Abstract
Cluster Headache and Other Trigeminal Autonomic Cephalalgias
EP-02-001
Cluster Headache: Investigating severity of pain, suicidality, personal burden, access to effective treatment, and demographics among a large International survey sample.
Larry I. Schor1,*
1Psychology, University of West Georgia, Carrollton, United States
Objectives
This research study examined Cluster Headache, with an emphasis on suicidality, severity of pain, personal burden, and access to effective treatment.
Methods
1,500 Cluster Headache patients from 51 countries completed an IRB approved Internet based survey consisting of more than 150 questions including psychometric measures of depression and hopelessness, comparison of Cluster Headache pain with other painful conditions (e.g. renal stones, pancreatitus, child birth, migraine, shingles, gunshot wound). Other constructs assessed included personal and financial burden, access to effective treatments, suicidality as well as risk and protective factors, and vocational disability.
P3 - Comparing each experience with Cluster Headache attacks, how painful would you rate each on a scale of 1 (least painful) to 10 (most painful)?
Results
Respondents ranged from 18 to 99 years of age, with slightly more men than women reporting Cluster Headache diagnosis. Age of onset ranged from childhood to 71 years old.
1. Cluster Headache patients indicated severity of pain was significantly worse than any other identified medical conditions.
2. Suicidality among Episodic Cluster Headache patients (ECH) increased significantly during cluster cycles and among those with Chronic Cluster Headache (CCH). Risk and protective factors were identified.
3. Cluster Headache patients experience significant personal and financial burden, as well as vocational disability.
4. Many patients have difficulty accessing safe and effective treatments.
5. Because of the severity of pain or impact of personal burden, psychological needs are not addressed sufficiently?
Conclusion
Despite the numerous statements regarding the severity of pain, the existing literature seems rather anecdotal and inferred. Consequently we asked specifically if this is the worst pain each subject has experienced and elicited their subjective comparison with other painful experiences. We obtained a sufficiently robust sample size to gather data from people who, in addition to Cluster Headache, have also experienced kidney stones, childbirth, gunshot wounds, migraine, etc. While this approach has not been validated, it is arguable that this approach has provided clearer data than existing pain measures.
Suicidality is significantly elevated among ECH patients who are in cycle as well as ECH patients, as are depression and hopelessness.
Many patients have significant barriers to accessing safe and effective treatments.
Physicians and patients would benefit from increased training in managing this condition and should assess for mental health problems and suicidality.
Cluster Headache and Other Trigeminal Autonomic Cephalalgias
EP-02-002
Cranial parasympathetic activation induces autonomic symptoms but no cluster headache attacks
Song Guo1,*, Anja S. Petersen2, Henrik W. Schytz2, Mads Barløse2, Anthony Caparso3, Jan Fahrenkrug4, Rigmor H. Jensen2 and Messoud Ashina2
1Danish Headache Center and Department of Neurology, igshospitalet, Faculty of Health and Medical Sciences, University of Copenhagen
2Danish Headache Center and Department of Neurology, Rigshospitalet, Faculty of Health and Medical Sciences, University of Copenhagen, 2600 Glostrup, Copenhagen, Denmark, Copenhagen, Denmark
3Autonomic Technologies Inc., Redwood City, United States
4Department of Clinical Biochemistry, Bispebjerg Hospital, University of Copenhagen, Copenhagen, Denmark
Objectives
To investigate if low frequency (LF) stimulation of the sphenopalatine ganglion (SPG) may increase parasympathetic outflow and provoke cluster headache (CH) attacks in CH patients implanted with an SPG neurostimulator.
Methods
In a double-blind randomized sham-controlled crossover study, 20 CH patients received LF or sham stimulation for 30 min on two separate days. We recorded headache characteristics, cephalic autonomic symptoms (CAS), plasma levels of parasympathetic markers such as pituitary adenylate cyclase-activating polypeptide-38 (PACAP38) and vasoactive intestinal peptide (VIP), and mechanical detection and pain thresholds as a marker of sensory modulation.
Results
In the immediate phase (0–60 min), 16 (80%) patients experienced CAS after LF stimulation, while 9 patients (45%) reported CAS after sham (P = 0.046). We found no difference in induction of cluster-like attacks between LF stimulation (n = 7) and sham stimulation (n = 5) (P = 0.724). There was no difference in mechanical detection and pain thresholds, and in PACAP and VIP plasma concentrations between LF and sham stimulation (P ≥ 0.162).
Conclusion
LF stimulation of the SPG induced autonomic symptoms, but no CH attacks. These data suggest that increased parasympathetic outflow is not sufficient to induce CH attacks in patients.
Cluster Headache and Other Trigeminal Autonomic Cephalalgias
EP-02-003
Injection of onabotulinum toxin A towards the sphenopalatine ganglion – a potential long-term treatment for chronic cluster headache patients?
Irina Aschehoug1,*, Daniel F. Bratbak1,2, Joan Crespi1,3, David W. Dodick1,4 and Erling A. Tronvik1,3
1Department of Neuromedicine and Movement Science, Norwegian University of Science and Technology
2Department of Neurosurgery
3Department of Neurology, St. Olavs University Hospital, Trondheim, Norway
4Department of Neurology, Mayo Clinic , Phoenix, United States
Objectives
The aim of this follow-up study was to investigate long-term outcomes in per-protocol (PP) chronic cluster headache (CCH) patients, 18 and 24 months after participation in the “Pilot study of sphenopalatine injection of onabotulinumtoxinA (BTA) for the treatment of intractable chronic cluster headache” (1).
1. Bratbak DF et al. Pilot study of sphenopalatine injection of onabotulinumtoxinA for the treatment of intractable chronic cluster headache. Cephalalgia. 2016;36(6):503–9.
Methods
This was a prospective observational follow-up study where all PP patients (n = 7) from the pilot study were invited to participate. The primary objective was to evaluate changes in cluster headache (CH) attack frequency 18 and 24 months after the initial BTA injection. Primary and secondary outcome measures are described in Table 1. After the pilot study, responding patients had access to repeated injections at timepoints as needed by patients (minimum 3 months between injections). These were performed with a new technique using percutaneous infrazygomatic (lateral) injection under local anesthesia on awake patients in an outpatient, office-based setting. Data were collected through headache diaries and questionnaires at months 18 and 24 after the initial BTA injection and were compared to the baseline period in the pilot study. Safety data were collected continuously.
Results
A significant reduction in CH attack frequency, reduction in attacks with severe and unbearable intensity and increase in CH attack-free days was found both at months 18 and 24 compared to baseline (Table 1). Five out of seven patients received repeated treatment during the 24 months and a significant long-term reduction ( ≥ 50%) in number of CH attacks was found in four out of five patients. Of the remaining two patients, one remained headache-free after the initial injection. The new injection technique was well accepted by all patients who got repeated treatment and the AEs observed in two out of five patients were transient and experienced as acceptable by the patients.
Conclusion
These 24 month results suggest that treatment with BTA injections towards the SPG may be an effective long-term treatment for intractable CCH patients. Randomized, placebo-controlled trials on a larger population, with long-term follow-up are needed to confirm the effect of BTA injections towards the SPG in CCH.
Primary and secondary outcome measures for baseline and at months 18 and 24 after initial injection with onabotulinumtoxinA towards the sphenopalatine ganglion (n = 7).
Results are presented as mean ± SD. P-values ≤ 0.05 are depicted in bold. acategorical intensity scale: Grade 1: mild; Grade 2: moderate; Grade 3: severe; Grade 4: unbearable. bminutes. cfour of seven patients use triptans as acute treatment. CH: Cluster headache.
Cluster Headache and Other Trigeminal Autonomic Cephalalgias
EP-02-004
Chronorisk in cluster headache: A tool for individualized therapy? Results from the Danish cluster headache survey
Nunu Lund1,*, Mads Barloese1,2, Bryan Haddock3, Anja S. Petersen1 and Rigmor H. Jensen1
1Danish Headache Center, Dept. of Neurology, Rigshospitalet - Glostrup, University of Copenhagen
2Department of Clinical Physiology, Nuclear Medicine and PET, Rigshospitalet-Glostrup, University of Denmark
3Department of Clinical Physiology, Nuclear Medicine and PET, Rigshospitalet-Glostrup, University of Copenhagen, Glostrup, Denmark
Objectives
Cluster headache (CH) attacks occur with a high degree of predictability yet we still know very little of what influences the timing of these attacks. We aimed to describe the 24 hour attack distribution (chronorisk) in subgroups of well characterized CH patients.
Methods
CH patients (n = 351) from the Danish CH-survey aged 18–65 years, diagnosed according to ICHD-II, completed a questionnaire and structured interview. Patients reported the most common hours of attacks and a chronorisk distribution (% of all attacks reported for each hour) of each subgroup was calculated. To identify periods of increased attack risk and to disentangle overlapping events, a multi modal Gaussian fit was calculated. Only peaks > 3% were included in the analysis. The Gaussian model was limited to maximum 5 modes. The Pittsburgh Sleep Quality Index (PSQI) was used to evaluate sleep quality and included patients with attacks within the last month.
Results
The Gaussian model identified three peaks of attacks at 21:41, 02:02 and 06:23 (R2 = 0.97) for patients reporting diurnal rhythmicity in attacks (n = 286, 82 %). Episodic patients had their nightly peak > one hour earlier than chronic patients (01:28 vs. 02:33), however there was no difference in the morning peak. Furthermore, chronic patients experienced 2 daytime peaks not seen in episodic patients (11:14 and 15:46). Taking verapamil advanced the nocturnal (01:53 vs. 02:43) and morning peak (06:04 vs. 06:51) compared with patients not taking verapamil. Patients with poor sleep quality (PSQI > 5) had three prominent peaks (21:46, 02:16, 06:03), whereas patients with good sleep quality (PSQI ≤ 5) had distinct peaks early in the night and throughout the day. The nocturnal peak was earlier in patients consuming tobacco, alcohol and coffee compared with abstainers (01:56 vs. 02:46, 01:10 vs. 02:07, and 01:48 vs. 03:26). Consuming tobacco and alcohol did not affect the morning peak, whereas the consumption of coffee advanced it (06:07 vs. 06.58). Time asleep varied across the groups. Not smoking and being episodic was associated with significantly earlier time asleep.
Conclusion
In CH, the chronorisk of diurnal attack occurrence was affected by several factors including phenotype, verapamil, sleep quality, and consuming tobacco, alcohol and coffee. Our findings also suggest that chronic patients have a relatively higher daytime risk of attacks, whereas episodic patients are more vulnerable at night. CH has very distinct chronobiological features and is therefore a ripe target for individualized chronotherapy –the administration of medicine tailored to time of day for maximum therapeutic effect and minimal side effects.
Cluster Headache and Other Trigeminal Autonomic Cephalalgias
EP-02-005
Non-invasive Vagus Nerve Stimulation for Acute Treatment of Episodic and Chronic Cluster Headache: Pooled Analysis of Data From Two Randomised, Double-blind, Sham-Controlled Clinical Trials
Ilse F. de Coo1,*, Juana Marin2, Stephen D. Silberstein3, Deborah I. Friedman4, Charly Gaul5, Alok Tyagi6, Eric Liebler7, Stewart J. Tepper8, Michel D. Ferrari1 and Peter J. Goadsby9
1Leiden University Medical Center, Leiden, Netherlands
2NIHR-Wellcome Trust CRF, King’s College Hospital, London, United Kingdom
3Jefferson Headache Center, Philadelphia
4UT Southwestern Headache and Facial Pain Program, Dallas, United States
5Migraine and Headache Clinic, Königstein, Germany
6The Southern General Hospital, Glasgow, United Kingdom
7electroCore, LLC, Basking Ridge
8Geisel School of Medicine at Dartmouth, Hanover, United States
9NIHR-Wellcome Trust CRF, King's College Hospital, London, United Kingdom
Objectives
Clinical observations and results from recent studies support the use of non-invasive vagus nerve stimulation (nVNS) for the acute treatment of cluster headache. We assessed the efficacy and safety of nVNS as acute cluster headache treatment in a large pooled data analysis.
Methods
Two prospective, randomised (1:1), double-blind, multicentre, sham-controlled clinical trials were used for our pooled data analysis, which consisted of 252 individuals fulfilling ICHD-II criteria for cluster headache. Both studies required three consecutive 120-second vagal nerve stimulations at attack onset. In ACT2, subjects were permitted to treat with an additional three stimulations if they were not pain free by nine minutes after the initiation of the first treatment. In the ACT1 study, all treatments were applied to the right cervical vagus nerve. In ACT2, the subjects were encouraged to treat ipsilateral to the pain.
Results
The first-order interaction between treatment group and cluster headache subtype was significant (P < 0.01) in models estimating the proportion of patients who achieved responder status at 15 minutes after treatment initiation for the first cluster headache attack (the ACT1 primary endpoint) in the ACT1, ACT2, and pooled populations. In models estimating the proportion of all treated attacks that achieved pain-free status at 15 minutes after treatment initiation (the ACT2 primary endpoint), the first-order interaction term between treatment group and cluster headache subtype was also significant (P < 0.05) in all three populations (i.e., ACT1, ACT2, and pooled). Thus, results are presented overall and by cluster headache subtype. The proportion of patients who achieved responder status at 15 minutes after treatment initiation for the first cluster headache attack (the ACT1 primary endpoint) was significant between the nVNS and sham treatment groups in episodic cluster headache patients in both ACT1 (34% vs. 11%; P = 0.01) and pooled analyses (39% vs. 12%; P < 0.01) but not in the ACT2 analysis (50% vs. 15%; P = 0.07). The proportion of all treated attacks that achieved pain-free status at 15 minutes after treatment initiation (the ACT2 primary endpoint) was significant between the nVNS and sham treatment groups in episodic cluster headache patients in ACT1 (15% vs. 6%; P < 0.05), ACT2 (35% vs. 7%; P < 0.05), and pooled analyses (24% vs. 7%; P < 0.01). There were no significant differences for these endpoints for the total cluster headache population or chronic cluster headache population in ACT1, ACT2, or pooled analyses. There were no serious adverse device effects reported.
Conclusion
As the largest investigation of a drug or device for the acute treatment of CH attacks, this pooled analysis supports the use of nVNS as a viable, safe, and effective acute treatment option in patients with episodic cluster headache. This analysis also provides the impetus for further research to explore the role of nVNS in the treatment of patients with chronic cluster headache.
Comorbidity of Primary Headaches
EP-02-006
Framingham cardiovascular risk estimate scores in women with migraine; the importance of lifetime changes
Khatera Ibrahimi1, Claire Carpenet2, Pamela M. Rist3,4, Julie E. Buring3,4, Antoinette MaassenVanDenBrink1,* and Tobias Kurth2,4
1Division of Vascular Medicine and Pharmacology, Department of Internal Medicine, Erasmus MC, Rotterdam, Netherlands
2Insitute of Public Health, Charité-Universitätsmedizin, Berlin, Germany
3Department of Epidemiology, Harvard T.H. Chan School of Public Health
4Division of Preventive Medicine, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, United States
Objectives
Migraine has consistently been reported to be associated with increased risk of cardiovascular disease (CVD) events. It is, however, not yet clear to what extent increased cardiovascular risk profile is associated with migraine status. Further, in most studies the development of migraine during follow-up was not considered. We studied the cross-sectional association of migraine status with vascular risk profiles and the prospective association with the development of migraine in women.
Methods
Female health professionals (Women’s Health Study, n = 27,604, age ≥ 45 years at baseline) without a history of CVD, cancer, or other major diseases and who provided a blood sample at baseline were enrolled in the study. The presence or development of migraine was assessed by questionnaire. Women were classified as having ‘no migraine’ (reference group), ‘history of migraine’ (have experienced migraine in the past but did not experience any migraine attacks in the year prior to inclusion in the Women’s Health Study), ‘migraine at baseline’ (active migraine at inclusion) or ‘incident migraine’ (presentation of migraine after inclusion in the study). Framingham risk scores estimating ten-year cardiovascular disease risk were calculated at baseline to classify women in vascular risk classes. We used multinominal logistic regression models to calculate odds ratios (ORs) of the association between migraine status and Framingham risk score categories.
Table:
Results
A total of 1499 reported history of migraine and 3575 having active migraine at baseline. Of the 21,790 women not reporting migraine at baseline, 740 women reported migraine during follow-up. Women with a history of migraine only were more likely to have a Framingham risk score ≥10 at baseline (OR 1.74, 95% CI 1.38 to 2.18). In contrast, women with active migraine at baseline (OR 0.55, 95% CI 0.44 to 0.68), and women with newly reported migraine during follow-up (OR 0.42, 95% CI 0.25 to 0.69) had a decreased risk of having a Framingham risk score ≥10. For risk scores <10, a similar pattern was observed.
Conclusion
Framingham risk scores are only increased in women with a history of migraine compared with women not reporting migraine. Our results suggest that (i) lifetime changes in migraine status should be considered when studying association with the vascular system , and (ii) that a relatively healthy cardiovascular system, as determined by the Framingham cardiovascular risk score, appears to be associated with having active migraine or to predict development of migraine in the future.
Comorbidity of Primary Headaches
EP-02-007
CLINICAL CHARACTERIZATION OF VISUAL SNOW
Francesca Puledda1,*, Tze Lau1, Christoph Schankin2 and Peter J. Goadsby1
1Headache Group, Department of Basic and Clinical Neuroscience, King’s College London, and NIHR-Wellcome Trust King’s Clinical Research Facility, King’s College Hospital, London, UK, King's College London, London, United Kingdom
2Department of Neurology, Inselspital, Bern University Hospital, University of Bern, Bern, Switzerland
Objectives
Patients with Visual Snow suffer a pan-field, dynamic visual disturbance described as continuous TV-static-like tiny flickering dots. The proposed diagnostic criteria require at least two additional visual symptoms from: palinopsia (afterimages and trailing), entoptic phenomena (floaters, blue field entoptic phenomenon, photopsia, self-light of the eye), photophobia and nyctalopia (1).
Methods
Visual Snow patients were characterized clinically with regard to the current criteria. An online survey was prepared in collaboration with the patient group Eye-on-Vision. Patients were directed to the site after they contacted us by email asking to be involved in research. The study was approved by the KCL Research Ethics Panel.
Results
Of n = 636 patients contacting the group, n = 570 matched the diagnostic criteria for Visual Snow; data is reported for these patients. The female to male ratio of the cohort was 1:1.1 and mean age of 29 ± 10 years. The mean age of symptom onset was 13 ± 13 years and 38.7% of subjects reported symptoms for their entire lifetime (data available for n = 323). Subjects presented with black and white (n = 317; 56%), colored (n = 249; 44%), flashing (n = 253; 45%) and transparent (n = 297; 52%) static, with an average of two types of static reported per patient. Floaters (n = 486) were the most common associated symptom, followed by afterimages (n = 467) and photophobia (n = 446). The non-visual symptom tinnitus was reported by 74% of patients. Data on headache comorbidity was available for n = 226 subjects, of which 83% reported at least one migraine episode in the past.
Conclusion
The data confirm earlier work on this unrecognized disorder and extend the analysis of the overlapping symptoms present in a wide range of subjects. Visual Snow can be a highly disabling syndrome that is now becoming better understood as it is recognized and systematically studied.
References
1) Schankin CJ, Maniyar FH, Digre KB, Goadsby PJ. Visual snow- a disorder distinct from persistent migraine aura. Brain. 2014;137:1419–28
Comorbidity of Primary Headaches
EP-02-008
White Matter Hyperintensities in Migraine: Clinical Significance and Central Pulsatile Hemodynamic Correlates
Chun-Yu Cheng1,2,*, Hao-Min Cheng3, Shih-Pin Chen2, Chen-Huan Chen3 and Shuu-Jiun Wang2
1Institute of Brain Science, National Yang-Ming University
2Department of Neurology, Neurological Institute, Taipei Veterans General Hospital
3Cardiovascular Research Center, National Yang-Ming University, Taipei, Taiwan, Republic of China
Objectives
To explore the role of central pulsatile hemodynamics in the pathogenesis of cerebral white matter hyperintensities (WMHs) in young migraine patients.
Methods
Sixty patients with migraine, 20 to 50 years old, without overt vascular risk factors and 30 demographically-matched healthy controls were recruited in this prospective study. Cerebral WMHs volume was determined by T1-weighted magnetic resonance imaging with CUBE-fluid-attenuated-inversion-recovery sequences. Central systolic blood pressure (cSBP), carotid-femoral pulse wave velocity (cf-PWV), and carotid augmentation index (AI) were measured by applanation tonometry. Carotid pulsatility index (CPI) was derived by Doppler ultrasound carotid artery flow analysis.
Image:
Results
Compared to controls, migraine patients had a higher WMHs frequency (OR, 2.75; P = 0.04) and greater WMHs volume (mean volume, 0.174 vs 0.049, cm3, P = 0.04). Multivariable regression analysis showed that WMHs volume in migraine patients was positively associated with cSBP (P = 0.04) and cf-PWV (P < 0.001), but negatively associated with CPI (P = 0.04) after controlling for potential confounding factors. The interaction effects observed indicated that the influence of cf-PWV (P < 0.001) and cSBP (P = 0.03) on WMHs formation was greater for the lower-CPI subgroup of migraine patients. WMHs volume in migraine patients increased with decreasing CPI and with increasing cSBP or cf-PWV levels.
Conclusion
WMHs are more common in patients with migraine than in healthy controls. Central pulsatile insults in the presence of low intracranial artery resistance may predispose patients with migraine to WMHs formation.
Comorbidity of Primary Headaches
EP-02-009
A DIARY STUDY IN VISUAL SNOW – SYMPTOM VARIATION OVER 30 DAYS
Francesca Puledda1, Fiona Greenwood1,*, Tze Lau1, Christoph Schankin2 and Peter J. Goadsby1
1Headache Group, Department of Basic and Clinical Neuroscience, King’s College London, and NIHR-Wellcome Trust King’s Clinical Research Facility, King’s College Hospital, King's College London, London, United Kingdom
2Department of Neurology, Inselspital, Bern University Hospital, University of Bern, Bern, Switzerland
Objectives
Patients with Visual Snow suffer a pan-field, dynamic visual disturbance consisting of tiny flickering dots resembling the “static” of a badly tuned analogue television. The symptoms are continuous and can persist over years. Proposed diagnostic criteria require at least two additional visual symptoms from: palinopsia, entoptic phenomena, photophobia and nyctalopia (1). In this study we wanted to monitor the symptoms over time of Visual Snow as well as to further characterize their variation in certain lighting conditions.
Methods
A questionnaire was prepared in collaboration with the patient group Eye-on-Vision and sent to subjects who had expressed an interest in research by directly contacting our study team. Patients were required to fill in a daily symptom scale for 30 days, scoring seven different parameters aimed at describing the static. These were static density, speed, colour, size, level of visibility on different surfaces, time variation during the day and level of distraction caused. Patients were also asked to give a one-off score from 1 to 7 to six different lighting conditions (outdoor sunny, outdoor cloudy, outdoor rainy, outdoor night-time, indoor, fluorescent) to indicate their effect on visual symptoms. The study was approved by the KCL Research Ethics Panel. Data were analysed using non-parametric methods.
Results
Ninety patients returned the 30-day diary. Table 1 shows the main values of static parameters across all patients. Of the different lighting conditions examined, outdoor sunny environments were considered as having the best effect on symptoms (median = 5, IQR = 3–6), while night-time was given the lowest scores (1, 1–3). A related-samples Friedman’s ANOVA showed that the difference between scores was significant (p < 0.001). Spearman rank correlation analysis demonstrated the level of distraction that the static caused was found to correlate at a significant level with the size (rs = 0.34, p < 0.001) and density (rs = 0.36, p < 0.001) of the static itself.
Conclusion
Visual Snow is a highly disabling syndrome, for which there is no clearly identified treatment. It presents a relatively constant symptomatology in most subjects and it appears to be worsened by certain lighting conditions, particularly in the context of low natural light.
References
1) Schankin CJ, Maniyar FH, Digre KB, Goadsby PJ. Visual snow- a disorder distinct from persistent migraine aura. Brain. 2014;137:1419–28
Comorbidity of Primary Headaches
EP-02-010
Obstructive sleep apnea and headaches in perimenopausal women
Joao E. Magalhaes1, Rodrigo Pinto Pedrosa2 and Pedro Sampaio Rocha Filho1,*
1Universidade Federal de Pernambuco e Universidade de Pernambuco
2Pronto Socorro Cardiológico de Pernambuco, Universidade de Pernambuco, RECIFE, Brazil
Objectives
Obstructive sleep apnea (OSA) and headaches are prevalent in middle-aged women. The aim of this study is to compare the frequency and characteristics of headaches among perimenopausal women with and without obstructive sleep apnea.
Methods
We consecutively recruited 304 women aged 45 to 65 years-old with more than 60 days of menstrual irregularity who were evaluated using semi-structured interview, the 6-item Headache Impact Test, hospital anxiety and depression scale. All patients underwent a portable overnight sleep recording in the sleep laboratory using a validated device (Resmed Embletta PDS; Medcare). Oxygen saturation, body position, airflow, and ribcage and abdominal movements during breathing using impedance belts were measured. Apnea was defined as a total absence of oronasal flow for more than 9 seconds and hypopnea as a clear decrease (more than 30%) in amplitude of oronasal flow for more than 9 seconds followed by a 4% desaturation. The apnea-hypopnea index (AHI) was calculated by dividing the total number of apneas and hypopneas by total time in bed. OSA and moderate to severe OSA (sOSA) were defined as AHI higher than 4 events per hours and AHI higher than 14 events per hour, respectively. Headaches were diagnosed according to the diagnostic criteria established by the third edition of the International Classification of Headache Disorders (ICHD-3 beta). All patients had given their informed consent. The study was approved by the Research Ethics Committee of the Oswaldo Cruz University Hospital.
Results
The final sample included 277 women of which 112 women (40.1%) had OSA and 31 women (11.1%) had sOSA. The OSA group was older and had more arterial hypertension and obesity, as well higher waist and neck circumference than non-OSA group. The prevalence of overall headache, morning headache, migraine, migraine with aura (MA), chronic migraine (CM) and TTH were respectively 66.7%, 42.9%, 40.0%, 16.7%, 6.9%, and 19.3%. Prevalence was not different comparing OSA or sOSA and non-OSA groups. There was no case of chronic TTH or sleep apnea headache. None of the characteristics of headache (quality, location, time of episodes, intensity and frequency of pain, and impact on quality of life) was significantly different comparing OSA or sOSA and non-OSA groups. Even the OSA women’s parameters of sleep study were not different comparing headache or morning headache and non-headache subgroup.
Conclusion
There were no differences in primary headaches frequency or headache characteristics among women with or without obstructive sleep apnea OSA.
Comorbidity of Primary Headaches
EP-02-011
BURDEN OF HEADACHE DISORDERS AT ATTENTION DEFICIT HYPERACTIVITY DIAGNOSED CHILDREN AND THEIR PARENTS
Meryem O. Kucuk1, Gülen Güler2, Evren Tufan3, Osman Ozgur Yalin4,*, Harika Gözükara5, Aynur Ozge6 and Fevziye Toros7
1Child and Adolescent Psychiatry, Başkent University, School of Medicine, Adana
2Child and Adolescent Psychiatry, Elazığ Mental Health Hospital, Elazıg
3Child and Adolescent Psychiatry, Abant Izzet Baysal University, Bolu
4Department of Neurology, Istanbul Training and Research Hospital, Istanbul
5Department of Biostatistics, İnönü University, School of Medicine, Malatya
6Neurology Department
7Child and Adolescent Psychiatry, Mersin University School of Medicine, Mersin, Turkey
Objectives
Attention deficit and hyperactivity disorder (ADHD) is common among children and adolescents with a worldwide prevalence of 5.3% and is considered to be an important factor leading to poor academic performance and poor quality of life. Headache is one of the most common chronic disorder with a prevalence of 10–20% in the school-age population and often accompanied by severe impairments, including low quality of life, low emotional functioning, school absenteeism, and poor academic performance.The prevalence of ADHD among children with headache are still contradictory and the prevalence of headache disorders in ADHD is not well studied. The clinical study aimed to evaluate burden of primary headache among ADHD children and parents and results compared age and sex matched healthy controls.
Methods
The study comprised children and adolescents aged 6–18 years with ADHD according to DSM-5, healthy controls and parents of these 2 groups were referred by the child and adolescent psychiatrist for neurological assessment to the neurologist at Mersin University Medical Faculty during drug navy period for patients. Both the interview and the questionnaire included questions regarding demographics, patient’ and families’ medical history, headaches characteristics, and other medical history obtained by experienced nerulogists and psychiatrists. Headache diagnosis based to ICHD-3 beta criteria.
Results
The study group comprised of 117 ADHD children and 111 age and sex matched healthy controls. Median of age was 11 years (6–18) in ADHD group and 12 (8–16) years for healthy controls. Headache was common for both groups and was significantly more common in ADHD patients (59,0% & 37,8%) (p = 0,002). While episodic and chronic migraine found significantly common in ADHD children, frequent episodic TTH was common in control group. The most frequent diagnosis was episodic migraine for ADHD and episodic TTH for control group. The overall prevalence of migraine for ADHD group estimated 26,5%, and 9,9% for healthy controls.
We analyzed characteristics of mothers of ADHD (ADHD-M) and healthy controls mothers (HC-M) headache. Primary headache disorders was significantly more common for ADHD-M (90,5% & 65,6%). While migraine, particularly chronic migraine was more common in ADHD-M, episodic tension type headache was more common at health controls mothers (HC-M). The overall prevalence of migraine for ADHD-Ms was 72% and estimated 42,9% for HC-Ms. The analyses of the fathers of study group performed. The prevalence of headache was similar at two groups. The most common headache disorder was infrequent TTH at ADHD fathers and frequent TTH at control groups’ fathers. The overall prevalence of migraine for ADHD fathers estimated 21% and was %13,7 for healthy controls fathers. Chronic migraine was significantly more common at ADHD fathers.
Conclusion
We observed headache is more prevalent in ADHD children than controls and also ADHD-mothers have more common headache. Migraine and chronic migraine is more prevalent in them, while tension type headache was more common in mothers of healthy controls. Knowledge of common biologic systems involved would not only help physicians provide better care for their patients but may also provide some clues regarding sources of heterogeneity of ADHD.
Genetics and Biomarkers of Headache Disorders
EP-02-012
Reproducible activation of the PAC1-receptor via maxadilan as target-engagement model in humans
Linde Buntinx1,*, Marleen Depré1, Els Ampe1, Anne Van Hecken1 and Jan de Hoon1
1Center for Clinical Pharmacology, Department of Pharmaceutical and Pharmacological Sciences, KU Leuven, Leuven, Belgium
Objectives
Maxadilan is a potent vasodilator peptide, isolated from the sand fly Lutzomyia longipalpis, which activates the mammalian PAC1 receptor, a promising target for migraine therapy. Therefore, maxadilan is suggested as a target-engagement tool to study PAC1 antagonists. The objectives of our study were: (1) to determine, as a first in human study, the dose response, safety and time course of the dermal blood flow (DBF) after intradermal (ID) injections of maxadilan in the human forearm, and (2) to assess the inter-arm and inter-period reproducibility of this response.
Methods
This was a single-center, open-label, placebo-controlled study in healthy subjects (age 18 to 45 year). The study consisted of 2 parts: dose-finding (n = 10) and reproducibility (n = 10). Study visits started with acclimatization for 30 minutes in a temperature controlled room before baseline. Laser Doppler Imaging (LDI) scans were performed with a PIMIII Laser Doppler Imager (Perimed®). A rubber O-ring was used to delineate the region of interest (ROI) around the injection site. The wheal and flare response was assessed using: (1) LDI, (2) measurement of the largest and smallest diameter with a ruler, and (3) photography-based software (Java®). Maxadilan was injected ID in the volar surface of the forearm and measurements were performed every 10 minutes for 1 hour and at 90, 120 and 180 minutes post-injection. To assess reproducibility, the concordance correlation coefficient (CCC), Bradley-Blackwood test (BB-test) and sample size calculations (SSC) were used.
Test-Retest reproducibility of DBF response and sample size calculations
L: Left, R: Right, V1: visit 1, V2: visit 2. BB-test: p-value < 0.05 indicates evidence of unequal means or unequal variances between 2 groups.
Results
Maxadilan ID injection was found to be safe based on AE reporting, ECG, vital signs, physical examination and laboratory safety assessments. ID maxadilan (0.9, 3 and 10 ng) produced a robust increase in DBF compared to baseline and placebo. DBF response to 0.9 ng ID injections of maxadilan was reproducible between periods (CCC > 0.7) and between arms (CCC > 0.7) when data were expressed as AUC0–180min (perfusion units (PU) *min) in the ROI (table 1). An increase in DBF was observed already 5 minutes after maxadilan injection and reached a plateau-phase after 60 minutes lasting until 72 hours, with an unexpected peak at 24 hours. Maxadilan ID injection induced a flare response for all doses but no wheal was observed. Flare area measured with LDI, ruler and photography was found to be less reproducible (CCC < 0.65) between arms and periods. SSC based on DBF in the ROI shows that samples of <10 subjects are sufficient to detect a 50% difference between 2 independent groups with 80% power.
Conclusion
ID injections of maxadilan induce reproducible changes in DBF over time and between arms when measured with LDI in the ROI. This study provides an appealing new target-engagement biomarker for the study of PAC1 receptor antagonists in early clinical development studies.
Genetics and Biomarkers of Headache Disorders
EP-02-013
Elevated circulating endothelial-associated microRNAs in migraine patients
Shih-Pin Chen1,2,*, Chun-Yu Cheng2,3, Yi-Chu Liao1,2, Jong-Ling Fuh1,2, Yen-Feng Wang1,2 and Shuu-Jiun Wang1,2
1Department of Neurology, Faculty of Medicine, National Yang-Ming University
2Department of Neurology, Taipei Veterans General Hospital
3Institute of Brain Science, National Yang-Ming University, Taipei, Taiwan, Republic of China
Objectives
Evidence of vascular dysfunction in migraine is increasing. MicroRNAs (miRs) have emerged as important regulators related to vascular endothelial functions. This study was to explore whether endothelial-associated miRs alterations occurred in migraine patients.
Methods
Thirty patients with migraine, aged 20 to 50 years old, without overt vascular risk factors and 30 sex- and age-matched healthy controls were recruited. Abundance of four endothelial-associated miRs (miR-155, miR-126, miR-21, Let-7 g) were quantified by quantitative real-time PCR and expressed by fold changes (2-ΔΔct) in relative to the average miR levels in the control group. The concentrations of three circulating biochemical factors implicated in the endothelial functions were measured by enzyme-linked immunosorbent assay. The miRs levels were correlated with headache profiles as well as syncope in migraine patients.
Results
Compared to controls, migraine patients were associated with upregulated expression of miR-155 (6.17-fold, P = 0.018), miR-126 (6.17-fold, P = 0.013), Let-7 g (7.37-fold, P = 0.005) and plasminogen activator inhibitor-1 level (P = 0.015). Migraine patients with all 6 migrainous symptoms (unilateral, throbbing, aggravation by physical activities, moderate or severe intensity, nausea/vomiting, photophobia and phonophobia) had the higher expression of miR-155 (P = 0.009), miR-126 (P = 0.008), miR-126 (P = 0.046) and Let-7 g (P = 0.028) than those without. Increased miR-155 (P = 0.041) and miR-126 (P = 0.041) were associated with numbers of syncope in the past year in migraine patients.
Conclusion
Circulating levels of endothelial-associated miRs are significantly increased in migraine patients, indicating a potential interplay between endothelial dysfunction and migraine pathogenesis.
Genetics and Biomarkers of Headache Disorders
EP-02-014
Increased thrombophilic predisposition in premenopausal females with chronic migraine
Piero Barbanti1,*, Patrizia Ferroni2,3, Cinzia Aurilia1, Gabriella Egeo1, Luisa Fofi1, Francesca La Farina4, Maria Giovanna Valente2, Laura De Marchis2, Antonella Spila2, Raffaele Palmirotta5, David Della Morte2,6 and Fiorella Guadagni2
1Headache and Pain Unit, Department of Neurological, Motor and Sensorial Sciences
2Interinstitutional Multidisciplinary Biobank (BioBIM), Biomarker Discovery and Advanced Technologies (BioDAT)
3San Raffaele Roma Open University, Rome, Italy
4Interinstitutional Multidisciplinary Biobank (BioBIM), Biomarker Discovery and Advanced Technologies (BioDAT), IRCCS San Raffaele Pisana, Rome
5Department of Biomedical Sciences and Human Oncology, University “A. Moro”, Bari
6Department of Systems Medicine, Tor Vergata University, Rome, Italy
Objectives
Migraine is associated with an increased risk for cardiovascular diseases (CVD), especially in women aged less than 45 years. Although the pathophysiological mechanisms linking migraine and CVD are still unclear, coagulation abnormalities have been regarded as a logical link. However, the majority of the studies investigating the procoagulant status of migraneurs focused on the presence of inherited thrombophilic factors with inconsistent results that, together with the high costs of laboratory testing, precludes a universal screening in favour of a selective history-based one. Therefore, the present study was designed to explore the thrombophilic potential of patients with migraine using a novel standardized assay for globally screening the patient thrombophilic state in a large, unselected, carefully clinically characterized population of episodic and chronic migraineurs.
Methods
Thrombophilic predisposition was evaluated in a cohort of 550 migraineurs (448 females, 102 males) using an easy-to-run and commercially available activated protein C (APC)-dependent thrombin generation assay [HemosIL ThromboPath (ThP)]. The assay is characterized by an overall sensitivity of 95% to all protein C pathway abnormalities (either acquired or inherited) and has been proposed as a potential screening tool in thrombophilia assessment. Association analysis of APC function with migraine clinical features was also investigated.
Results
APC function was impaired in 17% of migraineurs compared with 9% of otherwise healthy individuals (p = 0.037). Overall, ThromboPath correlated with age (Rs = 0.132, p = 0.002), female sex (Chi-square = 4.3, p = 0.038) and attack’s frequency (Chi-square = 3.9, p = 0.049), but not with major cardiovascular risk factors, the presence of overt cardiovascular disorders, or use of prophylaxis or drug abuse, suggesting that the underlying thrombophilic condition was not related to other conditions known to be associated with, or influenced by drugs possibly affecting the individual pro-coagulant status. None of the tested variables associated with APC function in the male cohort. Conversely, pre-menopausal status (OR = 2.86, 95%C.I.: 1.58–5.18, p = 0.0005) and oral contraceptive/ hormone replacement treatment (OR = 3.74, 95%C.I.: 1.28–10.9, p = 0.015) were associated with impaired APC function in the female cohort, independently of major cardiovascular risk factors, or migraine features.
Conclusion
Premenopausal females with near-daily chronic migraine ( > 25 day/months) revealed a thrombophilic predisposition, possibly due to impaired APC function, which might increase cardiovascular risk. Accordingly, we suggest a scrupulous attention to concomitant ischemic risk conditions and an accurate choice of acute/prophylactic migraine treatments in these patients. ThromboPath, for its part, might represent a first-step screening assay to investigate the thrombophilic potential in at risk migraineurs, providing the opportunity to rationalize the use of expensive individual assays.
Genetics and Biomarkers of Headache Disorders
EP-02-015
Identification of Novel FHM Genes by Whole Exome Sequencing
Lyn R. Griffiths1,*, Cassie L. Albury1, Miles C. Benton1, Robert A. Smith1, Neven Maksemous1 and Larisa M. Haupt1
1Genomics Research Centre, School of Biomedical Sciences, IHBI-QUT, Brisbane, Australia
Objectives
Familial Hemiplegic Migraine (FHM) is an autosomal dominant neurological condition with attacks characterised by severe head pain, nausea, aura, phono/photophobia and hemiparesis. FHM symptomology commonly overlaps with a number of similar neurological disorders, diagnostic success rates are low (<25%), and our understanding of the pathophysiological consequence of the geno-phenotype associations limited. The disease is considered to be a channelopathy, with mutations in several ion channel genes (CACNA1A, ATP1A2 and SCN1A) shown to be causative in large FHM family studies. In an effort to identify novel mutations causing FHM, we are performing Whole Exome Sequencing (WES) in a cohort (n = 209) of clinically suspected and genetically undiagnosed (ie negative for the known FHM1, 2 and 3 genes) FHM patients. Variant prioritisation analysis and in-silico prediction methods are being used to identify novel candidate mutations for further characterisation and functional assessment.
Methods
WES of patient DNA samples has been performed using the Ion Proton™ platform. Ion AmpliSeq™ Exome RDY – OT2 kits were used for exome capture and preparation and libraries quantified with Agilent High Sensitivity DNA kits. Prepared libraries were loaded on chips using Ion PI™ Hi-Q™ Chef reagents and the Ion Chef™ for 200 bp read NGS. WES data was analysed using an in-house bioinformatic pipeline. Briefly, first pass analysis removed common variants and functionally insignificant variants based on minor allele frequencies (<1%) and predictive functional scores (SIFT <0.05; Polyphen >0.80). Second pass analysis removed hotspot variants based on comparisons with unrelated controls. Benign variants reported in ClinVar were also removed. Priorities were placed on novel variants, indels and frameshift mutations. Third pass analysis classed variants based on their gene ontology into groups including vasogenic; neural and CNS; ion channels and metals; and hormones and the immune system. Short-listed variants were assessed based on IGV observation and read coverage with likely false positives (coverage <20x) removed. The remaining variants were checked against frequencies reported in the ExAC and gnomAD databases. Given the variations in phenotypic presentation and the polygenic nature of FHM, each sample was analysed in three ways: independently, according to symptomology and as a cohort. All candidate gene mutations on n = 23 cases to date, have been validated using Sanger Sequencing.
Results
Data was classified according to gene mechanism and FHM symptoms and reaffirmed the causative role of previously associated pathways: namely action potential homeostasis regulated by ion channels and enzyme production pathways indirectly involving mitochondrial influence. Independent analysis has to date identified 52 variants previously implicated in neurological disorders, including spinocerebellar ataxia, epilepsy and spastic paraplegia. Symptomology analysis has to date identified a plausible mutation in a physiologically relevant gene defined by amino acid changing, disease causing and low allele frequency in silico prediction status. Cohort analysis has to date identified an additional novel causative candidate with a potential disease causing amino acid changing variant in a transmembrane receptor regulatory protein.
Conclusion
These data confirm the power of WES, variant prioritization strategies and in-silico prediction methods to identify novel causative mutations for FHM. The identified mutations will be validated for pathogenicity using a two-staged functional approach using in vitro models. Further advances in these efforts will provide improved FHM diagnostics by substantially increasing the rate of diagnostic success toward improved patient outcomes.
Genetics and Biomarkers of Headache Disorders
EP-02-016
Serum Interleukin-6 and Interleukin-18 levels in migraineurs
Hiroshi Takigawa1,*, Hisanori Kowa1, Toshiya Nakano1 and Kenji Nakashima2
1Division of Neurology, Department of Brain and Neurosciences, Faculty of Medicine, Tottori University, Yonago
2Division of Neurology, Matsue Medical Center, Matsue, Japan
Objectives
There are some evidences suggesting that an immunologic dysfunction has been hypothesized to be involved in migraine pathogenesis. It is not yet clearly understood what immunological mechanism leadings to migraine headaches. The aim of this study was to investigate the serum Interleukin-6 (IL-6) and Interleukin-18 (IL-18) levels in patients with migraine.
Methods
IL-6 and IL-18 levels in serum were measured in 32 patients with migraine with aura (MA; 12 males and 20 females, average age: 32.8 years), 68 patients with migraine without aura (MO; 15 males and 53 females, average age: 37.3 years) and 15 patients with tension-type headache (TH; 4 males and 11 females, average age: 55.3 years). Thirty one normal healthy volunteers composed the control group (CTL; 11 males and 20 females, average age 39.9 years). IL-6 and IL-18 levels in serum were determined respectively using chemiluminescence enzyme immunoassay and latex immunology turbidimetric method. Comparisons among MA, MO, TH and CTL groups were assessed by the analysis of multivariate statistics. Acute phase (AP) and intermittent phase (IP) cases were defined respectively as the day of migraine attack and the other days after migraine attack and compared by the analysis of multivariate statistics. And difference between with medication overuse headache (with-MOH) and without MOH (without-MOH) groups were analyzed.
Results
Mean IL-6 levels in serum were 9.8 pg/mL in the patients with MA, 5.2 pg/mL in the patients with MO, 1.3 pg/mL in the patients with TH and 5.6 pg/mL in CTL. IL-6 level in the patients with MA was significantly higher than in the MO, TH and CTL (p = 0.0385). Mean IL-18 levels in serum were 185.7 pg/mL in the patients with MA, 227.5 pg/mL in the patients with MO, 204.9 pg/mL in the patients with TH and 246.8 pg/nL in CTL. IL-18 level in MA, MO, TH and CTL was not significantly different. IL-6 levels at the AP in the patients with MA were significantly higher than them at the IP (p = 0.0185). IL-6 level in AP/IP with MO and TH was not significantly different. IL-18 level in AP/IP with MA, MO and TH was not significantly different. IL-6 and IL-18 levels at the with-MOH in the patients with MA were significantly higher than them at the without-MOH (p = 0.0185, 0.0086). IL-6 and IL-18 level in with-MOH/without-MOH with MO and TH was not significantly different.
Conclusion
Some cytokines have recently been shown to have pain-mediating functions, in addition to their known immunological functions. Our results suggest that the immunological system relevant to IL-6 is involved in the acute migraine pathogenesis. The chronicity and severity of the migraine pathogens were associated with not only IL-6 but also IL-18.
Genetics and Biomarkers of Headache Disorders
EP-02-017
RNA-Sequencing of Trigeminal Ganglia and Dorsal Root Ganglia gives insight in transcriptomic differences between the trigeminal and spinal system.
Lisette J. A. Kogelman1,*, Rikke Elgaard-Christensen1, Sara Hougaard Pedersen1, Marcelo Bertalan2, Thomas Folkmann Hansen1, Inger Jansen-Olesen1 and Jes Olesen1
1Danish Headache Center, Department of Neurology, Glostrup Research Institute, Rigshospitalet Glostrup, University of Copenhagen, Glostrup
2Institute of Biological Psychiatry, Mental Health Center Sct. Hans, University of Copenhagen, Roskilde, Denmark
Objectives
The trigeminal ganglia (TG) and the dorsal root ganglia (DRG) are homologous handling sensory input involved in nociception, where the TG subserves the head and the DRG subserves the rest of the body. Even though they are homologous, we expect differences due to the fact that several signaling substances (such as nitroglycerin) cause a headache but are not leading to pain in the rest of the body. To date, very little is known about the differences between the two systems. Insight into the genetic differences between TG and DRG will help to unravel the mechanisms of pain specific to the head or the rest of the body. We therefore aim to reveal the basal gene expression levels in TG and DRG and furthermore, detect genes that show differential expression between TG and DRG.
Methods
We RNA-Sequenced the TG and DRG of six naïve rats (Wistar Han) using the Illumina HiSeq2500 technology. After alignment with STAR and read quantification using HTSeq, we detected differentially expressed (DE) genes by using DESeq2, edgeR and limma. Only genes that were detected to be DE in all three methods with a false-discovery rate < 0.05 were regarded to be DE. Post hoc/subsequent filtering was applied based on the coefficient of variation within each tissue, the expression level, and fold change. Detected DE genes were further investigated using pathway analysis (GOSeq) and functional annotation.
Results
Using strong filtering (|log Fold Change| > 2 and log2 expression > 5) we detected 64 genes with higher and 55 genes with lower expression in TG than in DRG. The most highly DE gene with higher expression in TG was Nipal4 and several of the DE genes lower expressed in TG were Hox genes. Pathway analysis of the DE genes higher expressed in TG showed an overrepresentation of phospholipase activity (Padj = 0.0047) and genes lower expressed in TG showed an association with tyrosine metabolism (Padj = 0.0142) and phenylalanine metabolism (Padj = 0.0035). Several genes were expressed in only one of the tissues, such as Gabra6 and Gabrd in TG (neurotransmitters in the brain) and Hox genes in DRG. Most pain-associated genes, based on previous studies, were moderately to highly expressed in one or both tissues.
Conclusion
We performed a comprehensive analysis of the transcriptomic profiles of TG (trigeminal system) and DRG (spinal system). We used a hypothesis-free approach to detect transcriptomic differences between the trigeminal and spinal system at a first order level, and homed in on the expression profiles of headache-related genes. This study is highly relevant for future pain-related studies.
Genetics and Biomarkers of Headache Disorders
EP-02-018
Predicting olfactory acuity in episodic and chronic migraine
Michael Marmura1,*
1Neurology, Thomas Jefferson University, Philadelphia, United States
Objectives
Many persons with migraine report olfactory symptoms both in general and during migraine attacks, including osmophobia, changes in olfaction during and before attacks, and olfactory halluncinations. Although olfactory acuity is generally normal in migraine when compared to age and sex-matched controls, a significant minority have olfactory impairment during acute attacks. In those with chronic migraine (CM) a significant number have olfactory impairment regardless of their migraine status during testing. We studied the relationship between predicted olfactory identification ability and actual olfaction scores at baseline and during acute migraine attacks or exacerbations.
Methods
We recruited 100 subjects, 50 with episodic migraine (EM) and 50 with chronic migraine (CM). For EM subjects we asked if their ability to smell (1) improved, (2) stayed the same or (3) worsened during migraine compared to headache-free days. For CM patients, we asked about their smell acuity on migraine compared to non-migraine days. Each subject completed the University of Pennsylvania Smell Identification Test (UPSIT), a standardized and well-validated olfactory 40-item test that is useful in detecting subtle olfactory deficits. The majority of subjects completed the UPSIT on both migraine and migraine-free days. Based on previous studies using UPSIT, we considered a difference of 3 points or greater to be significant.
Results
EM subjects: 6 predicted improved acuity during migraine, 6 predicted worsening acuity and 38 no change. Of the 6 who predicted improvement, 4 actually had significantly worse acuity during migraine and 2 were unchanged. Of the 6 who predicted worsening acuity, 3 had no change in UPSIT scores, 3 did not repeat the test. Of those who predicted no change in acuity, 9 were significantly worse during migraine, 1 improved, 21 unchanged and 7 did not repeat the test.
CM subjects: 22 predicted improved acuity during migraine, 5 predicted worsening acuity, and 23 predicted no change. Of the 22 predicting increased acuity, 6 actually had improved acuity, 3 worsened, 8 were unchanged and 5 provided no data. Of the 5 predicting worsening, 2 were unchanged and 3 provided no data. Of the 23 predicting no change, 2 actually improved, 4 worsened, 13 were unchanged and 4 did not repeat the test.
Conclusion
Multiple factors influence olfaction including anatomic, genetic, and sensory processing differences. While many patients with migraine can develop osmophobia or experience migraine triggered by odor, patients with migraine are not very good at predicting their olfactory abilities during migraine. This phenomenon of persons with a sense of hyperacute odor detection having normal or decreased olfactory acuity has been seen in other conditions, such as pregnancy. Specifically patients with EM who predict improved smell during attacks are probably incorrect. CM subjects reporting increased acuity were more likely to be correct but most are not. Changes in autonomic function, limbic system activation or alterations in higher order sensory processing may influence olfactory acuity in migraine.
Genetics and Biomarkers of Headache Disorders
EP-02-019
S100B protein, a marker of trigemino-vascular system glial activation, is not increased in chronic migraine
Nuria Riesco1, Eva Cernuda-Morollón1 and Julio Pascual2,*
1Neurology, Univ. Hospital Central de Asturias, Oviedo
2Neurology, Univ. Hospital Marqués de Valdecilla and IDIVAL, Santander, Spain
Objectives
SB100 protein is a marker of the activation of glial cells. Theoretically, S100B protein could be released in case of trigemino-vascular system (TVS) activation and contribute to sensitization of pain pathways in chronic migraine (CM). S100B levels have been studied in migraine with contradictory results. The aim of this study was to analyze serum levels of S100B protein as a possible biomarker of the glial TVS activation in CM.
Methods
We determined by ELISA and in peripheral blood samples interictal S100B levels in 48 CM patients. As control groups S100B levels were also measured in 20 patients with episodic migraine (EP), 22 with cluster headache (CH) and in 29 matched healthy volunteers (HV) with no headache history.
Results
S100B levels in CM patients (21.9 ± 9.9 pg/mL) were not significantly different when compared to those of EM patients (26.7 ± 26.4 pg/mL), CH patients (22.4 ± 7.8 pg/mL) or HV (20.6 ± 8.3 pg/mL).
Conclusion
In contrast to other pain-producing peptides, such as CGRP, interictal, peripheral serum level of S100B protein does not seem to be a useful biomarker of glial TVS activation in CM.
(This work was supported by the PI14/0020FISSS grant (Fondos Feder, ISCIII, Ministry of Economy, Spain)
Headache and Gender
EP-02-020
Headache in pregnant women at the emergency service: etiologies, predictors and usefulness of the ICHD 3B criteria.
Joe Munoz-Ceron1,*, Andrea Osorio1 and Edwin Vega1
1ASOCIACION COLOMBIANA DE NEUROLOGIA, Bogotá, Colombia
Objectives
To determine the main etiologies, predictors and usefulness of ICHD 3 B criteria to differentiate primary from non -primary headaches in pregnant women at the ER.
Methods
Cross-sectional study comparing the prevalence of ICHD3B fulfilled criteria, associated symptoms, history of headache and demographic features between primary vs non primary headaches.
Results
Headache was responsible for 152 (5.2%) out of 2952 admissions. Median age was 25.4 years, IQR (25%>75%): 23–28, range 13–43. Primary, non-primary and unclassified headaches were 68,2%, 26,2% and 5,6% respectively. Migraine and headache associated to hypertensive disorders were the most frequent etiologies for primary and non-primary groups 91.6% and 31.4% respectively.
Factors associated to primary headaches were ICHD 3B fulfilled criteria OR:102, (IC95%13.1–802) p < 0.001, history of migraine OR2.85 (IC 95% 1.18–5.94) p:0.013, history of similar episodes OR6.4 (IC 95% 2.78–14.0) p < 0,001 and description of phosphenes OR:4.2 (IC 95% 1,5–11,68) p:0.02.
Factors associated to non-primary etiologies were fever (OR12.8 IC 95%1,38–119) p:0.016, median blood pressure over 106.6 (OR:2.6 IC 95%1.7–3.5) p:0.03
Conclusion
ICHD 3 B criteria could be useful to differentiate primary from non-primary headaches. This observation is also valid for history of migraine, similar episodes, phosphenes, fever and high blood pressure.
Headache Classification
EP-02-021
N = 1 statistical approaches to examine risk factor profiles of ICHD-3beta classified migraines within individuals.
Ty Ridenour1, Francesc Peris2, Gabriel Boucher2, Alec Mian2,2, Stephen Donoghue2,* and Andrew Hershey3
1RTI International, Research Triangle Park
2Curelator Inc., Cambridge
3CCHMC, Cincinnati, United States
Objectives
The present investigation compares the strengths and limitations of two distinct analytic approaches to understand both incidence and severity patterns within individuals in relation to daily exposure to a wide spectrum of risk factors that included emotions, sleep qualities, environmental and weather, lifestyle, and diet. The two approaches used were Cox regression to define incidence and a form of hierarchical linear modeling to identify severity that is tailored for intensive within-person analyses. These two analytic techniques were compared in terms of which risk factors were identified as possible “triggers” of migraine onset as opposed to being associated with severity of a migraine.
Methods
Participants were 750 individuals with migraine identified by clinician referral or via the internet and registered to use a novel digital platform (Curelator HeadacheTM). Participants completed baseline questionnaires and then entered daily data on headache occurrence and severity (level of pain), ICHD-3beta migraine criteria, and exposure to 70 migraine risk factors. Nearly 88% of the sample was female. Risk factors spanned emotions, sleep qualities, environmental and weather, lifestyle, diet, substance use, travel, and three additional triggers selected by each patient. Cox regression analysis is models the binomial incidence of migraine attacks (versus no headache). Hazard ratios from Cox regression tested and computed strength of associations between occurrence of a migraine (binomial) and the triggers. These associations were re-tested for severity of migraine headache using mixed model trajectory analysis (MMTA), a form of hierarchical linear modeling analyses severity of migraine headaches (a continuum). MMTA statistically controlled for patient-specific time-related trends in pain severity, autocorrelation, and used statistical tests that generate conservative estimates for N = 1 analyses.
Results
Overall, a greater number of risk factors were associated with severity of migraine headaches (MMTA) than incidence of migraines (Cox regression). However, Cox regression also detected unique triggers that were associated only with incidence (not severity) of migraine attacks. Consistent with past evidence, the profile of risk factors that were associated with incidence and severity of migraines varied considerably among patients, demonstrating that comprehensive clinical research on migraines requires analytics at the N = 1 level.
Conclusion
Cox regression of migraine incidence and MMTA of migraine severity each provide unique insights regarding within-person patterns and correlates of migraine attacks. The power to detect associations may be greater for MMTA by virtue of the continuous pain severity outcome rather than the binomial outcome used in Cox regression. However, the fact that Cox regression detected unique risk factors for occurrence of migraine headaches suggests that different risk factors are associated with occurrence of migraine attacks versus severity of migraine pain.
Headache Classification
EP-02-022
Individual Differences in the Relation of Migraine and Menstruation: Examining the ICHD-3beta Time Window
James S. McGinley1, R. J. Wirth1, Gabriel Boucher2, Dawn C. Buse3, Stephen Donoghue2, Jelena Pavlovic3, Richard B. Lipton3 and E. Anne MacGregor4,*
1Vector Psychometric Group, LLC, Chapel Hill
2Curelator, Inc., Cambridge
3Albert Einstein College of Medicine and Montefiore Headache Center, Bronx, United States
4Barts and The London School of Medicine and Dentistry, London, United Kingdom
Objectives
Though the role of menses as a migraine trigger is well-known, most studies have focused on group level analyses that do not assess within person associations between menses and migraine. Herein, we use individual daily diary data to explore both inter- and intra-individual differences in the perimenstrual occurrence of migraine.
Methods
Individuals with migraine were identified by clinician referral or via the internet and registered to use a novel digital platform (Curelator HeadacheTM). Participants completed baseline questionnaires and then entered daily data on headache occurrence, symptoms and potential trigger factors. Migraine days were defined by applying the ICHD-3beta (b) case definition to reported symptoms. Perimenstrual days (PMD) were days considered −2 to +3 from the first day of bleeding (5 total days), as defined by ICHD-3b. For each woman, we calculated the individual association of migraine with menses using logistic regression. Models quantified each woman’s risk by comparing the relative odds of having a migraine on PMD in the ICHD-3b time window to days outside the window (odds ratios [OR] > 1 indicate increased risk).
Results
Among 82 menstruating females, the age range was 15 to 53 years (mean = 34.4 years old). Women reported on a median of 159.5 days, 6 menstrual cycles, and 47.5 migraine days. Almost one-fifth of the sample (18.3%) used contraceptive pills. Women varied substantially in the association of migraine with menses. We next classified individuals into three migraine risk categories based on their individual OR (“Low” OR ≤ 1: n = 28, 34.2%; “Moderate” 1 < OR < 3.47 : n = 48, 58.4%; “High” OR ≥ 3.47: n = 6, 7.3%). Importantly, there were individual differences in migraine risk within each of the three broad risk classifications. Lastly, n of 1 individual plots showed substantial individual differences in relation of migraine to menstruation.
Conclusion
This study shows that even within broader risk groups, there is still substantial individual variability in PMD risk based on the ICHD-3b time window. A limitation of this study is that it does not consider alternative PMD time windows. It is plausible that expanding the PMD time window beyond 5 days could provide further insights into inter- and intra-individual differences in migraine related to hormonal changes. The current study suggests a limitation in applying, aggregate, one-size-fits-all assumptions to all patients.
Headache Classification
EP-02-023
Evaluation of the Identify Chronic Migraine (ID-CM) screener in an accountable care organization
Justin S. Yu1,*, Jelena M. Pavlovic2, Stephen D. Silberstein3, Michael L. Reed4, Steve H. Kawahara5, Robert P. Cowan6, Firas Dabbous7, Karen Campbell1, Riya Pulicharam5, Hema N Viswanathan8 and Richard B. Lipton9
1Allergan plc, Irvine
2Montefiore Medical Center; The Saul R. Korey Department of Neurology, Albert Einstein College of Medicine, Bronx
3Jefferson Headache Center, Philadelphia
4Vedanta Research, Chapel Hill
5DaVita Medical Group, El Segundo
6Stanford University School of Medicine , Stanford
7HealthCare Partners, La Jolla
8Allergen, Irvine
9Montefiore Headache Center, Albert Einstein College of Medicine, Bronx, United States
Objectives
The objective of this analysis was to assess the sensitivity and specificity of the Identify Chronic Migraine (ID-CM) screener using a physician-administered Semi-structured Diagnostic Interview (SDI) as the gold standard for CM diagnosis.
Methods
Eligible patients were enrolled in an accountable care organization, had at least 12 months of complete medical and pharmacy claims data, and had at least 1 medical claim with an ICD-9/10 code for migraine (346.xx/G43.xxx) in the 12 months prior to the study enrollment date. The ID-CM was then administered by e-mail, in person, or over the telephone to all eligible patients. The ID-CM is based primarily on 30-day patient recall and consists of 12 questions that assess headache frequency, headache symptoms, medication use for headache, interference with activities due to headache, and planning disruption due to headache. Additionally, a SDI was administered by telephone to a subset of eligible patients by a physician trained to reliably administer the tool. The SDI assesses headache symptoms, frequency, disability, and medication use based on 30-day and 90-day patient recall. The SDI is scored in two ways: (1) A computer-based algorithmic diagnosis based on ICHD-3β criteria for migraine and modified Silberstein-Lipton criteria for CM; (2) A physician-based diagnosis taking into account the above criteria and clinical judgment. In the event that the algorithmic and physician diagnosis disagreed, a headache expert adjudicated the disagreement and assigned a final diagnosis of CM or non-CM. Although all included patients were administered the ID-CM, only those that were administered the SDI were included in order to have a gold standard with which to compare the ID-CM results. Additionally, migraine patients with a previous CM diagnosis based on an ICD-9/10 code (346.7x/G43.7xx) were excluded. Two-by-two tables that compared ID-CM and SDI classifications of CM status were used to assess sensitivity and specificity of the ID-CM.
Results
The analysis of the ID-CM included 120 patients with a migraine diagnosis who completed the ID-CM and the SDI. Based on the ID-CM findings, 61 (51%) met criteria for CM while 59 (49%) did not meet criteria for CM. Using the SDI as the diagnostic gold standard for CM, the ID-CM had a sensitivity of 73% (55/75) and a specificity of 87% (39/45).
Conclusion
An accurate diagnosis of CM is required in order to optimize treatment for the condition. Based on the SDI as the gold standard for CM diagnosis, the ID-CM demonstrated acceptable sensitivity and good specificity in determining CM status. The results support previous findings on the validity of the ID-CM screener, and the real-world utility of the ID-CM as a simple yet accurate tool to identify CM patients.
Headache Classification
EP-02-024
Prolonged migraine aura: new insights from a prospective diary-aided study.
Michele Viana1,*, Grazia Sances1, Mattias Linde2, Giuseppe Nappi1, Peter J. Goadsby3 and Cristina Tassorelli1,4
1Headache Science Center, C. Mondino National Neurological Institute, Pavia, Italy
2Department of Neuroscience, Norwegian University of Science and Technology, Trondheim, Norway
3Headache Group – NIHR-Wellcome Trust Clinical Research Facility, King’s College London, London, United Kingdom
4Dept. of Brain and Behavioral Sciences, University of Pavia, Pavia, Italy
Objectives
To characterize the phenotype of prolonged aura (PA), i.e. an aura that includes at least one symptoms lasting for >1 hr
Methods
We recruited 224 consecutive patients affected by migraine aura attending the Headache Centers of Pavia and Trondheim. Patients were asked to describe each aura symptom (AS) [visual symptom (VS), sensory symptoms (SS) and dysphasic symptoms (DS)] with their own words in a dedicated free-text box in a diary. They also were asked to insert the time of onset/end of AS and of the painful phase. Once the patient had recorded three attacks, they returned for a follow-up visit and the diaries were discussed with the neurologist. The features collected for every aura were: presence of VSs/SSs/DSs, number of elementary visual disturbances, presence of positive and/or negative visual disturbances and/or disturbance of visual perception (DVP) (Viana et al 2016a), and presence of headache.
Results
Seventy-two patients completed the diaries during three consecutive auras for a cumulative number of 216 auras recorded. Out of 216 auras, 38 (17%) were PA. Out of 72 patients, 19 (26%) have at least one PA. PA had the following characteristics: VSs were present in 37 auras (97%), SSs in 26 (68%), DSs in 12 (31%). Median duration of VSs was 135 min (IQR 630), for SSs was 180 min (IQR 390), for DSs was 70 min (IQR 35). Ten PA (26%) had three symptoms, 19 PA (50%) had two symptoms and 9 PA (23%) had one symptom. One PA had three symptoms prolonged (>1 hr), six PA had two symptoms prolonged (VS + SS = 5, VS + DS = 1), 31 PA had only one symptom prolonged (VS = 19, SS = 11, DS = 1). All PA were associated to headache. With respect to VSs, 23 (60%) had positive features, 12 (31% negative features and 19 (50%) included DVP. When comparing PA with the other auras (n = 178) with respect to the presence of VSs and/or SSs and/or DSs, total number of AS, number and type of elementary visual disturbances, and presence of headache, we found PA was characterized by a higher total number symptoms (p < 0.001), a higher frequency of SSs (p < 0.001) and a higher frequency of DSs (p < 0.001). No other differences were found. We performed the same analysis comparing auras including at least one AS lasting for > 2 hrs (PA > 2, n = 23) with the remaining ones (n = 193) and auras including at least one AS lasting for 4 hrs (PA > 4, n = 14) with the remaining ones (n = 202). In the first comparison the only differences were a higher frequency of SSs and a higher number of aura symptoms in PA > 2 (p = 0.001 and p = 0.005, respectively) and in the second comparison the only difference was a higher number of aura symptoms in PA > 4 (p = 0.043). With respect to the duration of each AS of all auras, when considering them as a whole (n = 297), 46 AS (15%) lasted for more than one hr, 25 AS (8%) lasted for more than two hrs, 15 (5%) lasted for more than 4 hrs.
Conclusion
Prolonged aura is quite common (17% of all auras) and phenotypically differs from the other auras only for a higher number of non-visual symptoms (non-VSs). This latter finding is not surprising if we consider that an AS with a longer duration is likely related to a cortical spreading depression (CSD) that proceeds along a longer path on the respective brain area. Such CSD therefore will involve more easily other adjacent brain areas, conferring a higher number of non-VSs to PA. The substantial phenotypical similarities between PA and the other auras is maintained also when we increase the limit of duration to 2 and/or 4 hrs. This finding should lead to a discussion of the use the term “prolonged aura” and how long its duration should be.
Viana et al. 2016a. Cephalalgia. Aug 29. pii: 0333102416657147.
Viana et al. 2016b Cephalalgia. 2016 Apr;36(5):413–21
Headache Classification
EP-02-025
Field testing the ICHD 3 beta diagnostic criteria of vestibular migraine
Mark Obermann1,2,*, Daria Lippegaus3, Eva Bock2, Zaza Katsarava4 and Dagny Holle2
1Asklepios Hospitals Seesen, Seesen
2University of Duisburg-Essen, Essen, Germany
3Department of Neurology, University of Duisburg-Essen, Essen
4Evangelic Hospital Unna, Unna, Germany
Objectives
To determine the diagnostic accuracy of the ICHD3 diagnostic criteria for vestibular migraine in a real-world clinical setting.
Methods
130 patients with vestibular migraine were re-evaluated by telephone interview with the new ICHD 3 beta diagnostic criteria. The initial diagnosis was made during outpatient consultation in a tertiary dizziness clinic. As control group 30 patients with a clinically confirmed diagnosis of migraine with or without aura were also re-evaluated using the same questionnaire. The initial diagnosis was made in a tertiary headache center. The Mean age was 46,3 +/- 14 years and 75% of participants were women.
Results
The ICHD 3 beta criteria showed a sensitivity of 76.5 % and a specificity of 72.5%. Only 50% of patients had a temporal association of headache and vestibular symptoms. Most important diagnostic factors were the total amount of endured vertigo attacks (≥5), presence of one of the following specific vertigo characteristics (internal, external, spontaneous, visual vertigo, positional vertigo and aggravation by head movement), the presence of headache, at least 2 out of 4 migraine criteria (unilateral location, pulsating character, moderate to severe pain intensity, aggravation by physical activity), phono-/photophobia, nausea/vomiting, and aura (visual, sensible, aphasia).
Conclusion
The sensitivity and specificity of the proposed vestibular migraine diagnostic criteria were comparable to other ICHD diagnostic criteria, but may be reduced to a few key criteria.
Headache Classification
EP-02-026
Migraine in Children Under the Age of 7 Years: limits of new classification.
Francesca Marchese1,*, Edvige Correnti1, Davide Trapolino1, Andrea Santangelo2, Filippo Brighina3, Vincenzo Raieli4 and Salvatore Mangano1
1Child Neuropsychiatry School
2University of Palermo, Palermo, Italy
3 Department of Clinical Neurosciences, University of Palermo
4Child NeuroPsychiatry Unit, PO "G.Di Cristina" ARNAS Civico, Palermo, Italy
Objectives
migraine is a common problem in childhood. The new classification criteria, defined by the International Headache Society (IHS), have few references for children, especially for the preschoolar age. Aim of this study is to evaluate if it is possible to classify a population of children under 7 years old with migraine using ICHD-3Beta criteria and compare these criteria to those were previously used
Methods
in this retrospective study we identified 74 children younger than 7 years, referred to our Headache Centre and classified as “migraine without aura (Mwo) patients” in the previous studies. We’ve reevaluated every characteristic of each of them, according to ICHD-3Beta criteria and comparing the results with those obtained using a different classification’s systems
Results
in our study the application of different classification’s criteria changed the percentage of Mwo diagnosis. In particular, when Winner’s criteria and ICHD-II criteria were used, the prevalence of Mwo was 85.1%, by contrast, using ICHD-3Beta, it changed to 55.4%; in addition, in Valquist 1955 and in IHS1988, the prevalence changed to 33.8% and 71.6%, respectively. Moreover, according to the ICHD-II criteria, a 14.9% of patients had a diagnosis of ‘probable migraine’ but when ICHD-3 beta criteria were used it changed to 25.6% and 18.9% of patients remained undiagnosed
Conclusion
Our results showed that the ICHD-3Beta owned a low sensitivity and specificity for Mwo rather than ICHD-II; that because the first is too restrictive and it is very poorly suited to Mwo in children
Headache Classification
EP-02-027
Prospective testing of ICHD-3 beta diagnostic criteria for migraine with aura and migraine with typical aura in patients with transient ischemic attacks
Elena R. Lebedeva1, Natalia M. Gurary2 and Jes Olesen3,*
1Neurology, International Headache Center “Europe-Asia”, the Urals State Medical University
2Neurology, Medical Union “New Hospital”, Yekaterinburg, Russian Federation
3Neurology, Danish Headache Center,Glostrup Hospital, , Copenhagen, Denmark
Objectives
The International Classification of Headache Disorders 3rd edition beta (ICHD-3 beta) gave alternative diagnostic criteria for 1.2 migraine with aura (MA) and 1.2.1 migraine with typical aura (MTA) in the appendix. The latter were presumed to better differentiate transient ischemic attacks (TIA) from MA. The aim of the present study was to field test that.
Methods
A neurologist interviewed soon after admission 120 consecutive patients diagnosed with TIA after MRI with DWI scans (n = 112) or CT (n = 8). Semi-structured interview forms addressed all details of the TIA episode and all information necessary to apply the ICHD-3beta diagnostic criteria for 1.2,1.2.1, A1.2 and A1.2.1.
Results
Requiring at least one identical previous attack, the main body and the appendix criteria performed almost equally well. But requiring only one attack, more than a quarter of TIA patients also fulfilled the main body criteria for 1.2. Specificity was as follows for one attack: 1.2: 0.73, A1.2: 0.91, 1.2.1: 0.88 and A1.2.1: 1.0. Sensitivity when tested against ICHD-2 criteria were 100% for the main body criteria (because they were unchanged) and 96% for A1.2 and 94% for A1.2.1
Conclusion
The appendix criteria performed much better than the main body criteria for 1.2 MA and 1.2.1 MTA when diagnosing one attack (probable MA). We recommend that the appendix criteria should replace the main body criteria in the ICHD-3.
Headache Disorders in Children and Adolescents
EP-02-028
A Comparison of Placebo Responders with Non-responders in the Zolmitriptan Nasal Spray Adolescent (TEENZ) Study
Andrew Hershey1,*, Sarita Khanna2, Suneel Gupta2, Heather Wray3 and Robert Rubens2
1Cincinnati Children's Hospital Medical Center, Cincinnati
2Impax Laboratories, Inc., Hayward, United States
3AstraZeneca, Molndal, Sweden
Objectives
To compare the reported baseline patient demographics, migraine headache characteristics, and pre-study use of preventive migraine medications in adolescent (aged 12–17 years) placebo responders versus non-responders in the Zolmitriptan Nasal Spray (ZNS) TEENZ Study.
Methods
The TEENZ Study was a global, multicenter, randomized, double-blind, parallel-group study of ZNS compared with placebo that was designed to assess the safety and tolerability of ZNS for the acute treatment of migraine headache in adolescents (NCT01211145). Patients (12–17 years old) with an established diagnosis of migraine with or without aura by the International Classification of Headache Disorders were enrolled if they reported an at least 1–year history of having a minimum of 2 moderate to severe migraines per month, each lasting at least 3 hours, prior to study enrollment. The study design included a single-blind run-in period during which subjects treated a single attack with 1 dose of placebo. During the run-in period, 38% of subjects responded to placebo. Non-responders were then randomized to ZNS or matching placebo. In this post-hoc analysis, the baseline demographic, headache, and preventive medication use characteristics of the placebo responders are compared to those subjects who did not respond to placebo during the run-in period.
Results
For the 325 subjects responding to placebo and the 784 subjects not responding to placebo, demographic characteristics such as age, gender, race, and body mass index (BMI) were similar. Additionally, migraine characteristics—age of onset of first migraine attack, average number of migraines and non-migraine headaches per month, duration of typical untreated migraine, and type of migraine—were also similar. Occurrence of the associated migraine symptoms of photophobia and phonophobia was similar between the two groups of migraineurs, but the placebo non-responders reported the associated symptoms of nausea and vomiting more frequently than the placebo responders (nausea 87% vs 75%, p < 0.0001; vomiting 48% vs 36%, p = 0.0003). Finally, as compared to the non-responders, more placebo responders were using preventive migraine medications (21% vs 13%, p = 0.0007).
Conclusion
In this exploratory analysis there were no remarkable differences in demographics and migraine characteristics of placebo responders compared to placebo non-responders. Non-responders reported a higher incidence of nausea and vomiting accompanying their typical migraine and less use of preventive migraine medications; both of these factors may be related to headache severity.
Headache Disorders in Children and Adolescents
EP-02-029
Correlation between red flags in pediatric headache and abnormalities on neuroimaging studies in emergency department: preliminary data.
Edvige Correnti1,*, Francesca Marchese1, Anna Tobia1, Antonio Lo Verso2, Melania Loiacono1, Andrea Santangelo2, Vincenzo Raieli3 and Francesca Vanadia3; Headache Center-Child Neuropsychiatry-A.R.N.A.S. Civico
1University of Palermo, Child Neuropsychiatry School, U.O. di NPI A.R.N.A.S. Civico - G. Di Cristina Hospital
2Faculty of Medicine, University of Palermo
3U.O. Child Neuropsychiatry, A.R.N.A.S. Civico - G.Di Cristina Hospital, Palermo, Italy
Objectives
Headache is a common cause of access to pediatric emergency department. To date in literature we don’t have clear evidence about when Brain Computed Tomography (CT) and Magnetic Resonance Imaging (MRI) are necessary. Aim of this study is to explore and verify the relationship between the presence of red flags and neuroimaging abnormalities in pediatric headache.
Methods
We collected clinical data of 400 children (195 males and 205 females) aged from 1 to 17 years old admitted in emergency department from October 2015 to September 2016. We used a predetermined list of red flags (acute onset, associated symptoms, abnormal neurologic examination and others) and we evaluate the number of children underwent neuroimaging studies (CT or MRI).
Results
We found that 400 (1.23%) of children admitted in emergency department suffering with headache. The age range more interested was 6- 12 years old children. As preliminary result we found that 265/400 (66,25%) showing one or more red flags at the access to hospital, 164/265 (61,8%) of these was investigated with neuroimaging studies. Children who had just one red flag presented with positive CT in 25.23% of cases, those ones who had two or more red flags showed in 74.7% altered CT.
Conclusion
These preliminary results show that there is a significant relationship between red flags and anomalies on neuroimaging studies in pediatric population suffering headaches (especially when red flags are more than one), which support the potential role of red flags like predictors.
Headache Disorders in Children and Adolescents
EP-02-030
Usefulness of an Algorithm for Primary Headache Diagnosis in Children and Adolescents
Shannon White1,*, Marielle Kabbouche1, Andrew Hershey1, Paula Manning1 and Janet Majors1
1Cincinnati Children's Hospital Medical Center, Cincinnati, United States
Objectives
The primary objective of this project was to develop and utilize an algorithm for primary headache diagnosis in children and adolescents in order to standardize and improve pediatric care and minimize practice variation. Improving and standardizing the diagnosis of primary migraine headaches in children can directly affect the quality and cost of pediatric headache care. The goal of this specific algorithm was to increase the accuracy of headache diagnosis to more than 80% of patients receiving the correct diagnosis by utilizing ICHD3 (International Classification of Headache Disorders 3 Beta) criteria.
Methods
A team of headache specialists, nurse practitioners, nurses, data analysts, and business specialists developed an algorithm based on available scientific evidence. The algorithm was presented to all general neurology faculty to review and provide feedback and final consensus was received prior to testing. The testing was done in limited general neurology clinics for further feedback, and the algorithm was adjusted according to process improvement models (plan-do-study-act/PDSA cycle) and tests of change. Patients presenting with a chief complaint of headache received a headache questionnaire and the provider independently evaluated and diagnosed the patients. Those charts were then reviewed by headache specialists to see if the algorithm was followed and correct diagnosis was attained. The testing cycle continued for 3 months and then the algorithm was spread to all general neurology clinics. The following information was gathered: number of providers following the algorithm; percentage of appropriate diagnosis as by ICHD3 criteria; percentage of appropriate testing ordered; and cost per headache visit.
Results
Correct diagnosis of primary headache by ICHD3 criteria in a pediatric neurology clinic improved from 72% at initiation of the project to 90% and the appropriate testing ordered improved from 80% to 94%.
By the end of the 6 months, 94% of the providers were correctly implementing the algorithm on a regular basis.
The cost of headache care was a secondary analysis. The initial cost was lower in the summer months and increased in the fall when school started. The impact of the algorithm on cost was limited due to the seasonal variation of headache. A year-long tracking will be needed to evaluate improvement in cost benefit due to the algorithm.
Conclusion
Standardization of primary headache diagnosis is the first step in this project to improve headache care delivery. The algorithm improved the diagnosis of headache in general neurology clinics. Expanding the algorithm to primary care providers and pediatric emergency rooms would have a greater impact on headache evaluation, diagnosis, and treatment. This should result in an improvement of care delivery and outcome with expected positive long term effects on the cost of headache care throughout the health system.
Headache Education for Clinicians and Patients
EP-02-031
Headache interest in US academic neurology leadership: a cross-sectional study
Matthew S. Robbins1,* and Noah L. Rosen2
1Neurology, Montefiore Headache Center, Albert Einstein College of Medicine, Bronx
2Pain and Headache Center, Cushing Neuroscience Institute, Department of Neurology, Hofstra-Northwell Health, Manhasset, United States
Objectives
Headache disorders are exceedingly common, debilitating neurological conditions, and there is a striking paucity of headache specialists nationally. However, headache education is underrepresented in the curriculum of neurology residency programs and few neurology residents elect to pursue headache medicine fellowships. We aimed to explore the possibility that a low degree of headache interest among neurology department chairs and residency program directors (PDs) belies this mismatch.
Methods
We performed a cross-sectional analysis of chairs and PDs associated with accredited neurology residency programs. Data sources included the accredited program list, faculty profiles on institutional webpages, Doximity profiles, the American Headache Society (AHS) membership directory, and the roster of United Council for Neurologic Specialties (UCNS) headache diplomates. A headache interest was deemed to be present with the presence of a declared headache or concussion interest, active AHS membership, or UCNS certification.
Results
Our review included 137 residency programs comprising 127 department chairs, 132 PDs, and 5 faculty who were both chairs and PDs. Of all faculty, 62 (23.5%) were women. Headache expertise was declared by 10 (7.6%) chairs and 13 (9.5%) PDs. Headache fellowship training was pursued by 1 (0.8%) chair and 5 (3.6%) PDs, and among all faculty was the 10th most common subspecialty fellowship pursued. Three (2.3%) chairs and 7 (5.1%) PDs were AHS members. Seven (5.3%) chairs and 10 (7.3%) PDs were UCNS headache certified. An overall headache interest was present in 29 (11.0%) faculty, including 14 (10.6%) chairs and 15 (10.9%) PDs. A graduate degree aside from an MD (e.g. PhD, MPH) was more likely to be achieved in faculty without a headache interest (29.4%) than faculty with a headache interest (6.9%, p = 0.0076). Residency programs where either the chair or PD had a headache interest were just as likely to feature a UCNS headache fellowship program than programs without chair or PD headache interest (25.0% vs 23.0%, p = 0.83).
Conclusion
Current neurology department chairs and residency PDs have low rates of headache interest, which may influence the emphasis of headache education in neurology training. Headache interest is associated with lower rates of other graduate degrees, and future analysis should examine if academic faculty interested in headache are less likely to be in leadership positions because of a lack of research funding, opportunities or accomplishments.
Headache Education for Clinicians and Patients
EP-02-032
National awareness campaign for medication-overuse headache in Denmark
Louise Ninett Carlsen1, Maria L. Westergaard1,*, Mette Bisgaard1, Julie Brogaard Schytz2 and Rigmor H. Jensen1
1Danish Headache Center, Neurology Department, Rigshospitalet, Glostrup
2Association of Danish Pharmacies, Copenhagen, Denmark
Objectives
Overuse of acute pain medication for headache plays a major role in transforming episodic headache to chronic forms. One aspect of preventing medication-overuse headache (MOH) is to increase the public’s awareness of the disorder. It is also important to increase healthcare professionals’ awareness in order to improve their skills in counselling patients on pain medication use, and to promote rational prescription of pain medication. The objective is to describe the implementation of the Danish national awareness campaign for MOH.
Methods
The Danish Headache Center (DHC), the Association of Danish Pharmacies, and the Migraine and Headache Patient Organization, planned and implemented a national awareness campaign in the autumn of 2016. Target groups were the general public, general practitioners and pharmacists. The key messages were: 1) overuse of acute pain medication can make headaches worse; 2) MOH prevalence can be reduced through rational use of pain medication; and 3) MOH can be treated. The following campaign components were developed for the general public: online videos, leaflets about MOH, and interviews with expert resource persons for TV, radio and print media outlets; for pharmacists: information and training materials; and for physicians: reviews and case studies in Danish medical journals, and information materials. A survey on knowledge of, and sources of information on MOH, was conducted before and four weeks after the implementation of the campaign. Formative evaluation was conducted.
Results
All planned campaign components were developed and implemented. Online videos were viewed 297.000 times during the campaign period. Four-hundred pharmacies were invited to participate, and received education material. Over 28.000 leaflets were distributed in 400 pharmacies. Two radio interviews were conducted and a television broadcast about headache, including MOH, reached approximately 520.000 persons. Forty articles were published in popular print media, and information about MOH came up at 32 websites and five online news agencies. Three papers in Danish scientific journals for medical doctors, and one scientific paper for pharmacists were published. There were about 100 visitors at an information table operated by volunteers from a patient organization and DHC staff members at an annual conference attended by about 3000 general practitioners. A survey conducted four weeks after implementation showed minor but encouraging increase in percentage of the general public who knew about MOH (from 31% to 38%).
Conclusion
A concerted campaign for rational use of acute pain medications for headache can be implemented through the involvement of many stakeholders. Long term changes in health behaviors, prescription patterns, and medicine consumption should be continually monitored.
Headache Epidemiology, Outcomes and Burden
EP-02-033
Transmission of migraine in families: Family-linkage data from the HUNT study.
Sigrid Børte1,2,*, Bendik S. Winsvold1, Synne Øien Stensland1,3 and John-Anker Zwart1,2
1Division of Neuroscience, Oslo University Hospital
2Institute of Clinical Medicine, Faculty of Medicine, University of Oslo
3Norwegian Centre for Violence and Traumatic Stress Studies, Oslo, Norway
Objectives
Migraine is known to run in families. While some clinic-based studies have indicated that migraine is disproportionally transmitted through the maternal line, this has not been examined in a population-based setting. We aimed to clarify the parent-offspring associations of migraine and non-migrainous headache in a large, unselected population, taking into account relevant psychosocial factors.
Methods
We utilized the large, population-based Nord-Trøndelag Health Study (HUNT) from Norway. Headache diagnoses were separated into migraine and non-migrainous headache. Our study sample consisted of 8985 individuals (aged 13–45 years), who had information about headache in at least one parent. We included 8029 mothers and 5726 fathers (aged 21–52 years). In a cross-sectional design, logistic regression was used to calculate odds ratios (OR) with 95% confidence intervals (CI) for offspring headache given parental headache. Potential confounders, including parental education, anxiety, depression, alcohol, smoke, overweight and physical activity, were tested by the Mantel-Haenszel method.
Results
We found a strong association between maternal migraine and offspring migraine, both in daughters (OR 2.46, 95% CI 1.95–3.09) and sons (OR 2.68, 95% CI 1.89–3.80). A weaker, but significant association was also found between paternal migraine and offspring migraine, both in daughters (OR 1.60, 95% CI 1.12–2.29) and sons (OR 1.73, 95% CI 1.08–2.78). For non-migrainous headache, the only significant association was seen between mothers and daughters (OR 1.30, 95% CI 1.11–1.51). None of the psychosocial or demographic factors affected the estimates significantly.
Conclusion
Migraine in parents is strongly associated with migraine in their offspring, with a stronger association for maternal than paternal migraine. A different pattern was seen for non-migrainous headache, where the only significant association was seen between mothers and daughters. This may indicate different causative mechanisms for migraine and non-migrainous headache.
Headache Epidemiology, Outcomes and Burden
EP-02-035
Reducing the Impact of Migraine on Functioning: Results from the STRIVE Trial: A Phase 3, Randomized, Double-Blind Study of Erenumab in Subjects with Episodic Migraine
Dawn C. Buse1, Richard B. Lipton1,*, Daniel D. Mikol2, Andrew V. Thach2, Pooja Desai2, Hernan Picard2, Yumi Kubo2, Asha Hareendran3 and Ariane K. Kawata4
1Montefiore Medical Center, Albert Einstein College of Medicine, Bronx, NY
2Amgen Inc., Thousand Oaks, CA, United States
3Evidera, London, United Kingdom
4Evidera, Bethesda, MD, United States
Objectives
To evaluate the effect of erenumab, a preventive treatment for migraine in adults, on functional outcomes using the Migraine Functional Impact Questionnaire (MFIQ).
Methods
MFIQ is a newly-developed 31-item patient-reported outcome (PRO) instrument assessing the impact of migraine on functional outcomes over the past seven days. MFIQ was completed at baseline and every 4 weeks for 24 weeks in a phase 3 clinical trial (NCT02456740) where 955 adults with episodic migraine (EM) aged 18–65 years were randomized 1:1:1 to subcutaneous, 1. monthly placebo, 2. erenumab 140 mg, or 3. erenumab 70 mg. MFIQ includes 4 domains: impact on physical function (PF), usual activities (UA), social function (SF), and emotional function (EF). Domain scores range from 0–100 where higher scores indicate greater impact; negative change scores represent reduction in impact (improvement). Exploratory endpoints based on MFIQ were evaluated as change from baseline to the last 3 months of the double blind treatment phase (defined as the average of scores in months 4–6 [i.e. weeks 13–24]); primary and secondary endpoints from the trial are reported separately. A generalized linear mixed model with covariates was estimated. Pairwise comparisons of least squares (LS) mean changes from baseline in MFIQ domain scores were assessed for each active treatment vs placebo. P-values are descriptive and not adjusted for multiplicity.
Results
Baseline MFIQ scores were similar in erenumab and placebo groups for PF (140 mg: mean ± standard deviation (SD) 36.60 ± 19.42; 70 mg: 37.09 ± 19.48; placebo: 37.78 ± 20.40), UA (140 mg: 29.91 ± 20.26; 70 mg: 31.21 ± 19.05; placebo: 30.10 ± 20.16), SF (140 mg: 29.1 ± 21.37; 70 mg: 31.32 ± 21.59; placebo: 29.92 ± 22.71), and EF (140 mg: 31.57 ± 23.84; 70 mg: 33.59 ± 23.67; placebo: 34.59 ± 34.59) domains. Greater reductions in impact from baseline were observed for each MFIQ domain in erenumab groups compared to placebo. On the PF domain, LS mean changes were −15.14 (95% confidence interval (CI): −16.96, −13.33), p < 0.001 in erenumab 140 mg and −13.72 (−15.54,−11.90), p < 0.001 in erenumab 70 mg compared to the placebo group −9.44 (−11.28,−7.61), indicating greater reduction in impact of migraine on PF. LS mean change scores on the UA domain in the erenumab 140 mg and 70 mg groups were −13.43 (−15.08,−11.78), p < 0.001 and −12.25 (−13.92,−10.59), p < 0.001, respectively, compared to placebo group change of −8.29 (−9.96,−6.62). Changes on the SF domain were −14.49 (−16.24,−12.75), p < 0.001 in erenumab 140 mg and −13.17 (−14.93, −11.42), p = 0.003 in erenumab 70 mg compared to the placebo group −9.50 (−11.26, −7.74). EF domain change scores were −18.38 (−20.30, −16.46), p < 0.001 and −16.43 (−18.36,−14.49), p < 0.001 in the erenumab 140 mg and 70 mg groups, respectively, compared to placebo group change of −11.17 (−13.11, −9.23).
Conclusion
Over 24 weeks, compared to the placebo group
Headache Epidemiology, Outcomes and Burden
EP-02-036
Study of headache after the Great East Japan Earthquake in Iwate coast area (1) Relationship between headache prevalence and medical and environmental factors
Yasuhiro Ishibashi1,*, Masako Kudo1, Hisashi Yonezawa2,3, Haruki Shimoda2, Kiyomi Sakata2, Seiichiro Kobayashi3, Akira Ogawa3 and Yasuo Terayama1
1Neurology and Gerontology
2Hygiene and Preventive Medicine
3Iwate Meddical University, Morioka, Japan
Objectives
To investigate prevalence of headache after The Great East Japan Earthquake and factors related to change of prevalence of headache.
Methods
In 2011, The Great East Japan Earthquake gave serious damage to the Pacific coast district of Japan. We conducted medical inquiries concerning headaches from 2012 to 2015 among municipalities with the greatest earthquake-related damage in Iwate prefecture including Yamada Town, Rikuzentakata City and Heita District of Kamaishi City. Fifty nine hundred and fifteen individuals in 2012, 5588 individuals in 2013, 5395 individuals in 2014 and 5318 individuals replied inquiries. We investigated prevalence of headache and compared age, gender, mental factors (stress, nervousness, K6score and sleep disorder), metabolic syndrome, smoking and drinking habits, daily physical exercise, post-traumatic stress disorder (PTSD)–related factors caused by the earthquake and social network factors (friendship, mutual aid and trust) between the group with and without headache.
Results
Prevalence of headache was gradually decreased (25.4% in 2012, 20.5% in 2013, 19.9% in 2014 and 17.2% in 2015. p < 0.001) significantly. For the investigated period, the significant factors affecting headache were younger age (p < 0.001), female gender (p < 0.001), mental factors (p < 0.001), PTSD–related factors (p < 0.001) and social isolation (p < 0.001 in almost all social network factors); and those avoiding headache were metabolic syndrome (p < 0.001) and drinking habit (p < 0.001). Exercise and smoking habit were not headache-relating factors. Changes in headache prevalence were well correlated with changes of prevalence in mental and PTSD–related factors of the previous year.
Conclusion
Headache prevalence after The Great East Japan Earthquake is affected by mental and PTSD–related factors of the previous year.
Headache Epidemiology, Outcomes and Burden
EP-02-037
Validation of a migraine questionnaire for use in the SAGA cohort study
Larus S. Gudmundsson1,*, Jon H. Eliasson2, Ann I. Scher3, Dawn Buse4, Gretchen Tietjen5, Richard B. Lipton4, Lenore J. Launer6 and Unnur A. Valdimarsdottir7
1Faculty of Pharmaceutical Scienses, University of Iceland, Reykjavik, Iceland
2Department of Neurology, Centralsjukhuset Kristianstad, Kristianstad, Sweden
3Department of Preventive Medicine and Biometrics, Uniformed Services University of the Health Scienses, Bethesda, Bethesda
4Department of Neurology, Albert Einstein College of Medicine of Yeshiva University, Bronx, 5Department of Neurology, University of Toledo, Toledo
6Laboratory of Epidemiology and Population Science, National Institute on Aging, Bethesda, United States
7Public Health Sciences, University of Iceland, Reykjavik, Iceland
Objectives
To describe the validation of a new migraine questionnaire for the SAGA cohort study.
Background: With a target enrollment of 100,000 Icelanders during the next 10 year period, the Stress-And-Gene-Analysis (SAGA) cohort is a population-based longitudinal study of the combined influence of inheritance, psychological stress, and modern lifestyle on various indices of health, including migraine. Participants answer an extensive online Icelandic language questionnaire on various exposures and health measures. Due to a high number of questions in the SAGA questionnaire it is not feasible to use the existing migraine questionnaires, thus, in order to reduce number of questions for participants, we developed a new questionnaire for the SAGA cohort study.
Methods
For validation of the new measure we used data from the SAGA cohort pilot study. Women were recruited through a routine cancer screening program offered to all women in Iceland aged 20–69 years. Men were a random sample (aged 20–69) from the national registry identified by Statistics Iceland. Participants answered an online questionnaire including 16 screening questions on headache symptoms (based on ICHD-3 beta criteria) and 3 questions on headache treatment. In addition, subjects with visual or sensory symptoms were asked 14 questions about their visual symptoms and 15 questions about their sensory symptoms. Participants with and without headache according to the questionnaire, were selected for telephone interview by a neurologist (JHE) during 2015 and 2016 to ascertain migraine based on ICHD-3 beta criteria.
Results
Of 1398 invited adults, 921 (66%) participated in the study; 402 men (average age 45.6 years, SD 13.2) and 519 women (52.6 years, SD 11.1). Out of the 921 participants, 242 participants with and without headache in the past 12 months, were invited to participate in the validation study, 150 (62.0%) of those subjects were interviewed by a neurologist (JHE). Among participants diagnosed with migraine by the neurologic assessment (n = 84; 56.0%) the questionnaire screened positive for migraine (n = 69) yielding a sensitivity of 82.1% (see Table). Conversely among the 66 individuals free of migraine by the neurologic assessment 57 did not have migraine by questionnaire for specificity of 86.4%. The relative odds of migraine by neurologic assessment given a questionnaire positive for migraine was 29.2 (95% CI: 11.9 to 71.4).
Conclusion
A self-administered screening questionnaire identified migraine with high sensitivity and specificity using a neurologist interview as the diagnostic gold standard.
Headache Epidemiology, Outcomes and Burden
EP-02-038
Alcohol as a risk factor for migraine attacks: an exploration
Pablo Prieto1,*, Gabriel Boucher1, Stephen Donoghue1, Alec Mian1 and Noah Rosen2
1Curelator Inc., Cambridge
2Northwell Health, New York, United States
Objectives
Various types of alcohol have long been suspected as a migraine risk factor (potential trigger) commonly resulting in avoidance and possible impact on quality of life. Numerous studies on alcohol have been inconclusive (1). To explore this question we statistically compare daily intake of alcohol and occurrence of migraine attacks.
Methods
Individuals with migraine registered to use a digital platform (Curelator HeadacheTM) (2) via website or the App Store (iOS only) and answered questions about personal suspected risk factors, including alcohol, and their importance (1 = low; 10 = maximal). They then used Curelator Headache daily for at least 90 days, entering details about headaches and exposure to factors that may affect migraine attack occurrence. Unless users stated that they never drank alcohol, alcohol consumption was collected as a dichotomous variable (yes/no) and also as a continuous variable (type and units of alcohol) daily. After 90 days all factors were analyzed and for each individual the association of alcohol intake with attacks was determined (3).
Results
Of 509 individuals with migraine (Table 1), alcohol was suspected as a risk factor by 328 (64%). Prevalence of consumption of alcohol was significantly different (p < 0.001) between those who did not suspect vs those who did (41% vs 91%). 136 (27%) users did not consume alcohol and 110 (30%) of those who did consume alcohol did not have data of adequate quality for analysis (including lack of data variability, e.g. avoidance of alcohol or too frequent consumption around migraine events) were not included on the analysis. Among the 373 (73%) users who consumed alcohol, comparisons between those who did not suspect versus those who did suspect alcohol as a risk factor were made as follows: adequacy of data for analysis (64% vs 72%); no association found between alcohol and migraine (89% vs 75%); alcohol found as a risk factor associated with increased migraine (6% vs 8%); alcohol found associated with decreased risk of migraine (4% vs 17%). In addition, no association was found between degree of suspicion of alcohol and the percentage of individuals in whom an association was identified.
Conclusion
Despite the common belief that alcohol is a risk factor for migraine, in the majority users no association was found. Interestingly, alcohol intake was less frequent in people not suspecting alcohol. This may be explained as follows: those practicing abstinence would also not suspect alcohol as risk factor. Irrespective of whether a user suspected of alcohol as a risk factor, or the degree of suspicion, in total 78% of users showed no association between alcohol and migraine. Surprisingly, when an association was found it was more often found to be associated with risk reduction (potential protector) than risk increase (potential trigger). The results presented here do not support the hypothesis that alcohol is a major risk factor for migraine.
User characteristics and risk factor associations in those suspecting alcohol as a risk factor, those who did not and all users.
(1) Panconesi A. J Headache Pain (2008) 9:19–27
(2) Spierings ELH. Curr Pain Headache Rep. 2014;18:455.
(3) Peris F. Cephalalgia. 2016 May 14
Headache Epidemiology, Outcomes and Burden
EP-02-039
Migraine is associated with intracranial carotid artery calcification: the Rotterdam Study
Ke-Xin Wen1,*, Daniel Bos1, M. A. Ikram1, Oscar H. Franco1 and Maryam Kavousi1
1Epidemiology, Erasmus MC, Rotterdam, Netherlands
Objectives
Migraine has been associated with increased risk of cardiovascular disease. The exact mechanisms remain unclear. We investigate whether migraine is associated with carotid intima media thickness (cIMT) and arterial calcification.
Methods
Migraine was assessed by questionnaire in 6961 participants of the Rotterdam Study. Mean cIMT was assessed by ultrasound of the common carotid artery, carotid bifurcation and the internal carotid artery. 6157 participants had data on both migraine and cIMT. Arterial calcification of the coronary arteries, aortic arch, and extracranial and intracranial carotid arteries was assessed by computed tomography. 1856 participants had data on migraine and arterial calcification. Analyses were performed using linear regression with adjustment for age, sex and cardiovascular risk factors.
Difference in carotid intima-media thickness or log-transformed calcification scores between persons with and without migraine.
Values given are difference in mean carotid intima-media thickness or log-transformed calcification scores and accompanying 95% CI for persons with migraine compared to persons without migraine. n= number of persons with migraine; N = number of persons without migraine. Model 1: adjusted for age, sex and cohort. Model 2: additionally adjusted for body-mass index, systolic blood pressure, diastolic blood pressure, total cholesterol, high-density lipoprotein, smoking, blood-pressure lowering medication use, lipid-lowering medication use, prevalent diabetes, and a history of cardiovascular disease.
Results
In the population for analysis of cIMT, 980 persons (15.9%) had migraine and the mean age was 60.6 years (standard deviation 7.5). In the population for analysis of arterial calcification, 279 persons had migraine (15.0%) and the mean age was 67.4 years (standard deviation 5.8). Migraine was associated with lower mean cIMT (unstandardized beta coefficient −0.01 (95% confidence interval (CI) −0.02, 0.00)) and lower intracranial carotid artery calcification score (−0.19 (95% CI −0.29, −0.08)). There was no association with coronary artery, aortic arch or extracranial carotid artery calcification.
Conclusion
Migraine is associated with lower cIMT and lower arterial calcification in the intracranial carotid artery, but not with calcification in the other arterial vessels. This suggests that there is less atherosclerosis in the intracranial carotid artery in persons with migraine compared to persons without migraine. More studies are needed to investigate the mechanism and implications.
Headache Pathophysiology - Basic Science
EP-02-040
PACAP, CGRP and Headache Targets in the Trigeminal Sensory Ganglion in Rats and Humans based on Immunohistochemistry
Simona D. Frederiksen1,*, Kristian A. Haanes1, Karin Warfvinge1,2 and Lars Edvinsson1,2
1Clinical Experimental Research, Glostrup Research Institute, Rigshospitalet, Glostrup, Denmark
2Vascular Experimental Research, Clinical Sciences, Lund University, Lund, Sweden
Objectives
Trigeminal ganglion (TG) activation and sensitization are well-established as pathophysiological effects in primary headache disorders, especially in migraine. Release of neurotransmitters, e.g. calcitonin gene related peptide (CGRP) and pituitary adenylate cyclase activating peptide (PACAP) by sensory ganglia, is considered a mechanism involved in cranial pain processing. Several therapeutic agents have shown efficacy in treating headache patients, however, with individual effects. The aim of this study was to investigate expression of PACAP and relate it to CGRP, vasoactive intestinal peptide (VIP)/PACAP receptors 1/2 (VPAC1/2), PACAP type I receptor (PAC1), 5-hydroxytryptamine receptors 1B/1D/1F (5-HT1B/1D/1F) and Onabotulinum toxin A (Botox) signaling elements synaptic vesicle glycoprotein 2 (SV2-A) and synaptomal-associated protein 25 kDa (SNAP25) in rat and human TG. Revealing the neurotransmitter and therapeutic target localizations might increase the understanding of sites of action and mechanisms related to headache therapy.
Methods
Using rat as a model, TG from Sprague-Dawley male rats, but also human TG, were dissected and processed for immunohistochemistry. Microscopically, single-labelling in rats and humans and double-labelling in rats were used to evaluate immunoreactivity in the various cells types.
Results
Expression of PACAP, CGRP and selected headache targets were detected in rat and human TG. PACAP receptors were confined to neurons and satellite glial cells (SGCs), however with variability between subtypes. For the 5-HT receptors, the immunoreactivity was consistently expressed on neuronal cell bodies and fibers with the following frequency for humans: 5-HT1D > 5-HT1B > 5-HT1F. SNAP25 was primarily expressed in SGCs in humans and neurons in rats while SV2-A was confined to SGCs and some neurons in both species. PACAP38 colocalized with CGRP in many neuronal cell bodies and fibers. Some PACAP38-positive cells, neurons and SGCs, also expressed PAC1, VPAC2, 5-HT1B, 5-HT1D, 5-HT1F, SNAP25 and SV2-A. Generally, VPAC1 was detected in SGCs surrounding neuronal cell bodies some expressing PACAP38.
Conclusion
Our study revealed colocalization and possible signaling mechanisms between neurotransmitters and headache targets thus potential sites of actions for anti-headache drugs such as PACAP receptor antagonists, Lasmiditan and Botox in humans acting through the sensory nervous system. Further, the results indicate the value of using the rat as a model for investigating the therapeutic targets in question.
Headache Pathophysiology - Basic Science
EP-02-041
Distribution of CGRP and CGRP receptor components in the rat brain
Karin Warfvinge1 and Lars Edvinsson1,2,*
1Dept of clinical experimental research, Glostrup research institute, Glostrup, Rigshospitalet Copenhagen, Copenhagen, Denmark
2Dept of clinical experimental sciences, Internal clinical medicine Lund, Lund, Sweden
Objectives
The present study was designed to comprehensively map the distribution of CGRP and its receptor elements CLR and RAMP1 in the rat brain in order to provide an overview of their localization in fibers and cells to add to the discussion of migraine/headache pathogenesis.
Methods
Sagittal rat brain sections spanning over 0.5 mm to 1.5 mm lateral to the midline were immunohistochemically processed with specific antibodies against CGRP and RAMP1/CLR.
Results
In the entire brain volume investigated, CGRP was
In the cerebral cortex, the density, size and morphology of CGRP immunoreactive cells indicate that all cortical neurons were positive for CGRP. Thin RAMP1 immunoreactive fibers were found spanning through the entire cortex, but also traversing through cortex in layer I and III.
In the hippocampal CA3 region, the cytoplasm of the pyramidal cells displayed intense immunoreactivity in a similar way as was seen in the cerebral cortex. The extension of RAMP1 immunoreactive fibers indicated that it was the mossy fibers (originating from the dentate granule cells) that were stained and not the dendritic tree of the pyramidal cells.
The thalamic and hypothalamic nuclei showed intense CGRP immunoreactivity. The RAMP1 immunohistochemistry showed similar pattern for all nuclei with a tight mass of positive slender processes.
In all brain stem nuclei, CGRP immunoreactivity was present in the neuronal cell somata, but not in the fibers. RAMP1 staining was found in slender fibers and, in addition, in the neuronal cell somata to a varying degree. CLR immunoreactivity was found in stubby fibers, cell somata and in vessels.
In a few regions of the examined volume of the brain, CGRP positive fibers were found. However, in the septal nucleus, pearl-like CGRP immunoreactive fibers, often also seen in TG and SPG, were found. In addition, neuronal cell somata were CGRP immunoreactive.
Conclusion
It is widely accepted that migraine involves trigeminovascular pathways as well as the brain stem, and nuclei of the thalamus and hypothalamus. Here we describe the distribution of CGRP and CLR/RAMP1 in a lateral slice of the entire brain. Clearly, further in depth analysis should be performed to understand the role of the CGRP system in general and other peptides and their receptors in the brain. However, we provide a careful interpretation of the immunoreactivity of the particular antibodies and thereby add to the understanding of CGRP and its receptor components in the CNS.
Headache Pathophysiology - Basic Science
EP-02-042
Endogenous signaling at kappa opioid receptors (KORs) in the central nucleus of the amygdala promotes a loss of diffuse noxious inhibitory controls (DNIC) in a rat model of medication overuse headache
Kelsey M. Nation1,*, Pablo I. Hernandez2, Xu Yue2, David Dodick3, Edita Navratilova2 and Frank Porreca2,3
1GIDP in Neuroscience
2Pharmacology, University of Arizona, Tucson
3Mayo Clinic, Scottsdale, United States
Objectives
The purpose of this study is to understand the neural mechanisms that lead to a loss of diffuse noxious inhibitory control (DNIC) in functional pain conditions. DNIC is an endogenous, bottom-up, pain modulatory system in which one painful stimulus inhibits another painful stimulus. In humans, DNIC is termed conditioned pain modulation (CPM). This DNIC response is evaluated by measuring the response to a noxious stimulus (i.e., the test stimulus) in the absence and in the presence of a second noxious stimulus (i.e., the conditioning stimulus) applied simultaneously to a somatotopically distinct region of the body. The change in response to the test stimulus is the DNIC response. The analgesic consequence of the conditioning stimulus is thought to reflect the strength of net descending inhibitory pain pathways. Humans with functional pain conditions including medication overuse headache (MOH) have been shown to have a loss of the CPM response. Stress is commonly reported as a trigger for such functional pain states and aversive responses to stress may be mediated by increased signaling at kappa opioid receptors (KOR) through the actions of dynorphin. Drugs used for acute treatment of migraine, including opiates, produce MOH in humans and promote increased responsiveness to stress in rodents. We hypothesized that the loss of DNIC in morphine-primed rats would be prevented by blockade of KOR signaling following systemic nor-BNI, a KOR antagonist. Additionally, we hypothesized that blockade of KOR signaling in the central nucleus of the amygdala (CeA), but not in the rostral ventromedial medulla (RVM) would prevent the loss of DNIC induced by morphine priming.
Methods
We used a MOH model in rats to test for a loss of DNIC. Male rats were given morphine sulfate (7.68 mg/kg/day) or vehicle continuously by miniosmotic pump for seven days. Two weeks after the end of drug treatment rats were stressed by exposure to bright lights (BLS) for one hour on two consecutive days. This model has previously been shown to induce allodynia and decrease the threshold to evoke cortical spreading depression. Two hours after BLS the DNIC response was tested by injecting capsaicin into the left forepaw as the conditioning stimulus and applying the Randall-Selitto paw pressure test to the hindpaws as the test stimulus. Nor-BNI was given by (a) subcutaneous injection, (b) into the left or the right CeA, or (c) bilaterally into the RVM one hour prior to each BLS session.
Results
We found that nor-BNI administered subcutaneously or into the right CeA prevented the loss of DNIC in morphine-primed male rats. In contrast, Nor-BNI administered into the left CeA or bilaterally to the RVM did not restore the DNIC response.
Conclusion
The CeA receives inputs from stress circuits and has outputs to descending pain modulatory centers highlighting the possibility of KOR-mediated enhanced descending facilitation as an amplifier of stress-induced hyperalgesia relevant to migraine pain. KOR receptors in the RVM are found on OFF (i.e., pain inhibitory) and neutral cells, but not on ON (pain facilitatory) cells suggesting that the loss of DNIC following morphine priming is unlikely to result from loss of descending inhibition. Thus, functional pain disorders may reflect net enhanced facilitation that may result from KOR signaling in the CeA.
Headache Pathophysiology - Basic Science
EP-02-043
CHANGES IN THE CONTRALATERAL CEREBRAL HEMISPHERE IN RESPONSE TO CORTICAL SPREADING DEPRESSION
Sajedeh Eftekhari1,*, Hanning Xing1, Guido Faas1, Serapio M. Baca1 and Andrew Charles1
1Neurology, David Geffen School of Medicine at UCLA, Los Angeles, United States
Objectives
It is often assumed that cortical spreading depression (CSD) is a unilateral event, affecting only the hemisphere in which it is evoked. The objectives of this study were to examine the neural and vascular changes in the hemisphere contralateral to spreading depression in mice in vivo.
Methods
Vascular and parenchymal responses to CSD in mice were recorded using optical intrinsic signal (OIS) and field potential recording techniques. Two thinned skull windows were prepared to visualize both hemispheres. Burrholes were made on each side. An electrode for measurement of local field potential (LFP) was placed on the contralateral side to the burrhole for KCl injection. In some experiments, an additional burrhole was placed for bilateral recording of LFP. Single or repetitive CSD events were evoked with transient or continuous application of 1M KCl. In control animals, saline was injected instead of KCl. In other experiments, CSD was evoked by light stimulation in an optogenetic model.
Results
A multiphasic deflection in local field potential was consistently observed in the contralateral hemisphere with a delay of 60–120 seconds following initiation of CSD. This was accompanied by a transient change in parenchymal OIS and vascular caliber. Sustained changes (30–60 minutes) in cortical bursting activity and associated vascular responses were also observed in the hemisphere contralateral to CSD initiation in some experiments. Similar changes on the contralateral hemisphere were observed with light-evoked CSD in an optogenetic model, indicating that these changes were not the result of KCl injection. Saline injections evoked no CSD or change in local field potential or OIS on either the ipsilateral or contralateral side.
Conclusion
The contralateral cerebral hemisphere can be affected in response to CSD with both rapid and sustained electrophysiological and vascular changes.
Headache Pathophysiology - Basic Science
EP-02-044
NON-MIGRAINE RELATED PAIN BEHAVIOURS IN A TRANSGENIC “MIGRAINE MOUSE” WITH CIRCADIAN DISRUPTION
Lauren C. Strother1,*, Douglas M. Lopes2, Louis J. Ptacek3, Christopher Holton1, Stephen B. McMahon2, Peter J. Goadsby1 and Philip R. Holland1
1Basic and Clinical Neuroscience
2Wolfson Centre for Age Related Disease, King's College London, London, United Kingdom
3Department of Neurology, University of California, San Francisco, San Francisco, United States
Objectives
Mice harbouring the human mutation responsible for familial advanced sleep phase syndrome (FASPS), a mutation in the circadian clock regulator gene casein kinase 1δ (CK1δ-T44A), have previously been shown to exhibit some aspects of migraine-related pain, akin to the human condition. Given the established circadian impact on pain more generally, we sought to confirm if CK1δ “migraine mice” demonstrated non-migraine-related pain phenotypes that could impact on migraine-related readouts, while also seeking to confirm aspects of the migraine phenotype previously described.
Methods
CK1δ (N = 28) and WT (N = 26) littermates underwent behavioural assessment of hind paw withdrawal thresholds, as well as spontaneous and neuropathic pain behaviours. Mechanical and thermal withdrawal thresholds were assessed using the von-Frey assay and hot-plate test, the formalin test to assess spontaneous pain behaviour, and the partial nerve ligation model to assess neuropathic pain. Migraine-related cortical spreading depression (CSD) threshold, induced with 1M potassium chloride, was determined.
Results
Overall, between CK1δ transgenic mice and WT littermates, there was no significant difference in hind paw mechano-sensitivity (t(15) = −0.530, p = 0.604), thermo-sensitivity (t(15) = −0.156, p = 0.878), formalin response (AUC t(15) = 0.560, p = 0.584), and mechano-sensitivity after peripheral nerve injury to induce neuropathic pain (F(18,72) = 1.295, p = 0.217). Regarding migraine-related CSDs, CK1δ showed a significant increase in the number of events over 1 hour compared to WT (CK1δ = 10.78 and WT = 7.63; t(15) = 3.574, p = ≤ 0.01), which is in agreement with the literature.
Conclusion
We have demonstrated that CK1δ-T44A transgenic mice experience no overt general pain phenotype that could impact on migraine-related pain readouts while confirming the presence of a migraine-specific phenotype in a model of cortical spreading depression.
This work is supported by the Medical Research Council (MR/P006264/1) and PhD funding from The Migraine Trust.
Headache Pathophysiology - Basic Science
EP-02-045
Inhibitory effects of the histone deacetylase inhibitor, Vorinostat, on early life stress-induced increases in CSD susceptibility and anxiety-like behavior in male rats
Stuart Collins1,* and Gretchen Tietjen1
1Neurology, The University of Toledo, Toledo, United States
Objectives
Childhood maltreatment, a form of early life stress (ELS), is associated with migraine as well as with psychiatric conditions comorbid with migraine, such as anxiety. Using a rodent model of ELS, we previously found that adult male rats exposed to maternal separation (MS), exhibited increased susceptibility to cortical spreading depression (CSD), the putative mechanism of migraine aura. In addition, we found a correlation between CSD susceptibility and anxiety-like behaviors. Studies on MS and its long-lasting effects on anxiety-like behavior suggest epigenetic processes as a potential mechanism. Thus, we investigated whether treatment of adult rats with Vorinostat, a histone deacetylase (HDAC) inhibitor, would reverse MS-induced effects on CSD susceptibility and anxiety-like behaviors.
Methods
Male and female Sprague-Dawley rat pups were exposed to MS for 3 hours daily or to a standard-reared (SR) control group for postnatal days (PND) 1–14. Pups were weaned on PND22 and on PND60-70 pups were treated with Vorinostat (10 mg/kg) or saline (1 mL/kg), which consisted of single daily peritoneal injections for 5 consecutive days. On the day following the last treatment (males) or during the earliest diestrous phase (females), we determined anxiety-like behavior using an open-field (OF) apparatus by measuring total grid crossings, center field entries and rearing behaviors. Four days following OF testing (males) or during subsequent diestrous phase, we measured the threshold electrical stimuli needed to evoke CSD from the occipital cortex. Two-way Anova analysis with Bonferroni posttests was performed on results from OF and CSD experiments.
Image:
Results
We found a significant main effect of MS on lowering CSD threshold in the combined male and female cohort (p = .04, n = 20–22 per group), and in males alone (p = .03, n = 10–11 per group), but not in females (p = .36, n = 10–11 per group). This corroborates our earlier findings. The CSD thresholds in saline-treated MS combined sex and male groups were significantly lower than in 1) saline-treated SR combined sex (55.9 V vs 69.0 V, p = .02) and male groups (54.5 V vs 74.0 V, p = .02) and in 2) Vorinostat-treated MS combined sex (55.9 V vs 68.6 V, p = .01) and male groups (54.5 V vs 71.8 V, p = .01). There was also a significant main effect of MS on increased anxiety-like behavior in males but not females, as indicated by reduced total grid crossings (p = .04) and center entries (p = .03). Saline treated MS males crossed fewer total grids (50.9) and entered the center area less frequently (.72) than saline-treated SR males (grids 50.9 vs 98.9, p = .003; center .72 vs 2.6, p = .002) or Vorinostat-treated MS males (grids 50.9 vs 94.0, p = .002; center .72 vs 2.4 p = .005).
Conclusion
The current experiments found that treatment with the HDAC inhibitor, Vorinostat, appears to reverse increased CSD susceptibility and anxiety-like behaviors found in adult MS male rats. These findings suggest that the effects of MS on CSD threshold and anxiety-like behavior may be mediated by epigenetic processes involving histone acetylation.
Headache Pathophysiology - Basic Science
EP-02-046
P2X7 receptor regulates CSD and CSD-induced TNF-α induction
Dongqing Ma1,2,*, Fan Bu1,2, Liwen Jiang1,2, John P. Quinn1 and Minyan Wang2,3
1Department of Molecular and Clinical Pharmacology, University of Liverpool, Liverpool, United Kingdom
2Department of Biological Sciences, Xi’an Jiaotong-Liverpool University, Suzhou, China
3University of Liverpool, Liverpool, United Kingdom
Objectives
Cortical spreading depression (CSD) is the substrate of migraine with aura. The ATP-gated P2X7 receptor (P2X7R) may participate in the pathogenesis of migraine, yet little is known about the role of cortical P2X7R in CSD. This study aimed to 1) examine the role of P2X7R in CSD elicitation by investigating how an anti-P2X7R antibody mediates on CSD in rats; 2) whether P2X7R contributes to the induction of IL-1β and TNF-α induced by CSD.
Methods
CSD was induced by K + -medium in the right cortex of rats and recorded by electrophysiology. Quantative PCR was used for gene expression analysis of IL-1β and TNF-α.
Results
Pretreatment of the anti-P2X7R antibody into the left i.c.v. significantly suppressed CSD with a marked reduction of CSD number and propagation rate as well as a significant prolongation of CSD latency in rats. Induction of gene expression of IL-1β (12.7-fold) and TNF-α (5-fold) was observed post-CSD. Interestingly, this induction of TNF-α, but not IL-1β, was markedly reduced by the anti-P2X7R antibody.
Conclusion
This study demonstrates that P2X7R not only mediates cortex susceptibility to CSD but also contributes to subsequent induction of inflammatory factor TNF-α post CSD, indicating a therapeutic potential of blockade of P2X7R in migraine prophylaxis and treatment.
Headache Pathophysiology - Basic Science
EP-02-047
Enhanced susceptibility to cortical spreading depression and different degree in two-types of Na+,K+-ATPase alpha2 subunit-deficient mice as a model of familial hemiplegic migraine 2
Miyuki Unekawa1,*, Keiko Ikeda2,3, Yutaka Tomita1, Kiyoshi Kawakami2 and Norihiro Suzuki1
1Neurology, Keio University School of Medicine, Tokyo
2Biology, Center for Molecular Medicine, Jichi Medical School, Shimotsuke
3Biology, Hyogo College of Medicine, Nishinomiya, Japan
Objectives
Patients with familial hemiplegic migraine type 2 (FHM2) have a mutated ATP1A2 gene (encoding Na+,K+-ATPase α2 subunit, mainly expressed in astrocytes) and show prolonged migraine aura. Cortical spreading depression (CSD), which involves mass depolarization of neurons and astrocytes that propagates slowly through the gray matter, is profoundly related to aura. In this study, we examined sensitivity and responsiveness to CSD in two types of Atp1a2-defective heterozygous mice, Atp1a2tm1Kwk (C-KO) and Atp1a2tm2Kwk (N-KO), compared with wild-type mice, in order to elucidate the mechanisms involved in the pathogenesis of FHM2.
Methods
Mutant and wild-type mice were examined under urethane anesthesia with mechanical ventilation (n = 45 in total). Sensitivity to CSD was evaluated as the minimum concentration of KCl required to elicit CSD by application of a 5 µl aliquot of 0.025 M KCl solution, followed by further aliquots with concentrations increasing successively by 0.025 M. Propagation velocity of CSD wave was calculated from the time-lag and distance between the proximal and distal electrodes for DC potential. Full width at half maximum (FWHM) was determined from the DC potential curves recorded at the distal electrode. The change of root-mean-square values of electroencephalogram (EEG) was evaluated as an electrophysiological effect. A high dose of KCl (0.3 M) was administered to elicit repeated CSD and the duration of CSD (until the final occurrence) was evaluated. Regional cerebral blood flow (rCBF) was simultaneously recorded by laser-Doppler flowmetry.
Results
Heterozygotes of N-KO exhibited a low threshold KCl concentration for induction of CSD (0.12 ± 0.04 vs 0.15 ± 0.04 M, p < 0.05), faster propagation velocity (4.2 ± 1.0 vs 3.4 ± 0.5 mm/min, p < 0.05), slower recovery from DC deflection (FWHM; 52.0 ± 14.2 vs 41.0 ± 8.6 s, p < 0.05), and profound suppression of the EEG (−43.1 ± 14.7 vs −31.9 ± 12.7 %, p < 0.05), compared to wild-type mice. A high dose of KCl elicited repeated CSDs for a longer period (95.7 ± 22.7 vs 80.7 ± 14.5 min, p < 0.05), with a tendency for a greater frequency of CSD occurrence (16.8 ± 3.5 vs 15.9 ± 3.6 times). The difference of every endpoint was slightly greater in N-KO than in C-KO. Change of rCBF in response to CSD showed no significant difference between the heterozygotes and wild-type mice.
Conclusion
Heterozygotes of Atp1a2-defective mice, considered to be a model of FHM2, exhibited high susceptibility to CSD rather than cortical vasoreactivity. The precise effects may differ depending upon the knockout strategy for gene disruption. These results indicated that Atp1a2-defective mice simulated FHM2, and suggest that patients with FHM2 may exhibit high susceptibility to migraine.
Headache Pathophysiology - Basic Science
EP-02-048
PHARMACOLOGICAL MANIPULATION OF THE LC MODULATES TRIGEMINOVASCULAR NOCICEPTION
Marta Vila-Pueyo1,*, Peter J. Goadsby1 and Philip R. Holland1
1Headache Group, King's College London, London, United Kingdom
Objectives
The noradrenergic locus coeruleus (LC) is a key regulator of the sleep-wake cycle, a modulator of nociception and is connected to areas involved in migraine pathophysiology. We have previously shown that the LC modulates neurons responsive to trigeminovascular nociceptive activation.
To explore further the role of the LC in migraine pathophysiology, we pharmacologically modulated the LC to test on effects on neurons responsive to trigeminovascular nociceptive activation.
Methods
Male Sprague-Dawley rats (n = 26) were anesthetized with isoflurane and maintained with propofol infusion (33–50 mg/kg/h). The interparietal bone was drilled for microinjections in the LC, the parietal bone was removed for electrical stimulation of the dura mater overlying the middle meningeal artery and a C1 laminectomy was performed to record from trigeminocervical complex (TCC) neurons. Following baseline responses to dural stimulation, 210nl of orexin A (0.1 mM), α2-adrenoceptor antagonist (yohimbine 10 mg/ml), α2-adrenoceptor agonist (clonidine 1, 5 and 10 mg/ml), glutamate (1M) or vehicle (saline) were microinjected in the LC (bregma −3.4 (anteroposterior), −1.3 (mediolateral), −6.25 (dorsoventral)) and TCC neural responses were recorded for 1 hour.
Results
Nociceptive dural-evoked neuronal firing in the TCC was significantly reduced by orexin A (F9,63 = 2.646, p = 0.011) and by the α2-adrenoceptor agonist clonidine in a concentration-dependent manner (F11,99 = 10.482, p < 0.01). Glutamate also induced a significant transient inhibition of the nociceptive evoked firing in the TCC (F11,55 = 7.428, p < 0.01) that was completely blocked with α2-adrenoceptor antagonist pretreatment (t(10) = −3.158, p = 0.01), that had no effect when given alone (F11,44 = 0.926, p = 0.525).
Conclusion
The results demonstrate a role for the LC in the modulation of trigeminal nociceptive processing that may provide a potential mechanistic link between sleep-wake disruption and migraine.
This work was funded by MRC grant (MR/P006264/1) and Welcome Trust (Synaptopathies).
Headache Pathophysiology - Basic Science
EP-02-049
Chronic and Intermittent administration of systemic nitroglycerin in the rat induces an increase in the expression of c-Fos and CGRP mRNA in areas involved in migraine pain
Rosaria Greco1, Chiara Demartini1,2, Anna Maria Zanaboni1,2, Germana Tonsi1,2, Attilio Iemolo3, Giuseppe Nappi1, Giorgio Sandrini1,2 and Cristina Tassorelli1,2,*
1Laboratory of Neurophysiology of Integrative Autonomic Systems, Headache Science Center, C. Mondino National Neurological Institute, Pavia
2Department of Brain and Behavioral Sciences, University of Pavia
3Laboratory of Functional Neurochemistry, Center for Research in Neurodegenerative Diseases, Center for Research in Neurodegenerative Diseases, “C. Mondino” National Neurological Institute, Pavia, Italy
Objectives
Calcitonin gene related peptide (CGRP) is a key neuropeptide involved in the activation of the trigeminovascular nociceptive system and it is likely implicated in migraine chronicization. In the present study we investigated the role of CGRP in migraine chronicization in an animal model that mimics the condition of chronic migraine.
Methods
The animal model was based on chronic and intermittent administration of nitroglycerin (NTG). Male Sprague-Dawley rats were injected with NTG (5 mg/kg, i.p.) or vehicle, every two days over a 10-day period (5 injections total). A group of animals was injected with Topiramate (30 mg/kg, i.p.) or vehicle every day for 10 days. Twenty-four hours after the last administration of NTG or vehicle, animals underwent a tail flick test for the evaluation of nociceptive threshold and a Von Frey test, for the evaluation of orofacial mechanical allodynia. Rats were subsequently sacrificed and their medulla-pons region, cervical spinal cord (C1-C2) and trigeminal ganglia were immediately chopped into parts for the evaluation of c-Fos and CGRP gene expression by real-time polymerase chain reaction (RT-PCR).
Results
Chronic and intermittent NTG administration caused a condition of hyperalgesia and orofacial allodynia, detected respectively as a reduction in the latency of the tail flick test and as a reduction in the threshold of mechanical sensitivity when compared either to baseline values or to control groups. NTG administration also induced a significant increase in the expression of c-Fos and CGRP mRNA in the medulla-pons region, cervical spinal cord and trigeminal ganglia. Topiramate treatment prevented the development of NTG-induced pain hypersensitivity, allodynia and gene expression in the above areas.
Conclusion
These findings describe the occurrence of neuronal activation and CGRP synthesis in the trigeminal ganglia and in specific areas of the CNS that are relevant for trigeminal pain processing in an animal model of chronic migraine. The inhibitory effect of topiramate, whose mechanisms of action involve blockade of voltage-dependent sodium channels, potentiation of GABAergic transmission and inhibition of glutamatergic transmission, points to an important role for these mechanisms in CGRP-mediated processes underlying pain chronification. From a translational clinic of view, these findings underline the possibility and opportunity to pharmacologically intercept and prevent migraine chronification.
Acknowledgements: This study was supported by a grant of the Italian Ministry of Health to Institute C. Mondino (RC 2014–2016).
Headache Pathophysiology - Basic Science
EP-02-050
A novel mouse model for familial hemiplegic migraine type 3 reveals increased susceptibility for cortical spreading depression
Eva Auffenberg1,2,*, Ulrike Hedrich1, Holger Lerche1, Martin Dichgans2, Nikolaus Plesnila2 and Tobias Freilinger1
1Department of Neurology and Epileptology, Hertie-Institute for Clinical Brain Research, Tuebingen
2Institute for Stroke and Dementia Research (ISD), Ludwig-Maximilians-University, Munich, Germany
Objectives
Familial hemiplegic migraine (FHM) is a rare and severe monogenic subtype of migraine, characterized by some degree of hemiparesis during the aura phase. Mutations in three causative genes, encoding ion channels / transporters in the central nervous system, have been identified (FHM1 - FHM3).
The FHM3 gene SCN1A encodes the alpha subunit of the voltage gated sodium channel Nav1.1, which is expressed on inhibitory interneurons. Previous functional studies in heterologous systems revealed diverse functional effects for FHM3-causing SCN1A mutations. Here, we set out to gain further insight into the pathophysiological mechanisms underlying FHM3 by creating a novel transgenic mouse model.
Methods
By means of homologous recombination, we generated the first FHM3 knock-in mouse model, carrying human point mutation L1649Q in the mouse ortholog Scn1a gene. To study the functional effects of the mutation on different levels, we used a combination of in vitro and in vivo approaches.
Results
In a first step, we performed electrophysiological studies in acute slices from FHM3 mice. In these experiments, fast spiking interneurons from both the cortex and the hippocampus of FHM3 mice were found to show a significantly higher frequency of action potential firing (i.e. gain-of-function). In line with these findings, pyramidal neurons in layer V were found to receive significantly higher inhibitory input.
Next, we moved to an in vivo setting to focus on experimentally induced cortical spreading depression (CSD), the correlate of migraine aura. Mutant mice were found to display a significantly increased CSD frequency. Likewise, the threshold for CSD induction was significantly lower in transgenic animals.
Conclusion
We here for the first time present functional data on a transgenic FHM3 knock-in mouse model. Our in vivo data provide unequivocal evidence that FHM3 is caused by an increased susceptibility to CSD, which is in line with previous observations in FHM1 and FHM2. Interestingly, this effect is paralleled by an increased activity of inhibitory interneurons in transgenic animals as a potentially novel mechanism underlying CSD susceptibility. Future studies will have to shed light on the mechanistic link between enhanced interneuron function and increased cortical excitability.
Headache Pathophysiology - Basic Science
EP-02-051
Neuronal circuits underlying light-aversive behavior in mice.
Levi P. Sowers1,2,*, Brandon J. Rea1, Rebecca J. Taugher3, Youngcho Kim4, John A. Wemmie2,3 and Andrew F. Russo1,2
1Physiology, University of Iowa
2Veterans Affairs
3Psychiatry
4Neurology, University of Iowa, Iowa City, United States
Objectives
Veterans returning from active duty are at an increased risk for post-traumatic headache (PTH) and migraine. Migraine alone affects 10% of men and 25% of women, with the lifetime risk increasing to 18% and 43% respectively. Sensory abnormalities are present in individuals with PTH and migraine including extreme light and sound sensitivity. Light sensitivity in patients with PTH or migraine can be debilitating and treatments are lacking. One reason interventions and treatments continue to fall short is that there is a poor understanding of the relevant neuroanatomical correlates that underlie sensory changes in headache. Calcitonin gene-related peptide (CGRP) is a critical neuropeptide involved in pain signaling and has recently come to the forefront of migraine research where it contributes to headache and associated sensory abnormalities. In this study we attempt to identify anatomical regions where CGRP could act to induce light-aversive behavior in migraine and PTH. The posterior thalamus (Po) has been suggested to be a brain region that could integrate light and pain. In addition to the Po, the periaqueductal grey (PAG) and amygdala are areas that may contribute to light-aversive behaviors in migraine. We hypothesized that CGRP acts as a neuromodulator in the Po and/or the PAG/Amygdala to induce light aversive behavior.
Methods
To test this hypothesis, we used two targeted approaches to probe these areas. The first was direct CGRP injection into the Po. The second was optogenetic stimulation using channelrhodopsin to stimulate the Po, PAG, or amygdala. To further understand the role of these brain regions in migraine-like phenotypes, we performed the mouse grimace assay and squint analysis to assess pain related behavior in these mice.
Results
We found that CGRP injection in the Po and optical stimulation of the Po induces significant light aversive behavior, without increased anxiety. In contrast to the Po, PAG stimulation led to both light aversion and light-independent anxiogenic behavior. These data suggest that the Po can induce light aversion associated with CGRP actions, while the PAG may trigger not only the Po, but also other brain regions involved in anxiogenic behaviors. Surprisingly, optical stimulation of the amygdala produced no light-aversive behavior or anxiety phenotype in open field. To further understand the role of these brain regions in migraine-like phenotypes, we performed the mouse grimace assay and squint analysis to assess pain related behavior in these mice.
Conclusion
These results may begin to shed light on the complex circuitry of light-aversive behaviors in mice.
Headache Pathophysiology - Basic Science
EP-02-052
Selective inhibition of trigeminovascular neurons by fremanezumab
Agustin Melo-Carrillo1,2,*, Rodrigo Noseda1,2, Rony-Reuven Nir1,2, Aaron Schain1,2, Jennifer Stratton3, Andrew Strassman1,2 and Rami Burstein1,2
1Anesthesia Critical Care and Pain Medicine, Beth Israel Deaconess Medical Center
2Anesthesia, Harvard Medical School, Boston
3TEVA Biologics, Redwood City, United States
Objectives
A large body of evidence supports an important role for CGRP in migraine pathophysiology. This evidence gave rise to a global effort to develop a new generation of therapeutics that inhibit the interaction of CGRP with its receptor in migraineurs. Recently, a new class of such drugs, humanized monoclonal anti-CGRP antibodies (CGRP-mAb) were found to be effective in reducing the frequency of migraine. The purpose of this study was to better understand how the CGRP-mAb fremanezumab (TEV-48125) modulates meningeal sensory pathways.
Methods
To answer this question we used single-unit recording to determine the effects of fremanezumab (30 mg/kg IV) and its isotype-conAb on spontaneous and evoked activity in naïve and CSD-sensitized trigeminovascular neurons in the spinal trigeminal nucleus of anesthetized male and female rats.
Results
The study demonstrates that in both sexes fremanezumab inhibited naïve high-threshold (HT) but not wide-dynamic range trigeminovascular neurons, and that the inhibitory effects on the neurons were limited to their activation from the intracranial dura but not facial skin or cornea. Additionally, when given sufficient time, fremanezumab prevents activation and sensitization of HT neurons by cortical spreading depression.
Conclusion
Mechanistically, these findings suggest that HT neurons play a critical role in the initiation of the perception of headache and the development of cutaneous allodynia and central sensitization. Clinically, the findings may help explain why the therapeutic effects of CGRP-mAb may be selective to headaches of intracranial origin such as migraine and why this therapeutic approach may not be effective for every migraine patient.
Headache Pathophysiology - Basic Science
EP-02-053
Pain suppression by MeCF in mice and rats using various in vivo models
Muhammad Liaquat Raza1,* and Husna Khan1
1Pharmacology, Hamdard University, Karachi, Pakistan
Objectives
Nature is highly enriched in therapeutic agents and researchers continuously investigate natural products for better therapeutic agents. Plant based compounds are used in broad spectrum therapeutics to treat variety of diseases. Pain is one of the most common symptoms associated with many of illnesses and the treatments, presently, available therapies are opioids and NSAIDs but they brought severe complications and toxicities. Thus, the need for safer and potent analgesic drug is still required. In this study we have test the effect of Cassia fistula in rodents for its analgesic potential.
Methods
Methanolic extract of C. fistula was prepared using simple extraction method. The extract was then subjected to various analgesic tests such as, acetic acid induced writhing, tail flick and tail immersion in mice or rats. Three different doses of MeCF were used however, diclofenac sodium and tramadol were used as standard analgesics. Phytochemical analysis was performed for the presence of various chemical constituents in the MeCF. Data was analyzed using SPSS and values were represented as ± SEM.
Results
Phytochemical examination confirmed the presence of different phytochemicals components that include terpenes, flavonoids, sugar moieties and alkaloids. However, in-vivo pain induced models testing assured approximately 12% and 22% increased in responses than standard analegsic drugs i.e. diclofenac and tramadol, respectively. In the acetic acid induced writhing, tail flick and tail immersion tests MeCF at 125, 250 and 500 mg/kg significantly exhibited analgesic activity. The results were comparable to standard analgesic drugs i.e. diclofenac sodium (10 mg/kg) and tramadol (12.5 mg/kg) *p < 0.05.
Conclusion
The present findings suggest that MeCF possess effective phytochemical that is responsible for its analgesic action. That could be good candidate for various type of headache also. However, further evaluation for mechanism of action is required to precisely explore it at molecular level.
Headache Pathophysiology - Basic Science
EP-02-054
Soluble guanylate cyclase is a critical regulator of migraine-associated pain
Amynah A. Pradhan1,*, Alycia Tipton1, Ronak Gandhi2, Manel Ben Aissa2, Laura Moye1, Yeiting Wang2 and Gregory Thatcher2
1Psychiatry
2Medicinal Chemistry & Pharmacognosy, University of Illinois at Chicago, Chicago, United States
Objectives
Migraine is an extraordinarily common brain disorder for which therapeutic options continue to be limited. The nitric oxide pathway has been heavily implicated in migraine, and the nitric oxide donor nitroglycerin (NTG) has been shown to reliably trigger migraine in humans. NTG stimulates soluble guanylate cyclase (sGC), the main NO receptor in the body, which increases production of cGMP. However, NTG is also a major source of reactive oxygen species, and this increased oxidative stress could also contribute to the induction of migraine. The aim of this study was to identify the precise role of sGC in acute and chronic migraine. Specifically, we determined if acute and chronic treatment with a novel sGC stimulator (VL-102) would induce migraine-associated pain. We also tested the effects of the sGC inhibitor, ODQ, within a NTG-based model of chronic migraine.
Methods
VL-102 (sGC stimulator), NTG, and ODQ (sGC inhibitor) were administered IP to male and female C57BL6/J mice every second day for 9 days. To determine if there was an upregulation of sGC activity in chronic migraine, ODQ was administered 24 h following the final -NTG treatment (day 10). On test days, basal and drug-evoked mechanical hypersensitivity was evaluated using von Frey hair stimulation.
Results
VL102-evoked acute and chronic mechanical hyperalgesia in a dose-dependent manner. This hyperalgesia was blocked by the migraine medications sumatriptan and topiramate. The sGC inhibitor ODQ inhibited acute and chronic hyperalgesia induced by NTG. Interestingly, ODQ also blocked hyperalgesia already established by chronic NTG treatment.
Conclusion
These results indicate that NTG causes migraine-related pain through activation of the sGC pathway, and that super-activation of sGC may be an important component of chronic migraine pain. Furthermore, this work indicates that sGC inhibitors would be promising new migraine therapies.