The crossover design for migraine preventives: an analyses of four randomized placebo-controlled trials.

AIMS: To evaluate the crossover design in migraine preventive treatment trials by assessing dropout rate, and potential period and carryover effect in four placebo-controlled randomized controlled trials (RCTs). METHODS: In order to increase statistical power, the study combined data from four different RCTs performed from 1998 to 2015 at St. Olavs Hospital, Norway. Among 264 randomized patients, 120 received placebo treatment before and 144 after active treatment. RESULTS: Only 26 (10%) dropped out during the follow-up period of 30-48 weeks, the majority (n = 19) in the first 12 weeks. No period effect was found, since the treatment sequence did not influence the responder rate after placebo treatment, being respectively for migraine 30.5% vs. 27.4% (p = 0.59) and for headache 25.0% vs. 24.8% (p = 0.97, Chi-square test) when placebo occurred early or late. Furthermore, no carryover effect was identified, since the treatment sequence did not influence the treatment effect (difference between placebo and active treatment). There was no significant difference between those who received active treatment first and those who received placebo first with respect to change in number of days per 4 week of headache (- 0.9 vs. -1.3, p = 0.46) and migraine (- 1.2 vs. -0.9, p = 0.35, Student's t-test). CONCLUSIONS: Summary data from four crossover trials evaluating preventive treatment in adult migraine showed that few dropped out after the first period. No period or carryover effect was found. RCT studies with crossover design can be recommended as an efficient and cost-saving way to evaluate potential new preventive medicines for migraine in adults.

Epilepsy patients with and without perceived benefit from vagus nerve stimulation: A long-term observational single center study.

PURPOSE: Vagus nerve stimulaton (VNS) has been used for adjunctive treatment of drug-resistant epilepsy for more than 25 years. The true efficacy has been debated, as blinded randomized controlled trials are unavailable. The aim of this study was to evaluate the patient-reported perceived benefit of VNS and to compare clinical characteristics of patients with and without benefit. METHODS: Observational study of all 43 adult patients receiving VNS for >2 years at one single center. Mean duration of treatment was 9 years. At inclusion, a semi-structured interview on VNS effectiveness was performed. In patients without benefit, the VNS was turned off. The outcome was evaluated after an observation period of one year. RESULTS: 21 patients (49%) reported no clear benefit and stopped VNS. Only one of them resumed treatment within one year. Patients without benefit had received more new antiepileptic drugs (AEDs) during VNS treatment than those reporting benefit (p = 0.05). Other differences between the two groups were not found. Ten patients (23%) had been seizure free >1 year at inclusion (5 in the benefit and 5 in the non-benefit group). Seizure control was attributed to the response of another new treatment in the majority of these patients. CONCLUSION: Half of the patients had not perceived clear benefit from VNS, and all but one terminated VNS without worsening of seizures within one year. The true outcome of long-term VNS is difficult to assess in real-world practice. The effect may be overestimated due to confounding factors, particularly the common introduction of novel AEDs and the natural course of the disorder. Patients without perceived benefit from long-term VNS should not routinely remain on treatment and be subject to undue generator re-implantations.

Zonisamide serum concentrations during pregnancy.

PURPOSE: To investigate the change in zonisamide (ZNS) serum concentration and its consequences in pregnant women with epilepsy. METHODS: Six hospitals in Norway and Denmark screened their records for women who had been using ZNS during pregnancy. Absolute serum concentrations as well as concentration/dose (CD)-ratios were compared to non-pregnant values. Descriptive data on seizure control and obstetrical data were also collected. RESULTS: 144 serum concentrations from 23 pregnancies in 15 individual women with epilepsy were included (six on monotherapy). The mean ZNS serum concentration fell to a minimum of 58.6 ±â€¯15.1%, while the C/D-ratio fell to as low as 55.1 ±â€¯15.3% of the non-pregnant-value. The lowest values were seen in gestational months six to nine, and the individual nadir varied considerably (range: 24-81% of the non-pregnant value). Four out of ten previously seizure-free patients experienced breakthrough seizures. Gestational age, weight at birth and head circumference of the newborns were within the reference ranges. CONCLUSIONS: ZNS serum concentrations may fall by over 40% during pregnancy, with large interindividual variability. In some patients, this may lead to worsened seizure control. These findings are in line with reports on other AEDs and suggest that regular therapeutic drug monitoring and dose adjustments may be useful.

The seizure precipitating effect of alcohol: A prospective observational cross-over study.

PURPOSE: The aim of this study was to investigate the association between alcohol use and seizures in acutely hospitalized patients. We wished to study the extent of the problem as well as the clinical characteristics of people with various forms of alcohol-related seizures, including their drinking pattern. METHOD: After admission, a semi-structured interview took place with 134 consecutive patients (epilepsy 92, single seizures 42). Alcohol use was assessed by the Alcohol Use Disorders Identification Test (AUDIT) and by the number of alcohol units consumed during 6 days prior to the seizure. Sleep time was recorded during the previous 3 days and nights. A follow-up telephone interview covering the same weekdays was performed on a seizure-free day at least 4 weeks later. RESULTS: 28% of patients had AUDIT scores ≥8 (hazardous drinking); 22% in epilepsy, 43% in single seizures (p = .012). Non-focal seizures were increased in single seizures, suggesting a withdrawal mechanism. In the 58 epilepsy patients with social drinking (excluded hazardous drinking or excessive binging), the alcohol intake was not different prior to seizure compared to follow-up, downgrading the role of modest alcohol intake as a seizure precipitant in epilepsy. On the other hand, a high percentage of binge drinkers had epilepsy (57%), and in the subgroup of Idiopathic Generalized Epilepsy (IGE) even social drinking was associated with seizures. Seizures peaked on Sundays and Mondays. Less sleep prior to the seizure was associated with hazardous drinking. CONCLUSION: Alcohol is a major seizure precipitant in the context of hazardous drinking and withdrawal. In people with epilepsy, occasional binge drinking is associated with loss of seizure control. Social drinking is an uncommon cause of seizure breakthrough in predominantly focal epilepsy, but caution is warranted in IGE. Alcohol intake prior to a seizure is often accompanied by other triggers, such as sleep loss. Alcohol alone should not always be blamed.

The epidemiology of headache disorders: a face-to-face interview of participants in HUNT4.

BACKGROUND: The primary aim of this cross-sectional population-based study was to evaluate the 1-year prevalence of common headache disorders by a face-to-face interview. METHODS: The fourth wave of Nord-Trøndelag Health Survey (HUNT4) started in September 2017. The study was undertaken as part of a project mainly focusing on sleep disorders, where a total of 232 (19.3%) out of 1200 invited HUNT4 participants underwent a face-to-face headache interview. RESULTS: The mean age of the 232 participants was 58.4 years (range 22-89). There were 71.6% (95% CI 65.7-77.4) who reported headache during the last year, and 18.5% (95% CI 13.5-23.6) had suffered from headache in the same period. The 1-year prevalence of tension-type headache (TTH) was 43.1% (95% CI 36.7-49.5), of idiopathic stabbing headache 34.1% (27.9-40.2), and of definite migraine 18.1% (95% CI 13.1-23.1). A total of 7.6% (95% CI 4.0-10.7%) had migraine with coexisting TTH. Lifetime prevalence of migraine was 32.8% (95% CI 26.7-38.8). Headache yesterday was reported by 12.1% (95% CI 7.9-16.3), and 5.6% (95% CI 2.6-8.6) had headache during the interview. CONCLUSION: In this population-based cross-sectional headache study performed by a face-to-face interview, the 1-year prevalence of TTH was 43.1% and of idiopathic stabbing headache 34.1%. A total of 18.1% had active migraine (18.1%), whereas the lifetime prevalence of migraine was 32.8%.

No association between non-bullous skin reactions from lamotrigine and heterozygosity of UGT1A4 genetic variants *2(P24T) or *3(L48V) in Norwegian patients.

PURPOSE: High initial serum concentrations increase the risk of cutaneous adverse reactions. Genetic variants of the main metabolizing isoenzyme, uridine diphosphate glucuronosyltransferase (UGT) 1A4 influence the elimination of lamotrigine (LTG). Our aim was to investigate the potential association between the two best studied variants, *2 (P24T) and *3 (L48V), and the occurrence non-bullous skin reactions from LTG. METHOD: The study included 29 patients of Caucasian ethnicity with a history of non-bullous skin reactions from LTG. 184 subjects tolerant to LTG for at least three months were used as controls. UGT1A4 genotyping was performed in all patients and controls by sequencing of the first part of exon 1. Six controls were excluded due to rare genetic variants. RESULTS: Two of 29 subjects (7%) with rash from LTG were heterozygous for UGT1A4 *2, compared to 23 of 178 (13%) tolerant controls (p=0.54). Four of 29 subjects (14%) with rash from LTG were heterozygous for UGT1A4 *3 compared to 25 of 178 (14%) tolerant controls (p=0.97). CONCLUSION: It is unlikely that heterozygosity of the UGT1A4 genetic variants *2(P24T) or *3(L48V) influences the risk of non-bullous skin reactions in patients treated with LTG.

The impact of sleep loss on the facilitation of seizures: A prospective case-crossover study.

PURPOSE: The relationship between sleep and seizures is intricate. The aim of this study was to assess whether sleep loss is an independent seizure precipitant in a clinical setting. METHODS: In this prospective, observational cross-over study, 179 consecutive hospital admissions for epileptic seizures were included. A semi-structured interview regarding several seizure precipitants was performed. The sleep pattern prior to the seizure, as well as alcohol, caffeine and drug use, were recorded. The interview was repeated by telephone covering the same weekday at a time when there had been no recent seizure. The Hospital Anxiety and Depression Scale (HADS) and a visual analogue scale for perceived stress were applied at admission. Student's t-test, Fisher exact test and ANOVA were used for statistical analyses. RESULTS: Complete data for analysis were retrieved in 144 patients. The sleep-time during the 24h prior to the seizure was lower (7.3h) compared to follow-up (8.3h; p<0.0005). Caffeine consumption and use of relevant non antiepileptic drugs (AED) were not different. HADS and stress scores at admission did not correlate with sleep-time difference. In ANOVA, controlled for alcohol consumption and AED use, the sleep-time difference remained significant (p=0.008). The interaction with alcohol intake was high, but the sleep-time difference remained highly significant also for the non- and low-consumption (≤2 units per day) subgroup (n=121, 7.50h vs 8.42h, p=0.001). CONCLUSION: Epileptic seizures are often precipitated by a combination of various clinical factors, but sleep loss stands out as an independent seizure trigger.

Treatment non-adherence in pseudo-refractory epilepsy.

Non-adherence to antiepileptic drug treatment strongly affects the outcome of epilepsy and is frequently clinically unrecognized. This review addresses current knowledge on medication-taking behavior in people with epilepsy, as well as the importance of tailoring interventions to the individual patterns of non-adherence. Non-adherence can be categorized as non-initiation, poor execution (accidental or intentional) or non-persistence and are related to clinical characteristics and health care barriers. All available methods to assess adherence are hampered by shortcomings. Self-reports are indirect and subjective. Pill-counts, electronic bottle-tops and pharmacy records are objective, but indirect measures of drug ingestion. Therapeutic drug monitoring is both direct and objective, but pharmacokinetic and diurnal variability must be taken into account. Young adults with generalized epilepsy may be particularly vulnerable to non-adherence. The drug burden in the form of polytherapy, multiple dosing and side effects are obvious obstacles. Poor understanding of the principles of prophylactic treatment as well as drug costs may be important in people with low socioeconomic status. Depression is also associated with low adherence. In people with multihandicaps, failed oral intake may be due to behavioral or physical problems, as well as insufficient education of the caregivers. Non-adherence often results in seizure breakthrough and hospital admissions, but the consequences may be more dramatic. It is the leading cause of status epilepticus in people with epilepsy, and the association with sudden death (SUDEP) is clear. The management of poor drug-taking behavior should be based on the identification of the specific causes in each individual and corresponding multiprofessional interventions. Non-adherence to antiepileptic drugs needs more clinical and scientific attention.

Frequencies of UGT1A4*2 (P24T) and *3 (L48V) and their effects on serum concentrations of lamotrigine.

The gene encoding uridine diphosphate glucuronosyltransferase (UGT) 1A4 shows considerable polymorphism. Several common drugs are metabolised by UGT1A4, among them lamotrigine (LTG). Experimental and clinical studies suggest that certain variants of UGT1A4 are associated with altered enzyme activity. However, results are conflicting. This clinical study aimed to investigate the frequencies of two common UGT1A4 variants, *2 (P24T) and *3 (L48V), and their potential effects on serum concentrations of LTG. The *2 variant was associated with a trend towards higher serum concentrations, while the *3 variant was associated with significantly lower serum concentrations of LTG. The calculated allele frequencies were in the same range as in earlier studies on Caucasian populations. To our knowledge, this is the first study suggesting a clinical effect of UGT1A4*2. Further study is needed to confirm this finding.

Do HLA-A markers predict skin-reactions from aromatic antiepileptic drugs in a Norwegian population? A case control study.

PURPOSE: Cutaneous adverse reactions (cADRs) from carbamazepine (CBZ) have been associated with human leukocyte antigens (HLA). Our aims were to assess the clinical usefulness of HLA-A*31:01 as a predictor of CBZ-induced cADRs in the Norwegian population and to explore whether cADRs from aromatic antiepileptic drugs (AEDs) in general might be linked with a common HLA-A-marker. MATERIALS AND METHODS: 86 ethnic Norwegians with a history of non-bullous cADRs from aromatic AEDs were included. 114 subjects tolerant to at least one aromatic AED were used as drug-specific controls. Complete HLA-A genotyping was performed. 1026 blood donors were used as population controls. RESULTS: Comparing all cADR subjects with controls and blood donors, there were no statistical differences for any HLA-A allele, except for HLA-A*24 (p=0.022 vs. controls and p=0.014 vs. blood donors). When comparing tolerant controls with patients having had a cADR to one of the two most used drugs, CBZ (n=48) and lamotrigine (n=28), we found no significant associations for CBZ to HLA-A*31:01 or HLA-A*24:02, but for lamotrigine there was an association with HLA-A*24:02 (p=0.027). In patients developing cross-reactivity (n=14) to aromatic AEDs, the presence of HLA-A*31:01 or HLA-A*24:02 was not different compared to patients with a single cARD tolerant to at least one other drug. CONCLUSION: We question the clinical usefulness of HLA-A*31:01 as a marker for CBZ rash in the Norwegian population. A previously suggested protective effect of aromatic AED cross-reactivity from HLA-A*24:02 was not confirmed. The association between HLA-A*24:02 and lamotrigine-induced rash should be further investigated.

Acetyl-l-carnitine versus placebo for migraine prophylaxis: A randomized, triple-blind, crossover study.

BACKGROUND: Preventive medication is indicated for many migraine patients, but is used in relatively few. The aim of the present study was to evaluate the efficacy of acetyl-l-carnitine as a prophylactic drug in migraine patients. METHODS: A single-center, randomized, triple-blind, placebo-controlled, crossover study was carried out. Men and women, age 18-65 years, with episodic migraine but otherwise healthy, were recruited mostly through advertisements. After a four-week run-in-phase, 72 participants were randomized to receive either placebo or 3 g acetyl-l-carnitine for 12 weeks. After a four-week washout, treatment was switched. The primary outcome was days with moderate or severe headache per four weeks. Secondary outcomes were days with headache, hours with headache, proportion of responders (>50% reduction in migraine days from baseline) and adverse events. RESULTS: In the complete case analyses, no statistically significant differences were found between acetyl-l-carnitine and placebo in severe or moderate headache days per month (3.0 versus 3.1, p = 0.80), headache days per month (5.1 versus 5.2, p = 0.73) or for the other secondary outcome measures. CONCLUSION: In this triple-blind crossover study no differences were found in headache outcomes between acetyl-l-carnitine and placebo. Our results do not provide evidence of benefit for efficacy of acetyl-l-carnitine as prophylactic treatment for migraine. TRIAL REGISTRATION: EUDRACT (2012-001624-36), ClinicalTrials.gov (NCT01695317).

Nonadherence to treatment causing acute hospitalizations in people with epilepsy: an observational, prospective study.

The aim was to assess the clinical relevance of antiepileptic drug (AED) nonadherence by means of therapeutic drug concentration monitoring (TDM). Two hundred eighty-two consecutive patients with epilepsy acutely admitted to hospital for seizures were included. Nonadherence was defined as having a serum concentration/dose ratio at admission of <75% of the patient's own control value (probable nonadherence: 50-75%; definite: <50%). Nonadherence was identified in 39% of patients (definite 24%; probable 15%). It was significantly more common in patients with generalized seizures compared to those with focal onset seizures, and in patients <30 years compared to older patients. When specifically asked, 44% of nonadherent patients claimed regular intake. Nonadherence is a major cause of seizure breakthrough in patients with epilepsy, particularly in young adults. Many patients seem to be unaware of missed drug intake. Prompt measurements of AED serum concentrations should be available as part of the emergency care for patients acutely hospitalized for seizures to permit this issue to be thoroughly addressed prior to discharge.

Carbamazepine-induced cutaneous reactions: a simple assay to identify patients carrying the HLA-A*31:01 allele.

AIMS: Treatment with the first-line antiepileptic drug, carbamazepine (CBZ), is associated with adverse cutaneous reactions in up to 10% of patients. One predisposition to these side-effects has been linked to the HLA-A*31:01 allele. HLA-typing is costly and time-consuming. A single nucleotide polymorphism (SNP, rs1061235A > T) has been suggested as a marker for the HLA-A*31:01 allele. We sought to develop and validate a simple, fast and inexpensive assay for rs1061235 to apply in the Norwegian population. METHODS: We designed a polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) assay for the SNP and tested it on a set of 16 samples with known HLA-A alleles. RESULTS: The assay identified all HLA-A*31:01 alleles present, but also marked for HLA-A*33:03. In a second set of 204 samples from Norwegian epilepsy patients with unknown HLA alleles, nine samples heterozygous for the rs1061235 were found. Subsequent HLA-typing showed that one sample was HLA-A*33:01, whereas the other eight were identified as HLA-A*31:01. The remaining 195 samples were correctly identified as neither carrying the rs1061235 SNP nor HLA-A*31:01. The sensitivity and specificity of the rs1061235 SNP test was 100% and 99.5%, respectively. Misinterpretation of the rare HLA-A*33 variants as HLA-A*31:01 has minor consequence, as it only would result in choosing an alternative drug to CBZ. CONCLUSION: We have designed and validated a simple, fast and inexpensive test for the rs1061235A> T SNP as a marker for HLA-A*31:01 in the Norwegian population for potential use in a personalized treatment approach to patients planned to receive CBZ.

Is dietary caffeine involved in seizure precipitation?

Caffeine acts as a central nervous stimulant by blocking A1 and A2A adenosine receptors. Its effect on seizures is complex. Animal studies and case reports indicate that acute caffeine exposure may induce seizures, whereas chronic exposure might have an opposite effect. Patients acutely hospitalized for seizures (n = 174) were asked for their consumption of caffeinated beverages 24 h prior to admission as well as their habitual caffeine intake. Twenty-four-hour caffeine consumption was also recorded in a later telephone interview on a seizure-free day (n = 154). Thus, the patients served as their own controls. Categorized data were analyzed using the Wilcoxon's signed-ranks test. No difference was found between the intake of caffeine 24 h prior to the seizure and the habitual consumption (p = 0.37) or the consumption on a seizure-free day (p = 0.13). Thus, caffeine does not appear to be a common seizure precipitant.

Lamotrigine and its N2-glucuronide during pregnancy: the significance of renal clearance and estradiol.

PURPOSE: To investigate the physiological mechanisms behind the pronounced decline of lamotrigine (LTG) serum concentrations during pregnancy. METHODS: Serum and urine concentrations of LTG and its main metabolite, LTG-N2-glucuronide (LTG-GLUC), were measured monthly in 21 pregnancies of 19 women using LTG. Simultaneously, a panel of biochemical variables was monitored to evaluate liver and kidney function and possible hemodilution effects. Pharmacokinetic parameters were calculated once at baseline and once in gestational month 8. RESULTS: Initially, LTG and LTG-GLUC serum concentrations fell simultaneously by 27% and 38%, respectively (gestational month 2). Subsequently, the ratio of the LTG-GLUC/LTG serum concentrations increased gradually, correlating strongly with rising serum estradiol concentrations. In gestational month 8, the ratio was 164% higher than at baseline. At that time, LTG total clearance had increased by 118%, and the amount of unchanged LTG in urine had dropped by 40% while the amount of LTG-GLUC had increased by a corresponding 37%. CONCLUSIONS: The simultaneous decline of LTG and LTG-GLUC serum concentrations in early pregnancy suggests that in this phase, increased renal blood flow is the major cause. After gestational month 2, estradiol-induced glucuronidation of LTG becomes more important, leading to a further fall of LTG serum concentrations and a gradual rise of the LTG-GLUC/LTG-ratio through the remaining pregnancy. An expanded volume of distribution may also contribute to reduced LTG serum concentrations in pregnancy.

Headache and migraine during pregnancy and puerperium: the MIGRA-study.

There is little prospectively gathered data on the course of headaches during pregnancy and postpartum, and the influence of breastfeeding is unclear. This is a large, prospective study, which invited all pregnant women in the catchment area during a defined period. All participants (n = 2,126) filled in questionnaires concerning headache. Among these, a total of 208 women with migraine according to the International Headache Society criteria also filled in detailed headache diaries during pregnancy and the puerperal period. Freedom from earlier headaches during pregnancy was significantly more common than new onset of headache during pregnancy (p < 0.001). This was not influenced by prior use of oral contraceptives. According to the diaries, there was a gradual decrease during pregnancy in the frequency of all headaches and of self-considered migraine. There was also a significant decrease in the duration of headaches (p < 0.001) during pregnancy compared to before. Earlier parity did not influence the course. Apart from a significant increase during the first week postpartum (p < 0.01), the overall occurrence of headaches during puerperium did not differ from the pregnancy period. Compared to pregnancy, there was a postpartum increase in the mean intensity (p < 0.01) and duration (p = 0.050) of headaches, as well as in the mean number of analgesics used (p < 0.001). Breastfeeding did not influence the occurrence of headaches postpartum. These data are of practical value for informing pregnant migraineurs about the typical clinical prospects and for giving advice on breastfeeding.

Onabotulinum toxin A treatment of cervicogenic headache: a randomised, double-blind, placebo-controlled crossover study.

AIMS: Preliminary reports regarding injections in the neck of onabotulinum toxin A have been positive in cervicogenic headache (CeH). The aim was to perform the first methodologically rigorous trial. METHODS: A randomised, placebo-controlled, patient-, injector- and evaluator-blinded crossover study included 28 adult patients with a long-standing and treatment-resistant CeH. After a baseline period, injections of either onabotulinum toxin A or placebo were given in fixed sites in the neck muscles on the pain side. Second injections were given after ≥8 weeks. Patients were thereafter followed for another 8 weeks. A detailed headache calendar was filled in, and patients were followed with quality-of-life (QoL) questionnaires, algometry and neck mobility measurements. RESULTS: There was no significant difference between verum and placebo in a mixed linear model analysis (p = 0.084) with regard to the primary end-point, reduction of days with moderate to severe headache. Six patients withdrew from the study before the second injections, but an intention-to-treat (ITT) analysis gave a similar result (p = 0.27). There were no significant differences favouring verum in any of the secondary efficacy measures. Side-effects of onabotulinum toxin A were minor and short-lasting. CONCLUSION: Onabotulinum toxin A in neck muscles does not seem to be beneficial in CeH.

A 4-year follow-up of patients with medication-overuse headache previously included in a randomized multicentre study.

The aim of this study was to evaluate the long-term outcome in 61 patients with medication-overuse headache (MOH) who 4 years previously had been included in a randomized open-label prospective multicentre study. Sixty patients still alive after 4 years were invited to a follow-up investigation. Fifty patients (83%) participated. Sixteen visited a neurologist, 22 were interviewed through telephone, 2 gave response by a letter, and 10 were evaluated through hospital records. The influence of baseline characteristics on outcome 4 years later was evaluated by non-parametric tests. p values below 0.01 were considered significant. At follow-up, the 50 persons had a mean reduction of 6.5 headache days/month (p < 0.001) and 9.5 acute headache medication days/month (p < 0.001) compared to baseline. Headache index/month was reduced from 449 to 321 (p < 0.001). Sixteen persons (32%) were considered as responders due to a ≥50% reduction in headache frequency from baseline, whereas 17 (34%) persons met the criteria for MOH. None of the baseline characteristics consistently influenced all five outcome measures. Total Hospital Anxiety and Depression Scale (HADS) score at baseline was predictors (p < 0.005) for being a responder after 4 years. At 4 years' follow-up, one-third of the 50 MOH patients had ≥50% reduction in headache frequency from baseline. A low total HADS score at baseline was associated with the most favorable outcome.

The validity of questionnaire-based diagnoses: the third Nord-Trøndelag Health Study 2006-2008.

The Nord-Trøndelag Health Study (HUNT 3) performed in 2006-2008 is a replication of the cross-sectional survey from 1995 to 1997 (HUNT 2). The aim of the present study was to assess the sensitivity and specificity of questionnaire-based headache diagnoses using a personal interview by a neurologist as a gold standard. For the questionnaire-based status as headache sufferer, a sensitivity of 88%, a specificity of 86%, and a kappa statistic of 0.70 were found. Chronic headache, chronic tension-type headache (TTH), and medication overuse headache (MOH) were diagnosed with a specificity of > or =99%, and a kappa statistic of > or =0.73. Lower figures were found for the diagnoses of migraine and TTH. For individuals with headache > or =1 day per month, a sensitivity of 58% (migraine) and 96% (TTH), a specificity of 91 and 69%, and a kappa statistic of 0.54 and 0.44 were found, respectively. The specificity for migraine with aura was 95%. In conclusion, the HUNT 3-questionnaire is a valid tool for identifying headache sufferers, and diagnosing patients with chronic headache, including chronic TTH and MOH. The more moderate sensitivity for migraine and TTH makes the questionnaire-based diagnoses of migraine and TTH suboptimal for determining the prevalence. However, the high specificity of the questionnaire-based diagnosis of migraine, in particular for migraine with aura, makes the questionnaire a valid tool for diagnosing patients with migraine for genetic studies.

A face-to-face interview of participants in HUNT 3: the impact of the screening question on headache prevalence.

The aim of this study was to evaluate the effect of the screening question phrasing on the 1-year prevalence figures of headache disorders, including migraine. Of a random sample of 563 invited participants in the Nord-Trøndelag Health Survey 2006-2008 in Norway, 297 (53%) met to a face-to-face interview. There were 74.1% that reported having had headache during the last year, whereas only 31.0% stated that they had suffered from headache in the same period. The 1-year prevalence of migraine was 17.2% and of tension-type headache (TTH) 51.9%. Migraine was ten times more likely (OR = 9.96, 95% CI 4.75-20.91) among those who stated that they were headache sufferers than among those who were not. Only headache sufferers had chronic TTH or medication-overuse headache. Thus "Have you suffered from headache?" can be a useful screening question in population-based questionnaire studies if the goal is to identify most migraineurs and almost all individuals with chronic headache.