Early indicators of primary brain tumours: a population-based study with 10 years' follow-up.

BACKGROUND AND PURPOSE: To improve diagnoses of primary brain tumours, knowledge about early indicators is needed. Nationwide Danish health registries were used to conduct a population-based case-control study including all persons diagnosed with a primary brain tumour between 2005 and 2014 in Denmark. METHODS: All 5135 adults diagnosed with a primary brain tumour in the Danish Cancer Registry were matched to 19 572 general population comparisons from the Danish Civil Registration System. Conditional logistic regression analyses were applied to estimate age- and multivariable-adjusted odds ratios (ORs) for the occurrence of a primary brain tumour up to 10 years after hospital diagnoses or prescription of medications related to nervous system diseases and mental and behavioural disorders. RESULTS: Increased odds for primary brain tumour after nervous system diseases and mental and behavioural disorders manifested up to 10 years before tumour diagnosis were found. Increased odds were seen especially for hospital contacts for inflammatory nervous system diseases [OR 11.3; 95% confidence interval (CI) 6.5-19.7], epilepsy (OR 9.0; 95% CI 7.6-10.7) and antiepileptic medications (OR 3.6; 95% CI 3.2-4.0), whilst antidementia medications provided a strong, protective association for primary brain tumours (OR 0.5; 95% CI 0.3-0.8). CONCLUSIONS: Sub-groups of patients diagnosed with or being prescribed certain medications targeting nervous system diseases and mental and behavioural disorders may be at increased risk of being diagnosed with a primary brain tumour. Further studies should disentangle the potential underlying common pathogenetic pathways. The results are important for the development of systematic clinical approaches to ensure early diagnosis of primary brain tumours.

Genetically determined high activity of IL-12 and IL-18 in ulcerative colitis and TLR5 in Crohns disease were associated with non-response to anti-TNF therapy.

Anti-tumour necrosis factor-α (TNF-α) is used for treatment of severe cases of inflammatory bowel diseases (IBD), including Crohn's disease (CD) and ulcerative colitis (UC). However, one-third of the patients do not respond to the treatment. A recent study indicated that genetically determined high activity of pro-inflammatory cytokines, including interleukin-1ß (IL-1ß), IL-6 and interferon gamma (IFN-γ), are associated with non-response to anti-TNF therapy. Using a candidate gene approach, 21 functional single-nucleotide polymorphisms (SNPs) in 14 genes in the Toll-like receptors, the inflammasome and the IFNG pathways were assessed in 482 and 256 prior anti-TNF naïve Danish patients with CD and UC, respectively. The results were analysed using logistic regression (adjusted for age and gender). Eight functional SNPs were associated with anti-TNF response either among patients with CD (TLR5 (rs5744174) and IFNGR2 (rs8126756)), UC (IL12B (rs3212217), IL18 (rs1946518), IFNGR1 (rs2234711), TBX21 (rs17250932) and JAK2 (rs12343867)) or in the combined cohort of patient with CD and UC (IBD) (NLRP3 (rs10754558), IL12B (rs3212217) and IFNGR1 (rs2234711)) (P<0.05). Only the association with heterozygous genotype of IL12B (rs3212217) (OR: 0.24, 95% CI: 0.11-0.53, P=0.008) among patients with UC withstood Bonferroni correction for multiple testing. In conclusion, Our results suggest that SNPs associated with genetically determined high activity of TLR5 among patients with CD and genetically determined high IL-12 and IL-18 levels among patients with UC were associated with non-response. Further studies will evaluate whether these genes may help stratifying patients according to the expected response to anti-TNF treatment.

Associations between functional polymorphisms in the NFκB signaling pathway and response to anti-TNF treatment in Danish patients with inflammatory bowel disease.

Antitumor necrosis factor-α (TNF-α) is used for treatment of severe cases of inflammatory bowel diseases (IBD), including Crohn's disease (CD) and ulcerative colitis (UC). However, one-third of the patients do not respond to the treatment. Genetic markers may predict individual response to anti-TNF therapy. Using a candidate gene approach, 39 mainly functional single nucleotide polymorphisms (SNPs) in 26 genes regulating inflammation were assessed in 738 prior anti-TNF-naive Danish patients with IBD. The results were analyzed using logistic regression (crude and adjusted for age, gender and smoking status). Nineteen functional polymorphisms that alter the NFκB-mediated inflammatory response (TLR2 (rs3804099, rs11938228, rs1816702, rs4696480), TLR4 (rs5030728, rs1554973), TLR9 (rs187084, rs352139), LY96 (MD-2) (rs11465996), CD14 (rs2569190), MAP3K14 (NIK) (rs7222094)), TNF-α signaling (TNFA (TNF-α) (rs361525), TNFRSF1A (TNFR1) (rs4149570), TNFAIP3(A20) (rs6927172)) and other cytokines regulated by NFκB (IL1B (rs4848306), IL1RN (rs4251961), IL6 (rs10499563), IL17A (rs2275913), IFNG (rs2430561)) were associated with response to anti-TNF therapy among patients with CD, UC or both CD and UC (P ⩽ 0.05). In conclusion, the results suggest that polymorphisms in genes involved in activating NFκB through the Toll-like receptor (TLR) pathways, genes regulating TNF-α signaling and cytokines regulated by NFκB are important predictors for the response to anti-TNF therapy among patients with IBD. Genetically strong TNF-mediated inflammatory response was associated with beneficial response. In addition, the cytokines IL-1ß, IL-6 and IFN-γ may be potential targets for treating patients with IBD who do not respond to anti-TNF therapy. These findings should be examined in independent cohorts before these results are applied in a clinical setting.

Secular changes in health care utilization and work absence for migraine and tension-type headache: a population based study.

OBJECTIVE: To assess changes in consultation rates, medication use and work absences due to migraine and tension-type headache (TTH) in Denmark over a 12-year period. METHODS: Surveys of the general population in 1989 and 2001. Medical doctors conducted all headache diagnostic interviews based on ICDH-I and II. The participation rate was 76% (740) in 1989 and 74% (711) in 2001. Headache status was categorized as pure migraine, pure frequent TTH (frequent episodic or chronic TTH), coexisting migraine and frequent TTH, and healthy subjects (no primary headache or only infrequent TTH). RESULTS: Headache-related consultation rates (OR = 1.6 (1.1-2.2)), especially specialist consultations (OR = 3.6 (2.3-5.6)), increased for all headache groups. Use of prescription medication because of headache increased moderately (OR = 2.1 (1.1-3.9)) while the use of prophylactic medication was stable (OR = 1.1 (0.3-4.0)). Both headache-related (OR = 1.1 (0.7-1.7)) and overall (OR = 0.9 (0.7-1.2)) absence rates were largely unchanged. Headache-related absence rates were higher for subjects with both headache types (OR = 7.5 (4.3-13.1)) or with pure migraine (OR = 3.6 (2.0-6.6)) than for subjects with frequent TTH alone. Triptans users had higher migraine headache frequency and tended to have higher absence rates than non-users. Overall absence rates were higher for subjects with both headache types (OR = 2.3 (1.3-4.0)) or with frequent TTH (OR = 1.9 (1.4-2.7)) than for healthy subjects. Pure migraine was not associated with higher overall absence rates (OR = 1.0 (0.6-1.6)). CONCLUSION: Despite an increase in headache consultation rates and in use of prescription medication and triptans, no improvement in work absence rates was observed. Consultations, medication use, and absence rates were highest for individuals with both migraine and frequent TTH.

Incidence of primary headache: a Danish epidemiologic follow-up study.

The incidence of migraine in a general population has been assessed in few longitudinal studies, and the incidence of tension-type headache has never been assessed. The authors aimed to assess the incidence of migraine and tension-type headache in Denmark by conducting a 12-year follow-up study of a general population (1989-2001). The design and methods of follow-up replicated the baseline study exactly, including use of the International Headache Society's diagnostic criteria and administration of headache diagnostic interviews by a physician. Of 740 persons aged 25-64 years examined in 1989, 673 were eligible in 2001 and 549 (81.6%) participated. The incidence of migraine was 8.1 per 1,000 person-years (male:female ratio, 1:6), and the incidence of frequent tension-type headache was 14.2 per 1,000 person-years (male:female ratio, 1:3). Both rates decreased with age. The incidence of migraine was higher than that previously calculated from cross-sectional studies. Risk factors for migraine were familial disposition, no vocational education, a high work load, and frequent tension-type headache. For tension-type headache, risk factors were poor self-rated health, inability to relax after work, and sleeping few hours per night. The gender difference for tension-type headache differed from that for migraine, and no association with educational level was observed.

Epidemiology of headache.

Headache disorders constitute a public-health problem of enormous proportions, with an impact on both the individual sufferer and society. Epidemiological knowledge is required to quantitate the significance of these disorders. The effects on individuals can be assessed by examining prevalence, distribution, attack frequency and duration, and headache-related disability. The socio-economic burden includes both direct costs associated with health care utilization and costs associated with missed work due to sickness absence or reduced efficiency. The individual and socio-economic burden of headaches is substantial. Headache disorders deserve more attention, especially concerning strategies leading to adequate primary prevention, diagnosis and treatment.

The impact of migraine: Epidemiology, risk factors, and co-morbidities.

In Western countries, recent community-based studies of migraine prevalence using standardized diagnostic criteria give 1-year prevalence estimates of around 10 to 12%. The prevalence of migraine is age- and gender-dependent. Age at onset of migraine is earlier in boys than in girls. Migraine is two to three times more common in women than in men, with peak prevalence occurring during mid-life in both sexes. Current evidence also indicates that migraine prevalence is higher in Caucasians than in Africans or Asians. In some migraineurs, attacks may be frequent or prolonged, leading to considerable pain and disability. There has been much debate over predisposing factors, which are not sufficient by themselves to cause an attack, as well as precipitants, which immediately precede the attack. However, convincing data are lacking for most of these. Significant associations have been reported between migraine and certain psychiatric disorders, epilepsy, and stroke in women under the age of 45. These findings demonstrate that migraine is common, has a substantial impact on sufferers, and may be associated with other disorders.

Epidemiology and socio-economic impact of headache.

Headache disorders constitute a public-health problem of enormous proportions, with an impact on both the individual sufferer and society. Epidemiological knowledge is required to quantitate the significance of these disorders. The effects on individuals can be assessed by examining prevalence, distribution, attack frequency and duration, and headache-related disability. The socio-economic burden includes both direct costs associated with healthcare utilization and costs associated with missed work due to sickness absence or reduced efficiency. The individual and socio-economic burden of headaches is substantial. Headache disorders deserve more attention, especially concerning strategies leading to adequate primary prevention, diagnosis, and treatment.

Basal serum pancreatic polypeptide is dependent on age and gender in an adult population.

This study is the first epidemiologically based study of basal levels of serum pancreatic polypeptide (s-PP). The basal level of serum PP has become a field of interest mainly due to the role of PP as an endocrine tumour marker, and as a marker of pancreatic neuroendocrine function after pancreas transplantation and in the case of diabetic autonomic neuropathy. The study population consisted of primarily Caucasian adults representative of a general population living around Copenhagen. Serum pancreatic polypeptide was measured in random serum samples from fasting persons (n = 623), aged 25-64 y, using a monospecific radioimmunoassay. Fasting serum pancreatic polypeptide depended on age and gender. The results demonstrated that fasting pancreatic polypeptide levels increase exponentially with age. Fitted separately for each sex, basal serum pancreatic polypeptide was found to increase by approximately 3% per year of age. Males had higher concentrations of pancreatic polypeptide in serum compared to age-matched females. Normal range and 95% reference intervals are given. The lower limit for the reference interval of the normal range was close to detection limit. We conclude that discrepancies among earlier reports on the fasting levels of serum pancreatic polypeptide are most likely due to lack of adjustment for age and gender. Thus, variation due to age and gender should be considered in evaluating fasting levels of serum pancreatic polypeptide. Whether similar considerations are important when evaluating stimulated serum pancreatic polypeptide levels remains to be elucidated.

The International Headache Society classification of chronic daily and near-daily headaches: a critique of the criticism.

The classification of the International Headache Society (IHS) published in 1988 has been positively received throughout the world. However, the classification of headaches occurring daily or almost daily has been criticized repeatedly. This criticisim is discussed in the present review. It is possible to classify virtually all chronic headache patients using the IHS Classification and there seems to be more need for emphasizing a correct application of the classification than for a revision in this regard. The entity of transformed migraine is disputed and so is the existence of hemicrania continua. Neither of these syndromes has been adequately defined nor studied. Chronic daily headache of sudden onset (new persistent daily headache) is not adequately classified at present and should be included as a separate entity in the next edition of the IHS Classification. In a future revision it should also be possible to classify drug-related headache simply on the basis of drug consumption and without mandatory demands for withdrawal. Better longitudinal studies of patients with chronic daily headache are necessary to evaluate finally whether a revision of the classification of these headache syndromes is necessary. Eventually the ongoing discovery of migraine genes is likely to change radically the classification of migraine.

Migraine without aura and migraine with aura are distinct clinical entities: a study of four hundred and eighty-four male and female migraineurs from the general population.

The clinical characteristics of migraine without aura (MO) and migraine with aura (MA) were compared in 484 migraineurs from the general population. We used the criteria of the International Headache Society. The lifetime prevalence of MO was 14.7% with a M:F ratio of 1:2.2; that of MA was 7.9% with a M:F ratio of 1:1.5. The female preponderance was significant in both MO and MA. The female preponderance was present in all age groups in MA, but was first apparent after menarche in MO, suggesting that female hormones are an initiating factor in MO, but not likely so in MA. The age at onset of MO followed a normal distribution, whereas the age at onset of MA was bimodally distributed, which could be explained by a composition of two normal distributions. The estimated separation between the two groups of MA was at age 26 years among the females and age 31 years among the males. The observed number of persons with co-occurrence of MO and MA was not significantly different from the expected number. The specificity and importance of premonitory symptoms are questioned, but prospective studies are needed. Bright light was a precipitating factor in MA, but not in MO. Menstruation was a precipitating factor in MO, but not likely in MA. Both MO and MA improved during pregnancy. The clinical differences indicate that MO and MA are distinct entities.

Muscular disorders in tension-type headache.

In order to evaluate the diagnostic criteria for muscular disorders in tension-type headache, pericranial muscle tenderness and pressure pain thresholds were studied in a random sample population of 735 adults aged 25-64. In addition, quantitative EMGs were recorded in 547 of these subjects. The correlation between the three diagnostic tests was assessed and the discriminality and cut-off points were analysed using Receiver Operating Characteristics analysis. Local tenderness from the temporal muscles was closely related to the total tenderness scores from 14 pairs of muscles. In chronic tension-type headache, tenderness was positively related to EMG and inversely related to pain thresholds. In the episodic from the total tenderness score was inversely related to pain thresholds, whereas no significant relation to EMG was noted. The Receiver Operating Characteristics curves indicated that tenderness recorded by manual palpation was the most specific and sensitive test, whereas EMG and pain thresholds were of limited diagnostic value. Eighty-seven percent of subjects with the chronic, and 66% of subjects with the episodic form were found to have a "muscular disorder" defined as increased tenderness recorded by either manual palpation or pressure algometry and/or increased EMG levels. However, muscle tenderness increased significantly during pain, so the headache state should be considered in future studies. Suggestions for revision of the present diagnostic criteria for muscular disorders are given.

[Prevalence and sex distribution of different forms of migraine]. / Praevalens og kønsfordeling af de forskellige former for migraene.

The aim of this study was to provide prevalence and sex-ratio of subtypes of migraine diagnosed by neurological interview according to the criteria of the International Headache Society. In all, 3000 males and 1000 females aged 40 years were randomly selected from the Danish population. They received a mailed questionnaire regarding migraine. The questionnaire response rate was 87%. People with self-reported migraine and a random sample of those reporting no migraine were invited to a headache interview, and a physical and a neurological examination. Those not reacting to the invitation were interviewed by telephone. Participation in the interview was 87%. Kappa was 0.77 validating self-reported migraine in the questionnaire against the diagnosis of the clinical interview. Lifetime prevalences of migraine without aura, migraine with aura, migraine aura without headache, and migrainous disorder were 8%, 4%, 1% and 1% in males and 16%, 7%, 3% and 2% in females. Overall lifetime prevalence of any type of migraine was 18%, 12% in males and 24% in females. This is lower than the sum of the prevalences since migraine diagnoses are not mutually exclusive. The male:female ratios of migraine without aura, migraine with aura, migraine aura without headache, and migrainous disorder were approximately 1:2.

Prevalence and sex-ratio of the subtypes of migraine.

BACKGROUND: The aim of this study was to provide the prevalence and sex-ratio of subtypes of migraine diagnosed by neurological interview according to the criteria of the International Headache Society. METHODS: In all, 3000 males and 1000 females aged 40 years were randomly selected from the Danish population. They received a mailed questionnaire regarding migraine. The questionnaire response rate was 87%. People with self-reported migraine and a random sample of those reporting no migraine were invited to a headache interview, and a physical and a neurological examination. Those not reacting to the invitation were interviewed by telephone. Participation at the interview was 87%. Kappa was 0.77 validating self-reported migraine in the questionnaire against the diagnosis of the clinical interview. RESULTS: Lifetime prevalences of migraine without aura, migraine with aura, migraine aura without headache, and migrainous disorder were 8%, 4%, 1% and 1% in males and 16%, 7%, 3% and 2% in females. Overall lifetime prevalence of any type of migraine was 18%; 12% in males and 24% in females. This is lower than the sum of the prevalences since migraine diagnoses are not mutually exclusive. The male:female ratios of migraine without aura, migraine with aura, migraine aura without headache, and migrainous disorder were approximately 1:2. CONCLUSIONS: Migraine is more prevalent than previously thought. There was a significant preponderance in females of all the subtypes of migraine except migrainous disorder.

Epidemiology of headache.

This thesis is based on nine previously published papers. It represents the first prevalence study of specific headache entities in a representative general population, where the diagnoses are based on a structural interview and examination by a physician using internationally accepted operational diagnostic criteria. The study population was a random sample of 1000 men and women aged 25-64. The participation rate was 76%. The prevalences of the different forms of headache are assessed and the study provides descriptive data concerning symptomatology, precipitating factors, impact of female hormones, use of medical services and work consequences of the headache disorders and describes various factors associated with the disorders. Only half of migraineurs and one-sixth of subjects with tension-type headache consulted their general practitioner because of headache and even less consulted a specialist. These consultation rates reflect the selection of cases that may bias studies in clinic populations. The study supports the notion that migraine and tension-type headache are separate clinical entities and that migraine without aura and migraine with aura are distinct subforms of migraine. Migraine and tension-type headache are sex- and age-dependent disorders with female preponderance and lower prevalence in older age groups. The female preponderance may be explained by clinical factors related to female hormones. There is no clear evidence of any association between sociodemographic variables and migraine or tension-type headache. Tension-type headache is related to a series of psychosocial variables while migraine is not. The results suggest that migraine is primarily a constitutional disorder and tension-type headache a more complex phenomenon influenced by several psychosocial factors. The limitations of cross-sectional data in pointing out risk factors with sufficient certainty are stressed. Longitudinal follow-up studies are the most important challenge in future epidemiological headache research.

Classification of primary headaches.

In 1988, the International Headache Society (IHS) classification committee published operational diagnostic criteria for the primary headaches and a broad range of other headache disorders. These criteria have been translated into more than ten languages, providing uniform terminology for clinical practice, multinational clinical trials, and biologic and epidemiologic research. The criteria have also been evaluated in a number of field studies intended to address their generalizability, exhaustiveness, reliability, and validity. In the present publication the IHS criteria for migraine and tension-type headache are presented.