Christoph Schankin

Brain activations in the premonitory phase of nitroglycerin-triggered migraine attacks

Our aim was identify brain areas involved in the premonitory phase of migraine using functional neuroimaging. To this end, we performed positron emission tomography scans with H2(15)O to measure cerebral blood flow as a marker of neuronal activity. We conducted positron emission tomography scans at baseline, in the premonitory phase without pain and during migraine headache in eight patients. We used glyceryl trinitrate (nitroglycerin) to trigger premonitory symptoms and migraine headache in patients with episodic migraine without aura who habitually experienced premonitory symptoms during spontaneous attacks. The main outcome was comparing the first premonitory scans in all patients to baseline scans in all patients. We found activations in the posterolateral hypothalamus, midbrain tegmental area, periaqueductal grey, dorsal pons and various cortical areas including occipital, temporal and prefrontal cortex. Brain activations, in particular of the hypothalamus, seen in the premonitory phase of glyceryl trinitrate-triggered migraine attacks can explain many of the premonitory symptoms and may provide some insight into why migraine is commonly activated by a change in homeostasis.

Malignant gliomas actively recruit bone marrow stromal cells by secreting angiogenic cytokines

The transplantation of progenitor cells is a promising new approach for the treatment of gliomas. Marrow stromal cells (MSC) are possible candidates for such a cell-based therapy, since they are readily and autologously available and show an extensive tropism to gliomas in vitro and in vivo. However, the signals that guide the MSC are still poorly understood. In this study, we show that gliomas have the capacity to actively attract MSC by secreting a multitude of angiogenic cytokines. We demonstrate that interleukin-8 (IL-8), transforming growth factor-ß1 (TGF-ß1) and neurotrophin-3 (NT-3) contribute to this glioma-directed tropism of human MSC. Together with the finding that vascular endothelial growth factor (VEGF) is another MSC-attracting factor secreted by glioma cells, these data support the hypothesis that gliomas use their angiogenic pathways to recruit mesenchymal progenitor cells.

Genome-wide association analysis of genetic generalized epilepsies implicates susceptibility loci at 1q43, 2p16.1, 2q22.3 and 17q21.32

Genetic generalized epilepsies (GGEs) have a lifetime prevalence of 0.3% and account for 20-30% of all epilepsies. Despite their high heritability of 80%, the genetic factors predisposing to GGEs remain elusive. To identify susceptibility variants shared across common GGE syndromes, we carried out a two-stage genome-wide association study (GWAS) including 3020 patients with GGEs and 3954 controls of European ancestry. To dissect out syndrome-related variants, we also explored two distinct GGE subgroups comprising 1434 patients with genetic absence epilepsies (GAEs) and 1134 patients with juvenile myoclonic epilepsy (JME). Joint Stage-1 and 2 analyses revealed genome-wide significant associations for GGEs at 2p16.1 (rs13026414, P(meta) = 2.5 × 10(-9), OR[T] = 0.81) and 17q21.32 (rs72823592, P(meta) = 9.3 × 10(-9), OR[A] = 0.77). The search for syndrome-related susceptibility alleles identified significant associations for GAEs at 2q22.3 (rs10496964, P(meta) = 9.1 × 10(-9), OR[T] = 0.68) and at 1q43 for JME (rs12059546, P(meta) = 4.1 × 10(-8), OR[G] = 1.42). Suggestive evidence for an association with GGEs was found in the region 2q24.3 (rs11890028, P(meta) = 4.0 × 10(-6)) nearby the SCN1A gene, which is currently the gene with the largest number of known epilepsy-related mutations. The associated regions harbor high-ranking candidate genes: CHRM3 at 1q43, VRK2 at 2p16.1, ZEB2 at 2q22.3, SCN1A at 2q24.3 and PNPO at 17q21.32. Further replication efforts are necessary to elucidate whether these positional candidate genes contribute to the heritability of the common GGE syndromes.

Characteristics of brain tumour-associated headache.

Eighty-five brain tumour patients were examined for further characteristics of brain tumour-associated headache. The overall prevalence of headache in this population was 60%, but headache was the sole symptom in only 2%. Pain was generally dull, of moderate intensity, and not specifically localized. Nearly 40% met the criteria of tension-type headache. An alteration of the pain with the occurrence of the tumour was experienced by 82.5%, implying that the preexisting and the brain tumour headaches were different. The classic characteristics mentioned in the International Classification of Headache Disorders (worsening in the morning or during coughing) were not found; this might be explained by the patients not having elevated intracranial pressure. Univariate analysis revealed that a positive family history of headache and the presence of meningiomas are risk factors for tumour-associated headache, and the use of β-blockers is prophylactic. Pre-existing headache was the only risk factor according to logistic regression, suggesting that patients with pre-existing (primary) headache have a greater predisposition to develop secondary headache. Dull headache occurs significantly more often in patients with glioblastoma multiforme, and pulsating headache in patients with meningioma. In our study, only infratentorial tumours were associated with headache location, and predominantly with occipital but rarely frontal pain.

Burden Analysis of Rare Microdeletions Suggests a Strong Impact of Neurodevelopmental Genes in Genetic Generalised Epilepsies

Genetic generalised epilepsy (GGE) is the most common form of genetic epilepsy, accounting for 20% of all epilepsies. Genomic copy number variations (CNVs) constitute important genetic risk factors of common GGE syndromes. In our present genome-wide burden analysis, large (≥ 400 kb) and rare (< 1%) autosomal microdeletions with high calling confidence (≥ 200 markers) were assessed by the Affymetrix SNP 6.0 array in European case-control cohorts of 1,366 GGE patients and 5,234 ancestry-matched controls. We aimed to: 1) assess the microdeletion burden in common GGE syndromes, 2) estimate the relative contribution of recurrent microdeletions at genomic rearrangement hotspots and non-recurrent microdeletions, and 3) identify potential candidate genes for GGE. We found a significant excess of microdeletions in 7.3% of GGE patients compared to 4.0% in controls (P = 1.8 x 10-7; OR = 1.9). Recurrent microdeletions at seven known genomic hotspots accounted for 36.9% of all microdeletions identified in the GGE cohort and showed a 7.5-fold increased burden (P = 2.6 x 10-17) relative to controls. Microdeletions affecting either a gene previously implicated in neurodevelopmental disorders (P = 8.0 x 10-18, OR = 4.6) or an evolutionarily conserved brain-expressed gene related to autism spectrum disorder (P = 1.3 x 10-12, OR = 4.1) were significantly enriched in the GGE patients. Microdeletions found only in GGE patients harboured a high proportion of genes previously associated with epilepsy and neuropsychiatric disorders (NRXN1, RBFOX1, PCDH7, KCNA2, EPM2A, RORB, PLCB1). Our results demonstrate that the significantly increased burden of large and rare microdeletions in GGE patients is largely confined to recurrent hotspot microdeletions and microdeletions affecting neurodevelopmental genes, suggesting a strong impact of fundamental neurodevelopmental processes in the pathogenesis of common GGE syndromes.

Self-reported muscle pain in adolescents with migraine and tension-type headache

Aim: To identify possible associations between muscular pain and headache in adolescents in a large population-based sample. Methods: Grammar school students were invited to fill in a questionnaire on headache and associated lifestyle factors. Headache was classified according to the German version of the International Classification of Headache Disorders (2nd edition). Muscular pain was assessed via denoting affected areas in schematic drawings of a body and via provoked muscular pain on controlled movements of head, neck and shoulder regions. Results: Prevalence of any headache within the previous 6 months exceeded 80%. In all subjects muscular pain or pain on movement was most prominent in the neck and shoulder region, ranging from 9% to 27% in the non-headache population to up to 63% for individuals with migraine or mixed migraine and tension-type headache (TTH). Frequency of muscular pain increased significantly with growing chronicity of TTH. Interpretation: A strong association between muscle pain in the neck/shoulder region and headache was observed, pointing to the importance of muscular pain for headache in adolescents. Also, in this age group muscular pain appears to be of particular importance in chronic TTH and – unexpectedly – in migraine, which is the most important new finding in our study.

Rare exonic deletions of the RBFOX1 gene increase risk of idiopathic generalized epilepsy

Structural variations disrupting the gene encoding the neuron‐specific splicing regulator RBFOX1 have been reported in three patients exhibiting epilepsy in comorbidity with other neuropsychiatric disorders. Consistently, the Rbfox1 knockout mouse model showed an increased susceptibility of seizures. The present candidate gene study tested whether exon‐disrupting deletions of RBFOX1 increase the risk of idiopathic generalized epilepsies (IGEs), representing the largest group of genetically determined epilepsies.

The Relation Between Migraine, Typical Migraine Aura and “Visual Snow”

To assess the relationship between the phenotype of the “visual snow” syndrome, comorbid migraine, and typical migraine aura on a clinical basis and using functional brain imaging.

Associations between stress and migraine and tension-type headache: results from a school-based study in adolescents from grammar schools in Germany.

Introduction: Stress is considered the major contributor to migraine and tension-type headache in adolescents. Previous studies have focused on general stressors, whereas the aim of the present study was to investigate associations between individuals’ stressful experiences and different types of headache. Methods: Adolescents from 10th and 11th grades of grammar schools filled in questionnaires. Stressful experiences were measured with the Trier Inventory of Chronic Stress. Type of headache was classified according to the International Classification of Headache Disorders. Linear regressions, adjusted for sex and grade, were calculated to estimate differences in stress scores that can be attributed to migraine, tension-type headache or miscellaneous headache. Results: A total of 1260 questionnaires were analysed. Tension-type headache, migraine and co-existing migraine plus tension-type headache were found in 48.7%, 10.2% and 19.8% of the participants. In subjects with migraine or co-existing migraine plus tension-type headache, high increases in stress scores were found in all investigated dimensions, whereas much weaker and inconsistent associations were found in subjects with tension-type headache only. Conclusions: The characteristic of migraine is more associated with stressful experiences than this is the case for tension-type headache. This suggests that adolescent migraine patients might especially benefit from behavioural interventions regarding stress.

Headache syndromes after acoustic neuroma surgery and their implications for quality of life

The patients of this prospective study were analysed for headache as a sequela of surgery for acoustic neuroma (AN). Thirty-two per cent (30/95) of patients complained about a persisting headache syndrome with a severity of at least 6/10 on the nominal analogue scale 6 months after surgery. The occurrence of headache was significantly correlated with the prospectively evaluated parameters preoperative headache and the number of perioperative complications. Postoperative failure to return to the preoperative level of activity was also associated with the occurrence of headache, but also with the risk of retirement after successful surgery of the AN. Headache is therefore, like postoperative ataxia, dysgeusia and probably facial paresis, an important factor for the overall outcome of patients after AN surgery. Hypacusis is not as important. The symptoms and course of each individual patient were analysed. The attempt to categorize the headaches according to the second edition of the International Classification of Headache Disorders revealed five headache syndromes, the most prevalent being tension-type-like headache (46.7%), followed by neuralgia of the occipital nerve (16.6%), trigeminal neuropathy (16.6%), neuropathy of the intermedian nerve (10.0%) and cervicogenic headache (10.0%). The respective pathophysiological mechanisms are discussed and treatment options based on the clinical picture are presented.