Christian Kienbacher

Psychosocial factors in children and adolescents with migraine and tension‐type headache: a controlled study and review of the literature

We investigated 341 children and adolescents to evaluate the relevance of psychosocial factors in idiopathic headache. According to the criteria of the International Headache Society, 151 subjects had migraine and 94 had tension-type headache (TTH). Ninety-six subjects were headache-free controls. Psychosocial factors covered family and housing conditions, school problems, relations in the peer group, and several other items. We found that migraine patients did not differ from headache-free controls. Patients with TTH more often had divorced parents than the headache-free controls, and they had fewer peer relations than migraineurs and controls. In addition, migraine patients were significantly more often absent from school due to headache. All other psychosocial factors failed to discriminate between the three study groups. In conclusion, this controlled study in children and adolescents suggests that migraine is not related to family and housing conditions, school situation, or peer relations, whereas TTH is associated with a higher rate of divorced parents and fewer peer relations.

Clinical Features, Classification and Prognosis of Migraine and Tension-Type Headache in Children and Adolescents: A Long-Term Follow-Up Study

We performed a long-term follow-up examination in children and adolescents with migraine and tension-type headache (TTH) in order to investigate the evolution of clinical features and headache diagnoses, to compare International Classification of Headache Disorders (ICHD)-I and ICHD-II criteria and to identify prognostic factors. We re-examined 227 patients (52.4± female, age 17.6 ± 3.1 years) 6.6 ± 1.6 years after their first presentation to a headache centre using identical semistructured questionnaires. Of 140 patients initially diagnosed with migraine, 25.7± were headache free, 48.6± still had migraine and 25.7± had TTH at follow-up. Of 87 patients with TTH, 37.9± were headache free, 41.4± still had TTH and 20.7± had migraine. The number of subjects with definite migraine was higher in ICHD-II than in ICHD-I at baseline and at follow-up. The likelihood of a decrease in headache frequency decreased with a changing headache location at baseline (P < 0.0001), with the time between baseline and follow-up (P = 0.0019), and with an initial diagnosis of migraine (P = 0.014). Female gender and a longer time between headache onset and first examination tended to have an unfavourable impact. In conclusion, 30± of the children and adolescents presenting to a headache centre because of migraine or TTH become headache-free in the long-term. Another 20–25± shift from migraine to TTH or vice versa. ICHD-II criteria are superior to those of ICHD-I in identifying definite migraine in children and adolescents presenting to a headache centre. The prognosis is adversely affected by an initial diagnosis of migraine and by changing headache location, and it tends to be affected by an increasing time between headache onset and first presentation.

Clinical features of migraine: a cross‐sectional study in patients aged three to sixty‐nine

We investigated 260 consecutive patients classified as migraine cases aged 3-69 at two tertiary headache centres, one for children and adolescents and the other for adults to evaluate the relationship between age and clinical features of migraine cross-sectionally. We only included subjects with definite migraine without or with aura and we excluded subjects with coexisting tension-type headache, medication overuse and/or other clinically relevant disorders. The percentage of males decreased markedly from childhood to adulthood and this affected the evalution of age-related changes in male patients, as only large differences reached the level of statistical significance. In females, the headache duration and the prevalence of unilateral, pulsating pain, photophobia and phonophobia increased, whereas the prevalence of aggravation by physical activity decreased with age. In conclusion, this cross-sectional, clinic-based study on a strictly defined sample of 260 consecutive patients with definite migraine covering a wide range of age from the very young to the old suggests marked age-related differences of the clinical features of migraine in females and failed to demonstrate similar differences in males due to the small number of adult male migraineurs.

A dopamine D4 receptor exon 3 VNTR allele protecting against migraine without aura.

As dopamine plays an important role in the pathophysiology of migraine and antimigraine drugs have an effect on the dopamine system, the objective of this study was to examine the dopamine D4 receptor gene for involvement in the cause of migraine.

Therapeutic Role of Bile Acids and Nuclear Receptor Agonists in Fibrosing Cholangiopathies

Chronic inflammatory bile duct diseases such as primary biliary cirrhosis (PBC) and primary sclerosing cholangitis (PSC) result in progressive fibrosis of the biliary tract and ultimately cirrhosis of the liver. Since the etiology and pathogenesis of these fibrosing cholangiopathies are still poorly understood, therapeutic options are rather limited at present. Ursodeoxycholic acid (UDCA) is the paradigm therapeutic bile acid and established standard treatment for PBC, but its role for medical therapy of PSC is still under debate. Promising novel bile acid-based therapeutic options include 24-norursodeoxycholic acid, a side chain-shortened C23 homologue of UDCA, and bile acid receptor/farnesoid X receptor agonists (e.g. obeticholic acid) which currently undergo clinical development for fibrosing cholangiopathies such as PBC and PSC. Other nuclear receptors such as vitamin D receptor and fatty acid-activated peroxisome proliferator-activated receptors are also of considerable interest. This review article is a summary of an overview talk given at Falk Symposium 191 on Advances in Pathogenesis and Treatment of Liver Diseases held in London, October 3-4, 2013, and summarizes the recent progress with novel therapeutic bile acids and bile acid derivatives as novel therapies for fibrosing cholangiopathies such as PBC and PSC.

Challenges and Management of Liver Cirrhosis: Practical Issues in the Therapy of Patients with Cirrhosis due to NAFLD and NASH.

Nonalcoholic fatty liver disease (NAFLD) is the hepatic manifestation of the metabolic syndrome and comprises a liver disease spectrum ranging from steatosis to nonalcoholic steatohepatitis (NASH) with risk of progression to liver cirrhosis and hepatocellular carcinoma (HCC). Associated metabolic conditions and comorbidities such as obesity, diabetes and cardiovascular diseases are common and require concerted management. Adiponutrin (PNPLA3) variants may help to identify NAFLD patients at higher risk for liver disease progression towards advanced fibrosis and HCC. The therapeutic options in NAFLD/NASH include lifestyle modification, pharmacological treatment, bariatric surgery for patients with morbid obesity and treatment of complications of liver cirrhosis and HCC, including liver transplantation. Insulin sensitizers and antioxidative treatment strategies with vitamin E are among the best-established pharmacological approaches, but both drugs have long-term safety issues and there is limited evidence in cirrhotic patients. Treatment of concomitant/underlying metabolic conditions with statins or metformin may also have beneficial effects on portal hypertension, complications of liver cirrhosis and HCC prevention. The bile acid receptor FXR may be a promising novel therapeutic target for the treatment of NAFLD/NASH, fibrosis and portal hypertension, but the prognostic implications of associated changes in low- and high-density lipoprotein cholesterol require further studies. Morbidly obese NASH patients can benefit from bariatric surgery which may reduce liver fibrosis but carries a risk of decompensation in patients with advanced liver cirrhosis. When carefully selected, patients with NASH cirrhosis undergoing liver transplantation have a good outcome. This review summarizes recent progress in the management of patients with liver cirrhosis due to NASH.

Low hepatic copper content and PNPLA3 polymorphism in non-alcoholic fatty liver disease in patients without metabolic syndrome

INTRODUCTION The pathogenesis of non-alcoholic fatty liver disease (NAFLD) is multifactorial including metabolic, genetic (e.g. PNPLA3 [patatin-like phospholipase domain-containing 3 gene]), viral factors and drugs. Besides, there is evidence for a role of copper deficiency. Aim of the study was to evaluate the role of hepatic copper content, PNPLA3 in NAFLD patients with and without metabolic syndrome (MetS). METHODS One-hundred seventy-four NAFLD patients, who underwent liver biopsy for diagnostic work-up, were studied. Diagnosis of MetS was based on the WHO Clinical Criteria. Steatosis was semiquantified as percentage of fat containing hepatocytes and was graded according to Brunt. Histological features of non-alcoholic steatohepatitis (NASH) were assessed using the Bedossa classification. Hepatic copper content (in μg/g dry weight) was measured by flame atomic absorption spectroscopy. SNP rs738409 in PNPLA3 was investigated by RT-PCR. RESULTS Mean hepatic copper content was 22.3 (19.6-25.1) μg/g. The mean percentage of histologically lipid containing hepatocytes was 42.2% (38.3-46.0) and correlated inversely with hepatic copper content (ρ=-0.358, P<0.001). By subgroup analysis this inverse correlation remained significant only in patients without MetS (OR: 0.959 [CI95%: 0.926-0.944], P=0.020). Presence of minor allele (G) of PNPLA3 was also associated with moderate/severe steatosis (≥33%) both in patients with (OR: 2.405 [CI95%: 1.220-4.744], P=0.011) and without MetS (OR: 2.481 [CI95%: 1.172-5.250], P=0.018), but was only associated with NASH (OR: 2.002 [CI95%: 1.062-3.772], P=0.032) and liver fibrosis (OR: 2.646 [CI95%: 1.299-5.389], P=0.007) in patients without MetS. CONCLUSION Hepatic copper content and PNPLA3 mutations are associated with disease activity in NAFLD patients without MetS. Presence of MetS appears to mask the effects of hepatic copper and PNPLA3.

Association analysis of STX1A gene variants in common forms of migraine

Objectives: To examine the association of genetic variants in the syntaxin 1A gene (STX1A) with common forms of migraine, and perform a combined analysis of the data from the current study and previously published reports. Methods: We investigated the parent-to-offspring transmission of rs6951030, rs4363087 and rs2293489 in 191 family trios, each with a proband with childhood-onset migraine, and performed a case-control analysis between the probands and 223 unrelated controls. In addition, we performed a combined data analysis with an overall sample of 567 migraine patients and 720 unrelated controls and performed a migraine-specific gene-network analysis. Results: The transmission disequilibrium test revealed significant transmission distortion of rs4363087 in migraine overall (OR = 1.56, p = 0.006; p = 0.01 after correction for multiple testing) and migraine without aura (OR = 1.58, p = 0.01; corrected p = 0.04). Two-marker haplotype analysis revealed transmission distortion of A-G (rs6951030-rs4363087; OR = 1.47, p = 0.01) and A-C (rs4363087-rs2293489; OR = 0.66, p = 0.01). Combined analysis showed significant association of rs941298 with migraine overall (OR = 1.28, p = 0.004) and migraine without aura (OR = 1.3, p = 0.008). Network analysis identified 24 genes relating STX1A to other migraine candidate genes, including KCNK18 (TRESK channel) involved in the cytoplasmatic calcium signalling together with syntaxin 1A. Conclusion: Our results provide support for the hypothesis that STX1A represents a susceptibility gene for migraine.

Family-based association analysis of functional VNTR polymorphisms in the dopamine transporter gene in migraine with and without aura

Summary.Because of the role of dopamine in triggering migraine attacks, genes of the dopamine system are candidates for involvement in migraine. We examined three VNTR polymorphisms in the dopamine transporter, the 5′UTR VNTR, the intron 8 VNTR and the intron 14 VNTR, in a sample of 205 family trios. We used the transmission disequilibirium test (TDT) to examine the transmission of these three markers and their haplotypes to offspring affected by migraine. We found no significant transmission distortion of any marker. Likewise haplotypes of the three markers did not show significant overall or individual association with migraine. Finally we examined migraine with and without aura, and likewise found no association between dopamine transporter VNTRs or their haplotypes and either classification of the disease. We conclude that functional genetic variation in the dopamine transporter does not act as a significant risk factor for migraine.

No Association Between Bipolar Disorder Risk Polymorphisms in ANK3 and CACNA1C and Common Migraine

(Headache 2011;51:713‐725)