The Journal of Headache and Pain

The primary headaches, migraine with (MA) and without aura (MO) and cluster headache, all carry a substantial genetic liability. Familial hemiplegic migraine (FHM), an autosomal dominant mendelian disorder classified as a subtype of MA, is due to mutations in genes encoding neural channel subunits. MA/MO are considered multifactorial genetic disorders, and FHM has been proposed as a model for migraine aetiology. However, a review of the genetic studies suggests that the FHM genes are not involved in the typical migraines and that FHM should be considered as a syndromic migraine rather than a subtype of MA. Adopting the concept of syndromic migraine could be useful in understanding migraine pathogenesis. We hypothesise that epigenetic mechanisms play an important role in headache pathogenesis. A behavioural model is proposed, whereby the primary headaches are construed as behaviours, not symptoms, evolutionarily conserved for their adaptive value and engendered out of a genetic repertoire by a network of pattern generators present in the brain and signalling homeostatic imbalance. This behavioural model could be incorporated into migraine genetic research.

Sir, I read with great satisfaction and enthusiasm the review article by Professor Montagna, ‘‘The primary headaches: genetics, epigenetics and a behavioural genetic model [1].’’ He presents a detailed outline of genetic studies in primary headaches, mostly migraine, and at the same time discusses the limitations associated with each of the approaches as mirrored by the inconsistent results. In addition, a comprehensive hypothesis on migraine pathophysiology, incorporating both the Darwinian perspective and recent advances in epigenetics, is presented. This is satisfying in two ways. First, it helps to understand why many of the results are controversial. Most importantly he calls our attention to something we all know: ‘migraine’ is a collective term for a set of symptoms, as defined by the International Headache Society [2]. This etiological heterogeneity is the main obstacle hampering genetic studies and any small or moderate genetic effect, that may be important for a subgroup of migraines of the same origin (same underlying syndrome or disease), will inevitably be diluted when we look at all migraines. Furthermore, environmental aspects (nutrients, living conditions, etc., with the potential to exert epigenetic changes) have so far been disregarded in genetic studies. Second, this novel hypothesis on migraine pathophysiology incorporates existing knowledge into a new, more complex framework, rather

Background Menstrual migraine (MM) encompasses pure menstrual migraine (PMM) and menstrually-related migraine (MRM). This study was aimed at investigating genetic variants that are potentially related to MM, specifically undertaking genotyping and mRNA expression analysis of the ESR1, PGR, SYNE1 and TNF genes in MM cases and non-migraine controls. Methods A total of 37 variants distributed across 14 genes were genotyped in 437 DNA samples (282 cases and 155 controls). In addition levels of gene expression were determined in 74 cDNA samples (41 cases and 33 controls). Association and correlation analysis were performed using Plink and RStudio. Results SNPs rs3093664 and rs9371601 in TNF and SYNE1 genes respectively, were significantly associated with migraine in the MM population (p = 0.008; p = 0.009 respectively). Analysis of qPCR results found no significant difference in levels of gene expression between cases and controls. However, we found a significant correlation between the expression of ESR1 and SYNE1, ESR1 and PGR and TNF and SYNE1 in samples taken during the follicular phase of the menstrual cycle. Conclusions Our results show that SNPs rs9371601 and rs3093664 in the SYNE1 and TNF genes respectively, are associated with MM. The present study also provides strong evidence to support the correlation of ESR1, PGR, SYNE1 and TNF gene expression in MM.

Chronic post-traumatic headache (CPTH) after mild head injury can be difficult to manage. Research is scarce and successful interventions are lacking.To evaluate the effect of a group-based CBT intervention in relation to headache, pain perception, psychological symptoms and quality of life in patients with CPTH. Ninety patients with CPTH according to ICHD-2 criteria were enrolled from the Danish Headache Center into a randomized, controlled trial. Patients were randomly assigned to either a waiting list group or to a nine-week Cognitive Behavioural Therapy (CBT) group intervention. At baseline and after 26 weeks all patients completed the Rivermead Post Concussion Symptoms Questionnaire, SF-36, SCL-90-R and a headache diary. The CBT had no effect on headache and pressure pain thresholds and only a minor impact on the CPTH patients' quality of life, psychological distress, and the overall experience of symptoms. The waiting-list group experienced no change in headache but, opposed to the treatment group, a significant decrease in somatic and cognitive symptoms indicating a spontaneous remission over time. Our primarily negative findings confirm that management of patients with CPTH still remains a considerable challenge. Psychological group therapy with CBT might be effective in an earlier stage of CPTH and in less severely affected patients but our findings strongly underline the need for randomized controlled studies to test the efficacy of psychological therapy.

The prevalence and characterization of migraine triggers have not been rigorously studied in children and adolescents. Using a questionnaire, we retrospectively studied the prevalence of 15 predefined trigger factors in a clinic-based population. In 102 children and adolescents fulfilling the Second Edition of The International Headache Classification criteria for paediatric migraine, at least one migraine trigger was reported by the patient and/or was the parents' interpretation in 100% of patients. The mean number of migraine triggers reported per subject was 7. Mean time elapsed between exposure to a trigger factor and attack onset was comprised between 0 and 3 h in 88 patients (86%). The most common individual trigger was stress (75.5% of patients), followed by lack of sleep (69.6%), warm climate (68.6%) and video games (64.7%). Stress was also the most frequently reported migraine trigger always associated with attacks (24.5%). In conclusion, trigger factors were frequently reported by children and adolescents with migraine and stress was the most frequent.

The purpose of this study was to analyse the comorbidity between headache and epilepsy in a large series of children with headache (1,795). Fifty-six cases (3.1%) suffered from idiopathic headache and idiopathic or cryptogenic epilepsy or unprovoked seizures. There was a strong association between migraine and epilepsy: in migraineurs (46/56) the risk of epilepsy was 3.2 times higher when compared with tension-type headache, without significant difference between migraine with and without aura (P = 0.89); children with epilepsy had a 4.5-fold increased risk of developing migraine than tension-type headache. In cases with comorbidity, focal epilepsies prevailed (43/56, 76.8%). Migraineurs affected by focal epilepsies (36/56) had a three times higher risk of having a cryptogenic epilepsy (27/36, 75%) than an idiopathic epilepsy (9/36, 25%) (P = 0.003). In migraine with aura, epilepsy preceded migraine in 71% of cases. Photosensitivity (7/56, 12.5%) and positive family history for epilepsy (22/56, 39%) were frequent in cases with comorbidity.

Background Though migraine and tension type headache are both commonly diagnosed in childhood, little is known about their determinants when diagnosed prior to puberty onset. Our aim was to determine psychosocial- and health-related risk factors of migraine and tension-type headache in 11 year old children. Methods 871 New Zealand European children were enrolled in a longitudinal study at birth and data were collected at birth, 1, 3.5, 7, and 11 years of age. Primary headache was determined at age 11 years based on the International Headache Society. Perinatal factors assessed were small for gestational age status, sex, maternal smoking during pregnancy, maternal perceived stress, and maternal school leaving age. Childhood factors assessed were sleep duration, percent body fat, television watching, parent and self-reported total problem behaviour, being bullied, and depression. Results Prevalence of migraine and tension-type headache was 10.5% and 18.6%, respectively. Both migraine and TTH were significantly associated with self-reported problem behaviour in univariable logistic regression analyses. Additionally, migraine was associated with reduced sleep duration, and both sleep and behaviour problems remained significant after multivariable analyses. TTH was also significantly associated with antenatal maternal smoking, higher body fat, and being bullied. For TTH, problem behaviour measured at ages 3.5 and 11 years both remained significant after multivariable analysis. Being born small for gestational age was not associated with either headache group. Conclusions Although they share some commonality, migraine and tension-type headache are separate entities in childhood with different developmental characteristics. The association between primary headache and problem behaviour requires further investigation.

The objective was to investigate the safety and efficacy of almotriptan in patients aged 11-17 years old with acute migraine. Fifteen patients aged 11-17 with a history of migraine with or without aura were treated with almotriptan. Reduction in headache severity, disability and adverse effects were studied. Almotriptan in doses ranging from 6.25 to 12.5 mg was well tolerated. There were virtually no adverse effects except for one case of transient mild stiffness. Of the 15 patients, only 2 demonstrated no efficacy without adverse effects. In the other 13 patients, not only was almotriptan effective, but again, no significant adverse effects were reported. Almotriptan is probably safe and effective in patients aged 11-17. This small open-label pilot study should support the feasibility of a large randomised controlled study to demonstrate tolerability and efficacy of almotriptan in children and adolescents with episodic migraine.

The objective was to investigate the importance of genetic and environmental factors for infrequent episodic, frequent episodic and chronic tension-type headache. Twin pairs recruited from the population-based Danish Twin Registry received a posted questionnaire. Only twin pairs where both twins replied were included. A total of 3523 monozygotic (MZ), 4150 dizygotic (DZ) same-gender and 3526 DZ opposite-gender twin pairs were included. The prevalence of frequent episodic and chronic tension-type headache was significantly more frequent in women than men, and significantly higher in those with co-occurrence of migraine. The concordance rates were significantly higher in MZ than same-gender DZ twin pairs with no or frequent episodic tension-type headache, while the difference was not significant in chronic tension-type headache. The concordance rates of infrequent episodic tension-type headache in MZ and same-gender DZ twin pairs was significantly different in women but not in men, although the difference was small in both genders. We conclude that genetic factors play a role in no and frequent episodic tension-type headache, while infrequent episodic tension-type headache is caused primarily by environmental factors. The data regarding chronic tension-type headache were limited, so no firm conclusion could be drawn.

The objective was to identify the sociodemographic and clinical characteristics of a large sample of patients with migraine in Mexico City. This cross-sectional study was performed in two tertiary centers in Mexico City and affiliated hospitals. We evaluated the presence of migraine through a standardised interview according to the criteria of the International Headache Society. We studied 1,147 patients. The mean age was 37.1+/-13.6 (6-77) years. Nine hundred and twenty one patients were female (80%). The age of onset of migraine was 19.4+/-10.3 (1-69) years. Six hundred and four patients had migraine with aura (53%) and 543 without aura (47%). The female/male ratio was 4:1. One hundred and forty-seven patients had cardiovascular problems (13%), 72 had neurological problems (6%), 233 had gastrointestinal problems (20%) and 323 had psychiatric problems (28%). In this study we described the clinical characteristics of a large sample of patients with migraine in Mexico City. Our sample has similar characteristics to other countries.

The objective is to give an introduction to methods and study designs used in headache epidemiologic studies, to discuss their merits and problems, and to show the potential of such studies. The distinction between descriptive and analytic studies is made, and methodological issues are discussed related to headache case definition, validation of diagnoses, time frame for headache, instruments for data collection, source population and sampling methods, as well as the problems with bias and confounding. Examples of how different designs (case series, ecological, cross-sectional, case-control and cohort studies) have been used in the headache field are then presented. Studies on headache epidemiology are important to document the prevalence and burden of headache disorders. It is as important that studies with an analytical design can prove to be potent tools to disclose causes and risk factors for headache, but a standardisation of methods is needed to increase comparability of studies.

Using a human Prostaglandin E(2) (PGE(2)) model of headache, we examined whether a novel potent and selective EP(4) receptor antagonist, BGC20-1531, may prevent headache and dilatation of the middle cerebral (MCA) and superficial temporal artery (STA). In a three-way cross-over trial, eight healthy volunteers were randomly allocated to receive 200 and 400 mg BGC20-1531 and placebo, followed by a 25-min infusion of PGE(2). We recorded headache intensity on a verbal rating scale, MCA blood flow velocity and STA diameter. There was no difference in headache response or prevention of the dilation of the MCA or the STA (P > 0.05) with either dose of BGC20-1531 relative to placebo, although putative therapeutic exposures were not reached in all volunteers. In conclusion, these data suggest that the other EP receptors may be involved in PGE(2) induced headache and dilatation in normal subjects.

Girolamo Fabrici d'Acquapendente (ca.1533-1619), in his olograph will donated to the Signoria of Venice a rich collection of anatomical paintings, which are today preserved in the Marciana Library. The third volume of these tabulae pictae, entitled De Anatomia Capitis Cerebri Nervorum, deals with the nervous system and contains the only known illustrations by Fabrici regarding neuroanatomy. Despite the realisation of this splendid collection of 21 coloured paintings, neither a systematic description nor an iconographic record regarding nervous structures were found to be published by Fabrici. For this reason, a thorough study of these plates is pivotal to a better understanding of the contribution made by d'Acquapendente to the knowledge of the nervous system. Besides their aesthetic quality, Fabrici's tabulae pictae appear as a unique document of exceptional scientific value, thanks to the unprecedented realism given to the anatomical structures by the innovative use of colours. These pictures represent the highest point reached by the 16th-century Paduan Medical School well demonstrating its aim for a sound naturalistic approach.

A prominent historian of Medicine, Henry Sigerist, quoted the Padua Medical School as "the cradle of modern medicine". This opinion is currently accepted worldwide. A short outline on the contribution of the Padua Medical School to the development of medical knowledge in its "golden age" is given. In this context, the work of a prominent figure of the 17(th) century Padua University and the founder of Occupational Medicine, Bernardino Ramazzini, is considered, with focus on his interest in headache.

Premenopausal migraines frequently are associated with fluctuations of estrogen levels. Both, migraine and combined hormonal contraceptives (CHC) increase the risk of vascular events. Therefore progestagen-only contraceptives (POC) are a safer alternative. A previous short-term study demonstrated a positive impact of the oral POC desogestrel on migraine frequency. To study the effect of the POC desogestrel 75μg on migraine frequency, intensity, use of acute medication and quality of life in a clinical setting over the period of 180 days. Patients' charts were screened for women with migraine, who had decided to use desogestrel for contraception. Charts were included, if routinely conducted headache diaries were complete for 90 days before treatment (baseline) and over a treatment period of 180 days. We also report about starters who stopped treatment early, because of adverse events. Baseline data (day 1-90 before treatment) were compared with first and second treatment period (treatment days 1-90 and days 91-180). Quality of life was evaluated using MIDAS questionnaires. Days with migraine (5.8 vs 3.6), with any kind of headache (9.4 vs 6.6), headache intensity (15.7 vs 10.7), days with severe headache (5.4 vs 2.4) and use of triptans (12.3 vs7.8) were significantly reduced after 180 days. MIDAS score and grade improved significantly. Contraception with desogestrel 75μg resulted in a significantly improved quality of life and a reduction of migraine days over the observation period of 180 days. A clinically meaningful 30% reduction in pain was observed in 25/42 (60%) participants. For counselling reasons it is of importance, that the major reduction in migraine frequency occured during the initial 90 days, however further improvement occurs with longer duration of use. Prospective studies are needed to confirm these results.

Brain white matter hyperintensities are more prevalent in migraine patients than in the general population, but the pathogenesis and the risk factors of these hyperintensities are not fully elucidated. The authors analyzed the routine clinical data of 186 migraine patients who were referred to the Outpatient Headache Department of the Department of Neurology, Medical School, University of Pécs, Hungary between 2007 and 2009: 58 patients with white matter hyperintensities and 128 patients without white matter hyperintensities on 3 T MRI. Significant associations between the presence of white matter hyperintensities and longer disease duration (14.4 vs. 19.9 years, p = 0.004), higher headache frequency (4.1 vs. 5.5 attacks/month, p = 0.017), hyperhomocysteinemia (incidence of hyperintensity is 9/9 = 100%, p = 0.009) and thyroid gland dysfunction (incidence of hyperintensity is 8/14 = 57.1%, p = 0.038) were found. These data support the theory that both the disease duration and the attack frequency have a key role in the formation of migraine-related brain white matter hyperintensities, but the effects of comorbid diseases may also contribute to the development of the hyperintensities.

Glossopharyngeal neuralgia is a rare condition with neuralgic sharp pain in the pharyngeal and auricular region. Classical glossopharyngeal neuralgia is caused by neurovascular compression at the root entry zone of the nerve. Regarding the rare occurrence of glossopharyngeal neuralgia, we report clinical data and magnetic resonance imaging (MRI) findings in a case series of 19 patients, of whom 18 underwent surgery. Two patients additionally suffered from trigeminal neuralgia and three from additional symptomatic vagal nerve compression. In all patients, ipsilateral neurovascular compression syndrome of the IX cranial nerve could be shown by high-resolution MRI and image processing, which was confirmed intraoperatively. Additional neurovascular compression of the V cranial nerve was shown in patients suffering from trigeminal neuralgia. Vagal nerve neurovascular compression could be seen in all patients during surgery. Sixteen patients were completely pain free after surgery without need of anticonvulsant treatment. As a consequence of the operation, two patients suffered from transient cerebrospinal fluid hypersecretion as a reaction to Teflon implants. One patient suffered postoperatively from deep vein thrombosis and pulmonary embolism. Six patients showed transient cranial nerve dysfunctions (difficulties in swallowing, vocal cord paresis), but all recovered within 1 week. One patient complained of a gnawing and burning pain in the cervical area. Microvascular decompression is a second-line treatment after failure of standard medical treatment with high success in glossopharyngeal neuralgia. High-resolution MRI and 3D visualization of the brainstem and accompanying vessels as well as the cranial nerves is helpful in identifying neurovascular compression before microvascular decompression procedure.

This tutorial describes different methods and results of genetic studies of primary headaches. A positive family history is imprecise, because it does not specify the number of affected, family size or relation to the proband. Nor does it include an interview of the possibly affected family members. Calculation of the familial aggregation after confirmation of the diagnosis by a physician is more precise. Compared to the general population, first-degree relatives of probands with migraine without aura, migraine with aura, chronic tension-type headache and cluster headache has a significantly increased risk of the proband's disorder. These data are confirmed in twin studies. The primary headaches are caused by a combination of genetic and environmental factors. A major breakthrough was identification of 3 different genes all causing the rare autosomal dominant inherited familial hemiplegic migraine. The genes encode ion channels. So far no genes have been identified to cause the more common types of primary headaches.

Although primary headache is the most frequent neurological disorder and there is some evidence that the prevalence rates have increased in recent years, no long-term data on the annual prevalence of headache are available for Germany. The objective of the study was therefore to obtain long-term data on the period prevalence of headache in the general population in Germany by means of population-based cross-sectional annual surveys (1995-2005 and 2009). These surveys were conducted as face-to-face paper-and-pencil interviews from 1995 through 2004, and from 2005 onwards as computer-aided personal interviews. The reported headaches were self-diagnosed by the interviewees. Per year, approximately 640 trained interviewers interviewed between 10,898 and 12,538 German-speaking individuals aged 14 and older and living in private households in the whole of Germany (response rate: 67.4% and 73.1%, gross samples: 16,026 to 18,176 subjects). A total of more than 146,000 face-to-face interviews were analyzed. The one-year headache prevalence remained stable over the entry period, with 58.9% (95%CI 57.7-60.1) to 62.5% (95%CI 61.3-63.7) (p=0.07). Women showed consistently higher prevalence rates than men (females: 67.3 (95%CI 65.7-68.9) to 70.7% (95%CI 69.1-72.3), males: 48.4% (95%CI 46.5-50.3) to 54.3% (95%CI 52.4-56.2)), and both sexes showed a bell-shaped age dependence with peaks in the 30-39 age group. A stable slightly higher prevalence was observed in urban versus rural areas (p<0.0001), and there was also a significant trend towards higher prevalence rates in groups with a monthly household income larger than 3,500 € (p=0.03). The overall headache prevalence remained stable in Germany in the last 15 years.

Transcutaneous supraorbital nerve stimulation (tSNS) with the Cefaly(R) device was recently found superior to sham stimulation for episodic migraine prevention in a randomized trial. Its safety and efficiency in larger cohorts of headache sufferers in the general population remain to be determined.The objective of this study was to assess the satisfaction with the Cefaly(R) device in 2,313 headache sufferers who rented the device for a 40-day trial period via Internet. Only subjects using specific anti-migraine drugs, and thus most likely suffering from migraine, were included in the survey. Adverse events (AEs) and willingness to continue tSNS were monitored via phone interviews after the trial period. A built-in software allowed monitoring the total duration of use and hence compliance in subjects who returned the device to the manufacturer after the trial period. After a testing period of 58.2 days on average, 46.6% of the 2,313 renters were not satisfied and returned the device, but the compliance check showed that they used it only for 48.6% of the recommended time. The remaining 54.4% of subjects were satisfied with the tSNS treatment and willing to purchase the device. Ninety-nine subjects out of the 2,313 (4.3%) reported one or more AEs, but none of them was serious. The most frequent AEs were local pain/intolerance to paresthesia (47 subjects, i.e. 2.03%), arousal changes (mostly sleepiness/fatigue, sometimes insomnia, 19 subjects, i.e. 0.82%), headache after the stimulation (12 subjects, i.e. 0.52%). A transient local skin allergy was seen in 2 subjects, i.e. 0.09%. This survey of 2,313 headache sufferers in the general population confirms that tSNS with is a safe and well-tolerated treatment for migraine headaches that provides satisfaction to a majority of patients who tested it for 40 days. Only 4.3% of subjects reported AEs, all of them were minor and fully reversible.

Sex hormones have some implications on headaches. The objective of the study was to investigate the effects of hormonal changes comparatively on tension-type headache (TTH) and migraine, in a population-based sample. A nationwide face-to-face prevalence study was conducted using a structured electronic questionnaire. 54.3 % of the migraineurs reported that the probability of experiencing headache during menstruation was high, whereas 3.9 % had headache only during menstruation. Forward logistic regression analysis revealed that menstruation was a significant trigger for migraine in comparison to TTH. On the other hand, nearly double the number of TTH sufferers reported “pure menstrual headache” compared to migraineurs (p = 0.02). Menstrual headaches caused significantly higher MIDAS grades. One-third of the definite migraineurs reported improvement during pregnancy and oral contraceptives significantly worsened migraine. Menopause had a slight improving effect on migraine compared to TTH. Sex hormonal changes have major impacts particularly on migraine; however, the effects of hormonal fluctuations on TTH should not be underestimated. Electronic supplementary material The online version of this article (doi:10.1007/s10194-012-0475-0) contains supplementary material, which is available to authorized users.

We analyzed the incidence, pattern and location of headache in consecutive 200 patients with proven diagnosis of CVT to identify an association between localization of headache and site of sinus involvement. Headache was present in 136 (68%) patients. The duration of headache (reported in 128 patients) was reported as acute (1-3 days), 81 patients (60%); sub-acute (4-14 days), 33 patients (24%); and chronic (more than 14 days), 14 patients (10%). The quality of headache (reported in 72 patients) was reported as throbbing 12 (9%), band like 27 (20%), thunderclap 7 (5%), and other (pounding, exploding, stabbing, etc.) 26 (20%). The location of headache (reported in 101 patients) was reported as unilateral (one side of head) 48 (37%), localized (frontal, temporal, occipital, and neck) 25 (19%), and diffuse (whole head) 28 (20%). 43 (32%) patients had normal neurological examination (normal mental status, cranial nerves, motor and sensory examination with down going planters). 93 (68%) patients have abnormal findings on neurological examination including papilledema 29 (15%) patients, altered mental status 38 (19%), and focal neurological deficit 45 (22%) patients. There was no association between headache and presence of hemorrhage on CT and MRI (P = 0.1) or hydrocephalus (P = 0.09). There was no association between localization of headache and site of sinus thrombosis except sigmoid sinus thrombosis, where 17 out of 28 patients with involvement of sigmoid sinus alone or in combination with transverse sinus had pain in the occipital and neck region (P < 0.05). There was no association between lateralization of pain and site of thrombosis (P = 0.66).