Trigeminal Ganglion – A Site of Action for CGRP Receptor Antagonists
S. Eftekhari1, C.A. Salvatore2, T.-B. Chen3, Z. Zeng3, L. Edvinsson1
1Department of Clinical Sciences, Division of Experimental Vascular Research, Lund University, Lund, Sweden; 2Department of Pain and Migraine Research, Merck Research Laboratories, West Point, PA, USA; 3Department of Imaging, Merck Research Laboratories, West Point, PA, USA.
Objectives: We designed the present study to examine the binding sites of a CGRP receptor antagonist and protein expression of CGRP and its receptor in rhesus trigeminal ganglion. In addition, we examined whether or not the trigeminal ganglion is protected by the blood-brain barrier.
Background: Calcitonin gene-related peptide (CGRP) has a key role in migraine and CGRP receptor antagonists have demonstrated clinical efficacy in the acute treatment of migraine. The remaining question is where do CGRP receptor antagonists act to inhibit migraine pain, peripherally or centrally? The trigeminal ganglion projects peripherally to the intracranial vasculature and centrally to various regions in the central nervous system.
Methods:In vitro autoradiography mapping studies were performed on rhesus monkey trigeminal ganglion. Trigeminal ganglion tissue slices were incubated with [3H]MK-3207 (a CGRP receptor antagonist) to define the CGRP receptor binding sites. Immunofluorescence was used to study the detailed distribution of CGRP and its receptor components, calcitonin receptor-like receptor (CLR) and receptor activity-modifying protein 1 (RAMP1) in rhesus monkey trigeminal ganglion. To evaluate if the trigeminal ganglion is located within or outside the blood-brain barrier, experiments with Evans blue were performed on rodents.
Results: High binding densities of [3H]MK-3207 were found in the trigeminal ganglion. The binding sites were mainly located in the ganglion where the cells were located. Immunofluorescence revealed expression of CGRP, CLR and RAMP1 in the trigeminal cells of rhesus monkey. CGRP was expressed in the small/medium sized cells whereas the receptor components were mainly expressed in the larger cells. In addition, CLR and RAMP1 expression was found in the satellite glial cells. CGRP and the receptor components were rarely co-expressed. Co-expression of CLR and RAMP1 was found in the large neurons and in the satellite glial cells. Evans blue revealed that the trigeminal ganglion is not protected by the blood-brain barrier.
Conclusions: The present study demonstrates for the first time CGRP receptor binding sites and protein expression of CGRP and its receptor components in trigeminal ganglion of rhesus monkey. In rodents, we demonstrated that the trigeminal ganglion is located outside the blood-brain barrier, suggesting that CGRP receptor antagonists do not need to be CNS-penetrant to block receptors in the trigeminal ganglion. This study suggests that the trigeminal ganglion may be a key site of action for CGRP receptor antagonists.
LBO2
Suboptimal Acute Treatment of Episodic Migraine (EM) Is Associated with an Increased Risk of Progression to Chronic Migraine (CM): Results of the American Migraine Prevalence and Prevention (AMPP) Study
R.B. Lipton1,2, D.C. Buse1,2, K.M. Fanning3, D. Serrano3, M.L. Reed3
1Neurology, Albert Einstein College of Medicine, Bronx, NY, USA; 2Montefiore Medical Center, Bronx, NY, USA; 3Vedanta Research, Chapel Hill, NC, USA.
Objectives: To test the hypothesis that suboptimal acute treatment of EM is associated with an increased risk of CM onset.
Background: Analyses of the AMPP Study have shown that among persons with EM, certain risk factors (e.g., headache frequency, medication use, depression) one year are associated with increased risk of CM onset the following year. Optimizing acute treatment may modify the risk of progression.
Methods: The AMPP Study is a longitudinal, US-population-based study. Study respondents with EM (ICHD-2 defined migraine with headache on average <15 days per month) in 2006 who completed the Migraine Treatment Optimization Questionnaire (mTOQ-4) and provided outcome data in 2007 were eligible for analyses. The mTOQ-4 assesses the frequency of four acute treatment outcomes: pain free at two hours, sustained pain free at 24 hours, perceived ability to plan daily activities and perceived control of migraine. Response options include: never (0), rarely (0), <half the time (1) ≥half the time (2). Sum scores ranged from 0–8 and were divided into four categories: very poor optimization= 0, poor optimization= 1–5, moderate optimization= 6–7, maximal optimization= 8. Logistic regression models were used to examine the dichotomous outcome of transition from EM to CM over the course of one year as a function of treatment optimization. Models were adjusted for age, sex and annual household income. Odds ratios (ORs) and p-values with 95% confidence intervals (CIs) were calculated with the reference group being staying EM.
Results: There were 4,625 eligible subjects with EM who completed the mTOQ-4 in 2006 and provided outcome data for 2007. 2,227 (48.2%) had very poor or poor optimization. Rates of CM onset were significantly higher among those with very poor optimization (8.1%) compared with those with maximal optimization (2.5%). Persons with very poor optimization were 3.5 times (p<0.001) and those with poor optimization were 1.8 times more likely to progress (p=0.007) to CM compared with maximal optimization.
Table. Rates of Optimization and Probability of Transition from EM to CM Based on Treatment Optimization (Using Maximal Optimization as the Reference).
95% C.I.
Level of Treatment Optimization
N (%)
Rate of CM Onset
Odds Ratio
Lower
Upper
Very Poor
308 (6.7%)
8.1%
3.46*
2.02
5.93
Poor
1,919 (41.5%)
4.4%
1.77*
1.17
2.68
Moderate
1,132 (24.5%)
2.9%
1.17
0.71
1.91
Maximal
1,266 (27.4%)
2.5%
1.0 (REF)
–
–
*Significant at p < 0.05.
Conclusions: Poorly optimized treatment in persons with EM is associated with an increased risk of CM onset. As treatment is increasingly optimized, the risk of progression declined in this observational study. Improved acute treatment may reduce the risk of progression. We recommend randomized trials to test this idea.
LBO3
Withdrawn by the author.
LBO4
Hypothalamic Changes during the Pre-Ictal Phase of Provoked Migraine Attacks
W.P.J. van Oosterhout1, G.G. Schoonman1, G.M. Terwindt1, J. van der Grond2, M.D. Ferrari1, M.C. Kruit2
1Neurology, Leiden University Medical Center, Leiden, South-Holland, The Netherlands; 2Radiology, Leiden University Medical Center, Leiden, South-Holland, The Netherlands.
Objectives: To assess hypothalamic metabolite concentrations in migraineurs vs. controls at baseline, during the pre-ictal and ictal phases of a migraine attack.
Background: The hypothalamus is suggested to be involved in migraine-pathophysiology, and its function seems to specifically alter hours before an attack. We hypothesise that in migraineurs hypothalamic metabolite concentrations differ from controls, notably preceding the headache phase. Therefore, we compared hypothalamic metabolite concentrations in migraineurs vs. controls, and assessed whether concentrations altered after induction of a migraine attack with GTN-infusion.
Methods: Female migraine without aura (MO) patients (n=20; attack frequency 2.6±1.3 per month) and age-, sex- and BMI-matched controls (n=16) were studied on two separate days. On day 1, Magnetic Resonance Spectroscopy (MRS) measurements of the hypothalamus were performed before and after challenging the hypothalamus with glucose ingestion. On day 2, a GTN infusion (0.5 micrograms*kg−1*min−1) was administered. After 1.5 hour, MRS-measurements were performed before and after the glucose-challenge, and again 4.5 hours after GTN. Clinically, premonitory and headache symptoms were scored. Spectral post-processing was carried out using LCModel. For statistical analysis, oneway ANOVAS (with post-hoc paired samples t-tests), and paired samples t-tests were used. Additionally, to assess effects of clinical symptoms adjusted for GTN effects, a Generalised Estimating Equation (GEE) model was applied.
Results: GTN resulted in a migraine attack after 4:54±2:06hin 12/16 (81.2%) of migraineurs, and in 0/16 controls. i) At baseline, metabolite concentrations did not differ between study groups. ii) GTN induced decreases in hypothalamic [CR] (creatine), [PCh] (choline), [NAA] and [NAANAAG] in migraineurs (all p<0.001), not in controls. The GEE model confirmed these GTN-induced decreases in migraineurs. iii) In addition, [PCh] and [NAANAAG] increased depending on clinical symptoms from baseline to premonitory to ictal phases (all p<0.03), adjusted for the GTN-effect. [NAANAAG] was also increased in spontaneous attacks (n=6), compared to baseline (p=0.027).
Conclusions: We found no evidence for a difference of hypothalamic function between migraineurs and controls at baseline. The induction of a migraine attack with GTN infusion, however, induced decreases in all measured hypothalamic metabolites only in migraineurs, which might either reflect migraine-specific transient vasogenic edema within the hypothalamus, or might actually reflect transient deficits in energy metabolism, at moments when highest energy levels are needed. Irrespective of the GTN effect, [PCh] and [NAANAAG] increased during the evolution of pre-ictal to ictal clinical symptoms. These findings confirm that the hypothalamus has a role in the early pathophysiology of a migraine attack.
LBO5
Transient Intracranial Pressure Changes during a Migraine Attack
1Neurology, Leiden University Medical Center, Leiden, South-Holland, The Netherlands.
Objectives: We aimed to assess changes in intracranial pressure during the course of a migraine attack.
Background: Case reports have suggested intracranial pressure (ICP) is increased during migraine attacks. Acute and chronic alterations in ICP – due to volume changes in the vascular, brain parenchyma or CSF compartments within the calvarium – are known to result in headache. We aimed to assess changes in ICP during the different phases of a migraine attack.
Methods: Intracranial pressure was studied in migraine without aura patients (male and female; n=45) and non-headache controls (male and female; n=33) using non-invasive distortion-product evoked otoacoustic emissions (EOAE). In migraineurs, measurements were performed at baseline, during the premonitory, ictal and post-ictal phases of a migraine attack, and >3 days after the attack. ICP in controls was measured at four timepoints, with a similar temporal distribution. ICP was studied with the subjects in standing, supine and Trendelenburg position. For statistical analysis, a Generalized Estimating Equation (GEE) model including a random subject variable was used to assess the effect of migraine phases on ICP.
Results: In migraineurs, intracranial pressure during the prodromal, ictal and post-ictal phases of a migraine attack differed from baseline ICP (overall p=0.004), reflecting changes ranging from approximately 0–30 cm H2O. At the second baseline, ICP was normalized again. In controls, ICP remained stable over the course of the different timepoints.
Conclusions: Intracranial pressure changes over the course of a migraine attack, with highest ICP during the ictal and post-ictal phases. After resolution of the migraine attack, ICP normalizes. These data suggest migraine headache is associated with increased intracranial pressure, and that the underlying ICP regulatory mechanism, either vascular, CSF or with regard to the brain itself, is different in migraine patients than in non-headache controls.
LBP1
Scopolamine-Induced Migrainous Headache
K. Ikeda1, K. Iwamoto1, T. Takazawa1, Y. Kawase1, T. Hirayama1, Y. Ishikawa1, K. Kawabe1, Y. Iwasaki1
1Neurology, Toho University Omori Medical Center, Tokyo, Japan.
Objectives: We encountered migraine sufferers who experienced a sudden migrainous headache after scopolamine butylbromide (SB) administration. We aimed to elucidate clinical features of SB-induced migraine attacks in migraineurs.
Background: A migraine attack is triggered by several components, including acute substance use. SB is an anti-muscarinic drug. Intramuscular administration of this drug is widely performed as pre-medication on gastric X-ray examination in Japanese physical check-up. SB is not listed as migraine-triggering medication in the International Classification of Headache Disorders, 2nd edition (ICHD-II). Little is known about SB-induced migrainous headache in migraineurs.
Methods: A board-certified neurologist and headache specialist (K.I.) performed interview of headache history and neurological examination when subjects complained of acute headache after SB injection. SB-induced headache was defined as headache that started within 20 minutes after intramuscular administration of SB (20 mg/body). Primary and secondary headaches were diagnosed according to the ICHD-II criteria. SB-induced headache was classified as headache induced by acute substance use or that due to exposure (ICHD-II code 8.1). Clinical features and background of subjects with SB-induced headache were analyzed. We estimated the frequency of SB-related headache between migraineurs and non-migraineurs.
Results: A total of 54 subjects (39 women and 15 men) experienced SB-induced headache. All subjects had the present history of migraine. Nine subjects had 2 times of the similar headache after SB injection. Mean age (SD) was 46.2 (9.7) years [46.2 (9.7) for women and 46.3 (10.0) for men]. Clinical hallmarks of headache showed that pulsating / throbbing pain occurred in diffuse or bilateral head sites. Headache worsened at 20–30 minutes from the onset and ameliorated gradually 8 hours later, and persisted for 6–18 hours. All subjects had repeated nausea and vomiting. Severity of headache revealed severe degree requiring complete bed rest in 50 subjects (92.6%). SB-induced headache had similar aspects to migraine without aura (MO) attacks. Heart, liver and renal functions were normal in all SB-related migraineurs. They had no allergic history of medication and food. In 1,865 non-migraine controls, one healthy young man had a mild degree of migraine like headache triggered by SB injection.
Conclusions: SB triggers a severe degree of MO like headache or worsens pre-existing migraine in some migraineurs. As different profiles between spontaneous and SB-induced migraine attacks, SB-associated migrainous headache exhibited no visual aura symptoms. Throbbing pain started in diffuse or bilateral head site. The clinical course of headache disclosed that SB-induced headache was classified to definite headache as an acute adverse event attributed to medication used for other indications (ICHD-II code 8.1.10). SB-induced migraine could contribute to disequilibrium between acetylcholine and other neuropeptides. We should use SB more carefully as it can be an aggravating drug of migraine.
LBP2
Open Label Study of Milnacipran in the Preventive Treatment of Migraine
E.R. Engel1, D. Kudrow2, A. Rapoport3
1Neurology, Dalessio Headache Center at Scripps Clinic, La Jolla, CA, USA; 2Neurology, California Medical Clinic for Headache, Santa Monica, CA, USA; 3Neurology, The David Geffen School of Medicine at UCLA, Los Angeles, CA, USA.
Objectives: To assess the efficacy and tolerability of milnacipran for migraine prophylaxis.
Background: Migraine is a highly prevalent episodic and chronic neurological disorder that impacts otherwise healthy men and women in their most productive years. Migraine exacts its toll by reducing work, school and social functionalty and inflicts severe pain and disability on the sufferer. Numerous safe and effective acute care pharmacotherapies are available but there is a recognized paucity of well tolerated and effective preventive treatments. Milnacipran, a serotonin and norepinephrine reuptake inhibitor with minimal activity outside these neurotransmitter systems, is safe and effective in the treatment of fibromyalgia, a chronic pain syndrome.
Methods: We enrolled 45 patients diagnosed with migraine with aura and/or migraine without aura, and 7 patients with chronic migraine in a 3 month open label study to determine the effectiveness and tolerability of milnacipran in reducing the number of all headache and migraine days.
Results: After three months of preventive therapy, milnacipran 100 mg daily, was associated with a significant improvement in headache and migraine frequency (p<0.001 and p<0.003, respectively). Overall, it proved to be a safe and effective treatment in headache and migraine prevention. The adverse event profile was consistent with prior reports of milnacipran for the treatment of other conditions.
Conclusions: The robust efficacy signal found in this study strongly suggests that a double-blind, placebo-controlled trial of milnacipran in migraine and chronic headache is warranted.
LBP3
Immunological Modulation by Yoga Therapy in Migraine Patients
S. Talakad1, R. Kisan1, M.U. Sujan1, R. Rao2, A. Nalini3, R. Trichur1
1Neurophysiology, National Institute of Mental Health & Neurosciences, Bangalore, Karnataka, India; 2C A M, HCG, Bangalore, Karnataka, India; 3Neurology, National Institute of Mental Health & Neurosciences, Bangalore, Karnataka, India.
Objectives: To study the effect of yoga therapy in patients with migraine.
Background: Neurogenic inflammation is a key mechanism in activating the trigeminal system and causing headache in migraine patients. Pro-inflammatory cytokines and anti-inflammatory cytokines are considered to be the possible pain mediators in neurovascular inflammation and so they may cause the generation of migraine pain. One of the trigger in migraine is stress. Yoga therapy, a traditional Indian psycho-philosophical-cultural method that has multiple health benefits including the improvement in the immunological system. Yoga has also shown to reduce stress arousal patterns, reduce stress hormones such as cortisol and reduce inflammation.
Methods: Twenty seven migraine patients (age 31.8±6.08 yrs; duration of illness 8.3±4.7 yrs) fulfilling the International classification of headache disorders (ICHD) II criteria, were recruited from the Neurology Outpatient Department, NIMHANS, Bangalore. Institute ethics committee approved the study & consent forms were obtained. Patients were randomized by concealed allocation protocol into conventional care group (14) and Yoga group (13). Conventional care group continued the conventional care. Yoga group in addition to the conventional treatment, patients advised to practice yoga therapy for 60 min 30 sessions in 45days. Patients were assessed before and after intervention by headache frequency and headache intensity by visual analogue scale (VAS) for pain and Immunological assessment. Five ml of blood sample was collected under aseptic precaution. Plasma was separated by centrifugation for 15 minutes at 3000 rpm. Plasma was stored at −80 ℃ till the cytokine assessment was done. Pro-inflammatory cytokines (IL1β, TNF α) and anti-inflammatory cytokines (IL4, IL1 receptor antagonist) levels were assessed by Enzyme-Linked Immunosorbent Assay (ELISA) technique.
Results: With Yoga therapy, patients exhibited significant improvement in clinical parameters (Headache frequency pre 9.1±4.6 post 2.5±1.6 per month; VAS pre 9.3±1.03 VAS post 2.6±1.12). Anti-inflammatory cytokine IL-4 increased significantly with yoga group when compared to conventional care only. (pre 0.76±0.12, post 0.86±0.12. p<0.05).
Conclusions: Our study shows that yoga therapy enhanced the anti-inflammatory cytokine IL-4 in addition to reducing the frequency and intensity of headaches and thus improving the quality of life in migraine patients.
LBP4
Withdrawn by the author.
LBP5
Headache as a Neurological Manifestation in SLE: Is It a Red Flag?
S.K. Jaiswal
Dept. of Neurology, Care Hospital of Medical Sciences, Hyderabad, India.
Objectives: Headache in Systemic Lupus Erythematosus (SLE) is a not very uncommon symptom. But, one should go for further evaluation, if it is severe, persistent and not relieved by NSAIDs.
Background: Headache is the commonest clinical manifestation of NPSLE (neuropsychiatric SLE). Headche has different spectrum of manifestations in SLE.
Migraine and tension headache may occur in upto 40% of SLE patient. Pseudotumor cerebri can also occur.
Cognitive dysfunction too occurs in 40% of patient. Other common neurological manifestations are seizures (15-20%), vasculitic neuropathy (15%), CVA(7%) etc.
Other uncommon neurological manifesatations are transverse myelitis, optic neuritis, meningitis etc.
Methods: A 36 year old female, diagnosed case of SLE, presented with history of severe headache, which was holocranial in nature, with throbbing in character, associated with nausea, not releived by NSAIDs and having disturbed sleep. There was no h/o fever, seizures and no meningeal signs or neurodefecit on examination. She underwent a battery of blood investigations to reconfirm her SLE status. In view of severe persistent headache, unrelieved by NSAIDs patient underwent neuroimaging- MRI brain. Later CSF studies were also performed.
Investigations
Value
Ref. Value
anti-dsDNA antibodies
349
<25
ANA
4.4
<1
RA factor
15.5 IU/ml
<10 IU/ml
CRP
positive
ASO
negative
C 3
81
75-135
C 4
07
9-36
S. Ferritin
337.9 ug/L
10-120ug/L
ESR
97 mm/hr
0-10mm/hr
TSH
1.3 mIU/L
0.5-4.5mIU/L
HBsAg
negative
HCV ab
negative
HIV ab(ELISA)
non-reactive
CSF cells
07 cells/cmm (100% L)
0-5cells/cmm
CSF protein
78 mg%
10-40mg%
Results: Her ANA profile with anti-dsDNA came strongly positive with elevated ESR value. Her MRI brain revealed flair hyperintensities in left fronto-parietal and right frontal region, which was suggestive of focal cerebritis. Her CSF showed cellular response with high protein (Table 1). She was treated with high dose of steroid, inj. Methylprednisolone 1 gm for 3 days and later was put on oral steroid. In next few days , her symptoms significantly reduced and she was relieved of headache.
Conclusions: Even though headache is the commonest clinical manifestation of NPSLE, one should go for further evaluation, if it is severe, persistent and not relieved by NSAIDS. Because it has great importance in patient management.
LBP6
Uncommon Cause of Iatrogenic Headache
N.V. Chaudhary
Neurology, Care Institute of Neurological Sciences, Hyderabad, India.
Objectives: To study the unusual etiology of nonspecific headache in a patient on treatment with anticoagulants.
Background: Till now, subarachnoid hemorrhage (SAH) associted with Heparin therapy has been mentioned in literatures, they were associtaed with thrombocytopenia.
Purely cortical SAH, presenting as headache has not been reported as a complication of Heparin therapy.
Methods: A 20 years old male came in our hospital E.D with history of sudden onset of giddiness since 4 hours of duration which was intermittent. There was no history of tinnitus or imbalance. On examination, he had irregular pulse rate with blood pressure 110/60 mm Hg. On examination there was no neurological deficits. His ECG showed intermittent tachycardia and bradycardia with paroxysmal Atrial fibrillation. It was suggestive of tachy -brady syndrome with paroxysmal Atrial fibrillation. He was admitted in cardiology ICU. He received intravenous Heparin as bolus followed by infusion with target APTT 3 fold more than control. On day 2, he started complaining of bitemporal headache which was severe, continuous in nature with tearing in character. Later we noticed, he developed right eye ptosis with swallowing difficulty with right sided ataxia. His MRI was performed in view of headache and Right medullary symptoms.
TESTS
RESULTS
HB
17.9 gm%
PCV
55 %
PLATELETS
3,52000 /cmm
PT/INR
12 sec/1.0
APTT
75 sec.
2 D-ECHO
NORMAL.
Results: MRI Brain showed Right posterio-lateral medullary infract (Figure 1) ith mild subarcachnoid hemorrhage in bilateral fronto parital cortical sulci (Figure 2). His basilar artery was partially occluded. MR venography was normal. In view of SAH, we stopped heparin and heart rate was monitored. His bradycardia worsened and underwent temporary pacemaker procedure. Headache symptoms gradually subsided and later CT Brain after 1 week showed resolution of SAH.
He was restarted oral anticoagulants after 2 weeks.
Conclusions: Severe headache in patients receiving anticoagulant if imaging is grossly normal, we need to search for cortical subarachnoid hemorrhage which may present with nonspecific headache.
LBP7
Juvenile Migraine and the Role of Autonomic Nervous System: A Clinical Study
G. Giordano1, C. Spitaleri1, B. Daniela1, F. Consolo1, M. D’Amelio2, V. Raieli1, G. Santangelo1, F. Vanadia1
1Neuropsichiatria Infantile, Ospedale dei Bamibi Civico, Palermo, Italy; 2Neurologia, Università Degli Studi di Palermo, Palermo, Italy.
Objectives: The aim of this study was to evaluate the prevalence of CAS during cephalalgic attacks in a juvenile population with primary headaches and to study the correlation between CAS and the main symptoms of migraine.
Background: Cranial Autonomic Symptoms (CAS) are frequently reported in adult migraineurs, but the prevalence of CAS inchildren affected by primary headaches is unknown. Recent studies suggest a role of NAS in pediatric migraine by the involvement of trigemino autonomic reflex.
Methods: 230 children suffering from headache (M46 F64, 4–17 years) were consecutively enrolled in two y period. A short questionnaire investigating the presence of CAS was administered to all children. This CAS were included: conjunctival injection, tearing, palpebral oedema, nasal congestion, rhinorrhoea, red ear, facial flushing, miosis, ptosis, forehead or facial sweating.
Results: 230 children (105M, 125F, 4–17 years [age 10.7 ± 3.1] were enrolled in this study. In total, 198 (86%) (94M, 104F) were found to be affected by migraine with/without aura (M without aura: 173 (75.21%), mean age 10.8 ± 3.1M 89 (51.4) F 84 (48.6%); M with aura: 25 subjects (24.79%), average age 11.7 ± 2.8 M 5 (20%) F 20 (80%), and 32 (14%) by Other Primary Headaches. The observed prevalence of (CAS) in headaches was: General population, 116/230 (50.4%);Other headache 9/32 (28.1%); Migraine 107/198 (54.04%) M without aura 89/173 (51.4%); M with aura 18/25 (72%). CAS occurring significantly more frequently in migraine than in the other primary headaches (107/198 versus 9/32) p = 0.008). The most common signs were facial flushing, red ear and conjunctival injection. At the univariate analysis CAS were significantly associated to the frequency of attacks (P<0.02). We also investigated the presence of general autonomic symptoms (GAS) type vasomotor (sweating, palpitations, pallor, flushing, intolerance to heat or cold), gastrointestinal (abdominal pain, constipation, diarrhea) and secretomotor (mouth or dry eyes, excessive sweating) in 50 migraine patients CAS + compared to 50 migraine patients CAS -. The results showed that 76% of CAS + patients also had GAS. The value of chi-square was equal to 8.33 with a significance p <0.01.
Conclusions: These findings indicate that CAS and GAS are rather common in the course of pediatric migraine attacks and prevalence differs high significantly than others headache. The prevalence of signs associated to local vasodilatation, suggest an important activation of parasympathetic control on cranial vascular tone in this sub group of pediatric migraineurs. The significative association between presence of CAS and frequency of attacks suggest that activation of parasympathetic system has a role about of severity of disease in pediatric migraine, supporting the role of the trigemino-autonomic reflex in the pathophysiology of migraine.
LBP8
Nosological Analysis of Migraine Trait Symptoms in Migraine with and without Aura: LHS and TPJ Contributed Equally
L.H. Schulte1, T.P. Jürgens1, A. May1
1Department of Systems Neuroscience, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.
Objectives: The aim of the study was to determine the occurrence of transient sensory and neuropsychological phenomena which are significantly associated with migraine but not necessarily with the migraine attack and which are not aura symptoms in a retrospective monocentric controlled epidemiological pilot study.
Background: Migraine is a common, disabling disorder originating in the central nervous system. Certain centrally driven phenomena have anecdotally been associated with migraine headache and/or migraine aura but larger epidemiologic studies are scarce.
Methods: Using a custom questionnaire, the frequency of transient sensory and neuropsychological phenomena in 219 patients with the diagnosis of migraine (150 without aura and 69 with aura) confirmed at a tertiary academic headache centre in Hamburg, Germany were compared with 161 age and sex-matched healthy controls without a history of migraine.
Results: The presence of both, migraine and aura was associated with significantly higher frequencies of autokinesis, dyschromatopsia, cinematographic vision, illusionary visual spread and synaesthesia (for all comparisons: p<0.05). Double vision, telopsia, inverted 2D/3D vision, complex visual hallucinations, and altered perception of body weight and size, were found more often in migraine without aura but not in migraine with aura. In contrast, aura was associated with the occurrence of visual splitting, corona phenomenon and altered perception of body position in space (for all comparisons: p<0.05). No relevant association with migraine was found for micro- and macropsia, pelopsia, inverted vision and Doppelgänger phenomenon.
Conclusions: Specific transient sensory and neuropsychological phenomena can be associated with migraine and/or aura biology. Especially aura biology seems to predispose to the frequent occurrence of these symptoms. Recognizing these clinical phenomena might have a significant impact on the classification of headache and the understanding of the pathophysiological background.
LHS and TPJ contributed equally.
LBP9
PACAP Infusion Causes Sustained Vasodilation of Middle Meningeal Artery in the Rat: Possible Involvement of Mast Cells
D.K. Bhatt1, S. Gupta1, I. Jansen-Olesen1, J. Olesen1
1Department of Neurology, Glostrup Hospital, Faculty of Health and Medical Sciences, University of Copenhagen, Glostrup, Denmark.
Objectives: To investigate the role of the mast cells (MCs) on the long lasting vasodilatory effect of PACAP on rat dural arteries in vivo. We hypothesized that the vascular responses to PACAP will be attenuated in mast cell depleted (MCD) rats due to a lack of vasodilatory products released during mast cell degranulation.
Background: In healthy human volunteers and in migraineurs, PACAP-38 infusion caused sustained vasodilation of middle meningeal artery (MMA) and immediate headache as well as delayed headache. All the study subjects experienced facial flushing lasting for several hrs. It has been shown that PACAP-38 has a much stronger degranulatory effect on rat peritoneal and dural mast cells than VIP and PACAP-27. As the MC degranulating substance promotes a prolonged state of excitation in primary afferent nociceptors in rats, MCs have been suggested to have a role in migraine pathogenesis.
Methods: MCs were depleted by chronic treatment with compound 48/80. The effect of 20 min intravenous (i.v.) and 1min intacarotid artery (i.c.) infusion of PACAP-38, PACAP-27 and VIP on the diameter of the middle meningeal artery (MMA) and on mean arterial blood pressure (MABP) in control and MCD rats was recorded by using the closed-cranial window (CCW) model.
Results: PACAP-38 infusion induced a prolonged dilation of rat MMA with a maximum 108 ± 20 % increase in MMA diameter and lasted for 30 min. In MCD rats the peak dilation was decreased to 40 ± 19 % and lasted for 20 min (Figure 1). PACAP-27 i.v. infusion gave 49 ± 12 % increase in MMA diameter and lasted for 20 min. In MCD rats PACAP-27 did not give any significant dilation. There was no significant difference in the potency (pED50) and % Emax values of i.c. administered PACAP-38, PACAP-27 and VIP induced MMA dilation (Table 1), except the % Emax value of PACAP-27 was significantly lower in MCD rats. The responses to calcitonin gene-related peptide on MMA diameter were not significantly different in control and MCD rats.
Table 1. Dilatory effects of various peptides on rat middle meningeal artery in vivo. Figure 2. Effect of PACAP-38 infusion (0.4 µg−1 kg−1 min−1 for 20 min, i.v.) on MMA diameter and on MABP in rat closed-cranial window model.
Middle Meningeal Artery (i.c. administration)
Control
Mast cell depleted
Emax (%)
pED50
Emax (%)
pED50
PACAP-38
112 ± 34 (7)
6.41 ± 0.15
114 ± 25 (5)
6.38 ± 0.15
PACAP-27
129 ± 17 (6)
6.23 ± 0.17
64 ± 19* (6)
6.02 ± 0.32
VIP
77 ± 21 (5)
6.06 ± 0.16
70 ± 20 (5)
5.98 ± 0.08
Conclusions: The MMA dilatory response to PACAP i.v. infusions were attenuated in MCD rats, indicating a role of MC degranulation in PACAP-induced dilatation of MMA.
LBP10
Transcranial Magnetic Stimulation for Migraine: A Quasi-Experimental Study
O. Miranda Rodríguez1, R.M. González Pérez2, H. Flores Podadera3, R. López Fernández4
1Specialized Ambulatory Center of the University Hospital “Dr. Gustavo Aldereguía Lima”, Cienfuegos, Cuba; 2Clinic Area IV, Cienfuegos, Cuba; 3Provincial Hospital “Abel Santamaría”, Pinar del Rio, Cuba; 4University of Medical Sciences “Dr. Raúl Dorticós Torrado”, Cienfuegos, Cuba.
Objectives: This paper was aimed at assessing whether combining conventional pharmacological treatment and single pulse Transcranial Magnetic Stimulation (sTMS) will result in improved outcomes for migraine patients.
Background: Migraine’s burdensome repercussion leads to use medications which are not effective in some cases. Transcranial magnetic stimulation, a poorly used alternative, has been pointed out as valid and innocuous for this purpose.
Methods: An interventional quasi-experimental study was performed, from March 2011 to February 2012. 60 patients out of 80, who were referred to the Neurologic Provincial Classification Consultation of Cienfuegos, Cuba, due to migraine, were selected according to the study inclusion criteria. An intervention (IG) and a control group (CG) were formed. The first one had received combined therapy. Magnetic stimuli were delivered by magneto regional equipment, MAG 80 Enrafnonium, equipped with a solenoid. It was set in number 5 position corresponding to the head, at 20 Gauss (%) of intensity and 8 Hz of frequency for the IG. Parameters were set at 0 for the other group. Both were given 10 sessions of 10 minutes each, from Monday to Friday during two consecutive weeks. After having measured the clinical variables referred to the patient’s conditions a month before, a second re-evaluation was applied a month and five months post-treatment. While episodes were reduced to or greater than 50.0 % in frequency and pain intensity decreased, migraine was assumed as improved. Abortive medication efficacy was evaluated by the Migraine Assessment of Current Therapy questionnaire. Statistics: X2, Odds ratio and comparison test for independent means were calculated.
Results: 86.6 % of patients in the IG classified as improved at five months post-treatment, this category was not achieved by any in CG (X2= 34.7; p= 0.00). It was more likely (OR 3.7; 95% CI 2.07–6.78) that patients who had received combined treatment would have had a better evolution. 63.3 % of the subjects in IG referred abortive medication as effective a month post-treatment and 73.3 % at five months post-treatment. In this group 20.0 % remained free of pain in both evaluative cutoffs. In CG, a month post-treatment, abortive medication was classified as not effective in 96.7 % vs. effective in 3.3 %. At the second cutoff the behavior was the same (X2= 39.14; p= 0.00). The absence of adverse events during sTMS was remarkable.
Conclusions: The fact that associating conventional pharmacological treatment and sTMS could be more effective for controlling migraine than the single use of pharmacological preventive treatment was favored.
LBP11
Headache Prevention with Cranial Electrotherapy Stimulation in Chronic Migraine. A Randomized Controlled Trial
G. Tietjen1, S. Thotakura1, J. Singh1, C. Utley1, V. Ramsey-Williams1, J. Khubchandani2, S. Khuder1
1University of Toledo, Toledo, OH, USA; 2Ball State University, Muncie, IN, USA.
Objectives: To assess efficacy and safety of cranial electrotherapy stimulation (CES) with a low intensity alternate current device (Fisher Wallace Stimulator, NY), FDA cleared for treatment of insomnia, anxiety, and depression.
Background: Chronic migraine affects 3% of the population and antimigraine drug efficacy is limited. There has been limited study of CES for migraine treatment, particularly for chronic, refractory headaches.
Methods: Double-blind, randomized, sham controlled trial conducted at a University headache clinic in persons with chronic migraine without satisfactory pain control on medication. After a 1-month run-in, patients were randomized to verum or sham stimulation for 20 minutes a day for one month. All patients received a verum device during a second, unblinded month. Primary outcome measures: change in monthly headache days, 50% responder rate. Secondary outcomes: change in scores for disability (HIT 6), depression (PHQ 9), anxiety (GAD 7), and somatic symptom severity (PHQ 15).
Results: 63 eligible patients were randomized. Completers (n=50) were included in the analysis. Between run-in and blinded treatment month, there was a non-significant decrease in mean number of headache days in verum (19.4 vs. 18.5, p=.18) and increase in sham group (19.6 vs. 20.1, p=.85), with no difference between groups (table). One participant (verum) had a 50% response rate. HIT 6 scores decreased within groups, without between group differences. There were no differences within or between groups on PHQ 9, PHQ 15. Scores on GAD 7 increased in verum, decreased in sham, and there was a difference between groups (p=.02). Adverse events: scalp irritation (1 verum, 2 sham), dizziness (2 verum), and visual flickering related to electrical pulse (6 verum), worsening of headaches (3 verum).
Characteristic
Verum (24)
Sham (26)
Headache (HA) days
19.38,18.50
19.56,20.07
Mean days run-in, blinded month
−0.88, −2.13 to 0.38 (0.18)
0.51, −2.49 to 1.45 (0.85)
Δ,95% CI (p value)
*p= .30
64.37, 63.15
Disability (HIT 6)
65.67, 63.54
−1.22, 0.19 to 2.64 (0.009)
Mean score run-in, blinded month,
−2.13, 0.15 to 4.10 (0.036)
5.85, 3.44
Δ, 95% CI (p value)
*p=.75
−2.41, −4.30 to −0.51 (0.013)
Anxiety (GAD 7)
5.29, 5.63
5.70, 5.41
Mean score run-in, blinded month
0.34, −0.76 to 1.42 (0.52)
−0.29, −1.49 to 0.89 (0.78)
Δ, 95% CI (p value)
*p=.02
9.44, 9.11
Depression (PHQ 9)
6.92,6.92
0.6, −0.21 to 1.54 (0.15)
Mean score run-in, blinded month
0, −1.37 to 1.37 (0.97)
Δ, 95% CI (p value)
*p=.98
Somatic Symptoms (PHQ 15)
9.38,9.00
Mean score run-in, blinded month
0.54, −0.57 to 1.65 (0.39)
Δ,95% CI (p value)
*p=.83
p = p value for comparison between groups
Δ = difference between values for run-in & blinded months
Conclusions: CES use for one month is safe and reasonably tolerated but ineffective in controlling headache, depression, anxiety and somatic symptoms in chronic migraine.
LBP12
A Randomized, Placebo Controlled, Double-Blind, Study To Evaluate the Pharmacokinetics, Safety and Tolerability of LBR-101 When Administered Intravenously
G. Wong2, K. Poulsen2, P. Garzone2, D. Shelton2, S. Walter1, M.E. Bigal1
1Labrys Biologics, Inc, San Mateo, CA, USA; 2Pfizer, Inc, South San Francisco, CA, USA.
Objectives: To evaluate the safety and tolerability of single doses of LBR-101 (RN-307/PF-04427429) administered intravenously (IV) to healthy volunteers, as well as to characterize its pharmacokinetic (PK) profile.
Background: CGRP is involved in the pathophysiology of migraine at many levels: peripherally, at the trigeminal ganglion, and inside the brain. Proof-of-efficacy was obtained for several CGRP receptor antagonists in the symptomatic relief of migraine, which were described as well tolerated and as not inducing coronary vasoconstriction. Targeting CGRP receptors using small molecules has been complicated by liver toxicity issues when these compounds were used as preventive treatments. LBR-101 is a fully humanized monoclonal antibody that potently and selectively blocks the binding of human CGRP to its receptor.
Methods: This was a randomized, placebo-controlled, double-blind study. Male healthy volunteers under the age of 50 (n = 40) were randomized to receive either placebo or one of the following doses of LBR-101: 10, 30, 100, 300, or 1000 mg. Blood samples for PK analyses were collected 6 times on the first day, and on several other days covering a follow-up time of 84 days. Extensive safety monitoring was conducted.
Results: Pharmacokinetics
Maximum plasma concentrations (Cmax) were reached shortly after the end of infusion. Median time to Cmax (Tmax) ranged from 1.0 to 2.0 hours, followed by a multiphasic decline. Cmax and total exposure increased with increasing doses. Terminal half-life (t½) ranged from 39.4 to 48.3 days. Figure 1 illustrates the median plasma concentration time profile (in hours) following single IV infusions of the various doses.
Treatment-related adverse events (AEs) were mild in all participants receiving LBR-101 but on one (reporting severe headaches). They were generally transient and resolved spontaneously, and a pattern of drug-related AEs did not emerge. No serious AEs were reported. Laboratory abnormalities were similar between subjects receiving placebo or drug. There were no relevant changes from baseline in vital signs data, including systolic BP, diastolic BP, pulse rate, pulse oximetry, and temperature. No ECG changes from baseline were seen.
Conclusions: Single IV doses of LBR-101 up to 1000mg were well tolerated with no safety concerns. LBR-101 has linear exposure over the dose ranges tested with a very long terminal t½ (ranging from 39.4 to 48.3 days). The safety and PK profiles make the compound attractive for future testing in individuals with frequent migraines.
LBP13
Relationship between Orofacial Pain and Coronoid Process of Mandible: Morphologycal and Electromyographic Comparisons
J. Stechman-Neto
Odontologia, Universidade Tuiuti do Parana, Curitiba, Parana, Brazil.
Objectives: The aim was to investigate the relationship between the coronoid process, temporal muscle activity and orofacial pain between the sides of patients with pain unilateral, bilateral and control group (no pain).
Background: Studies have shown the probable comorbidity between the primary headaches and temporomandibular disorders. In these studies, it was observed that most patients present with TMD diagnosis of primary headaches. Among the criteria for diagnosis of primary headache most migraine, are unilateral, coinciding with the characteristic of unilateral pain or preferred side of symptoms.
Methods: This is an exploratory study blind, and a quantitative survey of a random sample of patients. Approved CEP 0005769/12,CONEP 2184.0.000.0841. Patients (n=116) were examined by the criteria of the RDC /TMD-Axis I. After the clinical examination underwent EMG and panoramic radiographs. Worked with average values of EMG and panoramic radiographs that were stored images for marking the points related to mandible notch (Cs), coronoid process (Cr), the condyle (Co) and angle of the mandible (Go).
Results: It is observed that the difference between the measurements between the sides in unilateral pain only to variables CrCsA/B and CrGoA/B were (Table 1) coronoid has only the insertion of the tendon of the temporal muscle, and there is no other muscle bundle in this region5. In electromyography at rest, it was observed that there was a negative correlation between electrical activity and side pain, for the group of patients with unilateral pain (Table 2).
Table 1. Comparison between groups with significant difference between the measures.
GI (unilateral pain) n=43
GII (bilateral pain) n=35
GIII (no pain – control) n=38
Média
Valor p
Média
Valor p
Média
Valor p
CoCrA/B
(−0,38140)
0,4155
(−0,16829)
0,6668
(−1,03263)
0,1664
CoCsA/B
(−0,67093)
0,1269
(−0,84857)
0,0356
(−1,13158)
0,0469
CrCSA/B
(,61628)
0,0473
(,14286)
0,7284
(,73947)
0,1076
ACoCrSA/B
(1,71093)
0,7499
(−9,19714)
0,1358
(4,50474)
0,4979
CrGoA/B
(1,10000)
0,0344
(12,53714)
0,3562
(,08947)
0,8440
CoGoA/B
(−0,06512)
0,9436
(−1,35429)
0,0077
(−1,65789)
0,0005
ACoCrGoA/B
(−2,51814)
0,8869
(−14,91629)
0,4221
(−27,16421)
0,1314
Table 2. Correlation between EMG and medium measures the coronoid process and the mandibular notch.
GI (unilateral pain) n=43
GII (bilateral pain) n=35
GIII (no pain – control) n=38
CrCSA
CrCSB
CrCSA
CrCSB
CrCSA
CrCSB
TAAR
Pearson correlation
−0,302*
−0,213
,270
,202
,211
,178
Value p
0,049
0,171
0,117
0,244
0,204
0,284
TABR
Pearson correlation
−0,242
0,001
0,009
0,112
0,141
,233
Value p
0,118
0,996
0,957
0,521
0,400
0,160
TAAMIH
Pearson correlation
0,035
−0,038
0,091
0,304
0,125
−0,134
Value p
0,822
0,807
0,604
0,076
0,455
,423
TABMIH
Pearson correlation
0,049
0,220
−0,138
0,065
−0,064
−0,203
Value p
0,756
0,156
0,430
0,709
0,703
0,221
Conclusions: There was a correlation between the morphological and patients with unilateral pain. It´s suggested that these changes represent additional clinical sign in the diagnosis of orofacial pain. In groups of bilateral pain and control group (no pain) the measurement results obtained do not allow us to conclude the importance in the diagnosis of orofacial pain. There was a negative correlation between EMG at rest and symptomatic side in the unilateral group.
LBP14
Safety, Tolerability, and Pharmacokinetics of LBR-101 (RN-307 or PF-04427429) after Multiple Intravenous Injections – A Randomized, Double-Bind, Placebo Controlled Study
P. Garzone2, D. Shelton2, G. Wong2, K. Poulsen2, S. Walter1, R. Escandon1, M. Bronson1, M.E. Bigal1
1Labrys Biologics, Inc, San Mateo, CA, USA; 2Pfizer, Inc, South San Francisco, CA, USA.
Objectives: To evaluate the safety and tolerability of repeated doses of PF-04427429 administered intravenously (IV) to healthy volunteers; and to characterize the pharmacokinetic (PK) profile of LBR-101 (formerly known as RN-307 or PF-04427429) following repeated IV infusions.
Background: The potential role of calcitonin gene-related peptide (CGRP) in migraine pathophysiology was suggested more than 20 years ago. Since then, our knowledge surrounding its role in the pathophysiology of migraine has increased substantially, leading to robust interest in targeting CGRP to treat migraine. Unfortunately, targeting CGRP receptors using small molecules has been associated with liver toxicity. Unlike small molecules, monoclonal antibodies (mAbs) do not typically have issues with drug-drug interactions and targeting the CGRP peptide may avoid the hepatotoxicity associated with metabolism of receptor antagonists.
Methods: This was a randomized, placebo-controlled, double-blind, parallel-group study. Healthy volunteers were randomized to receive either placebo or LBR-101 at either 30 or 300 mg IV on Days 1 and 15. Following each dose, subjects were confined to the clinical research unit for a minimum of 7 days and returned for subsequent visits for up to 100 days or beyond following the initial dose. Extensive safety assessments were conducted during confinement and during the follow-up visits.
Results: Pharmacokinetics
Of the 21 enrolled subjects (10 men and 11 women), all subjects received at least 1 dose of LBR-101 and 18 subjects completed the study. Maximum concentrations and area under the concentration-time profile increased with increasing dose (Figure 1). The apparent terminal half-life (t½) after the second dose was 41.2 days (30 mg) and 49.9 days (300 mg) (arithmetic mean). The plasma accumulation ratio of LBR-101 after 2 IV doses administered 15 days apart was 1.5 (30 mg) and 1.4 (300 mg).
Safety
The proportion of individuals with adverse events (AEs) was similar across groups. Adverse events were primarily mild to moderate in severity and only one subject (placebo group) had a severe adverse event (anxiety attack). There were no clinically relevant patterns of change observed with vital signs, laboratory values, or ECG results.
Conclusions: Multiple IV doses of LBR-101 were well tolerated at 30 mg and 300 mg. LBR-101 exhibits a long circulating half-life, which should enable monthly dosing for future migraine prevention studies.
LBP15
Safety and Tolerability of LBR-101, a Humanized Monoclonal Antibody That Blocks the Binding of CGRP to Its Receptor
G. Wong2, P. Garzone2, D. Shelton2, K. Poulsen2, M. Bronson1, R. Escandon1, M.E. Bigal1
1Labrys Biologics, Inc, San Mateo, CA, USA; 2Pfizer, Inc, South San Francisco, CA, USA.
Objectives: To characterize the safety and tolerability of multiple doses of LBR-101 when administered intravenously (IV) to healthy volunteers.
Background: LBR-101 (RN-307/PF-04427429) is a fully humanized monoclonal antibody that potently and selectively blocks the binding of CGRP to its receptor. Small molecules targeting CGRP receptors have demonstrated efficacy for the acute treatment of migraine but their prolonged use has been associated with liver toxicity. CGRP mAbs are promising new therapies for migraine prophylaxis due to their targeted approach, prolonged circulating half-life, and reduced potential for hepatotoxicity and drug-drug interactions.
Methods: Safety data was pooled from 4 separate Phase 1 clinical studies that investigated various single and multiple dose levels of LBR-101 in healthy volunteers. All studies were randomized, placebo-controlled, double-blind. A total of 72 subjects received active drug (0.2 mg to 1000 mg), while placebo was administered to 27. In all studies, participants were confined for several days after dosing and were followed for up to 100 days or longer.
Results: Table 1 summarizes the number of patients experiencing treatment-related adverse events (TRAEs). Pooling doses, most common TR AEs were headache (LBR – 101 = 18.3%, Placebo = 26.9%), nasopharyngitis (9.8% vs. 3.4%), gastrointestinal symptoms (7.0% vs. 0) and back pain (7.0% and 0). TRAEs reported were predominantly limited to mild to moderate in severity. There were no deaths. One serious AE was reported in a subject receiving drug that was related to a subject’s prior history of aortic aneurysm, which was not considered to be related to the clinical trial procedure.
n
TR AEs
%
Placebo
27
7
25.9%
0.2 mg
6
0
0
1 mg
6
0
0
3 mg
6
1
16.7%
10 mg
6
1
16.7%
30 mg
12
5
41.6%
100 mg
6
1
16.7%
300 mg
24
6
25.0%
1000 mg
6
4
66.7%
All active doses
72
18
25.0%
>100 mg
36
11
30.5%
LBR-101 was not associated with any clinically relevant changes in vital signs, ECGs (including QTcF), infusion site reactions, or clinical laboratory values. There were no significant effects on liver function tests (AST, ALT, total bilirubin, and alkaline phosphatase). Two participants receiving placebo had Grade 1 increase in total bilirubin levels.
Conclusions: The safety and tolerability of LBR-101 has been investigated in healthy volunteers in multiple Phase 1 studies involving single dose escalation and two doses given once every 14 days. Based upon pooled data from 4 separate Phase 1 studies, single doses of LBR-101 up to 1000 mg IV and two doses up to 300 mg IV administered once every 14 days are safe and well tolerated. A maximum tolerated dose has not been identified to date. An ongoing Phase 1 study is being conducted in healthy women volunteers to investigate higher dose levels. The overall safety and tolerability profile of LBR-101 warrants future investigation in patients suffering from frequent migraines.
LBP16
Single Pulse Transcranial Magnetic Stimulation (sTMS) as a Non-Drug Treatment Option for Pregnant Patients with Migraine
R. Bhola1, N.J. Giffin2, F. Ahmed3
1eNeura Therapeutics, Sunnyvale, CA, USA; 2Department of Neurology, Royal United Hospital, Bath, United Kingdom; 3Department of Neurology, Hull and East Yorkshire Hospitals NHS Trust, Hull, United Kingdom.
Objectives: To understand the utility of sTMS as a non-drug treatment option for pregnant patients with disabling migraine.
Background: The majority of migraine sufferers find that their migraine improves during pregnancy especially after the first trimester. However a significant proportion of sufferers are seen by their doctors when the symptoms persist or worsen during pregnancy, where treatment options become essential. Here the Clinician has to weigh up the risk of untreated migraine symptoms to the mother and unborn baby with that of the medication risk to the foetus. The selected patients described here, presented to their Neurologists in the headache clinic, seeking advice and treatment for significantly disabling migraine attacks.
Methods: Limited medication options deemed relatively safe for use in pregnancy were already tried, without benefit eg paracetamol and codeine. sTMS was prescribed from the second trimester to use as per the MAB guidelines. Patients were reviewed at intervals by a clinical liaison with updates to the Neurologists.
Results: All three patients treated their attacks on a regular basis with benefit. They reported a reduction of pain severity, reduced attack duration and a reduction in severity of associated symptoms with early treatment, where the associated symptoms often did not develop. Two patients have given birth to healthy babies and continue to treat in the post-partum period and the third patient continues to treat during pregnancy.
No adverse effects were reported.
Conclusions: sTMS was safe and effective for use in pregnancy in these 3 patients. It appears to be an effective non-drug treatment option for pregnant patients who suffer disabling migraines.
LBP17
A Novel Program of Peer Review Training and Collaborative Peer Review
E.W. Loder1, J. Roberts2, P. Rizzoli1, R.C. Burch1, T.N. Ward3
1Division of Headache and Pain, Department of Neurology, Graham Headache Center/ Brigham and Women’s Faulkner Hospital, Boston, MA, USA; 2Headache, the Journal of Head and Face Pain, Plymouth, MA, USA; 3Headache Clinic, Department of Neurology, Dartmouth Hitchcock Medical Center, Hanover, NH, USA.
Objectives: Many small subspecialty journals face a critical shortage of subject matter experts who are capable peer reviewers. Our objective is to report on the implementation and feasibility of a program to train Headache Medicine fellows in peer review techniques and the performance of actual journal reviews.
Lessons learned from a novel program of peer review training and collaborative peer review
Challenge
Solution/Comments
Lack of support from fellowship directors for attendance
Contacted fellowship directors to emphasize importance of fellow participation
Convenient meeting time difficult to arrange
Experimented to find most acceptable time
Technical difficulties with videoconferencing
Pre-meeting connection testing encouraged
Multiple attachments emails resulted in designation as “spam”
Shared materials via Dropbox
Lack of variety in papers available for review
Chose “classic” papers from the existing headache literature to supplement teaching
Substantial time investment for faculty conference leaders
Invited guest faculty
Background: Competence in peer review is an integral element of clinical and research practice, but peer review skills are rarely taught to trainee physicians and little is known about the effect of training on the quality of peer reviews. In the US, a number of Headache Medicine fellowship programs are accredited by the United Council of Neurologic Subspecialties. They are widely dispersed geographically and each trains just 1–2 fellows per year. Most programs lack faculty with time or expertise to provide peer review training. In 2012 we developed a program to simultaneously train fellows in peer review techniques and improve the timeliness and quality of peer review for the journal Headache.
Methods: All 12 Headache Medicine fellows received an email with the training curriculum. We held Skype videoconferences regularly during the fellowship year. Before each conference fellows received an anonymized version of a paper for review and relevant supporting materials. Experienced editors (EL, RB) moderated meetings using a structured format. Leaders generated a draft peer review report based on discussion. This was circulated to participants for editing and approval. The final collaborative report was submitted to Headache as an external review for the paper.
Results: 10/12 fellows participated in some or all conferences despite locations in four time zones. There were few technical problems with Skype. Group peer reviews were completed within 4–7 days of the meeting. Our experience identified several key lessons that will inform future program adaptations.
Conclusions: A novel program of videoconference training and group peer review was feasible and may help redress the critical shortage of competent, expert peer reviewers in Headache Medicine and other subspecialties.
LBP18
Is PRRT2 the Fourth Hemiplegic Migraine Gene?
N. Pelzer1, B. de Vries2, J.T. Kamphorst2, L.S. Vijfhuizen2, M.D. Ferrari1, G.M. Terwindt1, J. Haan1,3, A.M.J.M. van den Maagdenberg1,2
1Neurology, Leiden University Medical Center, Leiden, The Netherlands; 2Human Genetics, Leiden University Medical Center, Leiden, The Netherlands; 3Neurology, Rijnland Hospital, Leiderdorp, The Netherlands.
Objectives: To reinvestigate a family suffering from benign familial infantile seizures (BFIS) and familial hemiplegic migraine (FHM), which phenotypes were previously reported to partially co-segregate with an ATP1A2 mutation. In addition, we aimed to investigate the link of PRRT2 with hemiplegic migraine (HM) in our extensive FHM database.
Background:PRRT2 mutations have recently been associated with BFIS and HM.
Methods: The PRRT2 gene was sequenced in the previously published FHM-BFIS family and in 27 FHM patients from 14 families who had no mutation in the FHM genes CACNA1A, ATP1A2 and SCN1A.
Results: All four tested BFIS patients from the FHM-BFIS family carry a novel PRRT2 mutation c.650delG p. Arg217GlnfsX12 and nine out of ten FHM patients carry the p. Arg689Gln ATP1A2 mutation. No PRRT2 mutations were identified in 27 FHM patients from our database.
Conclusions: The results in our FHM-BFIS family and FHM cohort are not in concordance with recent reports of an association of PRRT2 mutations with HM. There is insufficient evidence to claim that PRRT2 is the fourth FHM gene.
LBP19
A Randomized, Double-Blind, Placebo-Controlled, Proof of-Concept Study of LY2300559 for Migraine Prophylaxis in Patients with Migraine
C. Robertson-Plouch1, S. Silberstein2, C. Birch1, P. Ardayfio1, C. Brittain1
1Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, IN, USA; 2Thomas Jefferson University, Philadelphia, PA, USA.
Objectives: To measure the change in frequency of migraine attacks per 28 days in migraine patients treated orally with LY2300559 for 12 weeks.
Background: LY2300559 is a metabotropic glutamate 2 (mGlu2) potentiator and a cysteinyl leukotriene 1 antagonist. LY2300559 had favorable preclinical and safety profile. A previous small acute migraine study showed numerical separation of LY2300559 from placebo (PBO) for patients pain-free 4 hours postdose, suggesting activity in migraine.
Methods: This was a Phase 2, double-blind, randomized, PBO-controlled, migraine prophylaxis proof-of concept of LY2300559. Patients had 4–14 migraines during baseline month to enroll. LY2300559 300 mg or PBO was given daily for up to 12 weeks. A sample size of 118 was planned in order to achieve 90% power to detect a change of 1.2 migraines per month. Change from baseline migraine frequency was analysed by mixed-effects model repeated measures adjusting for pooled investigator site and baseline. Tests were conducted with 10% significance level.
Results: The study was stopped early due to clinically significant elevations of transaminases. 86 patients received ≥1 dose of study drug and had ≥4 migraines during baseline month; 56 patients completed the study. Results demonstrated statistically significant mean reduction of 1.0 migraines (p=0.085) at Month 3, but not at Months 1 or 2. A mean reduction in migraine days of 1.7 for LY2300559 compared to PBO was seen at Month 3, not statistically significant. Duration and severity of pain showed no improvement. There was a clinically significant higher number of responders, partial remitters and complete remitters at Month 3 for the LY2300559 group (59%) compared to the PBO group (29%), p=0.102.
The most common reason for early discontinuation was adverse events (AEs) (11.6%). Mean change in alanine aminotransferase (ALT) and aspartase aminotransferase (AST) was significantly higher in LY2300559 group compared to PBO group. Ten (10) of 41 (24.4%) of LY2300559 patients had clinically significantly elevated ALT and/or AST, vs none in the PBO group. These patients were identified after routine visits and per-protocol laboratory tests. None met Hy’s law, none had total bilirubin ≥2x upper limit of normal, and none were classified as a serious AEs by the investigator.
Conclusions: This study was stopped due to transaminase elevations among LY2300559-treated patients. Differences for primary or secondary efficacy measures were not evident at Months 1 or 2. However, at Month 3 there were significantly fewer migraine attacks compared to PBO, and clinically meaningful improvements in responder analyses. Although transaminase elevations resulted in stopping development, the efficacy data suggest that mGlu2 potentiation/cysteinyl leukotriene 2 antagonism could be a potential novel, dual mechanism for migraine prophylaxis.
LBP20
Is Migraine Associated with Stroke in Children?
A.A. Gelfand1, H.J. Fullerton1, A. Jacobson2, P.J. Goadsby1, S. Sidney2, M. Sorel2, A. Pressman2
1Neurology, UCSF, San Francisco, CA, USA; 2Division of Research, Kaiser Permanente Northern California, Oakland, CA, USA.
Objectives: To determine whether there is an association between pediatric migraine and stroke.
Background: Childhood stroke is more common than previously thought, however most children who suffer a stroke do not have a known stroke risk factor. In adults, migraine with aura is associated with a two-fold increase in stroke risk in young women. In this cohort study we sought to examine the association between migraine and stroke among children in Kaiser Permanente Northern California (KPNC).
Methods: Children ages 2–17 who were within the KPNC health care system for ≥ 6 months during the study period (1997–2007) constituted the study cohort. Stroke outcomes had been identified as part of the Kaiser Pediatric Stroke Study. Children with migraine met at least one of the following criteria: 1) had ≥ 1 ICD-9 visit code for migraine, 2) had migraine listed on their significant health problem list, or 3) had a prescription for a migraine specific medication. Those migraineurs whose stroke occurred before evidence of headache were excluded. We calculated stroke incidence rates stratified by the presence or absence of migraine and incidence rate ratios (IR) as a measure of relative risk. In order to minimize the presence of undiagnosed migraineurs in the comparison group, we excluded from this group anyone with evidence of headache.
Results: Of approximately 1.6 million eligible children within KPNC during the study period, 88,139 had migraine, and 1,323,062 had no evidence of headache. Of the migraineurs, 8 had a stroke during the study period (3 hemorrhagic, 5 ischemic). There were 80 strokes in children without headache, (66% hemorrhagic, 34% ischemic). The ischemic stroke incidence rate was 0.9/100,000 person-years in migraineurs vs. 0.4/100,000 person-years in those without headache; IR 2.0 (95% CI 0.8–5.2). The hemorrhagic stroke incidence rate was 0.5/100,000 person-years in migraineurs and 0.9/100,000 person-years in those without headache; IR 0.6 (95% CI 0.2–2.0).
Conclusions: Pediatric migraine was not statistically significantly associated with an increased rate of pediatric stroke in this study. However, the two-fold increase in the estimate of ischemic stroke rate is similar to that reported in adults, suggesting the negative finding in this study may be the result of underpowering. Further research is needed, with particular focus on aura status as migraine aura mediates stroke risk in adults.
LBP21
Occipital Nerve Block for the Preventive Treatment of Migraine: A Randomized, Double-Blinded, Placebo Controlled Study
E. Dilli1, R. Halker2, J. Hentz2, R. Rogers2, B. Vargas2, A. Starling2, T. Radam2, D. Dodick2
1Neurology, University of British Columbia, Vancouver, BC, Canada; 2Neurology, Mayo Clinic, Scottsdale, AZ, USA.
Objectives: To determine the efficacy of occipital nerve block (ONB) with local anesthetic and corticosteroid for the preventive treatment of migraine.
Background: Occipital nerve (ON) injections with corticosteroids and/or local anesthetics have been employed for the acute and preventive treatment of migraine for decades. However, to date there is no randomized, placebo-controlled evidence to support the use of ONB for the preventive treatment of migraine.
Methods: Subjects between 18–75 years old with ICHD-II defined episodic (>1 attack per week) or chronic migraine were randomized to receive either 2.5 ml 0.5% bupivicaine plus 0.5 ml 20 mg methylprednisolone over the ipsilateral (unilateral headache) or bilateral (bilateral headache) ON or 2.75 ml normal saline plus 0.25 ml 1% lidocaine without epinephrine (placebo). Key exclusion criteria included subjects with continuous headache, use of maintenance opioid medication, or the initiation of a medication with preventive efficacy for migraine within 2 months prior to screening. Patients completed a 1-month diary both at baseline and after the double-blind injection. The primary outcome measure was defined as a 50% or greater reduction in the frequency of days with moderate or severe headache in the 4-week post-injection compared to the 4 week pre-injection baseline period.
Results: Thirty-four patients received active and 35 patients received placebo treatment. Because of missing data, 33 patients in the Active and 30 patients in the placebo group were analyzed for efficacy. In the active and placebo groups respective, the mean frequency of at least moderate (mean 9.8 vs 9.5) and severe (3.6 vs 4.3) headache days and acute medication days (7.9 vs 10.0) was not substantially different at baseline. The percentage of patients with at least a 50% reduction in the frequency of moderate or severe headache days was 30% for both groups (Δ 0.00, 95% CI -0.22 to 0.23). There were also no significant between-group differences in the consumption of acute medications or post-injection ON tenderness. The treatment was generally well tolerated with injection site pain noted for 4 patients in the active and 2 patients in placebo group.
Conclusions: Greater occipital nerve block does not reduce the frequency of moderate to severe migraine days in patients with episodic or chronic migraine.
LBP22
Reliability and Validity of Malaysian Language Translated Version of Migraine Disability Assessment (MIDAS) Questionnaire
M.M. Shaik1, N.B. Hassan2, H.L. Tan1, S. Bhaskar3, S.H. Gan1
1Human Genome Centre, Universiti Sains Malaysia, Kubang Kerian, Kelantan, Malaysia; 2Department of Pharmacology, Universiti Sains Malaysia, Kubang Kerian, Kelantan, Malaysia; 3Department of Medicine, Universiti Sains Malaysia, Kubang Kerian, Kelantan, Malaysia.
Objectives: This study was designed to investigate the test-retest reliability, internal consistency and validity of a Malaysian language translated version of the Migraine Disability Assessment (MIDAS).
Background: Previous studies have demonstrated that the English version of MIDAS as reliable and valid instrument for the assessment of migraine related disability.
Methods: Study participants were recruited from the patient population attending the Specialised Medical Clinic of Hospital Universiti Sains Malaysia. Participants were eligible for study entry if they were diagnosed with migraine for more than six months. A standard translation procedure was used to translate and adapt the questionnaire into the Malaysian language, which was then tested on 30 Malaysian migraine patients (first compilation) and retested after 21 days later (second compilation).
Results: Patients between the ages of 18–70 years were recruited (29 women and 1 men). The majority of the patients (46.7%) were of MIDAS grade IV (severe disability), 36.7% were of MIDAS grade III (moderate disability) and 16.7% were of MIDAS grades I or II (minimal, mild or infrequent disability). Cronbach’s alpha was 0.673 at the first compilation and 0.68 at the second compilation. The test-retest Spearman correlation for the five disability questions was 0.661, the questions on average pain intensity was 0.865 and headache frequency was 0.976 (p<0.007). The test-retest Spearman correlation coefficient for the total MIDAS score was 0.741 (p<0.002) indicating that MIDAS questionnaire is reliable and valid and could be used in the clinical setting for the diagnosis of migraine.
Conclusions: Malaysian language translated version of MIDAS questionnaire is comparable with the English language version for its reliability and validity and can be used for the assessment of migraine in clinical settings.
LBP23
A Randomized Double-Blind Comparison of Three Different Intravenous Treatments for Patients Who Visit an Emergency Department with Acute Migraine
B.W. Friedman1, L. Garber1
1Emergency Medicine, Albert Einstein College of Medicine, Bronc, NY, USA.
Objectives: This study compared the efficacy and side effects of IV valproate to IV metoclopramide and to IV ketorolac for patients who presented to an emergency department with acute migraine.
Background: Sodium valproate, an established migraine preventive medication, may also alleviate acute migraine.
Methods: This was a randomized, double blind, 3-armed, comparative efficacy trial of ED patients presenting with acute migraine, as defined by the ICHD2. Patients were randomized to receive 1000 mg sodium valproate, 10 mg metoclopramide, or 30 mg ketorolac, each administered via IV drip over 15 minutes. Primary study outcome was the improvement in headache score at 1 hour post-baseline, as measured on a verbally administered 0 to 10 scale. Secondary outcomes included: need for rescue medication; sustained headache freedom defined as achieving complete relief in the ED without use of rescue medication and maintaining it for 24 hours; and whether the patient wished to receive the same medication during the next ED visit.
Results: 330 patients were enrolled. Baseline demographics and headache features were comparable among the three groups. On the primary outcome, patients in the valproate arm improved by 2.8 points (95% CI: 2.3, 3.3), the ketorolac arm improved by 3.9 points (95% CI: 3.3, 4.5), and the metoclopramide arm improved by 4.7 points (95% CI: 4.2, 5.2). On the secondary outcomes, 69% (95% CI: 60, 78%) of valproate patients required rescue medication, as did 52% (95% CI: 42, 63%) of ketorolac patients, and 33% (95% CI: 24, 42%) of metoclopramide patients. 4% (95% CI: 0, 7%) randomized to valproate reported sustained headache freedom, compared to 16% (95% CI: 9, 23%) of the ketorolac group and11% (95% CI: 5, 17%) of metoclopramide patients. 26% (95% CI: 18, 35%) of the valproate group, 40% (95% CI: 30, 50%) of the ketorolac group, and 61% (95% CI: 51, 70%) of the metoclopramide group wished to receive the same medication in the future. Of all patients, 7% (95% CI: 5, 10%) reported dizziness, which was evenly distributed among the study arms. Drowsiness was reported by 13% (95% CI: 8, 20%) of ketorolac patients, but was uncommon in the other arms. 6% (95% CI: 3, 12%) of metoclopramide subjects reported being “very restless” after receiving the investigational medication.
Conclusions: Among adult ED patients presenting with migraine, IV valproate is clinically and statistically less efficacious than either IV metoclopramide or IV ketorolac on both primary and secondary endpoints.
LBP24
Novel Transgenic Mouse Models for Monogenic Cerebral Small Vessel Diseases Related to Migraine
R.R. Klever1, J.W. Rutten1, S. Labruijere2, K. Ibrahimi2, L.A.M. Broos1, N. Rieff1, G.M. Terwindt3, M.D. Ferrari3, S.A.M.J. Lesnik-Oberstein4, E.A.M.J. Tolner3, A. Maassen-van den Brink2, A.M.J.M. van den Maagdenberg1,3
1Human Genetics, Leiden University Medical Center (LUMC), Leiden, The Netherlands; 2Pharmacology, Erasmus University Medical Center, Rotterdam, The Netherlands; 3Neurology, Leiden University Medical Center (LUMC), Leiden, The Netherlands; 4Clinical Genetics, Leiden University Medical Center (LUMC), Leiden, The Netherlands.
Objectives: To gain better insight into vascular changes in relation to migraine headache, we have developed novel transgenic mouse models for two monogenic migraine-related disorders of which vasculopathy of cerebral small vessels is an important clinical feature: Retinal Vasculopathy with Cerebral Leukodystrophy (RVCL) and Cerebral Autosomal Dominant Arteriopathy with Subcortical Infarcts and Leukoencephalopathy (CADASIL).
Background: Migraine is a prevalent, disabling, neurovascular brain disorder characterized by attacks of severe headache and associated symptoms of autonomic and neurological dysfunction. Monogenic diseases such as RVCL and CADASIL, in which migraine is a prominent clinical feature, are useful to investigate mechanisms underlying migraine pathophysiology. Genetic studies in RVCL and CADASIL patients revealed that RVCL is caused by frameshift mutations in the TREX1 gene, while CADASIL is caused by missense mutations in the NOTCH3 gene.
Methods: We generated transgenic RVCL mice through a knock-in approach introducing the V235fs mutation into the mouse Trex1 gene. For the CADASIL mouse model, a conventional transgenesis approach with a human NOTCH3 gene insertion was chosen. This uniquely allows pre-clinical testing of therapeutic gene targeting concepts in this novel CADASIL mouse model.
Results: We present a first molecular characterization of both the RVCL and CADASIL mouse models at the DNA, RNA and protein level. Pathological investigations are aimed at identifying possible vascular changes in the retina and brain. Already in CADASIL transgenic mice, we found vascular smooth muscle cell abnormalities consisting of positive Notch3 immunostaining and granular osmiophilic material (GOM) deposits as shown by electron microscopy. Characterization of vascular function by isolated vessel reactivity measurements as well as in vivo laser doppler measurements are ongoing, of which preliminary data might be suggestive of enhanced vessel stiffness in both models.
Conclusions: Our results introduce our novel transgenic mice as valuable models for RVCL and CADASIL and as promising tools to investigate vascular changes in the context of migraine pathophysiology.
LBP25
Third Cranial Nerve Palsy Associated with an Attack of Cluster Headache
F.A. Khan
Headache Division, Ochsner Neurosciences Institute, Ochsner Health System, New Orleans, LA, USA.
Objectives: To discuss a case report of a patient with an attack of cluster headache with associated ipsilateral third cranial nerve (CN) palsy. Review of literature.
Background: Cluster Headaches (CH) is a primary headache disorder classified under trigeminal autonomic cephalalgias. Cranial autonomic features of CH attacks can include ipsilateral lacrimation, conjunctival injection, nasal congestion or rhinorrhoea, ptosis, oedema of the eyelid or the face (or both), sweating of the forehead or the face, and miosis. Other features of the clinical presentation include restlessness and agitation, nausea, photophobia, aversion to loud sounds and strong smells. Ophthalmoplegia is extremely rare and has been previously reported (third and sixth cranial nerve involvement).
Methods: We report a case of an attack of cluster headache with involvement of ipsilateral third cranial nerve (CN).
Results: A 67-year-old right-handed Caucasian female with past medical history of diabetes type II, hypertension and CH presented with one of her typical CH attacks. Her symptoms included severe left sided lacerating headache mostly around the left eye, photophobia, swelling of left eye lids, and tearing of left eye. Five days after onset of the attack she developed complete ptosis and third CN palsy of the left eye. On exam both pupils were equal in size and reactive to light and no evidence of afferent pupilary defect was noted. Visual acuity and color vision were intact. Initially she was thought to have diabetic third CN palsy. She underwent an extensive unrevealing diagnostic work up except for a Hemoglobin A1c of 10.0% 3 months prior. Magnetic Resonance Imaging of the brain was unremarkable without evidence for left posterior communicating artery aneurysm. Oral steroids were initiated, and the patient noted rapid improvement in ptosis and ocular alignment and headaches. She completed a tapering course of oral steroids without recurrence.
Conclusions: Our patient presented with a typical attack of CH with autonomic involvement of the left eye. Five days after onset she developed a pupil sparing ipsilateral third cranial nerve palsy with unremarkable neuroimaging. The temporal association, ipsilateral involvement and rapid improvement of headache and third CN palsy with oral steroids further supports that the CN involvement was associated with CH. No other cause for the third CN palsy was identified. We hypothesize that the intracranial inflammatory vascular process during a CH attack may have extended to the blood supply of the third CN. The diagnosis was initially missed as it was confounded by history of poorly managed diabetes. We underscore importance of recognizing third CN palsy as a rare association with CH attacks.
LBP26
Update of the UK Post Market Pilot Programme with Single Pulse Transcranial Magnetic Stimulation (sTMS) for Acute Treatment of Migraine
R. Bhola1, S. Lipscombe2, N. Giffin3, G. Elrington4, M. Weatherall5, F. Ahmed6, P. Goadsby7
1eNeura Therapeutics, Sunnyvale, CA, USA; 2Royal Sussex County Hospital, Brighton, United Kingdom; 3Neurology, Royal United Hospital, Bath, United Kingdom; 4National Migraine Centre, London, United Kingdom; 5Neurology, Imperial College Healthcare, London, United Kingdom; 6Neurology, Hull and East Yorkshire Hospitals NHS Trust, Hull, United Kingdom; 7Headache Center, University of California San Francisco, San Francisco, USA.
Objectives: To evaluate patient response to sTMS in an open outpatient setting and to assess the impact of treating migraine attacks with single pulse sTMS on pain and associated migraine symptoms over at least three months.
Background: Some patients suffer disabling, frequent migraine without effective treatment as current pharmacological options are either contraindicated, poorly tolerated or overused. A post market pilot programme with the sTMS device was initiated for patients with migraine. With the introduction of this new treatment modality, it was important to understand the patient support and educational needs for using sTMS and to assist patients in establishing an optimal treatment scheme for their migraine.
Methods: Clinicians selected appropriate patients and prescribed the device. Patients subsequently received the device to use for a minimum of three months. A clinical liaison had first contact with the patient to discuss treatment and use. Telephone reviews were conducted at 4- to 6-weekly intervals to support and monitor the patients’ treatment and progress and survey data was collected at these time points, over the treatment period. The patients’ progress with treatment was reported to their clinician.
Results: Of patients prescribed sTMS (n = 123): 69 completed at least one survey; and 42 completed 2–3 surveys.
A reductionof pain that was maintained or improved over the treatment period was reported in 74% of patients.
Associated symptoms were improved in 63% of patients or for some, did not develop after treatment.
Fifty-eight per cent of patients (40 of 69) reported reduced attack duration, and these patients reported a 63% reduction in headache days over the 12-week treatment period.
The treatment was well tolerated with no serious adverse events reported.
Conclusions: The sTMS device is a new and effective acute migraine treatment. This CE marked device is safe to use in clinical practice and has reliable, reproducible effects on migraine over time.
LBP27
Withdrawn by the author.
LBP28
Effect of Sumatriptan, L-NAME, Olcegepant and a NK-1 Receptor Antagonist on GTN Induced Dural Mast Cell Degranulation in Awake Freely Moving Rats
S.H. Pedersen1, R. Ramachandran1, D.V. Amrutkar1, J. Olesen1, I. Jansen-Olesen1
1Department of Neurology, Danish Headache Center, Glostrup Research Institute, Glostrup Hospital, Glostrup, Denmark.
Objectives: To study the effect of glyceryl trinitrate (GTN) infusion to awake rats on dural mast cell degranulation. Furthermore, to investigate if drugs effective in migraine treatment and a drug being non-effective in migraine treatment can inhibit GTN-induced mast cell degranulation.
Background: Infusion of the nitric oxide (NO) donor, GTN, is a widely accepted migraine provocation model which induces an immediate headache followed by a delayed migraine-like headache exclusively in migraineurs. The delayed effect is probably secondary to the direct action of NO derived from GTN as GTN is rapidly degraded in the body. Meningeal inflammation and dural mast cell degranulation have been suggested to be implicated in migraine patophysiology. Using a newly developed animal model, we have previously shown upregulation of c-fos in laminae I and II of the trigeminal nucleus caudalis. This is blocked by pre-treatment with L-NAME, olcegepant, sumatriptan and a NK-1 receptor antagonist (L-733060).
Methods: GTN (4 µg/kg/min for 20 min, i.v.) was infused in awake rats with an implanted venous catheter. At different time points after treatment the animals were perfused with 4% paraformaldehyde. Dura mater was carefully removed and stained with 0.25% toluidine blue for visualization of mast cells. Mast cells were counted and evaluated for degranulation in the close proximity to the first branch of the middle meningeal artery (MMA). Some animals received pre-treatment with L-NAME, olcegepant, sumatriptan or L-733060 5 min before GTN infusion.
Results: GTN induced a time-dependent degranulation of dural mast cells with an overall significant increase from 30 min to 6 hrs. 30 min after GTN infusion the amount of mast cell degranulation increased from 8.7 ±1.3% to 20.3 ±3.0% (p<0.05) and at 2, 4 and 6 hrs after GTN infusion we observed a solid degranulation of 61.0 ±15.3%, 66.4 ±6.3% and 54.5 ±9.3% (p<0.05), respectively. Pre-treatment with sumatriptan and L-NAME reduced the degranulatory effect of GTN to 18.0 ±6.1% and 24.3 ±8.0%, respectively. Olcegepant and L-733060 did not display any inhibitory effect on GTN induced mast cell degranulation. Data is presented as mean ±SEM, n=4–6.
Conclusions: Rat dural mast cells degranulate shortly after GTN infusion followed and is further increased for the next 6 hrs after infusion. Pre-treatment with sumatriptan and L-NAME significantly inhibits this effect suggesting that serotonin and nitric oxide synthases are involved in the signaling cascade leading to mast cell degranulation. In contrast, olcegepant and L-733060 has no effect on GTN induced mast cell degranulation suggesting that CGRP and substance P are not involved.
LBP29
Dexketoprofen Trometamol in the Acute Treatment of Migraine Attack: A Phase II, Randomized, Double-Blind, Crossover, Placebo-Controlled, Dose Optimization Study
F. Mainardi1, F. Maggioni2, D. Pezzola3, D. Zava3, G. Zanchin2
1Headache Centre, Neurological Division, SS Giovanni e Paolo Hospital, Venice, Italy; 2Headache Centre, Department of Neurosciences, Padua University, Padua, Italy; 3Istituto Luso Farmaco d’Italia, Peschiera Borromeo, Milan, Italy.
Objectives: To assess efficacy and tolerability of two doses of dexketoprofen 25mg (DKP25) and 50 mg (DKP50) compared to placebo (PLB) for migraine treatment.
Background: The World Health Organization (WHO) has recently indicated migraine as one of the most disabling chronic diseases. NSAIDs are indicated for treatment of mild to moderate attacks or when triptans are contraindicated or ineffective.
Methods: This randomized, double-blind, single-centre, cross-over, placebo-controlled study was performed in Italy. 93 patients with at least one migraine attack per month in the preceding 6 months, were enrolled and randomized to DKP25, DKP50 and PLB. Primary endpoint was pain-free episodes 2h after drug intake. Secondary end points were pain relief episodes at 2h after drug intake, any functional disability and the presence of accompanying symptoms.
Results: 76 patients (mean age 40.5±10.9 and 61% female) completed the study. At baseline, mean number of attacks/month was 3.7±1.3, with a mean duration of 15.4±13.5h.
The results of primary end-point are show in figure 1. Asterik indicate a statistically significant difference (p=0.0065) between the group treated with DKP50 and the group treated with PLB. Both DKP 25 and 50 mg improved headache relief at 2h compared to PLB (DKP25: 57%; DKP50: 65%; PLB: 25%, p<0.001), and reduced the disability (DKP25 vs PLB: 40% vs 24%, p=0.045; DKP50 vs PLB: 46% vs 24%, p<0.0004). The proportion of patients showing complete recovery of photophobia and phonophobia after 2 hours was higher with DKP25 (46% and 52%) and with DKP50 (72% and 44%) compared to PLB (24% and 24%, p<0.05). Resolution of nausea was higher with both doses of DKP (62–64%) in comparison with PLB (33%). 18 patients reported not serious adverse events (AE), mostly gastro-intestinal symptoms without significantly differences with the respect to PLB (n=15; DKP25: 4; DKP50: 7; PLB: 5).
Conclusions: Both doses of DKP were effective for acute migraine treatment. The recurrence of AE was similar to placebo.
LBP30
Preclinical Characterization of LY2300559, a Dual Acting mGlu2 Receptor Positive Allosteric Modulator (PAM) and Leukotriene CysLT1 Receptor Antagonist, for Potential Use as a Migraine Therapy
K.W. Johnson1, A.C. Smith1, R.J. Davis1, J.M. Schkeryantz1, S. Swanson1, A. MaassenVanDenBrink2, R. de Vries2, M.P. Johnson1
1Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, IN, USA; 2Erasmus MC, Rotterdam, The Netherlands.
Objectives: To characterize LY2300559 in the rat trigeminal stimulation-induced dural plasma protein extravasation (PPE) model of neurogenic inflammation, establish the lack of vasoconstrictive activity in human coronary artery and describe a clinically-translatable biomarker potentially linked to efficacy.
Background: Plasma levels of glutamate are elevated in migraineurs and can be decreased with effective migraine prophylaxis treatment. Metabotropic glutamate (mGlu2) receptors are located presynaptically and inhibit the release of glutamate and other inflammatory agents from sensory afferents when activated. Positive allosteric modulators (PAMs) of mGlu2 enhance the effects of glutamate while having no effect on their own. We hypothesized that a mGlu2 PAM may have efficacy in the rat PPE model, decrease plasma glutamate levels and potentially have efficacy in the clinic as a migraine therapy. CysLT1 receptors have been localized on resident mast cells in the dura and shown to play a role in extravasation and increased LTD4-induced firing of trigeminal sensory neurons.
Methods: A selective mGlu2 PAM and CysLT1 antagonist were evaluated separately and combined in the PPE model, along with characterizing LY2300559, following a variety of treatment paradigms including pre-stimulation, post-stimulation and subchronic dosing. The effect of LY2300559 on plasma and csf levels of rat catecholamines, metabolites and amino acids was characterized using HPLC-EC techniques. The contractile effects of LY2300559 and sumatriptan were determined in human isolated coronary arteries obtained from donors who died of noncardiac disorders less than 24 hours prior.
Results: The selective mGlu2 PAM and CysLT1 antagonist were each able to inhibit dural PPE. However, the effect of both molecules administered together was greater than additive, suggesting a benefit of a molecule with both activities. LY2300559 was potent and efficacious in the PPE model following both oral and intravenous administration. LY2300559 had a long duration of effect in the PPE model (18 hours) and was active after five days of dosing. LY2300559 induced a statistically significant, dose-dependent decrease in plasma glutamate levels. LY2300559 did not induce coronary artery contraction in human vessels, nor did the compound significantly alter the contractile properties of sumatriptan.
Conclusions: The effects of LY2300559 in preclinical pharmacology, pharmacokinetic and animal model studies (PPE and neurochemistry), coupled with the lack of vasoconstrictive liability in human coronary artery, led to this molecule being selected for clinical evaluation for the treatment of migraine.
LBP31
Influence of the Type of Primary Headache on the Outcome of Medication Overuse Headache Following Detoxification
M. Allena1, C. Tassorelli1, R. De Icco1, R. Jensen2, Z. Katsarava3, M.J.A. Lainez4, J. Leston5, R. Fadic6, S. Spadafora7, M. Pagani8, G. Nappi1
1Headache Science Center, IRCCS Neurological Institute C. Mondino Foundation, University of Pavia, Pavia, Italy; 2Department of Neurology, Danish Headache Center, Glostrup Hospital, Faculty of Health Sciences, University of Copenhagen, Copenhagen, Denmark; 3Department of Neurology, University of Essen, Essen, Germany; 4Foundation of the Valencian Community, University Clinical Hospital, Valencia, Spain; 5Foundation for Combating Neurological Diseases of Childhood, Buenos Aires, Argentina; 6Dept. of Neurology, Pontificia Catolica University of Cile, Santiago, Chile; 7ISalud University, Buenos Aires, Argentina; 8Bioengeneering and Medical Informatics Consortium (CBIM), Pavia, Italy.
Objectives: To evaluate the influence of the type of primary headache on the outcome of MOH after the detoxification.
Background: Medication Overuse Headache (MOH) results from the chronification of primary headaches, usually migraine (M) and tension-type headache (TTH) or both (MT), as a consequence of the progressive increase in the intake of symptomatic drugs.
Methods: In the multicenter controlled study performed within the Project COMOESTAS1 we enrolled, detoxified and followed up for 6 months 501 MOH patients. Before the enrolment, the primary headache, confirmed by the daily diary, was M in 306 subjects, TTH in 35 subjects, MT in 160 subjects.
Results: At 6-month follow-up, 90.2% of the subjects were no longer overusing acute medications (cured) and 67.5% also reverted to an episodic pattern of headache (responders), while only 7% relapsed in overusing. The percentage of responders was statistically higher in the M group. No significant differences were detected between groups as regards the percentage of cured or responders. The reduction in headache frequency showed a progressive increase from month 1 to month 6 in all groups of patients and, at month 6, it was significantly more marked in the M and MT groups (p<.003), in whom we detected a reduction in headache days of 56.8%, from 22.6±6.1 to 9.3±5 days for M and of 52.6%, from 24.4±5.7 to 11.6±7.5 days for MT. In the TTH group the reduction was of 30.2%, from 28.2±3.1 to 19.7±9.9 days. The frequency of drugs intake was reduced similarly in all groups, by 67% (from 21.75+10.2 to 6.45±3.6 days) in the M group, by 67.6% (from 22.9±6.1 to 7.6±4.8 days) in the MT group and by 68.5% (from 27.1±4.3 to 8.33±9 days) in the TTH group.
Conclusions: Our results indicate a very good prognosis for detoxified patients with a higher rate of responders in migraineurs when compared to TTH and MT patients. It seems that TTH more rarely evolves toward MOH but, when it does, it is more difficult to revert it back to the episodic pattern. Taken together, these findings prove the high efficacy of detoxification in subjects with chronic headache overusing acute medications and they suggest that behavioral factors, associated to the type of original headache, should be taken into account for the outcome of the disease.
LBP32
Metabolic Diet Therapy in the Prophylactic Treatment of Migraine Headache in Adolescents
M.K. Farkas1, E. Mak2, E. Richter2, V. Farkas1
1First Dept. of Pediatrics, Semmelweis University, Budapest, Hungary; 2Dept. of Dietetics and Nutrition Sciences, Semmelweis University, Budapest, Hungary.
Objectives: The objective of our study was to evaluate the efficacy and tolerability of Ketogenic Diet (KD) in the prophylactic treatment of migraine in adolescents.
Background: The high-fat, low-carbohydrate KD is an important treatment option for children with medically intractable epilepsy. Anticonvulsants as topiramate and valproate can be helpful for migraine prophylaxis, however until now there is no accepted prophylactic treatment for pediatric patients. Recent works indicate that several mechanics may exist for the KD including disruption of glutamatergic synaptic transmission, inhibition of glycosis, activation of ATP-sensitive potassium channels and alteration of the mTOR pathway by modifying the brain excitability.
Methods: We have selected patients between the age of 12–17 years over a 3 month period beginning January 2013. The subjects had a minimum of two attacks per month before applying the diet, for at least 1 year. Migraine was diagnosed by IHS-R criteria. A total of 13 children were recruited including 8 females and 5 males. Migraine attack frequency prior to diet and 1, 2 and 3 months after the initiation of KD were compared and the clinical effect of the diet was evaluated. The efficacy was evaluated as completely headache free, markedly effective (attack reduction >75%), effective (reduction >50%) or invalid (reduction <50%). The ratio of fat to carbohydrate plus protein was 3:1. Urine ketones were checked randomly at least twice a week. The KD was started in outpatient care without using a fasting period. The diet was continued for a minimum of 3 months.
Results: Of the total 13 patients 6 discontinued the restrictive diet because of poor compliance (5) and gastrointestinal side effects (1). 7 patients (100%) continued the study for more than 1 month. From those 2 patients (29%) were interpreted as invalid responder and discontinued the diet because of lack of efficacy prior to the 2 months visit. 5 subjects (71%) completed the 3 months study period. At the end of the study no subject became completely attack free. The diet was markedly effective for 2 patients (28%) and effective for 3 patients (43%). During the 3 months period an obvious upper trend in the efficacy was observed.
Conclusions: The compliance of adolescents migraineurs with a restrictive KD is problematic, however at the beginning all of the subjects were open for a non-pharmacological “natural” treatment, moreover most of the patients were additionally motivated by potential weight loss, yet all of them had clinically normal weight at baseline. An obvious improvement in the headache frequency was observed in about 71% of the patients who were able to continue the restrictive diet for the 3 months period. The improvement correlated with the duration of therapy.
LBP33
Web-Based Headache History Questionnaire Produces an Expert Consultation and Searchable, Secure Database
R.P. Cowan1, A.M. Rapoport2, J. Blythe3, B. DeLury4
1Department of Neurology, Stanford University, Stanford, CA, USA; 2Department of Neurology, University of California, Los Angeles, Westwood, CA, USA; 3Computer Sciences, University of Southern California, Los Angeles, CA, USA; 4Rubicon, Los Angeles, CA, USA.
Objectives: To develop a web-based headache history questionnaire which would generate an expert consultation and populate a searchable database.
Background: Databases of headache patient characteristics have been generated via random phone calls followed by semi-structured telephone interviews, mailed questionnaires and individually inputted data of patients. Comprehensive, population based, patient-generated headache history and databases do not exist. We developed a program that allows patients to enter a detailed history via a deidentified , comprehensive questionnaire. We applied ICHD- 2 criteria to develop clinical impressions. An algorithm converts the data into an expert consultation letter to a doctor of the patient’s choice and populates a searchable, secure database.
Methods: A headache questionnaire developed by headache experts (AMR, RPC). using a rule-based engine and branch chain logic, created by an expert in artificial intelligence (JB). Between 58 and 389 data points can be entered by a patient. Output is the basis for a narrative report, clinical impression and the searchable database. Data points and the clinical impressions are stored in tables in a relational database. Data is anonymized within the database, but the questionnaire as answered by the respondent is maintained. Queries can be performed against the data to cross reference the way one or more questions have been answered with the presence of specific clinical impressions. For this study, queries were executed that aggregated positive and negative responses to questions about sleep in light of the presence of each of the ICHD-2 diagnoses in the resulting clinical impression. An earlier study validated the instrument and assessed its accuracy, usability and versatility.
Results: 357 patient histories completed during beta testing by new patients at Stanford’s Headache Clinic were analyzed. The most common clinical impressions were typical aura with migraine headache (MA) (n=39) and migraine without aura (MO) (n=96), probable typical aura withmigraine headache (PMA) (n=23), probable migraine without aura (PMO) (n-124) and chronic migraine (CM) (n=102). These patients were not randomly selected and therefore there is selection bias toward more frequent and severe headaches. To test the database we evaluated 2 screening sleep questions: “Do you sleep well?” and “Do you feel well rested in the morning?”. For MO, 71% were not good sleepers and 63% did not feel well rested. For: PMO: 77% and 69%. MA: 69% and 64%. PMA: 91% and 78%. CM: 82% and 75%.
Conclusions: This study demonstrates that an internet-based program can collect and organize a large set of variables in the headache history directly from the population. Data is searchable and can be mined for research and clinical purposes.
LBP34
Gender Difference Chronic Migraine in Elderly
A. Ozge1, D.U. Uludüz2, M. Selekler3, M. Ozturk4, B. Baykan5, N. Cinar6, F.M. Domaç7, M. Zarifoglu8, L.E. Inan9, A. Akyol10, H.B. Belen11, G.T. Uzuner12, A.K. Erdemoglu13, N. Oksuz14, G.O. Temel15
1Neurology, Mersin University School of Medicine, Mersin, Turkey; 2Neurology, Istanbul University Cerrahpasa Medical School, Istanbul, Turkey; 3Neurology, Kocaeli University Medical School, Kocaeli, Turkey; 4Neurology, Bakirköy Education and Research Hospital, Istanbul, Turkey; 5Neurology, Istanbul University Istanbul Medical School, Istanbul, Turkey; 6Neurology, Maltepe University Medical School, Istanbul, Turkey; 7Neurology, Erenkoy Education and Research Hospital, Istanbul, Turkey; 8Neurology, Uludag University Medical Faculty, Bursa, Turkey; 9Neurology, Ankara Education and Research Hospital, Ankara, Turkey; 10Neurology, Adnan Menderes University Medical Faculty, Aydin, Turkey; 11Neurology, Gazi University Medical Faculty, Ankara, Turkey; 12Neurology, Osmangazi University Medical Faculty, Eskidehir, Turkey; 13Neurology, Kirikkale University Medical Faculty, Kirikkale, Turkey; 14Neurology, Mersin University School of Medicine, Mersin, Turkey; 15Biostatistics, Mersin University School of Medicine, Mersin, Turkey.
Objectives: The main scope of this study defining and differentiating clinical features of chronic migraine in elderly. We also aimed comparing main clinical features of elderly CM with youngers in both gender.
Background: Chronic migraine is a growing important subtype of migraine with different risk factors and clinical features even in elderly relating to gender.
Methods: This study underwent using a data set (Turkish Headache Database) composed from 13 tertiary headache centers in Turkey. Dataset has been included detailed headache defining features according to ICHD-II diagnosis performed by headache specialist. Using according statistical methods clinical variables of CM in elderly have been compared with youngers.
Results: This study included 915 patients with CM (mean age: 43.80±13.95, 83.3 % was female). Totally 301 patients (32.9%) with over 50 years old (elder) compared with 614 patients with (younger) under 50 years old. Generally attack duration is longer in womens (p=0.001) and among them severity of attacks is higher in younger than older patients (p=0.034). Including aura (19.9%) main migraine defining features like nausea is common in younger female patiens than older ones. However younger mens (80.5%) but older womens (86.6%) reported positive family history of headache disorders compared to others.
Conclusions: CM is not only frequent type of migraine but also changes some phenotypic caharacters especially in womens after age 50.
LBP35
Localization of CGRP Receptor Components, CGRP and Receptor Binding Sites in Rhesus Brainstem: A Detailed Study Using In Situ Hybridization and Autoradiography
S. Eftekhari1, R.C. Gaspar2, R. Roberts2, S. Villarreal2, T.-B. Chen3, Z. Zeng3, L. Edvinsson1, C.A. Salvatore4
1Department of Clinical Sciences, Division of Experimental Vascular Research, Clinical Sciences, Lund, Sweden; 2Department of In Vivo Pharmacology, Merck Research Laboratories, West Point, PA, USA; 3Department of Imaging, Merck Research Laboratories, West Point, PA, USA; 4Department of Pain and Migraine Research, Merck Research Laboratories, West Point, PA, USA.
Objectives: A mapping study was performed to identify CGRP receptor mRNA expression and CGRP receptor binding throughout the brainstem of rhesus monkey.
Background: Functional imaging studies have revealed that certain brainstem areas are activated during a migraine attack. Calcitonin gene-related peptide (CGRP) has a key role in migraine pathophysiology and is associated with activation of the trigeminovascular system. The trigeminal ganglion, storing CGRP and its receptor, projects peripherally to the intracranial vasculature and centrally to different regions in the brainstem; this constitutes an essential part of the pain pathways activated in migraine attacks. Therefore it is of importance to identify the regions within the brainstem that process nociceptive information.
Methods: 3 rhesus monkeys (age 13–15 years, male) were used for this study. In situ hybridization was performed to detect calcitonin receptor-like receptor (CLR) and receptor activity modifying protein 1 (RAMP1) mRNA expression. In vitro autoradiography mapping studies were performed on rhesus monkey brainstem. Slices of brainstem were incubated with [3H]MK-3207 (a CGRP receptor antagonist) to define the CGRP receptor binding sites.
Results: CLR and RAMP1 mRNA expression were detected in; medial lemniscus, the pineal gland, medial mammillary nucleus, vagus nerve (10N, centrointermediate), gracile nucleus, solitary nucleus, inferior olive, area postrema, abducens nucleus (6N), central gray and spinal trigeminal nucleus. In addition, CLR and RAMP1 mRNA expression were detected in the spinal cord (ventral and dorsal horn). RAMP1 mRNA expression was also detected around the periaqueductal gray (PAG) area and motor trigeminal nucleus. [3H]MK-3207 showed high binding densities concordant with mRNA expression.
Conclusions: This is the first mapping study demonstrating CLR and RAMP1 mRNA localization and CGRP receptor binding throughout the brainstem of rhesus monkey. The present study suggests that several regions in the brainstem may be involved in CGRP signaling and migraine pathophysiology. Interestingly, we found mRNA expression and antagonist binding in areas that are not protected by the blood brain-barrier, suggesting that CGRP receptor antagonists may not need to be CNS-penetrant to functionally antagonize receptors in these brain regions.
LBP36
Expert Consensus on Acute Migraine Treatment in the ED and Inpatient Settings
C.O. Dougherty1, M.J. Marmura1
1Neurology, Thomas Jefferson University, Jefferson Headache Center, Philadelphia, PA, USA.
Objectives: The goal of this study was to determine the treatment preferences of headache specialists for migraine in the emergency department and during inpatient hospitalization.
Background: Migraineurs often seek acute headache treatment in the ED. In the US, 7% of migraine patients sought ED treatment for severe headache in the previous year, with many patients reporting multiple visits. Patients who are refractory to outpatient management may require inpatient hospitalization. In the US, the economic burden of these visits is significant with estimated costs of ED and inpatient hospitalizations for migraine at $700 million and $375 million respectively.
Despite this burden, there is no consensus on the standard of care for acute migraine management in the ED or during hospitalization. Parental medications available for migraine treatment include dopamine receptor antagonists, ergots, lidocaine, ketamine, non-steroidal anti-inflammatory drugs (NSAIDs), opioids and triptans. These treatments are often used sequentially or in combination. Opioids and barbiturates are commonly used as first line treatment despite the risks of dependence and increased headache recurrence.
Methods: We performed an internet based survey of all American Headache Society (AHS) members. The survey questions were developed by the AHS Special Interest Section for Inpatient and Emergency Care.
Results: There were 106 survey respondents with 83 respondents completing all questions. The most frequent choice for first line ED migraine treatment was dopamine antagonists. The most frequent second line treatments were valproic acid (31.7%), dihydroergotamine (DHE) (28.8%), and NSAIDs (26%). Opioids were chosen by 1% for first line and 4.8% for second line. No respondents selected barbiturate-containing medications for either treatment. Triptans and NSAIDs were the most common choices for outpatient use after ED discharge.
The most frequent medications for initial treatment during inpatient hospitalization for migraine were DHE (64.5%), dopamine antagonists (61.3%), and NSAIDs (37.6%). The most frequent adjunctive treatments were valproic acid (35.5%) and corticosteroids (34.4%). The majority of respondents (71%) indicated they would taper or stop opioid medication as a part of migraine treatment in patients admitted for intractable migraine who were taking opioids for an unrelated indication.
Conclusions: Expert consensus indicates that appropriate treatments for acute migraine in ED include dopamine antagonists, IV hydration and NSAIDs, with the addition of DHE and/or valproic acid for adjunctive treatment. Barbiturate-containing medications and opioids were not recommended for acute ED or inpatient treatment.
1Neurology, Lucus Augusti Universitary Hospital, Lugo, Spain.
Objectives: To analyze the pathophysiological relationship between cluster headache and atrial fibrillation.
Background: Cluster headache is a strictly unilateral excruciatingly severe head pain usually accompanied by autonomic features typically with a circadian and circannual rhythm. It has been suggested that the posterior hypothalamus could play an important role in their pathophysiology. Electrocardiographic abnormalities whithout structural or functional cardiopathy have been described during the pain periods of the trigeminal autonomic cephalalgias. We report a patient who was diagnosed of cluster headache and who complained of palpitations during the episode. Atrial fibrillation was demonstrated with noor other underlying etiology for the arrhythmia.
Methods: A 54-year-old caucasian male with a past history of migraine with aura and cluster headache came to the emergency room for three times with a typical cluster headache crisis accompanied by palpitations. Examination during each of these episodes revealed atrial fibrillation, with a rapid ventricular response rate, which was pharmacologically reverted to sinusal rhytm. Pain relief was achieved with 100% oxygen therapy. No cardiac abnormalities were demonstrated in the echocardiogram and in the electrocardiogram in pain free periods. A routine blood count and biochemistry including thyroid function was also normal. He was diagnosed of paroxystic atrial fibrillation, remaining asymptomatic without treatment between pain attacks.
Results: The pathophysiology of trigeminal autonomic cephalalgias (TAC) has not been completely elucidated. Clinical data such as clockwork regularity of attacks and seasonal recurrence of cluster periods, the presence of hormonal abnormalities, the hypothalamic activation observed during TAC attacks by use of functional neuroimaging, and the success of hypothalamic stimulation as a treatment, confirm that the posterior hypothalamus is crucial in the pathophysiology of these headaches.
Electrocardiographic abnormalities can occur during pain attacks in TAC. Autonomic dysfunction could be the first cause of this phenomenon. Even in the absence of structural cardiac abnormalities or other predisposing factors, it could lead to the emergence of premature auricular beats, potentially triggering paroxystic atrial fibrillation in our patient.
Conclusions: To the best of our knowledge only one case of paroxystic atrial fibrilation during cluster headache attack has been previously reported in the literature. Autonomous nervous system dysfunction with a hypothalamic origin could be the trigger of this phenomena. More studies are needed to link cluster headache, autonomic dysfunction and electrocardiographic abnormalities, such as atrial fibrillation.
LBP38
The Comorbidity Burden of Patients with Cluster Headache
S. Joshi1, E. Loder1
1Departmetn of Neurology, Graham Headache Center, Brigham and Women’s Faulkner Hospital, Boston, MA, USA.
Objectives: To assess the prevalence of selected comorbidities in patients with cluster headache (CH) compared with age and sex matched controls.
Background: Few large, high quality studies have examined the comorbidity burden of patients with CH. A recent web-based survey identified a high prevalence of suicidal ideation in this population, but those surveyed were not clearly representative of CH sufferers in general. Other studies or clinical experts have also suggested a higher prevalence of cigarette smoking or other forms of substance abuse in CH sufferers, although evidence is conflicting. CH patients may also have a higher prevalence than the general population of previous head trauma, peptic ulcer disease and coronary disease.
Methods: We used the Partners Research Patient Data Registry (RPDR) to identify unique patients diagnosed by headache specialists with cluster headache between 2002 and 2012. A set of two age and sex matched controls was obtained for the group of definite cluster headache patients.
Results: Of the initial 155 patients, 75 clearly met criteria for CH (“Definite CH”). 22 patients had headaches with some features of CH but the diagnosis was uncertain (“Unconfirmed CH”). 58 did not meet criteria and were excluded. The average age in the definite CH group at presentation to a specialist was 43 years (range 20–74) and 60/75 (80%) were men. The average number of yearly emergency department and outpatient visits for the group of definite CH patients was 4.5 and 25.4, respectively, compared with 1.1 and 7.3 in the entire RPDR population and 1.1 and 6.9 in age and sex matched controls. 13/75 (17%) of patients with definite CH had depression, compared with 11/152 (7%) of controls. The presence or absence of suicidal ideation was not routinely recorded, but in the 13 patients with definite CH where this was noted, the prevalence of suicidal ideation was 6/13 (46%) compared with 3/5 (60%) of controls. The prevalence of smoking in definite CH patients whose smoking status was recorded was 45/70 (64%) compared with 32/102 of controls (31%). The prevalence of hyperlipidemia, cardiovascular disease and hypertension were not substantially elevated in patients with definite CH compared with controls, but the prevalence of obesity and diabetes were lower. The prevalence of alcohol abuse was 12/75 (17%) in definite CH patients compared with 12/152 (8%) of controls.
Conclusions: Our findings provide high quality information in a representative sample. The pattern of patient characteristics and comorbidities that emerge from our study is remarkably similar to that of the “classic” CH patient: a lean middle-aged male who is more likely than age and sex matched controls to smoke, use or abuse alcohol, and more likely to suffer from depression. CH patients had a high medical burden. We did not find a higher than expected prevalence of cardiovascular conditions, despite the high prevalence of smoking. It is possible that these cardiovascular risk factors are counterbalanced by the low prevalence of diabetes and obesity in this group.
LBP39
Phase 2 Trial of LY2300559 for Treatment of Acute Migraine Headaches
D. Monteith1, R.S. Jones1, S.J. Verfaille1
1Chorus Division, Eli Lilly and Company, Indianapolis, IN, USA.
Objectives: To evaluate the efficacy of a single oral dose of LY2300559 in the acute treatment of migraine compared to placebo, as measured by a 2-hour pain-free response.
Background: LY2300559 is a potent and selective positive potentiator of metabotropic glutamate receptor 2, and an antagonist of the cys-leukotriene 1 receptor. Potentiation of mGluR2 by LY2300559 reduced neurogenic inflammation in dura blood vessels, and could thereby alleviate migraine pain through reduction in excitatory signals, while the CysLT1 receptor could effect proinflammatory response. Agents with combined activity at these targets are anticipated to have beneficial effects in neurogenic-related migraine headaches.1,2,3
Methods: This was a Phase II, multi-center, randomized, double-blind, placebo-controlled adaptive design study to treat patients with moderate or severe migraine headaches, as defined by the diagnostic criteria of the IHS. Eligible patients received a single oral dose treatment for one migraine attack.
A Bayesian statistical algorithm was used to allocate patients to doses that best informed about the efficacy and tolerability of LY2300559. The intent of the randomization was to determine the maximum “success” response (2-hour pain-free and well-tolerated) and the dose-response by allocating patients proportional to the probability of being the maximal dose in efficacy and tolerability to a minimally efficacious dose.
Results: The study was terminated for futility based on the 2-hour pain-free response among 68 subjects. Fifty-three subjects received LY2300559 and 15 subjects received placebo (PBO). No efficacy for LY2300559 was observed for the primary outcome variable of pain–free headache response at 2 hours (hrs). A higher proportion of PBO subjects (33%) than the highest percentage response among LY2300559 subjects (25%) indicated a headache pain-free response at 2 hrs. Evaluating pain-free response or change in headache pain from baseline at any time point did not indicate significantly greater efficacy of LY2300559 over pbo. However, numerical comparison of the response at 4 hrs indicated the high dose of LY2300559 with 78% of patients pain-free compared to PBO of 46% and a trend over time demonstrated possible efficacy. No serious adverse events were reported in this study. No AEs were identified as causally associated with LY2300559. The most frequent AEs were nausea and dizziness that occurred at a frequency of 5.7% in the LY2300559 group and 6.7% in the PBO group, respectively. Doses up to 300 mg of LY2300559 were well tolerated.
Conclusions: LY2300559 was safe and well tolerated in single dose administration; however, it failed to demonstrate efficacy in 2-hour pain free response in an adaptive trial design. However, the data indicated a numeric trend for a response at the high dose at 4 hrs. Reasons for relatively high PBO response rate is not clear, and could have influenced determination of efficacy with treatment.
LBP40
Withdrawn by the author.
LBP41
Systematic Review and Meta-Analysis: Prevalence of Migraine Headache and Its Weight on Neurological Burden in Africa
Objectives: To measure pooled migraine prevalence from available community-based studies in Africa, and compute the weight of migraine on neurological burden.
Background: Despite being the most common neurological complaint worldwide linked with chronic disability and reduction of economic productivity, headache burden is not adequately explored in Africa.
Methods: PubMed search was employed using ‘migraine headache’ and/or ‘headache in Africa’ for published literature from 1985 until March 31, 2013 inclusive. PRISMA guidelines were followed. Fifteen community-based studies with overall prevalence of migraine were included. Pooled prevalence rates were developed using fixed- and random-effects meta-analysis models displayed in forest plots. Disability adjusted life years (DALYs) for migraine and other neurologic disorders in Africa were extracted from Global Burden of Diseases (GBD) 2000, 2002, 2004, 2008, 2015, and 2030 to describe trend for burden of headache disorders throughout the 30-year period.
Results: Pooled random- and fixed-effect meta-analysis models revealed migraine prevalence rate to be 7.57 % (95% CI 5.37 to 10.11) and 6.63 (6.46 to 6.79) (Figure 1), respectively among general population; and 18.59% (10.71 – 28.04%) and 17.92% (16.70 – 19.17%), respectively among high school and medical students. Migraine burden is bound to increase by more than more than 10% within the next decade, with consistent weight on neurological burden.
Conclusions: In Africa, migraine has similar prevalence to that in Caucasian settings. This is further worsened by ongoing low awareness, low information on societal impact, and low quality of medical care delivery at primary-health-cares, and at facilities where lengthy referrals end up. Additional community-based studies can indicate higher burden. Improving access points for early headache management at community-level, developing health infra-structure, training and research at facility-level can help reduce this costly and disabling multi-faceted chronic health problem – whose reduction can in turn help improve economic productivity.
LBP42
Reduced Sleep Quality during the Active Phase of Cluster Headache
M. Barloese1, N. Lund1, A. Petersen1, R. Jensen1
1Department of Neurology, Danish Headache Center, Glostrup, Denmark.
Objectives: We aimed to evaluate self-reported sleep quality in cluster headache patients compared to a number of headache-free controls.
Background: Cluster headache (CH) is a severe chronobiological pain-condition with recurring attacks of high-intensity headache accompanied by autonomic symptoms and agitation. Many attacks occur at night which may directly disrupt sleep but even patients who do not have nightly attacks complain of daytime sleepiness and poor sleep quality as do those who are not in the active disease period. A direct effect on sleep is obvious when attacks occur during the night but how daytime attacks affect sleep is not understood. There is a direct anatomical overlap of regions involved in the pathogenesis of headache and those involved in the regulation of sleep.
Methods: Employing the Pittsburgh Sleep Quality Index we evaluated self-reported sleep quality in 129 patients suffering from CCH and ECH and 50 headache-free controls.
Results: For all CH patients the average PSQI indicated poor sleep quality compared to healthy controls (p<0.01). Comparing CH patients in active bout (attack within past month) with those outside of bout, sleep quality was significantly worse in the active group (p<0.01).
Conclusions: It is possible that headache occurring strictly during the daytime may affect sleep through an unknown pathway. That CH-patients also report poor quality of sleep in the inactive period of their disease suggests that the mechanisms leading to headache are reversible yet those leading to poor sleep quality are not. This may simply be an epiphenomenon or an intrinsic part of the disease mechanism and need further detailed investigations.
LBP43
Childhood Headache Attributed to Airplane Travel: Case Report
K. Rogers1, F. Akor1, S. Jahan1, P. Prabhakar2, M. Ahmed1
1Paediatric, Queen’s University Hospital, London, United Kingdom; 2Paediatric Neurology, Great Ormond Street Hospital, London, United Kingdom.
Background: Airplane headache is a relatively rare form of headache disorder. A recent report identified an increasing number of cases and led to the proposal of diagnostic criteria for this condition. In the literature, airplane headache is reported mainly in adults. A total of three cases within the paediatric age group have been published to date. Here we present a further paediatric case.
Case History: This is an 11 year old neurologically normal girl with a history of episodic migraine referred to our headache clinic with sharp, throbbing, stabbing, severe, unilateral frontal headaches that absolutely occurred during airplane travel. Each headache lasted for less than half an hour and was associated with dizziness and facial pallor. She denied any associated photophobia, phonophobia, nausea, vomiting, olfactory disturbances, autonomic features or any form of aura. There was no history of preceding viral infection, trauma, fever, lethargy or clinical evidence of sinusitis. Consciousness was maintained throughout the attacks and there were no prodromal or postictal phases.
Following a more detailed history, it was discovered that she experienced her first headache whilst on a long haul transatlantic flight. The headache was triggered when the aeroplane took off, it diminished during the flight with only a mild pain persisting, and remerged as the plane began to descend. Her symptoms disappeared shortly after landing. On a separate occasion, she suffered a similar attack during aeroplane descent only. Whilst travelling to Turkey, she experienced a sharp intense headache lasting 10–15 minutes with associated dizziness and pallor that completely and spontaneously subsided on arrival in the airport. Over the last year, she had embarked on a total of three aeroplane flights, on which all, her symptoms had manifested. She additionally reported similar headache attack triggered by a roller coaster ride.
Specialist ENT review did not identify any underlying inner ear pathology or ENT-related cause. Basic biochemical and haematological tests and brain magnetic resonance imaging revealed no abnormalities. Awake electroencephalographic recording showed normal background but intermittent bursts of generalised slow activity. Such abnormality was not associated with headaches or other clinical events.
Comment: Headaches in our patient exclusively occurred during airplane travel and fulfills the diagnostic criteria of airplane headache. This case is unusual in that only a few cases of airplane headache have been reported in children. To our knowledge, this is the fourth case. This case may provide further evidence to strengthen the argument that this unique type of headache should be formally recognised and added to the upcoming revision of the International Classification of Headache Disorders. We review the current literature on this rare syndrome and discuss various proposed pathophysiological mechanisms.
LBP44
Codeine, Increasing Pain & Medication Overuse Headache: The First Evidence of Codeine-Induced Hyperalgesia
J. Johnson1, M. Hutchinson1, D. Williams2, P. Rolan1
1University of Adelaide, Adelaide, SA, Australia; 2University of South Australia, Adelaide, SA, Australia.
Objectives: To determine if chronic codeine induces hyperalgesia to the same degree as chronic morphine & to ascertain if pre-existing glial activation primes for opioid-induced hyperalgesia.
Background: Chronic opioid therapy is associated with increased sensitivity to pain or noxious stimuli, known as opioid-induced hyperalgesia. Opioids are also strongly associated with medication overuse headache & it has been suggested the two conditions may share pathophysiology.
In Australia codeine is available over-the-counter, thus it is used widely in in the self-management of headache. Codeine relies upon partial metabolism (approximately 10%) to morphine to elicit its analgesic effects. Recent evidence indicates morphine can exacerbate pain in the long-term by non-specifically activating the innate immune receptor, toll-like receptor-4 (TLR4), on glial cells, evoking inflammation. Binding simulations suggest codeine also binds to TLR4, signifying it may be able to induce hyperalgesia independent of conversion to morphine. Thus, as greater doses of codeine relative to morphine are required to elicit the same analgesic response, an equipotent dose of codeine could cause significantly greater glial activation & hyperalgesia than morphine.
We hypothesise headache patients are predisposed to worsening headache following opioid use as nociceptive signalling during headache may prime glial cells, leading to increase proinflammatory mediator release when opioids activate TLR4. Evidence that codeine can induce hyperalgesia would sit in line with the hypothesis of glial activation in opioid overuse headache.
Methods: Hyperalgesia & allodynia were assessed using hot plate & von Frey tests respectively, at baseline, day 3 & day 5 in male BALB/c mice receiving intraperitoneal codeine 21 mg/kg (n=8), morphine 20 mg/kg (n=8) or saline (n=8), twice daily. This protocol was repeated in mice that had undergone partial nerve injury surgery to prime glial cells 2 weeks prior. Glial activation will be assessed via western blot analysis of spinal cord & trigeminal ganglion tissue.
Results: Hot plate latency (s) was reduced, indicating hyperalgesia, in codeine (-9.5, CI:4.70-14.34) & morphine (-7.3, CI:2.34–12.32) groups compared to saline at day 5. Following partial nerve injury codeine & morphine groups respectively exhibited reduced hot plate latency at days 3 (-4.4, CI:1.68–7.08 & -4.7, CI:1.99–7.39) & 5 (-3.3, CI:0.55–5.95 & -5.1, CI:2.36–7.76), compared with saline treated mice. An increase in von Frey paw withdrawals, demonstrating allodynia, only reached significance in the morphine group on day 5 of treatment (2.3, CI: 0.55–3.95).
Conclusions: Codeine can induce hyperalgesia, equivalent to that induced by morphine at an equimolar dose, suggesting codeine does not solely rely upon conversion to morphine to increase sensitivity to noxious stimuli. Glial priming leads to earlier development of hyperalgesia post codeine & morphine, supporting the two-hit glial activation hypothesis. Full interpretation will rely upon pharmacokinetic evaluation.
LBP45
Detection of PACAP Receptor Expression in Rat Peritoneal Mast Cells and Dura Mater Using RNA-Sequencing
S.H. Pedersen1, L. Maretty2, J.A. Sibbesen2, A. Krogh2, J. Olesen1, I. Jansen-Olesen1
1Department of Neurology, Danish Headache Center, Glostrup Research Institute, Glostrup Hospital, Glostrup, Denmark; 2Bioinformatics Centre, Department of Biology, University of Copenhagen, Copenhagen, Denmark.
Objectives: We used RNA-seq to investigate expression of three PACAP-receptors (PAC1, VPAC1 and VPAC2) in peritoneal mast cells and dura mater in the rat.
Background: Pituitary adenylate cyclase activating peptide-38 (PACAP-38) has been shown to induce migraine in migraineurs while the closely related vasoactive intestinal peptide (VIP) does not. PACAP has been found to activate three receptors, PAC1, VPAC1 and VPAC2, whereas VIP only acts through the latter two. We previously found that PACAP-38 has a much stronger degranulatory effect on rat peritoneal and dural mast cells ex vivo than the C-terminally truncated version PACAP-27 and VIP. It is known that the PAC1 receptor is present in several splice variants activating various signal transduction pathways involving diverse second messengers. Mast cell degranulation has been associated with migraine attacks and we hypothesize that PACAP-38 induces mast cell degranulation through a splice variant of the PAC1 receptor.
Methods: Peritoneal mast cells and dura mater were isolated from naïve male rats. Total RNA was isolated and RNA-seq libraries prepared using the TruSeq RNA Sample Preparation kit (Illumina). The libraries were sequenced on an Illumina HiSeq 2000 producing a total of 414 million 100 bp, paired-end reads. The RNA-seq data was mapped using TopHat2 (v. 2.0.8) and assembled using both Cufflinks (v. 2.0.2) and the Bayesembler package (manuscript in preparation).
Results: Neither PAC1 nor VPAC1 receptor mRNAs were detected in isolated rat peritoneal mast cells, whereas diminutive levels of the VPAC2 receptor mRNAs were observed. In dura mater, all PACAP receptors were expressed, however the PAC2 receptor was much more abundant than the PAC1 and VPAC1 receptors.
Conclusions: We found neither of the receptors PAC1 nor VPAC1 in mRNA from isolated rat peritoneal mast cells whereas diminutive levels were observed in dura mater. VPAC2 receptor mRNA was observed in dura mater but was hardly pressent in peritoneal mast cells. Our findings suggest that PACAP causes degranulation of peritoneal and dural mast cells through another receptor than PAC1 or VPAC1.
LBP46
Onabotulinum Toxin A for the Treatment of Chronic Post-Traumatic Headache in Service Members with a History of Mild Traumatic Brain Injury
J.A. Yerry1, A.G. Finkel1,2,3, S.C. Lewis1, D.R. Kuehn4
1Brain Injury Medicine, Womack Army Medical Center, Ft Bragg, NC, USA; 2Carolina Headache Institute, Chapel Hill, NC, USA; 3Psychiatry, University of North Carolina, Chapel Hill, NC, USA; 4Research, Womack Army Medical Center, Ft Bragg, NC, USA.
Objectives: To assess the utility of Onabotulinum toxin type A (Botox®) (OBA) in the preventive care of post traumatic headache (PTH) in Active Duty Service Members.
Background: Headache is a common complication of mild traumatic brain injury (mTBI) in active duty service members. Migraine and chronic migraine (CM) type are most common. The approved use of OBA in chronic migraine led us to hypothesize that OBA might be safe and effective in secondary headaches with features of CM.
Methods: Retrospective consecutive case series of mTBI patients treated with OBA for PTH in the Concussion Care Clinic at Womack Army Medical Center, Ft. Bragg, NC 8/2008 to 8/2012. Patient demographics, prior history of headache, injury characteristics, PTSD, and Global Evaluation of Change (GEC) were collected. We assessed and reported predictors of clinical and occupational outcomes including type of injury, headache characteristics and diagnosis, time from injury to injection, and association with a diagnosis of PTSD.
Results: 64 (63 male; mean age 31.3±7.5 years) were treated, 10.9% with a prior history of headache. Most common injuries were: blast (56.3%), parachute jumps (12.5%), and motor vehicle accidents (14.1%). 41.9% were diagnosed with PTSD. 56.3% reported more than one headache type. 75% had continuous headache. Most common diagnoses were Mixed Chronic Tension Type (CTTH)/Chronic Migraine (CM) (50%) and CM (28%).
First injections occurred at 30.9 + 22.0 (1–96) months after mTBI. Mean number of treatments was 3.3±3.8 (1–19). 62.5% were treated according to FDA (FDABTX) approved Chronic Migraine technique. 72.1% reported improvement. 3.1% stopped treatment for side effects.
In patients treated with FDABTX 63.2% with CTTH/CM (continuous) and 85.7% with CM improved (p = 0.32).
Treatment and occupational outcomes were significantly associated with non-continuous headache (p=0.03), time from injury to injection (p = 0.02); and were not predicted by injury type (blast: p = 0.06) or PTSD (p=0.77). OBA did not affect remaining on active duty vs. medical discharge (p= 0.21).
Conclusions: OBA appears to be well tolerated and effective in active duty service members treated for PTH associated with mTBI. Patients with Chronic Migraine (non-continuous) had the best clinical and occupational outcomes. A longer time between injury and injection was a strong predictor of improvement and retention. Blast and PTSD did not predict a negative outcome. These results suggest that patients with long-standing and persistent mTBI associated CM may benefit from treatment with OBA using the standard and FDA approved technique. Further studies of placebo response, efficacy and consistency in this large and unique population are warranted.
LBP47
Withdrawn by the author.
LBP48
Treatment Costs and Complications of Occipital Nerve Stimulation for Intractable Chronic Cluster Headache or Migraine
C. Gaul1,2, O. Müller3
1Migraine and Headache Clinic, Königstein (Taunus), Germany; 2Departement of Neurology, University Hospital Essen, Essen, Germany; 3Department of Neurosurgery, University Hospital Essen, Essen, Germany.
Objectives: To estimate the direct treatment costs due to surgical procedures and complications an analysis was performed in our case series of 27 patients.
Background: After failure of recommend prophylaxis some patients suffering from chronic cluster headache and migraine are refractory. In this situation Occipital nerve stimulation (ONS) has been shown to be effective for selected patients. However, invasive treatment is expensive on the one hand but might reduce burden of disease and illness of the patients on the other.
Methods: Twenty-seven patients with chronic cluster headache (CH) or chronic migraine (CM) underwent a trial phase with bilateral ONS and subsequent implantation of a permanent generator (IPG), if responsive to treatment according to predefined criteria. Procedural and long-term complications as well as direct treatment costs of neuromodulation therapy of ONS were recorded over a mean follow-up period of 20 months (range 5 – 47 months).
Results: The majority of the patients (25 out of 27; 93%) responded to treatment. Twenty-one complications in 14 patients were identified, necessitating reoperation in thirteen cases. This results in per case based cost of 9.445€ for hospitalization and 18.741€ for hardware costs, totaling 28.186€.
Conclusions: ONS for treatment refractory CH and CM is a cost-intensive treatment option with a significant complication rate. Nevertheless, patients with refractory primary headache disorders may experience a substantial relief of pain attacks, and headache days respectively. Cost for ONS are comparable to those of Multiple sclerosis (direct costs: 17,792€/year in Germany) or deep brain stimulation in Parkinsons disease (18,456 € for the initial implantation.
LBP49
The Efficacy and Tolerability of STOPAIN in the Treatment of a Single Migraine Attack
1Jefferson Medical College, Philadelphia, PA, USA; 2Thomas Jefferson University, Philadelphia, PA, USA.
Objectives: Evaluate efficacy and tolerability of menthol 6% gel in treatment of a migraine attack.
Background: Analgesics are used in the treatment of migraine. Menthol’s analgesic properties have led to use for treatment of muscle aches. When applied to the trigeminal area, menthol has been suggested to relieve migraine pain. If effective, it may have rapid onset of action and decreased systemic adverse events.
Methods: This was a single-center, open-label pilot trial of 25 migraineurs. Subjects had episodic migraine w/wo aura; 1 to 10 migraine attacks/month; <15 HA days/month. Subjects treated 1 migraine attack with topical menthol 6% gel applied at occiput within two hrs of headache onset and reported headache severity and associated symptoms pre-dose and at 6 intervals over 24 hrs.
Results: 32 subjects enrolled and 25 completed. Primary endpoint was rate of responders for study gel treatment at 2 hrs post application compared to pre-treatment. Responders were pts with moderate to severe headaches that attain pain relief or with mild headache that became pain free or had no pain progression. A secondary endpoint was headache severity 24 hrs post application. Of the 25 completed pts, 7 had mild pain, 13 had moderate pain, and 5 had severe pain pre-treatment. 7 pts had no pain/pain relief, 7 had mild pain, 6 had moderate pain, and 5 had severe pain 2 hrs after application. 22 pts had no pain/pain relief, 2 had mild pain, 1 had moderate pain, and no pts had severe pain 24 hrs after application. Using ordinal conversion of headache severity, the mean headache severity at pre-treatment = 1.92 (close to moderate pain), at 2 hrs = 1.36 (between mild and moderate pain), and at 24 hrs = 0.16 (very mild pain). The Wilcoxon Signed Ranks Test was used to compare pre-treatment pain severity to severity 2 hrs after application. Of the 25 completed pts, 13 (52%) had improvement in headache pain by at least one severity level, 4 (16%) had worse pain, and 8 (32%) had no pain progression 2 hrs after gel application. Asymp. Sig. (2-tailed) test statistics = .029 indicate that study gel treatment had statistically significant improvement of headache pain severity at 2 hrs after gel application compared to pre-treatment. Of the 25 completed pts, 24 (96%) had improvement in headache pain by at least one severity level, 1 had worse pain, and 0 had no pain progression 24 hrs after gel application. Asymp. Sig. (2-tailed) test statistics = .000 indicate that study gel treatment had statistically significant improvement of headache pain severity at 24 hrs after gel application compared to pre-treatment.
Conclusions: Study results show a statistically significant improvement in headache pain by at least one severity level in 52% of patients;16% of patients had worse pain, and 32% of patients had no pain progression 2 hrs after gel application. This pilot study shows that STOPAIN gel may be effective in the treatment of an acute migraine attack.
LBP50
Preferential Association of Migraine Loci with Migraine Characterized by Specific Traits on a Population Basis
D. Chasman1, M. Schürks2, V. Anttila3, T. Kurth1,4
1Brigham and Women’s Hospital, Boston, MA, USA; 2University Hospital, Essen, Germany; 3Massachusetts General Hospital, Boston, MA, USA; 4Inserm U708 and University of Bordeaux, Bordeaux, France.
Objectives: To explore whether any of 12 genetic loci (SNPs) from a recent genome-wide association study for migraine (Anttila et al., in press) are preferentially associated with migraine characterized by specific traits in a population-based setting.
Background: Migraine may be sub-classified by presence of specific characteristics (e.g. aura, pulsation, unilateral pain, sensitivity to light or sound, nausea, headache of long duration, aggravation by physical activity, inhibition of daily activities). Preferential association between any of the 12 recently identified SNPs and migraine characterized by aura status, other traits, or attack frequency may reflect distinct biological pathways underlying migraine pathophysiology.
Methods: Analysis was conducted in the population-based Women’s Genome Health Study (WGHS), in which 3003 participants reported active migraine compared with 18,108 without, all of whom were female, middle-aged health-care professionals of European ancestry with whole-genome genetic data. Aura status and migraine traits based on IHS classification were ascertained by a validated questionnaire (Cephalalgia [2009] 29:1086). For each of the 12 migraine-associated SNPs, a likelihood-based framework (Hum. Hered.[2011] 72:10) was used to distinguish among six possible alternative modes of differential association with migraine: association regardless of aura/trait, different associations for migraine with and without aura/trait, association only for migraine with or without aura/trait, association with aura/trait among migraineurs, and no association.
Results: In the WGHS, all 12 SNPs showed at least nominal association (p<0.05) with migraine. At significance levels consistent with correction for multiple hypothesis testing, SNPs rs2651899 at the PRDM16 gene and rs12134493 near the TSPAN2 gene were preferentially associated with migraine characterized by specific traits rather than migraine overall. Rs2651899 was associated with migraine characterized by light sensitivity, nausea, aggravation by physical activity, or inhibition of daily activities, while rs12144493 was associated with migraine characterized by unilateral pain, sensitivity to light or sound, or high attack frequency. For example, the effect of the minor allele of rs2651899 was larger (OR [95% CI] =1.16 [1.08-1.23]; p=1.9x10−5) for migraine with light sensitivity (N=1976) than migraine without light sensitivity (N=1027) (OR [95%CI]=1.04 [0.95–1.14]; p=0.35). Both SNPs were specific for migraine rather than non-migraine headache.
Conclusions: Two SNPs were significantly associated with specific traits of migraine rather than overall migraine, suggesting their potential contribution to heterogeneity underlying migraine pathophysiology.
LBP51
Investigating the Expression of the Mechanotransduction Channel Piezo2 in the Trigeminovascular System
L.N. Kimberly1, J.S. Valente1, J.T. Perez1, D. Friston1, J. Chamberlain1, I. Nagy1,2, A.P. Andreou1,2
1Headache Research – Anesthetics, Pain Medicine and Intensive Care Section, Division of Medicine, Imperial College London, London, United Kingdom; 2Pain Medicine, Chelsea and Westminster Hospital, London, United Kingdom.
Objectives: We aimed to investigate the expression of the mechanotransducer Piezo2 in the trigeminovascular system.
Background: It is believed that a key manifestation of headaches is activation, or the perception of activation, of trigeminal afferents which innervate pain-producing intracranial structures, such as the dura mater. Pressure mechanotransduction may be involved directly or indirectly in the pain sensation of some types of headaches, such as in tension type headache. Recently a novel class of pressure channels, the Piezo family, has been described in mammals.
Methods: Immunofluorescence was used to study the distribution of Piezo2 in the trigeminal ganglion, dura mater and trigeminocervical complex. Its relation to CGRP, its receptor subunit RAMP1, as well as to 5HT1B and 5HT1D receptors was investigated. Western blot analysis was used to examine the expression levels of Piezo2 in the trigeminal and dorsal root ganglia, as well as in the trigeminocervical complex and lower lumbar spinal cord.
Results: Piezo2 immunoreactivity was found in 27% of trigeminal neurons, as well as in both thin and thicker fibers in dura matter. Within the trigeminocervical complex, Piezo2 immunoreactivity was observed only in fibers within laminae I and II. Only 7% of Piezo2 expressing trigeminal neurons were CGRP positive, however 40% of Piezo2 expressing neurons were co-localized with the CGRP receptor subunit RAMP1. Furthermore, 40% of Piezo2 positive neurons were also stained for the 5HTIB receptor and 43% with the 5HT1D receptor. Western blot analysis retrieved a slight prevalence of Piezo2 expression in the trigeminal system compared to dorsal root ganglia and lower spinal cord.
Conclusions: The molecule(s), which detect mechanical stimuli at the terminals of trigeminal fibers embedded in the dura mater is currently unknown. Our study suggests that, given the wide distribution of Piezo2 in the trigeminovascular system, this channel may be a candidate molecule for detecting mechanical sensation of the peripheral arm of the trigeminal system.
LBP52
Analysis and Clinical Correlates of Photic Driving at 20 Hz on Routine EEG in Migraine
Y.F. Fogang1, P. Gerard1, V. De Pasqua1, D. Magis1, J. Schoenen1
1Neurology, Headache Research Unit, Liege, Belgium.
Objectives: To analyse photic driving power at 20Hz according to migraine characteristics and to correlate results of visual and spectral analysis.
Background: Photic driving is a time locked occipital cortex response to repetitive visual stimuli at a frequency greater than 5 Hz. Photic driving at 20 Hz (H response) on electroencephalogram is more frequent in migraineurs. Previous studies on photic driving in migraine included a relatively small number of patients.
Methods: We realized a prospective cross sectional study from March 2012 to February 2013 at the Headache Research Unit in Liège-Belgium. We included patients between 18 to 65 year-old consulting for recurrent headaches in a pain-free period with a diagnosis of migraine. Patients with structural brain lesions, epilepsy, dementia, many artefacts on EEG were excluded. Participants underwent an EEG exam including two flash train of photic stimulation at 20 Hz. Visual EEG analysis was done by a skilled neurologist. Driving power was determined by spectral analysis of EEG segments on occipital derivations with the Fast Fourier Transformation application. Visual and spectral analysis were blinded to migraine characteristics.
Results: We included 280 consecutive patients, with 141 visually diagnosed with photic driving (PD), and 139 with no photic driving (NPD). Mean age of participants was 37.20 ± 12.11 years. Male/Female sex ratio was 0.14. Mean migraine frequency was 6.25 ± 7.08 in the PD group versus 10.43 ± 10.71 in the NPD group (p<0.0001). Mean photic driving power was 18.59 ± 34.65 µV2 in the PD group versus 5.42 ± 6.56 µV2 in the NPD group (p<0.0001). There was no correlation between migraine frequency and driving power. However, there was a positive correlation between migraine with aura (r= 0.17, p<0.05), family history of migraine (r= 0.13, p<0.05) and PD power, and a negative correlation with migraine without aura (r=-0.17, p<0.05).
Conclusions: Electroencephalogram visual analysis for H response is a reliable tool. Photic driving power in migraine seems to be linked to a genetic predisposition rather than to disease severity.
