Research

JAMA Ophthalmology | Original Investigation

Association Between Dry Eye Disease and Migraine

Headaches in a Large Population-Based Study
Omar M. Ismail, BS; Zachary B. Poole, BS; Shane L. Bierly, BS; Eric D. Van Buren, BS; Feng-Chang Lin, PhD;
Jay J. Meyer, MD; Richard M. Davis, MD

IMPORTANCE Reports in the literature have conflicting findings about an association

between dry eye disease (DED) and migraine headaches.

OBJECTIVE 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.

EXPOSURES 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.

RESULTS 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
Author Affiliations: Department of
headache, and 9638 (13.2%) carried a diagnosis of DED. The odds of having DED given a Ophthalmology, University of North
diagnosis of migraine headaches was 1.72 (95% CI, 1.60-1.85) times higher than that of Carolina, Chapel Hill (Ismail, Poole,
patients without migraine headaches. After accounting for multiple confounding factors, Davis); medical student, School of
Medicine, University of North
the odds of having DED given a diagnosis of migraine headaches was 1.42 (95% CI, 1.20-1.68) Carolina, Chapel Hill (Bierly);
times higher than that of patients without migraine headaches. Department of Biostatistics, Gillings
School of Public Health, University
of North Carolina, Chapel Hill
CONCLUSIONS AND RELEVANCE These findings suggest that patients with migraine headaches
(Van Buren, Lin); Department of
are more likely to have comorbid DED compared with the general population. Although this Ophthalmology, University of
association may not reflect cause and effect if unidentified confounders account for the Auckland, Auckland, New Zealand
results, these data suggest that patients with migraine headaches may be at risk of carrying a (Meyer).
comorbid diagnosis of DED. Corresponding Author: Richard M.
Davis, MD, Department of
Ophthalmology, University of North
JAMA Ophthalmol. doi:10.1001/jamaophthalmol.2019.0170 Carolina, Chapel Hill, 2226 Nelson
Published online March 7, 2019. Hwy, Ste 200, Chapel Hill, NC 27517
(richard_davis@med.unc.edu).

D
ry eye disease (DED) is a disorder affecting a signifi-
cant proportion of the general population, with esti-
mated 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, in-
creased tear film osmolarity, and tear film instability, all of which
can lead to inflammation of the ocular surface and a dimin-
ished quality of life.4 Similar to DED, the prevalence of mi-
graine 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 be-
tween DED and migraine headaches, some have demon-
strated 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 head-
aches 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 rela-

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 Research Original Investigation Association Between Dry Eye Disease and Migraine Headaches

tively small sample sizes and have even shown the possibility
of no statistically significant difference in rates of migraine Key Points
headaches between patients with and without DED.11
Question What is the association between dry eye disease and
The above limitations illustrate the need for a large popu- migraine headaches?
lation-based study to establish the presence, or lack thereof,
Findings In this population-based case-control study of 72 969
of a statistically significant association between migraine head-
patients, the odds of having dry eye disease with a diagnosis of
aches and DED, given the lack of consensus in the literature
migraine headaches was at least 20% higher than that of
on this topic. Herein, we present the findings of a population- individuals without a diagnosis of migraine headaches.
based study of patients seen at University of North Carolina
Meaning Although this association may not reflect cause and
(UNC)–affiliated health care facilities during a 10-year period
effect if unidentified confounders account for the findings, these
and attempt to elucidate whether factors such as age and sex
results suggest that patients with migraine headaches may be at
play any role in determining the strength of the association risk of carrying a comorbid diagnosis of dry eye disease.
between these 2 ailments.

Table 1. Baseline Demographic Characteristics of Study Population

Methods No. (%) of Patients

Demographic (n = 72 969)a
Approval for this study was obtained from the institutional re- Sex
view board of UNC. All methods described herein adhered Male 41 764 (57.2)
strictly to the tenets of the Declaration of Helsinki and Health Female 31 205 (42.8)
Insurance Portability and Accountability Act regulations. Race
Because data were deidentified, informed consent was not White 42 618 (58.4)

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 per-
formed to identify unique patients among this group carry-
ing 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).
After 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 (tri-
cyclic antidepressants, antihistamines, or diuretics); a his-
tory 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 cata-
ract or refractive surgery (Current Procedural Terminology codes
66984, S0800, and S0810). All data were analyzed using SAS
software (version 9.4; SAS Inc).
Results
The base population consisted of 72 969 patients, including
41 764 men (57.2%) and 31 205 women (42.8%). Baseline demo-
graphic characteristics of the studied patient population are out-
lined in Table 1. Table 2 and Table 3 outline query results for the
entire population and stratified by sex and age group, before and
African American 16 043 (22.0)
Asian 1813 (2.5)
Native American or Alaskan 344 (0.5)
Other or unknown 12 151 (16.6)
Age group, y
18-34 15 207 (20.8)
35-54 17 671 (24.2)
55-64 12 806 (17.5)
≥65 27 285 (37.4)
a
Percentages have been rounded and may not total 100.
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 adjust-
ing for patient sex and age group. After excluding individuals
with confounding factors, the odds of having DED given a di-
agnosis 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.
Discussion
This study of a large, relatively diverse population identified
a 20% greater risk of carrying a diagnosis of DED given a

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 Association Between Dry Eye Disease and Migraine Headaches Original Investigation Research

Table 2. Aggregate Patient Demographic Data From the Carolina Data Table 3. Prevalence of DED in Patients With and Without a Diagnosis
Warehouse for Migraine Headaches and DED of Migraine Headache

No. (%) of Patients Prevalence, No. of Patients

Total No. With Migraine Diagnosis With DED Without DED
Age Group, y of Patients Headache With DED Total population
Total Population With migraine headache 1045 4298
Men Without migraine headache 8584 59 042
18-34 6935 277 (4.0) 220 (3.2) Excluding confounding factors
35-54 7556 340 (4.5) 718 (9.5) With migraine headache 166 1213
55-64 5418 244 (4.5) 615 (11.4) Without migraine headache 3179 34 748
≥65 11 289 282 (2.5) 1473 (13.0) Abbreviation: DED, dry eye disease.
Women
18-34 8272 871 (10.5) 449 (5.4)
Table 4. Odds Between Migraine Headache and DED Before and After
35-54 10 115 1581 (15.6) 1463 (14.5)
Accounting for Confounding Factors
55-64 7388 815 (11.0) 1454 (19.7)
OR (95% CI)
≥65 15 996 942 (5.9) 3246 (20.3)
Total Excluding
Excluding Confounding Factors Age Group, y Population Confounding Factors
Men All patients ≥18 1.72 (1.60-1.85) 1.42 (1.20-1.68)
18-34 5448 117 (2.1) 129 (2.4) Men

35-54 4898 127 (2.6) 364 (7.4) 18-34 1.65 (0.96-2.82) 1.47 (0.54-4.06)
35-54 1.34 (0.96-1.85) 0.95 (0.48-1.88)
55-64 2730 53 (1.9) 241 (8.8)
55-64 1.80 (1.31-2.50) 1.08 (0.42-2.73)
≥65 5061 69 (1.4) 451 (8.9)
≥65 1.32 (0.97-1.80) 1.96 (1.02-3.77)
Women
Women
18-34 5894 269 (4.6) 240 (4.1)
18-34 2.10 (1.65-2.67) 1.10 (0.61-2.00)
35-54 5438 403 (7.4) 591 (10.9) 35-54 1.50 (1.31-1.71) 1.33 (0.98-1.79)
55-64 3351 163 (4.9) 481 (14.4) 55-64 1.44 (1.23-1.70) 0.98 (0.62-1.54)
≥65 6486 178 (2.7) 848 (13.1) ≥65 1.84 (1.60-2.12) 2.47 (1.75-3.47)

Abbreviation: DED, dry eye disease. Abbreviations: DED, dry eye disease; OR, odds ratio.

coexisting diagnosis of migraine headaches, with the associa-
tion between the 2 disorders particularly pronounced in all
women and men aged 55 to 64 years. Previous studies of se-
lect populations support this association but possess substan-
tial 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 dis-
order (and Koktekir et al8 included a control group that was
“free of any known ocular disease, including dry eye syn-
drome,” potentially exaggerating this association). Yang et al7
and Lee et al14 used large patient populations to demonstrate
a statistically significant association between DED and mi-
graine headaches among South Koreans and US veterans, re-
spectively. Given that both studies were performed in select
populations, however, their generalizability is limited.
The exact mechanism underlying the relationship be-
tween 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 associ-
ated 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 progres-
sion of migraines.9,11,17,18 Similar to migraine headaches, prior
studies19,20 have established that T-lymphocyte–mediated in-
flammation 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 men-
tioned previously.8-10 Inflammatory changes in DED might trig-
ger similar events in neurovascular tissue, leading to the de-
velopment 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 associa-
tion between migraine headaches and DED. Before account-
ing for confounding factors, a statistically significant associa-
tion 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 mi-
graine 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 logi-
cally 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

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 Research Original Investigation Association Between Dry Eye Disease and Migraine Headaches

than men, particularly younger women, although the preva-
lence of migraine headaches decreases with age across
both sexes.22-25
We accounted for antihistamine, diuretic, and tricyclic an-
tidepressant 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 antide-
pressants are indicated for the prophylaxis of migraine head-
aches, which may have affected our results as well.28 Refrac-
tive 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 ac-
counted 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 ad-
vanced age after accounting for confounding factors.31-33
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 aggre-
gate, 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 intro-
duced an element of subjectivity into our study because no spe-
cific criteria for the diagnosis of DED could be used. However,
previous literature suggests a high degree of consistency be-
tween ICD-9 and ICD-10 codes and findings present within
medical records.12,34,35

Limitations
This study possesses several limitations that are inherent in
retrospective studies, including an inability to establish
whether a temporal association exists between migraine head-
aches 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 generalizabil-
ity of our results. However, our large study population and
resulting statistical analyses still illustrate a strong likely link
Conclusions
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 deter-
mining the strength of this association. Physicians caring for pa-
tients with a history of migraine headaches should be aware that
these patients may be at risk at risk for comorbid DED.

ARTICLE INFORMATION REFERENCES Eye Res. 2017;42(6):837-841. doi:10.1080/

Accepted for Publication: December 22, 2018. 1. Gayton JL. Etiology, prevalence, and treatment 02713683.2016.1262876

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.
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