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Ismail OM, Poole ZB, Bierly SL, et al. Association Between Dry Eye Disease and Migraine Headaches in a Large Population-Based Study. JAMA Ophthalmol. 2019;137(5):532–536. doi:10.1001/jamaophthalmol.2019.0170
What is the association between dry eye disease and migraine headaches?
In this population-based case-control study of 72 969 patients, the odds of having dry eye disease with a diagnosis of migraine headaches was at least 20% higher than that of individuals without a diagnosis of migraine headaches.
Although this association may not reflect cause and effect if unidentified confounders account for the findings, these results suggest that patients with migraine headaches may be at risk of carrying a comorbid diagnosis of dry eye disease.
Reports in the literature have conflicting findings about an association between dry eye disease (DED) and migraine headaches.
To determine the strength of the association between DED and migraine headaches.
Design, Setting, and Participants
This retrospective case-control study included 72 969 patients older than 18 years from University of North Carolina–affiliated health care facilities from May 1, 2008, through May 31, 2018. Deidentified aggregate patient data were queried; data were analyzed from June 1 through June 30, 2018.
Diagnosis of migraine headache.
Main Outcomes and Measures
Odds ratios calculated between DED and migraine headaches for participants as a whole and stratified by sex and age group.
The base population consisted of 72 969 patients, including 41 764 men (57.2%) and 31 205 women (42.8%). Of these, 5352 patients (7.3%) carried a diagnosis of migraine headache, and 9638 (13.2%) carried a diagnosis of DED. The odds of having DED given a diagnosis of migraine headaches was 1.72 (95% CI, 1.60-1.85) times higher than that of patients without migraine headaches. After accounting for multiple confounding factors, the odds of having DED given a diagnosis of migraine headaches was 1.42 (95% CI, 1.20-1.68) times higher than that of patients without migraine headaches.
Conclusions and Relevance
These findings suggest that patients with migraine headaches are more likely to have comorbid DED compared with the general population. Although this association may not reflect cause and effect if unidentified confounders account for the results, these data suggest that patients with migraine headaches may be at risk of carrying a comorbid diagnosis of DED.
Dry eye disease (DED) is a disorder affecting a significant proportion of the general population, with estimated prevalence rates ranging from 7.4% to 33.7%.1-3 This multifactorial disorder of the tear film and ocular surface results in symptoms of discomfort, visual disturbance, increased tear film osmolarity, and tear film instability, all of which can lead to inflammation of the ocular surface and a diminished quality of life.4 Similar to DED, the prevalence of migraine headaches among the general population is also quite high, with estimates as high as 14.2% in the United States alone.5
Among previous investigations regarding the link between DED and migraine headaches, some have demonstrated an association between the 2 disorders.6,7 Objective and clinical variables used to assess the presence and severity of DED, such as tear osmolarity, tear film breakup time, and Schirmer testing results, can also differ significantly between patients with migraine headaches and control individuals without the disorder.8-10 Although prior studies in this area shed some light on the possible link between migraine headaches and DED, they possess inherent limitations.
Such studies, including some of those cited above,2,7 are population-based cross-sectional studies that rely on patient-reported, subjective assessments of disease symptoms, such as questionnaires or surveys.7 Those studies that rely on more objective variables when assessing the presence or absence of DED and migraine headaches in patients may be limited by relatively small sample sizes and have even shown the possibility of no statistically significant difference in rates of migraine headaches between patients with and without DED.11
Quiz Ref IDThe above limitations illustrate the need for a large population-based study to establish the presence, or lack thereof, of a statistically significant association between migraine headaches and DED, given the lack of consensus in the literature on this topic. Herein, we present the findings of a population-based study of patients seen at University of North Carolina (UNC)–affiliated health care facilities during a 10-year period and attempt to elucidate whether factors such as age and sex play any role in determining the strength of the association between these 2 ailments.
Approval for this study was obtained from the institutional review board of UNC. All methods described herein adhered strictly to the tenets of the Declaration of Helsinki and Health Insurance Portability and Accountability Act regulations. Because data were deidentified, informed consent was not required. The data set was acquired from the Carolina Data Warehouse for Health (CDWH), a repository of deidentified patient information collected from patient visits at the UNC-affiliated hospitals and outpatient clinics.12 Using an online interface linked to the CDWH, 72 969 unique patients older than 18 years seen at UNC ophthalmology clinics from May 1, 2008, through May 31, 2018, were identified. Queries were performed to identify unique patients among this group carrying a diagnosis of migraine headaches (codes 346.0x and 346.1x from International Classification of Diseases, Ninth Revision [ICD-9] and G43.0x, and G43.1x from International Statistical Classification of Diseases and Related Health Problems, Tenth Revision [ICD-10]) or DED (codes 375.15 and 370.33 from ICD-9 and H04.12x and H16.22x from ICD-10).
Quiz Ref IDAfter data acquisition, we calculated odds ratios (ORs) and associated 95% CIs between migraine headaches and DED for the entire patient set and further stratified by age and sex. This process was repeated a second time after accounting for the presence of confounding factors associated with DED in our patient population, including use of specific medications (tricyclic antidepressants, antihistamines, or diuretics); a history of rheumatoid arthritis, Sjögren disease, or lupus (ICD-9 codes 710.0, 710.2, and 714.0 and ICD-10 codes M32.x, M35.0x, M05.79, M05.89, M06.09, and M06.89); and a history of cataract or refractive surgery (Current Procedural Terminology codes 66984, S0800, and S0810). All data were analyzed using SAS software (version 9.4; SAS Inc).
Quiz Ref IDThe base population consisted of 72 969 patients, including 41 764 men (57.2%) and 31 205 women (42.8%). Baseline demographic characteristics of the studied patient population are outlined in Table 1. Table 2 and Table 3 outline query results for the entire population and stratified by sex and age group, before and after accounting for confounding factors associated with the presence of dry eye. Of 72 969 patients, 5352 (7.3%) carried a diagnosis of migraine headache, and 9638 (13.2%) carried a diagnosis of DED. The odds of having DED given a diagnosis of migraine headaches was 1.72 (95% CI, 1.60-1.85) times higher than that of patients without migraine headaches after adjusting for patient sex and age group. After excluding individuals with confounding factors, the odds of having DED given a diagnosis of migraine headaches was 1.42 (95% CI, 1.20-1.68) times higher than that of patients without migraine headaches among a patient population of 39 306 individuals after adjusting for sex and age group. Before accounting for the confounding factors, men aged 55 to 64 years and women across all age groups exhibited ORs between migraine headaches and DED that suggest an association between the 2 disorders (Table 4). After accounting for confounding factors, men (OR, 1.96; 95% CI, 1.02-3.77) and women (OR, 2.47; 95% CI, 1.75-3.47) 65 years or older exhibited ORs suggesting an association between migraine headaches and DED.
This study of a large, relatively diverse population identified a 20% greater risk of carrying a diagnosis of DED given a coexisting diagnosis of migraine headaches, with the association between the 2 disorders particularly pronounced in all women and men aged 55 to 64 years. Previous studies of select populations support this association but possess substantial limitations. For example, Kinard et al13 had small sample sizes and did not include a control group, whereas Shetty et al10 included a biased control group with no preexisting ocular disorder (and Koktekir et al8 included a control group that was “free of any known ocular disease, including dry eye syndrome,” potentially exaggerating this association). Yang et al7 and Lee et al14 used large patient populations to demonstrate a statistically significant association between DED and migraine headaches among South Koreans and US veterans, respectively. Given that both studies were performed in select populations, however, their generalizability is limited.
The exact mechanism underlying the relationship between migraine headaches and DED is unclear. However, it is well established that underlying inflammatory processes play a significant role in the pathogenesis of both disorders. Prior studies have shown that migraine headaches can be associated with increases in the levels of inflammatory markers and cytokines, such as C-reactive protein and interleukin 10.15,16 Neurogenic inflammatory mediators are thought to trigger the extravasation of plasma and increase the hypersensitivity of neurons constituting the trigeminal ganglion, a phenomenon that plays a significant role in the development and progression of migraines.9,11,17,18 Similar to migraine headaches, prior studies19,20 have established that T-lymphocyte–mediated inflammation is one of the major mechanisms underlying the pathogenesis and progression of DED. Objective and clinical variables used to assess the presence and severity of DED are correlated with the presence of migraine headaches, as mentioned previously.8-10 Inflammatory changes in DED might trigger similar events in neurovascular tissue, leading to the development and propagation of migraine headaches, or vice versa. Furthermore, excessive dryness of the ocular surface can trigger reflex tearing via the trigeminal nerve, which could subsequently trigger auras and acute migraine attacks, given the role of the trigeminal ganglion in the pathophysiology of migraine headaches.9
Table 4 illustrates the role that advancing age and female sex may both play in determining the strength of the association between migraine headaches and DED. Before accounting for confounding factors, a statistically significant association was observed across women in all age groups, in addition to the overall patient population. Only men aged 55 to 64 years displayed a statistically significant association between migraine headaches and DED. After accounting for confounding factors, a statistically significant association was observed for men and women older than 65 years. These findings are logically consistent with prior studies in the literature. Advanced age and female sex are both risk factors for the development of DED resulting from hormonal and age-related changes.21 Migraine headaches are significantly more common in women than men, particularly younger women, although the prevalence of migraine headaches decreases with age across both sexes.22-25
We accounted for antihistamine, diuretic, and tricyclic antidepressant use in our secondary analyses because each of these medication classes is associated with the development or worsening of DED and, thus, could have interfered with the interpretation of our results.26,27 In addition, tricyclic antidepressants are indicated for the prophylaxis of migraine headaches, which may have affected our results as well.28 Refractive surgery and cataract surgery can precipitate or worsen DED.29,30 Autoimmune diseases such as lupus, rheumatoid arthritis, and Sjögren syndrome (all 3 of which were accounted for in this study) are also associated with DED and predominantly affect women, which may explain why sex no longer appeared to play as large an effect on our results as advanced age after accounting for confounding factors.31-33
Quiz Ref IDThis study possesses several limitations that are inherent in retrospective studies, including an inability to establish whether a temporal association exists between migraine headaches and DED. Furthermore, we were only able to draw on data for patients who have received care in UNC-affiliated hospitals and clinics, which could mitigate the generalizability of our results. However, our large study population and resulting statistical analyses still illustrate a strong likely link between DED and migraine headaches, and this association is likely affected in some form or fashion by sex, age, or both. In addition, as a tertiary referral center, UNC hospitals and clinics draw on patients of varying socioeconomic status from a large catchment area that likely includes territory in surrounding states.
Data from the CDWH are also only available in the aggregate, which limited our ability to examine population-based trends in migraine headaches and DED rates based on more individualized variables, such as tear film breakup time or Schirmer testing results. In addition, the use of diagnostic codes to select patients for our analysis could have introduced an element of subjectivity into our study because no specific criteria for the diagnosis of DED could be used. However, previous literature suggests a high degree of consistency between ICD-9 and ICD-10 codes and findings present within medical records.12,34,35
Despite these limitations, the results of this study suggest a link between migraine headaches and DED. Our results suggest that female sex and advanced age play an important role in determining the strength of this association. Physicians caring for patients with a history of migraine headaches should be aware that these patients may be at risk at risk for comorbid DED.
Accepted for Publication: December 22, 2018.
Corresponding Author: Richard M. Davis, MD, Department of Ophthalmology, University of North Carolina, Chapel Hill, 2226 Nelson Hwy, Ste 200, Chapel Hill, NC 27517 (email@example.com).
Published Online: March 7, 2019. doi:10.1001/jamaophthalmol.2019.0170
Author Contributions: Mr Ismail had full access to all the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis.
Concept and design: Ismail, Poole, Meyer, Davis.
Acquisition, analysis, or interpretation of data: Ismail, Poole, Bierly, Van Buren, Lin, Meyer.
Drafting of the manuscript: Ismail, Poole, Meyer.
Critical revision of the manuscript for important intellectual content: All authors.
Statistical analysis: Ismail, Poole, Van Buren, Lin.
Administrative, technical, or material support: Bierly, Davis.
Supervision: Lin, Meyer.
Conflict of Interest Disclosures: Dr Lin reported receiving grants from the National Center for Advancing Translational Sciences, National Institutes of Health (NIH) during the conduct of the study. No other disclosures were reported.
Disclaimer: This content is solely the responsibility of the authors and does not necessarily represent the official views of the NIH.
Additional Contributions: i2b2 software was used in conducting this study. i2b2 is the flagship tool developed by the i2b2 (Informatics for Integrating Biology and the Bedside) Center, an NIH-funded National Center for Biomedical Computing based at Partners HealthCare System. The i2b2 instance at the University of North Carolina is supported by grant UL1TR002489 from the National Center for Advancing Translational Sciences, NIH.