Is the genetic liability in multifactorial disorders higher in concordant than discordant monozygotic twin pairs? A population-based family twin study of migraine without aura.

Migraine without aura (MO) is a multifactorial disorder. Expression of a disorder with multifactorial inheritance depends on the genetic liability and on environmental factors. A high liability is reflected by a high frequency of affected relatives. We have previously shown that monozygotic (MZ) twin pairs have a significant higher concordance of MO than dizygotic twin pairs. The incomplete concordance among MZ twin pairs may be due to a lower genetic liability among discordant than concordant MZ twin pairs. The present study analysed the genetic liability in MZ twin pairs concordant and discordant for MO by the population-relative risk of MO among parents and siblings. The twin pairs were from the population-based Danish Twin Register. First-degree relatives of 29 concordant and 34 discordant MZ twin pairs were blindly telephone interviewed by a physician. The participation rate of the eligible first-degree relatives was 96%. The population-relative risk of MO among parents and siblings was 2.73 (2.39-3.06) in concordant and 2.37 (2.03-2.71) in discordant MZ twin pairs. The relative risk of MO was significantly higher in female first-degree relatives of concordant than of discordant MZ male and female twin pairs. An opposite effect was observed in male first-degree relatives, although this was not significant for male first-degree relatives of female MZ twin pairs. The present study found no statistically significant difference in genetic liability to MO among concordant and discordant MZ twin pairs. However, a difference in genetic liability among MZ and DZ twin pairs is anticipated to be small. Thus, it may be possible to show the effect in a larger study population or by investigating a more frequent trait than MO.

[The significance of genetic and environmental factors for migraine with aura. A genetic epidemiologic study of Danish twins]. / Betydningen af arv og miljø for migraene med aura. En genetisk epidemiologisk undersøgelse af danske tvillingpar.

We studied the genetic and environmental influence on migraine with aura (MA) by analysing a twin population. The twin sample consisted of 2,026 monozygotic (MZ) pairs and 3,334 same-gender dizygotic (DZ) pairs recruited from the population-based Danish Twin Register. A total of 211 pairs were identified, of whom 77 were MZ and 134 were DZ. The pairwise concordance rate was significantly higher in MZ-than in DZ-pairs, i.e. 34% and 12%, respectively, emphasizing the importance of genetic factors in MA. However, environmental factors are also important, as the pair wise concordance rate was less than 100% in MZ-pairs. Similarly, the recurrence risk of MA was 50% in MZ- and 21% in DZ-pairs which was a significant difference. In non-twin siblings, the recurrence risk of MA is 27%, which is similar to the recurrence risk in DZ-pairs. This indicates that MA is not developed due to specific environmental factors shared by the twins.

Possible risk factors and precipitants for migraine with aura in discordant twin-pairs: a population-based study.

The aim of the present study was to detect possible risk factors in migraine with aura (MA) by analysis of discordant twin-pairs. In a recent population-based twin study we established that environmental factors account for approximately 50% of the variation in liability to MA. A cohort of 5,360 same-gender twin-pairs from the general population was screened for migraine. All twin-pairs with possible migraine were interviewed by a physician. A questionnaire provided information about living conditions and lifestyle. Of the 169 discordant twin-pairs 51 were monozygotic and 118 were dizygotic twin-pairs. Several putative risk factors-schooling, education, marital status, smoking status and alcohol consumption-showed no association with MA. The presence of migraine without aura or tension-type headache did not increase the risk of MA. Stress and mental tension, and bright light precipitated attacks of MA in, respectively, 44% and 28% of the twins.

Migraine without aura: a population-based twin study.

To investigate the importance of genetic and environmental factors to the etiology of migraine without aura and to compare the symptomatology of migraine without aura in monozygotic and dizygotic twins, 2,680 twin pairs were recruited from the population-based Danish Twin Registry. Monozygotic (MZ) and same-sex dizygotic (DZ) twin pairs, where at least one twin had self-reported migraine or self-reported severe headache with accompanying symptoms, were telephone interviewed by a physician. The participation rate in the telephone interview was 90%. The pairwise concordance rate was significantly higher in MZ than in DZ twin pairs (28% vs 18%). The probandwise concordance rate was 40% (95% CI, 33-48%) in MZ and 28% (95% CI, 23-33%) in DZ twin pairs. The pairwise concordance rates for the different pain characteristics and accompanying symptoms were not significantly different in MZ and DZ twin pairs. However, comparing all of the pairwise concordance rates of pain characteristics and accompanying symptoms together, MZ twin pairs were significantly more concordant than DZ twin pairs. Our data demonstrate a significant genetic factor in migraine without aura. The size of this factor is modest and the demonstration of susceptibility genes is predicted to be laborious and difficult.

The relative role of genetic and environmental factors in migraine without aura.

OBJECTIVE: To clarify the relative role of genetic and environmental factors in the etiology of migraine without aura (MO). METHODS: The study population consisted of 5,360 twins, 1,013 monozygotic (MZ) and 1,667 same-gender dizygotic (DZ) twin pairs, from the population-based Danish Twin Registry. A total of 87% completed a simple validated questionnaire screening for migraine. All twin pairs, in whom at least one twin had self-reported migraine or severe headache with accompanying symptoms, were interviewed via telephone by a physician. Ninety percent of the eligible twins were interviewed. Probandwise concordance rates and correlations in liability were calculated, and structural equation model-fitting analyses were applied to quantitate the relative role of genetic and environmental factors in the etiology of MO. RESULTS: The probandwise concordance rate was higher in MZ than DZ twin pairs (0.43 versus 0.31; 95% CI, 0.36 to 0.49 versus 0.26 to 0.36). The correlation in liability was higher in MZ than in DZ twin pairs (0.62 versus 0.41; 95% CI, 0.50 to 0.74 versus 0.29 to 0.53). Structural equation model fitting indicated a highly significant genetic component, because a model with both genetic and environmental components fitted significantly better than a model with only environmental components. The best fitting model implied that the liability to MO resulted from additive genetic effects (61%; 95% CI, 49 to 71%)) and individual-specific environmental effects (39%; 95% CI, 29 to 51%). CONCLUSION: This study indicates that genetic factors play a role in the etiology of migraine without aura. The genetic variability is additive, with a negligible contribution of nonadditive genetic effects. The genetic contributions were similar in men and women despite a higher prevalence in women. Environmental factors are equally important and these factors are individual to the migraineurs.

The inheritance of migraine with aura estimated by means of structural equation modelling.

Studies of migraine with aura (MA) have shown familial aggregation of the disorder, which cannot be explained by simple mendelian inheritance. The interest in a genetic basis for the disorder has increased after identification of three genetic loci for familial hemiplegic migraine (FHM), which is a rare subtype of MA with autosomal dominant inheritance. Both genetic and environmental factors seem to be important in the expression of MA. To elucidate the molecular pathogenesis of MA, knowledge of the relative role of genetic and environmental factors is essential. Twin studies are a classic way to analyse this. We applied structural equation modelling on MA with twin data obtained from a population based twin register in order to evaluate the effects of genes and environment. The correlation in liability of MA was 0.68 in monozygotic (MZ) and 0.22 in dizygotic (DZ) twin pairs, indicating a high degree of genetic determination in the total variance of liability. The best fitting model combined additive genetic effects and environmental effects that were not shared by the twins. The estimate of heritability was 0.65 and similar in males and females.

Evidence of a genetic factor in migraine with aura: a population-based Danish twin study.

We studied the genetic influence on cause of migraine with aura (MA) by analyzing a twin population. The twin sample consisted of 2,026 monozygotic (MZ) twins and 3,334 same-sex dizygotic (DZ) twins, born from 1953 to 1960, from the population-based New Danish Twin Register. A validated questionnaire was used to screen for migraine, the response rate being 87%, and similar among MZ and DZ twins. All twin pairs with at least 1 twin with possible MA were interviewed by a physician experienced in headache diagnoses. The answers from the questionnaire as well as the zygosity of the twins were blinded for the interviewer. A total of 211 twin pairs were identified, of whom 77 pairs were MZ and 134 pairs were DZ. The lifetime prevalence of MA was 7% and with a male-to-female ratio of 1:1.1. The pairwise concordance rates were significantly higher in MZ (34%) than in DZ twin pairs (12%), emphasizing the importance of genetic factors in MA. However, environmental factors are also important, as the pairwise concordance rate was less than 100% in MZ twin pairs. The recurrence risk of MA was 50% in MZ and 21% in DZ twin pairs. In nontwin siblings, the recurrence risk of MA is 27%, which is similar to the recurrence risk in DZ twins. This indicates that MA is not developed due to specific environmental factors shared by the twins.

The prevalence and characteristics of migraine in twins from the general population.

We examined whether prevalence, age at onset, and cessation of migraine without aura and migraine with aura are different among twins and singletons. The study population was recruited from the population-based New Danish Twin Register and comprised 2026 monozygotic and 3334 same-sex dizygotic twins born during 1953 to 1960. A simple questionnaire was used to screen for migraine. Twin pairs with at least one twin with possible migraine were interviewed by telephone by two physicians. A total of 1136 twin pairs were included in the telephone interviews. The criteria of the International Headache Society were used for diagnosis. The questionnaire response rate was 87%, and the telephone interview participation rate was 90%. Of the 715 migraineurs, 498 had migraine without aura, 264 had migraine with aura, and 47 had both migraine with and without aura. The lifetime prevalence, age at onset, and cessation of migraine with and without aura did not differ in monozygotic and dizygotic twins. Males and females had a lifetime prevalence of migraine without aura of 7% and 19%, respectively. The female preponderance of migraine without aura was first apparent after aged 14 years; this may be related to an influence of female hormones. The lifetime prevalence of migraine with aura was 7% in males and 8% in females. The observed and expected number of those with both migraine with and without aura was not significantly different, suggesting that migraine without aura and migraine with aura are distinct types of migraine. Males with migraine without aura had a significantly lower mean age at onset than females with migraine without aura (16.5 years versus 21.5 years), while males and females with migraine with aura had similar ages at onset (20.8 years versus 21.8 years). About 20% of the twins had ceased having attacks of migraine with or without aura. More males than females with onset of migraine without aura before aged 15 years had ceased having attacks. The prevalence of migraine without aura and migraine with aura in twins was similar to the prevalence in the general population. Being a twin did not affect age at onset or cessation of migraine. Previous observations on differences of migraine without aura and migraine with aura regarding gender was confirmed.

[Clinical value of SPECT scanning in children with neurological disorders]. / Den kliniske vaerdi af SPECT-scanning hos børn med neurologiske sygdomme.

We retrospectively evaluated the clinical value of Tc-99-HMPAO brain single photon emission tomography (SPECT) in 21 children with neurological disorders of varied aetiology. All 21 patients were examined with electroencephalograms (EEGs), 17 with computed tomography (CT) and ten with magnetic resonance imaging (MR). New relevant information was obtained from SPECT in all 21 cases and in four of these cases the investigation directly led to a change in diagnosis and better assessment of the prognosis. It is concluded that SPECT is an important investigational method in children with neurological symptoms of partly or completely unknown aetiology.

Screening for migraine in the general population: validation of a simple questionnaire.

We present validation of a simple questionnaire designed to screen the general population for migraine. It comprises four questions: (1) "Have you ever had migraine?" (2) "Have you ever had severe headache accompanied by nausea?" (3) "Have you ever had severe headache accompanied by hypersensitivity to sound and light?" (4) "Have you ever had visual disturbances lasting 5-60 min followed by headache?" A telephone interview carried out by a physician was used as an index of validity. The study population was 5,360 twins from the population-based Danish Twin Registry. All twin pairs where at least one twin had answered "yes" to at least one of our questions were eligible for the telephone interview (n=2,272 twins). The response rate to the questionnaire was 87%; the participation rate in the telephone interview was 90%. The questionnaire ascertained 85% of all migraineurs (sensitivity). A combination of two questions (questions 1 and 4) extracted 93% of the twins with migraine with aura and 74% of the twins with migraine without aura, yet only 26% of the sample needed to be interviewed. We conclude that in the Danish population two simple questions are sufficient to screen for migraine in selecting participants for a diagnostic clinical interview. Our questionnaire clearly merits further study to document its universal applicability.

[Headache in children]. / Hovedpine hos børn.

In this article the last 30 years of research concerning headaches in children, especially migraine headaches, is reviewed. The article is directed towards epidemiology, identification, classification, pathophysiology and management. Headache is a common medical complaint in children and adolescents, but diagnosis can be difficult, particularly in the very young. Many know far too little about how to recognise a child with headache and how to deal with it.

Influence of compensated radioiodine therapy on thyroid volume and incidence of hypothyroidism in Graves' disease.

OBJECTIVES: To investigate the long-term effect of radioactive iodine (131I) on thyroid function and size in patients with Graves' disease. SETTING: Out-patient clinic in Herlev Hospital. SUBJECTS: One hundred and seventeen consecutive patients (104 women) with Graves' disease selected for 131I treatment and followed for a minimum of 12 months (range 1-10 years, median 5 years). INTERVENTIONS: 131I dose was calculated based on thyroid volume and 24-h 131I uptake. MAIN OUTCOME MEASURES: Standard thyroid function variables and ultrasonically determined thyroid volume before treatment as well as 0.75, 1.5, 3, 6 and 12 months after treatment, and then once a year were investigated. RESULTS: Seventy-eight patients were cured by one 131I dose and 30 by two doses, while the remaining nine patients received additional doses (range one to five doses, median one dose). Within one year, 25% developed hypothyroidism, and hereafter, hypothyroidism developed at a constant rate of 3% per year independent of antithyroid pretreatment. The cumulative 10-year risk of hypothyroidism was 60%. Initial median thyroid volume was 33 mL (range 9-106 mL). At 12 months after the last 131I dose, median thyroid volume was reduced to 14 mL (range 6-36 mL) (P < 0.00001). The median reduction being 58% (range 0-80%), hereafter no further reduction occurred. A significant reduction in thyroid volume was also noted in patients needing subsequent 131I doses and in those developing hypothyroidism within the first year. CONCLUSIONS: 131I normalizes thyroid volume in patients with Graves' disease. Hypothyroidism seems an inevitable end result of this treatment. The present study suggests that it will be impossible to modify 131I therapy in a way to achieve both early control of hyperthyroidism and a low incidence of hypothyroidism.

[Long-term effect of 131I therapy of multinodular non-toxic goiter]. / Langtidseffekten af 131I-behandling ved multinodøs atoksisk struma.

The aim of this study was to investigate the long term effect of 131I treatment on thyroid function and size in patients with non-toxic multinodular goitre. The subjects were 69 consecutive patients with multinodular non-toxic goitre selected for 131I treatment and followed for a minimum of 12 months. Outcome measures were standard thyroid function variables and ultrasonically determined thyroid volume before and after treatment. Fifty-nine patients were treated with a single dose of 131I, 12 with two doses, and one with four doses. In 45 patients treated with one dose who remained euthyroid the median thyroid volume was reduced from 73 (interquartile range 50-106) ml to 29 (interquartile range 23-48) ml at 24 months. The median reduction was 40 (22-48) ml, half of which occurred within three months. Patients treated with two doses as well as those developing hypo- or hyper-thyroidism also had a significant reduction in thyroid volume. Eleven patients developed hypothyroidism (cumulative five year risk 22%). Side effects were few. In conclusion we find that 131I treatment of multinodular non-toxic goitre is an attractive alternative to surgery.

High frequency of thyroid dysfunction in patients with vitiligo.

An association between vitiligo and autoimmune thyroid disease has previously been suspected. This study was undertaken to determine the frequency and type of thyroid disease in 35 consecutive patients admitted because of vitiligo compared with a matched control group. One or more signs of thyroid disease was demonstrated in 15 out of 35 patients (43%) with vitiligo, as compared to 7 out of 35 (20%) in the matched control group (p = 0.04). Thyroid dysfunction - 6 patients with hyperthyroidism and 2 with hypothyroidism - was found in 8 out of 35 patients, as compared to no patient in the control group (p = 0.003). Nine patients had thyroid autoantibodies, compared to 2 controls, and 6 had an enlarged thyroid gland, compared to 5 subjects in the control group. There appears to be an increased frequency of clinical as well as subclinical thyroid disease in patients with vitiligo. Our findings support the theory of vitiligo being an autoimmune disease and indicate a need for screening vitiligo patients for thyroid disease.

Radioiodine treatment of multinodular non-toxic goitre.

OBJECTIVE: To investigate the long term effect of radioactive iodine on thyroid function and size in patients with non-toxic multinodular goitre. DESIGN: Consecutive patients with multinodular non-toxic goitre selected for radioactive iodine treatment and followed for a minimum of 12 months (median 48 months) after an intended dose of 3.7 MBq/g thyroid tissue corrected to a 100% uptake of iodine-131 in 24 hours. PATIENTS: 69 patients with a growing multinodular non-toxic goitre causing local compression symptoms or cosmetic inconveniences. The treatment was chosen because of a high operative risk, previous thyroidectomy, or refusal to be operated on. MAIN OUTCOME MEASUREMENTS: Standard thyroid function variables and ultrasonically determined thyroid volume before treatment as well as 1, 2, 3, 6, and 12 months after treatment and then once a year. RESULTS: 56 patients were treated with a single dose of 131I, 12 with two doses, and one with four doses. In 45 patients treated with one dose and remaining euthyroid the median thyroid volume was reduced from 73 (interquartile range 50-106) ml to 29 (23-48) ml at 24 months in the 39 patients in whom this was measured during follow up. The median reduction was 40 (22-48) ml (60% reduction, p < 0.0001), half of which occurred within three months. Patients treated with two doses as well as those developing hypothyroidism and hyperthyroidism had a significant reduction in thyroid volume. Eleven patients developed hypothyroidism (cumulative five year risk 22%, 95% confidence interval 4.8% to 38.4%). Side effects were few: three cases of hyperthyroidism and two cases of radiation thyroiditis. Only one patient was dissatisfied with the result; she was referred for operation six months after treatment. CONCLUSIONS: A substantial reduction in thyroid volume accompanied by a low incidence of hypothyroidism and few side effects makes the use of radioactive iodine an attractive alternative to surgery in selected cases of non-toxic multinodular goitre.