Markus Färkkilä

Genome-wide association study of migraine implicates a common susceptibility variant on 8q22.1

Migraine is a common episodic neurological disorder, typically presenting with recurrent attacks of severe headache and autonomic dysfunction. Apart from rare monogenic subtypes, no genetic or molecular markers for migraine have been convincingly established. We identified the minor allele of rs1835740 on chromosome 8q22.1 to be associated with migraine (P = 5.38 × 10−9, odds ratio = 1.23, 95% CI 1.150–1.324) in a genome-wide association study of 2,731 migraine cases ascertained from three European headache clinics and 10,747 population-matched controls. The association was replicated in 3,202 cases and 40,062 controls for an overall meta-analysis P value of 1.69 × 10−11 (odds ratio = 1.18, 95% CI 1.127–1.244). rs1835740 is located between MTDH (astrocyte elevated gene 1, also known as AEG-1) and PGCP (encoding plasma glutamate carboxypeptidase). In an expression quantitative trait study in lymphoblastoid cell lines, transcript levels of the MTDH were found to have a significant correlation to rs1835740 (P = 3.96 × 10−5, permuted threshold for genome-wide significance 7.7 × 10−5). To our knowledge, our data establish rs1835740 as the first genetic risk factor for migraine.

Genome-wide meta-analysis identifies new susceptibility loci for migraine

Migraine is the most common brain disorder, affecting approximately 14% of the adult population, but its molecular mechanisms are poorly understood. We report the results of a meta-analysis across 29 genome-wide association studies, including a total of 23,285 individuals with migraine (cases) and 95,425 population-matched controls. We identified 12 loci associated with migraine susceptibility (P < 5 × 10−8). Five loci are new: near AJAP1 at 1p36, near TSPAN2 at 1p13, within FHL5 at 6q16, within C7orf10 at 7p14 and near MMP16 at 8q21. Three of these loci were identified in disease subgroup analyses. Brain tissue expression quantitative trait locus analysis suggests potential functional candidate genes at four loci: APOA1BP, TBC1D7, FUT9, STAT6 and ATP5B.

Genome-wide association analysis identifies susceptibility loci for migraine without aura

Migraine without aura is the most common form of migraine, characterized by recurrent disabling headache and associated autonomic symptoms. To identify common genetic variants associated with this migraine type, we analyzed genome-wide association data of 2,326 clinic-based German and Dutch individuals with migraine without aura and 4,580 population-matched controls. We selected SNPs from 12 loci with 2 or more SNPs associated with P values of <1 × 10−5 for replication testing in 2,508 individuals with migraine without aura and 2,652 controls. SNPs at two of these loci showed convincing replication: at 1q22 (in MEF2D; replication P = 4.9 × 10−4; combined P = 7.06 × 10−11) and at 3p24 (near TGFBR2; replication P = 1.0 × 10−4; combined P = 1.17 × 10−9). In addition, SNPs at the PHACTR1 and ASTN2 loci showed suggestive evidence of replication (P = 0.01; combined P = 3.20 × 10−8 and P = 0.02; combined P = 3.86 × 10−8, respectively). We also replicated associations at two previously reported migraine loci in or near TRPM8 and LRP1. This study identifies the first susceptibility loci for migraine without aura, thereby expanding our knowledge of this debilitating neurological disorder.

A randomised, double blind, placebo controlled trial with vitamin D3 as an add on treatment to interferon β-1b in patients with multiple sclerosis

Objectives To study the safety and efficacy of vitamin D3 as an add on therapy to interferon β-1b (IFNB) in patients with multiple sclerosis (MS). Methods 1 year, double blind, placebo controlled, randomised study in 66 MS patients. The primary outcomes were T2 burden of disease (BOD) on MRI scans, proportion of patients with serum levels of 25-hydroxyvitamin D (25(OH)D) ≥85 nmol/l or intact parathyroid hormone (PTH) ≤20 ng/l, and number of adverse events. Secondary outcomes were number of MRI enhancing T1 lesions and new T2 lesions, annual relapse rate, changes in the Expanded Disability Status Scale score, timed 25 foot walk test and timed 10 foot tandem walk tests. Results Median change in BOD was 287 mm3 in the placebo group and 83 mm3 in the vitamin D group (p=0.105). Serum levels of 25(OH)D increased from a mean of 54 (range 19–82) nmol/l to 110 (range 67–163) nmol/l in the vitamin D group. 84% of patients reached a serum 25(OH)D level >85 nmol/l in the vitamin D group and 3% in the placebo group (p<0.0001). Patients in the vitamin D group showed fewer new T2 lesions (p=0.286) and a significantly lower number of T1 enhancing lesions (p=0.004), as well as a tendency to reduced disability accumulation (p=0.071) and to improved timed tandem walk (p=0.076). There were no significant differences in adverse events or in the annual relapse rate. Conclusion Vitamin D3 add on treatment to IFNB reduces MRI disease activity in MS. Trial registration number EudraCT number 2007-001958-99 and ClinicalTrialsGov number NCT01339676.

A Susceptibility Locus for Migraine with Aura, on Chromosome 4q24

Migraine is a complex neurovascular disorder with substantial evidence supporting a genetic contribution. Prior attempts to localize susceptibility loci for common forms of migraine have not produced conclusive evidence of linkage or association. To date, no genomewide screen for migraine has been published. We report results from a genomewide screen of 50 multigenerational, clinically well-defined Finnish families showing intergenerational transmission of migraine with aura (MA). The families were screened using 350 polymorphic microsatellite markers, with an average intermarker distance of 11 cM. Significant evidence of linkage was found between the MA phenotype and marker D4S1647 on 4q24. Using parametric two-point linkage analysis and assuming a dominant mode of inheritance, we found for this marker a maximum LOD score of 4.20 under locus homogeneity (P=.000006) or locus heterogeneity (P=.000011). Multipoint parametric (HLOD = 4.45; P=.0000058) and nonparametric (NPL(all) = 3.43; P=.0007) analyses support linkage in this region. Statistically significant linkage was not observed in any other chromosomal region.

Infections of the central nervous system of suspected viral origin: a collaborative study from Finland.

We studied 3231 patients with acute central nervous system (CNS) symptoms of suspected viral origin to elucidate the current etiologic spectrum. In 46% of the cases, a viral finding was observed. Varicella-zoster virus (VZV) was the main agent associated with encephalitis, as well as meningitis and myelitis. VZV comprised 29% of all confirmed or probable etiologic agents. Herpes simplex virus (HSV) and enteroviruses accounted 11% each, and influenza A virus 7%. VZV seems to have achieved a major role in viral infections of CNS. In encephalitis in our population, VZV is clearly more commonly associated with these neurological diseases than HSV. The increase in VZV findings may in part be a pseudophenomenon due to improved diagnostic methods, however, a true increase may have occurred and the pathogenetic mechanisms behind this should be elucidated.

Boron neutron capture therapy of brain tumors: clinical trials at the Finnish facility using boronophenylalanine

SummaryTwo clinical trials are currently running at the Finnish dedicated boron neutron capture therapy (BNCT) facility. Between May 1999 and December 2001, 18 patients with supratentorial glioblastoma were treated with boronophenylalanine (BPA)-based BNCT within a context of a prospective clinical trial (protocol P-01). All patients underwent prior surgery, but none had received conventional radiotherapy or cancer chemotherapy before BNCT. BPA-fructose was given as 2-h infusion at BPA-dosages ranging from 290 to 400 mg/kg prior to neutron beam irradiation, which was given as a single fraction from two fields. The average planning target volume dose ranged from 30 to 61 Gy (W), and the average normal brain dose from 3 to 6 Gy (W). The treatment was generally well tolerated, and none of the patients have died during the first months following BNCT. The estimated 1-year overall survival is 61%. In another trial (protocol P-03), three patients with recurring or progressing glioblastoma following surgery and conventional cranial radiotherapy to 50–60 Gy, were treated with BPA-based BNCT using the BPA dosage of 290 mg/kg. The average planning target dose in these patients was 25–29 Gy (W), and the average whole brain dose 2–3 Gy (W). All three patients tolerated brain reirradiation with BNCT, and none died during the first three months following BNCT. We conclude that BPA-based BNCT has been relatively well tolerated both in previously irradiated and unirradiated glioblastoma patients. Efficacy comparisons with conventional photo radiation are difficult due to patient selection and confounding factors such as other treatments given, but the results support continuation of clinical research on BPA-based BNCT.

Acute central nervous system complications in varicella zoster virus infections

BACKGROUND In a previous multicenter study on central nervous system (CNS) viral infections varicella zoster virus (VZV) appeared the most frequent etiologic agent and appeared often without rash. OBJECTIVE To evaluate the appearance and diagnostics of VZV in CNS more thoroughly, we studied the cases systematically by using sensitive and specific methods to learn the best diagnostic approach in order to start specific therapy. STUDY DESIGN We analyzed all serum and cerebrospinal fluid samples of 174 patients, 88 females and 86 males, with acute CNS symptoms associated with VZV infection diagnosed in the multicenter study on viral CNS infections. RESULTS About 38 patients (22%) had chickenpox, 59 (34%) had shingles, and 77 (44%) had no cutaneous symptoms at all. The mean age of chickenpox patients was 8.6 years, of the others 46.6 and 41.4 years. VZV-specific nucleic acid was detected in the CSF in one fourth of the patients in all groups, primarily during the first week of illness. In serum specimens, specific IgM was present in two thirds of the patients with chickenpox, whereas in the others in one third of the cases. In CSF, specific IgM was present in 15-17% of patients with skin manifestations, compared with 6% of those without rash. CONCLUSIONS The role of VZV infections in CNS complications seems remarkable, often presenting without rash. Even these cases should be promptly recognized in order to conduct proper antiviral therapy. In children, a combination of PCR and IgM tests is the best approach. In adults, PCR, together with the measurement of intrathecal antibody production yields best results.

Speed of Onset and Efficacy of Zolmitriptan Nasal Spray in the Acute Treatment of Migraine A Randomised, Double-Blind, Placebo-Controlled, Dose-Ranging Study versus Zolmitriptan Tablet

AbstractObjective: Zolmitriptan oral tablet is highly effective and well tolerated in the acute treatment of migraine with and without aura in adults. A nasal spray formulation has now been developed. The objective of this study was to compare the efficacy and tolerability of fixed doses of zolmitriptan administered via a nasal spray with placebo and zolmitriptan oral tablet in the acute treatment of migraine. Patients and study design: This was a randomised, double-blind, double-dummy, placebo-controlled, parallel-group, multicentre, dose-ranging study. 1547 patients aged 18–65 years with an established diagnosis of migraine with or without aura (as defined by International Headache Society criteria) who had at least a 1-year history of migraine and an age of onset <50 years were included. Patients were able to distinguish typical migraine from nonmigraine headaches and had experienced an average of one to six migraine headaches per month during the 2 months preceding the study. Patients were randomised to zolmitriptan (Zomig®1) nasal spray (5.0, 2.5, 1.0 or 0.5mg), zolmitriptan oral tablet (2.5mg) or placebo for the treatment of three moderate or severe migraine attacks. The primary outcome measure was headache response at 2 hours following treatment, defined as reduced intensity of migraine pain (using a scale of none, mild, moderate or severe) from severe or moderate at baseline to mild or no pain at 2 hours after treatment. Secondary outcome measures included early headache response at 15, 30 and 45 minutes and headache response at 1 and 4 hours postdose, as well as pain-free rates at 15, 30 and 45 minutes and 1, 2 and 4 hours postdose. Laboratory assessments, vital signs, 12-lead ECGs and nose and throat examinations were performed at screening and follow-up visits. Adverse events were recorded throughout the study using Coding Symbols for Thesaurus of Adverse Reaction Terms (COSTART) terminology. Results: Each dose of zolmitriptan nasal spray produced a greater 2-hour headache response rate than placebo (70.3%, 58.6%, 54.8% and 41.5% for zolmitriptan nasal spray 5.0, 2.5, 1.0 and 0.5mg, compared with 30.6% for placebo [all p < 0.001 vs placebo]). The 2-hour headache response rate for zolmitriptan nasal spray 5.0mg was significantly higher than that of the zolmitriptan 2.5mg oral tablet (61.3%; p < 0.05), while comparisons of nasal spray 0.5, 1.0 and 2.5mg with zolmitriptan 2.5mg oral tablet were not statistically significant. The nasal spray 5.0 and 2.5mg showed a rapid onset of action, with a significant difference in headache response compared with placebo from 15 minutes through 4 hours after administration and a significant difference between the nasal spray 5.0mg and 2.5mg oral tablet from 15 minutes through to 2 hours (the other nasal spray doses were not statistically significant compared with 2.5mg oral tablet). Zolmitriptan nasal spray resulted in pain-free rates that were dose dependent. While all doses from l.0mg upwards produced significant pain-free outcomes from 30 minutes versus placebo, only the 5.0mg dose produced pain-free rates significantly superior to both placebo and the 2.5mg oral tablet. Zolmitriptan nasal spray was well tolerated, with the most common adverse events being unusual taste and paresthesia. The majority of adverse events were of short duration and mild or moderate intensity. Only ten patients were withdrawn from the trial because of adverse events. Serious adverse events were reported by nine patients after taking study medication, but none was considered to be causally related to study medication. Zolmitriptan was not associated with any clinically significant changes in laboratory test values or vital signs. Conclusion: All doses of zolmitriptan nasal spray produced significant 2-hour headache response rates compared with placebo. The 5.0 and 2.5mg doses were also significantly more effective than placebo for the majority of secondary efficacy measures. Zolmitriptan nasal spray 5.0mg provided a headache response statistically superior to both placebo and the 2.5mg tablet as early as 15 minutes after administration, while demonstrating pain-free outcomes significantly superior to placebo and the 2.5mg tablet as early as 30 minutes after administration. All doses of zolmitriptan nasal spray were well tolerated, resulting in an optimal therapeutic index and clinical recommendation for the 5.0mg dose.

Efficacy and tolerability of lasmiditan, an oral 5-HT1F receptor agonist, for the acute treatment of migraine: a phase 2 randomised, placebo-controlled, parallel-group, dose-ranging study

BACKGROUND Lasmiditan (COL-144) is a novel, centrally acting, highly selective 5-HT(1F) receptor agonist without vasoconstrictor activity that seemed effective when given as an intravenous infusion in a proof-of-concept migraine study. We aimed to assess the efficacy and safety of oral lasmiditan for the acute treatment of migraine. METHODS In this multicentre, double-blind, parallel-group, dose-ranging study in 43 headache centres in five European countries, patients with migraine with and without aura and who were not using prophylaxis were randomly assigned (1:1:1:1:1) to treat one moderate or severe attack at home with 50 mg, 100 mg, 200 mg, or 400 mg lasmiditan, or placebo. Study drug and placebo were supplied in identical numbered tablet packs. The randomisation code was generated by an independent statistician. Patients and investigators were masked to treatment allocation. The primary endpoint was dose response for headache relief (moderate or severe becoming mild or none) at 2 h. The primary analysis was done in the modified intention-to-treat population. This study is registered with ClinicalTrials.gov, number NCT00883051. FINDINGS Between July 8 2009, and Feb 18, 2010, 512 patients were randomly assigned to treatment, 391 of whom received treatment. 86 patients received placebo (81 included in primary analysis) and 305 received lasmiditan (50 mg n=79, 100 mg n=81, 200 mg n=69, and 400 mg n=68 included in primary analysis). There was a linear association between headache response rate at 2 h and lasmiditan dose (Cochran-Armitage test p<0·0001). Every lasmiditan treatment dose significantly improved headache response at 2 h compared with placebo (lasmiditan 50 mg: difference 17·9%, 95% CI 3·9-32·1, p=0·022; 100 mg: 38·2%, 24·1-52·4, p<0·0001; 200 mg: 28·8%, 9·6-39·9, p=0·0018; 400 mg: 38·7%, 23·9-53·6, p<0·0001). The proportion of patients with treatment-emergent adverse events increased with increasing doses (53/82 [65%], 59/82 [72%], 61/71 [86%], and 59/70 [84%] for lasmiditan 50, 100, 200, and 400 mg, respectively vs 19/86 [22%] for placebo). Most adverse events were mild or moderate in intensity, with 16 of 82 (20%), 23 of 82 (28%), 28 of 71 (39%), and 31 of 70 (44%) of patients on lasmiditan 50, 100, 200, and 400 mg, respectively reporting a severe adverse event compared with five of 86 (6%) on placebo. The most common adverse events were CNS related and included dizziness, fatigue, vertigo, paraesthesia, and somnolence. INTERPRETATION Oral lasmiditan seems to be safe and effective in the acute treatment of migraine. Further assessment in larger placebo-controlled and triptan-controlled trials are needed to assess the potential role of lasmiditan in acute migraine therapy. FUNDING CoLucid Pharmaceuticals.