LO-01
Migraine Pathophysiology
Visual sensitivity is more enhanced in migraineurs with aura than in migraineurs without aura
M Perenboom, A Zamanipoor Najafabadi, R Zielman, E Tolner, J Carpay, M Ferrari
Neurology, Leiden University Medical Center, Leiden, Netherlands
Background: Migraine is often accompanied by sensitivity for light and patterns. This is usually interpreted as manifestation of ‘cortical hyperexcitability’, as is the migraine aura. It is not known if migraineurs with and without aura differ in visual sensitivity.
Aim: To quantify ictal and interictal visual sensitivity of migraine patients with and without aura using the Visual Sensitivity Questionnaire (VSQ, IHC-abstract Zamanipoor Najafabadi et al), a self-report scale quantifying sensitivity to light and patterns.
Methods: Migraineurs with (MA, n = 89) and without (MO, n = 76) aura completed the VSQ twice: to assess visual sensitivity a) outside and b) during attacks of the last month. VSQ sum-scores were compared between MA, MO and healthy controls (n = 99).
Results: We found differences in VSQ score between controls and MA and MO outside attacks using one-way ANOVA (F(2,264) = 48.4, p < .0001). Tuckey post-hoc testing revealed that scores of MA (12.1 ± 6.3) and MO (9.00 ± 5.6) were higher than of controls (4.6 ± 3.4, both p < .0001). Outside attacks MA also scored significantly higher than MO (p < .001). VSQ score increased during an attack compared to outside an attack for MO (18.6 ± 7.7) and MA (21.8 ± 6.7, paired t-test, both p < .0001). In addition, the score for MA during an attack was higher than for MO (unpaired t-test, p = .004).
Conclusions: Migraine patients with aura report enhanced visual sensitivity to light and patterns compared to patients without aura, both outside and during the attacks. This suggests cortical hyperexcitability may be more severe in migraineurs with aura compared to those without aura.
LO-02
Migraine Pathophysiology
Cerebral FDG uptake changes after supraorbital transcutaneous electrical stimulation with the Cefaly device in patients with migraine
K D'Ostilio1, A Thibaut2, S Laureys2, A Cosseddu1, SL Sava1, P Gérard1, J Schoenen1, D Magis1
1University Department of Neurology, CHR Citadelle, Liege, Belgium
2Coma Group Cyclotron Research Centre, University of Liege, Liege, Belgium
Background: A recent multicentre RCT has shown that supraorbital transcutaneous stimulation (STS) targeting branches of the ophtalmic nerve with the Cefaly® device is effective as a preventive therapy for migraine (Schoenen et al., Neurology 2013). However, the mechanisms of action in the central nervous system remain unknown. Here, we conducted voxel-based analyses of [18]FDG-PET to evaluate metabolic changes immediately after the first STS session and after 3 months of treatment in patients with migraine.
Methods: Twenty-eight subjects participated in the experiment: 14 patients with episodic migraine (ICHD3 beta criteria) and 14 age-matched controls. Healthy volunteers underwent only one [18]FDG-PET scan whereas patients were scanned at baseline, directly after a first session of STS and after 3 months of daily treatment.
Results: Compliant patients showed a significant decrease in the number of attacks (p = 0.03). When compared to controls, patients (n = 14) at baseline were hypometabolic in the fronto-temporal regions (p < 0.001), especially in the orbitofrontal (OFC) and perigenual anterior cingulate cortex. OFC hypometabolism was not correlated with medication intake. In compliant patients, daily STS for 3 months was followed by a normalization of the fronto-temporal hypometabolism (p < 0.001; OFC: pFWE < 0.01).
Conclusion: Our study suggests that the OFC is hypoactive in episodic migraine. STS with the Cefaly° device is able to normalize this hypoactivity. This indicates that STS exerts its beneficial effect via slow neuromodulatory mechanisms, as also previously shown for percutaneous occipital nerve stimulation in refractory cluster headache (Magis et al., BMC Neurology 2011).
LO-03
Migraine Pathophysiology
Transciptional changes in the trigeminal ganglion in response to glyceryl trinitrate infusion in the rat
S Hougaard Pedersen1, L Maretty2, J Sibbesen2, R Ramachandran1, V Yakimov2, R Elgaard-Christensen1, A Krogh2, J Olesen1, I Jansen-Olesen1
1Danish Headache Center, Rigshospitalet Glostrup, Glostrup, Denmark
2Department of Biology, University of Copenhagen, Copenhagen, Denmark
Background: Infusion of glyceryl trinitrate (GTN), a donor of nitric oxide (NO), induces immediate headache in humans, which in migraine patients is followed by a delayed migraine attack. We have developed a rat GTN-infusion model mimicking the human model and aim to investigate transcriptomic changes in the trigeminal ganglion (TG) at different time points after GTN infusion using RNAseq.
Methods: Nine awake rats were infused with vehicle or GTN and sacrificed at 30 min (vehicle and GTN) or 90 min (GTN) after the infusion (approved by the Danish Animal Experiments Inspectorate). TG was dissected for RNA extraction and the samples were paired-end sequenced using next generation sequencing. The RNA-seq data was mapped against the rat genome (rn5) using TopHat2 and tests for differential gene expression conducted using DESeq2. Six significantly regulated genes were chosen for qPCR validation. Significantly regulated pathways were identified using Gene Set Analysis Of Variance (GSANOVA).
Results: 15 genes (RT1-A3, RT1-A2, Per1, Rgs7bp, Tapbp, Rps10, Trim16, Glul, Lxn, Dpysl4, Myh6, Prune2, Daf1, P2rx3 and Apod) exhibited significant changes in expression after GTN infusion. Validation by qPCR showed a similar expression pattern as found with RNA-seq. Among the 30 most significantly regulated pathways we identified changes involving satellite glia cell-neuron signaling, immune responses and neuroplasticity.
Conclusion: GTN infusion results in transcriptional changes in the TG pointing towards activation of satellite glial cells, the immune system and neuroplastic changes. Future in-depth studies of these pathways might increase our knowledge of migraine pathophysiology.
LO-04
Migraine Pathophysiology and CGRP as a Therapeutic Target
TRV250: A novel biased ligand at the delta receptor for the potential treatment of migraine
A Crombie1, J Arezzo2, C Cowan3, S DeWire3, W Gowen-MacDonald3, M Hawkins1, E Jutkiewicz4, M Kramer5, M Koblish3, M Lark6, G Liu1, T Miskowski1, L Nguyen3, P Pitis1, A Pradhan7, D Rominger3, E Schwartz3, D Yamashita1, J Violin3
1Department of Chemistry, Trevena Inc., King of Prussia, USA
2Department of Neuroscience and Neurology, Albert Einstein College of Medicine, New York, USA
3Department of Biology, Trevena Inc., King of Prussia, USA
4Department of Pharmacology, University of Michigan Medical School, Ann Arbor, USA
5Department of Non-Clinical Development, Trevena Inc., King of Prussia, USA
6Research and Development, Trevena Inc., King of Prussia, USA
7Department of Psychiatry, University of Illinois at Chicago, Chicago, USA
Background: The delta opioid receptor (DOR) has long been of interest as a target for potentially non-addictive treatments for a variety of CNS disorders. Recent evidence suggests that DOR activation may be beneficial in the treatment of migraine. However, DOR agonists have caused seizure in preclinical species, hindering the development of selective drugs targeting the DOR.
Aim: We sought to harness ligand bias at the DOR to discover a DOR modulator with efficacy in animal models of migraine and other CNS disorders while minimizing seizure liability.
Methods: Based on data suggesting that G protein coupling without beta-arrestin2 engagement at the DOR would reduce seizure liability, we identified TRV250, a novel small molecule targeting the DOR. Rat and mouse models of migraine pain, and seizure liability were used to assess the potential therapeutic index of TRV250.
Results: Compared to unbiased agonists AZD2327 and SNC80, TRV250 has potent, full efficacy for G protein coupling, but much weaker engagement of beta-arrestin2. TRV250 is highly selective for the DOR over the mu and kappa opioid receptors. In rodent nitroglycerin-induced hyperalgesia models of migraine, TRV250 showed robust efficacy after both subcutaneous and oral dosing. TRV250 was also active in models of nociception, depression, and anxiety. Compared to AZD2327, TRV250 showed a markedly improved margin between efficacious doses and doses associated with seizure.
Conclusion: TRV250 shows promise as a potential new class of therapy for the treatment of migraine, as well as other CNS disorders. Preclinical development to support future clinical trials of TRV250 is underway.
LO-05
Migraine Pathophysiology and CGRP as a Therapeutic Target
A multicenter, randomized, double-blind, double-dummy, placebo-controlled, multi-dose study comparing the efficacy and safety of subcutaneous TEV-48125 with placebo for the preventive treatment of chronic migraine
M Bigal1, L Edvinsson2, A Rapoport3, R Lipton4, E Spierings5, H Diener6, M Ma7, J Hudson8, S Silberstein9
1Clinical Development, Teva Pharmaceuticals, Frazer, USA
2Medicine, Lund Universit, Lundt, Sweden
3Neurology, UCSF, Palo Alto, USA
4Neurology, Albert Einstein College of Medicine, New York, USA
5Clinical Research, MedVadis Research, Boston, USA
6Neurology, Essen Headache Center, Essen, Germany
7Statistics, Teva Pharmaceuticals, Frazer, USA
8Neurology, FutureSearch Trials of Neurology, Austin, USA
9Neurology, Jefferson Headache Center, Philadelphia, USA
Background: Disrupting calcitonin-gene related peptide (CGRP) signaling has proven efficacy in the treatment of episodic migraine, but benefits have not been established for the preventive treatment of chronic migraine (CM).
Objectives: To evaluate the efficacy and safety of two doses of subcutaneous TEV-48125 (LBR-101), a monoclonal anti-CGRP antibody, in the preventive treatment of CM.
Methods: This was a multicenter, randomized, double-blind, double-dummy, placebo-controlled, parallel-group study comparing two doses of TEV-48125 with placebo. Following a 28 day run-in period, participants were randomized and treated subcutaneously once monthly for three months. Headache information was captured daily using an electronic headache diary. The study was conducted in approximately 60 centers in the USA. The primary (change from baseline in the number of hours with headache in month 3), and secondary (change in number of headache days of moderate or severe intensity in month 3) variables were analyzed using a Repeated Measures Mixed-Effects Model with a 2-sided alpha level of 0.05 and adjustments for multiplicity.
Results: Results are being fully analyzed and will be presented at the meeting. Sample consisted of 261 patients. Both doses of TEV-48125 achieved the primary (p = 0.030 and p = 0.006) and secondary endpoints (p = 0.034 and p = 0.023). Both doses were also superior to placebo at 1 month for headache hours (p = 0.003 and p < 0.0001) and days (p = 0.009 and p < 0.001). Treatment was well tolerated and no treatment-related serious adverse events were reported.
Conclusion: Primary, secondary and safety endpoints were achieved, for the first time demonstrating that CGRP inhibition is effective in the preventive treatment of CM.
