Migraine with aura and migraine without aura: an epidemiological study
Birthe Krogh Rasmussen, Jes Olesen
The Glostrup Population Studies, Department of Internal Medicine C, Glostrup Hospital, University of Copenhagen and Department of Neurology, Gentofte Hospital, University of Copenhagen, Denmark Cephalalgia
Rasmussen BK, Olesen J. Migraine with aura and migraine without aura: an epidemiological study. Cephalalgia 1992;12:221-8. Oslo. ISSN 0333-1024 In a cross-sectional study of headache disorders in a representative general population of 1,000 persons the epidemiology of migraine with aura (MA) and migraine without aura (MO) was analysed in relation to sex and age distribution, symptomatology and precipitants. The headache disorders were classified on the basis of a clinical interview as well as a physical and a neurological examination using the operational diagnostic criteria of the International Headache Society (IHS). Lifetime prevalence of MA was 5%, male:female ratio 1:2. Lifetime prevalence of MO was 8%, M:F ratio 1:7. Women, but not men, were significantly more likely to have MO than MA. Neither MA nor MO showed correlation to age in the studied age interval (25-64 years). Premonitory symptoms occurred in 16% of subjects with MA and in 12% with MO. One or more precipitating factor was present in 61% with MA and in 90% with MO. In both MA and MO the most conspicuous precipitating factor was stress and mental tension. Visual disturbances were the most common aura phenomenon occurring in 90% of subjects with MA. Aura symptoms of sensory, motor or speech disturbances rarely occurred without coexisting visual disturbances. The pain phase of MA fulfilled the criteria for MO of the IHS. Headache was, however, less severe and shorter lasting in MA than in MO. Onset at menarche, menstrual precipitation, menstrual problems, influence of pregnancy and use of oral contraceptives all showed some relationship with the presence of MO and less with MA. The present findings suggest that MA and MO share the pain phase. Among subjects with MA and MO, 50% and 62%, respectively, had consulted their general practitioner because of migraine. Selection bias in previous clinical studies is demonstrated by comparisons with the present unselected sample. • Epidemiology, migraine with aura, migraine without aura, precipitants, selection bias, symptomatology Birthe Krogh Rasmussen, The Glostrup Population Studies, Department of Internal Medicine C, Glostrup Hospital University of Copenhagen and Department of Neurology, Gentofte Hospital University of Copenhagen, Denmark. Received 10 December 1991, accepted 13 April 1992
The operational diagnostic criteria of the International Headache Society (IHS) (1) distinguishes migraine with aura (MA) (previously classic migraine) and migraine without aura (MO) (previously common migraine) as the major subforms of migraine. This distinction is based on the clinical presence of aura, i.e. the complex of focal neurological symptoms which initiates or accompanies migraine attacks with aura. Whether or not MA and MO are distinct syndromes, different manifestations of the same disorder or part of a continuum have been much disputed (2-6). Studies of regional cerebral blood flow in acute migraine have shown spreading hypoperfusion in the early phase of the attack in MA and not in MO, indicating differences in pathophysiology of the two disorders (7, 8). Most recently, studies using combined rCBF and transcranial Doppler sonography have shown dilatation of the middle cerebral artery during the pain-phase in both MA and MO, indicating a possible common mechanism of the pain-phase in these disorders (9). Correspondingly, several drug trials have shown equal efficacy on the pain-phase of MA and MO of various anti-migrainous drugs (10-13). Clinical studies comparing features of MA and MO in patients from headache clinics have also tried to elucidate whether or not MA and MO are different conditions (I3-16). When such data demonstrated a considerable overlap of symptoms in MA and MO and a high proportion of patients with coexistence of both types of migraine it was considered as support for a single clinical entity. But these studies yielded conflicting results and are difficult to compare because of the different methodology and diagnostic criteria that were used. Most previous studies include only subjects from clinics and comparisons of these highly selected groups of patients may lead to spurious findings. As early as in 1946, Berkson warned against the use of hospital or clinic materials for epidemiological research, since these selected groups may differ widely from unselected subjects with the disorder (17). In a previous report on this same random general population only 56% of all migraineurs had consulted their general practitioner at some time because of migraine and 16% had consulted a specialist (18). Thus, the selection bias in clinical studies may be considerable. In the present paper we compare demographic and nosographic characteristics of MA and MO in
an unselected population with the purpose of describing similarities and differences between the disorders. By necessity, the random selection and time-consuming diagnostic procedure has limited the number of migrainous subjects. Thus, the quality of the data is high, but the power in some of the calculations is low, and some of the results are primarily hypothesis generating. Material and methods
A random sample of 1,000 25-64-year-old men and women was drawn from the Danish National Central Person Registry, in which all Danish residents are recorded. The sampling area was representative of the total Danish population in regard to most sociodemographic variables (19). All members of the sample received a standardized written invitation to a general health survey with focus on headache disorders; 387 men and 353 women participated. Excluding those individuals who had died or left the survey area since the random sample was obtained, the participation rate was 76%. A detailed description of the general study design, representativeness of the population, and characteristics of the non-participants has been published previously (19, 20). Non-participants did not differ from participants. The headache disorders were classified according to a structured diagnostic headache interview and a neurological examination using the operational diagnostic criteria of the IHS (1). Comparing the features of the pain-phase in MA and MO is problematic due to diagnostic bias, since operational diagnostic criteria are given for MO and not for MA for which only criteria for the aura symptoms are specified. In order to reduce the influence of this bias, subjects with migrainous disorder not quite fulfilling the criteria (IHS diagnosis 1.7) are also included in the analyses. In the interview, all migraineurs were asked if they had ever consulted their general practitioner or a specialist because of migraine. A question concerning family occurrence was also included. From a self-ad-ministered questionnaire completed by all participants, we collected information on 14 diseases to study their possible relationship with migraine. The questions were phrased as for example, Do you have or have you ever had epilepsy?' Statistical methods. The chi-square tests for unpaired and paired (McNemar's test) data, the Mantel-Haenszel c2 test (M-H test) and the Mann-Whitney test (M-W test) were included. A logistic regression analysis was used to account for age confounding, and odds ratio (OR) was calculated by exp(log coeff). A 5% level of significance and 95% exact confidence intervals by binomial distribution were used. Results
Prevalence The lifetime and one-year prevalence of migraine with aura (MA) and migraine without aura (MO) and coexisting MA and MO and their relation to age and sex are given in Table 1. The lifetime prevalence of MA (excluding subjects with coexisting MO) was 5% (95% conf. lim. 4-7) with a male:female ratio of 1:2 and of MO (excluding subjects with coexisting MA) 8% (95% conf. lim. 6-10) with a male:female ratio of 1:7. Correspondingly, the one-year prevalence of MA was 3% (c.1. 2-5), M:F ratio 3:4 and of MO 5% (c.1. 4-7), M:F ratio 1:4. Only 1-2% had both MA and MO. No significant age differences in prevalence rates of MA and MO emerged. The lifetime prevalence of other Table 1. Lifetime and one-year prevalence of migraine with aura (MA), migraine without aura (MO) and coexisting MA and MO (MA + MO). Relation to age and sex. The diagnostic groups are mutually exclusive. N = denominator. Prevalence Lifetime
One-year *
Age 25-44 45-64
% 3 4
All ages
3
MA (n) % (6) 7 (7) 8 (13) 7*
25-44 45-64
2 4
(4) (7)
4 4
(8) (6)
2 0.6). Familial occurrence A family history of migraine among first-degree relatives (father, mother, brothers, sisters, children) was reported by 56% of all migraineurs (40% with MA and 64% with MO). In women with migraine 60% stated a family history and in men 47% stated so (p > 0.2). Relation to other diseases or disorders After adjusting for the effect of age in a logistic regression analysis, including age as a confounding continuous variable, no association was found between the following diseases and migraine (using the IHS classification at the 1-digit level) in either men or women: epilepsy, angina pectoris, coronary occlusion (AMI), cerebral hemorrhage/stroke, asthma, seasonal rhinitis, eczema, psoriasis, peptic ulcer, gall stone, kidney stone, back disorder, abdominal disorder. In women, migraine was positively associated with menstrual disorder (OR = 1.41 (1.10-1.81). When MA and MO were analysed separately MO was significantly related to menstrual disorder (OR = 1.48 (1.09-2.00)) while MA was not. Discussion
This study is the first epidemiologic study of migraine with and without aura in a representative general population using operational diagnostic criteria in which all subjects were interviewed and examined by a physician. Given this rigorous study design, the number of subjects surveyed is large, yet the number of migraineurs in each subgroup is relatively small for some comparisons, which prompts caution when interpreting the results and prevents some statistical evaluations. The lack of significant differences between MA and MO in some instances may therefore be a type two statistical error (lack of power). On the other hand, studies of large clinic populations may have more power, but they suffer from selection bias. A combined evaluation of studies of both types is at present most likely to give the true picture. Prevalence, sex distribution and symptomatology The prevalence rates of migraine without aura (MO) and migraine with aura (MA) have briefly been discussed elsewhere (21). The sex distribution of MO and MA was somewhat different, indicating that sex-related factors may be of greater importance in MO than in MA. Menstrual precipitation, menstrual problems, influence of pregnancy and use of oral contraceptives all showed some relationship with MO and less with MA. The earlier onset of MO could be a function of the menarche. Overall, the relationship between female horomones and MO was clearly stronger than with MA. Premonitory symptoms occur hours or several days before the onset of migraine and usually consist of mood variations, tiredness, craving for special foods and similar atypical symptoms. These symptoms have never been studied in an unselected group of subjects and control groups have not been used. Blau (22) reported in a study of 50 consecutive migraineurs that 34% had prodromes. Other studies have suggested even higher figures (23, 24), although this may be due to biased patient selection. In the present study of a representative general population, premonitory symptoms were relatively rare among migraineurs (12-16%) and no more frequent than in tension-type headache. The distribution of aura symptoms reported in the present study is entirely in agreement with previous studies of selected patient materials (25-28). Visual disturbances were the most common aura symptom and other aura symptoms (somatosensory symptoms, motor disturbances and speech difficulties) nearly always occurred with visual symptoms. Some of the aura symptoms were, however, non-specific (e.g. vertigo and decreased level of consciousness) and in some cases may be misinterpreted as they may be coincident with anxiety and hyperventilation. MA fulfilled the criteria of the pain-phase demanded for MO by the IHS, although MA had less severe and shorter-lasting headache. In agreement with the present study, several previous clinical studies found the pain-phase of MA and MO to be nearly identical (13, 15, 16). Our finding of a less severe and shorter-lasting pain-phase in MA was found in previous studies (14, 15). Selby and Lance (13), in their study of 500 cases of migraine and allied vascular headache, reported a uniform clinical picture in various diagnostic subgroups. When comparing clinical features of MA and MO in a questionnaire-based study of 1259 headache clinic patients using Vahlquist's criteria, Davies et al. found the two forms of migraine to be fundamentally similar in their clinical characteristics, apart from aura (15). In a study analyzing the clinical features of MA and MO, using the criteria of the Ad Hoc Committee on Classification of Headache, Manzoni et al. (14) found marked clinical differences between MA and MO, suggesting the disorders to be two distinct entities. In a study of 50 patients from the City of London Migraine Clinic (16) using the diagnostic
criteria of the International Headache Society, no major differences were found between MA and MO. In a previous epidemiological study of young adults (21-30 years) using modified IHS criteria both migraine pain characteristics and associated symptoms were more frequent in MA than in MO (29). Due to the modification of the IHS criteria in this study however, the validity of the migraine subtyping was uncertain, as is also correctly emphasized in the previous paper. Comparison of our nosographic data with clinical data is difficult due to variability in diagnostic criteria, but it is clear that the frequency of attacks of both MA and MO is much higher in clinical studies (15, 16, 25). In the present study, 50% of subjects with MA had consulted a general practitioner and 62% with MO had done so. The consultation rate of a specialist was 16% in MA and 19% in MO. Those who had seen a medical doctor had more frequent attacks. Clinical cases may, thus, be unrepresentative due to selection. This selection may also influence the proportions of individuals with coexisting MA and MO reported in clinical studies. Subjects with more than one disease may be more likely to consult a physician than subjects with only one disease (17, 30, 31). In the present study, six of nine subjects with coexisting MA and MO had consulted a physician because of headache. Spuriously high proportions of subjects with both MA and MO may be expected in headache-prone populations and indeed several previous clinical studies have reported that MA and MO usually occur in the same patients (15, 16, 28). We found that 19% of subjects who have ever had MA had also at some time had MO. Of subjects with MA in the previous year, 17% had in addition had MO in this year. In agreement, Manzoni found that 25.6% of a series of MA patients had also had attacks of MO (14). Selby and Lance (13) reported in a series of 290 migraine patients that 231 (80%) had pure migraine without major visual disturbances or focal cerebral disturbances. These studies support our finding that concurrence of MA and MO, adjusted for age and sex, is not, or at least only marginally, more common than expected by chance. Inaccuracy in the diagnosis of aura symptoms may be an important problem in both clinical and population-based studies. The aura symptoms may be extremely difficult to describe. Patients frequently have difficulties in remembering their symptoms and in translating their experience into words, even upon systematic questioning by a physician. The retrospective character of the present study may induce bias due to problems of recall of aura symptoms, but also with respect to recall of variables such as age at onset, relation to pregnancy, vague premonitory symptoms, family history and associated conditions. Summarizing our nosographic data and results from the literature it seems reasonable that the painphases of migraine with aura and migraine without aura are clinically almost identical, indicating shared pathophysiology. Recent pathophysiological studies and drug trials also support this conclusion (9, 12). The two forms differ, however, in the initial phases of the attacks, i.e. in the presence of aura symptoms and associated cerebral blood flow findings. Different sensitivity to female hormones and lack of significant concurrence also suggest differing initiating mechanisms. Further clarification of the relationship between MA and MO may be obtained by longitudinal follow-up studies of large samples and by further pathophysiological studies. Familial occurrence and associated conditions A positive family history in 56% of migraineurs in our study is similar to previous reports (32-35). A family history of migraine is found in approximately 18% of controls (34, 36). These figures may, however, be somewhat distorted by family information bias (31) and in clinical series also by referral bias. In clinical studies a number of diseases have been reported previously in association with migraine: transient ischaemic attacks (37), stroke (14, 38), hypertension (39, 40), angina (14, 41), Raynaud's phenomenon (41), bilious attacks (13, 42), systemic lupus erythematosus (43), a number of allergic disorders (13, 44, 45), and epilepsy (13, 36, 46). Several of these studies may have been influenced by Berkson's bias, since an over-representation of subjects with more than one disease is likely in a hospital or clinic setting. In the present study only menstrual disorder was associated with migraine. The lack of association with other diseases may, however, be due to low statistical power. Previously we have reported equal prevalence of arterial hypertension in migraineurs and non-migraineurs (47). Acknowledgements.-We thank Dr Rigmor Jensen for her valuable assistance in collecting data and, along with Professor Marianne Schroll, Dr Torben Jørgensen and statistician Mette Madsen, for fruitful discussions and comments on the manuscript. This study was supported by grants from the Danish Health Insurance Foundation (H11/238-88, H 11/262-89, H 11/276-90). References
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Birthe Krogh Rasmussen, Jes Olesen
The Glostrup Population Studies, Department of Internal Medicine C, Glostrup Hospital, University of Copenhagen and Department of Neurology, Gentofte Hospital, University of Copenhagen, Denmark Cephalalgia
Rasmussen BK, Olesen J. Migraine with aura and migraine without aura: an epidemiological study. Cephalalgia 1992;12:221-8. Oslo. ISSN 0333-1024 In a cross-sectional study of headache disorders in a representative general population of 1,000 persons the epidemiology of migraine with aura (MA) and migraine without aura (MO) was analysed in relation to sex and age distribution, symptomatology and precipitants. The headache disorders were classified on the basis of a clinical interview as well as a physical and a neurological examination using the operational diagnostic criteria of the International Headache Society (IHS). Lifetime prevalence of MA was 5%, male:female ratio 1:2. Lifetime prevalence of MO was 8%, M:F ratio 1:7. Women, but not men, were significantly more likely to have MO than MA. Neither MA nor MO showed correlation to age in the studied age interval (25-64 years). Premonitory symptoms occurred in 16% of subjects with MA and in 12% with MO. One or more precipitating factor was present in 61% with MA and in 90% with MO. In both MA and MO the most conspicuous precipitating factor was stress and mental tension. Visual disturbances were the most common aura phenomenon occurring in 90% of subjects with MA. Aura symptoms of sensory, motor or speech disturbances rarely occurred without coexisting visual disturbances. The pain phase of MA fulfilled the criteria for MO of the IHS. Headache was, however, less severe and shorter lasting in MA than in MO. Onset at menarche, menstrual precipitation, menstrual problems, influence of pregnancy and use of oral contraceptives all showed some relationship with the presence of MO and less with MA. The present findings suggest that MA and MO share the pain phase. Among subjects with MA and MO, 50% and 62%, respectively, had consulted their general practitioner because of migraine. Selection bias in previous clinical studies is demonstrated by comparisons with the present unselected sample. • Epidemiology, migraine with aura, migraine without aura, precipitants, selection bias, symptomatology Birthe Krogh Rasmussen, The Glostrup Population Studies, Department of Internal Medicine C, Glostrup Hospital University of Copenhagen and Department of Neurology, Gentofte Hospital University of Copenhagen, Denmark. Received 10 December 1991, accepted 13 April 1992
The operational diagnostic criteria of the International Headache Society (IHS) (1) distinguishes migraine with aura (MA) (previously classic migraine) and migraine without aura (MO) (previously common migraine) as the major subforms of migraine. This distinction is based on the clinical presence of aura, i.e. the complex of focal neurological symptoms which initiates or accompanies migraine attacks with aura. Whether or not MA and MO are distinct syndromes, different manifestations of the same disorder or part of a continuum have been much disputed (2-6). Studies of regional cerebral blood flow in acute migraine have shown spreading hypoperfusion in the early phase of the attack in MA and not in MO, indicating differences in pathophysiology of the two disorders (7, 8). Most recently, studies using combined rCBF and transcranial Doppler sonography have shown dilatation of the middle cerebral artery during the pain-phase in both MA and MO, indicating a possible common mechanism of the pain-phase in these disorders (9). Correspondingly, several drug trials have shown equal efficacy on the pain-phase of MA and MO of various anti-migrainous drugs (10-13). Clinical studies comparing features of MA and MO in patients from headache clinics have also tried to elucidate whether or not MA and MO are different conditions (I3-16). When such data demonstrated a considerable overlap of symptoms in MA and MO and a high proportion of patients with coexistence of both types of migraine it was considered as support for a single clinical entity. But these studies yielded conflicting results and are difficult to compare because of the different methodology and diagnostic criteria that were used. Most previous studies include only subjects from clinics and comparisons of these highly selected groups of patients may lead to spurious findings. As early as in 1946, Berkson warned against the use of hospital or clinic materials for epidemiological research, since these selected groups may differ widely from unselected subjects with the disorder (17). In a previous report on this same random general population only 56% of all migraineurs had consulted their general practitioner at some time because of migraine and 16% had consulted a specialist (18). Thus, the selection bias in clinical studies may be considerable. In the present paper we compare demographic and nosographic characteristics of MA and MO in
an unselected population with the purpose of describing similarities and differences between the disorders. By necessity, the random selection and time-consuming diagnostic procedure has limited the number of migrainous subjects. Thus, the quality of the data is high, but the power in some of the calculations is low, and some of the results are primarily hypothesis generating. Material and methods
A random sample of 1,000 25-64-year-old men and women was drawn from the Danish National Central Person Registry, in which all Danish residents are recorded. The sampling area was representative of the total Danish population in regard to most sociodemographic variables (19). All members of the sample received a standardized written invitation to a general health survey with focus on headache disorders; 387 men and 353 women participated. Excluding those individuals who had died or left the survey area since the random sample was obtained, the participation rate was 76%. A detailed description of the general study design, representativeness of the population, and characteristics of the non-participants has been published previously (19, 20). Non-participants did not differ from participants. The headache disorders were classified according to a structured diagnostic headache interview and a neurological examination using the operational diagnostic criteria of the IHS (1). Comparing the features of the pain-phase in MA and MO is problematic due to diagnostic bias, since operational diagnostic criteria are given for MO and not for MA for which only criteria for the aura symptoms are specified. In order to reduce the influence of this bias, subjects with migrainous disorder not quite fulfilling the criteria (IHS diagnosis 1.7) are also included in the analyses. In the interview, all migraineurs were asked if they had ever consulted their general practitioner or a specialist because of migraine. A question concerning family occurrence was also included. From a self-ad-ministered questionnaire completed by all participants, we collected information on 14 diseases to study their possible relationship with migraine. The questions were phrased as for example, Do you have or have you ever had epilepsy?' Statistical methods. The chi-square tests for unpaired and paired (McNemar's test) data, the Mantel-Haenszel c2 test (M-H test) and the Mann-Whitney test (M-W test) were included. A logistic regression analysis was used to account for age confounding, and odds ratio (OR) was calculated by exp(log coeff). A 5% level of significance and 95% exact confidence intervals by binomial distribution were used. Results
Prevalence The lifetime and one-year prevalence of migraine with aura (MA) and migraine without aura (MO) and coexisting MA and MO and their relation to age and sex are given in Table 1. The lifetime prevalence of MA (excluding subjects with coexisting MO) was 5% (95% conf. lim. 4-7) with a male:female ratio of 1:2 and of MO (excluding subjects with coexisting MA) 8% (95% conf. lim. 6-10) with a male:female ratio of 1:7. Correspondingly, the one-year prevalence of MA was 3% (c.1. 2-5), M:F ratio 3:4 and of MO 5% (c.1. 4-7), M:F ratio 1:4. Only 1-2% had both MA and MO. No significant age differences in prevalence rates of MA and MO emerged. The lifetime prevalence of other Table 1. Lifetime and one-year prevalence of migraine with aura (MA), migraine without aura (MO) and coexisting MA and MO (MA + MO). Relation to age and sex. The diagnostic groups are mutually exclusive. N = denominator. Prevalence Lifetime
One-year *
Age 25-44 45-64
% 3 4
All ages
3
MA (n) % (6) 7 (7) 8 (13) 7*
25-44 45-64
2 4
(4) (7)
4 4
(8) (6)
2 0.6). Familial occurrence A family history of migraine among first-degree relatives (father, mother, brothers, sisters, children) was reported by 56% of all migraineurs (40% with MA and 64% with MO). In women with migraine 60% stated a family history and in men 47% stated so (p > 0.2). Relation to other diseases or disorders After adjusting for the effect of age in a logistic regression analysis, including age as a confounding continuous variable, no association was found between the following diseases and migraine (using the IHS classification at the 1-digit level) in either men or women: epilepsy, angina pectoris, coronary occlusion (AMI), cerebral hemorrhage/stroke, asthma, seasonal rhinitis, eczema, psoriasis, peptic ulcer, gall stone, kidney stone, back disorder, abdominal disorder. In women, migraine was positively associated with menstrual disorder (OR = 1.41 (1.10-1.81). When MA and MO were analysed separately MO was significantly related to menstrual disorder (OR = 1.48 (1.09-2.00)) while MA was not. Discussion
This study is the first epidemiologic study of migraine with and without aura in a representative general population using operational diagnostic criteria in which all subjects were interviewed and examined by a physician. Given this rigorous study design, the number of subjects surveyed is large, yet the number of migraineurs in each subgroup is relatively small for some comparisons, which prompts caution when interpreting the results and prevents some statistical evaluations. The lack of significant differences between MA and MO in some instances may therefore be a type two statistical error (lack of power). On the other hand, studies of large clinic populations may have more power, but they suffer from selection bias. A combined evaluation of studies of both types is at present most likely to give the true picture. Prevalence, sex distribution and symptomatology The prevalence rates of migraine without aura (MO) and migraine with aura (MA) have briefly been discussed elsewhere (21). The sex distribution of MO and MA was somewhat different, indicating that sex-related factors may be of greater importance in MO than in MA. Menstrual precipitation, menstrual problems, influence of pregnancy and use of oral contraceptives all showed some relationship with MO and less with MA. The earlier onset of MO could be a function of the menarche. Overall, the relationship between female horomones and MO was clearly stronger than with MA. Premonitory symptoms occur hours or several days before the onset of migraine and usually consist of mood variations, tiredness, craving for special foods and similar atypical symptoms. These symptoms have never been studied in an unselected group of subjects and control groups have not been used. Blau (22) reported in a study of 50 consecutive migraineurs that 34% had prodromes. Other studies have suggested even higher figures (23, 24), although this may be due to biased patient selection. In the present study of a representative general population, premonitory symptoms were relatively rare among migraineurs (12-16%) and no more frequent than in tension-type headache. The distribution of aura symptoms reported in the present study is entirely in agreement with previous studies of selected patient materials (25-28). Visual disturbances were the most common aura symptom and other aura symptoms (somatosensory symptoms, motor disturbances and speech difficulties) nearly always occurred with visual symptoms. Some of the aura symptoms were, however, non-specific (e.g. vertigo and decreased level of consciousness) and in some cases may be misinterpreted as they may be coincident with anxiety and hyperventilation. MA fulfilled the criteria of the pain-phase demanded for MO by the IHS, although MA had less severe and shorter-lasting headache. In agreement with the present study, several previous clinical studies found the pain-phase of MA and MO to be nearly identical (13, 15, 16). Our finding of a less severe and shorter-lasting pain-phase in MA was found in previous studies (14, 15). Selby and Lance (13), in their study of 500 cases of migraine and allied vascular headache, reported a uniform clinical picture in various diagnostic subgroups. When comparing clinical features of MA and MO in a questionnaire-based study of 1259 headache clinic patients using Vahlquist's criteria, Davies et al. found the two forms of migraine to be fundamentally similar in their clinical characteristics, apart from aura (15). In a study analyzing the clinical features of MA and MO, using the criteria of the Ad Hoc Committee on Classification of Headache, Manzoni et al. (14) found marked clinical differences between MA and MO, suggesting the disorders to be two distinct entities. In a study of 50 patients from the City of London Migraine Clinic (16) using the diagnostic
criteria of the International Headache Society, no major differences were found between MA and MO. In a previous epidemiological study of young adults (21-30 years) using modified IHS criteria both migraine pain characteristics and associated symptoms were more frequent in MA than in MO (29). Due to the modification of the IHS criteria in this study however, the validity of the migraine subtyping was uncertain, as is also correctly emphasized in the previous paper. Comparison of our nosographic data with clinical data is difficult due to variability in diagnostic criteria, but it is clear that the frequency of attacks of both MA and MO is much higher in clinical studies (15, 16, 25). In the present study, 50% of subjects with MA had consulted a general practitioner and 62% with MO had done so. The consultation rate of a specialist was 16% in MA and 19% in MO. Those who had seen a medical doctor had more frequent attacks. Clinical cases may, thus, be unrepresentative due to selection. This selection may also influence the proportions of individuals with coexisting MA and MO reported in clinical studies. Subjects with more than one disease may be more likely to consult a physician than subjects with only one disease (17, 30, 31). In the present study, six of nine subjects with coexisting MA and MO had consulted a physician because of headache. Spuriously high proportions of subjects with both MA and MO may be expected in headache-prone populations and indeed several previous clinical studies have reported that MA and MO usually occur in the same patients (15, 16, 28). We found that 19% of subjects who have ever had MA had also at some time had MO. Of subjects with MA in the previous year, 17% had in addition had MO in this year. In agreement, Manzoni found that 25.6% of a series of MA patients had also had attacks of MO (14). Selby and Lance (13) reported in a series of 290 migraine patients that 231 (80%) had pure migraine without major visual disturbances or focal cerebral disturbances. These studies support our finding that concurrence of MA and MO, adjusted for age and sex, is not, or at least only marginally, more common than expected by chance. Inaccuracy in the diagnosis of aura symptoms may be an important problem in both clinical and population-based studies. The aura symptoms may be extremely difficult to describe. Patients frequently have difficulties in remembering their symptoms and in translating their experience into words, even upon systematic questioning by a physician. The retrospective character of the present study may induce bias due to problems of recall of aura symptoms, but also with respect to recall of variables such as age at onset, relation to pregnancy, vague premonitory symptoms, family history and associated conditions. Summarizing our nosographic data and results from the literature it seems reasonable that the painphases of migraine with aura and migraine without aura are clinically almost identical, indicating shared pathophysiology. Recent pathophysiological studies and drug trials also support this conclusion (9, 12). The two forms differ, however, in the initial phases of the attacks, i.e. in the presence of aura symptoms and associated cerebral blood flow findings. Different sensitivity to female hormones and lack of significant concurrence also suggest differing initiating mechanisms. Further clarification of the relationship between MA and MO may be obtained by longitudinal follow-up studies of large samples and by further pathophysiological studies. Familial occurrence and associated conditions A positive family history in 56% of migraineurs in our study is similar to previous reports (32-35). A family history of migraine is found in approximately 18% of controls (34, 36). These figures may, however, be somewhat distorted by family information bias (31) and in clinical series also by referral bias. In clinical studies a number of diseases have been reported previously in association with migraine: transient ischaemic attacks (37), stroke (14, 38), hypertension (39, 40), angina (14, 41), Raynaud's phenomenon (41), bilious attacks (13, 42), systemic lupus erythematosus (43), a number of allergic disorders (13, 44, 45), and epilepsy (13, 36, 46). Several of these studies may have been influenced by Berkson's bias, since an over-representation of subjects with more than one disease is likely in a hospital or clinic setting. In the present study only menstrual disorder was associated with migraine. The lack of association with other diseases may, however, be due to low statistical power. Previously we have reported equal prevalence of arterial hypertension in migraineurs and non-migraineurs (47). Acknowledgements.-We thank Dr Rigmor Jensen for her valuable assistance in collecting data and, along with Professor Marianne Schroll, Dr Torben Jørgensen and statistician Mette Madsen, for fruitful discussions and comments on the manuscript. This study was supported by grants from the Danish Health Insurance Foundation (H11/238-88, H 11/262-89, H 11/276-90). References
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