Published Ahead of Print on December 17, 2014 as 10.1212/WNL.0000000000001124
ARTICLES
Increased risk of Bell palsy in patients with migraine A nationwide cohort study
Kuan-Po Peng, MD* Yung-Tai Chen, MD* Jong-Ling Fuh, MD Chao-Hsiun Tang, PhD Shuu-Jiun Wang, MD
Correspondence to Dr. Wang: [email protected]
ABSTRACT
Objective: To evaluate the association between migraine and Bell palsy and to examine the effects of age, sex, migraine subtype, and comorbid risk factors for Bell palsy.
Methods: This nationwide cohort study was conducted using data from the Taiwan National Health Insurance Research Database. Subjects aged 18 years or older with neurologistdiagnosed migraine from 2005 to 2009 were included. A nonheadache age- and propensity score–matched control cohort was selected for comparison. All subjects were followed until the end of 2010, death, or the occurrence of a Bell palsy event. Cox proportional hazards regression was used to calculate the adjusted hazard ratios and 95% confidence intervals to compare the risk of Bell palsy between groups. Results: Both cohorts (n 5 136,704 each) were followed for a mean of 3.2 years. During the follow-up period, 671 patients (424,372 person-years) in the migraine cohort and 365 matched control subjects (438,677 person-years) were newly diagnosed with Bell palsy (incidence rates, 158.1 and 83.2/100,000 person-years, respectively). The adjusted hazard ratio for Bell palsy was 1.91 (95% confidence interval, 1.68–2.17; p , 0.001). The association between migraine and Bell palsy remained significant in sensitivity analyses, and tests of interaction failed to reach significance in all subgroup analyses. Conclusion: Migraine is a previously unidentified risk factor for Bell palsy. The association between these 2 conditions suggests a linked disease mechanism, which is worthy of further exploration. Neurology® 2015;84:1–9 GLOSSARY aHR 5 adjusted hazard ratio; CCI 5 Charlson Comorbidity Index; CI 5 confidence interval; HR 5 hazard ratio; ICD-9-CM 5 International Classification of Diseases, Ninth Revision, Clinical Modification; NHI 5 National Health Insurance; NHIRD 5 National Health Insurance Research Database.
Editorial, page 108 Supplemental data at Neurology.org
Bell palsy is an acute, idiopathic, unilateral peripheral facial palsy, although bilateral involvement has been reported rarely.1,2 This condition affects patients of all ages; the incidence is the lowest among children and increases gradually with age.3 The annual incidence rate ranges from 11 to 40 per 100,000 persons,4 and both sexes are affected equally.5 The pathophysiology of Bell palsy is largely unknown. Common hypotheses include acute or reactivation of latent viral infection, vascular ischemia, and inflammatory responses.6–9 Several predisposing factors, such as diabetes mellitus, hypertension, pregnancy, and the use of inactivated intranasal influenza vaccine,3 have been recognized. Other conditions can also present with unilateral facial palsy, such as Ramsay Hunt syndrome, HIV infection, Lyme disease, autoimmune diseases, amyloidosis, and spaceoccupying lesions.3 Migraine is a common and disabling disorder with an annual global prevalence of approximately 10% and a female/male ratio of 2–3:1.10,11 It is associated with vascular disorders of the CNS, i.e., ischemic and hemorrhagic strokes.12 Cranial nerve symptoms, such as *These authors contributed equally to this work. From the Department of Internal Medicine (K.-P.P.), Taipei Veterans General Hospital, Taoyuan Branch, Taoyuan; Institute of Brain Science (K.-P.P., S.-J.W.), National Yang-Ming University, Taipei; Faculty of Medicine (K.-P.P., Y.-T.C., J.-L.F., S.-J.W.), National Yang-Ming University School of Medicine, Taipei; Department of Nephrology (Y.-T.C.), Institute of Internal Medicine, Taipei City Hospital Heping Fuyou Branch, Taipei; Department of Neurology (J.-L.F., S.-J.W.), Neurological Institute, Taipei Veterans General Hospital, Taipei; and School of Health Care Administration (C.-H.T.), Taipei Medical University, Taipei, Taiwan. Go to Neurology.org for full disclosures. Funding information and disclosures deemed relevant by the authors, if any, are provided at the end of the article. © 2014 American Academy of Neurology
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1
ophthalmoplegia, have also been reported in some patients.13 We recently reported an association between migraine and sudden sensorineural hearing loss.14 An association with isolated peripheral facial palsy has been reported rarely,15 although facial and limb weakness is common in patients with hemiplegic migraine.16 Vascular ischemia remains a possible etiology of Bell palsy,9 and a recent report identified asymmetrical facial blood perfusion in patients with migraine.17 Thus, this study was conducted to determine whether migraine is associated with Bell palsy. METHODS Data source. Taiwan’s mandatory universal National Health Insurance (NHI) program, launched in 1995, currently provides comprehensive medical coverage to 99% of the population of 23 million residents. The NHI covers outpatient, inpatient, emergency, dental, and traditional Chinese medicine services, as well as prescription drugs. Data for this study were drawn from the nationwide population-based National Health Insurance Research Database (NHIRD) including enrollment files, claims data, and drug prescription registry, managed and publicly released by the National Health Research Institute. These databases provide comprehensive utilization and enrollment information for all patients in the NHI program. Diseases were coded according to the 2001 ICD-9-CM.18 The accuracy of diagnoses listed in the NHIRD has been validated for several diseases and this database has served as the basis for several published studies.14,19,20
Standard protocol approvals, registrations, and patient consents. All information that would potentially expose individual patient identities has been encrypted, and the confidentiality of data is ensured according to the regulations of the Bureau of NHI and the National Health Research Institute. The institutional review board of Taipei Veterans General Hospital approved the present study.
Study design and cohorts. This nationwide, observational cohort study was conducted to determine the association between Bell palsy and migraine in a Taiwanese population. The study involved 2 cohorts: the migraine cohort, composed of all patients in Taiwan who visited neurologists with a diagnosis of migraine (ICD-9-CM code 346.x) between January 2005 and December 2009; and the nonheadache control cohort, composed of individuals free from diagnosis of migraine (code 346.x), tension-type headache (code 307.81), and headache (code 784.0), extracted from a dataset of 1 million beneficiaries randomly sampled from the original NHIRD (figure). Three subgroups of migraine were defined: migraine with aura (ICD9-CM codes 346.00–346.01), migraine without aura (ICD9-CM codes 346.10–346.11), and migraine unspecified (ICD-9-CM codes 346.90–346.91). Each subject with migraine entered the cohort on the day of the first clinical visit associated with a neurologist’s registry of the diagnosis of migraine in the dataset. Only subjects aged 18 years or older were included in this study, and subjects with antecedent Bell palsy were excluded. Subjects in whom migraine and Bell palsy were both diagnosed within a 30-day period were also excluded to minimize the possibility of alternative diagnoses that might contribute to facial palsy and migraine-like headache. Subjects with a follow-up period 2
Neurology 84
of ,30 days were excluded in both the migraine and control cohorts. Patients in the control cohort were free from the diagnosis of migraine, and no index date could be assigned. Thus, we randomly assigned a “pseudodiagnostic date” to each patient in the control cohort corresponding to the index of diagnosis of one pool of patients with migraine so that both cohorts were enrolled at a similar time. The same exclusion criteria in the migraine cohort were applied to the control cohort.
Propensity score matching. We used multivariate logistic regression to calculate the propensity score for the predicted probabilities of migraine status. The covariates used in generating the propensity scores are listed in table e-1 on the Neurology® Web site at Neurology.org. In addition, we performed 1:1 case/control matching based on propensity scores. The use of propensity score matching in observational studies resembles certain characteristics of randomized controlled trials.21 For each patient in the migraine cohort, we identified one control patient with similar demographic characteristics, matched in terms of age (65 years) and propensity score (60.1) for the likelihood of a migraine diagnosis. Subjects in the migraine cohort who could not be matched with control subjects were excluded from this study. Outcome. The primary outcome was the occurrence of Bell palsy, defined as the first hospitalization or ambulatory visit associated with an ICD-9-CM code of 351.0, during the follow-up period. Patients with concomitant diagnoses of Bell palsy and herpes zoster infection (ICD-9-CM code 053.xx) within a 30-day period were excluded to minimize the chance of misclassification of Ramsay Hunt syndrome as Bell palsy. Both cohorts were followed until December 31, 2010, death, or the occurrence of Bell palsy.
Baseline characteristics. Baseline demographic data, including age, sex, medical care utilization (ambulatory visits in the past year), income, and urbanization level, were collected. The Charlson Comorbidity Index (CCI) score was used to determine subjects’ overall systemic health22; a higher CCI score is inversely associated with the 10-year survival rate, i.e., a score of 0 is associated with a 10-year survival rate of 99% and a score of 5 is associated with a rate of 34%.22 Data on other systemic diseases not included in the CCI were also recorded; these included atrial fibrillation, valvular heart disease, hypertension, asthma, dyslipidemia, and drug abuse. Data on subjects’ concomitant use of medications with potential anti-inflammatory effects and those associated with patients’ physical conditions and immune system function, according to the World Health Organization’s Anatomical Therapeutic Chemical Classification System,23 were extracted. These medications included antiplatelet agents, warfarin, angiotensin-converting enzyme inhibitors, angiotensin II receptor blockers, b-blockers, calcium-channel blockers, diuretics, nitrate, statin, dipyridamole, steroids, estrogen, progesterone, nonsteroidal anti-inflammatory drugs, proton-pump inhibitors, and antihyperglycemic drugs.
Statistical analysis. Descriptive statistics were used to examine the baseline characteristics of the study cohorts. The characteristics of the 2 groups were compared using the Pearson x2 test for categorical variables, the independent t test for parametric continuous variables, and the Mann–Whitney U test for continuous data without normal distributions. The incidence rates of Bell palsy in both groups were calculated using Poisson distributions. We calculated adjusted absolute incidence rates of Bell palsy to evaluate the contribution of each risk factor to the occurrence of Bell palsy using the macro developed by Zhao.24 The SAS GENMOD function of this macro was used with the Poisson distribution option to calculate predicted adjusted rates at mean levels of the independent variables, including age, sex, medical utilization, socioeconomic status,
January 13, 2015
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Figure
Enrollment of patients
ICD-9-CM 5 International Classification of Diseases, Ninth Revision, Clinical Modification; NHIRD 5 National Health Insurance Research Database.
urbanization, CCI score, migraine, diabetes mellitus, and hypertension. The adjusted absolute rates are presented with upper and lower 95% confidence intervals (CIs) per 100,000 person-years. The risk of Bell palsy was compared between groups using hazard ratios (HRs) from Cox regression models with a conditional approach using stratification. Adjusted HRs were calculated by Cox regression models with adjusted propensity score as a continuous covariate. Cox regression models were also used to examine the influences of age, sex, CCI score, diabetes mellitus, hypertension, and migraine subtype on the incidence of Bell palsy after the diagnosis of migraine. Interactions were examined in these subgroups using likelihood ratio tests. Sensitivity analysis was conducted to validate our results in the following patients: (1) those without a diagnosis of pregnancy within 30 days preceding and after the diagnosis of Bell palsy; (2) those with the initial diagnosis of Bell palsy made by neurologists or nonneurologists; and (3) those with steroid prescription after diagnosis of Bell palsy. The Microsoft SQL Server (2012; Microsoft Corporation, Redmond, WA) was used for data linkage, processing, and sampling. Propensity scores and adjusted absolute incidence rates were calculated with SAS software (version 9.2; SAS Institute, Inc., Cary, NC). All other statistical analyses were conducted using STATA statistical software (version 12.0; StataCorp, College Station, TX). Statistical significance was defined as p , 0.05. RESULTS Characteristics of the study population.
Using data from January 2005 to December 2009,
we identified 182,292 patients with migraine and 415,744 control subjects. The mean age of subjects with migraine was 42.2 (SD, 14.9) years, and the female/male ratio was approximately 3:1. Compared with control subjects, patients with migraine utilized medical care more frequently, and had more comorbidities in certain fields (table 1). After age and propensity score matching (figure), 136,704 patients each were assigned to the migraine and matched control cohorts. The demographic characteristics of the study population are summarized in table 1. Incidence rates of Bell palsy. During a mean follow-up period of 3.2 6 1.6 years, 671 patients (424,372 person-years) in the migraine cohort and 365 patients (438,677 person-years) in the matched control cohort were newly diagnosed with Bell palsy. The incidence rates of Bell palsy were thus 158.1 per 100,000 person-years in the migraine cohort and 83.2 per 100,000 person-years in the control cohort. The male/female ratios of Bell palsy were 1.4:1 in the migraine cohort and 1.1:1 in the control cohort. Patients with migraine were at greater risk of subsequently developing Bell palsy (adjusted HR [aHR], 1.91; 95% CI, 1.68–2.17; p , 0.001; table 2). Neurology 84
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Table 1
Demographic and clinical characteristics of the migraine and control cohorts No propensity score matching
Propensity score–matched
p
Migraine cohort
Matched control cohort
136,704
136,704
43.6 (16.6)
,0.001
42.0 (15.6)
42.0 (15.7)
0.945
48,785 (26.7)
235,862 (56.7)
,0.001
43,845 (32)
43,846 (32)
0.997
0
2,018 (1.1)
45,314 (10.8)
2,018 (1.4)
2,023 (1.4)
1–5
22,240 (12.2)
132,122 (31.7)
21,759 (15.9)
21,759 (15.9)
6–10
31,109 (17)
90,732 (21.8)
28,475 (20.8)
28,474 (20.8)
>10
126,925 (69.6)
147,576 (35.4)
84,452 (61.7)
84,448 (61.7)
Characteristic
Migraine cohort
Control cohort
No. of patients
182,292
415,744
Mean age (SD), y
42.2 (14.9)
Males
,0.001
Outpatient visits in past year
Incomea
p
1.000
,0.001
1.000
Dependent
43,547 (23.8)
93,737 (22.5)
33,387 (24.4)
33,387 (24.4)
NT$ 0–19,100
39,694 (21.7)
100,436 (24.1)
30,016 (21.9)
30,016 (21.9)
NT$ 19,100–42,000
80,101 (43.9)
174,419 (41.9)
58,804 (43)
58,804 (43)
>NT$ 42,000
18,950 (10.3)
47,152 (11.3)
14,497 (10.6)
14,497 (10.6)
1
86,587 (47.4)
248,727 (59.8)
70,327 (51.4)
70,330 (51.4)
2
85,893 (47.1)
135,428 (32.5)
58,631 (42.8)
58,626 (42.8)
3
8,390 (4.6)
26,729 (6.4)
6,590 (4.8)
6,592 (4.8)
4
1,422 (0.7)
4,860 (1.1)
1,156 (0.8)
1,156 (0.8)
0
81,661 (44.7)
273,794 (65.8)
72,903 (53.3)
72,903 (53.3)
1
50,175 (27.5)
77,991 (18.7)
34,529 (25.2)
34,529 (25.2)
2
24,817 (13.6)
30,927 (7.4)
14,301 (10.4)
14,302 (10.4)
‡3
25,639 (14)
33,032 (7.9)
14,971 (10.9)
14,970 (10.9)
9,361 (5.1)
16,212 (3.8)
6,411 (4.6)
6,411 (4.6)
1.000
Urbanization level
b
,0.001
1.000
Charlson comorbidity index score
Concomitant medications Antiplatelet agentc
,0.001
Warfarin
359 (0.1)
818 (0.1)
269 (0.1)
271 (0.1)
0.931
ACE inhibitor or ARB
11,113 (6)
20,857 (5)
,0.001
0.988
7,740 (5.6)
7,740 (5.6)
1.000
b-Blocker
22,595 (12.3)
16,180 (3.8)
,0.001
10,002 (7.3)
9,995 (7.3)
0.959
Calcium-channel blocker
16,269 (8.9)
25,439 (6.1)
,0.001
10,646 (7.7)
10,649 (7.7)
0.983
Diuretic
6,307 (3.4)
10,499 (2.5)
,0.001
4,162 (3)
4,164 (3)
0.982
Nitrate
2,525 (1.3)
4,053 (0.9)
,0.001
1,725 (1.2)
1,723 (1.2)
0.973
Statin
5,252 (2.8)
8,779 (2.1)
,0.001
3,536 (2.5)
3,537 (2.5)
0.990
Dipyridamole
3,185 (1.7)
3,844 (0.9)
,0.001
1,960 (1.4)
1,961 (1.4)
0.987
Steroid
11,134 (6.1)
10,949 (2.6)
,0.001
6,140 (4.4)
6,138 (4.4)
0.985
Estrogen or progesterone
6,025 (3.3)
3,136 (0.7)
,0.001
2,632 (1.9)
2,631 (1.9)
0.989
NSAID
57,064 (31.3)
35,822 (8.6)
,0.001
28,451 (20.8)
28,443 (20.8)
0.970
Proton-pump inhibitor
3,996 (2.1)
2,824 (0.6)
,0.001
1,820 (1.3)
1,817 (1.3)
0.960
Antihyperglycemic drug
7,528 (4.1)
18,273 (4.3)
,0.001
5,633 (4.1)
5,634 (4.1)
0.992
40,156 (22)
66,888 (16)
,0.001
26,660 (19.5)
26,659 (19.5)
0.996
Coexisting conditions Hypertension Myocardial infarction
753 (0.4)
2,010 (0.4)
,0.001
573 (0.4)
574 (0.4)
0.976
Chronic pulmonary disease
36,077 (19.7)
48,809 (11.7)
,0.001
22,580 (16.5)
22,576 (16.5)
0.984
Continued
4
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Table 1
Continued No propensity score matching
Propensity score–matched
Migraine cohort
Control cohort
p
Migraine cohort
Matched control cohort
p
Asthma
15,293 (8.3)
18,700 (4.4)
,0.001
9,153 (6.6)
9,154 (6.6)
0.994
Heart failure
3,622 (1.9)
6,659 (1.6)
,0.001
2,542 (1.8)
2,542 (1.8)
1.000
Characteristic
Valvular heart disease
11,352 (6.2)
8,923 (2.1)
,0.001
5,406 (3.9)
5,405 (3.9)
0.992
Atrial fibrillation
915 (0.5)
2,530 (0.6)
,0.001
669 (0.4)
674 (0.4)
0.891
Peripheral vascular disease
2,837 (1.5)
3,131 (0.7)
,0.001
1,590 (1.1)
1,589 (1.1)
0.986
Dyslipidemia
31,441 (17.2)
45,598 (10.9)
,0.001
19,551 (14.3)
19,549 (14.3)
0.991
Diabetes
16,383 (8.9)
34,924 (8.4)
,0.001
11,554 (8.4)
11,554 (8.4)
1.000
Rheumatoid disease
5,270 (2.8)
4,671 (1.1)
,0.001
2,776 (2)
2,775 (2)
0.989
Peptic ulcer disease
54,808 (30)
54,312 (13)
,0.001
31,274 (22.8)
31,273 (22.8)
0.996
Chronic liver disease
26,342 (14.4)
36,071 (8.6)
,0.001
16,291 (11.9)
16,289 (11.9)
0.991
Chronic renal disease
6,810 (3.7)
10,540 (2.5)
,0.001
4,405 (3.2)
4,404 (3.2)
0.991
Drug abuse
3,632 (1.9)
5,746 (1.3)
,0.001
2,131 (1.5)
2,129 (1.5)
0.975
Abbreviations: ACE 5 angiotensin-converting enzyme; ARB 5 angiotensin II receptor blocker; NSAID 5 nonsteroidal anti-inflammatory drug; NT$ 5 New Taiwan dollar. a Currently, 1 US$ 5 30.1 NT$. b The National Health Research Institute has defined 4 urbanization levels in Taiwan.40 c Including aspirin, clopidogrel, ticlopidine, and cilostazol. Data are n (%) unless otherwise indicated.
As single contributors, migraine, diabetes mellitus, hypertension, and older age were associated with higher adjusted absolute event rates (table e-2). The association between migraine and the subsequent development of Bell palsy was similar with and without propensity score matching (table 2). Sensitivity analysis of the risk of Bell palsy. The association between Bell palsy and migraine remained significant using different diagnostic criteria for Bell palsy (table 3), although aHRs were lower when stricter diagnostic criteria were adopted. Subgroup analyses of the risk of Bell palsy. Tests of interaction failed to reach statistical significance
Table 2
in all subgroup analyses. The association between migraine and Bell palsy remained consistent in subgroups defined according to sex, age, CCI score, diabetes, hypertension, and migraine subtype (table 4). Frequency of clinical visits and risk of Bell palsy. In patients with migraine later diagnosed with Bell palsy (n 5 671), the median clinical visits with migraine diagnosis were 0.94 per year (25th–75th percentile, 0.46–2.21). The aHRs of Bell palsy were 2.18 (95% CI, 1.81–2.63; p , 0.001) and 5.70 (95% CI, 4.95– 6.55; p , 0.001) among those in the third and fourth quartiles using the first quartile (0–25th percentile) as the reference (table e-3).
Incidence and risk of Bell palsy in the migraine and control cohorts Adjustedb
Crude No. of events
Personyears
Incidence ratea
Hazard ratio (95% CI)
Control
1,145
1,317,736
89.3
Reference
Migraine
946
562,061
173.8
1.95 (1.79–2.12)
Control
365
438,677
83.2
Reference
Migraine
671
424,372
158.1
1.91 (1.68–2.18)
Cohort
p
Hazard ratio (95% CI)
p
No age and propensity score matching Reference ,0.001
1.87 (1.70–2.07)
,0.001
Age and propensity score–matched Reference ,0.001
1.91 (1.68–2.17)
,0.001
Abbreviation: CI 5 confidence interval. a Per 100,000 person-years. b Adjusted for propensity score. Neurology 84
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Table 3
Sensitivity analysis of the risk of Bell palsy in the migraine and matched control cohorts Adjusteda
Crude No. of events
Personyears
Incidence rateb
Hazard ratio (95% CI)
Control cohort
365
438,677
83.2
Reference
Migraine cohort
671
424,372
158.1
1.91 (1.68–2.18)
Control cohort
361
438,665
82.3
Reference
Migraine cohort
664
424,361
156.47
1.92 (1.68–2.18)
Control cohort
158c
438,677
36.0
Reference
Migraine cohort
269c
424,372
63.4
1.78 (1.46–2.17)
Control cohort
221c
438,677
50.4
Reference
Migraine cohort
413c
424,372
97.3
1.94 (1.65–2.28)
Control cohort
235
438,677
53.6
Reference
Migraine cohort
345
424,372
81.3
1.53 (1.29–1.80)
Control cohort
109
438,677
24.9
Reference
Migraine cohort
165
424,372
38.9
1.59 (1.25–2.03)
p
Hazard ratio (95% CI)
p
Bell palsy Reference ,0.001
1.91 (1.68–2.17)
,0.001
Bell palsy, without pregnancy Reference ,0.001
1.91 (1.68–2.18)
,0.001
1.78 (1.46–2.17)
,0.001
1.94 (1.65–2.28)
,0.001
1.53 (1.29–1.80)
,0.001
Bell palsy, initial diagnosis by neurologists Reference ,0.001
Bell palsy, initial diagnosis by nonneurologists Reference ,0.001
Bell palsy, with steroid treatment Reference ,0.001
Bell palsy, initial diagnosis by neurologist, without pregnancy, with steroid treatment Reference ,0.001
1.59 (1.25–2.03)
,0.001
Abbreviation: CI 5 confidence interval. a Adjusted for propensity score. b Per 100,000 person-years. c Fourteen patients in the control cohort and 11 patients in the migraine cohort were initially diagnosed with Bell palsy by both a neurologist and nonneurologist on the same day.
The results of this study indicated that the risk of subsequent development of Bell palsy is approximately doubled in patients with migraine compared with age- and propensity score–matched control subjects. This association was not affected by sex, migraine subtype, or other risk factors for Bell palsy. To our knowledge, this epidemiologic study found a novel association between migraine and Bell palsy. The annual incidence rate of Bell palsy in our control cohort (83.2/100,000 person-years) was higher than previously reported (13.1–53.3/100,000 personyears).5,25–27 This discrepancy might be accounted for by the accessibility and global coverage of the NHI in Taiwan; an average of 15.6 clinical visits per person were recorded in 2010.28 In line with the results of previous studies,5,26,27 the occurrence of Bell palsy showed no obvious sex-based predilection in our cohort. Furthermore, the finding of higher adjusted absolute event rates of Bell palsy in patients with hypertension or diabetes mellitus, compared with those without these conditions, is also in agreement with the documentation of these conditions as risk factors for Bell palsy.29,30 DISCUSSION
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Several mechanisms may underlie the association between migraine and Bell palsy. Neuritis or demyelination after viral infection/reactivation remains the most frequently accepted hypothesized pathogenesis of Bell palsy.6–9 During migraine attacks, trigeminovascular system activation triggers regional neuropeptide release.31 Recurrent migraine attacks result in neurogenic inflammation of nearby cranial nerves,32,33 and may predispose the facial nerve to demyelination after viral infection. In addition, Bell palsy can be attributed to ischemia in some cases, which is reflected in its increased incidence in elderly subjects and those with vascular risk factors, such as hypertension and diabetes.3 Migraine is associated with various vascular disorders34 and asymmetrical facial blood perfusion,17 which raises the suspicion of ischemic mononeuropathy of the facial nerve. Of note, migraine with aura is associated with hypertension, unfavorable cholesterol profiles, and higher Framingham risk scores35; however, the HRs remained similar in all migraine subgroups in the current study. Thus, migraine per se, rather than certain comorbidities, might be associated with subsequent development of Bell palsy. In
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Table 4
Subgroup analyses of the risk of Bell palsy in the migraine and matched control cohorts Case
Control
Adjusteda
No. of events/no. of patients
No. of events/no. of patients
Hazard ratio (95% CI)
p
Male
264/43,845
125/43,846
2.16 (1.75–2.68)
,0.001
Female
407/92,859
240/92,858
1.77 (1.51–2.08)
,0.001
18–39
224/67,039
124/67,176
1.98 (1.58–3.19)
,0.001
40–60
278/50,329
159/49,893
1.76 (1.44–2.13)
,0.001
169/19,336
82/19,635
2.01 (1.54–2.62)
,0.001
0
294/72,903
165/72,903
1.91 (1.58–3.28)
,0.001
1
180/34,529
95/34,529
1.92 (1.50–2.47)
,0.001
2
93/14,301
48/14,302
1.96 (1.38–2.78)
,0.001
‡3
104/14,971
57/14,970
1.78 (1.29–2.46)
,0.001
Characteristic b
Sex
c
Age, y
>60 d
Charlson comorbidity index score
e
Diabetes mellitus Yes
102/11,554
55/11,554
1.86 (1.34–2.59)
,0.001
No
569/125,150
310/125,150
1.92 (1.67–2.20)
,0.001
f
Hypertension Yes
214/26,660
112/26,659
1.88 (1.49–2.36)
,0.001
No
457/110,044
253/110,045
1.91 (1.63–2.22)
,0.001
Migraine type
g
With aura
74/16,865
39/16,865
2.02 (1.37–2.99)
,0.001
Without aura
164/36,584
81/36,584
2.15 (1.65–2.81)
,0.001
Unspecified
433/83,255
245/83,255
1.82 (1.55–2.12)
,0.001
Abbreviation: CI 5 confidence interval. a Adjusted for propensity score. b pinteraction 5 0.119. c pinteraction 5 0.677. d pinteraction 5 0.977. e pinteraction 5 0.812. f pinteraction 5 0.874. g pinteraction 5 0.519.
addition, migraine patients with more clinical visits for migraine were more likely to develop Bell palsy. A possible explanation is that higher disease activities might link to the development of Bell palsy. Nonetheless, a higher clinical awareness of Bell palsy among patients or physicians, or drug-related effects in this subset of patients remains possible. Overall, these explanations remain provisional, and further studies exploring this association are needed. Our findings have several pathologic and clinical implications. First, migraine is an unidentified risk factor for Bell palsy. However, whether migraine per se or the frequency of migraine attacks contributes more to the development of Bell palsy remains uncertain. Thus, the exploration of migraine history in patients receiving treatment for Bell palsy could be a first step of future investigation. In addition, the link between migraine
and Bell palsy suggests that a common mechanism underlies both diseases. Patients with diabetes tend to have worse functional recovery after Bell palsy than nondiabetic patients,36 but whether the outcome of Bell palsy differs in patients with migraine warrants further study. At present, the best treatment regimen is early steroid37; the optimal treatment strategy in this subgroup of patients requires further investigation. The major strengths of this study include the large sample, given that the migraine cohort was taken from a nationwide population-based database. In addition, we enrolled only patients with neurologist-diagnosed migraine to increase the validity of migraine diagnoses. A previous report confirmed that neurologists’ diagnoses of migraine according to the International Classification of Headache Disorders, 2nd Edition, criteria in Taiwan were 91.6% accurate.38 Third, an age- and propensity Neurology 84
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7
score–matched control cohort was used to minimize selection bias and any imbalance in medical care– seeking behavior. Fourth, patients diagnosed with herpes zoster infection and Bell palsy within a 30-day period were excluded from our cohort because Ramsay Hunt syndrome is a major consideration in the differential diagnosis of Bell palsy. Several limitations of this study should also be considered. First, because the diagnosis of Bell palsy is primarily clinical and limited clinical information could be obtained from the database, the proper exclusion of other less-common causes of acquired facial weakness could not be assured, which may have led to overestimation of the occurrence of Bell palsy in both cohorts. Second, although most patients with Bell palsy achieve complete recovery,39 the NHIRD contains neither the prognostic information nor the duration and frequency of migraine, preventing the exploration of potential differences in the clinical course of Bell palsy in patients with migraine. Third, all patients enrolled in the migraine cohort had active migraine, leading to the underrepresentation of subjects with previous or nonactive migraine. Fourth, in the current study, we used a neurologist-diagnosed migraine cohort. Thus, this cohort might be subject to Berkson bias, i.e., a migraine patient with neurologic consultation might be more likely to be diagnosed with Bell palsy; however, the HRs of Bell palsy determined by neurologists and nonneurologists were similar (table 3). Finally, the control cohort may have included patients with migraine who did not seek medical assistance, potentially leading to underestimation of the risk of Bell palsy in the migraine cohort. Migraine is a previously unidentified risk factor for Bell palsy with at least equal importance as hypertension and diabetes. The association between migraine and Bell palsy suggests that a common mechanism underlies these diseases, which is worthy of further exploration. AUTHOR CONTRIBUTIONS K.-P. Peng, Y.-T. Chen, and S.-J. Wang conceived and designed the study. K.-P. Peng and Y.-T. Chen researched the data for the article and provided the first draft equally. C.-H. Tang was responsible for the acquisition of the database. All authors interpreted the data, revised the manuscript for intellectual content, and gave the final approval of the final version of the draft. S.-J. Wang is the guarantor.
STUDY FUNDING This study was supported in part by grants from the National Science Council of Taiwan (NSC 102-2321-B-010-030, 100-2314-B-010-018-MY3, and 992314-B-075-036-MY3), Taipei Veterans General Hospital (VGHUST102G7-6-1, V102C-118, V102E9-001), NSC support for Center for Dynamical Biomarkers and Translational Medicine, National Central University, Taiwan (NSC 101-2911-I-008-001), Brain Research Center, National Yang-Ming University, and a grant from Ministry of Education, Aim for the Top University Plan. No additional external funding was received for this study.
DISCLOSURE K.-P. Peng and Y.-T. Chen report no disclosures relevant to the manuscript. J.-L. Fuh is a member of a scientific advisory board of Eli Lilly, 8
Neurology 84
and has received research support from the Taiwan National Science Council, Taipei Veterans General Hospital, and Eli Lilly. C.-H. Tang reports no disclosures relevant to the manuscript. S.-J. Wang has served on the advisory boards of Allergan and Eli Lilly Taiwan. He has received speaking honoraria from local companies (Taiwan branches) of Pfizer, Eli Lilly, and GSK. He has received research grants from the Taiwan National Science Council, Taipei Veterans General Hospital, and Taiwan Headache Society. Go to Neurology.org for full disclosures.
Received February 10, 2014. Accepted in final form July 28, 2014. REFERENCES 1. Kim YH, Choi IJ, Kim HM, Ban JH, Cho CH, Ahn JH. Bilateral simultaneous facial nerve palsy: clinical analysis in seven cases. Otol Neurotol 2008;29:397–400. 2. Price T, Fife DG. Bilateral simultaneous facial nerve palsy. J Laryngol Otol 2002;116:46–48. 3. Gilden DH. Clinical practice: Bell’s palsy. N Engl J Med 2004;351:1323–1331. 4. De Diego-Sastre JI, Prim-Espada MP, FernandezGarcia F. The epidemiology of Bell’s palsy [in Spanish]. Rev Neurol 2005;41:287–290. 5. Hauser WA, Karnes WE, Annis J, Kurland LT. Incidence and prognosis of Bell’s palsy in the population of Rochester, Minnesota. Mayo Clin Proc 1971;46:258–264. 6. Abiko Y, Ikeda M, Hondo R. Secretion and dynamics of herpes simplex virus in tears and saliva of patients with Bell’s palsy. Otol Neurotol 2002;23:779–783. 7. Lazarini PR, Vianna MF, Alcantara MP, Scalia RA, Caiaffa Filho HH. Herpes simplex virus in the saliva of peripheral Bell’s palsy patients. Braz J Otorhinolaryngol 2006;72:7–11. 8. Adour KK, Byl FM, Hilsinger RL Jr, Kahn ZM, Sheldon MI. The true nature of Bell’s palsy: analysis of 1,000 consecutive patients. Laryngoscope 1978;88:787–801. 9. Paolino E, Granieri E, Tola MR, Panarelli MA, Carreras M. Predisposing factors in Bell’s palsy: a casecontrol study. J Neurol 1985;232:363–365. 10. Wang SJ, Fuh JL, Young YH, Lu SR, Shia BC. Prevalence of migraine in Taipei, Taiwan: a population-based survey. Cephalalgia 2000;20:566–572. 11. Jensen R, Stovner LJ. Epidemiology and comorbidity of headache. Lancet Neurol 2008;7:354–361. 12. Schurks M, Rist PM, Bigal ME, Buring JE, Lipton RB, Kurth T. Migraine and cardiovascular disease: systematic review and meta-analysis. BMJ 2009;339:b3914. 13. Lal V, Sahota P, Singh P, Gupta A, Prabhakar S. Ophthalmoplegia with migraine in adults: is it ophthalmoplegic migraine? Headache 2009;49:838–850. 14. Chu CH, Liu CJ, Fuh JL, Shiao AS, Chen TJ, Wang SJ. Migraine is a risk factor for sudden sensorineural hearing loss: a nationwide population-based study. Cephalalgia 2013;33:80–86. 15. Zachariah J, Patel P. Facial pain with recurrent facial palsy. Headache 2003;43:700–701. 16. Russell MB, Ducros A. Sporadic and familial hemiplegic migraine: pathophysiological mechanisms, clinical characteristics, diagnosis, and management. Lancet Neurol 2011; 10:457–470. 17. Zaproudina N, Teplov V, Nippolainen E, et al. Asynchronicity of facial blood perfusion in migraine. PLoS One 2013;8:e80189. 18. Centers for Disease Control and Prevention. International Classification of Diseases, Ninth Revision, Clinical Modification: ICD-9-CM [online]. Available at: http://www. cdc.gov/nchs/icd/icd9cm.htm. Accessed May 23, 2014.
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systemic hypertension: a systematic review. Am J Hypertens 2013;26:351–356. Adour K, Wingerd J, Doty HE. Prevalence of concurrent diabetes mellitus and idiopathic facial paralysis (Bell’s palsy). Diabetes 1975;24:449–451. Goadsby PJ, Lipton RB, Ferrari MD. Migraine: current understanding and treatment. N Engl J Med 2002;346: 257–270. Carlow TJ. Oculomotor ophthalmoplegic migraine: is it really migraine? J Neuroophthalmol 2002;22:215–221. Chen PK, Wang SJ. Ophthalmoplegic migraine: migraine variant or cranial neuralgia? Cephalalgia 2012; 32:515–517. Sacco S, Ricci S, Carolei A. Migraine and vascular diseases: a review of the evidence and potential implications for management. Cephalalgia 2012;32:785–795. Scher AI, Terwindt GM, Picavet HS, Verschuren WM, Ferrari MD, Launer LJ. Cardiovascular risk factors and migraine: the GEM population-based study. Neurology 2005;64:614–620. Kanazawa A, Haginomori S, Takamaki A, Nonaka R, Araki M, Takenaka H. Prognosis for Bell’s palsy: a comparison of diabetic and nondiabetic patients. Acta Otolaryngol 2007;127:888–891. Gronseth GS, Paduga R. Evidence-based guideline update: steroids and antivirals for Bell palsy: report of the Guideline Development Subcommittee of the American Academy of Neurology. Neurology 2012;79:2209–2213. Wang SJ, Fuh JL, Huang SY, et al. Diagnosis and development of screening items for migraine in neurological practice in Taiwan. J Formos Med Assoc 2008;107: 485–494. Peitersen E. The natural history of Bell’s palsy. Am J Otol 1982;4:107–111. Liu CY, Hung YT, Chuang YL, et al. Incorporating development stratification of Taiwan townships into sampling design of large scale health interview survey. J Health Manag 2006;4:1–22.
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Increased risk of Bell palsy in patients with migraine: A nationwide cohort study Kuan-Po Peng, Yung-Tai Chen, Jong-Ling Fuh, et al. Neurology published online December 17, 2014 DOI 10.1212/WNL.0000000000001124 This information is current as of December 17, 2014 Updated Information & Services
including high resolution figures, can be found at: http://www.neurology.org/content/early/2014/12/17/WNL.0000000000 001124.full.html
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This article, along with others on similar topics, appears in the following collection(s): All Headache http://www.neurology.org//cgi/collection/all_headache Cranial neuropathy http://www.neurology.org//cgi/collection/cranial_neuropathy Migraine http://www.neurology.org//cgi/collection/migraine
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Neurology ® is the official journal of the American Academy of Neurology. Published continuously since 1951, it is now a weekly with 48 issues per year. Copyright © 2014 American Academy of Neurology. All rights reserved. Print ISSN: 0028-3878. Online ISSN: 1526-632X.
ARTICLES
Increased risk of Bell palsy in patients with migraine A nationwide cohort study
Kuan-Po Peng, MD* Yung-Tai Chen, MD* Jong-Ling Fuh, MD Chao-Hsiun Tang, PhD Shuu-Jiun Wang, MD
Correspondence to Dr. Wang: [email protected]
ABSTRACT
Objective: To evaluate the association between migraine and Bell palsy and to examine the effects of age, sex, migraine subtype, and comorbid risk factors for Bell palsy.
Methods: This nationwide cohort study was conducted using data from the Taiwan National Health Insurance Research Database. Subjects aged 18 years or older with neurologistdiagnosed migraine from 2005 to 2009 were included. A nonheadache age- and propensity score–matched control cohort was selected for comparison. All subjects were followed until the end of 2010, death, or the occurrence of a Bell palsy event. Cox proportional hazards regression was used to calculate the adjusted hazard ratios and 95% confidence intervals to compare the risk of Bell palsy between groups. Results: Both cohorts (n 5 136,704 each) were followed for a mean of 3.2 years. During the follow-up period, 671 patients (424,372 person-years) in the migraine cohort and 365 matched control subjects (438,677 person-years) were newly diagnosed with Bell palsy (incidence rates, 158.1 and 83.2/100,000 person-years, respectively). The adjusted hazard ratio for Bell palsy was 1.91 (95% confidence interval, 1.68–2.17; p , 0.001). The association between migraine and Bell palsy remained significant in sensitivity analyses, and tests of interaction failed to reach significance in all subgroup analyses. Conclusion: Migraine is a previously unidentified risk factor for Bell palsy. The association between these 2 conditions suggests a linked disease mechanism, which is worthy of further exploration. Neurology® 2015;84:1–9 GLOSSARY aHR 5 adjusted hazard ratio; CCI 5 Charlson Comorbidity Index; CI 5 confidence interval; HR 5 hazard ratio; ICD-9-CM 5 International Classification of Diseases, Ninth Revision, Clinical Modification; NHI 5 National Health Insurance; NHIRD 5 National Health Insurance Research Database.
Editorial, page 108 Supplemental data at Neurology.org
Bell palsy is an acute, idiopathic, unilateral peripheral facial palsy, although bilateral involvement has been reported rarely.1,2 This condition affects patients of all ages; the incidence is the lowest among children and increases gradually with age.3 The annual incidence rate ranges from 11 to 40 per 100,000 persons,4 and both sexes are affected equally.5 The pathophysiology of Bell palsy is largely unknown. Common hypotheses include acute or reactivation of latent viral infection, vascular ischemia, and inflammatory responses.6–9 Several predisposing factors, such as diabetes mellitus, hypertension, pregnancy, and the use of inactivated intranasal influenza vaccine,3 have been recognized. Other conditions can also present with unilateral facial palsy, such as Ramsay Hunt syndrome, HIV infection, Lyme disease, autoimmune diseases, amyloidosis, and spaceoccupying lesions.3 Migraine is a common and disabling disorder with an annual global prevalence of approximately 10% and a female/male ratio of 2–3:1.10,11 It is associated with vascular disorders of the CNS, i.e., ischemic and hemorrhagic strokes.12 Cranial nerve symptoms, such as *These authors contributed equally to this work. From the Department of Internal Medicine (K.-P.P.), Taipei Veterans General Hospital, Taoyuan Branch, Taoyuan; Institute of Brain Science (K.-P.P., S.-J.W.), National Yang-Ming University, Taipei; Faculty of Medicine (K.-P.P., Y.-T.C., J.-L.F., S.-J.W.), National Yang-Ming University School of Medicine, Taipei; Department of Nephrology (Y.-T.C.), Institute of Internal Medicine, Taipei City Hospital Heping Fuyou Branch, Taipei; Department of Neurology (J.-L.F., S.-J.W.), Neurological Institute, Taipei Veterans General Hospital, Taipei; and School of Health Care Administration (C.-H.T.), Taipei Medical University, Taipei, Taiwan. Go to Neurology.org for full disclosures. Funding information and disclosures deemed relevant by the authors, if any, are provided at the end of the article. © 2014 American Academy of Neurology
ª 2014 American Academy of Neurology. Unauthorized reproduction of this article is prohibited.
1
ophthalmoplegia, have also been reported in some patients.13 We recently reported an association between migraine and sudden sensorineural hearing loss.14 An association with isolated peripheral facial palsy has been reported rarely,15 although facial and limb weakness is common in patients with hemiplegic migraine.16 Vascular ischemia remains a possible etiology of Bell palsy,9 and a recent report identified asymmetrical facial blood perfusion in patients with migraine.17 Thus, this study was conducted to determine whether migraine is associated with Bell palsy. METHODS Data source. Taiwan’s mandatory universal National Health Insurance (NHI) program, launched in 1995, currently provides comprehensive medical coverage to 99% of the population of 23 million residents. The NHI covers outpatient, inpatient, emergency, dental, and traditional Chinese medicine services, as well as prescription drugs. Data for this study were drawn from the nationwide population-based National Health Insurance Research Database (NHIRD) including enrollment files, claims data, and drug prescription registry, managed and publicly released by the National Health Research Institute. These databases provide comprehensive utilization and enrollment information for all patients in the NHI program. Diseases were coded according to the 2001 ICD-9-CM.18 The accuracy of diagnoses listed in the NHIRD has been validated for several diseases and this database has served as the basis for several published studies.14,19,20
Standard protocol approvals, registrations, and patient consents. All information that would potentially expose individual patient identities has been encrypted, and the confidentiality of data is ensured according to the regulations of the Bureau of NHI and the National Health Research Institute. The institutional review board of Taipei Veterans General Hospital approved the present study.
Study design and cohorts. This nationwide, observational cohort study was conducted to determine the association between Bell palsy and migraine in a Taiwanese population. The study involved 2 cohorts: the migraine cohort, composed of all patients in Taiwan who visited neurologists with a diagnosis of migraine (ICD-9-CM code 346.x) between January 2005 and December 2009; and the nonheadache control cohort, composed of individuals free from diagnosis of migraine (code 346.x), tension-type headache (code 307.81), and headache (code 784.0), extracted from a dataset of 1 million beneficiaries randomly sampled from the original NHIRD (figure). Three subgroups of migraine were defined: migraine with aura (ICD9-CM codes 346.00–346.01), migraine without aura (ICD9-CM codes 346.10–346.11), and migraine unspecified (ICD-9-CM codes 346.90–346.91). Each subject with migraine entered the cohort on the day of the first clinical visit associated with a neurologist’s registry of the diagnosis of migraine in the dataset. Only subjects aged 18 years or older were included in this study, and subjects with antecedent Bell palsy were excluded. Subjects in whom migraine and Bell palsy were both diagnosed within a 30-day period were also excluded to minimize the possibility of alternative diagnoses that might contribute to facial palsy and migraine-like headache. Subjects with a follow-up period 2
Neurology 84
of ,30 days were excluded in both the migraine and control cohorts. Patients in the control cohort were free from the diagnosis of migraine, and no index date could be assigned. Thus, we randomly assigned a “pseudodiagnostic date” to each patient in the control cohort corresponding to the index of diagnosis of one pool of patients with migraine so that both cohorts were enrolled at a similar time. The same exclusion criteria in the migraine cohort were applied to the control cohort.
Propensity score matching. We used multivariate logistic regression to calculate the propensity score for the predicted probabilities of migraine status. The covariates used in generating the propensity scores are listed in table e-1 on the Neurology® Web site at Neurology.org. In addition, we performed 1:1 case/control matching based on propensity scores. The use of propensity score matching in observational studies resembles certain characteristics of randomized controlled trials.21 For each patient in the migraine cohort, we identified one control patient with similar demographic characteristics, matched in terms of age (65 years) and propensity score (60.1) for the likelihood of a migraine diagnosis. Subjects in the migraine cohort who could not be matched with control subjects were excluded from this study. Outcome. The primary outcome was the occurrence of Bell palsy, defined as the first hospitalization or ambulatory visit associated with an ICD-9-CM code of 351.0, during the follow-up period. Patients with concomitant diagnoses of Bell palsy and herpes zoster infection (ICD-9-CM code 053.xx) within a 30-day period were excluded to minimize the chance of misclassification of Ramsay Hunt syndrome as Bell palsy. Both cohorts were followed until December 31, 2010, death, or the occurrence of Bell palsy.
Baseline characteristics. Baseline demographic data, including age, sex, medical care utilization (ambulatory visits in the past year), income, and urbanization level, were collected. The Charlson Comorbidity Index (CCI) score was used to determine subjects’ overall systemic health22; a higher CCI score is inversely associated with the 10-year survival rate, i.e., a score of 0 is associated with a 10-year survival rate of 99% and a score of 5 is associated with a rate of 34%.22 Data on other systemic diseases not included in the CCI were also recorded; these included atrial fibrillation, valvular heart disease, hypertension, asthma, dyslipidemia, and drug abuse. Data on subjects’ concomitant use of medications with potential anti-inflammatory effects and those associated with patients’ physical conditions and immune system function, according to the World Health Organization’s Anatomical Therapeutic Chemical Classification System,23 were extracted. These medications included antiplatelet agents, warfarin, angiotensin-converting enzyme inhibitors, angiotensin II receptor blockers, b-blockers, calcium-channel blockers, diuretics, nitrate, statin, dipyridamole, steroids, estrogen, progesterone, nonsteroidal anti-inflammatory drugs, proton-pump inhibitors, and antihyperglycemic drugs.
Statistical analysis. Descriptive statistics were used to examine the baseline characteristics of the study cohorts. The characteristics of the 2 groups were compared using the Pearson x2 test for categorical variables, the independent t test for parametric continuous variables, and the Mann–Whitney U test for continuous data without normal distributions. The incidence rates of Bell palsy in both groups were calculated using Poisson distributions. We calculated adjusted absolute incidence rates of Bell palsy to evaluate the contribution of each risk factor to the occurrence of Bell palsy using the macro developed by Zhao.24 The SAS GENMOD function of this macro was used with the Poisson distribution option to calculate predicted adjusted rates at mean levels of the independent variables, including age, sex, medical utilization, socioeconomic status,
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ª 2014 American Academy of Neurology. Unauthorized reproduction of this article is prohibited.
Figure
Enrollment of patients
ICD-9-CM 5 International Classification of Diseases, Ninth Revision, Clinical Modification; NHIRD 5 National Health Insurance Research Database.
urbanization, CCI score, migraine, diabetes mellitus, and hypertension. The adjusted absolute rates are presented with upper and lower 95% confidence intervals (CIs) per 100,000 person-years. The risk of Bell palsy was compared between groups using hazard ratios (HRs) from Cox regression models with a conditional approach using stratification. Adjusted HRs were calculated by Cox regression models with adjusted propensity score as a continuous covariate. Cox regression models were also used to examine the influences of age, sex, CCI score, diabetes mellitus, hypertension, and migraine subtype on the incidence of Bell palsy after the diagnosis of migraine. Interactions were examined in these subgroups using likelihood ratio tests. Sensitivity analysis was conducted to validate our results in the following patients: (1) those without a diagnosis of pregnancy within 30 days preceding and after the diagnosis of Bell palsy; (2) those with the initial diagnosis of Bell palsy made by neurologists or nonneurologists; and (3) those with steroid prescription after diagnosis of Bell palsy. The Microsoft SQL Server (2012; Microsoft Corporation, Redmond, WA) was used for data linkage, processing, and sampling. Propensity scores and adjusted absolute incidence rates were calculated with SAS software (version 9.2; SAS Institute, Inc., Cary, NC). All other statistical analyses were conducted using STATA statistical software (version 12.0; StataCorp, College Station, TX). Statistical significance was defined as p , 0.05. RESULTS Characteristics of the study population.
Using data from January 2005 to December 2009,
we identified 182,292 patients with migraine and 415,744 control subjects. The mean age of subjects with migraine was 42.2 (SD, 14.9) years, and the female/male ratio was approximately 3:1. Compared with control subjects, patients with migraine utilized medical care more frequently, and had more comorbidities in certain fields (table 1). After age and propensity score matching (figure), 136,704 patients each were assigned to the migraine and matched control cohorts. The demographic characteristics of the study population are summarized in table 1. Incidence rates of Bell palsy. During a mean follow-up period of 3.2 6 1.6 years, 671 patients (424,372 person-years) in the migraine cohort and 365 patients (438,677 person-years) in the matched control cohort were newly diagnosed with Bell palsy. The incidence rates of Bell palsy were thus 158.1 per 100,000 person-years in the migraine cohort and 83.2 per 100,000 person-years in the control cohort. The male/female ratios of Bell palsy were 1.4:1 in the migraine cohort and 1.1:1 in the control cohort. Patients with migraine were at greater risk of subsequently developing Bell palsy (adjusted HR [aHR], 1.91; 95% CI, 1.68–2.17; p , 0.001; table 2). Neurology 84
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3
Table 1
Demographic and clinical characteristics of the migraine and control cohorts No propensity score matching
Propensity score–matched
p
Migraine cohort
Matched control cohort
136,704
136,704
43.6 (16.6)
,0.001
42.0 (15.6)
42.0 (15.7)
0.945
48,785 (26.7)
235,862 (56.7)
,0.001
43,845 (32)
43,846 (32)
0.997
0
2,018 (1.1)
45,314 (10.8)
2,018 (1.4)
2,023 (1.4)
1–5
22,240 (12.2)
132,122 (31.7)
21,759 (15.9)
21,759 (15.9)
6–10
31,109 (17)
90,732 (21.8)
28,475 (20.8)
28,474 (20.8)
>10
126,925 (69.6)
147,576 (35.4)
84,452 (61.7)
84,448 (61.7)
Characteristic
Migraine cohort
Control cohort
No. of patients
182,292
415,744
Mean age (SD), y
42.2 (14.9)
Males
,0.001
Outpatient visits in past year
Incomea
p
1.000
,0.001
1.000
Dependent
43,547 (23.8)
93,737 (22.5)
33,387 (24.4)
33,387 (24.4)
NT$ 0–19,100
39,694 (21.7)
100,436 (24.1)
30,016 (21.9)
30,016 (21.9)
NT$ 19,100–42,000
80,101 (43.9)
174,419 (41.9)
58,804 (43)
58,804 (43)
>NT$ 42,000
18,950 (10.3)
47,152 (11.3)
14,497 (10.6)
14,497 (10.6)
1
86,587 (47.4)
248,727 (59.8)
70,327 (51.4)
70,330 (51.4)
2
85,893 (47.1)
135,428 (32.5)
58,631 (42.8)
58,626 (42.8)
3
8,390 (4.6)
26,729 (6.4)
6,590 (4.8)
6,592 (4.8)
4
1,422 (0.7)
4,860 (1.1)
1,156 (0.8)
1,156 (0.8)
0
81,661 (44.7)
273,794 (65.8)
72,903 (53.3)
72,903 (53.3)
1
50,175 (27.5)
77,991 (18.7)
34,529 (25.2)
34,529 (25.2)
2
24,817 (13.6)
30,927 (7.4)
14,301 (10.4)
14,302 (10.4)
‡3
25,639 (14)
33,032 (7.9)
14,971 (10.9)
14,970 (10.9)
9,361 (5.1)
16,212 (3.8)
6,411 (4.6)
6,411 (4.6)
1.000
Urbanization level
b
,0.001
1.000
Charlson comorbidity index score
Concomitant medications Antiplatelet agentc
,0.001
Warfarin
359 (0.1)
818 (0.1)
269 (0.1)
271 (0.1)
0.931
ACE inhibitor or ARB
11,113 (6)
20,857 (5)
,0.001
0.988
7,740 (5.6)
7,740 (5.6)
1.000
b-Blocker
22,595 (12.3)
16,180 (3.8)
,0.001
10,002 (7.3)
9,995 (7.3)
0.959
Calcium-channel blocker
16,269 (8.9)
25,439 (6.1)
,0.001
10,646 (7.7)
10,649 (7.7)
0.983
Diuretic
6,307 (3.4)
10,499 (2.5)
,0.001
4,162 (3)
4,164 (3)
0.982
Nitrate
2,525 (1.3)
4,053 (0.9)
,0.001
1,725 (1.2)
1,723 (1.2)
0.973
Statin
5,252 (2.8)
8,779 (2.1)
,0.001
3,536 (2.5)
3,537 (2.5)
0.990
Dipyridamole
3,185 (1.7)
3,844 (0.9)
,0.001
1,960 (1.4)
1,961 (1.4)
0.987
Steroid
11,134 (6.1)
10,949 (2.6)
,0.001
6,140 (4.4)
6,138 (4.4)
0.985
Estrogen or progesterone
6,025 (3.3)
3,136 (0.7)
,0.001
2,632 (1.9)
2,631 (1.9)
0.989
NSAID
57,064 (31.3)
35,822 (8.6)
,0.001
28,451 (20.8)
28,443 (20.8)
0.970
Proton-pump inhibitor
3,996 (2.1)
2,824 (0.6)
,0.001
1,820 (1.3)
1,817 (1.3)
0.960
Antihyperglycemic drug
7,528 (4.1)
18,273 (4.3)
,0.001
5,633 (4.1)
5,634 (4.1)
0.992
40,156 (22)
66,888 (16)
,0.001
26,660 (19.5)
26,659 (19.5)
0.996
Coexisting conditions Hypertension Myocardial infarction
753 (0.4)
2,010 (0.4)
,0.001
573 (0.4)
574 (0.4)
0.976
Chronic pulmonary disease
36,077 (19.7)
48,809 (11.7)
,0.001
22,580 (16.5)
22,576 (16.5)
0.984
Continued
4
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Table 1
Continued No propensity score matching
Propensity score–matched
Migraine cohort
Control cohort
p
Migraine cohort
Matched control cohort
p
Asthma
15,293 (8.3)
18,700 (4.4)
,0.001
9,153 (6.6)
9,154 (6.6)
0.994
Heart failure
3,622 (1.9)
6,659 (1.6)
,0.001
2,542 (1.8)
2,542 (1.8)
1.000
Characteristic
Valvular heart disease
11,352 (6.2)
8,923 (2.1)
,0.001
5,406 (3.9)
5,405 (3.9)
0.992
Atrial fibrillation
915 (0.5)
2,530 (0.6)
,0.001
669 (0.4)
674 (0.4)
0.891
Peripheral vascular disease
2,837 (1.5)
3,131 (0.7)
,0.001
1,590 (1.1)
1,589 (1.1)
0.986
Dyslipidemia
31,441 (17.2)
45,598 (10.9)
,0.001
19,551 (14.3)
19,549 (14.3)
0.991
Diabetes
16,383 (8.9)
34,924 (8.4)
,0.001
11,554 (8.4)
11,554 (8.4)
1.000
Rheumatoid disease
5,270 (2.8)
4,671 (1.1)
,0.001
2,776 (2)
2,775 (2)
0.989
Peptic ulcer disease
54,808 (30)
54,312 (13)
,0.001
31,274 (22.8)
31,273 (22.8)
0.996
Chronic liver disease
26,342 (14.4)
36,071 (8.6)
,0.001
16,291 (11.9)
16,289 (11.9)
0.991
Chronic renal disease
6,810 (3.7)
10,540 (2.5)
,0.001
4,405 (3.2)
4,404 (3.2)
0.991
Drug abuse
3,632 (1.9)
5,746 (1.3)
,0.001
2,131 (1.5)
2,129 (1.5)
0.975
Abbreviations: ACE 5 angiotensin-converting enzyme; ARB 5 angiotensin II receptor blocker; NSAID 5 nonsteroidal anti-inflammatory drug; NT$ 5 New Taiwan dollar. a Currently, 1 US$ 5 30.1 NT$. b The National Health Research Institute has defined 4 urbanization levels in Taiwan.40 c Including aspirin, clopidogrel, ticlopidine, and cilostazol. Data are n (%) unless otherwise indicated.
As single contributors, migraine, diabetes mellitus, hypertension, and older age were associated with higher adjusted absolute event rates (table e-2). The association between migraine and the subsequent development of Bell palsy was similar with and without propensity score matching (table 2). Sensitivity analysis of the risk of Bell palsy. The association between Bell palsy and migraine remained significant using different diagnostic criteria for Bell palsy (table 3), although aHRs were lower when stricter diagnostic criteria were adopted. Subgroup analyses of the risk of Bell palsy. Tests of interaction failed to reach statistical significance
Table 2
in all subgroup analyses. The association between migraine and Bell palsy remained consistent in subgroups defined according to sex, age, CCI score, diabetes, hypertension, and migraine subtype (table 4). Frequency of clinical visits and risk of Bell palsy. In patients with migraine later diagnosed with Bell palsy (n 5 671), the median clinical visits with migraine diagnosis were 0.94 per year (25th–75th percentile, 0.46–2.21). The aHRs of Bell palsy were 2.18 (95% CI, 1.81–2.63; p , 0.001) and 5.70 (95% CI, 4.95– 6.55; p , 0.001) among those in the third and fourth quartiles using the first quartile (0–25th percentile) as the reference (table e-3).
Incidence and risk of Bell palsy in the migraine and control cohorts Adjustedb
Crude No. of events
Personyears
Incidence ratea
Hazard ratio (95% CI)
Control
1,145
1,317,736
89.3
Reference
Migraine
946
562,061
173.8
1.95 (1.79–2.12)
Control
365
438,677
83.2
Reference
Migraine
671
424,372
158.1
1.91 (1.68–2.18)
Cohort
p
Hazard ratio (95% CI)
p
No age and propensity score matching Reference ,0.001
1.87 (1.70–2.07)
,0.001
Age and propensity score–matched Reference ,0.001
1.91 (1.68–2.17)
,0.001
Abbreviation: CI 5 confidence interval. a Per 100,000 person-years. b Adjusted for propensity score. Neurology 84
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Table 3
Sensitivity analysis of the risk of Bell palsy in the migraine and matched control cohorts Adjusteda
Crude No. of events
Personyears
Incidence rateb
Hazard ratio (95% CI)
Control cohort
365
438,677
83.2
Reference
Migraine cohort
671
424,372
158.1
1.91 (1.68–2.18)
Control cohort
361
438,665
82.3
Reference
Migraine cohort
664
424,361
156.47
1.92 (1.68–2.18)
Control cohort
158c
438,677
36.0
Reference
Migraine cohort
269c
424,372
63.4
1.78 (1.46–2.17)
Control cohort
221c
438,677
50.4
Reference
Migraine cohort
413c
424,372
97.3
1.94 (1.65–2.28)
Control cohort
235
438,677
53.6
Reference
Migraine cohort
345
424,372
81.3
1.53 (1.29–1.80)
Control cohort
109
438,677
24.9
Reference
Migraine cohort
165
424,372
38.9
1.59 (1.25–2.03)
p
Hazard ratio (95% CI)
p
Bell palsy Reference ,0.001
1.91 (1.68–2.17)
,0.001
Bell palsy, without pregnancy Reference ,0.001
1.91 (1.68–2.18)
,0.001
1.78 (1.46–2.17)
,0.001
1.94 (1.65–2.28)
,0.001
1.53 (1.29–1.80)
,0.001
Bell palsy, initial diagnosis by neurologists Reference ,0.001
Bell palsy, initial diagnosis by nonneurologists Reference ,0.001
Bell palsy, with steroid treatment Reference ,0.001
Bell palsy, initial diagnosis by neurologist, without pregnancy, with steroid treatment Reference ,0.001
1.59 (1.25–2.03)
,0.001
Abbreviation: CI 5 confidence interval. a Adjusted for propensity score. b Per 100,000 person-years. c Fourteen patients in the control cohort and 11 patients in the migraine cohort were initially diagnosed with Bell palsy by both a neurologist and nonneurologist on the same day.
The results of this study indicated that the risk of subsequent development of Bell palsy is approximately doubled in patients with migraine compared with age- and propensity score–matched control subjects. This association was not affected by sex, migraine subtype, or other risk factors for Bell palsy. To our knowledge, this epidemiologic study found a novel association between migraine and Bell palsy. The annual incidence rate of Bell palsy in our control cohort (83.2/100,000 person-years) was higher than previously reported (13.1–53.3/100,000 personyears).5,25–27 This discrepancy might be accounted for by the accessibility and global coverage of the NHI in Taiwan; an average of 15.6 clinical visits per person were recorded in 2010.28 In line with the results of previous studies,5,26,27 the occurrence of Bell palsy showed no obvious sex-based predilection in our cohort. Furthermore, the finding of higher adjusted absolute event rates of Bell palsy in patients with hypertension or diabetes mellitus, compared with those without these conditions, is also in agreement with the documentation of these conditions as risk factors for Bell palsy.29,30 DISCUSSION
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Several mechanisms may underlie the association between migraine and Bell palsy. Neuritis or demyelination after viral infection/reactivation remains the most frequently accepted hypothesized pathogenesis of Bell palsy.6–9 During migraine attacks, trigeminovascular system activation triggers regional neuropeptide release.31 Recurrent migraine attacks result in neurogenic inflammation of nearby cranial nerves,32,33 and may predispose the facial nerve to demyelination after viral infection. In addition, Bell palsy can be attributed to ischemia in some cases, which is reflected in its increased incidence in elderly subjects and those with vascular risk factors, such as hypertension and diabetes.3 Migraine is associated with various vascular disorders34 and asymmetrical facial blood perfusion,17 which raises the suspicion of ischemic mononeuropathy of the facial nerve. Of note, migraine with aura is associated with hypertension, unfavorable cholesterol profiles, and higher Framingham risk scores35; however, the HRs remained similar in all migraine subgroups in the current study. Thus, migraine per se, rather than certain comorbidities, might be associated with subsequent development of Bell palsy. In
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Table 4
Subgroup analyses of the risk of Bell palsy in the migraine and matched control cohorts Case
Control
Adjusteda
No. of events/no. of patients
No. of events/no. of patients
Hazard ratio (95% CI)
p
Male
264/43,845
125/43,846
2.16 (1.75–2.68)
,0.001
Female
407/92,859
240/92,858
1.77 (1.51–2.08)
,0.001
18–39
224/67,039
124/67,176
1.98 (1.58–3.19)
,0.001
40–60
278/50,329
159/49,893
1.76 (1.44–2.13)
,0.001
169/19,336
82/19,635
2.01 (1.54–2.62)
,0.001
0
294/72,903
165/72,903
1.91 (1.58–3.28)
,0.001
1
180/34,529
95/34,529
1.92 (1.50–2.47)
,0.001
2
93/14,301
48/14,302
1.96 (1.38–2.78)
,0.001
‡3
104/14,971
57/14,970
1.78 (1.29–2.46)
,0.001
Characteristic b
Sex
c
Age, y
>60 d
Charlson comorbidity index score
e
Diabetes mellitus Yes
102/11,554
55/11,554
1.86 (1.34–2.59)
,0.001
No
569/125,150
310/125,150
1.92 (1.67–2.20)
,0.001
f
Hypertension Yes
214/26,660
112/26,659
1.88 (1.49–2.36)
,0.001
No
457/110,044
253/110,045
1.91 (1.63–2.22)
,0.001
Migraine type
g
With aura
74/16,865
39/16,865
2.02 (1.37–2.99)
,0.001
Without aura
164/36,584
81/36,584
2.15 (1.65–2.81)
,0.001
Unspecified
433/83,255
245/83,255
1.82 (1.55–2.12)
,0.001
Abbreviation: CI 5 confidence interval. a Adjusted for propensity score. b pinteraction 5 0.119. c pinteraction 5 0.677. d pinteraction 5 0.977. e pinteraction 5 0.812. f pinteraction 5 0.874. g pinteraction 5 0.519.
addition, migraine patients with more clinical visits for migraine were more likely to develop Bell palsy. A possible explanation is that higher disease activities might link to the development of Bell palsy. Nonetheless, a higher clinical awareness of Bell palsy among patients or physicians, or drug-related effects in this subset of patients remains possible. Overall, these explanations remain provisional, and further studies exploring this association are needed. Our findings have several pathologic and clinical implications. First, migraine is an unidentified risk factor for Bell palsy. However, whether migraine per se or the frequency of migraine attacks contributes more to the development of Bell palsy remains uncertain. Thus, the exploration of migraine history in patients receiving treatment for Bell palsy could be a first step of future investigation. In addition, the link between migraine
and Bell palsy suggests that a common mechanism underlies both diseases. Patients with diabetes tend to have worse functional recovery after Bell palsy than nondiabetic patients,36 but whether the outcome of Bell palsy differs in patients with migraine warrants further study. At present, the best treatment regimen is early steroid37; the optimal treatment strategy in this subgroup of patients requires further investigation. The major strengths of this study include the large sample, given that the migraine cohort was taken from a nationwide population-based database. In addition, we enrolled only patients with neurologist-diagnosed migraine to increase the validity of migraine diagnoses. A previous report confirmed that neurologists’ diagnoses of migraine according to the International Classification of Headache Disorders, 2nd Edition, criteria in Taiwan were 91.6% accurate.38 Third, an age- and propensity Neurology 84
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7
score–matched control cohort was used to minimize selection bias and any imbalance in medical care– seeking behavior. Fourth, patients diagnosed with herpes zoster infection and Bell palsy within a 30-day period were excluded from our cohort because Ramsay Hunt syndrome is a major consideration in the differential diagnosis of Bell palsy. Several limitations of this study should also be considered. First, because the diagnosis of Bell palsy is primarily clinical and limited clinical information could be obtained from the database, the proper exclusion of other less-common causes of acquired facial weakness could not be assured, which may have led to overestimation of the occurrence of Bell palsy in both cohorts. Second, although most patients with Bell palsy achieve complete recovery,39 the NHIRD contains neither the prognostic information nor the duration and frequency of migraine, preventing the exploration of potential differences in the clinical course of Bell palsy in patients with migraine. Third, all patients enrolled in the migraine cohort had active migraine, leading to the underrepresentation of subjects with previous or nonactive migraine. Fourth, in the current study, we used a neurologist-diagnosed migraine cohort. Thus, this cohort might be subject to Berkson bias, i.e., a migraine patient with neurologic consultation might be more likely to be diagnosed with Bell palsy; however, the HRs of Bell palsy determined by neurologists and nonneurologists were similar (table 3). Finally, the control cohort may have included patients with migraine who did not seek medical assistance, potentially leading to underestimation of the risk of Bell palsy in the migraine cohort. Migraine is a previously unidentified risk factor for Bell palsy with at least equal importance as hypertension and diabetes. The association between migraine and Bell palsy suggests that a common mechanism underlies these diseases, which is worthy of further exploration. AUTHOR CONTRIBUTIONS K.-P. Peng, Y.-T. Chen, and S.-J. Wang conceived and designed the study. K.-P. Peng and Y.-T. Chen researched the data for the article and provided the first draft equally. C.-H. Tang was responsible for the acquisition of the database. All authors interpreted the data, revised the manuscript for intellectual content, and gave the final approval of the final version of the draft. S.-J. Wang is the guarantor.
STUDY FUNDING This study was supported in part by grants from the National Science Council of Taiwan (NSC 102-2321-B-010-030, 100-2314-B-010-018-MY3, and 992314-B-075-036-MY3), Taipei Veterans General Hospital (VGHUST102G7-6-1, V102C-118, V102E9-001), NSC support for Center for Dynamical Biomarkers and Translational Medicine, National Central University, Taiwan (NSC 101-2911-I-008-001), Brain Research Center, National Yang-Ming University, and a grant from Ministry of Education, Aim for the Top University Plan. No additional external funding was received for this study.
DISCLOSURE K.-P. Peng and Y.-T. Chen report no disclosures relevant to the manuscript. J.-L. Fuh is a member of a scientific advisory board of Eli Lilly, 8
Neurology 84
and has received research support from the Taiwan National Science Council, Taipei Veterans General Hospital, and Eli Lilly. C.-H. Tang reports no disclosures relevant to the manuscript. S.-J. Wang has served on the advisory boards of Allergan and Eli Lilly Taiwan. He has received speaking honoraria from local companies (Taiwan branches) of Pfizer, Eli Lilly, and GSK. He has received research grants from the Taiwan National Science Council, Taipei Veterans General Hospital, and Taiwan Headache Society. Go to Neurology.org for full disclosures.
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Increased risk of Bell palsy in patients with migraine: A nationwide cohort study Kuan-Po Peng, Yung-Tai Chen, Jong-Ling Fuh, et al. Neurology published online December 17, 2014 DOI 10.1212/WNL.0000000000001124 This information is current as of December 17, 2014 Updated Information & Services
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