Migraine Comorbidities - A Discussion
Vivek Lal*, Monika Singla**
Abstract
Comorbidity refers to the presence of an additional co-existing ailment in a patient with a particular index disease.
Migraine co-morbidities have been reported in various clinical and case control studies. Comorbidities impose a high
socio-economic burden on society and compromise the quality of life in migraineurs. There are several factors which
can complicate the investigation of co-morbidity. They have to be differentiated from migraine equivalents. Abdominal
pain, vertigo or visual hallucinations in migraineurs may suggest an alternative diagnosis or may be confused with comorbidities. The goal of this review is to help identify comorbidities in diagnosed cases of migraine and to understand
their overall impact on this complex headache disorder.
Introduction
T
co-morbid depression and migraine.7 Therefore the presence of
migraine should be considered an important physical symptom
in clinic-based major depressive disorder samples. Simultaneous
management of depression and severe headaches, especially
migraine, might improve the Health Related Quality of Life in
these patients. A previous study conducted at the same setting
found that more than 10% of study patients had depressive
personality and this was highest of all the other personality types.
he term ‘comorbidity’ was introduced by Feinstein. 1 A
coexisting disorder is likely to cause more distress, poor
response to treatment and may also lead to unnecessary
investigations and referral. Migraine is a common neurological
disorder affecting 18% of females and 6% of males.2 Patients with
migraine are more likely than non-migraineurs to have coexisting
disorders. Merikangas and Fenton, after analyzing data from an
epidemiological study in the U.S. population found migraine to
be associated with disorders of cardiovascular, gastrointestinal,
neurologic and psychiatric disorders.3 The following conditions
may occur more frequently in persons with migraine.4,5
Cross-sectional associations and bidirectional associations
between migraine and a variety of psychiatric and somatic
conditions have been reported in literature. Patel and colleagues
assessed the prevalence of major depression in individuals with
migraine.8 The overall prevalence of major depression was 28.1%
for migraine, 19.5% for probable migraine, 23.9% for migraine
and probable migraine pooled together and 10.3% for the control
group. A cross-sectional study of more than 50,000 adults by
Zwart and colleagues9 measured the co-occurrence of headache
and depression or anxiety disorders. Overall, individuals with
migraine headache were more likely to have depression (odds
ratio [OR] = 2.7 [2.3–3.2]) or anxiety disorders (OR = 3.2 [2.8–3.6])
than non-headache controls. Similar associations were seen for
non-migraine headache and depression (OR = 2.2 [2.0–2.5])
or anxiety disorders (OR = 2.7 [2.4–3.0]). There was a linear
trend associated with headache frequency. Thus, for migraine
headache less than 7 days per month, 7–14 days per month, >15
days per month, respectively, the association with depression
was OR = 2.0 (1.6–2.5), OR = 4.2 (3.2–5.6), and OR = 6.4 (4.4–9.3).
1.
Psychiatric disorders
a.
Depression
b.
Anxiety
c.
Panic disorder
d.
Bipolar disorders
2.
Neurologic disorders
a.
Epilepsy
b.
Stroke
c.
Multiple Sclerosis
3.
Cardiovascular disorders
a.
Hypertension
b.
Heart Disease
c.
Patent Foramen Ovale
4.
Miscellaneous disorders
a.
Epilepsy
a.
Asthma/allergy
b.
Gastro-intestinal disorders
c.
Coeliac disease
Epilepsy and migraine may share a similar pathophysiology.
Antiepileptic drugs are used as effective prophylactic
migraine treatment, suggesting common mechanisms in
migraine and epilepsy. Genetic studies also have suggested
a link between epilepsy and some types of migraine.10
The median prevalence of epilepsy in migraineurs is 6%,
compared with 0.5% in the general population. Among
people with epilepsy, 8%-23% have migraine headaches,
compared with 12% in the general population. Patients
with partial and generalised forms of epilepsy are likely to
have migraines, with the maximum incidence in those with
posttraumatic epilepsy.
b.
Stroke
Ischemic stroke
The association between migraine and ischemic stroke is
well proven. A meta-analysis of 11 case-control studies
and three cohort studies showed that the risk of stroke was
Neurologic Disorders
Psychiatric Disorders
People with migraine are more likely to have psychiatric
disorders and vice-versa. The co-morbidity of depression with
migraine has received most attention for several reasons. The
prevalence of migraine is relatively high in women, and women
are also more prone to depression. Depression is four times more
common in migraine than in the general population. 6 Lipton
et al. examined the effect on Health Related Quality of Life (
HRQoL ) in co-morbid migraine and depression and found that
the quality of life was significantly reduced in subjects with
Additional Professor, **Senior Resident, Dept. of Neurology, PGIMER,
Chandigarh 160012.
*
18
© SUPPLEMENT OF JAPI • april 2010 • VOL. 58
increased in migraineurs (pooled relative risk [RR] = 2.16,
95% confidence interval [CI] = 1.9–2.5) compared to nonmigraineurs.11 This risk was nominally higher for migraine
with aura (MA), (RR = 2.27; 95% CI, 1.61–3.19) but was also
apparent in patients with migraine without aura, (RR = 1.83;
95% CI, 1.06–3.15).
other neurological deficits can cause diagnostic confusion.
One case-control study has shown association of MS with
migraine and they reported migraine as being the second
highest associated risk factor for developing MS. 16 These
results support the hypothesis that the etiology of MS
includes both genetic and environmental risk factors.
Two large longitudinal studies added to the evidence linking
migraine and ischemic stroke. The relationship between
migraine and stroke was assessed, as a part of the Women’s
Health Study, using a large cohort and data prospectively
gathered over an average of more than 10 years.12 Compared
with non-migraineurs, participants reporting history of
migraine or migraine without aura had no increased risk
of any stroke type. Participants who reported migraine
with aura had increased adjusted hazards ratios (HRs)
of 1.53 (95% CI, 1.02–2.31) for total stroke and 1.71 (95%
CI, 1.11–2.66) for ischemic stroke but no increased risk for
hemorrhagic stroke. The increased risk for ischemic stroke
was further magnified (HR = 2.25; 95% CI, 1.30 to 3.91)
for the youngest age group in this cohort (45–54 years).
The associations remained significant after adjusting for
cardiovascular risk factors and the same was not apparent
with non-migraine headache.
3.
Cardiovascular Diseases
Cardiovascular conditions that can be comorbid with
migraine include stroke, hypertension and these cardiac
manifestations have been widely studied.
a.
Though various large scale community surveys could
not prove any correlation between hypertension and
migraine, in a cross sectional survey of adults in general
population Rasmussen and Olesen17 found that women
with migraine had significantly higher diastolic blood
pressure than those without migraine. In contrast to
these epidemiological studies, nearly all case control
studies have reported a positive association. Gardener
et al 18 found that mean systolic blood pressure was
higher in migraineurs over age 40 than among age
matched controls.
The second prospective study used data from the
Atherosclerosis Risk in Communities Study and included
more than 12,000 men and women aged 55 and older.
Compared with participants without migraine or other
headache, migraineurs had a 1.8-fold increased risk of
ischemic stroke (RR = 1.84; 95% CI, 0.89–3.82). Similarly,
in the Stroke Prevention in Young Women study, women
with MA had 1.5 greater odds of ischemic stroke (95% CI,
1.1–2.0).13
Heart Disease
Subclinical Brain Lesions
Deep brain lesions, found incidentally on neuroimaging,
have been reported more frequently in migraineurs. . In
a population-based study from the Netherlands, Kruit
and colleagues14,15 randomly selected approximately 150
individuals from each of three groups for neuroimaging
( MA , M O, a n d n o n m i gra i n e co nt ro l s ) . I n d i v i d u a l s
with a history of stroke, transient ischemic attack (TIA)
or abnormal neurologic examination were excluded.
This study included evaluation of magnetic resonance
imaging by a neuro-radiologist who was blinded and aura
classification was performed under the supervision of
expert headache diagnosticians without knowledge of the
magnetic resonance imaging results. Overall, there were
no differences between migraineurs and controls in the
prevalence of clinically relevant infarcts. However, those
with Migraine with aura (MA) had significant increase of
subclinical infarcts in the cerebellar region of the posterior
circulation. The highest risk for these lesions was seen in
those with MA and with more than one headache attack per
month (OR = 15.8; 95% CI, 1.8–140). In addition, women
with migraine were about twice as likely to have deep white
matter lesions as nonmigraineurs (OR = 2.1; 95% CI, 1.0–4.1).
Consistent with earlier studies on clinical stroke and white
matter abnormalities, these findings were independent of
the presence of cardiovascular risk factors.
c.
Multiple Sclerosis
Headache and migraine are common features of multiple
sclerosis (MS) and can influence diagnosis and treatment.
Likewise, MRI lesions found in migraine patients without
© SUPPLEMENT OF JAPI • april 2010 • VOL. 58 b.
Hypertension
Hear t diseases including mitral valve prolapse,
coronary artery disease, ischemic heart disease, angina,
and arrhythmias have also been associated with
migraine. There have been no large-scale, prospective
epidemiologic studies specifically examining the
association between migraine and these heart diseases.
Results from case-control studies could not establish
positive association between migraine and heart
disease after control of well established risk factors.18
Patent Foramen Ovale
c.
Patent Foramen Ovale (PFO) is a small flap-like opening
between the right atrium and the left atrium that
persists after age 1 year. It is present in upto 25% of the
population. PFO has been linked to stroke and previous
studies indicated an increased prevalence of patent
foramen ovale (PFO) in migraineurs with aura and an
increased prevalence of migraine and migraine with
aura in persons with PFO.19 In quantitative systematic
review of articles on migraine and PFO, the estimated
strength of association between PFO and migraine, the
OR was 5.13 (95% CI, 4.67–5.59] and between PFO and
migraine with aura the OR was 3.21 (95% CI, 2.38–4.17).
The association between migraine and PFO was OR 2.54
(95% CI, 2.01–3.08). The grade of evidence was low to
moderate. Research is currently on to establish whether
or not the link exists and if it does to investigate whether
or not closing the PFO leads to an improvement in
migraine.
Miscellaneous Disorders
a.
Asthma and Allergy
The association between migraine and allergic conditions
including food allergies, asthma and bronchitis has also been
well investigated. Von Behren et al.20 in a community-based
survey of adults, reported that migraine was associated
with asthma among women. Earlier studies have reported
relative risks of 1.9 for asthma and 4.1 for allergies.
Irrespective of the specific type of allergic condition assessed
19
in the studies, a strong and consistent association between
allergic conditions and migraine has been found in clinical
studies of both children and adults.
7.
Lipton RB, Hamelsky SW, Kolodner KB, Steiner TJ, Stewart WF.
Migraine, quality of life, and depression: a population based casecontrol study. Neurology. 2000; 55: 629-635.
b.
Gastrointestinal Disorders
8.
The lack of a clear distinction between recurrent abdominal
pain and undiagnosed abdominal migraine often presents
problems when examining the relationship between
migraine and abdominal pain.
Patel NV, Bigal ME, Kolodner KB, et al: Prevalence and impact
of migraine and probable migraine in a health plan. Neurology,
2004; 63 (8): 1432-1438.
9.
Zwart JA, Dyb G, Hagen K, et al: Depression and anxiety disorders
associated with headache frequency. The Nord-Trondelag Health
Study. Eur J Neurol, 2003; 10 (2): 147-152.
The association with gastric ulcers was observed in casecontrol samples from clinical settings and yielded relative
risks ranging from 1.9 to 2.5, whereas Chen et al. 21 reported
that ulcers were only associated with migraine among
smokers
c.
Coeliac Disease
An Italian study found that about 4% of migraine sufferers
may have coeliac disease compared to less than 0.4% of the
general population. 22
10. Terwindt GM, Ophoff RA, Haan J, Sandkuijl LA, Frants RR, Ferrari
MD. Migraine, ataxia and epilepsy: a challenging spectrum of
genetically determined calcium channelopathies. Dutch Migraine
Genetics Research Group. Eur J Hum Genet. 1998; 6: 297-307.
11. Etminan M, Takkouche B, Isorna FC, et al: Risk of ischemic stroke
in people with migraine: systematic review and meta-analysis of
observational studies. BMJ, 2005; 330 (7482): 63.
12.
13. MacClellan LR, Mitchell BD, Cole JW, et al: Familial aggregation of
ischemic stroke in young women: the stroke prevention in young
women study. Genet Epidemiol, 2006; 30 (7): 602-608.
Conclusion
Migraine has been found to have a strong association with
mood and anxiety disorders, stroke, epilepsy and allergies. As
these associations can alter the clinical course by affecting the
prognosis and therapeutic options, these can also lead to poor
response to treatment, therefore co-morbidities associated with
migraine need to be classified and analysed separately.
14. Kruit MC, Van Buchem MA, Hofman PA, et al: Migraine as a risk
factor for subclinical brain lesions. J Am Med Assoc, 2004; 291 (4):
427-434. 15. Kruit MC, Launer LJ, Ferrari MD, et al: Brain stem and cerebellar
hyperintense lesions in migraine. Stroke, 2006; 37 (4): 1109-1112.
16. Zorzon M, Zivadinov R, Nasuelli D, et al. Risk factors of multiple
sclerosis: a case-control study. Neurol Sci. 2003; 24 (4): 242-247.
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