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- clinical variables used to assess the presence and severity of
cant proportion of the general population, with esti- DED, such as tear osmolarity, tear film breakup time, and
mated prevalence rates ranging from 7.4% to 33.7%.1-3 Schirmer testing results, can also differ significantly between
This multifactorial disorder of the tear film and ocular surface patients with migraine headaches and control individuals
results in symptoms of discomfort, visual disturbance, in- without the disorder.8-10 Although prior studies in this area
creased tear film osmolarity, and tear film instability, all of which shed some light on the possible link between migraine head-
can lead to inflammation of the ocular surface and a dimin- aches and DED, they possess inherent limitations.
ished quality of life.4 Similar to DED, the prevalence of mi- Such studies, including some of those cited above,2,7 are
graine headaches among the general population is also quite population-based cross-sectional studies that rely on patient-
high, with estimates as high as 14.2% in the United States alone.5 reported, subjective assessments of disease symptoms, such
Among previous investigations regarding the link be- as questionnaires or surveys.7 Those studies that rely on more
tween DED and migraine headaches, some have demon- objective variables when assessing the presence or absence of
strated an association between the 2 disorders.6,7 Objective and 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 African American 16 043 (22.0)
Asian 1813 (2.5)
Warehouse for Health (CDWH), a repository of deidentified
Native American or Alaskan 344 (0.5)
patient information collected from patient visits at the UNC-
Other or unknown 12 151 (16.6)
affiliated hospitals and outpatient clinics.12 Using an online
Age group, y
interface linked to the CDWH, 72 969 unique patients older
18-34 15 207 (20.8)
than 18 years seen at UNC ophthalmology clinics from May 1,
35-54 17 671 (24.2)
2008, through May 31, 2018, were identified. Queries were per-
55-64 12 806 (17.5)
formed to identify unique patients among this group carry-
≥65 27 285 (37.4)
ing a diagnosis of migraine headaches (codes 346.0x and 346.1x
a
Percentages have been rounded and may not total 100.
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 after accounting for confounding factors associated with the
Revision [ICD-10]) or DED (codes 375.15 and 370.33 from ICD-9 presence of dry eye. Of 72 969 patients, 5352 (7.3%) carried a
and H04.12x and H16.22x from ICD-10). diagnosis of migraine headache, and 9638 (13.2%) carried a
After data acquisition, we calculated odds ratios (ORs) and diagnosis of DED. The odds of having DED given a diagnosis of
associated 95% CIs between migraine headaches and DED for migraine headaches was 1.72 (95% CI, 1.60-1.85) times higher
the entire patient set and further stratified by age and sex. This than that of patients without migraine headaches after adjust-
process was repeated a second time after accounting for the ing for patient sex and age group. After excluding individuals
presence of confounding factors associated with DED in our with confounding factors, the odds of having DED given a di-
patient population, including use of specific medications (tri- agnosis of migraine headaches was 1.42 (95% CI, 1.20-1.68) times
cyclic antidepressants, antihistamines, or diuretics); a his- higher than that of patients without migraine headaches among
tory of rheumatoid arthritis, Sjögren disease, or lupus (ICD-9 a patient population of 39 306 individuals after adjusting for sex
codes 710.0, 710.2, and 714.0 and ICD-10 codes M32.x, M35.0x, and age group. Before accounting for the confounding factors,
M05.79, M05.89, M06.09, and M06.89); and a history of cata- men aged 55 to 64 years and women across all age groups
ract or refractive surgery (Current Procedural Terminology codes exhibited ORs between migraine headaches and DED that
66984, S0800, and S0810). All data were analyzed using SAS suggest an association between the 2 disorders (Table 4). After
software (version 9.4; SAS Inc). 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.
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-
Discussion
lined in Table 1. Table 2 and Table 3 outline query results for the This study of a large, relatively diverse population identified
entire population and stratified by sex and age group, before and 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- studies19,20 have established that T-lymphocyte–mediated in-
tion between the 2 disorders particularly pronounced in all flammation is one of the major mechanisms underlying the
women and men aged 55 to 64 years. Previous studies of se- pathogenesis and progression of DED. Objective and clinical
lect populations support this association but possess substan- variables used to assess the presence and severity of DED are
tial limitations. For example, Kinard et al13 had small sample correlated with the presence of migraine headaches, as men-
sizes and did not include a control group, whereas Shetty et al10 tioned previously.8-10 Inflammatory changes in DED might trig-
included a biased control group with no preexisting ocular dis- ger similar events in neurovascular tissue, leading to the de-
order (and Koktekir et al8 included a control group that was velopment and propagation of migraine headaches, or vice
“free of any known ocular disease, including dry eye syn- versa. Furthermore, excessive dryness of the ocular surface can
drome,” potentially exaggerating this association). Yang et al7 trigger reflex tearing via the trigeminal nerve, which could
and Lee et al14 used large patient populations to demonstrate subsequently trigger auras and acute migraine attacks, given
a statistically significant association between DED and mi- the role of the trigeminal ganglion in the pathophysiology of
graine headaches among South Koreans and US veterans, re- migraine headaches.9
spectively. Given that both studies were performed in select Table 4 illustrates the role that advancing age and female
populations, however, their generalizability is limited. sex may both play in determining the strength of the associa-
The exact mechanism underlying the relationship be- tion between migraine headaches and DED. Before account-
tween migraine headaches and DED is unclear. However, it is ing for confounding factors, a statistically significant associa-
well established that underlying inflammatory processes play tion was observed across women in all age groups, in addition
a significant role in the pathogenesis of both disorders. Prior to the overall patient population. Only men aged 55 to 64 years
studies have shown that migraine headaches can be associ- displayed a statistically significant association between mi-
ated with increases in the levels of inflammatory markers and graine headaches and DED. After accounting for confounding
cytokines, such as C-reactive protein and interleukin 10.15,16 factors, a statistically significant association was observed for
Neurogenic inflammatory mediators are thought to trigger the men and women older than 65 years. These findings are logi-
extravasation of plasma and increase the hypersensitivity of cally consistent with prior studies in the literature. Advanced
neurons constituting the trigeminal ganglion, a phenomenon age and female sex are both risk factors for the development
that plays a significant role in the development and progres- of DED resulting from hormonal and age-related changes.21
sion of migraines.9,11,17,18 Similar to migraine headaches, prior 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- between DED and migraine headaches, and this association
lence of migraine headaches decreases with age across is likely affected in some form or fashion by sex, age, or both.
both sexes.22-25 In addition, as a tertiary referral center, UNC hospitals and
We accounted for antihistamine, diuretic, and tricyclic an- clinics draw on patients of varying socioeconomic status
tidepressant use in our secondary analyses because each of from a large catchment area that likely includes territory in
these medication classes is associated with the development surrounding states.
or worsening of DED and, thus, could have interfered with the Data from the CDWH are also only available in the aggre-
interpretation of our results.26,27 In addition, tricyclic antide- gate, which limited our ability to examine population-based
pressants are indicated for the prophylaxis of migraine head- trends in migraine headaches and DED rates based on more
aches, which may have affected our results as well.28 Refrac- individualized variables, such as tear film breakup time or
tive surgery and cataract surgery can precipitate or worsen Schirmer testing results. In addition, the use of diagnostic
DED.29,30 Autoimmune diseases such as lupus, rheumatoid codes to select patients for our analysis could have intro-
arthritis, and Sjögren syndrome (all 3 of which were ac- duced an element of subjectivity into our study because no spe-
counted for in this study) are also associated with DED and cific criteria for the diagnosis of DED could be used. However,
predominantly affect women, which may explain why sex no previous literature suggests a high degree of consistency be-
longer appeared to play as large an effect on our results as ad- tween ICD-9 and ICD-10 codes and findings present within
vanced age after accounting for confounding factors.31-33 medical records.12,34,35

Limitations
This study possesses several limitations that are inherent in
retrospective studies, including an inability to establish
Conclusions
whether a temporal association exists between migraine head- Despite these limitations, the results of this study suggest a link
aches and DED. Furthermore, we were only able to draw on between migraine headaches and DED. Our results suggest that
data for patients who have received care in UNC-affiliated female sex and advanced age play an important role in deter-
hospitals and clinics, which could mitigate the generalizabil- mining the strength of this association. Physicians caring for pa-
ity of our results. However, our large study population and tients with a history of migraine headaches should be aware that
resulting statistical analyses still illustrate a strong likely link these patients may be at risk at risk for comorbid DED.

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