INTRODUCTION

 

Migraine is a painful neurological condition, of which the most common symptoms is an intense and disabling episodic headache on one or both sides of the head. It is often accompanied by photophobia, phonophobia and nausea and may be preceded by aura¹. 

Both migraine and stroke are associated with altered cerebral blood flow, focal neurological deficits, and headache².

The relationship between migraine and stroke encompassing at least 4 issues: migraine as a cause of ischemic stroke (migrainous infarcts), migraine and ischemic stroke sharing a common cause (symptomatic migraine), migraine attacks triggered by cerebral ischemia, and migraine as a risk factor for ischemic stroke. There seems to be no sex difference regarding the first 3 issues in contrast to the fourth issue, migraine as a risk factor for ischemic stroke, which seems to apply mostly to young women³.

Migrainous infarcts are said to be frequent causes of ischemic stroke in the young, its annual rate has been estimated at 3.36 cases per 100,000. Stroke appears to be most strongly associated with migraine with aura. Recent cross sectional study provided evidence that patients with migraine have increased risk of sub- clinical infarcts⁴.

Ischemic induced migraine attacks were more frequent than migrainous infarctions^5.

 

Aim of the work:

This study aimed to determine whether migraine is a risk factor for stroke; the characteristics, degree of disability and prognosis of acute stroke in patients with migraine in comparison with patients without migraine; and to study the association of migraine to known stroke risk factors.

 

PATIENTS AND METHODS

 

Patients and control:

This study was carried out on 40 consented patients suffering from first ever cerebro-vascular stroke. They were 19 males and 21 females and their age ranged from 45-70 years with mean age 60.00±11.7. They were randomly selected from neurology department of Minoufiya University Hospital in the period from March to December, 2007. They were compared with 40 consented control patients selected randomly from orthopedic department of Menoufiya University Hospital. They were 19 males and 21 females and their age ranged from 41-68 years with mean age 58.7±11.0.

 

Exclusion Criteria includes:

1-      Patients with previous history of cerebro-vascular stroke or transient ischemic attacks (TIAs),

2-      Patients with other neurological disorders.

                Both groups (patients and control) were divided according to history of migraine into migrainous and non-migrainous.

 

Methods:

both patients and control groups were subjected to:

1-      Thorough medical and neurological history taking including their history of vascular risk factors.

2-    Interview about their history of headache using headache sheet^6. Migraine patients were identified according to the IHS criteria (2004) ⁷.

3-      Complete neurological examination.

4-      Laboratory investigations for stroke risk factors as complete blood picture, serum glucose level, serum creatinine, liver function tests, serum uric acid and lipid profile.

5-      ECG, Echocardiography and carotid duplex.

6-      CT brain at the onset of stroke (first 72 hours) to determine site and size of the lesion that was repeated 3 days later if the lesion not appeared at the onset.

7-      Stroke patients were subjected to clinical outcome scale of National Institute of Health Stroke Scale (NIHSS) ⁸ and functional outcome scale of Barthel Index of Activities of Daily Living (ADL)⁹, at onset of stroke, and every two weeks for eight weeks to determine the degree of disability and prognosis of acute stroke in patients with migraine in comparison with patients without migraine.

 

Statistical Method

Data was collected, tabulated and analyzed by SPSS version 11.0 statistical package (SPSS Inc. Chicago, Illinois, USA). Quantitative data expressed as mean and standard deviation (X ± SD). Student t-test was used to compare two groups of normally distributed variables and Mann-Whitney (U – test) for non – normally distributed variables. Qualitative data expressed as number and percentage and analyzed by Chi-square test with or without Yale's Continuity Correction when appropriate. Level of significance was set as P-value <0.05.                                                          

 

RESULTS

 

Regarding history and type of migraine; 10 out of 40 (25%) stroke patients had history of migraine (out of them 1 (10%) patient had migraine with aura and 9 patients (90%) had migraine without aura), while in control group only 5 (12.5%) persons had history of migraine non of them had migraine with aura. These differences was statistically significant (P<0.05) as regard history of migraine only (Table 1).

 

Frequency and duration of migraine were higher in stroke than control group with no significant difference. As regard triptan use, no significant difference was noticed between migrainous stroke patients and migrainous control group (Table2).

 

As regard side of unilateral headache in relation to side of lesion in C.T brain in migrainous stroke patients; 5 (50%) patients had bilateral headache, 5 (50%) patients had unilateral headache out of them 3 (30%) on right side and 2 (20%) on left side (Table 3).

 

The most important risk factors in migrainous stroke patients were contraceptive pills administration reported 5 (50%) patients, diabetes mellitus in 4 (40%) patients, and hypercholesterolemia, hyperuricemia, while family history of migraine and stroke in 3 (30%) patients for each. The most important risk factors non-migrainous stroke patients; were hypertension in 15 (50%) patients, smoking and hyperuricemia in 11 (36.7%) patients, diabetes mellitus in 10 (33.3%) patients, and cardiac diseases in 9 (30%) patients, while contraceptive pills and family history of migraine were only a risk factor in 4 (13.3%) patients and 1 (3.3%) patient respectively. There was a significant difference between the two groups as regard contraceptive pills (P <0.001), hypercholesterolemia, and family history of migraine only (P <0.05) (Table 4).

 

The prevalence of infarction was higher than hemorrhage in both migrainous and non-migrainous stroke patients, with ratio of infarction to hemorrhage is 9 to 1. Results also showed that about 50% of migrainous stroke patients had affection of posterior cerebral artery (PCA) in comparison to 13.3% in non-migrainous stroke patients. Middle cerebral artery (MCA) was affected in about 40% of migrainous stroke patients while it was affected in about 83.4% of non-migrainous stroke patients. As regard site of the lesion, it showed a significant difference (P<0.05) only in thalamic lesions which was higher in migrainous stroke patients (Table 5).

 

Figure (1) and (2): showed the difference in NIHSS score and Barthel Index scale between migrainous (A) and non-migrainous (B) stroke patients at onset and every two weeks for eight weeks. It showed that the outcome of migrainous stroke patients was better than non-migrainous patients at different follow up periods that it was significant (P<0.05) as regard functional daily activities that assessed by Barthel Index scale, but not significant as regard NIHSS.

Table 1. History of migraine and its type among the studied groups.

 

Variables	Studied groups				Total		X²	P-value
	Stroke Group		Control Group
	Number	Percentage	Number	Percentage	Number	Percentage
History of migraine:	10	25.0	5	12.5	15	18.8	2.1	< 0.05*
Type of migraine: With aura Without aura	1 9	10.0 90.0	0 5	0.0 100.0	1 14	6.7 93.3	0.54	> 0.05

X² chi square

* Statistically significant at p<0.05

 

 

Table 2. Difference between stroke and control migrainous subjects as regards use of Triptans, frequency and duration of migraine attacks per year.

 

Variables	Migrainous				X²	P- value
	Stroke		Control
	Number (n=10)	Percentage	Number (n=5)	Percentage
Use of Triptans	3	30.0	2	40.0	0.15	> 0.05
Frequency of migraine per year (X±SD)	7.6±13.37		5.2±9		t- test	> 0.05
					0.36
Duration of migraine per years  (X±SD)	6.7±32.5		5.0±10.7		0.11	> 0.05

SD standard deviation, X ² chi square

 

 

Table 3. Side of unilateral headache in relation to side of lesion in C.T in migrainous stroke patients.

 

Variables	Headache on same side of CT lesion		Headache on opposite side of CT lesion		Total		Z-test	p- value
	Number	Percentage	Number	Percentage	Number	Percentage
Side of the lesion	3	60.0	2	40.0	5	100.0	-0.01	> 0.05

CT computerized tomography

 

Table 4. Distribution of risk factors for cerebrovascular stroke in stroke patients.

 

Variables	Stroke patients				Total		X²	P-value
	With migraine (No=10)		Without migraine (No=30)
	Number	Percentage	Number	Percentage	Number	Percentage
Smoking:	3	30.0	11	36.7	14	35.0	0.15	> 0.05
Hypertension:	3	30.0	15	50.0	18	45.0	1.2	> 0.05
Cardiac disease:	2	20.0	9	30.0	11	27.5	0.38	> 0.05
Diabetes mellitus:	4	40.0	10	33.3	14	35.0	0.15	> 0.05
Hypercholesterolemia:	3	30.0	2	6.7	5	12.5	3.7	< 0.05*
Hyperuricaemia:	3	30.0	11	36.7	14	35.0	0.15	> 0.05
Contraceptive pills administration:	5	50.0	4	13.3	9	22.5	5.8	< 0.001**
Family history of migraine	3	30.0	1	3.3	4	10.0	5.39	< 0.05*
Family history of stroke	3	30.0	3	10.0	6	15.0	2.35	> 0.05
Total	10	100.0	30	100.0	40	100.0	----	----

X² chi square

* Statistically significant at p<0.05** Statistically significant at p<0.01

Table 5. Distribution of C.T results among migranous and non-migranous stroke patients.

 

ACA anterior cerebral artery, MCA middle cerebral artery, PCA posterior cerebral artery

* Statistically significant at p<0.05

 

 

 

Figure 1. Difference in NIHSS score among migrainous (A) and non-migrainous,

(B) stroke patients at onset and every two weeks for eight weeks.

 

Figure 2. Difference in Barthel index among migrainous (A) and non-migrainous,

(B) stroke patients at onset and every two weeks for eight weeks.

 

 

DISCUSSION

 

Many studies have suggested a complex bidirectional relation between migraine and stroke, including migraine as a cause of stroke, migraine as a risk factor for or as a consequence of cerebral ischemia, and migraine and cerebral ischemia sharing a common cause⁴.

In this study, 25% of patients who had a stroke reported a personal history of migraine compared to 12.5% in control group.

This is in agreement with Agostoni and Rigamonti² who reported that the risk of stroke doubled or slightly more than doubled in patients with migraine as the adjusted relative risk (RR) of clinical stroke in migraine subjects ranged from 1.7 to 2.33.

Results of this study differs from the results reported by Etminan et al.¹⁰, who found that, the prevalence of migraine in the whole group of patients with ischemic stroke was not different from that in the matched controls, so that migraine was not a risk factor for stroke.

Also Milhaud et al.¹¹, who studied the characteristics of patients with ischaemic stroke  and  migraine found that, the prevalence of  migraine in patients with ischaemic stroke (3.7%) was lower than that reported in the controls (6% in men and 17.6 in women).

Possible explanations of our results include that vasospasm of the brain arteries and regional cerebral blood flow changes are present among patients with migraine, leading to 30 to 40% reduced flow in the affected vascular territories. Although there is evidence that the local oxygenation in the brain is adequate during migraine attacks, a combination of vasospasm and activation of the clotting system may lead to an increased risk of embolism, thrombosis, or ischemia¹¹.

Friberg et al.¹² suggested that increased local changes during migraine attacks, including neuronal activation and associated neurogenic inflammation, may contribute to increased risk of brain ischemia.

Sixty percent of migrainous stroke patients in this study were female, 40% were males with male to female ratio 2 to 3. This result was in line with Milhaud et al.¹¹ who found that, 6% of migrainous stroke patients were males and 17.6% were females. This difference in sex could be due to the fact that the prevalence of migraine is higher in female as around 25% of women experience a migraine at least once a year, compared with fewer than 10% of men¹³.

With respect to the age, in this study, mean age in migrainous stroke patients was lower than mean age in non-migrainous stroke patients (51.2±8.7 versus 59.7±10.9 respectively), but the difference was statistically insignificant between both groups.

These findings are coincident with Milhaud et al.¹¹, who found that, in the subgroup of population aged 45 and older, the prevalence of migrainous was lower than that in the general population, suggesting that, brain infarcts after 45 years may be less frequent in migrainous than in non migrainous. Buring et al.¹⁴ conducted a large population-based studies on both men and women of all ages have suggested that, migraine is a risk factor for brain infarct, but that the risk decreases with age.

A potential explanation by which migraine may be associated with ischemic stroke in younger women but not for the older age group may be that other major risk factors for ischemic stroke acquire greater importance with increasing age or interact with the mechanism by which migraine may lead to stroke. This hypothesis is supported by the finding that in the absence of classic cardiovascular risk factors, migraine remained associated with ischemic stroke in our data and other studies¹¹. However Merikangas et al.¹⁵ reported no increased risk of ischemic stroke among the elderly (age 60 and older) with a history of migraine.

In this study, one patient in stroke group has migraine with aura whether rest of patients had simple migraine without aura. This was in agreement with results of Chang et al.¹⁶, who investigated the extent to which simple or classical migraine predispose to all stroke (combined ischemic, hemorrhagic and unclassified stroke); and found increased risk among participants with migraine without aura.

Also, in the study of Tzourio et al.¹⁷, who studied 37 patients with migraine, 31 had migraine without aura, 5 had migraine with aura, and 1 could not be classified due to uncertainty by the patient.

On contrary, Leah et al.¹⁸ studied 386 women aged 15 to 49 years with first ischemic stroke and 614 age and ethnicity-matched controls. Based on their responses to a questionnaire on headache symptoms, subjects were classified as having no migraine, migraine without, or migraine with aura. They found that, overall and subgroup analyses did not indicate any association between migraine without aura and stroke but prevalence of migraine with aura is two folds more in stroke than control patients.

As regard frequency and duration of migraine, migrainous stroke patients had longer duration and more frequency than migrainous control patients. These results are inconsistent with Tzourio et al.¹⁷, who reported mean frequency 2.6±3.2 in migrainous stroke patients vs. 1.8±1.5 in migrainous control patients.

Also, Donaghy et al.¹⁹ conducted a study on 86 cases of ischemic stroke and 214 controls reported that, the adjusted risk of ischemic stroke was significantly associated with (1) migraine of more than 12 years duration, (2) initial migraine with aura, and, (3) particularly if attacks were more frequent than 12 times per year.

In respect to side of the migrainous headache, 5 (50%) had bilateral headache, 5 (50%) had unilateral headache (with 3 (30%) of them on the side of cerebral lesion and 2 (20%) on the opposite side). These results were inconsistent with results of Peatfield²⁰, who found that, 55 out of 111 patients had headache on the same side of lesion and 20 patients on the opposite side.

In this study, use of triptans reported only in 3 (30%) of migrainous stroke patients and in 2 (40%) of migrainous control patients. This is in agreement with results of Hall et al.²¹, who stated that, out of 63,575 migraine patients (21.5%) was prescribed a triptan. The larger group of migraine patients not prescribed a triptan had an increased risk of stroke.

These results could be explained by the fact that sumatriptan has no direct effect on platelet aggregation; it has even been shown that triptans can normalize the increased platelet activation of patients with migraine with aura ²². Also triptans have no adrenergic activity; that is why it is unlikely that these drugs could induce marked vasoconstriction and decreased arterial vessel wall distensibility in extracerebral vessels²³.

As regard stroke risk factors, in this study, there was no significant difference between migrainous and non-migrainous stroke patients except for hyper-cholesterolaemia which show significant difference, and contraceptive pills administration which show highly significant difference in migrainous in comparison to non-migrainous patients.

These findings are in line with that of Kurth et al.²⁴, who reported that, compared with participants who did not report ever having migraine, women who reported migraine with aura were younger, more likely to have reported a history of cholesterol level of >240 mg/dL, and to have used oral contraceptives, and to be currently on hormone therapy.

Chang et al.¹⁶ found that, regarding the risk of ischemic and hemorrhagic stroke among women with and without a history of migraine associated with: use of oral contraceptives; a history of high blood pressure and smoking, the coexistence of each of these factors has a greater than multiplicative effect on the odds ratios for ischaemic stroke associated with a history of migraine, although the apparent synergy was only statistically significant for smoking.

As regard CT findings, there was no statistically significant difference between migrainous and non-migrainous stroke patients regarding side, size and type of lesion. In migrainous group prevalence of infarction was higher and there was predominance of posterior cerebral artery (PCA) affection 5 (50.0%) and thalamic lesions were the most frequent site involved.

This was in agreement with Milhaud et al.¹¹, who found that, Stroke in the posterior circulation, especially in the PCA territory, is more often associated with headache than stroke in the anterior circulation and the infarct occurs more commonly in the thalamus.

In the study of Hoekstra et al.²⁵ infarction involved the occipital lobe in 11 of the 14 patients with migraine, whereas this occurred in 4 patients with non migrainous. This could be explained by the fact that the occipital cortex may be the most vulnerable to infarcts because of both its neuronal and arterial characteristics, being the site where the spreading depression originates and being supplied by the posterior cerebral artery, the most densely innervated of the major vessels arising from the circle of Willis²⁶.

According to results of NIHSS score in different follow up visits in this study, there was no statistically significant difference between migrainous and non-migrainous stroke patients, but according to Barthel index there was no statistically significant difference between migrainous and non-migrainous stroke patients at onset and at 8 weeks, but there was statistically significant difference at 2 weeks, 4 weeks and 6 weeks.

This was in agreement with Milhaud et al.¹¹ who mentioned a hint in their data that migraineurs may more frequently have a favorable outcome at 1 month than non migraineurs approximately in younger and older patients.

Another study done by Waters et al.²⁷ showed that, in a 12-years follow-up of a population of 1,310 women, patients without headache had a higher mortality than those with headache or migraine. The outcome at 4 weeks was favorable in 72% of migraineurs compared with 63% of non migrainous control subjects.

This could be explained by the fact that stroke in migrainous patients occur usually in younger age and on top of less atherosclerotic vessels hence the better recovery on both clinical and cellular  level²⁸.

In Conclusion, a personal history of migraine was associated with increased risk of cerebro-vascular stroke with no significant difference regarding type of stroke (ischemic and hemorrhagic) and type of migraine (with or without aura). The outcome of stroke was favorable in migrainous compared with non migrainous. Also, coexistence use of oral contraceptive pills had more than multiplicative effects on risk for cerebrovascular stroke.

 

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