Migraine before rupture of intracranial aneurysms
© Lebedeva et al.; licensee Springer. 2013
Received: 16 November 2012
Accepted: 7 February 2013
Published: 20 February 2013
Rupture of a saccular intracranial aneurysm (SIA) causes thunderclap headache but it remains unclear whether headache in general and migraine in particular are more prevalent in patients with unruptured SIA.
In a prospective case–control study 199 consecutive patients with SIA (103 females and 96 males, mean age: 43.2 years) received a semistructured face to face interview focusing on past headaches. All were admitted to hospital mostly because of rupture (177) or for unruptured aneurysm (22). In parallel we interviewed 194 blood donors (86 females, 108 males, mean age: 38.4 years). Diagnoses were made according to the International Headache Society criteria. Aneurysms were diagnosed by conventional cerebral angiography.
During the year before rupture, 124 (62.3%) had one or more types of headache. These headaches included: migraine without aura (MO): 78 (39.2%), migraine with aura (MA): 2 (1%), probable migraine (PM): 4 (2%), tension-type headache (TTH): 39 (19.6%), cluster headache (CH): 2 (1%), posttraumatic headaches (PH): 2 (1%). 1-year prevalence of headaches in controls was 32.5% (63 patients out of 194), they included: TTH: 45 (23.1%), MO: 17(8.8%), PH: 1(0.5%). Only the prevalence of MO was significantly higher in patients with SIA (OR 6.7, 95% CI 3.8-11.9, p < 0.0001).
Unruptured SIA cause a marked increase in the prevalence of migraine without aura but not in the prevalence of other types of headache.
KeywordsMigraine Headache Risk factor Intracranial aneurysm Unruptured aneurysm Subarachnoid heamorrhage
While the thunderclap headache associated with rupture of saccular intracranial aneurysm (SIA) is well known (ICHD-2) [1–5], it is much less certain if an unruptured SIA can cause headache. SIA of the internal carotid artery can cause severe pain around the eye including radiation to the head because of compression of the third nerve [6–8]. Likewise, giant aneurysms causing compression or distortion of intracranial structures are an accepted cause of headache [9, 10]. However, SIA that does not cause compression of a cranial nerve or other structures is not an intuitively obvious cause of headache.
Perhaps for that reason, the question has received little scientific study. In the chapter devoted to aneurysms in a standard reference book on headache , it is stated that unruptured SIA may be a cause of headache but the underlying literature references are case stories or uncontrolled studies. Recently the effect of operating unruptured SIA was described . The study showed a reduction of approximately 2/3 of headache prevalence after closure of the aneurysm, but the material was too small to determine the prevalence of headache before treatment and there was no control group . Currently, the importance of cerebral arteries in the pathogenesis of migraine is hotly debated and central mechanisms are generally favored . Any influence of unruptured aneurysms would support a role of cerebral arteries or their innervation in migraine.
On this background it is important to gather reliable information about the prevalence of headache in patients with unruptured SIA and to classify such headaches according to the International Classification of Headache Disorders . To definitively answer these questions, we did a very large, prospective case controlled study interviewing patients shortly after rupture about their headaches before rupture using a purpose-developed standardize semistructured interview that we simultaneously applied to matched blood donors. Our hypothesis was that SIA patients have an increased prevalence of migraine.
Clinical characteristics of patients with SIA and controls
Patients with SIA (n = 199)
Controls (n = 194)
OR (95% CI)
age range and mean age
patients with arterial hypertension
patients with systemic CTD
patients who have relatives with stroke
patients who have relatives with SIA
patients who have relatives with headaches
patients with alcohol consumption
patients with increased BMI (>25)
patients with headaches
3.4 (2.3 -5.2)
patients who used analgetics more than 15 times per month
The patient had at least one saccular intracranial aneurysm confirmed by cerebral angiography
The patient lived in Yekaterinburg or in the Urals region.
The patient agreed to conduct additional examinations.
The patient had fusiform, traumatic or mycotic aneurysm.
Patients who were unable to give a coherent headache history.
The patient had contraindications to additional methods of investigation.
The patient refused further examination.
The patient had no history of stroke, intracranial haemorrhage or other serious neurological and somatic disease, or hereditary connective tissue diseases.
The patient had no first degree relatives with intracranial aneurysms, or inherited connective tissue diseases.
The patient’s age and sex were matched to patients with SIA.
The patient agreed to additional examinations.
We did not perform MR-angiography in control patients since the frequency of aneurysms in the adult population without specific risk factors is only 2-3% .
All patients and controls were examined using a specially designed semistructured interview which included detailed information about the history of present and past diseases and the history of their pedigree, results of physical and neurological examinations, physician consultations and treatment. The semistructured interview contained detailed questions about present and past headache disorders allowing diagnosing headaches according to the International Classification of Headache Disorders . The interviews were all performed by the first author (ERL) during examination of patients with SIA at regional neurosurgical center after diagnosis of SIA and before surgical treatment. We asked patients with SIA and controls about headaches during their lifetime and about characteristics of headaches during 1 year before diagnosis of SIA or 1 year before interview in controls. Hypertension was defined as a history of high blood pressure (systolic values ≥140 mm Hg and/or diastolic pressure ≥90 mm Hg) or, if physician observed blood pressure of 140/90 mmHg or above on three consecutive measurements at least six hours apart. Systemic connective tissue dysplasia (CTD) was defined if patient had 3 or more visible markers of connective tissue dysplasia . Smoking was categorized as follows: never smoked, former (regular) cigarette smokers, and current cigarette smoker. Current cigarette smokers were defined as people who reported having smoked ≥100 cigarettes during their lifetime and who still smoked. We also asked about alcohol drinks, how many times per week and quantity in milliliters. Body mass index (BMI) was calculated as the weight in kilograms divided by height in meters squared. 194 patients with SIA (100 females and 94 males) and in 193 age- and sex-matched control patients were asked about occurrence of stroke, SIA, headache and some other disorders in their first degree relatives.
The Medical Ethics Committee of the Urals State Medical Academy approved this study. Informed consent was obtained from all participants.
The differences in mean values or frequencies between patients with SIA and controls were statistically examined by an unpaired t-test and chi-square test. Odds ratio (OR) and 95% confidence interval (CI) were estimated using multiple conditional logistic regression models.
Types of headaches in patients with SIA compare to controls
Types of headaches
Patients with SIA (n = 199)
Controls (n = 194)
Migraine without aura (MO)
Migraine with aura (MA)
Probable migraine (PM)
Tension type headache (TTH)
Cluster headache (CH)
Posttraumatic headaches (PH)
Side of SIA and side of migraine with single aneurysms (n = 63)
Side of SIA/Side of headache
Localization of SIA
AcoA-ACA (n = 18)
MCA (n = 16)
ICA (n = 23)
Posterior circulation (n = 6)
Basilar artery/alternating sides
Localization of migraine in patients with SIA of different localization (n = 80)
Localization of migraine
Localization of SIA
AcoA-ACA (n = 18)
MCA (n = 16)
ICA (n = 23)
Posterior circulation (n = 6)
Multiple SIA (n = 17)
Always same localization of migraine headache
Variable localization of migraine headache
Temporal + parietal
Fronto-temporal + occipital
Fronto-temporal + half-side
Fronto-temporal + parietal
Fronto-temporal + Parietal + occipital
Temporal + parietal + occipital + half-side
Temporal + occipital
Temporal + occipital + half-side
Parietal + occipital
Parietal + occipital + half-side
Parietal + half-side
Factors that might influence the frequency of migraine in patients with aneurysms
Patients with migraine (n = 80)
Patients without migraine (n = 119)
1.5 – 10.9
large SIA (11-25 mm)
giant SIA (>25 mm)
normal size SIA (5-10 mm)
small SIA (<5 mm)
stroke in relatives
SIA in relatives
Headaches in relatives
Localization of SIA
posterior circulation (vertebral, basilar, PICA)
The main result of this large case control study was that 1-year prevalence of migraine without aura (MO) was significantly higher in patients with saccular intracranial aneurysms (42.2%) than in controls (8.8%) and also significantly higher than in the general population of Russia (20.8%) . Migraine with aura was not increased although all patients were interviewed in detail about aura symptoms. 1-year prevalence of tension type headaches was almost the same in patients with SIA (19.6%) and controls (23.1%) but it was below the prevalence of TTH in the general population of Russia (30.8%) (17). We did not interview about rare headaches which may be the reason for our low prevalence of TTH in SIA and controls. The frequency of migraine in our controls was lower than in the general population of Russia, possibly because blood donors could perhaps be healthier than the general population.
Previous studies of unruptured intracranial aneurysms and headache
The literature before the use of the International Classification of Headache Disorders (ICHD-1) [14, 18, 19] is impossible to judge today. Only very few more recent studies are available. Raps et al. described headaches in 18 out of 111 patients (16.2%) with unruptured SIA . Most other publications were case reports about patients with SIA who suffered migraine [21–25]. The low frequency of headache in previous studies can be explained by a lack of purpose to study headache and no use of a detailed interview about headaches. An interesting study was performed by Schwedt et al. . They analyzed headache patterns prior to and following treatment of unruptured intracranial aneurysms in 44 patients and identified factors associated with different headache outcomes. The majority of patients (approximately 2/3) with pretreatment headaches had substantial reductions in headache frequency during the 6 months following treatment. Potential predictors for the absence of headache improvement following aneurysm treatment were: having migraine prior to treatment, having more severe headaches prior to treatment, stent-assisted coiling and higher pretreatment trait anxiety. Baron EP et al. (2011) found that stent-assisted coiling may provoke development of post-procedural headache .
Strengths and weaknesses of the present study
In relation to the previous literature the present study has many advantages. It has a very large study population. Its cases and comparable controls were interviewed prospectively and in parallel, interviews were conducted entirely by one of the authors (E.R.L.) – a neurologist with an interest in headache and subarachnoid hemorrhage – and the patient material is very large. Random statistical variation is thus highly unlikely to explain the results. All patients and controls originated from one defined geographical region of Russia and the great majority were ethnic Russians – thus limiting variability. The semi structured interview was designed specifically for the present study and included all items necessary to classify patients according to the International Classification of Headache disorders second edition. Since such a neurologist conducted interview is the gold standard of headache diagnosis, it was not validated. Finally, extensive information about the aneurysms and their rupture allowed a correlation between the location of headache and the location and type of aneurysm. A weakness of the present study is the lack of information about rare and mild headaches. The fact that patients were interviewed after rupture about the headache before rupture could possibly influence the results(missing of very rare headache and sometimes headache characteristics in rare headache) but the most likely effect of the bleed would be a lack of memory about previous headaches, which would probably decrease the prevalence of reported headache. Furthermore it would be impossible to accrue a sufficiently large material of patients with unruptured aneurysms. Patients who were aphasic, confused or with decreased level of consciousness were excluded from the present study. The presence of migraine with aura, 1%, was surprisingly low. However, the one year prevalence in the population is only 4% or 8 out of 200 subjects. We had 2 and this difference could be due to random variation. On balance, the present results are the most reliable data so far about the relationship between headache and unruptured SIA.
Reasons for increased prevalence of MO in SIA
There are several possible explanations for the increased prevalence of MO in SIA. The patients had a markedly increased prevalence of arterial hypertension (AH) compared to the normal control subjects. However, the relation between AH and migraine is uncertain. Some studies have found an increased prevalence of arterial hypertension in migraine  while others studies have shown no association to blood pressure  or revealed that only the diastolic blood pressure is elevated in migraine patients . While AH is clearly a risk factor for SIA  it is therefore much less clear that it is a risk factor for MO. In our own material, SIA patients with migraine had a significantly higher prevalence of hypertension than SIA patients without migraine. This can, however, explain only a small part of the increased risk of migraine without aura in SIA patients. SIA is associated with an increased prevalence of systemic connective tissue abnormalities  but in the present study there was no difference in the prevalence of MO in SIA patients with or without connective tissue abnormalities. Thus, systemic factors can explain only a small part of the increased prevalence of migraine in SIA patients. Aneurysms compressing cranial nerves or other structures are known to cause headache but usually it does not have the characteristics of MO. Furthermore, only 4 patients had compression of the third nerve and only 11 patients had giant aneurysms which were likely to compress intracranial structures. Out of these 15 patients 48% had MO which is similar to the whole material. On balance, neither systemic nor these two local factors explain the observed marked increase in the prevalence of MO.
It seems most likely, therefore, that it is the aneurysm itself which in some way is triggers MO. When headaches were always on the same side, it was on the side of the aneurysm in 14/16 cases. Furthermore, a fronto-temporal localization was most prevalent with aneurysms of the anterior communicating artery and anterior circulation aneurysms were most often associated with anterior migraine pain. There is, thus, some correlation between the localization of the aneurysm and migraine headache. On the other hand, the majority of cases had migraine headache on alternating sides just like in MO patients without SIA. On this basis it seems unlikely that a stimulus from the aneurysm is directly responsible for the migraine pain. More likely, input from perivascular sensory nerve terminals around the aneurysm may be a stimulus that increases sensitization in the central nervous system. This would lower the threshold for migraine to be elicited by a host of other factors, factors that probably are identical to those triggering MO in patients without SIA. Many experimental studies have demonstrated how increased sensory input by a localized stimulus e.g. inflammatory soup on the dura mater [31–33], can induce a wide spread and even contralateral sensitization. Such mechanisms are likely to operate also in patients with SIA and to explain the increased prevalence of otherwise typical attacks of MO in these patients. It would be interesting to follow patients with unruptured aneurysms with repeated quantitative sensory testing in the face and scalp.
One might ask why MO but not MA had increased prevalence. MO has been associated with sensory input from the big arteries at the base of the brain, i.e. where SIA is typically located. MA is believed to be secondary to cortical spreading depression which is more likely to be induced by cortical pathology. These relations have recently been discussed .
In conclusion, the present study demonstrates a markedly increased prevalence of migraine without aura in patients with unruptured saccular intracranial aneurysms. There was a correlation between the localization of aneurysms and the localization of migraine attacks but there were even bigger discrepancies. Systemic factors explained only a small part of the increased prevalence. We suggest that increased sensory input from sensory nerve endings around the aneurysms may sensitize the central nervous system and thus decrease the threshold for developing spontaneous migraine attacks.
The study was done voluntarily. No funding.
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