (mean age: 62 years; SD: 10 years; 92% men). Age was negatively correlated with DE discordance score (Pearson r=−0.30, p<0.0005), while mental health indices were positively correlated. Chronic pain elsewhere in the body (ie, non-ocular pain conditions) and intensity ratings of prolonged aftersensations of pain evoked by noxious hot and cold stimuli were also significantly correlated with DE discordance score. Multiple linear regression demonstrated that post-traumatic stress disorder and non-ocular pain intensity were important predictors of DE discordance score, Dry Eye Questionnaire-5 and Ocular Surface Disease Index and that DE discordance was also sensitive to QST as well. Conclusions The present study provides evidence that the degree of discordance between DE symptom report and measurable signs of ocular surface disease is associated with comorbidities related to clinical pain and to hyperalgesia as demonstrated with QST. Understanding the epidemiology of DE discordance can aid in interpreting the DE exam and individualising treatment.

Photophobia and sensations of dryness in patients with migraine occur independent of baseline tear volume and improve following botulinum toxin A injections

Background To evaluate the efficacy of botulinum toxin A (BoNT-A) in reducing photophobia and dry eye symptoms in individuals with chronic migraine. Additionally, we aimed to evaluate tear film volume as a potential contributor to symptoms in these patients. Methods Retrospective review of 76 patients who received BoNT-A for chronic migraine between 23 August 2017 and 13 December 2017 at the Miami Veterans Affairs Medical Center Neurotoxin Clinic. Demographic data and all comorbidities were queried via chart review. Standardised validated surveys were administered to assess symptoms prior to and after BoNT-A injection. Preinjection tear volumes were obtained using the phenol red thread (PRT) test. Results Preinjection migraine, photophobia and dry eye symptom scores were all significantly correlated, p<0.05, and none were associated with preinjection PRT results. After BoNT-A, improvements in migraine, photophobia and dry eye symptoms were also significantly correlated, p<0.05 and similarly did not associate with preinjection PRT results. Photophobia scores significantly improved following BoNT-A, while dry eye symptoms significantly improved in those with severe symptoms at baseline (DEQ-5 score ≥12), p=0.027. In logistic regression analysis of all individuals with dry eye symptoms (DEQ-5 ≥6), individuals with more severe dry eye symptoms were more likely improve, OR 1.27, 95% CI 1.06 to 1.51, p<0.01. Conclusions BoNT-A significantly improved photophobia in patients being treated for migraine and also improved dry eye symptoms in patients with severe symptoms at baseline, independent of baseline tear film volume. These improvements may be due to modulation of shared trigeminal neural pathways.

Evidence that dry eye is a comorbid pain condition in a U.S. veteran population

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. &khgr;2 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.