HEADACHE IN A NON-CLINIC TWIN POPULATION Dewey K. Ziegler, M.D.* Ruth Stephenson Hassanein, M.S.P.H.* David Harris, M.D.+ and Roberta Stewart, R.N.* *From
the Department of Neurology and the Department of Biometry, University of Kansas Medical School, Kansas City, Kansas 66103 +Pediatric
Geneticist, Childrens Mercy Hospital, Kansas City, Missouri
Supported in part by Grant No 5 T01 NS5023, National Institute of Neurological Diseases and Stroke, the Lettie B. McLlvain and the Elmer F. Pierson Funds. A LARGE BODY OF medical literature has reported the frequency of migraine in the immediate relatives of patients suffering from this disorder and there have been several studies documenting the occurrence of migraine in several generations of families.1,2,3 It is well known on the other hand that large numbers of patients with migraine do not have a positive family history. There has been a wide divergence of opinion as to the place of genetic predisposition in the migraine syndrome. Twin studies with comparison of concordance between monozygotic and dizygotic twins have been carried out on apparently only four occasions. It has been stated that the concordance of migraine in monozygotic twins is strongly supportive of the presence of some genetic factor. The present study was designed to explore the headache history in detail in a large group of twins derived from non-clinic population. The concordance both of overall headache severity and of specific details of the headache history were then compared for monozygotic and dizygotic pairs. MATERIAL AND METHOD Twins were sought as volunteers for the study by the means of advertisements in newspapers, announcement over radio by appeal to "twin clubs," and also by the use of the twin registry that is maintained by the National Research Council. Every effort was made to conceal the fact that the purpose of the study was to investigate headache. Volunteers were told that they were being asked to answer a questionnaire concerning health problems, would be asked to have a blood test, and submit to an electroencephalogram. A modest fee was offered for participation in the study. Only twin pairs were accepted in which both individuals could be personally interviewed and examined. The twins were then interviewed by a member of the team who filled out the standard detailed questionnaire on the basis of the answers to the questions. It was explained to the subjects that we were interested in dividing headaches into three categories, namely, disabling, which were defined as headaches that prevented any type of normal activity, severe--headaches that were extremely uncomfortable and caused some impairment in normal functioning--and mild. Subjects were then asked if they had been afflicted with any of these three varieties of headache. Because of the uncertainty of the defining features of migraine, the possibility of concordance in specific characteristics relative to headache was therefore studied. All subjects were asked concerning all kinds of headaches, age of onset, duration, course with advancing age, precipitating factors, symptoms before, during and after headache (including neurologic phenomena, nausea, unilaterality of headache, tenderness of the scalp), provocative factors and response to therapy. Numerical scores were coded for answers, usually on the basis of a particular phenomenon occurring never, occasionally, frequently or always. Blood was drawn for typing, All subjects also had an electroencephalogram and took the Minnesota Multiphasic Personality In-
ventory test; results of the latter two studies will not be reported here. METHODOLOGY Probablility of zygosity for same sex twin pairs was determined by blood grouping. Standard tube agglutination tests were done for the following systems: ABO, Rhesus, MS, P, Duffy, Kidd and Kell. Salivas were tested for secretor by hemagglutination inhibition with anti-H lectin according to the manufacturer's instructions (Hyland). The phenotypes at the serum protein markers haptoglobin, transferrin and group specific component were determined by acrylamide gel electrophoresis.4 Red cell isozyme systems for phosphoglucomutase 1, 6-phosphogluconate dehydrogenase and adenylate kinase were done by a modification of the method of Goedde and Benkmann.5 The relative probability of monozygosity, given identical typing for as many systems as was done for each pair, was calculated by the method of Maynard-Smith and Penrose.6 Gene frequencies for all systems except Rhesus were calculated from a sample composed of one randomly chosen member of each pair tested. We used the published table of probabilities for the Rhesus system. Height, weight, and physical appearance of the twins was also noted and the interviewer (R.S.) recorded her opinion as to whether the pair was monozygotic or dizygotic. In addition, the twins were given a series of questions concerning their similarity in appearance and their own impression as to whether or not they were identical. Answers to these questions have been claimed to be reliable indicators of zygosity.7 In the present study these latter clinical data were not used in the judgment as to zygosity except in the first few sets of twins. In these the complete set of blood types had not been performed; thus in some pairs probability percentages were not low enough to determine zygosity with great certainty. Where this problem occurred (i.e., the probability of dizygosity was greater than 5 %, in spite of identical serological results) appearance and interviewer impression were the decisive factors. RESULTS One hundred and six twin pairs were examined in whom it was concluded that 65 were dizygotic (61.3 %) and 41 monozygotic (38.7%). Of the monozygotic twin pairs 25 were male, 16 female and of the dizygotic twins, 39 pairs were male, 16 female, and 10 pairs were of different sex. The age range of individuals was from 18 to 55. (a) Headache frequency in the total sample Of the 138 male individuals in this population, one recorded disabling headaches (0.7%) and 14 recorded severe headaches (10.1%). (Table I) Of the 74 female individuals, 5 (6.8%) recorded disabling headaches, 11 (14.9%) severe headache. There was a statistically significant difference in the prevalence of disabling and/or severe headaches in the male versus the female population; they were reported in 15 (10.9%) of the 138 men as compared to 16 (21.6%) of the 74 women. Mild headaches were reported by 81 (58%) of the men and 55 (74%) of the women. (b) Concordance of twin pairs as to headache severity Of the 41 monozygotic twin pairs there were four in whom at least one member of the twin pair recorded disabling headaches. Of these four twin pairs, only one was concordant for disabling headaches--both individuals recording this type of headache. (Table II) In 8 of the 41 monozygotic twin pairs at least one individual complained of severe headache but in none of these was there concordance in the pair. Combining the numbers of those who reported disabling or severe headaches or both (disabling and/or severe headaches), there were 11 such individuals. These included two twin pairs (4 individuals) concordant for disabling and/or severe headache, and 7 discordant pairs. Dizygotic twin pairs were studied in two groups, those of the same sex and those of different sex. In the 55 twin pairs comprising the dizygotic twin group of the same sex, 12 individuals suffered from disabling and/or severe headaches, among whom
TABLE l
Males No. of Individuals % 1 0.7 14 10.0 8l 58
Disabling Severe Mild *
Headache Prevalence in a Non-Clinic Twin Population of 212 Individuals Females No. of Total Individuals % No. % 5 6.8 6 2.8 11 14.9 25 11.8 55 74 136 64.2
It should be noted that many individuals had no headache, others more than one degree of severity.
TABLE II Headache in Twins (No. Pairs With Occurrence) No. pairs with at least one affected indiv.
No. pairs with both affected
Disabling
4
1
Severe
8
0
11
2
Disabling
1
0
Severe
11
2
12
2
Disabling
0
0
Severe
4
0
4
0
Monozygotic
-
41 pairs
(Dis. and/or Sev. )
Dizygotic
-
55 pairs
same sex
(Dis. and/or Sev.)
Dizygotic
-
10 pairs
diff. sex
(Dis. and/or Sev.)
there were 2 concordant twin pairs and 8 discordant pairs. In the dizygotic group of 10 twin pairs of different sex, 4 individuals suffered from disabling and/or severe headaches; there were no concordant twin pairs. (Table II) (c)
Concordance as to specific symptoms
On the possiblility that certain clinical features of headache (e.g. method of provocation, premonitory symptoms, occurrence of certain neurological phenomena) might show more concordance than the overall occurrence of disabling and/or severe headaches, the responses to each question were studied with respect to twin concordance, in those reporting disabling and/or severe, and those reporting only mild headache. In no clinical feature was there a significant difference in concordance between monozygotic and dizygotic pairs. DISCUSSION A.
Comparison with Previous Twin Studies
The reason for the familial aggregation of
headache sufferers continues to be debated. There have been supporters of theories of autosomal dominant, autosomal recessive, and polygenic inheritance. All types of variation in gene penetrance have been invoked to explain the reported pedigrees. The two accepted methods of ascertaining the possible genetic basis for a biological characteristic have been the study of twins, and the complete study of all family members. Most previous studies of headache in twins have dealt with populations in which one twin member was a member of a clinic population or have reported a very small number of pairs selected for some special reason (e.g. epilepsy). Thus Juel-Nielsen reported concordance as to migraine in three of five pairs of monozygotic twins who were studied because they had been raised separately.8 Lennox reported five sets of twins, all allegedly concordant for migraine; three of these twin pairs, however, also had seizures.9 Ebbing reported 13 twin pairs of whom three were monozygotic--none concordant for "migraine", but all three having "a minor degree of concordance"--meaning non-migrainous headache. Four of 10 dizygotic pairs had similar kinds of concordance. 10 The most extensive, and unselected, non-clinic twin study in the field was the brief report of Harvald and Hauge who in a questionnaire survey of 1,900 unselected twins in Denmark recorded "migraine" in 84 individuals or 2.2% of this population, an unusually low figure.11 No details however are given as to the criteria for the diagnosis of migraine. Of this group of 84 individuals, 24 were members of monozygotic twin pairs including 6 concordant pairs of monozygotic twins and 12 individuals who were members of discordant pairs a concordance ratio of 33%. Of 57 dizygotic twin pairs, three were found to be concordant and 54 discordant. It is clear that comparison of these various twin studies is obscured by (a) lack of precision in the definition of migraine and (b) uncertainty in many series as to accuracy of the zygosity judgment. Experts have disagreed over the years as to whether the definition of migraine should include hemicrania, nausea, visual symptoms, relief by ergotamine and/or family history.12,13,14 All agree, however, on the history base of severe recurrent headache. For this reason, we based our twin data on this criterion alone. As to accuracy of zygosity determination, only the Harvald and Hauge study confirmed zygosity by study of blood typing, and discrepancies between clinical judgment and serological evidence as to zygosity do occur. Where studies are based on a small number of twin pairs, a few errors in correct identification could be critical. Considering the cases with severe and/or disabling headache as roughly equivalent to migraine, our prevalence figure in this small population (13%) is somewhat large compared to most others reported,9,15,16 where the usual figure varies from 2-10%. It is possible that some bias was introduced into the study by self-selection of interested persons, although we attempted to minimize this occurrence by offering fees and stating the study purpose in a non-specific manner. Our actual prevalence figure is lower than the recent one reported by Waters, who performed a careful community survey of a large population.17 We do feel that the recording of data by an experienced interviewer probably increased the figure for headache prevalence by lessening the chance of false negative data being reported on a questionnaire. It is very doubtful, however that any bias leading to slightly increased numbers of headache sufferers volunteering for the study would affect the question at issue--concordance in monozygotic versus dizygotic twins. It is of interest that we found as have others, that severe headache is reported in women approximately twice as often as in men. Dalsgaard-Neilsen15 has postulated that the reason for this finding is that the disturbances of fluid balance occurring with the menstrual cycle and pregnancy are potent precipitating factors in "predisposed" individuals. Other reasons are conceivable--the possible difference in "stress" in women, if they are viewed as a minority group, and the possible difference in the acceptance of the complaint of headache in women as opposed to men.
B.
Relevance to the Problem of the Genetic Component in Migraine
The present study does not support the thesis that concordance in a history of severe headache is greater among monozygotic than among dizygotic twins. How can this finding be reconciled with the massive amount of data on the "family history" of headache? Many studies in the literature on family history of migraine have not reported systematic search for all available data on family members of both the patient (headache) population and a control (non-headache) population. With a phenomenon as common as severe headache (occurring in anywhere from 5-20% of the population) the absence of controls and of complete family data on both groups could well lead to the spurious appearance of a genetic pattern. The recent epidemiological study by Waters in which equally detailed family history was obtained for migraine patients and controls resulted in the finding that migraine in the immediate relative of the migraine patient was more common than that among the controls, but that the numbers did not reach statistical significance.18 The presence of familial aggregations and the dubious evidence as to twin concordance would seem to strengthen the possibility that a common environment or at least a common environment affecting certain individuals may be the reason for the familial aggregation in migraine. Certainly, this absence of increased concordance among monozygotic twins indicates that any search for a simple type of inheritance pattern of some single entity is doomed to failure. The common finding of striking pedigrees in large numbers of "migraine" sufferers, and the large body of medical literature discussing the genetics of migraine indicate that although migraine as an entity may not be inherited, some particular clinical characteristic related to headache might be. Of all the many clinical features of headache we studied, however, we did not find concordance in any that was significantly different in monozygotic versus dizygotic twins. It is, of course, still possible that among the large population of headache patients there are small groups with a genetically determined characteristic. Certainly the evidence for a genetic factor in hemiplegic migraine is impressive.19,20 Migraine might well be considered a heterogeneous condition14 with some still unidentified inherited predisposing factors that require interaction with environment to produce symptoms. There also may be a very small group of individuals who have a simply inherited syndrome (e.g. some hemiplegic migraine). BIBLIOGRAPHY 1. Goodell, H., Lewontin, R., and Wolff, H.G.: Familial occurrence of migraine headache. Arch. Neurol. Psychiat.72: 325-334, 1954. 2. Refsum S.: Genetic aspects of migraine. Chap 25 in Handbook of Clinical Neurology, Vol 5, P.J. Vinken and G.W. Bruyn (Eds.), North-Holland Publishing Co., Amsterdam, 1968. 3.
Barolin, G.S., and Sperlich, D.: Migrane-familien. Fortschr. Neurol. Psychiat. 37: 521-544, 1969.
4. Brown, K.S. and Johnson. R.S.: Population studies on southwestern Indian tribes. III. Serum protein variations of Zuni and Papago Indians. Hum. Hered. 20: 281-286, 1970. 5. Goedde, H.W. and Benkmann, H.G.: GPT, 6-PGD, PGM, and AK phenotyping in one starch gel. Humangenetik 15: 277-278, 1972. 6. Maynard-Smith, S. and Penrose, L.S.: Monozygotic and dizygotic twin diagnosis. Ann. Hum. Genet. 19: 273-289, 1955. 7.
Nichols, R.C. and Bilbro, W.C., Jr.: The diagnosis of twin zygosity. Acta genet., Basel 16:265-275, 1966.
8.
Juel Nielsen, N.: Individual and environment. Acta Psychiat. Scand. 40 (Suppl. 183): 1-292, 1964.
9. Lennox, W.G. and Lennox, M.A.: Epilepsy and Related Disorders, Vol 1. Boston, Little, Brown and Co., 1960. 10.
Ebbing, H.C.: Migrane bei Zwillingen, Vorlaufige Mitteilung. Acta Genet. Med. (Roma) 5:371 382, 1956.
11.
Harvald, B. and Hauge, M.: A catamnestic investigation of Danish twins. Danish Med. Bull. 3: 150-158, 1956.
12. Ostfeld, A.M.: The natural history of epidemiology of migraine and muscle contraction headache. Neurology 13: 1l-15, 1963. 13. Lance. J.W., and Anthony, M.: Some clinical aspects of migraine. A prospective survey of 500 patients. Arch. Neurol. 15:356-361. 1966. 14. Ziegler, D.K., Hassanein, R.S. and Hassanein, K.: Headache syndromes suggested by factor analysis of symptom variables in headache prone population. J. Chron. Dis. 25: 353-363, 1972. 15.
Dalsgaard-Nielsen, T.: Migraine and heredity.
Acta Neurol. Scandinav. 41: 287-300, 1965. 16.
Vahlquist, B.: Migraine in children. lnt Arch. Allergy 7: 348-355, 1955.
17.
Waters, W.E.: Community studies of the prevalence of headache. Headache 9: 178-186, 1970
18.
Waters, W.E.: Migraine: Intelligence, social class, and familial prevalence. Brit. Med. J. 2: 77-81, 1971.
19.
Bradshaw, P. et Parsons, M.: Hemiplegic migraine, a clinical study. Quat. J. Med. 34: 65-85, 1965.
20.
Whitty, C.W.M.: Familial hemiplegic migraine. J. Neurol. Neurosurg. Psychiat. 16: 172-177, 1953. ACKNOWLEDGMENTS
We acknowledge the help of the National Academy of Sciences-National Research Council (NAS-NRS) Twin Registry. This registry, a part of the activities of the NAS-NRC Medical Follow-up Agency, was supported by Public Health Service Grant MH-18820 from the National Institute of Mental Health and HL-13668 from the National Heart and Lung Institute. Grateful acknowledgment is also made to the Kansas City Blood Center, to Mr. William Whyte for technical assistance, and to Ms. Deborah Alstrup for computer programming. Address Reprint Request To: Dewey K. Ziegler, MD Dept. of Neurology Kansas University Medical Center 39th and Rainbow Blvd. Kansas City, Kansas 66103
the Department of Neurology and the Department of Biometry, University of Kansas Medical School, Kansas City, Kansas 66103 +Pediatric
Geneticist, Childrens Mercy Hospital, Kansas City, Missouri
Supported in part by Grant No 5 T01 NS5023, National Institute of Neurological Diseases and Stroke, the Lettie B. McLlvain and the Elmer F. Pierson Funds. A LARGE BODY OF medical literature has reported the frequency of migraine in the immediate relatives of patients suffering from this disorder and there have been several studies documenting the occurrence of migraine in several generations of families.1,2,3 It is well known on the other hand that large numbers of patients with migraine do not have a positive family history. There has been a wide divergence of opinion as to the place of genetic predisposition in the migraine syndrome. Twin studies with comparison of concordance between monozygotic and dizygotic twins have been carried out on apparently only four occasions. It has been stated that the concordance of migraine in monozygotic twins is strongly supportive of the presence of some genetic factor. The present study was designed to explore the headache history in detail in a large group of twins derived from non-clinic population. The concordance both of overall headache severity and of specific details of the headache history were then compared for monozygotic and dizygotic pairs. MATERIAL AND METHOD Twins were sought as volunteers for the study by the means of advertisements in newspapers, announcement over radio by appeal to "twin clubs," and also by the use of the twin registry that is maintained by the National Research Council. Every effort was made to conceal the fact that the purpose of the study was to investigate headache. Volunteers were told that they were being asked to answer a questionnaire concerning health problems, would be asked to have a blood test, and submit to an electroencephalogram. A modest fee was offered for participation in the study. Only twin pairs were accepted in which both individuals could be personally interviewed and examined. The twins were then interviewed by a member of the team who filled out the standard detailed questionnaire on the basis of the answers to the questions. It was explained to the subjects that we were interested in dividing headaches into three categories, namely, disabling, which were defined as headaches that prevented any type of normal activity, severe--headaches that were extremely uncomfortable and caused some impairment in normal functioning--and mild. Subjects were then asked if they had been afflicted with any of these three varieties of headache. Because of the uncertainty of the defining features of migraine, the possibility of concordance in specific characteristics relative to headache was therefore studied. All subjects were asked concerning all kinds of headaches, age of onset, duration, course with advancing age, precipitating factors, symptoms before, during and after headache (including neurologic phenomena, nausea, unilaterality of headache, tenderness of the scalp), provocative factors and response to therapy. Numerical scores were coded for answers, usually on the basis of a particular phenomenon occurring never, occasionally, frequently or always. Blood was drawn for typing, All subjects also had an electroencephalogram and took the Minnesota Multiphasic Personality In-
ventory test; results of the latter two studies will not be reported here. METHODOLOGY Probablility of zygosity for same sex twin pairs was determined by blood grouping. Standard tube agglutination tests were done for the following systems: ABO, Rhesus, MS, P, Duffy, Kidd and Kell. Salivas were tested for secretor by hemagglutination inhibition with anti-H lectin according to the manufacturer's instructions (Hyland). The phenotypes at the serum protein markers haptoglobin, transferrin and group specific component were determined by acrylamide gel electrophoresis.4 Red cell isozyme systems for phosphoglucomutase 1, 6-phosphogluconate dehydrogenase and adenylate kinase were done by a modification of the method of Goedde and Benkmann.5 The relative probability of monozygosity, given identical typing for as many systems as was done for each pair, was calculated by the method of Maynard-Smith and Penrose.6 Gene frequencies for all systems except Rhesus were calculated from a sample composed of one randomly chosen member of each pair tested. We used the published table of probabilities for the Rhesus system. Height, weight, and physical appearance of the twins was also noted and the interviewer (R.S.) recorded her opinion as to whether the pair was monozygotic or dizygotic. In addition, the twins were given a series of questions concerning their similarity in appearance and their own impression as to whether or not they were identical. Answers to these questions have been claimed to be reliable indicators of zygosity.7 In the present study these latter clinical data were not used in the judgment as to zygosity except in the first few sets of twins. In these the complete set of blood types had not been performed; thus in some pairs probability percentages were not low enough to determine zygosity with great certainty. Where this problem occurred (i.e., the probability of dizygosity was greater than 5 %, in spite of identical serological results) appearance and interviewer impression were the decisive factors. RESULTS One hundred and six twin pairs were examined in whom it was concluded that 65 were dizygotic (61.3 %) and 41 monozygotic (38.7%). Of the monozygotic twin pairs 25 were male, 16 female and of the dizygotic twins, 39 pairs were male, 16 female, and 10 pairs were of different sex. The age range of individuals was from 18 to 55. (a) Headache frequency in the total sample Of the 138 male individuals in this population, one recorded disabling headaches (0.7%) and 14 recorded severe headaches (10.1%). (Table I) Of the 74 female individuals, 5 (6.8%) recorded disabling headaches, 11 (14.9%) severe headache. There was a statistically significant difference in the prevalence of disabling and/or severe headaches in the male versus the female population; they were reported in 15 (10.9%) of the 138 men as compared to 16 (21.6%) of the 74 women. Mild headaches were reported by 81 (58%) of the men and 55 (74%) of the women. (b) Concordance of twin pairs as to headache severity Of the 41 monozygotic twin pairs there were four in whom at least one member of the twin pair recorded disabling headaches. Of these four twin pairs, only one was concordant for disabling headaches--both individuals recording this type of headache. (Table II) In 8 of the 41 monozygotic twin pairs at least one individual complained of severe headache but in none of these was there concordance in the pair. Combining the numbers of those who reported disabling or severe headaches or both (disabling and/or severe headaches), there were 11 such individuals. These included two twin pairs (4 individuals) concordant for disabling and/or severe headache, and 7 discordant pairs. Dizygotic twin pairs were studied in two groups, those of the same sex and those of different sex. In the 55 twin pairs comprising the dizygotic twin group of the same sex, 12 individuals suffered from disabling and/or severe headaches, among whom
TABLE l
Males No. of Individuals % 1 0.7 14 10.0 8l 58
Disabling Severe Mild *
Headache Prevalence in a Non-Clinic Twin Population of 212 Individuals Females No. of Total Individuals % No. % 5 6.8 6 2.8 11 14.9 25 11.8 55 74 136 64.2
It should be noted that many individuals had no headache, others more than one degree of severity.
TABLE II Headache in Twins (No. Pairs With Occurrence) No. pairs with at least one affected indiv.
No. pairs with both affected
Disabling
4
1
Severe
8
0
11
2
Disabling
1
0
Severe
11
2
12
2
Disabling
0
0
Severe
4
0
4
0
Monozygotic
-
41 pairs
(Dis. and/or Sev. )
Dizygotic
-
55 pairs
same sex
(Dis. and/or Sev.)
Dizygotic
-
10 pairs
diff. sex
(Dis. and/or Sev.)
there were 2 concordant twin pairs and 8 discordant pairs. In the dizygotic group of 10 twin pairs of different sex, 4 individuals suffered from disabling and/or severe headaches; there were no concordant twin pairs. (Table II) (c)
Concordance as to specific symptoms
On the possiblility that certain clinical features of headache (e.g. method of provocation, premonitory symptoms, occurrence of certain neurological phenomena) might show more concordance than the overall occurrence of disabling and/or severe headaches, the responses to each question were studied with respect to twin concordance, in those reporting disabling and/or severe, and those reporting only mild headache. In no clinical feature was there a significant difference in concordance between monozygotic and dizygotic pairs. DISCUSSION A.
Comparison with Previous Twin Studies
The reason for the familial aggregation of
headache sufferers continues to be debated. There have been supporters of theories of autosomal dominant, autosomal recessive, and polygenic inheritance. All types of variation in gene penetrance have been invoked to explain the reported pedigrees. The two accepted methods of ascertaining the possible genetic basis for a biological characteristic have been the study of twins, and the complete study of all family members. Most previous studies of headache in twins have dealt with populations in which one twin member was a member of a clinic population or have reported a very small number of pairs selected for some special reason (e.g. epilepsy). Thus Juel-Nielsen reported concordance as to migraine in three of five pairs of monozygotic twins who were studied because they had been raised separately.8 Lennox reported five sets of twins, all allegedly concordant for migraine; three of these twin pairs, however, also had seizures.9 Ebbing reported 13 twin pairs of whom three were monozygotic--none concordant for "migraine", but all three having "a minor degree of concordance"--meaning non-migrainous headache. Four of 10 dizygotic pairs had similar kinds of concordance. 10 The most extensive, and unselected, non-clinic twin study in the field was the brief report of Harvald and Hauge who in a questionnaire survey of 1,900 unselected twins in Denmark recorded "migraine" in 84 individuals or 2.2% of this population, an unusually low figure.11 No details however are given as to the criteria for the diagnosis of migraine. Of this group of 84 individuals, 24 were members of monozygotic twin pairs including 6 concordant pairs of monozygotic twins and 12 individuals who were members of discordant pairs a concordance ratio of 33%. Of 57 dizygotic twin pairs, three were found to be concordant and 54 discordant. It is clear that comparison of these various twin studies is obscured by (a) lack of precision in the definition of migraine and (b) uncertainty in many series as to accuracy of the zygosity judgment. Experts have disagreed over the years as to whether the definition of migraine should include hemicrania, nausea, visual symptoms, relief by ergotamine and/or family history.12,13,14 All agree, however, on the history base of severe recurrent headache. For this reason, we based our twin data on this criterion alone. As to accuracy of zygosity determination, only the Harvald and Hauge study confirmed zygosity by study of blood typing, and discrepancies between clinical judgment and serological evidence as to zygosity do occur. Where studies are based on a small number of twin pairs, a few errors in correct identification could be critical. Considering the cases with severe and/or disabling headache as roughly equivalent to migraine, our prevalence figure in this small population (13%) is somewhat large compared to most others reported,9,15,16 where the usual figure varies from 2-10%. It is possible that some bias was introduced into the study by self-selection of interested persons, although we attempted to minimize this occurrence by offering fees and stating the study purpose in a non-specific manner. Our actual prevalence figure is lower than the recent one reported by Waters, who performed a careful community survey of a large population.17 We do feel that the recording of data by an experienced interviewer probably increased the figure for headache prevalence by lessening the chance of false negative data being reported on a questionnaire. It is very doubtful, however that any bias leading to slightly increased numbers of headache sufferers volunteering for the study would affect the question at issue--concordance in monozygotic versus dizygotic twins. It is of interest that we found as have others, that severe headache is reported in women approximately twice as often as in men. Dalsgaard-Neilsen15 has postulated that the reason for this finding is that the disturbances of fluid balance occurring with the menstrual cycle and pregnancy are potent precipitating factors in "predisposed" individuals. Other reasons are conceivable--the possible difference in "stress" in women, if they are viewed as a minority group, and the possible difference in the acceptance of the complaint of headache in women as opposed to men.
B.
Relevance to the Problem of the Genetic Component in Migraine
The present study does not support the thesis that concordance in a history of severe headache is greater among monozygotic than among dizygotic twins. How can this finding be reconciled with the massive amount of data on the "family history" of headache? Many studies in the literature on family history of migraine have not reported systematic search for all available data on family members of both the patient (headache) population and a control (non-headache) population. With a phenomenon as common as severe headache (occurring in anywhere from 5-20% of the population) the absence of controls and of complete family data on both groups could well lead to the spurious appearance of a genetic pattern. The recent epidemiological study by Waters in which equally detailed family history was obtained for migraine patients and controls resulted in the finding that migraine in the immediate relative of the migraine patient was more common than that among the controls, but that the numbers did not reach statistical significance.18 The presence of familial aggregations and the dubious evidence as to twin concordance would seem to strengthen the possibility that a common environment or at least a common environment affecting certain individuals may be the reason for the familial aggregation in migraine. Certainly, this absence of increased concordance among monozygotic twins indicates that any search for a simple type of inheritance pattern of some single entity is doomed to failure. The common finding of striking pedigrees in large numbers of "migraine" sufferers, and the large body of medical literature discussing the genetics of migraine indicate that although migraine as an entity may not be inherited, some particular clinical characteristic related to headache might be. Of all the many clinical features of headache we studied, however, we did not find concordance in any that was significantly different in monozygotic versus dizygotic twins. It is, of course, still possible that among the large population of headache patients there are small groups with a genetically determined characteristic. Certainly the evidence for a genetic factor in hemiplegic migraine is impressive.19,20 Migraine might well be considered a heterogeneous condition14 with some still unidentified inherited predisposing factors that require interaction with environment to produce symptoms. There also may be a very small group of individuals who have a simply inherited syndrome (e.g. some hemiplegic migraine). BIBLIOGRAPHY 1. Goodell, H., Lewontin, R., and Wolff, H.G.: Familial occurrence of migraine headache. Arch. Neurol. Psychiat.72: 325-334, 1954. 2. Refsum S.: Genetic aspects of migraine. Chap 25 in Handbook of Clinical Neurology, Vol 5, P.J. Vinken and G.W. Bruyn (Eds.), North-Holland Publishing Co., Amsterdam, 1968. 3.
Barolin, G.S., and Sperlich, D.: Migrane-familien. Fortschr. Neurol. Psychiat. 37: 521-544, 1969.
4. Brown, K.S. and Johnson. R.S.: Population studies on southwestern Indian tribes. III. Serum protein variations of Zuni and Papago Indians. Hum. Hered. 20: 281-286, 1970. 5. Goedde, H.W. and Benkmann, H.G.: GPT, 6-PGD, PGM, and AK phenotyping in one starch gel. Humangenetik 15: 277-278, 1972. 6. Maynard-Smith, S. and Penrose, L.S.: Monozygotic and dizygotic twin diagnosis. Ann. Hum. Genet. 19: 273-289, 1955. 7.
Nichols, R.C. and Bilbro, W.C., Jr.: The diagnosis of twin zygosity. Acta genet., Basel 16:265-275, 1966.
8.
Juel Nielsen, N.: Individual and environment. Acta Psychiat. Scand. 40 (Suppl. 183): 1-292, 1964.
9. Lennox, W.G. and Lennox, M.A.: Epilepsy and Related Disorders, Vol 1. Boston, Little, Brown and Co., 1960. 10.
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We acknowledge the help of the National Academy of Sciences-National Research Council (NAS-NRS) Twin Registry. This registry, a part of the activities of the NAS-NRC Medical Follow-up Agency, was supported by Public Health Service Grant MH-18820 from the National Institute of Mental Health and HL-13668 from the National Heart and Lung Institute. Grateful acknowledgment is also made to the Kansas City Blood Center, to Mr. William Whyte for technical assistance, and to Ms. Deborah Alstrup for computer programming. Address Reprint Request To: Dewey K. Ziegler, MD Dept. of Neurology Kansas University Medical Center 39th and Rainbow Blvd. Kansas City, Kansas 66103
