Advertisement

12th European Headache Federation Congress jointly with 32nd National Congress of the Italian Society for the Study of Headaches

Florence, Italy. 28-30 September 2018
Open Access
Meeting abstracts

EHF Invited Speakers

S1 KATP channels

Mohammad Al-Mahdi Al-Karagholi (mahdi.alkaragholi@gmail.com)

Danish Headache Center, Department of Neurology, Faculty of Health and Medical Sciences, University of Copenhagen, Denmark

This abstract was not included as it has been previously published [1].

Reference

[1] Al-Karagholi MAM, Hansen JM, Severinsen J, Jansen-Olesen I, Ashina M. The KATP channel in migraine pathophysiology: a novel therapeutic target for migraine. J Headache Pain. 2017; 18(1):90. doi: 10.1186/s10194-017-0800-8.

S2 The secondary headaches: a cul de sac for the headache expert ?

Christian Lampl (Christian.Lampl@ordensklinikum.at)

Headache Medical Center, Seilerstätte, Ordensklinikum Linz Barmherzige Schwestern, Austria

Background

According to the new ICHD 3 diagnostic criteria a de novo headache occurring with another disorder recognized to be capable of causing it is always diagnosed as secondary. For example, when a new headache occurs for the first time in close temporal relation to trauma or injury to the head and/or neck, it is coded as a “secondary headache attributed to the trauma or injury”. However, it may be possible, that this headache phenomenologically appears to be a primary headache. But, when a pre-existing headache with the characteristics of a primary headache disorder becomes chronic or is made significantly worse in close temporal relation to such trauma or injury, both the initial (primary) headache diagnosis and a diagnosis of “Headache attributed to trauma or injury to the head and/or neck (or one of its types or subtypes)” should be given. In other words, since headache is very prevalent, it can occur simultaneously with another disorder with and without a causal relation. Primary or secondary headache or both – clinically/scientifically spoken a dead end? These entities are a challenging diagnostic problem as can be primary or secondary and the etiologies for secondary cases differ depending on the headache type. Secondary headache can be definitely diagnosed only when solid evidence exists from published scientific studies that the disorder is capable of causing headache. Scientific evidence can come from large clinical studies observing close temporal relationships between the disorder and headache outcomes after treatment of the disorder, or from smaller studies using advanced scanning methods, blood tests or other paraclinical tests.

Conclusion

As all secondary headache disorders can be associated with a wide range of underlying etiologies such as infection, anatomical abnormalities, trauma, and immunological disease or sleep disorders, it is possible that these underlying pathophysiological processes generate long-standing activation of nociceptive mechanisms involved in headache. These can lead to chronification and refractoriness of the headache symptomatology.

References

1. Headache Classification Committee of the International Headache Society (IHS) (2018) The international classification of headache disorders, 3rd edition. Cephalalgia 38:1–211

S3 Hormonal contraceptives: how they impact on migraine course

Simona Sacco (simona.sacco@univaq.it)

Department of Applied Clinical Sciences and Biotechnology, Section of Neurology, University of L’Aquila, L’Aquila, Italy

The role of female hormones in the pathogenesis of migraine is well-recognized [1,2]. Migraine is more prevalent in women than in men, it usually starts after puberty and in many women improves during pregnancy and after the menopause [1,3,4]. The menstrual phase of the female cycle represents a trigger for migraine attacks in many women [1,4]. Additionally, exogenous hormones may change the course of migraine by inducing de novo migraine, inducing de novo aura, worsening previous migraine but also improving migraine particularly those attacks related to menstruation [5,6]. Several attempts were made to manipulate the female hormonal cycle to try to improve migraine. A working group including headache experts, gynaecologists, stroke experts, and epidemiologists developed a first consensus document about the safety of hormonal contraceptives in female migraineurs of reproductive age [7]. Currently, no formal guidelines specifically address hormonal treatment of migraine. A further consensus document was developed by representatives of the European Headache Federation and the European Society of Hormonal Contraceptives and Reproductive Health. The aim of this consensus document is to provide recommendations on the management of migraine with the use of estrogens and progestogens in women of reproductive age. We systematically reviewed data about the effect of exogenous estrogens and progestogens on the course of migraine during reproductive age. Thereafter a consensus procedure among international experts was undertaken to develop statements to support clinical decision making, in terms of possible effects on migraine course of exogenous estrogens and progestogens and on possible treatment of headache associated with the use or with the withdrawal of hormones. Overall, quality of current evidence is low. Recommendations are developed for all the compounds with available evidence including the conventional 21/7 combined hormonal contraception, the desogestrel only oral pill, combined oral contraceptives with shortened pill-free interval, combined oral contraceptives with estradiol supplementation during the pill-free interval, extended regimen of combined hormonal contraceptive with pill or patch, combined hormonal contraceptive vaginal ring, transdermal estradiol supplementation with gel, transdermal estradiol supplementation with patch, subcutaneous estrogen implant with cyclical oral progestogen. As the quality of available data is poor, further research is needed on this topic to improve the knowledge about the use of estrogens and progestogens in women with migraine. There is a need for better management of headaches related to the use of hormones or their withdrawal.

References

1. MacGregor EA (2014) Oestrogen and attacks of migraine with and without aura. Lancet Neurol 3:354-361.

2. Vetvik KG, MacGregor EA (2017) Sex differences in the epidemiology, clinical features, and pathophysiology of migraine. Lancet Neurol 16:76-87.

3. Ripa P, Ornello R, Degan D, Tiseo C, Stewart J, Pistoia F, Carolei A, Sacco S (2015) Migraine in menopausal women: a systematic review. Int J Womens Health 7:773-782.

4. Sacco S, Ricci S, Deagn D, Carolei A (2012) Migraine in women: the role of hormones and their impact on vascular diseases. J Headache Pain 13:177-189.

5. Loder EW, Buse DW, Golub JR (2005) Headache and combination estrogen-progestin oral contraceptives: integrating evidence, guidelines, and clinical practice. Headache 45:224-231.

6. Warhurst S, Rofe CJ, Brew BJ, Bateson D, McGeechan K, Merki-Feld GS, Garrick R, Tomlinson SE (2018) Effectiveness of the progestin-only pill for migraine treatment in women: a systematic review and meta-analysis. Cephalalgia 38:754-764.

8. Sacco S, Merki-Feld GS, Ægidius KL, Bitzer J, Canonico M, Kurth T, Lampl C, Lidegaard Ø, MacGregor EA, MaassenVanDenBrink A, Mitsikostas DD, Nappi RE, Ntaios G, Sandset PM, Martelletti P; European Headache Federation (EHF) and the European Society of Contraception and Reproductive Health (ESC) (2017) HCs and risk of ischemic stroke in women with migraine: a consensus statement from the European Headache Federation (EHF) and the European Society of Contraception and Reproductive Health (ESC). J Headache Pain 18:108

S4 EHF Guidelines on the use of CGRP(r) MAbs in migraine

Simona Sacco (simona.sacco@univaq.it)

Department of Applied Clinical Sciences and Biotechnology, Section of Neurology, University of L’Aquila, L’Aquila, Italy

Great enthusiasm is preceding the marketing of new treatments for migraine prevention which act on the calcitonin gene-related peptide (CGRP) pathway. This offsets the lack of significant novelties in treatment of migraine for many years since in the 80s triptans were marketed. Factors that contribute to the increasing enthusiasm are that those new treatments are, as triptans, migraine specific whereas all the other available preventive drugs were developed for indications other than migraine and have an unclear mechanism of action considering migraine pathophysiology. Poor tolerability and side effects which may particularly troublesome for patients are important limitations of available preventive treatments [1]. Efficacy is not always as expected by patients. Those factors are the main responsible of medication discontinuation and poor adherence which is very often observed with available treatments [2-4]. From a physician perspective, comorbidities limit the possibility of using those drugs in some patients.

We have now, four monoclonal antibodies (mAb) available acting on the CGRP pathway: one targeting the CGRP receptor (erenumab) and three targeting the CGRP peptide (galcanezumab, eptinezumab, and fremanezumab).

The European Headache Federation (EHF) set up a panel of experts to develop evidence-based guideline to clinicians for the management of episodic and chronic migraine with mAb acting on the CGRP or on its receptor. The guidelines included recommendations about safety and efficacy for each of the available drug and suggestions on how to use them in daily clinical practice. Guidelines were developed using the GRADE approach where feasible. Additionally, experts’ suggestions were provided for clinical questions which were considered relevant for the use of mAb acting on the CGRP. Consensus among experts was reached by using the Delphi method.

The EHF on the use of mAb acting on the CGRP will hopefully represent a useful tool for the use of those drugs in the clinical practice. The guidelines will be systematically updated as far as new evidence about those drugs will become available.

References

1. Blumenfeld AM, Bloudek LM, Becker WJ, Buse DC, Varon SF, Maglinte GA, Wilcox TK, Kawata AK, Lipton RB (2013) Patterns of use and reasons for discontinuation of prophylactic medications for episodic migraine and chronic migraine: results from the second international burden of migraine study (IBMS-II). Headache 53:644-655.

2. Berger A, Bloudek LM, Varon SF, Oster G (2012) Adherence with migraine prophylaxis in clinical practice. Pain Pract 12:541-549.

3. Diamond S, Bigal ME, Silberstein S, Loder E, Reed M, Lipton RB (2007) Patterns of diagnosis and acute and preventive treatment for migraine in the United States: results from the American Migraine Prevalence and Prevention study. Headache 47:355-363.

4. Loder EW, Rizzoli P (2011) Tolerance and loss of beneficial effect during migraine prophylaxis: clinical considerations. Headache 51:1336-1345.

S5 Novel Insight into Post Traumatic Headache: Lessons learned from Blast Exposed Civilians

Gal Ifergane (gal.ifergane@gmail.com)

Department of Neurology, Division of Brain Medicine, Soroka University Medical Center, Ben-Gurion University of the Negev, Beer-Sheva, Israel

Although extremely common, Post Traumatic Headache (PTH) deserves little attention in Headache medicine and in research. The strict criteria for PTH, defining its onset less than 7 days from a head trauma and the lack of specific headache phenotype limit the ability to study clinical samples. The limited ability to evaluate traumatic exposure, , and the association of PTH with multi symptom syndromes e.g. Post Concussion Syndrome (PCS) or Post Traumatic Stress Disorder (PTSD), further complicate the study PTH.

We had the opportunity to study the Neuro Psychiatric sequelae in civilians residing next to missile impact sites. This population allows us to define the level of exposure to explosion as direct (participants residing in direct line of sight from the explosion), and indirect (residing in 500m radius of explosion but without direct line to the explosion).

Brain MRI scans of 42 participants with blast exposure (direct or indirect) exhibited significant white-mater diffusion alterations, as compared with 16 non-exposed participants. Notwithstanding, individuals with direct exposure demonstrated differential white matter diffusion characteristics as compared to individuals with indirect exposure.

Clinical evaluation using semi-structured interviews of 289 exposed participants (direct exposure 58, 20%) demonstrated that neither PTSD, nor PCS were associated with the degree of blast exposure. Interestingly, they were associated with the emotional experience of fear and helplessness felt in the explosion.

Active headache was reported by 109 participants (38%) who expressed higher PCS and PTSD symptomatology and poorer sleep quality compared to participants without active headache. Headache phenotype (migraine or tension) and severity were similarly not associated with the degree of blast exposure.

Our data suggests that while MRI diffusion abnormalities are exposure related, headache, as well as PCS and PTSD are not necessarily so, and that the emotional experience plays an important role in its development.

S6 Imaging inflammation in animal models of migraine

Aaron Schain, Agustin Melo-Carrillo, Andrew Strassman, Rami Burstein

Department of Anesthesia, Critical Care and Pain Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA
Correspondence: Aaron Schain (aschain@bidmc.harvard.edu)

Inflammation is likely to have a key role in the pathophysiology of migraine. NSAIDs and anti-inflammatory agents have success in its treatment, and inflammatory molecules such as nitric oxide, CGRP, and cytokines are able to recreate migraine pain. Our lab has shown that cortical spreading depression (CSD), the neural correlate of migraine aura, can activate rodent dural nociceptors. Because CSD is an event that takes place within the brain, yet dural nociceptors lie outside, there must be some chain of events linking the two environments, which likely involves inflammation.

To better understand how inflammation might be involved in CSD’s activation of dural nociceptors, we developed an in vivo imaging strategy that allows us to follow inflammatory processes that begin in the brain and end in the dura. We used a state-of-the-art 2-photon microscope to create three-dimensional images through the lightly thinned skulls of mice that allow us to see all the layers of the meninges and the superficial cortex at cellular resolution. We used genetically modified mice to study the shape and behavior of macrophages and dendritic cells, immune cells that are very sensitive to changes in inflammatory environment, in each meningeal layer before and after propagation of CSD.

We found that both cell types had predictable characteristics that were modified by CSD. Macrophages at baseline had large dynamic phagocytic cytoplasmic extensions that were pulled into the cell body post CSD. This happened first in macrophages within the brain, and 10-20 minutes later with the macrophages outside the brain, on the dura. A subset of dendritic cells was found to be highly migratory at baseline, but stopped immediately post CSD. These cells were able to migrate freely within the subarachnoid space near the pia and the dura. Notably both macrophages and dendritic cells exhibiting these behaviors were found adjacent to or in contact with TRPV1-positive fibers in the dura.

Our findings raise the possibility that activation of immune cells in the pia and dura after CSD may be involved in the activation of meningeal nociceptors, potentially by altering the environment in which nociceptors reside – a condition shown previously as sufficient for activation of nociceptors. Furthermore, our study underscores the ability of in vivo imaging to connect inflammatory processes within the brain to outside the brain.

S7 What have we learned from cellular and circuit mechanisms of the primary brain dysfunctions that cause familial hemiplegic migraine?

Daniela Pietrobon1,2 (daniela.pietrobon@unipd.it)

1Department of Biomedical Sciences and Padova Neuroscience Center University of Padova, 35121 Padova, Italy; 2CNR Institute of Neuroscience, 35121 Padova, Italy

Migraine is much more than an episodic headache disorder. It is a complex brain disorder, characterized by a global dysfunction in multisensory information processing. The headache is associated with one or more symptoms indicating amplification of sensory gain and, in the interictal period, migraineurs show several alterations in sensory information processing. In a third of migraineurs, the headache is preceded by transient sensory disturbances, the so called migraine aura, whose neurophysiological correlate is cortical spreading depression (CSD). In animal studies CSD can activate the trigeminovascular pain network and hence the headache mechanisms. The molecular, cellular and network mechanisms of the primary brain dysfunctions that underlie migraine onset, susceptibility to CSD and altered interictal sensory processing remain largely unknown and are major open issues in the neurobiology of migraine. To tackle these questions we studied the functional consequences of mutations causing familial hemiplegic migraine (FHM), a rare monogenic subtype of migraine with aura, in knock-in mouse models carrying either a FHM type 1 (FHM1) or a FHM type 2 (FHM2) mutation. FHM1 is caused by gain-of-function mutations in the neuronal CaV2.1 channel, a voltage-gated calcium channel that plays a dominant role in controlling neurotransmitter release at brain excitatory and inhibitory synapses. FHM2 is caused by loss-of-function mutations in the glial α2 Na/K-ATPase. Both FHM1 and FHM2 mouse models have a lower threshold for induction of experimental CSD and a higher velocity of CSD propagation. We investigated the mechanisms underlying the facilitation of experimental CSD in FHM1 and FHM2 knock-in mice by studying synaptic transmission at different cortical excitatory and inhibitory synapses and the rates of glutamate and K+ clearance during neuronal activity in slices of somatosensory cortex. We will summarize some of our findings supporting the conclusions that i) excessive cortical excitatory synaptic transmission and excessive activation of NMDA receptors, due either to enhanced glutamate release in FHM1 or impaired glutamate clearance in FHM2, are the main mechanisms underlying facilitation of experimental CSD in the genetic migraine models; ii) the dynamic regulation of the excitatory-inhibitory balance during thalamocortical activity is dysfunctional in FHM1 mice. The data from our genetic migraine models are consistent with the hypothesis that a reduced ability to dynamically maintain an appropriate excitatory/inhibitory balance in specific brain networks may underlie the dysfunctional sensory information processing in migraine and, in certain conditions, may favor CSD ignition and the onset of a migraine attack.

S8 What is the evidence for role of inflammation in migraine? Why do NSAIDs work so effectively in acute treatment

M. Ashina (ashina@dadlnet.dk)

Danish Headache Center, Department of Neurology, Rigshospitalet Glostrup, University of Copenhagen, Denmark

In 1968, the first study linking prostaglandins and migraine pathogenesis was conducted and reported that an intravenous injection of prostaglandin E1 induced a migraine-like headache. The mechanism of action of NSAIDs is primarily inhibition of prostaglandin formation and inflammation. Aspirin and other NSAIDs are widely used drugs for acute treatment of migraine and comparative randomized clinical trials demonstrated efficacy similar to triptans. Preclinical migraine models have suggested that migraine pain is associated with local inflammation in the meninges involving mast cells and subsequent activation of trigeminal nociceptive neurons. However, definitive evidence for inflammation in dura or perivascular space in migraine patients is still lacking.

S9 Emerging targets for treatment – apart from CGRP – PAC1 receptor and PACAP

Luise Haulund Vollesen

Danish Headache Centre and Department of Neurology, Rigshospitalet Glostrup, Faculty of Health and Medical Sciences, University of Copenhagen, Denmark

Pituitary adenylate cyclase-activating peptide-38 (PACAP38), a vasoactive signaling molecule involved in parasympathetic and sensory signaling, belongs to the glucagon/secretin superfamily of peptides and is found in several key structures of interest in migraine pathophysiology such as the trigeminovascular system. PACAP38 provokes migraine attacks in migraine patients without aura. Interestingly, the structurally related vasoactive intestinal peptide (VIP) does not induce migraine. Both PACAP38 and VIP have affinity for at least three different receptors: the VPAC1, VPAC2, and PAC1 receptors. However, PACAP38 shows higher affinity on the PAC1 receptor than VIP. Studies suggested three potential targets of interest in migraine treatment; the PAC1 receptors, PACAP38 itself, or a de novo receptor. An ongoing phase II trial will reveal whether targeting the PAC1 receptor shows clinical efficacy in migraine treatment.

S10 Counting cost: disability and lost productivity

T. J. Steiner (t.steiner@imperial.ac.uk)

Norwegian University of Science and Technology, Trondheim, Norway

Headache disorders are now recognized as the second cause of disability worldwide, after low back pain. Among specific diseases, migraine is top cause in people under 50. Disability, especially during the productive years up to age 50, translates into lost productivity and thence into financial cost, which is very high wherever it has been measured.

Empirical evidence for these statements comes from various sources. Population-based studies estimate headache prevalence. The Global Burden of Disease (GBD) studies multiply population prevalence, mean proportion of time in the ictal state (essentially a product of attack frequency and duration) and a disability weight (DW) reflecting the loss of health attributed, through a very large global consultation, to the ictal state. The result, expressed in years lived with disability (YLDs), is reported as disability but, as a measure of lost health, might more accurately be considered as impairment. A minority of population-based studies have simultaneously reported lost productive time, using measures such as the MIDAS (Migraine Disability Assessment) instrument. These, too, have reported their results as disability, although they better reflect behavioural response to impairment (there is, unless headache is very bad, an element of choice in working or not working with headache). Lost productive time is not a measure of disability, although it might be expected to correlate strongly with disability. However, it is not clear that an independent measure of headache-attributed disability exists.

Whether arising from impairment or disability, and whatever external factors influence it, lost productive time is an important consequence of headache, assumed to reduce output, with financial penalty. It would be helpful to understand the relationships between these.

This presentation takes examples from population-based studies conducted by Lifting The Burden, using individual-participant data obtained contemporaneously to describe symptom severity (impairment), YLDs and lost productive time. Focusing on migraine, it explores the relationships between these variables, and shows that past assumptions may not have been correct. There are implications for cost-effectiveness analyses that value interventions according to their expected impact on indirect financial costs.

S11 The migraine brain is inheritably hyper-responsive

Magis Delphine (dmagis@chuliege.be)

Headache Research Unit, University Department of Neurology CHR, Liège, Belgium

Increased responsivity to environmental stimuli is associated with migraine attacks but is also reported interictally. The way the migraine brain responds to sensory stimuli has been intriguing researchers for a long time. Electrophysiology provides an evaluation of neural responses to different stimuli and thus constitutes one of the most direct methods of sensory processing analysis. Neurophysiological studies demonstrated three functional features of migraine patients compared to healthy controls: habituation modifications, cortical dysexcitability and abnormal functional connexions and circuits within the CNS (chiefly thalamo-cortical dysrhythmia). Whether these (controversial) peculiarities are genetically determined or only result from a favourable environment can be a matter of debate. Both genetic and environmental factors may actually influence the electrophysiological behaviour of each subject and therefore partially account for the differences observed between subgroups. This presentation will review the arguments in favour of an inherited hyperresponsivity of the migraine brain.

S12 Seizure activates the trigeminovascular system differently than CSD: Implications to differences between post-ictal headache and migraine

Agustin Melo Carrillo (amelo1@bidmc.harvard.edu)

Department of Anesthesia, Critical Care and Pain Medicine. Beth Israel Deaconess Medical Center. Harvard Medical School, Boston, MA, USA

Summary

Seizures affect 50 million people worldwide and are followed by headache in up to 50% of patients. These headaches are called Post-Ictal Headaches (PIH), they are commonly migraineous in nature, can last many hours, be very painful and since they strikes repetitively, they drive patients to endure a significant hardship. Given that seizures occur in the cortex, we hypothesized that PIH are intracranial at origin and accordingly, aimed in this study to determine whether and how seizures (both generalized and focal) activate peripheral and central neurons of the meningeal sensory pathway.

Aim of investigation

To investigate the mechanism of post-ictal headache.

Methods

Single-unit electrophysiological techniques were used to study the physiological properties and response profile of C- and Aδ meningeal nociceptors and high-threshold (HT) and wide-dynamic range (WDR) neurons in the spinal trigeminal nucleus – in response to occurrence of seizure underneath their dural receptive fields. Cortical electrodes were used to trace the magnitude, extent and progression of epileptiform seizure.

Results

The induction of seizure triggered prolonged activation in both meningeal nociceptors and central trigeminovascular neurons. In the ganglion, activity began to increase minutes after the seizure reached their receptive fields and remained elevated for as long the seizure activity continued. In the medullary dorsal horn, neurons exhibited a biphasic response following seizure onset that consisted of an initial inhibition of the spontaneous activity followed by a gradual increase in activity that remained above baseline for at least 2 hours after seizure onset. In separate experiments, we created a focal seizure that was restricted to either the parietal or occipital cortex. Induction of focal seizure in the parietal cortex did not produce any changes in neuronal activity, but induction of focal seizure in the occipital cortex produced the same neuronal changes that we observed with the generalized seizure.

Conclusions

This study provides evidence for activation of the trigeminovascular pathway by generalized and focal seizures. The importance of this study is that it uses a model of abnormal cortical activity to which there are ample of evidence in human subjects suffering epilepsy (and PIH), and thus, it bypass the bitter debate over the validity of studying the headache phase of migraine using the controversial cortical spreading depression model – to which evidence for actual occurrence in humans are scarce.

Acknowledgments

NIH Grant: RO1-NS094198.

S13 Cortical Spreading Depression as a trigger for migraine headache

Rami Burstein

Department of Anesthesia and Critical Care, Beth Israel Deaconess Medical Center

Cortical spreading depression (CSD) has long been implicated in migraine attacks that begin with visual aura. Over the years, it was hotly debated whether aura can trigger a headache. This lecture will focus on data that show that a single wave of CSD can trigger long-lasting activation and sensitization of peripheral and central trigeminovascular neurons in 2 manners. In the first, neurons become activated 10-40 minutes after occurrence of CSD and in the second they become activated immediately. These findings will be discussed in the context of the headache and the possible role activation of peripheral trigeminovascular neurons play in migraine chronification.

The process by which CSD, a cortical event that occurs within the blood brain barrier (BBB), results in nociceptor activation outside the BBB is complex and likely mediated by multiple molecules and cells. This lecture will also present up-to-date data on the possible mechanisms and processes that occur between the cortical aura and the nociceptor activation.

S14 Migraine onset in childhood is a genetic disease

Andrew Hershey (Andrew.Hershey@cchmc.org)

Cincinnati Children’s Hospital Medical Center, 3333 Burnet Avenue, MLC 2015, Cincinnati, OH 45229,USA

Migraine has long been noted to “run in families.” Studies have suggested a strong familial pattern that is influenced by environmental contributions. In this talk, I will review the population genetic studies suggesting migraine as a genetic condition, including family and twin studies. These observations have been further advanced by genetic tools including genome wide association studies (GWAS), individual gene identification studies – especially for hemiplegic migraine, polymorphism identification, and more recently by whole exome sequencing. This can be combined with genomic expression to identify pathways that contribute to the genetic lode and the phenotypic development of migraine. All these techniques and their stages in leading to the understanding of migraine as a genetic disease will be discussed.

S15 Providing care: Cost-effective and affordable

Michela Tinelli (m.tinelli@lse.ac.uk)

Personal Social Services Research Unit, London School of Economics (LSE), Houghton Street, London WC2A 2AE, UK

Introduction and objectives: Headache disorders are real illnesses, often causing lifelong disabilities. Migraine, tension-type headache (TTH) and medication-overuse headache (MOH) are of major public-health importance: collectively, they are the 2nd highest cause of disability in populations throughout the world, leading to much lost productivity and very high indirect costs (>€100 billion per year in EU). The Value of Treatment (VoT) Project is a timely and ground-breaking initiative of the European Brain Council (EBC) in collaboration with the LSE, Lifting The Burden (LTB), European Headache Federation and other partner institutions. It argues that optimizing interventions in brain disorders can bring not only positive outcomes for patients but also economic gains for society. As part of the VoT project, the headache economic case study estimated cost/effectiveness of implementing structured headache services (SHSs) based in primary care and supported by educational initiatives aimed at both patients and health-care providers.

Methods: We modelled cost-effectiveness of SHSs delivering treatments for each of the headache types (migraine, TTH, MOH), with efficacy known from randomized controlled trials. Three health-care systems – of Russia, Spain and Luxemburg – brought different experiences of health service delivery and financing into the model. We made annual (short-term) and 5-year cost estimates from health-care provider and societal perspectives (2017 figures, euros). We expressed effectiveness as healthy life years (HLYs) gained, and cost-effectiveness as incremental cost-effectiveness ratios (ICERs) (cost to be invested/HLY gained).

Results: In short-term modelling from the health-care provider perspective, the intervention is cost effective overall and across headache types – well below WHO framework thresholds. Over 5 years, the intervention is even more cost effective. Results are consistent across health-care systems. From the societal perspective, the intervention is not only cost-effective but also cost-saving over 1 year and 5 years, for all types of headache and across health-care systems. The greater the country’s wage levels, the greater are the economic savings for society (Luxemburg > Spain > Russia).

Discussion: For the first time, the effectiveness and cost effectiveness of introducing hypothetical SHSs in Europe was evaluated across health-care systems. Our results study showed that such services, based in primary care and supported by patient and provider education, are effective and cost-effective solutions to headache disorders and the disability they cause. From the health-care provider perspective, cost-effectiveness is least (ICERs greatest) for TTH because of its much lower disability weight compared with those for migraine and MOH. In practice, structured headache services will not discriminate: they must manage all headache types; however, people with TTH are least likely to require them.

Acknowledgments

This study was part of the EBC-led Value of Treatment Project. The headache economic study team included Michela Tinelli *1, Timothy Steiner*2, Matilde Leonardi3, Dimos Mitsikostas4, Koen Paemeleire4, Elena Ruiz de la Torre5,6. 1The London School of Economics and Political Science; 2Lifting The Burden; 3European Brain Council (EBC) WHO Liaison; 4European Headache Federation; 5European Federation of Neurological Associations (EFNA); 6European Headache Alliance (EHA). *These authors contributed equally.

S16 Expression of CGRP family of neuropeptides in the trigeminal system

Lars Edvinsson1,2, Karin Warfvinge1,2

1Departments of Internal Medicine, Lund University Hospital, Lund, Sweden; 2Department of Clinical Experimental Research, Copenhagen University Hospital, Glostrup, Denmark.
Correspondence: Lars Edvinsson (lars.edvinsson@med.lu.se)

Background. The calcitonin gene-related peptide (CGRP) family of neuropeptides consists besides CGRP of adrenomedullin, amylin and calcitonin (CT). They share receptor components and structure, and have several similar biological actions. The receptors consist of either calcitonin receptor like-receptor (CLR) or calcitonin receptor (CTR) which for function needs an accessory protein, receptor activity-modifying proteins (RAMPs). These define the receptor subtype and can interact and produce different effects via signal transduction and receptor trafficking. It is by now well known that CGRP has a pivotal role in primary headaches but the role of the other members of the CGRP family of peptides and their receptors is not known. Here, we describe the expression of these molecules in the trigeminal ganglion (TG) to understand the role they may have in headaches.

Methods. Single or double immunohistochemistry were applied on frozen sections of rat trigeminal ganglia using primary antibodies against CGRP, adrenomedullin, amylin, CT, RAMP1/2/3, CLR and CTR.

Results. CGRP and CT showed similar results with expression in TG small to medium-sized neurons. Immunoreactive fibers were also found. Adrenomedullin immunoreactivity was found in the satellite glial cells (SGC) and on the fibers, probably staining of the myelinating cells. Amylin was found in the cytoplasm in many TG neurons and in some SGC.

When it comes to the receptor components, many large neurons showed immunoreactivity to both CLR and RAMP1, and also to fibers, most likely neuronal processes. In addition, SGCs were immunoreactive to the two receptor components. RAMP2 and RAMP3 were expressed in all nuclei. CTR was found in almost all cells, both neurons and SGCs.

Conclusion. Several of the diverse biological actions of the CGRP family of peptides are clinically relevant. Our findings demonstrate the specific ligand and receptor sites in the rat TG, highlighting recognition mechanisms to facilitate drug development.

Key words. CGRP peptides family, ligands, receptors

S17 Managing secondary headaches with a multimodal expertise

Henrik Winther Schytz (henrikschytz@hotmail.com)

Danish Headache Center, Department of Neurology, Rigshospitalet Glostrup, Denmark

Secondary headaches are often a huge challenge to clinicians at all levels and there is a general lack of evidence-based managment of secondary headaches. At the Danish Headache Center 30 % of the patients treated suffer from secondary headaches with medication overuse headache being the most frequent. The lecture managing secondary headaches with a multimodal expertise will present the approach to managing secondary headaches such as medication-overuse headache, post-traumatic headache, headache attributed to spontaneous intracranial hypotension and headache attributed to idiopathic intracranial hypertension. Perspectives on how to approach the patient in tertiary headache center will be presented as well.

S18 Hormonal contraceptives in women with migraine: pros and cons

E. Anne MacGregor (anne@annemacgregor.com)

Barts Health NHS Trust, London UK

Since migraine is most prevalent during women of reproductive age, many women with migraine will be using contraception. Further, since some migraine medication is contraindicated in pregnancy, for women with migraine using such medication, it is important that contraception is highly effective and does not adversely affect migraine. Indeed, irrespective of the need for contraception, several contraceptive strategies may also benefit migraine, particularly for women who experience exacerbation of migraine perimenstrually. Menstruation is associated with two independent migraine triggers – estrogen ‘withdrawal’ which typically occurs premenstrually, and prostaglandin release, often associated with menorrhagia and/or dsymenorrhoea. Understanding how the different methods of hormonal contraception affect either one, or both, of these potential mechanisms is useful for management.

Hormonal methods are the most popular methods of contraception and include combined hormonal contraceptives (combined oral contraceptives [COC], contraceptive vaginal ring [CVR], and combined transdermal patch [CTP]) and progestogen-only methods (progestogen-only pill [POP], subdermal implant [SDI], intramuscular/subcutaneous depot medroxyprogesterone acetate [DMPA], and levonorgestrel intrauterine system [LNG-IUS]), all of which, with the exception of DMPA, are immediately reversible.

Combined hormonal contraceptives contain estrogen, usually synthetic ethinylestradiol, and a progestogen. The addition of ethinylestradiol provides greater ovarian suppression and better cycle control than progestogen-only methods, although the incidence of breakthrough bleeding increases as the dose of ethinylestradiol is reduced. The older first- and second-generation progestogens, derived from testosterone, tend to exhibit androgenic actions, counterbalancing the estrogenic activity. Newer third- and fourth-generation progestins have been designed to have neutral androgenic or estrogenic actions. Traditional regimens include a 7-day contraceptive-free interval (CFI) following 21-days of hormones in order to mimic a monthly menstrual bleed. Hormone ‘withdrawal’ can also occur during hormone treatment as recruited follicles undergo atresia, resulting in a drop in endogenous estradiol levels. Continuous or extended regimens with a shorted CFI have the potential to reduce the frequency and severity of estrogen-withdrawal symptoms.

The desogestrel POP and implant inhibit ovulation but do not predictably inhibit ovarian activity. This can result in fluctuating estrogen levels and unscheduled bleeding. DMPA inhibits ovarian activity and bleeding, although it can take 6-9 months before bleeding is fully suppressed. The LNG-IUS allows the normal menstrual hormone cycle fluctuations but maintains a thin endometrium, reducing menstrual blood loss and prostaglandin release.

The efficacy, risk and non-contraceptive benefits of each of these methods will be discussed.

S19 Cortical spreading depression as mechanism of the migraine aura: new mechanisms

Martin Lauritzen (martin.johannes.lauritzen@regionh.dk)

Department of Clinical Neurophysiology, Rigshospitalet and Institute for Neuroscience, University of Copenhagen, Glostrup, DK-2600, Denmark

Cortical spreading depression and depolarization waves (CSD) are associated with dramatic failure of brain ion homeostasis, efflux of excitatory amino acids from nerve cells, increased energy metabolism and changes in cerebral blood flow (CBF). There is strong clinical and experimental evidence to suggest that CSD is involved in the mechanism of migraine, stroke, subarachnoid hemorrhage and traumatic brain injury. The implications of these findings are wide-spread and suggest that intrinsic brain mechanisms have the potential to worsen the outcome of cerebrovascular episodes or brain trauma. The consequences of these intrinsic mechanisms are intimately linked to the composition of the brain extracellular microenvironment and to the level of brain perfusion and in consequence brain energy supply. This presentation summarizes the evidence provided by novel experiments in rodents using twophoton microscopy imaging which reveal new mechanisms of CSD of importance for our perception of CSD as a pathophysiological mechanism of migraine and for a group of acute neurological disorders. Specifically, the talk will summarize new mechanisms that implicates involvement of organelles in neurons and the cortical microcirculation at the level of brain capillaries in CSD. The findings are likely to have implications for how we understand migraine with aura and for new strategies for migraine treatment.

S20 Pain regulation by non-neuronal cells and inflammation

Ru-Rong Ji (ru-rong.ji@duke.edu)

Center for Translational Pain Medicine, Departments of Anesthesiology and Neurobiology, Duke University Medical Center, Durham, North Carolina, 27710, USA

Acute pain is protective and a cardinal feature of inflammation. Chronic pain after tissue and nerve injury is detrimental and associated with chronic inflammation. Accumulating evidence suggests that non-neuronal cells such as immune cells and glial cells play active roles in the pathogenesis of pain via neuron-immune and neuro-glial interactions. Neuroinflammation, as characterized by infiltration of immune cells, activation of glial cells, and production of inflammatory mediators in the peripheral and central nervous system, plays an important role in the induction and maintenance of chronic pain. I will discuss distinct roles of inflammation, neurogenic inflammation, and neuroinflammation in the induction and maintenance of pain including headache. I will also discuss how macrophages and specialized pro-resolving mediators promote the resolution of inflammation and pain.

S21 Occipital Migraine and the Cerebellum

Rodrigo Noseda, Rami Burstein

Department of Anesthesia, Critical Care & Pain Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston MA, USA
Correspondence: Rodrigo Noseda (rnoseda@bidmc.harvard.edu)

The neural substrate of occipital headache in migraine and other headaches is little understood. In theory, this type of headache could emerge extracranially from tension, stiffness or tenderness in neck and shoulder muscles or intracranially from activation of meningeal nociceptors in the dura overlying the cerebellum, of the posterior fossa. That the cerebellum is affected in migraineurs is convincingly demonstrated by multiple imaging studies showing altered activation and connectivity of the cerebellum in the migraine brain. Yet, little is known about the role it may play in the initiation of headache. Anecdotally, patients whose migraine headaches involve mainly or exclusively the occipital region appear to experience vertigo – a symptom attributed mainly to the cerebellum – more than patients whose migraine are restricted to the periorbital and frontal regions of the head. Given the above scenario, we sought to identify the anatomical origin and trajectory of the sensory innervation of the cerebellar dura, characterize the functional properties of neurons processing nociceptive input from this area, and determine their susceptibility to activation and sensitization by inflammatory agents.

In this presentation, we will revisit current understanding of the causes of occipital headache, discuss potential pathological scenarios for its occurrence, and provide anatomical data obtained in the rat that shows in unprecedented detail the nerve trajectories and terminal sensory innervation of the intracranial dura overlying the cerebellum by C2-3 upper cervical DRGs. We will also provide electrophysiological data from central neurons processing nociceptive input from the posterior dura under experimental pathological conditions. These novel anatomical and functional data will be discussed in the context of occipital migraine.

S22 The migraine brain is not hyper-responsive

Trond Sand1,2 (trond.sand@ntnu.no)

1Department of Neuromedicine and Movement Science, Faculty of Medicine and Health Sciences, NTNU - Norwegian University of Science and Technology, Trondheim, Norway; 2Department of Neurology and Clinical Neurophysiology, St. Olavs hospital HF, Trondheim University Hospital, 7006, Trondheim, Norway

Obligatory and common symptoms like phonophobia, photophobia and allodynia clearly suggest neural hypersensitivity during a migraine attack. Reliable premonitory symptoms like photophobia are also reported in the preictal phase 24 hours before headache. However, the variety of migraine triggers is huge, and the most reliable triggers are unspecific like “sleep” and “stress”. Hence, even from a clinical viewpoint it is more uncertain if an interictal CNS-hyper-responsitivity exists.

The extremely well-known theory about “deficient interictal CNS-habituation in migraine” has regretably not been confirmed in fully blinded visual evoked potential (VEP) studies, neither in Norway nor in the Netherlands. It is of course very important to blind both recording and analysis to achieve a reliable confirmation of initial and preliminary evidence.

Another measure of CNS-hyperexcitability is transcranial magnetic stimulation (TMS). Again, results from TMS-studies in migraine are widely divergent, although this variability is often neglected in the literature. Also,TMS is not a natural sensory stimulus, and the method does not convey information about “responsitivity” defined as a sensory stimulus-response function.

Different modalities may have different excitability and responsitivity. It will be of great interest to test if thalamocortical somatosensory excitability changes, measured with somatosensory evoked potential (SEP) and pain evoked potential methods can be confirmed to be abnormal also with fully blinded methodology. It is also of great interest to use other EEG-based methods like event-related synchronization/desynchronization to confirm if frequency.specific rhythm responsivity is abnormal in interictal and preictal phases.

The simplistic idea about a general hyper- or hypo-responsitivity for the whole brain should be abandoned. Instead, it is likely that states of hypo-, normal, and hyper-excitability occur in succession and differs among various brain networks. Indeed, excessive variability within and between different networks may be hypothesized as the most probable abnormality in migraine. Another challenge is to identify new methods that are able to reliably measure stimulus-response functions in different CNS network subsystem in humans.

S23 MRI studies can predict progression of disease years before it occurs

Roberta Messina, Maria A. Rocca, Massimo Filippi

Neuroimaging Research Unit, Institute of Experimental Neurology, Division of Neuroscience, San Raffaele Scientific Institute, Vita-Salute San Raffaele University, Milan, Italy
Correspondence: Roberta Messina (messina.roberta@hsr.it)

Over the last two decades, a series of neuroimaging studies has changed the way we understand the pathophysiology of migraine. Conventional and advanced magnetic resonance imaging (MRI) techniques have been applied extensively to the study of migraine patients, both in the course of an acute attack and during the interictal phase. It is now accepted that migraine should be viewed as a complex brain network disorder that involves multiple cortical, subcortical and brainstem regions, rather than a purely vascular disorder.

Numerous studies have consistently demonstrated that patients with migraine experience not only abnormalities of function but also important and distributed structural abnormalities of the brain gray matter (GM) and white matter (WM). In particular, a selective involvement of key brain regions and networks involved in multisensory processing, including pain, has been shown to occur in the brain of migraineurs. Whether such alterations represent a predisposing trait or are the consequence of the recurrence of headache attacks is still a matter of debate. Many studies have indicated that structural brain abnormalities in migraineurs might be dynamic, since they differ according to the migraine phase, attack frequency and disease duration. Recent longitudinal studies revealed that the migraine brain changes over time and different pathophysiological mechanisms are associated to disease severity. Other investigations have shown morphometric alterations that are not influenced by migraine patients’ clinical characteristics and revealed that GM volume abnormalities are detectable from the early stages of the disease, thus representing a potential migraine biomarker.

Numerous conventional MRI studies have also described an increased risk of harbouring brain WM hyperintensities in patients with migraine, that might be influenced by headache frequency, disease duration and the presence of aura. All of this is critical not only to improve the understanding of migraine pathophysiology, but also to develop imaging biomarkers to be applied in treatment trials of new experimental drugs.

S24 Three dimensional approch for DDI evaluation in Precision Medicine

Leda Marina Pomes1, Giovanna Gentile2, Maurizio Simmaco2, Marina Borro2, Paolo Martelletti3,4,5,6

1Residency Program in Laboratory Medicine, Gabriele d’Annunzio University, Chieti, Italy; 2Department of Neurosciences, Mental Health and Sensory Organs, Sapienza University, Rome Italy; 2Department of Clinical and Molecular Medicine, Sapienza University, Rome Italy; 3Residency Program in Internal Medicine, Sapienza University, Rome, Italy; 4Master in Headache Medicine, Sapienza University, Rome, Italy; 5Internal Medicine and Emergency Medicine Unit, Sant’Andrea Hospital, Rome, Italy; 6Regional Referral Headache Center, Sant’Andrea Hospital, Rome, Italy
Correspondence: Paolo Martelletti (paolo.martelletti@uniroma1.it)

The evidence of multiple comorbidities in migraine population, especially at cardio-cerebrovascular, psychiatric, metabolic and musculoskeletal levels, has led to an increase in the observation in clinical practice of patients undergoing multiple pharmacological therapies. The use of different drugs in the same migraine patient significantly increases the risk of potentially serious adverse events (AEs). As a consequence, the development and implementation in clinical practice of precision medicine addresses this increased clinical risk, allowing to evaluate in advance the possible drug/drug interactions (DDIs) and guiding the clinical prescription and monitoring. We have also to consider that in a real-world scenario each migraine patient might also suffer from other (episodic or chronic) not comorbid pathologies that require additional therapies. These adjunctive treatments may result in additional DDIs and AEs risking to produce a decrease in the clinical efficacy of prescribed drug(s).

The evidence of daily polypharmacy (≥5 different drugs) in headache patients have been recently reported in a large cross-sectional study and this misuse occurs in 40.7% of this cohort. The chronic headache patients’ subset of this cohort reached an awesome 58.8% for ≥5 drugs and 5% for ≥10 drugs administration at the same time.

Considering these complex drug-drug cross-interactions the application of personalized medicine can help the clinician to evaluate the individual profile of the subject and according to it to proceed to a specific therapeutic strategy not competing with the same metabolic pathway.

The more drugs are present in the polytherapy, the more possible interactions are established. Notably, these kind of DDIs are largely predictable using open source, knowledge-based reporting the ADME profile for each drug. A useful one is Transformer (http.//bioinformatic.charite.de/transformer), which provides information on DDIs based on drug transport and metabolism of over 3000 drugs and more than 350 foods and supplements. Transformer analyzes an input drug list comparing the interactions (substrate, induction or inhibition) existing between each drug and different metabolic enzymes and, through a color code, highlights potential unfavorable DDIs; furthermore, through a drop-down menu, it allows to compare the metabolic route of equivalent drugs on the same screen, providing a tool to make an alternative prescription choice. Another web – based database that provides updated information about drug specific ADMEs proteins (enzymes and transporters) and the pharmacological interactions that can occur in polytherapies is DrugBank (http://www.drugbank.ca/). It returns information about the metabolism and mechanism of action of 10523 molecules with pharmacological action.

As pharmacogenomics sciences revealed that genes encoding many important DMEs are characterized by the presence of functional polymorphisms affecting the enzyme activity level and thus the expected PKs profile of drugs interacting with such enzymes, this genomic information started to be used to adjust the prediction of drug safety and tolerability made using a simple DDIs checker.

S25 The EMA-EHF Documento for migraine

Efstratia Vatzaki1*, Sabine Strauss2, Jean-Michel Dogne3, Juan Garcia Burgos1, Thomas Girard1 and Paolo Martelletti4

1European Medicine Agency, London, UK; 2Medicines Evaluation Board, The Netherlands; 3Head of the Department of Pharmacy, Namur Thrombosis and Hemostasis Centre - Narilis University of Namur, Belgium; 4European Headache Federation, Rome, Italy
Correspondence: Efstratia Vatzaki (Efstratia.Vatzaki@ema.europa.eu)

Migraine is a common and burdensome neurological condition which affects mainly female patients during their childbearing years. Valproate has been widely used for the prophylaxis of migraine attacks and is also included in the main European Guidelines. Previous (2014) European recommendations on limiting the use of valproate in women of childbearing age did not achieve their objective in terms of limiting the use of valproate in women of child bearing age and raising awareness regarding the hazardous effect of valproate to children exposed in utero. The teratogenic and foetotoxic effects of valproate are well documented, and more recent studies show that there is an even greater neurodevelopmental risk to children exposed to valproate in the womb. The latest 2018 European review from the European Medicines Agency, with the active participation of the European Headache Federation, concluded that not enough has been done to mitigate the risks associated with in utero exposure to valproate. The review called for more extensive restrictions to the conditions for prescribing, better public awareness, and a more effective education campaign in migrainous women.

Keywords: migraine prophylaxis, valproate, pregnancy, teratogenic risk, foetotoxic effect, neurodevelopmental retard, pregnancy prevention programme, clinical recommendations, education, public awareness.

S26 Precision medicine general concept in clinical pratice

Marina Borro, Giovanna Gentile, Maurizio Simmaco

Department of Neurosciences, Mental Health and Sensory Organs, Faculty of Medicine and Psychology, Sapienza University of Roma and Sant'Andrea Hospital of Rome, Laboratory of Clinical Biochemistry
Correspondence: Maurizio Simmaco (maurizio.simmaco@uniroma1.it)

Inefficacy/safety of pharmacological treatment remain main challenges for healthcare systems. The biological inter-individual variability in drug response is a multi-factorial phenomenon modified by both static factors, as the genomic background, and by dynamic factors, as ageing, life-style, environment. Furthermore, polypharmacy presents the peculiar risk of drug-drug interactions which could alter the drug pharmacokinetics and pharmacodynamics, causing adverse effects or low response.

The personal genomic profile is a “static” contributor of the expressed phenotype, which is determined by a plethora of dynamic factors. The advent of modern technologies, as Next Generation Sequencing and mass spectrometry, has allowed to deeply characterize genomic profiles as well as molecular signatures that are a clue to define more exactly the clinical phenotype of the patient.

We developed a strategy aimed to make actionable the clinical use of genomics and other molecular signatures. The foundation of this strategy is the high-level integration of molecular data with clinical and environmental data. Taking advantage from a multi-disciplinal environment, a new cultural model in medical practice has taken root at the Sant’Andrea Hospital of Rome, allowing step by step establishment of a patient-centered care model, embedded in the workflow of the Italian National Health System.

S27 Correlation of migraine attacks with neck pain and tension

E Anne MacGregor1, Stephen Donoghue2, Marina Vives-Mestres2

1Barts Health NHS Trust, London UK; 2Curelator Inc., Cambridge MA, USA
Correspondence: E Anne MacGregor (anne@annemacgregor.com)

Background: Neck pain associated with migraine attacks is common and usually first noticed close to time of headache onset [1,2]. However, because it can occur prior to headache, it can be perceived as a migraine trigger. We used a digital platform (Curelator Headache®) to determine 1) how many individuals suspect neck pain/tension as a migraine trigger and 2) for how many individuals an association between neck pain/tension and migraine attacks can be identified statistically.

Methods: Individuals with migraine registered to use Curelator Headache® (now called N1-Headache®) and answered questions about which factors they suspect contribute to attack occurrence, including neck pain/tension, and rate their importance (0=none; 10=maximal). They then used Curelator Headache® daily for 90 days, entering details of headaches and factors possibly associated with attack occurrence: presence of neck pain/tension was determined by a Yes/No response to the daily question ‘Did you notice neck pain or tension (today)?’. After 90 days all factors were analyzed and for each individual the association between neck pain/tension and migraine attacks was determined via a univariate Cox proportional hazard model [3] using a) all data and b) relating attack occurrence with previous day neck pain data (lagged analysis).

Results: Table 1 shows statistical associations between neck pain/tension and attack risk according to the degree of suspicion as a trigger in 774 individuals (non-lagged analysis).

Neck pain/tension was associated with increased risk of attacks (‘trigger’) in about one-fifth of individuals, but never found as a ‘protector’. There was an association between degree of neck pain/tension suspicion as a trigger and frequency of statistical confirmation of an association with attacks. Not analyzed individuals had insufficient data for analysis, due to constant or low variability in neck pain/tension (128: 46.9%), low number of attacks or convergence problems in the Cox model. In the lagged analysis, only 4.9% of individuals had an association between attacks and preceding day neck pain/tension.

Conclusion: Neck pain/tension was widely suspected as a migraine trigger. In one-third of individuals with adequate data there was a statistical association between same day neck pain/tension and migraine headache. However, neck pain/tension the day before headache started was much less commonly correlated with attacks: this supports the view that neck pain/tension is more likely a migraine symptom rather than a trigger.

References

1. Calhoun AH et al. Headache 2010;50:1273-1277

2. Lampl C et al. J Headache Pain 2015;16:80-84

3. Peris F et al. Cephalalgia 2017; 37(5): 452-463
Table 1 (abstract S27).

See text for description

Suspected? →

Not suspected

Low (levels 1-3)

Medium (levels 4-6)

High (levels 7-10)

No answer

TOTAL

n (%)

Association? ↓

Associated ‘trigger’

19

13

31

92

6

161 (20.8)

Associated ‘protector’

0

0

0

0

0

0 (0)

No association

56

40

81

147

16

340 (43.9)

Not analyzed

72

37

47

99

18

273 (35.3)

TOTAL n (%)

147 (19)

90 (11.6)

159 (20.5)

338 (43.7)

40 (5.2)

774

S28 Brainstem aura is not real

Anne Ducros (a-ducros@chu-montpellier.fr)

University of Montpellier, and Headache Centre, Neurology department, Montpellier University Hospital, France

According to ICHD-3, migraine with brainstem aura is defined as a migraine with aura including at least two of the following symptoms: dysarthria, vertigo, tinnitus, hypacusis, diplopia, ataxia and/or decreased level of consciousness.

Whereas the typical migraine aura symptoms are thought to be the clinical consequence of cortical spreading depression (CSD), the mechanisms of migraine with brainstem aura remain debated. One hypothesis could be that “brainstem” aura does not originate in the brainstem but in the cerebral cortex.

Even though any symptom of brainstem aura can be observed in patients with brainstem lesions, numerous clinical observations and functional mapping data show that these latter symptoms can also originate within the cortex. Vertigo can result from a vestibular cortex dysfunction while tinnitus and hypacusis can originate within the auditory cortex. Diplopia can reflect a parieto-occipital involvement. Dysarthria can be caused by dysfunctions located in precentral gyri. Ataxia can reflect abnormal processing of vestibular, sensory or visual inputs by the parietal lobe. Alteration of consciousness can be caused by abnormal neural activation within specific consciousness networks that include prefrontal and posterior parietal cortices.

Any symptom of so-called brainstem aura can originate within the cortex. Based on these data, we suggest that brainstem aura could have a cortical origin. A potential cortical origin of “brainstem” aura would explain the frequent association between symptoms of brainstem and of typical aura during attacks and the frequency of “brainstem” aura symptoms in hemiplegic migraine. Moreover, a cortical origin of any aura symptom (e.g typical, brainstem-like and hemiplegic) would fit with the theory of CSD as the underlying mechanism of migraine aura. In conclusion, patients with brainstem aura are real, but migraine with brainstem aura is not real and could be called migraine with brainstem-like aura.

S29 Migraine with brainstem aura does exist

Jes Olesen (jes.olesen@regionh.dk)

Rigshospitalet and university of Copenhagen, Denmark

Migraine with brainstem aura has been a recognized entity for decades. It was first described by Bickerstaf as basilar artery migraine. He believed that it was caused by spasms of the basilar artery. At the time of the first international headache classification in 1988 it was clear that spasms do not explain any kind of migraine. The diagnosis was therefore renamed basilar migraine. In ICHD-2 it was called basilar-type migraine in order to get further away from the basilar artery and finally, in ICHD-3, it was renamed migraine with brainstem aura. Formally applying the diagnostic criteria of the ICHD-II to a large material of systematically phenotyped migraine with aura patients resulted in a surprisingly high number patients who fulfilled the criteria [1]. While formally migraine with brain stem aura thus exists and formally is quite common, we as experts do not believe that it is common. On the other hand we have identified a number of patients at the Danish Headache Center who undoubtedly have brainstem symptoms as an aura of migraine and we shall present some cases.

References

[1] Li, D., A.F., C., & J., O. (2015, August). Field-testing of the ICHD-3 beta/proposed ICD-11 diagnostic criteria for migraine with aura. Cephalalgia, pp. 748-756.

S30 Manual Approach to Tension-Type Headache: Is this a Reliable Approach?

César Fernández-de-las-Peñas (cesar.fernandez@urjc.es)

Departamento de Fisioterapia, Terapia Ocupacional, Rehabilitación y Medicina Física. Universidad Rey Juan Carlos, Alcorcón, Madrid, Spain

The etiology of tension type headache (TTH) is not completely understood yet. Current evidence suggests a potential role of muscle referred pain, particularly trigger points (TrPs) in the development and maintenance of pain and sensitization mechanisms in TTH. In addition, other factors such as mood disorders or sleep disturbances are also involved in the chronification process. Understanding the integration of musculoskeletal disorders may help to develop better management regimes for patients with TTH. The current lecture will provide updated discussion of the clinical reasoning for application of physical manual therapy approaches in TTH since different therapeutic options are currently proposed for these patients. Current evidence supports the concept that not all manual therapies are equally effective for patients with TTH and that the effectiveness of these interventions will depend on a proper clinical reasoning. Since the pathogenesis of TTH is mainly associated to muscular impairments, manual therapies should be targeted to muscle trigger points and other related tissues. This could explain the inconsistent results in the current literature in relation to effectiveness of manual therapy for TTH. In addition, multimodal approaches including different interventions are more effective than isolated therapeutic approaches for TTH since they can focus on both peripheral and central mechanisms. All these topics will be discussed in this lecture.

S31 Differences and similarities observed in functional imaging of headache studies

Anders Hougaard (ahougaard@dadlnet.dk)

Danish Headache Center & Dept. of Neurology, Righospitalet Glostrup, University of Copenhagen, Denmark

Neuroimaging studies have substantially enhanced our possibilities for investigating pathophysiological mechanisms of primary headache disorders and experimental head pain. In recent years, an immense number of imaging studies in headache have been published, often with diverging findings. New technologies and imaging data analysis methods are being developed at an increasing speed. Future studies have the potential not only to advance our understanding of headache-relevant disease mechanisms, but also to improve diagnostics, to elucidate the effects of treatment, and to monitor treatment effects in an objective and non-invasive way.

This presentation focuses on highlights of studies using positron emission tomography, functional MRI, MR angiography, and MR spectrometry and possible future directions of this field of research

S32 Migraine in childhood is an environmental disease - focus on the role of epigenetic

G. Natalucci1, N. Faedda2, G. Turturo1, V. Guidetti1

1Department of Human Neuroscience, “Sapienza” University of Rome, Rome, Italy; 2Behavioural Neuroscience, Department of Human Neuroscience, “Sapienza” University of Rome, Rome, Italy
Correspondence: V. Guidetti (vincenzo.guidetti@uniroma1.it)

In 1942 Conrad Waddington defined for the first time the term “epigenetics”. Synthetically, it refers to environmental factors and events that can affect gene expression or chromatin structure, for example trough post-translational changes of the tails of histone proteins, DNA methylation or RNA-associated silencing, resulting in changes in DNA structure without altering the genetic code. In this contest, several recent theories have supposed that in a disease like migraine, epigenetic mechanisms may explicate how non-genetic endogenous and exogenous factors and possibly influence frequency, intensity and genesis of migraine. In fact, while there are several evidences and studies on the role of specific genes on migraine’s development, the impact of biological, neural, molecular and environmental factors is still uncertain and difficult to scientifically assess without significant bias [1]. Some studies have demonstrated, for example, that hormonal changes, especially in women, sleep deprivation, skipping meals and stress can have a high influence on the different expression of migraine attacks. Specifically, it seems that female hormones, through epigenetic mechanism, can change the balance between inhibitory and excitatory neurotransmission, increasing excitatory neuronal activity. Other important factors that can have an epigenetic influence are early stressing experiences. It has been demonstrated a high prevalence of headache and migraine and substantial changes on neural circuits in adults who experienced a type of abuse in their life (sexual, emotional, physical or domestic abuse) [2]. In fact, many researchers have found how early negative adversity may have long-term effects on hypothalamic–pituitary–adrenal (HPA) axis function and immune system activity through epigenetic modifications, and these mechanisms may explain how attack frequency is modulated by non-genetic factors. Moreover, experiences like childhood maltreatment can lead to severe migraine manifestations which can be also more refractory to treatment. Early negative life experiences and female hormones are shared factors by both migraine and depression. Studies on animal models demonstrated how aberrant epigenetic gene regulation may be associated with the pathophysiology of mood disorders and consequently, they could be the same pathways of headache and migraine. So, causal pathways shared between migraine and its comorbid disorders may be moderated by epigenetic mechanisms [3]. Because of prophylactic medication used to prevent migraine is only effective in half of the patients, more studies on epigenetic migraine mechanism may provide a new conception of migraine pharmacotherapy, specifically acting to modulate chromatin structure at migraine features.

References

1) Hershey AD, Faedda N. Guidetti V. “Epigenetics” In: Guidetti V., Arruda M., Ozge A. (Eds) “Headache and Comorbidities in Childhood and Adolescence” Springer International Publishing 2017 page 31-37 ISBN 978-3-319-54726-8

2) Tietjen GE Childhood Maltreatment and Headache Disorders. Curr Pain Headache Rep. 2016 Apr;20(4):26. doi: 10.1007/s11916-016-0554-z.

3) Eising E, A Datson N, van den Maagdenberg AM, Ferrari MD. Epigenetic mechanisms in migraine: a promising avenue? BMC Med. 2013 Feb 4;11:26. doi: 10.1186/1741-7015-11-26. Review.

S33 Sports and headache

Randolph W. Evans

Department of Neurology, Baylor College of Medicine, Houston, Texas

Sports are commonly associated with headaches. Concussions can lead to post-traumatic migraines, tension- type headaches, medication overuse, occipital neuralgia, and cervicogenic. Minor head injury can trigger migraine with aura (footballer's migraine). The usual acute and preventive treatments can be considered for the phenotype. Neurologists treating collegiate and professional athletes should be familiar with prohibited substances for treatment as listed by the World Anti-Doping Agency. Non-traumatic headaches associated with sports include the following: exertional, cough (weightlifter's), and external compression headaches.

S34 Post-traumatic headache is a unique headache disorder

Mattias Linde (mattias.linde@ntnu.no)

Department of Neuromedicine and Movement Science, NTNU Norwegian University of Science and Technology, Trondheim, Norway

According to the new version of the International Classification of Headache Disorders (ICHD-3), persistent headache attributed to traumatic injury to the head (HAIH) is among the most common headache disorders. Epidemiological evidence to support this statement has, however, been lacking. Only two previous studies using non-injured comparison groups have investigated the causal relationship between head injury and headache, and they show conflicting results.

Since HAIH does not differ from migraine and tension-type headache (TTH) based on clinical characteristics, some experts are disputing its existence, arguing that it may be nothing other than a primary headache being misattributed to a head injury

The speaker will present the findings of the so far largest controlled, population-based study on HAIH with known pre-trauma headache status. More than one thousand traumas were classified according to the Head Trauma Severity Scale (HISS). Adjusting for potential confounders, it can now be concluded that HAIH is a true secondary headache entity. Prognostic markers at the time of admission, headache phenotypes, and dose-response relationships will be reviewed.

S35 Fifty years of Norwegian contributions to headache research

L. J. Stovner (lars.stovner@ntnu.no)

Norwegian Advisoy Unit on Headaches, Department of Neuromedicine and Movement Science, Norwegian University of Science and Technology (NTNU), and St. Olavs Hospital, Trondheim, Norway

For a small country, Norway has made substantial contributions to the headache field. The founder of this tradition is without doubt professor Ottar Sjaastad, who from he started his work in the sixties, described several new headache entities (Chronic paroxysmal hemicranias, Hemicrania continua and SUNCT), was among the founding fathers of IHS and the Scandinavian Migraine Society, was the founding editor of Cephalagia which he edited for almost 10 years. In his older days performed the Vågå study, in which he personally interviewed almost all 1800 inhabitants in a Norwegian community. In the same period, professor Tor-Erik Widerøe made the first proper trials proving that a beta-blocker (propranolol) was affective as migraine preventative. In the same tradition, professor Harald Schrader made the observations leading to the development of lisinioril and later candesartan as migraine prophylactics. The large epidemiological survey in Nord-Trøndelag county (the HUNT study) from around 1995 became an arena for headache epidemiological studies, through the work of professors John-Anker Zwart, Knut Hagen, Gunnar Bovim and myself. This tradition in epidmiology, together with the establishment of The Norwegian National Headache centre from the start of the 2000, has made the headache group at the Norwegian University of Science and Technology in Trondheim the academic basis for the NGO Lifting the Burden, running the Global campaign against headache. This has also led to the work to demonstrate the huge societal impact of headache, as collaborators of the Global Burden of Disease project. The group is now performing innovative research for treating chronic cluster headache and migraine.

S36 Correlation of migraine attacks with neck pain and tension

E. Anne MacGregor1, Stephen Donoghue2, Marina Vives-Mestres2

1Barts Health NHS Trust, London UK, 2Curelator Inc., Cambridge MA, USA
Correspondence: E. Anne MacGregor

Background: Repetitive yawning is a common premonitory migraine symptom [1,2]. In contrast to other common premonitory symptoms such as neck pain and tiredness, repetitive yawning is more specific and has a high predictive value for a migraine attack [3]. We used a digital platform (Curelator Headache® - now called N1-Headache®) to determine 1) how many individuals recorded excessive yawning and 2) for how many individuals an association between excessive yawning and migraine attacks can be identified statistically.

Methods: Individuals with migraine registered to use Curelator Headache®. They then used this daily, entering details of headaches and factors possibly associated with attack occurrence: presence of yawning was determined by a Yes/No response to the daily question ‘Did you notice excessive yawning (today)?’. To be eligible for analysis, data must include 90 tracked days or more, at least five migraine attacks, more than 50 answers to the yawning question, and excessive yawning must be reported on at least 5% of days, but not all days. After 90 days all factors were analysed and for each individual the association between excessive yawning and migraine occurrence was determined via a univariate Cox proportional hazard model [4].

Results: Of 852 individuals with migraine, 285 (33.5%) were eligible for analysis. Excessive yawning was associated with increased risk of migraine attack in 72 (25.3%), with decreased risk in 4 (1.4%) and no significant within-person association was identified in 189 (66.3%). Risk could not be assessed in 20 (7%) due to convergence problems in the Cox model. Of the 72 with increased risk, the median hazard ratio was 3 (IQR=4-2.2) meaning that, for them, when yawning is present the occurrence of migraine is about three times the rate per unit time as when there is no yawning.

Conclusion: In some individuals excessive yawning is a discernible symptom that is a sensitive predictor of migraine. Early identification of migraine provides an opportunity for early intervention. Future studies can assess effective strategies during the premonitory stage to abort an attack.

References

1. Laurell K et al. Cephalalgia 2016; 36(10): 951-959

2. Guven B et al. Headache 2018; 58(2): 210-216

3. Giffin NJ et al. Neurology 2003; 60(6): 935-940

4. Peris F et al Cephalalgia 2017; 37(5): 452-463

SISC Invited Speakers

S37 Comorbidities of Migraine - Sleep Disorders

Catello Vollono (lvol@libero.it)

Department of Neurology, Catholic University, Fondazione Policlinico Universitario Agostino Gemelli IRCCS, Rome, Italy

Background

Migraine is a pleomorphic relapsing, remitting disorders characterized by recurrent attacks that can be triggered or precipitated by a large number of internal and external factors. The relationship between sleep and migraine has always been known, but current knowledge on the exact nature of the link between migraine and sleep remains incomplete and unclear.

In other primary headaches, such as Hypnic Headache and Cluster Headache, sleep studies has shown dysfunction of arousal mechanisms, associated with the brain's ability to process exogenous and endogenous stimuli during sleep.

Different sleep studies were performed in order to define also the complex link between sleep and migraine.

Results

Fragmentation of sleep, insomnia and hypersomnia all showed relationships with migraine. Primary sleep disorders such as insomnia, hypersomnia, sleep breathing disorders are all associated with primary headaches, may cause headache, can worsen migraine and are risk factors for migraine chronification. Medical, psychiatric and rheumatic diseases are associated with sleep disorders and migraine.

Migraine is associated with modifications in sleep: circadian changes in the sleep-wake rhythm [1], modifications of the ultradian rhythm (more frequent than 24h, and therefore shorter than a day, the alternation of NREM / REM phases in the sleep cycles) [2], changes in arousals mechanisms [3].

Sleep-related migraine is characterized by a marked reduction in the CAP rate in NREM sleep and a lower incidence of 'cortical' arousal in REM sleep (cortical hypoarousability) that could predispose to the appearance of migraine episodes during sleep [4].

In migraineurs the autonomic balance during sleep changes more evidently than in controls and the oscillations of the arousal levels change in a concordant manner [5].

Conclusions

Migraine has close clinical correlation with sleep and sleep disorders. Moreover, widespread pathophysiological links have been shown between migraine and sleep, expression of reduced effectiveness of the mechanisms of processing of the incoming stimuli.

The study of sleep/wake pattern in order to know and try to change the influence of biological rhythms, sleep and trigger factors on migraine can allow the clinicians to control the frequency and intensity of attacks and, above all, to avoid the chronicity of the disorder.

References

[1] Ahn AH, Goadsby PJ. Migraine and sleep: new connections. Cerebrum. 2013 Dec 1;2013:15

[2] Jennum P, Jensen R. Sleep and headache. Sleep Med Rev. 2002 Dec;6(6):471-9

[3] Bruni O, Russo PM, Violani C, Guidetti V. Sleep and migraine: an actigraphic study. Cephalalgia. 2004 Feb;24(2):134-9

[4] Della Marca G, Vollono C, Rubino M, Di Trapani G, Mariotti P, Tonali PA. Dysfunction of arousal systems in sleep-related migraine without aura. Cephalalgia. 2006 Jul;26(7):857-64

[5] Vollono C, Gnoni V, Testani E, Dittoni S, Losurdo A, Colicchio S, Di Blasi C, Mazza S, Farina B, Della Marca G. Heart rate variability in sleep-related migraine without aura. J Clin Sleep Med. 2013 Jul 15;9(7):707-14.

S38 Nutraceuticals and headache

Lidia Savi (lsavi@cittadellasalute.to.it)

Headache Center LBS, Lugano, 6900, Switzerland

Headache disorders are in many cases inadequately managed with the existing treatments. Also, given the myriad side effects of traditional prescriptions medications, there is an increasing demand for “natural” treatment like vitamins, minerals, herbal preparations and food supplements.

The term “ nutraceutical “ was created by Defelice in 1979 and is derived from “nutrition” and “pharmaceutical” industries in the idea that some foods can be effective in treating diseases.

In the last years the use of nutraceuticals is expanding in patients with headache and particularly with migraine. The National Health Interview Study reported that 49,5% of the patients suffering from migraine use nutraceutical products and do not discuss this with their health care providers while only 33.9% of general population use them, .

Headache Therapy Guidelines of Scientific Societies from different countries (USA, Italy, England, Switzerland , etc) consider these products with sometimes conflicting information. Although the understanding of migraine pathophysiology has increased dramatically in recent years, the exact etiology remains to be defined. The current prevailing theory is based on a hyperexcitable “trigeminovascular complex” in patients who are genetically predisposed to migraine. In these people, there is a lowered threshold for migraine attacks and vulnerability to environmental triggers. In susceptible individuals, the trigeminovascular neurons release neurotransmitters, such as calcitonin gene-related peptide and substance P, when headache triggers are encountered. This lead to vasodilation, mast cells degranulation, increased vascular permeability and meningeal edema, resulting in neurogenic inflammation. This nociceptive information is transmitted from the trigeminal nerve to the brainstem nuclei, thalamic nuclei, and the cortex, where migraine pain is ultimately perceived.

Although the mechanisms of action of these molecules in migraine prevention are poorly known, their effects on vessel wall, neurons, as well as on specific neurotransmitters involved in migraine pathophysiology have been hypothesized based on numerous pre-clinical observations.

Many different nutraceuticals are currently used in migraine prophylaxis other than in patients who do not want a pharmacological traditional therapy, in those cases when the pharmacological therapy cannot be used or it is better to avoid it (children, old patients using many different drugs, severe liver or renal diseases, pregnancy, etc), but in any case is important to know the possible even rare side-effects of each one of these and when it is better to avoid them.

S39 Community pharmacies as epidemiological sentinels of headache

Paola Brusa1,2, Gianni Allais3,8, Cecilia Scarinzi4, Francesca Baratta1, Marco Parente1, Sara Rolando3, Roberto Gnavi4, Teresa Spadea4, Giuseppe Costa4, Chiara Benedetto3, Massimo Mana5,6, Mario Giaccone2,7, Andrea Mandelli7, Gian Camillo Manzoni8, Gennaro Bussone8

1Department of Science and Technology of Drugs, University of Turin, via Pietro Giuria 9, 10125, Turin, Italy; 2Order of Pharmacists of Turin, Via Sant'Anselmo, 14, 10125, Turin, Italy; 3Department of Surgical Sciences, Women’s Headache Center, University of Turin, Via Ventimiglia 3, 10126, Turin, Italy; 4Epidemiology Unit, ASL TO3, Via Sabaudia 164, 10095, Grugliasco (Turin), Italy; 5ATF Informatics, Via Cascina Colombaro 56, 12100, Cuneo, Italy; 6Federfarma Piemonte, Via Sant'Anselmo, 14, 10125, Turin, Italy; 7FOFI, Federation of the Orders of Italian Pharmacists, Via Palestro 75, 00185, Rome, Italy; 8FI.CEF Onlus, Italian Headache Foundation, via Celoria 11, 20133 Milan, Italy
Correspondence: Paola Brusa (paola.brusa@unito.it)

Background. A study was carried out in Italy with the objective of analysing the patterns of use of drugs in subjects who entered a pharmacy requesting OTC medications in order to treat a headache attack. In this context, the objective is to analyse the association of headaches with socio-demographic and clinical characteristics and with the pathway of care followed by the patients.

Methods. a questionnaire was administered to subjects who entered a pharmacy requesting self-medication for a headache attack. The questionnaire consisted of 14 items covering socio-demographic factors, pathway of care and clinical information. The clinical section included the items of the ID Migraine TM Screener (ID-MS), resulting in a four-level variable that classifies patients as suffering from definite migraine, probable migraine, unlikely migraine, or other headaches, based on symptoms, occurrence and severity of headaches. A single national online training course was employed to prepare the pharmacists in order to ensure that the data were collected as homogeneously as possible. At the end of the training course, each pharmacist had to pass a final test before being enrolled in the project.

Results. Out of 610 trained pharmacists, 445 collected at least one questionnaire, 4424 questionnaires had been correctly completed. The ID-MS shows a strong association with gender. The prevalence of definite migraines was significantly higher among the two lower educational levels.

Our study, confirming data found in investigations carried out among the general population, indicates that about half of headache sufferers and about a third of migraineurs do not consider their condition as a disease and tend to self-medicate, which leads to inappropriate treatment of the condition.

Conclusions. The pharmacy can be a valuable observatory for the study of headaches and can be the first important step in seeking to build a good management relationship for subjects with headache.

Refrences

1. Brusa P, Parente M, Allais G et al. Community pharmacies as epidemiological sentinels of headache: first experience in Italy Neurol Sci 2017; 38(Suppl 1): 15-20.

2. Lipton RB, Dodick D, Sadovsky R et al. A self-administered screener for migraine in primary care. The ID MigraineTM validation study. Neurology 2003; 61: 375–382

3. Rapoport AM, Bigal ME. ID-migraine. Neurol Sci 2004; 25:S258–S260

4. Headache Classification Committee of the International Headache Society: The international classification of headache disorders, 3rd edition (beta version). Cephalalgia 2013, 33:629-808.

5. Manzoni GC, Bonavita V, Bussone G, Cortelli P, Narbone MC, Cevoli S, D’Amico D, De Simone R, Torelli P on behalf of ANIRCEF (Associazione Neurologica Italiana Ricerca Cefalee): Chronic migraine classification: current knowledge and future perspectives. J Headache Pain 2011, 12:585-592.

S40 Digital health and clinical decision support : the HealthSOAF project and the Calabria Headache Network

Rosario Iannacchero1, Carmela Mastrandrea1, Domenico Conforti2

1Regional Headache Centre , Neurology Division “ Pugliese-Ciaccio “ Hospital Catanzaro Italy; 2 Department of Mechanical Energy Management Engineering, University of Calabria Rende Italy
Correspondence: Rosario Iannacchero (centrocefaleeaopc@gmail.com)

Introduction: Good clinical governance of headache implies efficient and accessible diagnostic and therapeutic pathways involving different levels of health care. Headache syndromes are often diagnosed and treated inadequately. Information and communication technology (ICT) can play a key role in improving access to treatment and, from the clinical management perspective, in increasing the levels of quality , efficiency and prevention.The HealthSOAF ( Service-Oriented Architecture Framework ) is a networking and interoperability technology platform, designed to assist healthcare decision making and improve access to care at appropriate levels. The Headache Network operating in the Italian region Calabria provide the HealthSOAF platform with its first real tes bed in Europe, with the aim of helping clinicians working at different levels of health care to correctly diagnose , manage and refer headache patients.

Materials and Methods : Between December 2014 and June 2015 primary care general practitioners in Catanzaro Lido, Borgia and Soverato , three secondary care neurologists, and one multidisciplinary tertiary care team from the Headache Centre the Pugliese-Ciaccio Hospital in Catanzaro , used the pilot client software and accessed the HealthSOAF platform.In the period considered , GP recruited 197 patients with headache diagnoses made with the support of techonological platform : 19 ( 9,64%) had a suspected diagnosis of secondary headache and were referred to emergency room ; 74 ( 37,56% ) were diagnosed with episodic primary headache and managed exclusively by GP at primary headache level; 36 ( 18,27% ), also with episodic primary headache, were managed by both GP and outpatient neurologists , again in the primary setting ; 68 patients ( 34,52% ) were sent to the reference headache centre. The preliminary data from the pilot study , showing an approximately 50% reduction in inappropriate referrals to the hospital reference centre ( 15,42% vs 7,35% ), indicate enhanced diagnostic accuracy and appropriateness of referrals within the coded diagnostic, therapeutic and care pathways.

Conclusion: The use of ICT support in clinical decision making and management processes is a valuable aid in clinical practice. The HealthSOAF project is the first at a national level and among the first at international level to study , define, test and validate a new approach in the software development cycle, designed to guarantee interoperability of distributed and highly heterogeneous health information system , of the kind that are increasingly necessary to support continuity of care , diagnostic processes , integrated therapeutic care , prevention activities and public health protection.

References

1. Commision of the European Communities: An action plan for European e-Health Area 2004

2 European Commision , Horizon 2020 . The EU Framework Programme for Research and Innovation

S41 Headaches and cranio-cervico-mandibular disorders: EBP manual therapy

Riccardo Rosa1,2 (clinicadelmalditesta@gmail.com)

1La Sapienza University of Roma, Italy; 2Clinica del Mal di Testa, via campania 37, Roma, 00161, Italy

Headaches are one of the most disabling disorders [1]. The 3rd edition of the International Classification of Headache Disorders (ICHD-III) describes the diagnostic criteria of primary, secondary and other headache disorder types. Interestingly, Migraine and Cervicogenic Headache (CGH) , Tension Type Headache (TTH), Headache attributed to temporo-mandibular disorder (TMD), Headache attributed to cervical myofascial pain and Occipital Neuralgia share similarities in some criteria and clinical presentation. Moreover, Neck Pain associated disorders (NAD) and Temporo-Mandibular Disorders (TMD) are a very common presentation in primary headache population as Migraine and Tension Type Headache [2,3]. Moreover, recent knowledge have suggested that physical examination for provocative procedures should be done on each patient with sidelocked headaches as many of these headaches may closely mimic primary headaches [4]. There have been identified eleven physical tests to properly assess cervical disorders. When these dysfunctions are present, they support a reciprocal interaction between the trigeminal and the cervical systems as a trait symptom in migraine [6,7,8]. The ICHD-III also does recommend the use of diagnostic criteria evolved by the International RDC/TMD Consortium Network and Orofacial Pain Special Interest Group to assess disorder involving structures in the temporomandibular region contributing to primary headache [9,10]. In this presentation, an evidence based protocol of manual tests and rehabilitation proposal it will be provided by a physiotherapist to assess and treat musculoskeletal disorders associated to the most common primary headaches as Migraine and Tension Type Headache. Moreover, the integration of this examination and approach in a multidisciplinary team it will be discussed [11].

References

1. Stovner LJ. Migraine prophylaxis with drugs influencing the reninangiotensinsystem. Eur J Neurol. 2007;14(7):713-4. doi:10.1111/j.1468-1331.2007.01760.x.

2. Ashina S, Bendtsen L, Lyngberg AC, Lipton RB, Hajiyeva N, Jensen R. Prevalence of neck pain in migraine and tension-type headache: a population study. Cephalalgia. 2015;35(3):211-9. doi:10.1177/0333102414535110.

3. Tomaz-Morais JF, Lucena LB, Mota IA, Pereira AK, Lucena BT, Castro RD,Alves GA. Temporomandibular disorders is more prevalent among patients with primary headaches in a tertiary outpatient clinic. Arq Neuropsiquiatr. 2015 Nov;73(11):913-7. doi: 10.1590/0004-282X20150145.

4. Prakash S, Rathore C. Side-locked headache: an algorithm based approach. The Journal of Headache and Pain 2016; 17:95

5. Luedtke K, Boissonnault W, Caspersen N, Castien R, Chaibi A, Falla D et al. International consensus on the most useful physical examination tests used by physiotherapists for patients with headache: A Delphi study. Man Ther. 2016;23:17-24. doi:10.1016/j.math.2016.02.010.

6. Luedtke K, Starke W, May A. Musculoskeletal dysfunction in migraine patients. Cephalalgia. 2017; Jan 1:333102417716934. doi:10.1177/0333102417716934.Headache Classification Committee of the International Headache Society (IHS). The International Classification of Headache Disorders, 3rd edition (beta version) 2013 Jul;33(9):629-808. doi: 10.1177/0333102413485658.

7. Luedtke and May A. Stratifying migraine patients based on dynamic pain provocation over the upper cervical spine. The Journal of Headache and Pain (2017) 18:97 DOI 10.1186/s10194-017-0808-0

8. Headache Classification Committee of the International Headache Society (IHS). The International Classification of Headache Disorders, 3rd edition (beta version) 2013 Jul;33(9):629-808. doi: 10.1177/0333102413485658.

9. Schiffman E, Ohrbach R, Truelove E, et al. Diagnostic Criteria for Temporomandibular Disorders (DC/TMD) for Clinical and Research Applications: Recommendations of the International RDC/TMD Consortium Network and Orofacial Pain Special Interest Group. Journal of oral & facial pain and headache. 2014;28(1):6-27.

10. Garrigòs-Pedròn M, La Touche R, Navarro-Desentre P, Gracia-Naya M, Segura-Ortì E. Effects of a Physical Therapy Protocol in Patients with Chronic Migraine and Temporomandibular Disorders: A Randomized, Single-Blinded, Clinical Trial. J Oral Facial Pain headache. 2018 Spring;32(2):137-150. doi:10.11607/ofph.1912.

S42 Spontaneous intracranial hypotension headache

Enrico Ferrante (enricoferrante@libero.it)

Neurology Department San Carlo Hospital- Potenza

Schaltenbrand, in 1938 first described spontaneous intracranial hypotension (SIH). In 1991 Mokri, published the first report on diffuse pachymeningeal enhancement (DPE) in SIH. In 1993 Ferrante, published the first Italian report on SIH. SIH results from spinal CSF leaks, sometimes asociated with underlying connective tissue disorders. The decrease in CSF volume is compensated by an increase in intracranial venous blood volume according to the Monro-Kellie doctrine. The associated prevalence and incidence has been estimated at 2–5:100,000. Female are affected twice to fifth as often as males. The peak incidence is in 30–50 year [1]. The triggers for the symptoms can be trivial or minor; however, no clear precipitant was identified in most cases. Orthostatic headache (OH), generally occipital-nuchal bilaterally, worsening during Valsalva manoeuvres, is the main symptom of SIH. In our case series over 400 cases we have observed about 70% of cases with cochlear-vestibular signs associated with OH and seven patients who had only a Valsalva manoeuvre headache. The diagnostic criteria for SIH are described in the International Classification of Headache Disorders, (ICHD) 3rd edition. Brain CT is often normal while brain MRI generally shows the indirect SIH signs (DPE, subdural fluid collections, venous structures engorgement, pituitary hyperemia, and sagittal sagging). Spinal MRI may show cervical pachymeningeal enhancement, spinal epidural collection, or fluid collection in cervical soft tissues, meningeal diverticula, dilated nerve root sleeves, and epidural venous plexus engorgement. MRI myelography is more sensitive to identify a spinal CSF leak. CT myelography should be reserved for patients without identified leak on spinal MRI, who have failed to respond to two or three EBPs, and in whom a targeted EBP at the site of CSF leak is being considered. In 15–30% of cases, SIH is resolved spontaneously or with conservative treatment (bed rets and overhydration) within a period of 1–2 weeks. The success rate with each EBP is variable (30% -90%) [2]. In our experience, the EBP success depends on the adequate volume of blood injected, which has to be sufficient to fill the epidural space, and on strict bed rest in Trendelenburg position for at least 8 hours after the procedure. Targeted EBP in the upper thoracic or cervical regions or surgical approaches could be useful if two or three attempts at a lumbar EBP have failed and the CSF leak site is located.

References

1) Mokri B. Spontaneous Intracranial Hypotension. Continuum (Minneap Minn) 2015;21(4):1086–1108.

2) Ferrante E, Arpino I, Citterio A, Wetzl R, Savino A. Epidural blood patch in Trendelenburg position pre–medicated with acetazolamide to treat spontaneous intracranial hypotension. Eur J Neurol 2010, 17: 715–19.

S43 The standard of care for chronic migraine in lombardia SISC centres: results of a collaborative study

Paola Merlo1*, Valentina Rebecchi2, Natascia Ghiotto3, Lucia Princiotta Cariddi2, Fabio Antonaci4,5, Andrea Giorgetti6, Franco Di Palma7, Edgard Matta8, Giorgio Dalla Volta9, Grazia Sances3 on behalf of SISC - Società Italiana per lo Studio delle Cefalee - Sezione Lombardia, Italy

1UO Neurologia - Centro Cefalee, Humanitas Gavazzeni, Bergamo; 2Centro Cefalee UOC Neurologia –Varese - ASST Settelaghi – Univ. Insubria; 3Headache Science Centre, National Neurologic Institute C. Mondino, Pavia; 4UC Neurologia Speciale d'Urgenza, Istituto Neurologico Nazionale, Pavia; 5Dipartimento di Scienze del Sistema Nervoso e del Comportamento Università di Pavia; 6Centro Cefalee, Dipartimento di Neuroscienze H di Legnano ASST Ovest milanese; 7Centro Cefalee UOC Neurologia della ASST Lariana - Ospedale S. Anna, Como; 8Centro Cefalee UOC Neurologia ASST Bergamo ovest; 9Centro Cefalee UO Neurologia - Istituto Clinico Città di Brescia, Brescia
Correspondence: Paola Merlo (paola.merlo@gavazzeni.it)

Background

Although the diagnosis of Chronic Migraine with and without Medication Overuse (CM/CM-MOH) are based on well-established criteria (ICHD-III β) the definition of international guidelines for its management is still work in progress, especially as far as the long term management and the sustainability of the cost/benefit ratio are concerned. Thus, the present observational study was aimed to evaluate methods for CM management among different headache structures with a common cultural background and SISC standards (local resources, structural standards, operators qualification).

Methods

This study involved different neurological structures belonging to SISC-Lombardia and operating in or for Italian National Health System, that boast a documented practice in headache management, adherence to the locally approved protocols for CM, open access to detoxification programs and to onabotulinumtoxin A treatment. As far as the patients are concerned, they had to have a history of CM for at least 2 years prior to screening and to be willing and able to return to the clinic for the follow-up evaluations.

Results

We enrolled a population of 1940 patients over one year: 1140 (58.7%) had been diagnosed with CM and 800 (41.2%) with CM-MOH. In the CM-MOH group 685 patients (85.6%) underwent pharmacological detoxification treatment during the previous year. There are no great differences in the assessment methods and treatment plans among the structures: headache diaries are used everywhere (100%), while disability assessments are scored with MIDAS and HIT-6 questionnaires in 62.5% and 50% respectively. A protocol for detoxification was performed as inpatients (87.5%) or outpatients (12.5%). The average duration of detoxification was 5-7 days. Pharmacological methods for detoxification and the treatment of rebound headache showed some differences in the kind of drugs. In 3 structures (37.5%) a prophylaxis treatment with Onabotulinumtoxin A every 3 months followed detoxification (122 of CM-MOH, 15.25%). The follow-up methods were not homogeneous and showed controversial results; the same methods and parameters were used to evaluate the effectiveness of treatment but with different scheduling: the follow up period implied a 3 (37.5% of the Centres), 6 (25%) or 12 (37.5%) months evaluation. In one centre the follow-up included 3-6-12 months clinical controls for each patient. A strong variability was found in the response to treatments: the detoxification and prophylaxis treatment were effective from 20 to 97%; onabotulinumtoxin A alone was effective from 40% to 70%.

Conclusion

Our data showed a similar clinical approach in management of CM/CM-MOH. On the other hand the different therapeutic methods showed a lower concordance both for the clinical follow-up and to the evaluation of the treatments among the various structures. There was more agreement in the Onabotulinumtoxin A efficacy among the different centres.

References

1. MA Giamberardino, MD Dimos-Dimitrios Mitsikostas, MD Paolo Martelletti. Update on medication-overuse headache and its treatment. Curr Treat Options Neurol. 2015; 17:37

2. C Chiang, TJ Schwedt, S Wang, DW Dodick. Treatment of medication-overuse headache: a systematic review. Cephalagia 2016; 36(4): 371.

3. C Tassorelli, R Jensen, M Allena, R De Icco, G Sances, Z Katsarava, M Lainez, JA Leston, R Fadic, S Spadafora, M Pagani, G Nappi and the COMOESTAS Consortium. A consensus protocol for the management of medication-overuse headache: Evaluation in a multicentric, multinational study

4. C Tassorelli, G Sances, M Avenali, R De Icco, D Martinelli, V Bitetto, G Nappi, G Sandrini. Botulinum toxin for chronic migraine: Clinical trials and technical aspects. Toxicon. 2018 Jun 1;147:111-115.

S44 Migraine pathophysiology

Gianluca Coppola (gianluca.coppola@gmail.com)

Sapienza University of Rome Polo Pontino, Department of Medico-Surgical Sciences and Biotechnologies, Latina, Italy

Presently, migraine is considered a brain disorder. Many independent research groups have observed that the brain of migraine patients abnormally processes information of any sensory modality. These functional abnormalities are under continuous fluctuations following the migraine cycle and the frequency of the attacks and are under the influence of endogenous and environmental factors. Recent evidence provided by modern neuroimaging techniques tends to show that plastic (mostly reversible) changes in brain metabolism, connectivity, and micro-/macro- structure accompany functional abnormalities. However, whatever the origin of these cerebral morpho-functional abnormalities, migraine clinical manifestation requires ignition of the central and peripheral trigeminal system. The heterogeneous clinical presentation of visual migraine aura symptoms runs in parallel with heterogeneous BOLD fMRI responses within the visual areas. Malfunctioning descending pain control systems in the frontal cortex and brainstem, and abnormal thalamic and hypothalamic connectivity- alone or in combination- seem to be major permissive interictal factors for the preictal cascade of events that leads to sequential sensitization of first- and/or second-order trigeminovascular nociceptors resulting in transient (episodic migraine) or persistent (in CM) central sensitization.

S45 The use of a phytotherapic compound containing Tanacetum Parthenium and Andrographis, in combination with CoQ10 and Riboflavin, for migraine prophylaxis: a randomized double blind versus placebo clinical trial

Cherubino Di Lorenzo (cherub@inwind.it)

IRCCS Fondazione Don Carlo Gnocchi, Milan, Italy

Background. The most of migraineurs patients referred to a headache clinic for a specialist consultation is characterized by a middle to high frequency of migraine attacks. These patients need prophylactic treatments to reduce the burden of disease in terms of attacks, days with headache, and symptomatic drugs consumption. So far, pharmacologic prophylactic treatments are characterized by a sub-optimal efficacy due to the high number of patients that do not respond to the treatments, and the elevated incidence of side effects. To match the patient needs, waiting for the next generation treatments, the use of herbal medicine is very common among migraine population. In the last years, phytoextracts of feverfew (tanacetum partenium) were studied and adopted to treat migraineurs. In particular, there is a fixed combination of Tanacetum Parthenium, Andrographis, Coenzyme Q10, and Riboflavin, that is widely used in Italy. In order to verify the efficacy of that association, we designed a randomized double blind versus placebo clinical trial. Here we present the preliminary results of our study.

Results. Twenty-four patients were enrolled and randomly assigned to receive the verum or the placebo treatment for 3 months. Each treatment kit, blinded by a unique code that was coupled to each patient, was composed by 120 pills, enough for 3 months: (1 pill b.i.d. in the first month, 1 per day in the second and third month). Eleven of twelve patients assigned to the verum arm of the study improved their headache, with a responder rate (reduction of at least 50% of headaches) of 60%. On the contrary, only 4/12 patients that received the placebo treatment improved their headache, with a 0% responder rate. No side effects were reported.

Conclusions. The traditional use of herbal medicine is as old as the history of medicine and that ancient practice is present in almost all cultures. Our results show that the examined combination is effective in the migraine prophylaxis if compared to placebo and safe if compared with data about synthetic drugs, as they are reported in literature.

S46 Migraine and Metabolic Syndrome

Cherubino Di Lorenzo (cherub@inwind.it)

IRCCS Fondazione Don Carlo Gnocchi, Milan, Italy

Background. Although migraine is a neurological disorder in which a peripheral trigemino-vascular activation is elicited in response to central sensitization processes, several studies payed attention on metabolic features among migraineurs, and their influence on migraine clinical characteristics.

Results. By a literature review, it is possible to assess that MetS is more prevalent in migraineurs (21.8% with aura, 16.8% without aura) than in controls (14.5%), and that it is related to the development of a chronic form of headache, the so-called ‘medication overuse headache’. These data are consistent to epidemiological studies that evidenced an increased risk to develop cerebrovascular disorders (CVDs) in migraineurs patients (both with and without aura), since CVDs are the more expected outcome of MetS. It is well known that obesity and hypertension are risk factors for migraine development and its chronification, while their improvement leads to a migraine improvement. Besides, the most of attention was recently payed to the oral glucose tolerance test to examine insulin sensitivity. In migraineurs patients, after glucose load, there is a significant increase of both plasmatic insulin and glucose concentrations in comparison with controls, while is common to find in migraineurs a very late hypoglycemic response that may trigger the migraine attack. The role of hypoglycemia, one of the early characteristics of the so-called insulin-resistance, is indirectly confirmed by the observation that the development of diabetes (characterized by a state of stable hyperglycemia) seems to be protective against migraine attacks. The insulin-resistance is characterized by an alteration of insulin receptor signaling that has shown to be also altered in migraineurs. All these metabolic abnormalities are related to the low-grade inflammation that could, in turn, be related to release of inflammatory cytokines (among these, the CGRP) that lead to the migraine attack.

Conclusions. One of the theories to explain the high prevalence of MetS among the population is the so called “thrifty gene theory”. According to this theory, the high levels of well-being of western population are related to an increase of nutritional intake that has stressed the metabolism of people genetically fitted to survive in famine, leading to MetS development. If common genetic and biological backgrounds underpin both migraine and MetS, according to this theory is possible to explain the high prevalence of migraine among general population.

S47 Migraine and Ketogenic Diet

Francesco Pierelli1, Gianluca Coppola2, Cherubino Di Lorenzo3

1INM Neuromed IRCCS, Pozzilli (IS), Italy; 2G. B. Bietti Foundation-IRCCS, Department of Neurophysiology of Vision and Neurophthalmology, Rome, Italy; 3IRCCS Fondazione Don Carlo Gnocchi, Milan, Italy
Correspondence: Francesco Pierelli; Cherubino Di Lorenzo (cherub@inwind.it)

Background. Ketogenic diet (KD) is a dietetic regimen characterized by a very low intake of carbohydrate in order to induce the metabolic ketosis (the physiologic endogenous production of ketones) to replace sugars as energetic substrate for the brain. Ketones are a very efficient fuel for the brain, since they induce to an increase of ATP production with a reduction of oxidative stress related to mitochondrial activity. On the other hand, they have an anti-inflammatory effect and are able to modulate the cortical excitability by their direct and indirect GABAergic effects. Several different types of KDs wer developed across the decades, all characterized by the low glycemic intake. They could be normo-caloric (rich in fats that have to replace the missing carbohydrate in the caloric balance), or hypocaloric (poor in fats to induce the lepidic metabolism from adipose tissue). Since 1921 this diet was proposed to treat drug resistant epilepsy in children. Even if in 1928 and in 1930 two papers reported about the efficacy of KDs in migraineurs patients, they did not meet the expected success, since at that time several symptomatic treatments were already available. Only in the recent years, the awareness about symptomatic overuse related troubles, and the efforts to reduce the number of treatment resistant patients, seems to rekindle the interest in this procedure.

Results. Our group started to study the application of KDs in the field of headache since the 2009, using both normo-caloric and hypocaloric, according to patients’ exigences. We found the KD an useful tool in the treatment of patients with migraine, both in episodic and chronic form, and in cluster headache patients. On the contrary, KD seems to be ineffective in tension type and cervicogenic forms of headache.

Conclusions. According to early literature reports, KDs seem to be a useful opportunity to improve the quality of life of our patients. One possible application is, for instance, the weight reduction (that could improve per se migraine), maybe induced by some prophylactic treatments. Another opportunity given by KD is the improvement of headache in drug-resistant patients. As future perspective, a there is a wide interest in the use of exogenous ketones, the so called “ketogenic diet in pills”.

S48 Headache attributed to disorder of homoeostasis

Federico Mainardi (fmainardi@iol.it)

Headache Centre, Neurological Division, SS Giovanni e Paolo Hospital, Venice, Italy

As in the previous version, chapter 10 of the current International Classification of Headache Disorders (ICHD 3) [1] is dedicated to the forms of headache attributed to disorders of homeostasis. All the nosographic entities of the provisional ICHD 3 beta version (2013) [2] are confirmed in this final edition, both in their digit code and in their diagnostic criteria.

The main rehash of chapter 10 was performed in the passage from ICHD-1 (1988) [3] to ICHD-2 (2003) [4], when the chapter was extensively remodeled. Hypoxic and hypercapnic headaches were unified in a unique headline (10.1), including High altitude headache (10.1.1), Diving headache (10.1.2) and Sleep apnoea headache (10.1.3). Moreover, Headache attributed to arterial hypertension and its subtypes, previously collocated in chapter 6 - Headaches associated to vascular disorders, were moved at the third digit of the first level (10.3), between Dyalisis headache (10.2) and Headache attributed to hypothyroidism (10.4). Headache attributed to fasting (10.5) substituted the older denomination “Hypoglicemia”, and the new Cardiac cephalalgia (10.6), a rare occurrence characterized by a close temporal relationship between the onset of headache and cardiac ischemia, appeared for the first time.

In 2013, the provisional ICHD 3 [2] confirmed the structure of the chapter. The main modifications regarded the merger of Headache attributed to pre-eclampsia and eclampsia in an unique digit (10.3.4), the disappearance of Headache attributed to acute pressor response to an exogenous agent, and the addition of two new entities.

The first one, Headache attributed to aeroplane travel (10.1.2), placed together with other forms of headache attributed to hypoxia and/or hypercapnia, is characterized by very severe unilateral pain attacks that appear during take-off or, more frequently, landing of the aeroplane, lasting up to 30 min after the ascent or descent of the vehicle is completed. Recently, the coexistence of headache attacks with the same features but triggered by the rapid ascent after free/scuba diving and/or the descent from high mountain altitude has been described and suggests a possible common causal mechanism, that is an imbalance between intrasinusal and external air pressure [5].

Headache attributed to autonomic dysreflexia (10.3.5), the second new entry, appears in the subchapter dedicated to Headache attributed to arterial hypertension. These sudden-onset severe headache attacks, accompanied by symptoms of autonomic dysfunction and triggered by stimuli of visceral or somatic origin (including bladder or bowel distension, pressure ulcers, trauma or surgical diagnostic procedures), affect patients with spinal cord injury.

References

1. Headache Classification Committee of the International Headache Society (IHS). The International Classification of Headache Disorders, 3rd edition. Cephalalgia 2018; 38: 1-211

2. Headache Classification Committee of the International Headache Society. The International Classification of Headache Disorders: 3rd edition (beta version). Cephalalgia. 2013; 33: 629-808

3. Headache Classification Committee of the International Headache Society. Classification and diagnostic criteria for headache disorders, cranial neuralgia and facial pain. Cephalalgia 1988;8(suppl 7):1-96.

4. Headache Classification Subcommittee of the International Headache Society: The International Classification of Headache Disorders, 2nd edn. Cephalalgia 2004;24(Suppl 1):1-160.

5. Mainardi F, Maggioni F, Zanchin G. Aeroplane headache, mountain descent headache, diving ascent headache. Three subtypes of headache attributed to imbalance between intrasinusal and external air pressure? Cephalalgia 2018;38:1119-1127. Epub ahead of print 8 August 2017. DOI: 10.1177/033310417724154.

S49 Chronic primary headaches

Paolo Rossi (paolo.rossi9079@gmail.com)

INI Grottaferrata

According to the ICHD-3 classification primary headaches may exist in episodic and chronic form. Chronic headaches have a significantly greater effect on quality of life than episodic headaches. Chronic headaches patients are more difficult to manage and more prone to miss work or have decreased productivity. They have more comorbidity including psychiatric disorders and use more health resources than the episodic ones. The most prevalent subtypes of chronic headaches are chronic migraine and chronic tension-type headaches. Migraine and tension-type headaches are defined as chronic when the headache occur on more than 15 days/month for more than 3 months. In both forms the chronification of the headache is usually the result of a process of transformation under the influence of pain system sensitizing factors such as recurring untreated headaches, medication overuse, comorbid pain or psychiatric disorders and others. When the headache is chronic from the onset and very soon unremitting the diagnosis should be oriented to the New Daily Persistent Headache a syndrome that should be rapidly identified because can transform in a highly refractory headache. This review will focus on some relevant unanswered question on chronic headaches: 1) Is the new classification of the pain disorders helpful for the management of these patients ? 2) are the mechanism of transformation of the headache into a chronic form a potential therapeutic target ? 3) is the comorbidity a potential therapeutic target ?

S50 Nocturnal onset headache

Carlo Lisotto (carlo.lisotto@aas5.sanita.fvg.it)

Headache Centre, Department of Neurology, Azienda Sanitaria Friuli Occidentale, Pordenone, Italy

Headache and sleep disturbances represent some of the most commonly reported disorders in clinical practice, causing considerable individual disability and socio-economical burden. The link between headache and sleep includes five different possible types of relationship : 1. headache disorders occurring exclusively or mainly during sleep; 2. sleep disorders directly causing headache; 3. sleep disturbances caused by headache; 4. comorbidity of sleep disturbances and headache disorders; 5. underlying disorders leading both to headache and sleep disturbances [1]. A preferential or exclusive occurrence of attacks at night-time is well documented in some primary headaches, such as migraine, cluster headache (CH) and hypnic headache (HH). In case of recent-onset nocturnal headaches, it is mandatory to rule out a secondary form, in particular intracranial hypertension and uncontrolled arterial hypertension. The occurrence of attacks at night-time or in the early morning has been extensively ascertained in migraine without aura. The preferential emergence of migraine attacks during sleep and/or upon awakening progressively increases in relation to the age of patients. The percentage of subjects with sleep-related migraine was found to be 16% in patients aged 20-30 and 58% in migraineurs aged 60-70, respectively [2]. The association between CH and sleep has been long recognised, due to the extremely frequent occurrence of attacks during nocturnal sleep. In the majority of patients attacks occur with “clock-like regularity” at particular times during 24 hours, often awakening patients from sleep. Approximately 75% of CH attacks occur between 9 pm and 10 am. Attacks usually occur about 90 minutes after the patient falls asleep, which coincides with the first REM sleep, although this is less apparent in chronic CH [3]. HH is a primary headache that is characterized by recurring headache attacks developing only during sleep (occurring mostly between 2 am and 4 am), generally in the elderly population. HH is significantly more common in women. The pain is usually mild to moderate, but may be severe, whereas the duration of attacks ranges from 15 to 240 minutes. Most HHs are bilateral and the most mentioned location of pain are the fronto-temporal area or holocranial/diffuse. The natural course of HH remains unknown. Some patients show an episodic course, while other subjects present and episodic-relapsing remitting trend over time. A history of migraine is common in HH patients, possibly due to a common pathophysiological predisposition. In some patients HH appears to be as an evolution from a pre-existing migraine condition over time.

References

1. Freedom T, Evans RW. Headache and sleep. Headache 2013;53: 1358-1366.

2. Gori S, Lucchesi C, Morelli N, Maestri M, Bonanni E, Murri L. Sleep-related migraine occurrence increases with aging. Acta Neurol Belg 2012;112: 183-187.

3. Rains JC, Poceta JS. Sleep-related headaches. Neurol Clin 2012;30: 1285-1298.

S51 Headache and Physiotherapy

César Fernández-de-las-Peñas (cesar.fernandez@urjc.es)

Departamento de Fisioterapia, Terapia Ocupacional, Rehabilitación y Medicina Física, Universidad Rey Juan Carlos, Alcorcón, Madrid, Spain

Headache is the medical problem most commonly observed by neurologists. Non-pharmacological treatments, particularly physical therapy, are commonly demanded by individuals with headaches, but their scientific evidence of effectiveness is conflicting. The current lecture will provide an updated discussion on what is supported by current scientific evidence about physical therapy for tension type headache (TTH), migraine, or cervicogenic headache (CeH) and which gaps there still may be in our understanding of these interventions. Today, there are several physical therapies including spinal joint manipulation/mobilization, soft tissue interventions, therapeutic exercises and needling therapies that are proposed to be effective for the management of headaches. Current evidence has shown that the effectiveness of these interventions will depend on proper clinical reasoning since not all interventions are equally effective for all headache pain conditions. For instance, since the pathogenesis of TTH is associated to musculoskeletal disorders, particularly muscular impairments, manual therapies targeting muscle trigger points and other related tissues may be effective for this headache. On the contrary, the evidence of physiotherapy in migraine is less robust than for TTH, which seems to be expected since migraine pathogenesis involves activation of sub-cortical structures and the trigemino-vascular system. Finally, since CeH may be more related to upper cervical spine, spinal manipulations or mobilizations should be the therapeutic options. In fact, the inconsistent results in the current literature can be related to the fact that maybe not all therapeutic interventions are appropriate for all patients with TTH, migraine or CeH, or maybe not all individuals with a particular headache will benefit from a specific intervention. In addition, multimodal approaches including different interventions are more effective than isolated therapeutic approaches for with TTH, migraine and CeH. All these topics will be further discussed in this plenary lecture.

S52 Migraine and Psychiatric Comorbidity

Maria Pia Prudenzano

Headache Center, “L. Amaducci” Clinic, Department of Basic Medical Sciences, Neurosciences and Sense Organs, University of Bari, Italy

Most of the studies concerning psychiatric comorbidity in migraine have focused on anxiety and depression disorders. According to these investigations results, migraineurs are two to four more likely to suffer from depression than non-migraineurs. When considering anxiety disorders, panic disorder and generalised anxiety disorder have been found more frequently in migraine than in non-migraine individuals. Rates of psychiatric comorbidity are higher in chronic when compared with episodic migraine. More recently also other psychiatric disorders have gained attention. A meta-analysis found a migraine prevalence of 34,8% in subjects with bipolar disorder. Post-Traumatic Stress Disorder was found to be more prevalent in migraine patients than in the general population. Psychiatric comorbidity is associated with more severe migraine symptoms and disability. Longitudinal studies demonstrated that the comorbidity with anxiety and depression may be a risk for migraine chronification. Available data supports a bidirectional relationship between migraine and depression. Several other theories have been proposed to explain psychiatric comorbidity of migraine. Migraine and comorbid disorders might share a genetic or environmental risk factor producing a brain state which predisposes to both disorders. Neurotransmitter dysfunctions, inflammatory activity, hormonal influences, sensitization of both sensory and emotional brain network might all contribute. Neuroimaging studies in migraineurs show structural, functional and connectivity abnormalities of brain regions playing an role in emotional response to pain, affectivity and mood. Similar findings were obtained with analogous methods in people with psychiatric disorders. Further investigations are needed to determine if such imaging findings might express a brain state predisposing to both migraine and psychiatric comorbidity, if they might be the result of recurrent migraine attacks enhancing emotional responses and leading to psychiatric comorbidity or if the psychiatric disease might induce both these brain changes and altered emotional responses to painful stimuli. Comorbid psychiatric conditions should always be screened by appropriate diagnostic interviews and tools before planning a treatment for a patient with migraine. In the case of psychiatric comorbidity, drugs that are known to be effective for migraine prevention but also to worsen the comorbid psychiatric disorder should be avoided (i.e. topiramate in migraine and depression). Drugs able to control both disorders, possibly in monotherapy, should be preferred (i.e. propranolol in migraine and mild anxiety). The migraine treatment plan might need to be discussed and coordinated with a psychiatrist. An integrated non pharmacologic and a behavioural therapy may be combined with drug therapy to obtain a synergistic effect with enduring benefits.

References

1. Buse DC, Silberstein SD, Manack AN, Papapetropoulos S, Lipton RB. Psychiatric comorbidities of episodic and chronic migraine. J Neurol. 2013; 260(8):1960-9.

2. Seng EK, Seng CD. Understanding migraine and psychiatric comorbidity. Curr Opin Neurol. 2016;29(3):309-13

3. Minen MT, Begasse De Dhaem O, Kroon Van Diest A, Powers S, Schwedt TJ, Lipton R, Silbersweig D. Migraine and its psychiatric comorbidities. J Neurol Neurosurg Psychiatry. 2016 Jul;87(7):741-9

EHF Oral Presentation

O1 New pharmacology, expression profiles and probes of CGRP receptors

Debbie L. Hay1 (dl.hay@auckland.ac.nz)

School of Biological Sciences, The University of Auckland, Auckland, New Zealand

There is high interest in blocking the actions of the neuropeptide calcitonin gene-related peptide (CGRP) for the treatment of migraine and other headache disorders. Small molecule antagonists and antibodies that target CGRP itself or a CGRP receptor have been developed for clinical use. Most efforts have focussed on the canonical CGRP receptor, comprising the calcitonin receptor-like receptor (CLR) with receptor activity-modifying protein 1 (RAMP1). However, CGRP can potently activate a closely-related receptor; the AMY1 receptor, which is a complex of RAMP1 with the calcitonin receptor (CTR). Very few studies have directly compared the pharmacology and expression profile of both of these receptors and the relevance of the AMY1 receptor to CGRP biology is still an open question.

We profiled the affinity of a peptide antagonist (CGRP8-37) and four small molecule antagonists (olcegepant, telcagepant, MK-3207 and rimagepant) at both CGRP-responsive receptors. Selectivity of these antagonists between these two receptors varied but was generally lower than expected. We developed a novel high affinity peptide antagonist of both CGRP-responsive receptors to use as a probe for global blockade of CGRP receptor activity. We also expanded the molecular toolbox for studying both CGRP receptors through the synthesis of fluorescent peptides and validation of antibodies for CTR and RAMP1. Using these tools, we have been probing the brain for AMY1 receptor expression.

The data show that many CGRP receptor antagonists are not highly selective for the CLR/RAMP1 CGRP receptor and have significant affinity at the CTR/RAMP1 AMY1 CGRP-responsive receptor. Our studies are providing new insights into the pharmacology and spatial relationships of CGRP receptors in physiologically relevant tissues, and collectively suggest that the AMY1 receptor could be of importance to CGRP activity in migraine.

O2 Efficacy, Safety, and Tolerability of Orally Administered Atogepant for the Prevention of Episodic Migraine: Results from a Phase 2b/3 Study

Peter J. Goadsby1 David W. Dodick,2 Joel M. Trugman,3 Michelle Finnegan,3 Hassan Lakkis,3 Kaifeng Lu,3 Armin Szegedi3

1NIHR-Wellcome Trust King’s Clinical Research Facility, King’s College London, UK; 2Mayo Clinic, Phoenix, AZ, USA; 3Allergan plc, Madison, NJ, USA
Correpondence: Peter J. Goadsby (kuang_amy@allergan.com)

Objectives: Atogepant is a novel, oral CGRP receptor antagonist in development for the prevention of migraine. This study evaluated the efficacy, safety, and tolerability of atogepant versus placebo for the prevention of episodic migraine.

Methods: Multicenter, randomized, double-blind, placebo-controlled, parallel-group study (NCT02848326). Adult patients with a history of migraine, with or without aura, were included. Patients with 4-14 migraine days in the 28-day baseline period were randomized 2:1:2:1:2:1 to placebo, atogepant 10 mg QD, 30 mg QD, 30 mg BID, 60 mg QD, or 60 mg BID, respectively, and treated for 12 weeks for the prevention of episodic migraine. Primary efficacy endpoint was change from baseline in mean monthly migraine days across the 12-week treatment period. Safety and tolerability were evaluated.

Results: Of patients randomized (n=834), 825 were in the safety population, and 795 were included in the primary efficacy population. Mean age was 40.1 years; majority white (76.1%), female (86.5%), and had not taken preventive treatment for migraine in the past (n=593, 71.9%). At baseline, patients reported an average 7.67 (SD=2.49) migraine days. Mean change in migraine days across the 12-week treatment period (adjusted p-values for comparisons versus placebo): placebo (-2.85), atogepant 10 mg QD (-4.00, p=0.0236), 30 mg QD (-3.76, p=0.0390), 60 mg QD (-3.55, p=0.0390), 30 mg BID (-4.23, p=0.0034), 60 mg BID (-4.14, p=0.0031). A total of 480 patients (58.2%) reported treatment-emergent adverse events (AEs); 170 (20.6%) were considered treatment-related. The most common treatment-emergent AEs were nausea, fatigue, constipation, upper respiratory tract infection, nasopharyngitis, urinary tract infection, and blood creatine phosphokinase increase (reported in >5% of patients in at least one treatment group). Seven patients (0.8%) reported serious AEs; none were considered related to treatment. Following daily dosing, 11 cases of ALT/AST elevations ≥3x the upper limit of normal were reported; the number of cases were balanced across treatment groups (placebo [n=3], 10mg QD [n=2], 30mg QD [n=1], 60mg QD [n=3], 30mg BID [n=1], 60mg BID [n=1]).

Conclusions: All 5 atogepant treatment arms showed statistically significant differences from placebo in reductions from baseline in mean migraine days across the 12-week treatment period. Reductions in mean migraine days and treatment differences versus placebo were clinically relevant. Atogepant was well-tolerated with no treatment-related serious adverse events.

O3 Alterations in CGRP and PACAP38 levels in cluster headache

Agneta Snoer1&, Anne Luise Haulund Vollesen1&, Rasmus Paulin Beske1, Song Guo1, Jan Hoffmann2, Jan Fahrenkrug3, Niklas Rye Jørgesen4,5, Torben Martinussen6, Rigmor Højland Jensen1, Messoud Ashina1

1Danish Headache Center and Department of Neurology, Rigshospitalet Glostrup, Faculty of Health and Medical Sciences, University of Copenhagen, Denmark; 2Department of Systems Neuroscience, University Medical Center Hamburg-Eppendorf, Hamburg, Germany; 3Department of Clinical Biochemistry, Bispebjerg Hospital, University of Copenhagen, Denmark; 4Department of Clinical Biochemistry, Rigshospitalet Glostrup, Denmark; 5OPEN, Odense Patient Data Explorative Network, Odense University Hospital/Institute of Clinical Research, University of Southern Denmark, Odense, Denmark; 6Section of Biostatistics, University of Copenhagen, Denmark
Correspondence: Messoud Ashina (ashina@dadlnet.dk)

& The first two authors contributed equally to the study

Background and aim: A key element in the cluster headache (CH) attack is activation of the trigemino-autonomic reflex of which the vasoactive peptides calcitonin gene-related peptide (CGRP), vasoactive intestinal polypeptide (VIP) and pituitary adenylate cyclase-activating polypeptide-38 (PACAP38) are known mediators. Here, we investigated these peptides during CGRP induced CH attacks.

Methods: We included patients with episodic CH in bout (eCHa)-, in remission (eCHr) and chronic patients (cCH). The study was conducted as a randomized, double-blind, placebo controlled, two-way cross-over study during which we measured CGRP, VIP and PACAP38 at baseline, in response to CGRP and placebo infusion. In addition, we compared our baseline findings with historical data on migraine patients and healthy controls.

The study was approved by the Regional Committee on Health Research Ethics of the Capital Region (H-15006836) and registered at clinicaltrials.gov (identifier NCT02466334).

Results: In total 31 (9 eCHa, 9 eCHr and 13 cCH) patients completed the study. Blood samples from 11 CGRP induced CH attacks were collected. At baseline CGRP levels were significantly higher in eCHr patients compared to cCH patients (100.6 ± 36.3 pmol/l vs. 65.9 ± 30.5 pmol/l, p=0.0114), and post-hoc analyses revealed significantly higher CGRP levels in eCHa (88.4 ± 29.1 pmol/l, p<0.0001), eCHr (p<0.0001) and cCH (p=0.0202) compared to controls (44.8 ± 11.4 pmol/l). PACAP38 levels in eCHa patients were significantly higher compared to cCH patients (4.0 ± 0.8 pmol/l vs. 3.3 ± 0.7 pmol/l, p=0.0326). We found no change in PACAP-38 levels in response CGRP infusion or to CH attacks. There was no difference in baseline levels of VIP in between CH group. CGRP infusion caused a significant increase in VIP (p<0.0001), but no additional increase was seen in response to attack.

Conclusion: This is the first study to investigate CGRP, PACAP38 and VIP in all three disease states. The lower baseline levels of CGRP in cCH patients suggest basic pathophysiological differences in between phenotypes.

O4 Medication overuse in a post-hoc analysis of phase 3 placebo-controlled studies of galcanezumab in the prevention of episodic and chronic migraine

Sheena K. Aurora, Paula A Morrow, Dustin D Ruff, Eric Pearlman

Eli Lilly and Company, Indianapolis, IN 46285, USA
Correspondence: Sheena K. Aurora (sheena.aurora@lilly.com)

Background: Galcanezumab, a humanised monoclonal antibody that selectively binds to the calcitonin gene-related peptide, was superior to placebo in the prevention of episodic and chronic migraine in three phase 3 studies. Medication overuse is common among migraine patients. This study investigated medication overuse in a post-hoc analysis of phase 3 placebo-controlled studies of galcanezumab.

Methods: This post-hoc analysis comprised EVOLVE-1 and -2 (pooled), and REGAIN, which were phase 3, double-blind, randomised, placebo-controlled studies in patients with episodic migraine (4 to 14 monthly migraine headache days [MHDs]; EVOLVE-1 and -2) and chronic migraine (≥15 monthly MHDs per month for >3 months; REGAIN). Patients in each study were randomised 2:1:1 to monthly subcutaneous injections of placebo or galcanezumab 120 or 240 mg/month for 3-6 months. Headache medication overuse was collected in the electronic patient-reported outcome diary and determined using criteria adapted from the International Classification of Headache Disorders third edition. Mean changes in MHDs and the proportion of patients with medication overuse after randomisation were estimated via mixed modelling.

Results: The number of patients with baseline medication overuse in the placebo, galcanezumab 120-mg or galcanezumab 240-mg groups, respectively, was: 298 (39.5%), 140 (18.8%), and 139 (19.5%) for EVOLVE-1 and -2, and 353 (79.5%), 178 (66.0%), and 177 (62.0%) for REGAIN. Both galcanezumab doses demonstrated a statistically significant improvement compared with placebo (p<0.001) for overall least square mean change in monthly MHD in patients with baseline medication overuse (EVOLVE-1 and -2: placebo = -3.07; galcanezumab 120 mg = -5.89; galcanezumab 240 mg = -5.42; REGAIN: placebo = -2.46; galcanezumab 120 mg = -5.29; galcanezumab 240 mg = -4.74). Patients with baseline medication overuse had significantly lower average monthly medication overuse rates for both galcanezumab doses relative to placebo (p<0.001) in all three studies (EVOLVE-1 and -2: placebo = 39.5%; galcanezumab 120 mg = 18.8%; galcanezumab 240 mg = 19.5%; REGAIN: placebo = 79.5%; galcanezumab 120 mg = 66.0%; galcanezumab 240 mg = 62.0%). These findings were consistent with those in patients without baseline medication overuse, as well as in the overall intent-to-treat population in all three studies.

Conclusions: Both doses of galcanezumab significantly improved mean monthly MHDs compared with placebo in patients with baseline medication overuse. Average monthly medication overuse decreased with galcanezumab compared with placebo in patients with baseline medication overuse. Galcanezumab is at least as efficacious in patients who overuse acute medications as in those who do not.

Trial registration: ClinicalTrials.gov Identifiers: NCT02614183, NCT02614196, NCT02614261

Ethics approval

This study was conducted in accordance with the International Conference on Harmonization Guidelines for Good Clinical Practice, the Declaration of Helsinki, and with approval by each institution’s ethical review board. Patients provided written informed consent.

O5 Study CGAL: a placebo-controlled study of galcanezumab in patients with episodic cluster headache: results from the 8-week double-blind treatment phase

James M. Martinez1, Peter J. Goadsby2,3, David Dodick4, Jennifer N. Bardos1, Tina M. Myers Oakes1, Brian A. Millen1, Chunmei Zhou1, Sherie A. Dowsett1, Sheena K. Aurora1, Jyun Yan Yang1, Robert R. Conley1,5

1Eli Lilly and Company, Indianapolis, IN, USA; 2University of California, San Francisco, CA, USA; 3NIHR-Wellcome Trust King’s Clinical Research Facility, King’s College London, London, UK; 4Mayo Clinic, Phoenix, AZ, USA; 5University of Maryland School of Medicine, Baltimore, MD, USA
Correpondence: Sherie A. Dowsett (dowsett_sherie_a@lilly.com)

Objective: We assessed the efficacy and safety of galcanezumab, a humanized monoclonal antibody that selectively binds to calcitonin gene-related peptide (CGRP), in individuals with episodic cluster headache.

Methods: This study comprised a screening period; a prospective baseline period; an 8-week, double-blind, placebo-controlled treatment period; and a washout period. We present findings from the double-blind treatment period. Participants were randomized 1:1 to galcanezumab 300 mg (N=49) or placebo (N=57) subcutaneously (SC) once monthly. The primary endpoint was overall mean change from baseline in weekly cluster headache attack frequency across Weeks 1- 3. The key (gated) secondary endpoint was the proportion of participants achieving a reduction from baseline of ≥50% in weekly cluster headache attack frequency at Week 3.

Results: The mean change in weekly cluster headache attack frequency across Weeks 1-3 was -8.7 for galcanezumab versus -5.2 for placebo (treatment groups difference in mean change, -3.5 [95% CI -6.7, -0.2]; p=0.036). The percentage of participants achieving ≥50% reduction in weekly cluster headache attack frequency at Week 3 was 76% for galcanezumab versus 57% for placebo (p=0.04). Four participants (8%) in the galcanezumab group discontinued during the double-blind period versus 12 (21%) in placebo. In the placebo group, 8 (14%) discontinued due to lack of efficacy versus 1 (2%) with galcanezumab (p=0.036). There were no clinically meaningful differences between treatment groups on tolerability or safety parameters except for a greater incidence of injection site pain with galcanezumab versus placebo (8.2% vs 0%, p=0.043).

Conclusion: In individuals with episodic cluster headache, galcanezumab reduced the weekly cluster headache attack frequency across Weeks 1-3 and resulted in a greater percentage achieving a ≥50% reduction in the weekly cluster headache attack frequency at Week 3. The safety profile of galcanezumab in this population was similar to that seen previously in patients with episodic or chronic migraine.

O6 Migraine with prolonged aura: a rare and peculiar condition? Results form a prospective diary-aided study

Michele Viana1, Grazia Sances G1, Mattias Linde2, Giuseppe Nappi1, Peter Goadsby3 and Cristina Tassorelli1,4.

1Headache Science Center, C. Mondino National Neurological Institute, Pavia, Italy; 2Department of Neuroscience, Norwegian University of Science and Technology, Trondheim, Norway; 3Headache Group – NIHR-Wellcome Trust Clinical Research Facility, King’s College London, London, UK; 4Department of Brain and Behavioral Sciences, University of Pavia
Correspondence: Michele Viana (michele.viana@ymail.com)

Introduction: Migraine with prolonged aura (PA - defined as an aura including at least one symptom for >1hr) it is considered to be a rare phenomena. Indeed, while the first version of the ICHD included migraine with PA, the subsequent two versions of the ICHD removed PA from the classification. Those auras with at least one symptom lasting more than 60 minutes and less than 7 days are classified as “probable migraine with aura (PA)”. The term “probable” used in such classification indicates suspicion as to whether the symptom is migraine aura and we feel it does not help to categorise auras of a longer duration. Moreover there is limited literature on PA with no prospective studies. The aim of this study is to characterize prospectively the phenotype and prevalence of PA.

Results: Two hundred and twenty-four patients suffering from migraine with aura were recruited from the Headache Centers of Pavia and Trondheim. Patients prospectively described, on an ad hoc diary, each aura symptom (AS), the duration of AS and headache, and headache features. Seventy-two patients recorded three consecutive auras in their diaries. 19 (26%) of patients suffered at least one PA. Out of 216 recorded auras, 38 (17%) were PAs. We compared PAs with non-PAs with respect to 20 features (Table 1); PAs were characterized by a higher number of non-visual symptoms (non-VS) (p<0.001). No other differences were found. We obtained similar results when we compared auras with at least one symptom with a duration of >2 hrs (n=23) or >4 hrs (n=14) with the the others (n=193 and n=202 respectively). Five per cent of aura symptoms were longer than four hours.

Conclusion: PAs are quite common representing 17% of all auras and occurring in 26% of patients. PAs phenotypically are similar to other auras except for a higher number of non-visual symptoms (non-VSs). This latter finding is not surprising if we consider that an AS with a longer duration is likely related to a cortical spreading depression (CSD) that proceeds along a longer path on the respective brain area. Such CSD therefore will involve more easily other adjacent brain areas, conferring a higher number of non-VSs to PA. The substantial phenotypical similarities between PA and the other auras is maintained also when we increase the limit of duration to 2 and/or 4 hrs.

Table 1 (abstract O6).

Characteristics of PA (auras with at least 1 symptoms lasting >1 h) and NON-PA

Variable

PROLONGED AURAS (PA)

NON-PA

Sig.

Number

38

178

 

Visual symptoms (VS)

37 (97)

175 (98)

0.69

 • DVP

19 (50)

77 (43)

0.44

 • Positive

23 (60)

119 (67)

0.45

 • Negative

12 (31)

70 (39)

0.37

 • Number of elementary visual disturbance^ per aura

1.97 (1.05)

1.94 (0.93)

0.83

Sensory symptoms (SS)

26 (68)

49 (27)

<0.0001

Dysphasic symptoms (DS)

12 (31)

10 (7)

<0.0001

Number of symptoms (VS, SS, DS)/aura

  

<0.0001

 • 1

10 (26)

127 (71)

 

 • 2

19 (50)

46 (26)

 • 3

9 (23)

5 (3)

Time relation between aura symptoms in one aura

  

0.28

 • B* starts simultaneously with A*

11 (42)

14 (27)

 

 • B starts during A

11 (42)

18 (37)

 • B starts when A ceased

2 (8)

5 (10)

 • B starts after an interval of time after A has ceased

2 (8)

12 (24)

Headache

38 (100)

159 (83)

0.10

 • Started before/together with Aura (n=157)

7 (22)

27 (21)

0.88

 • Intensity (n=192)

2.3 (0.8)

2.2 (0.8)

0.59

 • Unilateral pain (n=192)

27 (75)

100 (64)

0.21

 • Throbbing pain (n=187)

17 (47)

71 (47)

0.98

 • Pain aggravated by physical activity (n=189)

27 (73)

98 (65)

0.32

 • Associated symptom: nausea (n=192)

23 (62)

101 (65)

0.73

 • Associated symptom: vomiting (n=189)

8 (23)

25 (16)

0.35

 • Associated symptom: photophobia (n=192)

29 (78)

126 (81)

0.68

 • Associated symptom: phonophobia (n=191)

23 (62)

99 (64)

0.81

 • Associated symptom: osmophobia (n=189)

6 (43)

53 (34)

0.31

Data are presented as means (SD) for continuous data and as n (% of column) for categorical data. DVP: disturbances of visual perception (i.e. blurred/foggy vision, ‘like looking through heat waves or water’, deformed images,…). . ^In the analysis, the authors dissected every visual into elementary disturbance as reported by Viana et al. 2017 (Cephalalgia 37: 979–989). *A and B can be referred to 1st and 2nd aura symptoms or 2nd and 3rd aura symptoms (67 auras had at least 2 symptoms, 14 auras had 3 symptoms). When two symptoms started simultaneously, we designated the first completing symptom as A

O7 Ten factors associated to migraine chronification: a cross-sectional study on 318 long-term migraine sufferers

Michele Viana1, Sara Bottiroli1, Grazia Sances1, Giuseppe Nappi1, Cristina Tassorelli1,2

1Headache Science Center, National Neurological Institute C. Mondino; 2Department of Brain and Behavioural Sciences, University of Pavia, Pavia, Italy
Correspondence: Michele Viana (michele.viana@ymail.com)

Introduction: Factors implicated in the evolution of episodic migraine (EM) into chronic migraine (CM) are mostly elusive. Medication overuse (MO) is considered to be one of the main determinants, but other possible clinical and psychological factors can play a role. The aim of this study was to identify some of these factors.

Method: We enrolled consecutive migraine patients in two groups: long history of episodic migraine (EM) and CM with medication overuse (CM-MO) and compared their clinical (n=49) and psychological variables (n=8) in a cross-sectional study. The study was approved by the Local Ethic Committee (on 5th March 2014) and informed consent was obtained from all the patients.

Results: Three hundred and eighteen patients were enrolled, of which 156 were EM and 162 were CM-MO patients. The mean age was 42.1±10.3, 80.8% were female. The duration of migraine (before CM-MO onset in the CM-MO group) was 24.6 years in EM and 24.0 years in CM-MO (p=0.57). After the multivariate analysis (Table 1), the factors associated to CM-MO were: age of onset of migraine (earlier), use of at least one migraine preventive medication, marital status (married or separated/divorced/widowed marital status versus unmarried), physical inactivity, history of depression, insomnia associated to use of hypnotics (versus absence of insomnia), previous use of migraine preventive medications, traumatic head injuries, snoring, use of combined oral contraceptives and childhood traumas.

Conclusion: We considered several aspects that may be involved in the development of CM-MO. A multivariate analysis identified ten factors belonging to five different areas (migraine history, socio-demographic/lifestyle habits, medical history, gynaecological and psychological factors), meaning that CM-MO onset is likely influenced by a complex mixture of factors. This information is useful when planning strategies to prevent and manage CM-MO.

Funding

This work was supported by grants of the Italian Ministry of Health to RC 2013-2015.

Table 1 (abstract O7).

Second multivariate logistic regression equations performed for predicting the tendency to be a CM-MO versus EM patient

Variable

Sign

OR 95% CI

SOCIO-DEMOGRAPHIC and LIFESTYLE VARIABLES

 Marital Status

  - Single

 

Ref

  - Married

0.002

3.65 (1.63-8.19)

  - Separated/divorced/Widowed

0.031

4.19 (1.13-15.47)

 Physical Activity

0.029

0.42 (0.19-0.91)

MIGRAINE CHARACTERISTICS

 Age of onset

0.016

0.94 (0.89-0.98)

 Use of at least one migraine preventive medication (whenever for EM, before chronification + MO onset for CM-MO)

0.014

2.36 (1.18-4.71)

OBSTETRICIAN AND GYNECOLOGICAL HISTORY

 Combined Oral Contraceptives (previous/current use vs absent use)

0.031

3.38 (1.10-10.3)

FAMILY HYSTORY

 Family history for headache

0.082

2.63 (0.88-7.86)

MEDICAL HYSTORY

 Depression

0.012

2.91 (1.25-6.73)

 Traumatic head injuries

0.002

3.54 (1.57-7.99)

 Insomnia

  - no

 

Ref

  - only insomnia

0.94

1.02 (0.47-2.20)

  - insomnia + use of hypnotic drugs

0.006

5.59 (1.65-18.93)

 Snoring

0.036

2.24 (1.05-4.79)

PSYCHOLOGICAL VARIABLES

 Childhood Trauma Questionnaire (total score)

0.012

1.48 (1.09-2.02)

O8 Long-term effects of the non-paralytic botulinum toxin A molecule BiTox in migraine animal models

Ramla AbuukarAbdullahi1,2, Joseph O. Lloyd1, Martyn G Jones1, Giorgio Lambru2, Adnan Al-Kaisy3, Bazbek Davletov4, Anna P. Andreou1,2

1Headache Research, Wolfson CARD, King's College London; 2Headache Centre, Guy's and St Thomas' NHS Trust; 3Pain Management and Neuromodulation Centre, Guy's and St Thomas' NHS Trust; 4Department of Biomedical Science, University of Sheffield
Correspondence: Anna P. Andreou (anna.andreou@headache-research.com)

Background

Although botulinum toxin A is an established preventive treatment for migraine, its toxicity and the unwanted muscle paralysis are major limitations of the achieved efficacy. Recombinant botulinum Clostridial chimeras that lack this paralytic effect, have been recently developed. Of them, BiTox preserves its inhibitory actions on neurotransmitter release from sensory neurons, while it lacks muscle paralytic effects. In this project we aimed to investigate the long-term actions of BiTox in the trigeminal ganglia and trigeminocervical system (TCC) in migraine animal models.

Methods

In male rats, Bitox (200 ng) or saline were injected over the peri-orbital areas (100 nl). Seven days later, mechanical (von Frey) and electrical trigeminovascular activation thresholds were assessed bilaterally on first order neurons in the trigeminal ganglia by means of extracellular electrophysiology, by a researcher blinded to experimental groups. In a separate set of experiments, seven days following injections, the superior sagittal sinus was electrically stimulated and TCC tissue was collected and processed for the presence of Fos -positive cells, using a standard immunohistichemistry protocol. Cell counting was performed by a researcher blinded to experimental groups.

Results

In first order neurons in the trigeminal ganglia, BiTox significantly increased the mechanical thresholds of Aδ-fibers compared to saline (P < 0. 005). Electrical activation thresholds, assessed as the minimum voltage required to induce evoked action potentials, were significantly increased in the BiTox treated group compared to saline in both Aδ- and C-fibers (P < 0. 005). The number of Fos-positive cells was significantly lower in the TCC tissue collected from animals treated with BiTox, compared to the saline treated group (P < 0. 05).

Conclusion

Non-paralytic botulinum-like molecules can be important modulators of trigeminovascular nociceptive processing, offering a promising and significant advancement in the preventive therapeutic options for migraine patients.

Ethics Approval

All experiments were conducted under UK Home Office project licence in accordance with the Animal (Scientific Procedures) Act (1986) and conformed to the ARRIVE guidelines. All researchers involved in the conduction of experiments were personal licence holders and approval was granted by the King’s College London Animal Welfare and Ethical Review Board.

O9 White matter microstructure changes in migraine: a diffusional kurtosis imaging study

Sait Ashina1, Bettina Conti2, Benjamin Ades-Aron2, Yvonne Lui2, Mia Minen3, Dmitry Novikov2, Timothy Shepherd2, and Els Fieremans2

1Departements of Neurology, Anesthesia, Critical Care and Pain Medicine, Harvard Medical School, Beth Israel Deaconess Medical Center, Boston, MA, USA; 2Department of Radiology, New York University School of Medicine, NYU Langone Medical Center, New York, NY, USA; 3Department of Neurology, New York University School of Medicine, NYU Langone Medical Center, New York, NY, USA
Correspondence: Sait Ashina (sashina@bidmc.harvard.edu)

OBJECTIVES: Migraine can be associated with increased risk for stroke and white matter (WM) abnormalities, though the linking mechanisms remain unknown. Diffusion MRI is a powerful method to study microstructural changes in WM non-invasively. Diffusion tensor imaging (DTI) studies have revealed conflicting whether WM integrity is altered in migraine patients. We investigated the normal-appearing WM in migraineurs using diffusional kurtosis imaging (DKI), a clinically-feasible extension of DTI, which also examines the non-Gaussian diffusion effects of water known to occur in the brain.

METHODS: The local institutional review board approved a retrospective analysis of 3-T MRI diffusion data (1.7x1.7mm in-plane resolution, 3.0mm slice-thickness,50 slices, b = 0, 250, 1000, & 2000 s/mm2 along 84 diffusion directions, TR/TE = 3500/95ms) of 49 migraine patients (age range 21-65, mean 40.65 +/- 12.77 years; 8 male) and 37 non-migraine controls (age range 18-64, mean 41.16 +/- 13.11 years; 11 male). Migraine diagnosis was assigned using ICHD-3 criteria. Patients were also divided in 2 groups: episodic migraine (EM) and chronic migraine (CM). Diffusion data was processed to generate parameter maps of standard DTI metrics (mean, radial, axial diffusivity and fractional anisotropy), as well as mean, radial and axial kurtosis (MK, RK & AK). Using Tract-Based Spatial Statistics (TBSS), skeletonized voxel-wise analysis was performed to identify areas of differences between the groups for the diffusion metrics using FSL's 'randomise' feature while co-varying for age and gender.

RESULTS: Of the 49 migraine patients, 20 reported chronic migraine (CM) (age range 21-58, mean 40.05 +/- 11.84 years; 4 men), and 29 reported episodic migraines (EM) (age range 22-65, mean 41.07 +/- 13.60 years; 4 men). Sixteen patients, with age ranging from 22 to 65 (mean 36.87 +/- 13.32; 3 men), reported migraine with aura. TBSS analysis revealed significantly (p < 0.05) decreased RK and increased AK in migraineurs compared to controls. Secondary TBSS analysis also found significantly increased AK, and decreased RK in EM compared to controls, while we found no differences between CM and controls, or between EM and CM. TBSS also found increased AK and MK between migraineurs with aura (MA) and without aura (MO), while RK was decreased in both MA and MO compared to controls and MA. No changes were found in any DTI metric.

CONCLUSION: This cross-sectional study found DKI parameters being more sensitive than DTI parameters in detecting WM alterations in migraineurs compared to controls. Changes were found in the genu corpus callosum, corona radiata and internal capsule, regions previously (with DTI) shown to be affected in migraine. Remarkably, the observed increase in AK in migraineurs versus controls is the same directional change (increase), though to a smaller extent, as seen in acute stroke infarcts compared to normal appearing white matter, and potentially could be explained here by changes in the intra-axonal environment. The decrease in RK, on the other hand, may suggest myelin breakdown or atrophy. A prospective longitudinal study to explore the role of DKI in predicting migraine course, disease progression and development of comorbidities is warranted.

O10 Meningeal contribution to migraine pain: a 3T magnetic resonance angiography study

Sabrina Khan1*, Faisal Mohammad Amin1, Casper Emil Christensen1, Hashmat Ghanizada1, Samaira Younis1, Anne Christine Rye Andersen1, Patrick J. H. de Koning2, Henrik B. W. Larsson3, Messoud Ashina1

1Danish Headache Center and Department of Neurology, Rigshospitalet Glostrup, Faculty of Health and Medical Sciences, University of Copenhagen, Denmark; 2Division of Image Processing, Department of Radiology, Leiden University Medical Center, Leiden, Netherlands; 3Functional Imaging Unit, Department of Clinical Physiology, Nuclear Medicine and PET, Rigshospitalet, Faculty of Health and Medical Sciences, University of Copenhagen, Denmark
Correspondence: Sabrina Khan (sksabrinakhan@gmail.com)

The origin of migraine pain is unknown but possibly implicates the dura mater, which is pain sensitive in proximity to the meningeal arteries. Therefore, subtle changes in vessel caliber on the head pain side could reflect activation of dural perivascular nociceptors that leads to migraine headache. To test this hypothesis, we measured circumference changes of cranial arteries in patients with cilostazol-induced unilateral migraine without aura using 3T high-resolution magnetic resonance angiography (MRA). The middle meningeal artery (MMA) was of key interest, as it is the main supply of the dura mater. We also measured the superficial temporal (STA) and external carotid (ECA) arteries as additional extracranial segments, and the middle cerebral (MCA), the cerebral and cavernous parts of the internal carotid (ICAcerebral and ICAcavernous), and the basilar (BA) arteries as intracranial arterial segments. MRA scans were performed at baseline, migraine onset, after sumatriptan, and ≥27 hours after migraine onset.A total of 30 patients underwent MRA scans, of which 26 patients developed unilateral attacks of migraine without aura and were included in the final analysis. Eleven patients treated their migraine with sumatriptan while the remaining 15 patients did not treat their attacks with analgesics or triptans.

At migraine onset, only MMA exhibited greater circumference increase on the pain side (0.24 ± 0.37 mm) compared to the non-pain side (0.06 ± 0.38 mm) (p=0.002). None of the remaining arteries revealed any pain-side specific changes in circumference (p>0.05), but exhibited bilateral dilation. Sumatriptan constricted all extra-cerebral arteries (p<0.05). In the late phase of migraine, we found sustained bilateral dilation of MMA.

In conclusion, onset of migraine is associated with increase in MMA circumference specific to the head pain side. Our findings suggest that vasodilation of MMA may be a surrogate marker for activation of dural perivascular nociceptors, indicating a meningeal site of migraine headache.

O11 Migraine induction with calcitonin gene-related peptide in patients from erenumab trials

Casper Emil Christensen&; Samaira Younis&; Marie Deen; Sabrina Khan; Hashmat Ghanizada; Messoud Ashina

1Danish Headache Center and Department of Neurology, Rigshospitalet Glostrup, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
Correspondence: Messoud Ashina (ashina@dadlnet.dk)

& These authors contributed equally to this work.

Background: Erenumab has recently been approved by the US Food and Drug Administration as a monoclonal antibody against the calcitonin gene-related peptide (CGRP) receptor for migraine-specific preventive treatment. Identifying those patients with the greatest potential to benefit from erenumab treatment could have a major impact on clinical practice. CGRP provokes migraine attacks and the question is whether hypersensitivity to CGRP infusion might be a predictor of erenumab efficacy, serving as a biomarker of treatment efficiency.

Objective: To explore a possible correlation between individual efficacy of anti-CGRP treatment and susceptibility to migraine induction by CGRP.

Methods: Thirteen migraine patients, previously enrolled in erenumab anti-CGRP receptor monoclonal antibody trials, received CGRP in a double-blind, placebo-controlled, randomized design to investigate their susceptibility to migraine induction. A standardized questionnaire was used to assess efficacy of antibody treatment. The patients were stratified into groups of high responders and poor responders.

Results: Ten high responders and three poor responders were included. CGRP induced migraine-like attacks in ten (77%) patients, whereof two were poor responders, compared to none after placebo (p=0.002). The area under the curve for headache intensity was greater after CGRP, compared to placebo, at 0–90 min (p=0.009), and 2–12 h (p=0.014). The median peak headache intensity score was 5 (5–9) after CGRP, compared to 2 (0–4) after placebo (p=0.004).

Conclusions: Patients with an excellent effect of erenumab are highly susceptible to CGRP provocation. A large-scale prospective CGRP provocation study in patients should confirm whether hypersensitivity to CGRP could be a biomarker for predicting antibody treatment efficacy.

Trials Registration number: ClinicalTrials.gov identifier: NCT03481400.

Ethics approval and consent

The study was approved by the Ethics Committee of the Capital Region of Denmark (H-16014580) and is registered at ClinicalTrials.gov (NCT03481400). All participants provided written informed consent to participate in accordance with the Declaration of Helsinki of 1964, with later revisions.

O12 Incidence, clinical characteristics and long-term course of headache in patients with stroke (DMKG multicenter study)

Thomas Dresler1,2, Sarah Dietrich3, Andrea Düring4, Daniel Rothkirch5, Filipp Filippopulos6, Ozan Eren6, Andreas Straube6, Stephan Zierz3, Gudrun Goßrau4, Torsten Kraya3

1Department of Psychiatry and Psychotherapy, University of Tuebingen, Tuebingen, Germany; 2LEAD Graduate School & Research Network, University of Tuebingen, Tübingen, Germany; 3Department of Neurology, Martin-Luther-University Halle-Wittenberg, Halle/ Saale, Germany; 4University Pain Center, University of Dresden (coop.: Elblandklinikum, Meißen), Germany; 5Department of Neurology, BG Clinic Bergmannstrost, Halle/ Saale, Germany; 6Department of Neurology, Ludwig-Maximilians-University Munich, Munich-Grosshadern, Germany
Correspondence: Thomas Dresler (thomas.dresler@med.uni-tuebingen.de)

Background:

Post stroke headache (symptomatic headache, ICHD 6.1-6.2.) has not been investigated in Germany. According to previous European and American studies it is a common accompanying symptom. Nevertheless, other stroke symptoms (e.g., palsy, aphasia) are dominating, clinical assessments and treatments focus on acute therapy. However, headache is an essential symptom in subarachnoid bleeding or cerebral venous thrombosis and it is unclear which risk factors modulate symptoms and occurrence of headache in stroke [1,2]. Therefore, we planned a prospective multicenter register study to record the history of the patient, the characteristic of headache symptoms and long-term prognosis, as well as stroke characteristics.

Methods:

Patients were included within 24 hours after onset of stroke symptoms and interviewed for headache from day 1 to 3 with a newly generated questionnaire according to ICHD-3 beta [3]. Follow-up data were collected after months 3, 6 and 12. The study was approved by the study centers’ ethics committees and all patients gave their informed consent.

Results:

707 stroke patients were included. Diagnoses were: ischemic stroke (67%), TIA (transient ischemic attack, 22%), hemorrhagic stroke (5%), SAH (subarachnoid hemorrhage, 0.8%), cerebral venous thrombosis (0.5%) other diagnoses than stroke (4.7%).

40% complained about headache on at least one of the first three days (46% in females, 36% in males, p<0.02). Headache affected 38% of patients with ischemic stroke and 47% with TIA. The most common stroke affected vessel was the middle cerebral artery (62%). Headache frequency decreased from day 1 to 3. Headache intensity was low in 19% (NRS 1-2), moderate in 67% (NRS 3-6), and high in 14% (NRS 7-10). Headache was most often frontal (70%), followed by occipital (42%). 72% of the patients with previous headache complained about headache on day 1 to 3. Average follow-up response rates were about 55%.

Discussion:

Headache prevalence was higher than previously reported (25-35%, [4,5]). One explanation could be that the patients were consequently asked on the stroke unit. Headache prevalence was still that high, when excluding strokes associated with headache (hemorrhagic stroke, cerebral venous thrombosis, SAH). Risk factors are being female and having a history of primary headaches. We conclude that headache is a frequent, yet often unrecognized symptom in stroke which needs specific attention.

References:

1. Bederson JB, Connolly ES Jr, Batjer HH, Dacey RG, Dion JE, Diringer MN, Duldner JE Jr, Harbaugh RE, Patel AB, Rosenwasser RH; American Heart Association Guidelines for the management of aneurysmal subarachnoid hemorrhage: a statement for healthcare professionals from a special writing group of the Stroke Council, American Heart Association. Stroke. 2009; 40(3):994-1025.

2. Carolei A, Sacco S. Headache attributed to stroke, TIA, intracerebral haemorrhage, or vascular malformation. Handb Clin Neurol. 2010; 97:517–528.

3. Headache Classification Committee of the International Headache Society (IHS). The International Classification of Headache Disorders, 3rd edition (beta version). Cephalalgia. 2013, 33(9):629-808.

4. Hansen AP, Marcussen NS, Klit H, Kasch H, Jensen TS, Finnerup NB. Pain following stroke: a prospective study. Eur J Pain. 2012; 16(8):1128–1136.

5. Wasay M, Kojan S, Dai AI, Bobustuc G, Sheikh Z. Headache in Cerebral Venous Thrombosis: incidence, pattern and location in 200 consecutive patients. J Headache Pain. 2010; 11(2):137–139.

O13 Headache in transient ischemic attacks

Elena R. Lebedeva1,2, Natalia M. Gurary3, Jes Olesen4

1Department of Neurology and Neurosurgery, the Ural State Medical University, 620000, Yekaterinburg, Russia; 2International Headache Center “Europe-Asia”, Yekaterinburg, 620144, Russia,cosomos@k66.ru; 3Medical Union “New Hospital”, Yekaterinburg, 620000, Russia; 4Danish Headache Center, Department of Neurology, Rigshospitalet-Glostrup, University of Copenhagen, Copenhagen, 2600, Denmark
Correspondence: Elena R. Lebedeva (elenalebedeva1971@gmail.com)

Background: Headache is a common feature in acute cerebrovascular disease but no studies have evaluated the prevalence of specific headache types in patients with transient ischemic attacks (TIA). The purpose of the present study was to analyze all headaches within the last year and the last week before TIA and at the time of TIA.

Methods: Eligible patients with TIA (n=120, mean age 56.1, females 55%) had focal brain or retinal ischemia with resolution of symptoms within 24 hours without presence of new infarction on MRI with DWI (n=112) or CT (n=8). All patients were evaluated within one day of admission by a single neurologist. As a control group we used patients (n=192, mean age 58.7, females 64%) admitted with diagnoses “lumbago”, “lumbar spine osteochondrosis” or “gastrointestinal ulcer”.

Results: One-year prevalence of migraine without aura was significantly higher in TIA patients than in controls: 20.8% and 7.8% respectively (p=0.002, OR 3.1, 95% CI 1.6-6.2). 22 patients (18.3%) had sentinel or warning headache within the last week before TIA. At the time of TIA a new type of headache was observed in 16 patients (13.3%). No controls had a new type of headache. 12 of these 16 patients had migraine-like headache, 8 patients had tension-type-like headache and one patient thunderclap headache. Posterior circulation TIA was associated with headaches within last week before TIA and at the time of TIA much more frequently than anterior circulation TIA.

Conclusions: The one year prevalence of migraine was significantly higher in TIA patients than in controls and so was the prevalence of headache within the last week before TIA and at the time of TIA. A previous headache that worsens and a new type of headache can be a warning of impending TIA.

O14 OPTIMIZATION OF VAGUS NERVE STIMULATION EFFICACY ON CORTICAL SPREADING DEPRESSION

Andreia Lopes de Morais1,3, Tsubasa Takizawa1, Inge Mulder1, Tao Qin, BS1, Bruce Simon4, Rubem Carlos Araujo Guedes3, Cenk Ayata1,2

1Department of Radiology, Massachusetts General Hospital, Boston, MA, USA; 2Department of Neurology, Massachusetts General Hospital, Boston, MA, USA; 3Department of Nutrition, UFPE, Recife, Pernambuco, Brazil; 4Electrocore LLC, Basking Ridge, NJ, USA
Correnspondence: Cenk Ayata (cayata@mgh.harvard.edu)

Introduction: Vagus nerve stimulation (VNS) acutely suppresses cortical spreading depression (CSD) susceptibility, which is a clinically-relevant animal model to screen for migraine therapies. We aimed to optimize VNS efficacy on CSD using various stimulation protocols.

Methods: VNS (1ms pulse of 5kHz sine waves at 25 Hz) was delivered non-invasively (nVNS) using cutaneous bipolar disc electrodes. Stimulus trains were generated using a customized stimulator modified from the current gammaCore nVNS device (electroCore LLC, Basking Ridge, NJ). Systemic physiology was monitored during the stimulation. CSD susceptibility was evaluated 40 min after the last stimulation. Experiment 1 determined the optimal nVNS protocol among sham (N=8), 1x2-min (N=5), 2x2-min 5 min apart (N=8), 3x2-min 5 min apart (N=9), and 1x6-min (N=8) stimulation protocols. Experiment 2 evaluated chronic daily nVNS for 4 weeks using the most efficient protocol from Experiment 1. Daily femoral nerve stimulation (nFNS) was used as control.

Results: Among the studied protocols 2x2-min 5 min apart was the most efficient in suppress CSD susceptibility. This protocol increased electrical threshold by 68% and decreased in 22% KCl- induced CSD frequency. Other protocols yielded weaker efficacy (Fig. 1). Chronic nVNS was responsible for 68% increase in electrical CSD threshold and 35% decrease in KCl-induced CSD frequency when compared to nFNS.

Discussion: Our results suggest that chronic nVNS may be more effective than the acute stimulation in suppressing CSD.

Ethics Approval

Experiments were carried out in accordance with the Guide for Care and Use of Laboratory Animals (NIH Publication No. 85-23, 1996), and approved by the institutional review board.

Fig. 1 (abstract O14).

Summary of the data. A) Experimental timeline. B) Electrical Threshold and KCl-induced repetitive SDs assessment. C) Effects of different nVNS protocol on SD susceptibility. D) Effects of 4 weeks daily nVNS on SD susceptibility. Graphs shows Mean ± SE.

O15 DNA methylation pattern of CALCA gene in patients with migraine

Elisa Rubino1, Silvia Boschi1,2, Alessandro Vacca1, Salvatore Gentile3, Lorenzo Pinessi3, Maria Teresa Giordana1,3, Innocenzo Rainero1,3

1Department of Neuroscience “Rita Levi Montalcini”, University of Torino, Italy; 2Department of Neuroscience, Psychology, Drug Research and Child Health (NEUROFARBA), University of Florence, Italy; 3Department of Neuroscience and Mental Health, AOU Città della Salute e della Scienza di Torino, Italy
Correpondence: Elisa Rubino (elisa.rubino@unito.it)

Background. Migraine is a common neurological disorder characterized by intense, recurrent or chronic pain, representing a cause of extreme disability for the affected subjects. For complex disorders as migraine, both genetic and environmental components play an important role in disease pathogenesis. Epigenetic markers are heritable changes in phenotype or gene expression in the absence of changes in DNA sequence. DNA methylation is the most common type of epigenetic modification, and plays a key role in several disorders as cancer, neurodegenerative disorders, and aging. Changes in global DNA methylation have been associated with environmental factors. To date, little is known about DNA methylation in migraine. Several studies have shown that the neuropeptide calcitonin gene–related peptide (CGRP), encoded by CALCA gene, has a key role in migraine pathogenesis, and successful new drugs for treatment of migraine target CGRP. The aim of the study was to screen DNA methylation of CALCA gene in patients with migraine.

Methods. Twenty-two patients with migraine (F/M 15/7; mean age± SD: 39.7± 13.4 years) and 20 controls (F/M 12/8; mean age± SD: 40.5± 14.8 years) were recruited for the study at the Department of Neuroscience, University of Torino. The diagnosis of migraine was made according to the ICHD-III beta version criteria. Genomic DNA was extracted from peripheral blood. Cytosine-to-thymine conversion by sodium bisulfite and DNA purification were performed using EZ DNA Methylation™ Kit (Zymo Research, Orange, CA, USA). The genomic region around the CpG islands in the promoter region (from -582 to -138 bp) of CALCA gene was amplified. Sequencing was performed on an ABI Prism 3130 DNA sequencer.

Results. DNA methylation of CALCA gene in both patients and controls was more pronounced at 5’ flanking region. No overall difference was found in the global methylation of CALCA in patients with migraine and controls. Interestingly, stratification analysis showed that in migraineurs the methylation level was lower in 2 out of 6 analysed CpG islands (CpG -302, p=0.04, and -256, p=0.04, respectively).

Conclusions. This study provides the first evidence that DNA methylation of CALCA gene promoter could play a role in migraine. Global DNA methylation of CALCA gene in migraineurs does not differ from controls, However, DNA methylation status in two CpG islands of the promoter region is lower in patients with migraine. Further studies with larger sample size are needed in order to confirm these preliminary results.

O16 The impact of chronic headache on workdays, unemployment and disutility in the general population

Espen Saxhaug Kristoffersen1,2, Knut Stavem3,4,5, Christofer Lundqvist1,3,5,6, Michael Bjørn Russell1,3

1Head and Neck Research Group, Research Centre, Akershus University Hospital, Lørenskog; 2Department of General Practice, Institute of Health and Society, University of Oslo, Oslo 3Institute of Clinical Medicine, Campus Akershus University Hospital, University of Oslo, Nordbyhagen; 4Department of Pulmonary Medicine, Medical Division, Akershus University Hospital, Lørenskog 5HØKH, Research Centre, Akershus University Hospital, Lørenskog; 6Department of Neurology, Akershus University Hospital, Lørenskog, Norway
Correspondence: Espen Saxhaug Kristoffersen (e.s.kristoffersen@medisin.uio.no)

Introduction

Data on the socioeconomic burden of chronic headache (≥15days/last month or ≥180 days/year) is lacking. This study investigated the impact of chronic headache on sickness absence, unemployment and disutility in the general population in Norway.

Methods

30,000 persons aged 30─44 from the general population were screened for chronic headache. The International Classification of Headache Disorders was used. We analysed the association of chronic headache with lost workdays, days with >50% reduced productivity, sick leave, unemployment and disutility, as assesses with the SF6D in separate regression analyses.

Results

Eighty-three% (427/516) of the eligible participants completed the data on workdays and utility. They reported a mean of 9.7 (SD 24.8) workdays lost over the last 3 months, because of headache. The mean disutility score (1-SF6D score) was 0.41. Thirty-three% were on long term (>1 year) sick leave. The odd ratio (OR) for being on sick leave was 1.9(95% CI 1.1-3.2,p=0.017) for those with secondary compared with primary chronic headache. Similarly, the OR for increased number of workdays lost to headache was 3.5(1.8-6.5,p<0.001) and for unemployment 1.7(1.0-2.9,p=0.07), for those with secondary compared with primary chronic headache. Secondary chronic headache, high headache frequency and high psychological distress were significantly associated with higher disutility score.

Conclusions

The burden of chronic headache in the general population is substantial with high rates of lost workdays and disutility.

Ethics approval and consent to participate

The Regional Committee for Medical Research Ethics and the Norwegian Social Science Data Services approved the study. All participants gave informed consent.

O17 Phase 3 studies (EVOLVE-1 & EVOLVE-2) of galcanezumab in episodic migraine: subgroup analyses of efficacy by low- versus high-frequency of migraine headaches

Stephen Silberstein1, Virginia L Stauffer2, Katie Day2, Qi Zhang2, Sarah Lipsius3, Maria-Carmen Wilson4

1Thomas Jefferson University, Philadelphia, Pennsylvania, 19102, USA; 2Lilly Research Laboratories, Lilly Corporate Center, Indianapolis, Indiana, 46285, USA; 3Syneos Health, Raleigh, North Carolina, 27604, USA; 4Ochsner Health System, Covington, Louisiana, 70433, USA
Correspondence: Stephen Silberstein; Virginia L Stauffer (stauffer_virginia@lilly.com)

Objective: To investigate the efficacy of galcanezumab in episodic migraine (EM) by subgroups of low- versus high-frequency of migraine headaches.

Methods: Data were pooled from two phase 3 randomized trials. Headaches were tracked via an electronic patient-reported outcome system, and randomization was stratified by low-frequency (LFEM; 4-7 monthly migraine headache days [MHDs]) or high-frequency (HFEM; 8-14 monthly MHDs). Patients were 18-65 years old and experienced 4-14 MHDs, with ≥2 monthly migraine attacks, determined during the prospective 1-month baseline period. Patients had history of migraine for ≥1 year prior onset, and onset was before age 50. Subgroup analysis of efficacy data, including functional impact and disability measures, were conducted for LFEM and HFEM subgroups with a linear or generalized linear mixed model repeated measures approach.

Results: For intent-to-treat patients (N=1773), mean age was 41.3 years, most patients were white (75%), female (85%), and HFEM was present in 66% of patients. There were no statistically significant (p<.05) subgroup-by-treatment interactions for all measures. In both the LFEM and HFEM subgroups, the least square mean (LSM) change differences from baseline in monthly MHDs and monthly MHDs with acute medication use compared with placebo were statistically significantly reduced for galcanezumab 120-mg and 240-mg (Tables 1 and 2). In both LFEM and HFEM subgroups, the mean percentage of patients with ≥50%, ≥75%, and 100% reduction from baseline in overall monthly MHDs during treatment was statistically significantly greater in both galcanezumab dose-groups compared with placebo (p<.001). Galcanezumab treatment statistically significantly improved the Migraine-Specific Quality of Life Questionnaire (MSQ) role function-restrictive domain score compared to placebo (p<.001) and the migraine disability assessment (MIDAS) total score compared with placebo (Table 3) for patients in both LFEM and HFEM subgroups.

Conclusions: Overall, treatment effects of both doses of galcanezumab were similar with regard to reduction in monthly MHDs, improved functioning, and reduced disability for both LFEM and HFEM subgroups. The percentage of patients with ≥50%, ≥75%, and 100% reduction from baseline in MHDs were similar between LFEM and HFEM subgroups.

Trial Registration: NCT02614183, NCT02614196

Ethics approval: These studies were approved by the appropriate institutional review board for each of the study sites. They were all conducted according to Good Clinical Practice and the Declaration of Helsinki guidelines

Table 1 (abstract O17).

Monthly migraine headache days, average of months 1-6

 

LFEM

HFEM

 

Treatment

Baseline meana (SD)

N

LSM change from baseline ± SE

LSM change difference ± SE

p-valueb

Baseline meana (SD)

N

LSM change from baseline ± SE

LSM change difference ± SE

p-valueb

p-valuec

Placebo

5.8 (1.1)

295

-0.9 ± 0.2

  

10.9 (2.0)

580

-3.4 ± 0.2

   

Galca 120mg

5.8 (1.1)

150

-2.8 ± 0.3

-1.8 ± 0.3

<.001

10.9 (2.0)

286

-5.4 ± 0.3

-2.0 ± 0.3

<.001

.642

Galca 240mg

5.8 (1.2)

145

-2.3 ± 0.3

-1.4 ± 0.3

<.001

10.7 (2.0)

283

-5.5 ± 0.3

-2.1 ± 0.3

<.001

.101

Galca galcanezumab, N number of subjects who have a non-missing baseline value and at least one post-baseline value;

aBased upon subjects with a non-missing baseline value; bp-value vs. placebo; cTreatment-by-subgroup interaction p-value vs. placebo

Table 2 (abstract O17).

Monthly migraine headache days with acute medication use, average of months 1-6

 

LFEM

HFEM

 

Treatment

Baseline meana (SD)

N

LSM change from baseline ± SE

LSM change difference ± SE

p-valueb

Baseline meana (SD)

N

LSM change from baseline ± SE

LSM change difference ± SE

p-valueb

p-valuec

Placebo

4.8 (1.7)

295

-0.8 ± 0.2

  

8.9 (3.3)

580

-2.7 ± 0.2

   

Galca 120mg

4.8 (1.8)

150

-2.4 ± 0.2

-1.7 ± 0.2

<.001

8.8 (3.4)

286

-4.6 ± 0.2

-1.9 ± 0.2

<.001

.493

Galca 240mg

4.9 (1.7)

145

-2.1 ± 0.2

-1.4 ± 0.2

<.001

8.7 (3.1)

283

-4.6 ± 0.2

-1.9 ± 0.2

<.001

.152

Galca galcanezumab, N number of subjects who have a non-missing baseline value and at least one post-baseline value;

aBased upon subjects with a non-missing baseline value; b p-value vs. placebo; cTreatment-by-subgroup interaction p-value vs. placebo

Table 3 (abstract O17).

Migraine disability assessment total score, month 6

 

LFEM

HFEM

 

Treatment

Baseline meana (SD)

N

LSM change from baseline ± SE

LSM change difference ± SE

p-valueb

Baseline meana (SD)

N

LSM change from baseline ± SE

LSM change difference ± SE

p-valueb

p-valuec

Placebo

25.7 (22.6)

241

-9.8 ± 1.4

  

36.9 (31.5)

483

-15.1 ± 1.2

   

Galca 120mg

25.1 (21.8)

126

-18.6 ± 1.8

-8.8 ± 1.9

<.001

35.3 (30.2)

254

-22.3 ± 1.5

-7.2 ± 1.5

<.001

.557

Galca 240mg

28.7 (24.6)

124

-15.9 ± 1.8

-6.2 ± 1.9

.001

37.2 (29.7)

241

-22.1 ± 1.5

-7.0 ± 1.6

<.001

.737

Galca galcanezumab, N number of subjects who have a non-missing baseline value and at least one post-baseline value;

aBased upon subjects with a non-missing baseline value; bp-value vs. placebo; cTreatment-by-subgroup interaction p-value vs. placebo

O18 Persistence of effect of galcanezumab in patients with episodic or chronic migraine: phase 3, randomized, double-blind, placebo-controlled EVOLVE-1, EVOLVE-2 and REGAIN studies

Sheena K. Aurora, Qi Zhang1*, Virginia L. Stauffer1

Eli Lilly and Company, Indianapolis, IN, USA

Correspondence: Qi Zhang (zhang_qi_x1@lilly.com)

Objectives: To describe the persistence of effect following treatment with galcanezumab in adult patients with episodic or chronic migraine.

Methods: Data from two parallel studies (EVOLVE-1=NCT02614183, EVOLVE-2=NCT02614196) of patients with episodic migraine (between 4 and 14 migraine headache days [MHD] and at least 2 migraine attacks per month during baseline) and one study (REGAIN= NCT02614261) of patients with chronic migraine (headache ≥15 days/month for >3 months, with features of migraine headache ≥8 days/month at baseline) were analyzed. In all three studies, patients randomized in a 1:1:2 ratio received a subcutaneous (SC) injection of galcanezumab at 120 mg/month or 240 mg/month or a SC placebo. Persistence of effect during the double-blind phase was evaluated based on a comparison of the percentages of galcanezumab- and placebo-treated patients with maintenance of ≥50% response (defined as ≥50% reduction from baseline in monthly MHDs) for at least 3 and 6 consecutive months for the episodic study and 3 months for the chronic study. Logistic regression analyses were used for between treatment comparisons. The studies were approved by the appropriate Institutional Review Board for each study site.

Results: A total of 1773 adult patients with episodic migraine (n=444 for galcanezumab 120 mg; n=435 for galcanezumab 240 mg; n=894 for placebo for two episodic studies pooled) and 1113 patients with chronic migraine (n=278 for galcanezumab 120 mg; n=277 for galcanezumab 240 mg; n=558 for placebo) were evaluated. In patients with episodic migraine, significantly higher percentages of patients maintained ≥50% response for at least 3 consecutive months in the galcanezumab 120 mg (41.5%; p<.001) and 240 mg (41.1%; p<.001) groups or for 6 consecutive months (19.0% and 20.8%, respectively; p<.001) compared with the placebo group (21.4% at 3 months and 8.0% at 6 months). In patients with chronic migraine, significantly higher percentages of patients in the galcanezumab 120 mg (16.8%) and 240 mg (14.6%) groups maintained ≥50% response for all 3 months of the double-blind treatment phase compared with placebo (6.3%; all p<.001).

Conclusions: Treatment with galcanezumab 120 mg or 240 mg demonstrated statistically significant and clinically meaningful persistence of effect in patients with episodic migraine (at least 3 and 6 consecutive months) and in patients with chronic migraine (for 3 months).

O19 Efficacy of galcanezumab in patients who failed prior preventive treatments for migraine: results from EVOLVE-1, EVOLVE-2 and REGAIN studies

Grazia Dell’Agnello1, Antje Tockhorn-Heidenreich2, Qi Zhang3, Dustin D. Ruff3, Eric M. Pearlman3, Sheena K. Aurora3, Janet H. Ford3

1Eli Lilly SpA, Sesto Fiorentino, Italy; 2Eli Lilly and Company Limited, Erl Wood Manor, Windlesham, Surrey, UK; 3Eli Lilly and Company, Indianapolis, IN, USA

Background

Galcanezumab (GMB) is a humanised monoclonal antibody against calcitonin gene-related peptide under development for prevention of migraine. Objective of this post-hoc analysis of three Phase 3 studies of GMB was to assess if there were any differential treatment effects in patients who had failed ≥2 previous preventives due to all-cause (efficacy and/or safety/tolerability) versus those who had not.

Methods

EVOLVE-1 (NCT02614183), EVOLVE-2 (NCT02614196) and REGAIN (NCT02614261) were Phase 3, randomised, double-blind, placebo-controlled studies in patients with episodic (EVOLVE-1/2) or chronic (REGAIN) migraine. Patients were randomised 2:1:1 to receive placebo (PBO), GMB_120mg or GMB_240mg during double-blind treatment period lasting 6 months (EVOLVE-1/2) or 3 months (REGAIN). Post-hoc analyses were conducted for change from baseline in the number of monthly migraine headache days (MHD) and ≥50% response (reduction in the number of MHDs) for patients who failed ≥2 prior preventive treatments or preventive treatment classes. Subgroup-by-treatment interactions were calculated using linear or generalised linear mixed models.

Results

In the integrated analysis of EVOLVE studies (PBO=90, GMB_120mg=51, GMB_240mg=45) and in the REGAIN study (PBO=175, GMB_120mg=72, GMB_240mg=104), GMB_120/240mg statistically significantly improved overall mean reduction from baseline of monthly MHD compared with PBO (EVOLVE 1/2 p<0.001; and REGAIN p<0.01). For the subgroup who failed prior preventives, mean monthly reductions from baseline (MHD [Standard Error]) in EVOLVE 1/2 were: PBO: 0.46 (0.64); GMB_120mg: 3.06 (0.74); GMB_240mg: 3.83 (0.80); and in REGAIN were: PBO: 1.01 (0.54); GMB_120mg: 5.35 (0.71); GMB_240mg: 2.77 (0.66). Significant treatment-by-subgroup interactions were seen for GMB_240mg (EVOLVE-1/2) and for GMB_120mg (REGAIN) suggesting better efficacy compared with PBO for these doses in patients who failed prior preventives. Estimated mean proportions (SE) of patients with ≥50% response were significantly higher compared with PBO (EVOLVE-1/2, PBO: 0.225 [0.033]; GMB_120mg: 0.536 [0.050]; GMB_240mg: 0.611 [0.053], p<0.001;), REGAIN, PBO: 0.094 [0.019]; GMB_120mg: 0.295 [0.047]; p<0.001 and GMB_240mg: 0.186 [0.033]; p<0.01). The results are consistent also when considering failure due to all-cause for ≥2 previous treatment classes.

Conclusions

GMB_120/240mg is efficacious compared with PBO in reducing monthly MHDs in both in the overall population and the patients who failed ≥2 prior preventive treatments. Treatment-by-subgroup interactions may be driven by lower PBO response in patients who failed prior preventive treatments, as magnitude of change for GMB-treated patients were similar in both subgroups.

Trial Registration: Each study was approved by a central Ethics Review Board and registered on ClincalTrials.gov (NCT02614183 (EVOLVE-1); NCT02614196 (EVOLVE-2); NCT02614261 (REGAIN); NCT02614287 (Study CGAJ)).

O20 Cephalic and extracephalic neurophysiological effects of botulinum toxin type A treatment in chronic migraine

Gianluca Coppola1*, Francesca Cortese1, Davide Di Lenola1, Cherubino Di Lorenzo2, Vincenzo Parisi3, Francesco Pierelli1,4.

1Sapienza University of Rome Polo Pontino, Department of Medico-Surgical Sciences and Biotechnologies, Latina, Italy; 2Don Carlo Gnocchi Onlus Foundation, Milan, Italy; 3G.B. Bietti Foundation IRCCS, Research Unit of Neurophysiology of Vision and Neurophthalmology, Rome, Italy; 4IRCCS-Neuromed, Pozzilli (IS), Italy
Correspondence: Gianluca Coppola (gianluca.coppola@gmail.com)

Background

Injection botulinum toxin type A (BTX-A) has been approved for the treatment of chronic migraine (CM). Although different studies have shown that this treatment is highly effective and safe, the neurophysiological mechanisms underlying its clinical efficacy are still debated widely. This study assessed the segmental, suprasegmental, cephalic, and extra-cephalic effects of BTX-A injection in a group of patients with CM.

Materials and methods

We assessed the excitability of the trigeminal system in a group of 13 CM patients (11 with and 2 without medication overuse), by simultaneously recording the blink reflex (nBR), the trigemino-cervical reflex (nTCR), and the pain-related evoked potential (PREP), following stimulation of the right supraorbital nerve with a nociception specific concentric electrode. Further, we recorded the non-noxious somatosensory evoked potentials (SSEPs) amplitude and habituation to verify the influence of BTX-A prophylaxis on the cortical excitability in extracephalic sensory areas. Neurophysiological measurements were recorded before (T0), and 1 month (T1) and 3 months (T3) after BTX-A injections.

Results

At month 3, BTX-A significantly reduced the mean monthly headache days, severity of headache (1-3), and the mean monthly tablet intake (all p=<0.001). A significant increase in pain threshold, but not in perception threshold was noted 3 months after treatment compared to baseline (T0=8.3 mA, T2=12.0 mA; p=0.04). Despite a non-significant variation of the 1st nBR and nTCR amplitude blocks, we found that the initial nBR and nTCR lack of habituation was replaced by normal habituating response at 3 months after treatment (p=0.005 for nBR, p<0.05 for nTCR). There were no variations in the initial PREP and SSEP after BTX-A, despite a trend for an increased habituation for PREP and lack of SSEP amplitudes.

Conclusions

This is the first study to show that the clinical improvement induced by a single session of BTX-A injection in CM patients may be attributed to the neurophysiological changes that occur at the brainstem and that BTX-A may have an active in modulating the habituation of subcortical trigemino-cervical circuits. Further, our findings suggest that the responsiveness to a single session of BTX-A may be related to the blockage of sensitization of the nociceptive neurons in the dorsal horn, without an evident involvement of cortical circuitries.

O21 Idiopathic Intracranial Hypertension: Consensus Guidelines on Management

S. P. Mollan1,2, B. Davis3, N. C. Silver4, S. Shaw5, C. Malucci6,7, B. R. Wakerley8,9, A. Krishnan4, S. V. Chavda10, S. Ramalingam10, J. Edwards11,12, K. Hemmings13, M. Williamson13, M. A. Burdon2, G. Hassan-smith1,13, K. Digre14, G. T. Liu15, R. H. Jensen16, A. J. Sinclair1,2,13,17

1Neurometabolism, Institute of Metabolism and Systems Research, University of Birmingham, Edgbaston, B15 2TT, UK; 2Birmingham Neuro-Ophthalmology, Queen Elizabeth Hospital, Birmingham, B15 2WB, UK; 3Department of Neurology, University Hospital North Midlands NHS Trust, Stoke-on-Trent, ST4 6QG; 4Department of Neurology, The Walton Centre NHS Foundation Trust, Liverpool, L9 7LJ, UK; 5Department of Neurosurgery, University Hospital North Midlands NHS Trust, Royal Stoke University Hospital, Newcastle Road, Stoke-on-Trent, ST4 6QG, UK; 6Department of Neurosurgery, The Walton Centre NHS Foundation Trust, Liverpool, L9 7LJ, UK; 7Department of Paediatric Neurosurgery, Alder Hey Children's NHS Foundation Trust, Liverpool L12 2AP, UK; 8Department of Neurology, Gloucestershire Hospitals NHS Foundation Trust, GL53 7AG, UK; 9Nuffield Department of Clinical Neurosciences, Oxford OX3 9DU, UK; 10Department of Neuroradiology, University Hospitals Birmingham, Queen Elizabeth Hospital, Birmingham, B15 2WB, UK; 11Department of Neurology, Sandwell and West Birmingham NHS Trust, City Hospital, Dudley Road, Birmingham, UK; 12Department of Neurology, University Hospitals Birmingham, Queen Elizabeth Hospital, Birmingham, B15 2WB, UK; 13IIH-UK, Tyne & Wear, NE38 7JX, UK; 14Departments of Ophthalmology and Neurology, Moran Eye Center, University of Utah, Salt Lake City, Utah, USA; 15Neuro-ophthalmology Services, Children's Hospital of Philadelphia and Hospital of the University of Pennsylvania, Philadelphia, PA 19104, USA; 16Danish Headache Center, Department of Neurology, Rigshospitalet-Glostrup, University of Copenhagen, Denmark; 17Centre for Endocrinology, Diabetes and Metabolism, Birmingham Health Partners, B15 2TH, UK
Correspondence: S. P. Mollan (soozmollan@doctors.org.uk)

Background

Idiopathic intracranial Hypertension (IIH) is commonly associated with obesity, younger age and females. Patients present acutely to many different specialities, and often through the course of their disease will have multiple acute visits. Headache is the major morbidity in IIH.

Objectives

The aim was to capture interdisciplinary expertise from a large group of clinicians, reflecting practice from across the UK and further, to inform subsequent development of a national consensus guidance for optimal management of Idiopathic Intracranial Hypertension.

Methods

Between September 2015 and October 2017 a specialist interest group including neurology, neurosurgery, neuro-radiology, ophthalmology, nursing, primary care doctors, and patient representatives met. A comprehensive systematic literature review was performed to assemble the foundations for the working group. Population, Interventions, Controls and Outcomes (PICO) questions were defined and through a large Delphi group exercise, expertise was captured from a wide-reaching group of clinicians reflecting practice from across the United Kingdom and internationally. The statements were then critically reviewed key opinion leaders and by Association of British Neurologists, British Association for the Study of Headache, the Society of British Neurological Surgeons and the Royal College of Ophthalmologists.

Results

Over twenty questions were constructed: One based on the diagnostic principles for optimal investigation of papilloedema and twenty-one for the management of IIH. 3 main principles were identified: 1, to treat the underlying disease; 2, to protect the vision and 3, to minimise the headache morbidity. Statements presented provide insight to uncertainties in IIH where research opportunities exist.

Evaluation of the headache phenotype was found to be essential, so that targeted treatment can be used and help identification of medication overuse headache. Acute exacerbation of headache often leads to re-investigation with lumbar puncture, and the collective expert opinion reflected that lumbar puncture only provides temporary relief, can lead in some to longer term complications and exacerbation of headache. In those with acute exacerbation of headache, optic nerve examination is essential and in those found not to have papilloedema, investigation with LP and brain imaging is not required as long as no other secondary causes of headache are suspected.

Conclusions

In collaboration with many different specialists, professions and patient representatives we have developed guidance statements for the investigation and treatment of adult IIH. This is the first consensus guidance for optimal management of IIH.

O22 Long-term outcomes after reversible cerebral vasoconstriction syndrome: recurrence, cardiovascular events and mortality in a prospective follow-up study

Rosalie Boitet1, Solène De Gaalon2, Grégory Marin3, Claire Duflos3, Caroline Roos2, Jérôme Mawet2, Cécilia Burcin2, Ursula Fiedler2, Marie-Germaine Bousser4 et Anne Ducros1

1Neurology Department & 3Statistics, Montpellier University Hospital, Montpellier; 2Emergency Headache Centre & 4Neurology Department, Lariboisière Hospital, APHP, Paris, France
Correspondence: Rosalie Boitet (rosalie.boitet@gmail.com)

Introduction: Long-term outcomes >5 years after reversible cerebral vasoconstriction syndrome (RCVS) have not been previously studied.

Objective: To determine rates of recurrent thunderclap headache, recurrent RCVS, incident stroke, and cardiovascular mortality (CVM) after a first RCVS (RCVS1).

Methods: Of 173 RCVS patients recruited from 2004 to 2013 in Lariboisière, 172 completed a follow-up >6 months and were included in this study. Follow-up visits were clinical at 1, 3, 6, 12 and 18 months after RCVS, thereafter by consultations, phone calls, emails or letters with a final contact between March 2017 and February 2018.

Results: Of the 172 patients who completed a mean follow-up of 110 ± 40 months (range 6–196), 28 had a new thunderclap-like headache, and 10 (5.8%) had a confirmed recurrent RCVS (0.65 per 100 person-years, 95% CI 3.29 – 11.54). The second RCVS occurred a mean of 78 ± 46 (median 81, interquartile range 35 – 93) months after the first. One woman had a third RCVS (0.6%). The only two significant independent predictors of recurrent RCVS were exertion as a trigger for the RCVS1 (OR = 6, 95% CI 1.5–23.7) and having a newly diagnosed hypertension after RCVS1 (OR = 4.8; 95% CI 1.3–19.2). Of the 7 women who delivered during follow-up, one (14%) had a recurrent RCVS in postpartum. One 46 years-old man (0.6%) had a sudden cardiac death 5 years after RCVS1. One patient had a stroke (0.6%) during her recurrent RCVS.

Conclusions: RCVS patients have a low but significant risk of recurrent RCVS and CVM. Exertion as a trigger for RCVS1 and developing hypertension after RCVS1 are potential predictors of recurrent RCVS.

O23 Complete detoxification is the most effective in reducing disability in patients with medication-overuse headache: A randomized controlled open-label trial

Mia Nielsen, Louise N. Carlsen, Rigmor H. Jensen, Signe B. Munksgaard, Ida M. S. Engelstoft, Lars Bendtsen

Danish Headache Center, Neurological Clinic, Rigshospitalet, Glostrup, Denmark
Correspondence: Louise N. Carlsen (louise.ninett.carlsen@regionh.dk)

Background: Complete stop of acute medication and/or migraine medication for treatment of medication-overuse headache (MOH) has previously been reported more effective in reducing headache days and migraine days per month compared with restricted intake of acute medication. It is well known that treatment of MOH reduces disability and increases quality of life for patients.

Aim: To compare changes in disability and quality of life between two detoxification programs for medication-overuse headache (MOH).

Methods: In a prospective, outpatient study patients with MOH were randomized to program A (two months with no acute analgesics or migraine-medications) or program B (two months with acute medications restricted to two days/week). At 6 and 12 months follow-up, disability and headache burden were measured by Headache Under Response to Treatment-8 (HURT-8) and HURT-3, respectively. Quality of life was estimated by EUROHIS QOL 8-item (QOL-8) at 2, 6 and 12 months follow-up.

Results: We included 72 MOH patients with a primary migraine and/or tension-type headache diagnosis. Fifty-nine patients completed detoxification. At 12 month-follow-up, 41 completed HURT and 38 patients EUROHIS QOL-8. At month 12, HURT-8 was reduced by 24.5% in program A and 7.1% in program B (p=0.027). HURT-3 in program A was reduced by 33.3% versus 3.1 % in program B (p=0.005). At 12 months, QOL-8 was increased by 8.2% in total, without any significant difference between the programs (p=0.297). However, there was significant difference in favor of program A in QOL-8 at 2 months (p=0.006).

Conclusion: Both detoxification programs reduced disability and improved quality of life. Detoxification without acute medication was the most effective in reducing headache burden and disability.

Trial registration: Clinicaltrials.gov (NCT02903329).

Ethical approval

The study was approved by the Regional Ethical Committee in Denmark (H-1-2012- 105 116)

O24 The economic and humanistic burden of episodic and chronic migraine in Europe

Hicham Benhaddi1; Timothy Fitzgerald2; Sophie McCabe3; Ruth Zeidman3

1Teva Pharmaceuticals, Wilrijk, Belgium; 2Teva Pharmaceuticals, Frazer, Pennsylvania, USA; 3Covance Market Access, London, UK
Correspondence: Hicham Benhaddi (mhowell@hcg-int.com)

BACKGROUND:

Migraine is a debilitating neurological disorder characterized by attacks that may last 4–72 hours, with a high burden in Europeans.

OBJECTIVE:

This systematic literature review examined the clinical, humanistic, and economic burden associated with chronic and episodic migraine (CM and EM, respectively) in Europe.

METHODS:

Literature searches and evidence screening were structured according to the PICOS (population, intervention, comparators, outcomes, and study types) framework. Reviews and original observational studies in adults (≥18 years) with EM (<15 headache days per month) or CM (≥15 headache days with ≥8 migraine days per month) were included. Searches focused on resource utilization, treatment costs, productivity, quality of life (including generic and migraine-specific instruments and functioning), and utility outcomes (published 2007– February 1, 2018; geographical limitation: United Kingdom, France, Germany, Spain, Italy, the Netherlands, Poland, Denmark, Finland, Iceland, Norway and Sweden). Searches included: Embase, MEDLINE, and the Cochrane Library databases; specialty medicine associations; and health technology assessment agency websites.

RESULTS:

Analysis included 68 publications. Data from the World Health Organization indicated that in Europe, migraine burden weighed higher than that of epilepsy, multiple sclerosis, and Parkinson’s disease. Up to 57% of individuals with migraine report severe disability, and many find treatments ineffective. Nausea and/or vomiting occurred in up to 74% of individuals with migraine. Depression and/or anxiety occur up to three times more often in individuals with migraine than in the general population. People with migraine have reported poorer health-related quality of life than those without migraine, which worsens with increasing migraine attack frequency. Europeans with migraine perceive that it has a negative impact on work (up to 76%), family situations, leisure time, studies, sexual life, social position, love, financial situation, career, and friendships. The prevalence of migraine is highest for men and women during their peak years of economic productivity (ages 25–55 years). In Europe, the estimated total annual cost was up to €111 billion (2008–2009), of which 72%–98% was indirect costs (two-thirds of indirect costs due to reduced productivity). Annual direct costs for CM were up to four times higher than those for EM.

CONCLUSIONS:

This research demonstrates that migraine has a substantial humanistic and economic burden on Europeans and affects all aspects of life.

O25 Headache outcome measures in medically refractory chronic migraine patients treated with OnabotulinumtoxinA

Lagrata Susie1, Ahmed Maha1, Miller Sarah1,2, Matharu Manjit1,2

1Headache Group, National Hospital for Neurology and Neurosurgery, Queen Square, London; 2Institute of Neurology, University College London, National Hospital for Neurology and Neurosurgery, Queen Square, London
Correspondence: Matharu Manjit (m.matharu@uclmail.net)

Introduction

OnabotulinumtoxinA is standard care of management for chronic migraine (CM). Few studies on the use of OnabotulinumtoxinA on CM have identified factors associated with a positive response to OnabotulinumtoxinA treatment. There are currently no data on outcome measures that might predict subjective perceived outcome (SPO) to OnabotulinumtoxinA in reported by patients with medically-refractory chronic migraine (rCM).

Aim

To identify components of headache characteristics (frequency, intensity, duration) or disability score (Headache Impact Test-6, HIT-6) that predicts SPO.

Method

100 patients who had completed at least two full treatment cycles and had at least six months follow up were identified. Data on SPO, clinical and headache characteristics were collected prospectively on all patients using headache diaries, feedback forms and validated disability scores. Variables analysed for predictors of SPO were headache characteristics (frequency, intensity and duration) and disability score (HIT-6) using multivariate analysis.

Results

Response rates are shown in Fig. 1. Multivariate analysis showed change in pain intensity (p<0.001) and pain duration (p=0.022) were significantly positively associated with SPO. Change in headache days (p=0.294) and HIT-6 score (p=0.321) were not significantly positively associated with SPO. Table 1 shows results of multivariate analysis.

Conclusion

Our data suggest that improvement in pain intensity and headache duration predicts SPO to onabotulinumtoxinA in rCM. The results of this study suggest that for rCM the use of pain intensity and headache duration appear to be the more appropriate outcome measure to assess. The current NICE guidelines which state that response should be assessed using headache days alone may not be appropriate for rCM.

Fig. 1 (abstract O25).

Response rate for each outcome measure. Responders ≥ 30% improvement on each outcome measure; ≥3 HIT-6 points improvement. HA: headache, SPO: subjective perceived outcome

Table 1 (abstract O25).

Results of univariate and multivariate analysis

Variables

Univariable Analysis

r2

Multivariable Analysis

β, Standard error

p=value

Change in headache days

0.292

1.126, 0.120

0.294

Change in pain intensity

0.488

0.539, 0.090

<0.001

Change in pain duration

0.303

0.194, 0.083

0.022

HIT-6 points

0.130

0.216, 0.217

0.321

Dependent Variable: Patient subjective perceived outcome (SPO)

O26 Searching for a neural signature of hallodynia in migraine: a volumetric MRI study

Francesca Pistoia1, Claudia Marsecano2, Antonio Carolei1, Riccardo Cornia1, Luana Evangelista1, Alessandra Splendiani2, Simona Sacco1

1Neurological Institute, Department of Applied Clinical Science and Biotechnology, University of L’Aquila, L’Aquila, Italy; 2Radiology section, Department of Applied Clinical Science and Biotechnology, University of L’Aquila, L’Aquila, Italy
Correspondence: Francesca Pistoia (francesca.pistoia@univaq.it)

Background

Allodynia is a phenomenon of central pain sensitization, characterized by the occurrence of a painful sensation following the administration of innocuous stimuli like a light touch. It occurs frequently in patients with migraine and it seems to be associated with the duration and severity of the disease [1-2]. The aim of the present study was to investigate the presence of structural brain changes in migraine patients with hallodynia as compared to migraine patients without hallodynia.

Materials and methods

Consecutive eligible patients referring to our Regional Headache Center within a six-month period and with a diagnosis of migraine were screened for the inclusion in the study. Hallodynia was investigated through the Allodynia Symptom Checklist [3]. All patients underwent a neuroradiological assessment through a 3 Tesla Magnetic resonance Imaging (MRI) scanner (Discovery MR750w). MRI images were analyzed through the Freesurfer 6.0 software to evaluate volume cortical differences between the two groups. Groups’ analyses were performed through the QDec software for cortical volumes (level of significance fixed at p 0.01)

Results

Sixteen women with clinical signs of hallodynia (mean age±SD 45.2±9.2) were included and compared to 16 women not showing hallodynia (mean age±SD 44.8±8.8). The two groups were comparable referring to disease duration (19.3±13.9 vs 20.8±9.6, respectively; p>0.05) and number of days with migraine per month (mean±SD 7.0±4.8 vs 8.0±5.8, respectively; p>0.05). Migraine patients with hallodynia showed a selective cortical volume loss involving the pars triangularis (p< 0.001), the rostral anterior cingulate cortex (p< 0.001), the precuneus (p< 0.005) and the rostral middle frontal cortex (p< 0.005) in the left hemisphere, and the precuneus in the right hemisphere (p< 0.005). No correlation was found between the migraine duration and the extent of volumetric decrease in patients with allodynia.

Conclusions

We found a selective cortical volume loss associated with the phenomenon of hallodynia in some areas, which are functionally linked to the experience of pain. Specifically, the anterior cingulate cortex has been previously reported to have a role in registering the pain intensity and in modulating the individual emotional reaction to pain [4]. Similarly, the activity of the precuneus may be linked to the perception of the environment, the cue reactivity and the affective responses to pain [5]. Further studies are necessary to establish whether the above areas belong to critical hub networks influencing the development of hallodynia and whether they can become the target of specific pharmacological and behavioral therapies [6].

References
  1. 1.

    Levinsky Y, Zeharia A, Eidlitz-Markus T. Cephalic cutaneous allodynia in children and adolescents with migraine of short duration: A retrospective cohort study. Cephalalgia. 2018 Jan 1:333102418776018.

     
  2. 2.

    Tietjen GE, Brandes JL, Peterlin BL, Eloff A, Dafer RM, Stein MR, Drexler E, Martin VT, Hutchinson S, Aurora SK, Recober A, Herial NA, Utley C, White L, Khuder SA. Allodynia in migraine: association with comorbid pain conditions. Headache 2009;49:1333-44.

     
  3. 3.

    Lipton RB, Bigal ME, Ashina S, Burstein R, Silberstein S, Reed ML, Serrano D, Stewart WF. Cutaneous allodynia in the migraine population. Ann Neurol 2008;63:148-158.

     
  4. 4.

    Barthas F, Sellmeijer J, Hugel S, Waltisperger E, Barrot M, Yalcin I. The anterior cingulate cortex is a critical hub for pain-induced depression. Biol Psychiatry 2015;77:236-245.

     
  5. 5.

    Cavanna AE, Trimble MR. The precuneus: a review of its functional anatomy and behavioural correlates. Brain 2006;129:564-583.

     
  6. 6.

    Pistoia F, Sacco S, Carolei A. Behavioral therapy for chronic migraine. Curr Pain Headache Rep 2013;17:304.

     

O27 Dopaminergic symptoms in migraine: a case series on 1148 patients

P. Barbanti1, P. Ferroni2,3, G. Egeo1, L. Fofi1, C. Aurilia1

1Headache and Pain Unit IRCCS San Raffaele Pisana, Rome, Italy; 2Department of Human Sciences and Quality of Life Promotion, San Raffaele Roma Open University, Rome, Italy; 3Interinstitutional Multidisciplinary Biobank (BioBIM), IRCCS San Raffaele Pisana, Rome, Italy
Correpondence: P. Barbanti (piero.barbanti@sanraffaele.it)

Background: Dopamine (DA) plays a major role in migraine pathogenesis as suggested by clinical, genetic, biochemical and pharmacological evidence. Some migraineurs show intense dopaminergic symptoms (DAs) during the attack and might represent a distinctive endophenotype. The present study is aimed to assess frequency and characteristics of DAs in migraineurs during the different attack phases.

Methods: We studied all patients affected by episodic and chronic migraine consecutively seen at our Headache and Pain Unit from 1 April 2017 to 31 March 2018. Following a careful physical and neurological examination, all patients were evaluated with face-to face interviews using a semi-structured questionnaire addressing three main issues: 1) life-style, behavioral and socio-demographic factors; 2) comorbidities and concomitant medications; and 3) clinical migraine features encompassing family history, disease duration, site, quality and intensity of pain, attack duration and frequency, presence, type and duration of aura, prodromes, accompanying symptoms, postdromes, DAs, allodynia, unilateral cranial parasympathetic symptoms, triggers and alleviating factors, previous and current acute or preventive treatments, patients’satisfaction with triptans. The presence of DAs was determined by asking the following question: “During prodromes, headache stage or postdromes do you also have at least one of the following symptoms: yawning, somnolence, fatigue, severe nausea, vomiting, mood changes or diuresis?”.

Results: We studied 1148 migraine patients (F/M: 902/246; without aura, MwA: 679; with aura, MA: 66; MwA + MA: 37; chronic migraine, CM: 366; medication overuse headache, MOH: 284). A total of 374 patients (32.6%) reported the presence of ≥1 DAs during the attack: 143 patients with DAs (DAs+) (38.2%) reported 1 DAs, 107 (28.6%) 2 DAs and 124 (33.2%) ≥3 DAs. The most frequent DAs was yawning (64.4%) followed by somnolence (58.6%), severe nausea (42%), vomiting (27.3%), fatigue (17%), mood changes (7%) and diuresis (3%). DAs mostly occurred during headache stage (54%), less frequently during prodromes (33.7%) or postdromes (27%). Migraineurs with and without DAs did not differ for life-style, behavioral and socio-demographic factors and other migraine variables. Stepwise logistic regression analysis revealed that DAs+ patients had more frequently long-lasting attacks (p <0.0001), osmophobia (p<0.0001), allodynia (p=0.0077), and unilateral autonomic symptoms (p=0.0426) than general migraine population.

Conclusions: More than 1/3 or migraineurs show DAs, mostly yawing and somnolence, especially during the headache phase. Their attacks are longer and more frequently associated with allodynia, osmophobia and unilateral autonomic symptoms than general migraine population. DAs+ patients could represent a migraine endophenotype.

O28 Non-invasive vagus nerve stimulation (nVNS) for the acute treatment of episodic migraine: additional findings from the randomised, sham-controlled, double-blind PRESTO trial

Paolo Martelletti1, Licia Grazzi2, Giulia Pierangeli3, Innocenzo Rainero4, Pierangelo Geppetti5, Anna Ambrosini6, Paola Sarchielli7, Piero Barbanti8, Cristina Tassorelli9,10, Eric Liebler11, Marina de Tommaso12

1Department of Clinical and Molecular Medicine, Sapienza University, Rome, Italy; 2Headache Center, Carlo Besta Neurological Institute and Foundation, Milano, Italy; 3Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS) Istituto delle Scienze Neurologiche di Bologna, Bologna, Italy; 4Department of Neuroscience, University of Turin, Turin, Italy; 5Headache Centre, University Hospital of Careggi, Florence, Italy; 6IRCCS Neuromed, Pozzilli (IS), Italy; 7Neurologic Clinic, Santa Maria della Misericordia Hospital, Perugia, Italy; 8Headache and Pain Unit, IRCCS San Raffaele Pisana, Rome, Italy; 9Headache Science Centre, IRCCS C. Mondino Foundation, Pavia, Italy; 10University of Pavia, Pavia, Italy; 11electroCore, LLC, Basking Ridge, New Jersey, USA; 12Neurophysiology and Pain Unit, University of Bari Aldo Moro, Bari, Italy
Correspondence: Paolo Martelletti (paolo.martelletti@uniroma1.it)

Background: The randomised sham-controlled PRESTO trial provided Class I evidence that for patients with an episodic migraine, non-invasive vagus nerve stimulation (nVNS; gammaCore®) significantly increases the probability of having mild pain or being pain-free 2 hours post‑stimulation. Here, we used a range of end points beyond those previously reported to evaluate the consistency and durability of the efficacy of nVNS in PRESTO.

Methods: The methods for PRESTO were previously reported [1]. Additional end points reported here include the percentages of all treated attacks that were aborted (pain-free) and of those with pain relief (decrease from moderate or severe pain to mild or no pain) at 30, 60, and 120 minutes, mean change in pain score at 30, 60, and 120 minutes, sustained pain-free and pain relief response rates through 24 and 48 hours, and acute medication use.

Results: Response rates at 120 minutes for all treated attacks were significantly higher with nVNS than with sham for pain freedom (22.9% vs 14.8%; p=0.026) and pain relief (35.2% vs 24.4%; p=0.018). Superiority of nVNS vs sham was also shown at 60 minutes. Mean changes in pain score from baseline to 120 minutes were –0.62 (nVNS) vs –0.23 (sham) for the first attack (p=0.011) and –0.50 (nVNS) vs –0.28 (sham) for all attacks (p=0.057), with similar results seen at 60 minutes. Sustained response rates were high in both treatment groups (24 h: ≥75%; 48 h, ≥58%) for the first attack and all attacks. Acute medications used per attack decreased from the run-in period (0.86) to the double-blind period (nVNS, 0.45; sham, 0.55; p=0.054). All results from the nVNS group in the double-blind period were consistent with those from the open-label period.

Conclusions: These findings from the PRESTO trial further support the efficacy and reliability of acute nVNS for migraine. nVNS was effective when measured by first attack or all attacks, suggesting that nVNS is an attractive option for treating multiple attacks while reducing the need for current acute medications and any associated adverse events or concerns of overuse.

Acknowledgements

PRESTO was sponsored by electroCore, LLC. We present this abstract on behalf of the PRESTO Study Group.

Trial registration: NCT02686034

Ethics approval

PRESTO was approved by the local ethics committee for each study site.

Reference

1. Tassorelli C, Grazzi L, de Tommaso M, et al. Non-invasive vagus nerve stimulation as acute therapy for migraine: the randomized PRESTO study. Neurology. In press.

Author Disclosures:

P. Martelletti has received research grants, advisory board fees, or travel fees from ACRAF; Allergan S.p.A.; Amgen Inc.; electroCore, LLC; Novartis AG; and Teva Pharmaceutical Industries Ltd.

L. Grazzi has received consultancy and advisory fees from Allergan S.p.A. and electroCore, LLC.

G. Pierangeli has nothing to disclose.

I. Rainero has received consultancy fees from electroCore, LLC, and Mylan N.V. and research grants from the European Commission – Horizon 2020. He is also a principal investigator for RCTs sponsored by Axovant Sciences Ltd. and TauRx Pharmaceuticals Ltd.

P. Geppetti has received consultancy fees from Allergan S.p.A.; electroCore, LLC; Evidera; Novartis AG; Pfizer Inc.; and Sanofi S.p.A. and research grants from Chiesi Farmaceutici S.p.A. He is also a principal investigator for RCTs sponsored by Eli Lilly and Company; Novartis AG; and Teva Pharmaceutical Industries Ltd.

A. Ambrosini has received consultancy fees from Almirall, S.A., and travel grants from Allergan S.p.A. and Almirall, S.A.

P. Sarchielli has received clinical study fees from Allergan S.p.A.

P. Barbanti has received consultancy fees from Allergan S.p.A.; electroCore, LLC; Janssen Pharmaceuticals, Inc.; Lusofarmaco; and Visufarma and advisory fees from Abbott Laboratories; Merck & Co., Inc.; Novartis AG; and Teva Pharmaceutical Industries Ltd. He is also a principal investigator for RCTs sponsored by Alder BioPharmaceuticals Inc.; Eli Lilly and Company; GlaxoSmithKline Pharmaceuticals Ltd.; and Teva Pharmaceutical Industries Ltd.

C. Tassorelli has received consultancy fees from Allergan S.p.A.; electroCore, LLC; Eli Lilly and Company; and Novartis AG and research grants from the European Commission and the Italian Ministry of Health. She is also a principal investigator or collaborator for RCTs sponsored by Alder BioPharmaceuticals Inc.; Eli Lilly and Company; and Teva Pharmaceutical Industries Ltd.

E. Liebler is an employee of electroCore, LLC, and receives stock ownership.

M. de Tommaso has received advisory fees from Allergan S.p.A.; Neopharmed; and Pfizer Inc.

O29 Tocilizumab in patients with giant cell arteritis: results from a Phase 3 randomized controlled trial

Susan P. Mollan1*, Katie Tuckwell2, Sophie Dimonaco2, Micki Klearman3, Neil Collinson2, John H. Stone4

1Birmingham Neuro-Ophthalmology Unit, Department of Ophthalmology, University Hospitals Birmingham NHS Trust, Queen Elizabeth Hospital Birmingham, Birmingham, United Kingdom; 2Roche Products Ltd., Welwyn Garden City, United Kingdom; 3Genentech, South San Francisco, California; 4Massachusetts General Hospital Rheumatology Unit, Harvard Medical School, Boston, Massachusetts, United States
Correspondence: Susan P. Mollan (susan.mollan@uhb.nhs.uk)

Introduction: The efficacy and safety of tocilizumab (TCZ), an IL-6 receptor-α inhibitor, was evaluated in patients with giant cell arteritis (GCA) in GiACTA, a randomized, double-blind, placebo-controlled trial with blinded glucocorticoid regimens of variable dose and duration1. Data for the week-52 primary outcome measurement are presented.

Methods: Patients aged ≥50 years had active GCA previously confirmed by temporal artery biopsy or cross-sectional imaging and documented acute-phase reactant elevation attributable to GCA. Randomization was stratified by baseline prednisone dose (≤30 or >30 mg/day) as selected by the investigator (20-60 mg/day). Patients were randomized 1:1:2:1 to 4 groups: short-course prednisone (SCP) or long-course prednisone (LCP) (26-week or 52-week prednisone taper + weekly subcutaneous [SC] placebo, respectively); or weekly (TCZ-QW) or every other week (TCZ-Q2W) SC TCZ 162 mg + 26-week prednisone taper. Prednisone doses <20 mg/day were blinded. Patients who flared or could not adhere to the protocol-defined tapering schedule received open-label prednisone escape therapy but continued on double-blind TCZ/placebo. Sustained remission was defined as the absence of flare at week 52, normalization of C-reactive protein after week 12, and adherence to the protocol-defined prednisone taper. The primary and key secondary endpoint was the proportion of patients in sustained remission, comparing TCZ groups with the SCP and LCP groups (significance level, 0.005). A dose hierarchy of statistical testing was implemented. Prednisone exposure was a secondary endpoint.

Results: Among 251 patients randomized, the mean ± SD age was 69 ± 8.2 years, and 75% were female. A total of 56% and 53.1% of patients in the TCZ-QW and TCZ-Q2W groups, respectively, achieved sustained remission compared with 14% in the SCP group (p< 0.0001; primary endpoint) and 17.6% in the LCP group (p≤ 0.0002; key secondary endpoint). The median cumulative steroid exposure was 1862.0 in both TCZ groups, and 3296.0, and 3817.5, in the SCP and LCP groups, respectively. The incidence of adverse events (AEs) was similar among the 4 groups. Serious AEs were reported in 15.0%, 14.3%, 22.0%, and 25.5% of TCZ-QW, TCZ-Q2W, SCP, and LCP patients, respectively. No deaths or new vision loss occurred.

Conclusion: TCZ plus 26-week prednisone taper was superior to SCP and LCP tapers for sustained remission at 52 weeks. TCZ plus prednisone also led to a substantial reduction in the cumulative prednisone doses required to control GCA.

Trial registration: NCT01791153 / EudraCT 2011-006022-25. This study was funded by F. Hoffmann-La Roche Ltd.

Ethics approval

Protocol approval was obtained from institutional review boards, ethics committees, and/or regulatory authorities in accordance with the Declaration of Helsinki and Good Clinical Practice was followed.

Reference

1. Stone J.H, Tuckwell K, Dimonaco S, et al. N Engl J Med 2017;377:317-28.

O30 Response to lasmiditan for acute treatment of migraine based on prior response to triptan therapy

Kerry Knievel1, Louise Lombard2, Andrew Buchanan2, Simin Baygani2, Joel Raskin2, Joshua Tobin3

1Barrow Neurological Institute, Phoenix, AZ 85013, USA; 2Eli Lilly and Company, Indianapolis, IN 46285, USA; 321st Century Neurology, Xenoscience, Phoenix, AZ 85013, USA
Correspondence: Kerry Knievel; Joshua Tobin (josh.bytheway@rxcomms.com)

Background: In the American Migraine Prevalence and Prevention Study, >40% of patients with episodic migraine had unmet acute treatment needs with current therapies, including lack of efficacy and intolerance; those with ≥1 unmet need were more likely to have used triptans in the past 3 months [1]. Lasmiditan, a novel, central nervous system penetrant, highly selective 5-hydroxytryptamine1F receptor agonist, has demonstrated superiority to placebo in the acute treatment of migraine in adults. In two Phase 3 studies, SAMURAI (NCT02439320) and SPARTAN (NCT02605174), the percentage of patients who were migraine pain-free 2 hours post-first dose was significantly greater with lasmiditan 200mg and 100mg (all comparisons p<0.001 vs placebo) taken within 4 hours of a single migraine attack. This post-hoc analysis determined whether response to lasmiditan differed according to prior triptan therapy response in participants in SAMURAI and SPARTAN.

Methods: Both studies included patients with moderate/severe migraine disability (MIDAS score ≥11). Current analyses considered combined data from participants reporting triptan use within 3 months prior to screening randomized to receive lasmiditan 100mg or 200mg, or placebo, as first dose. At baseline, patients rated themselves as good, poor or nonresponders prior to triptan therapy. To determine whether therapeutic benefit varied according to prior triptan response, treatment-by-subgroup analyses of 2-hour outcomes used a logistic regression model, including study, treatment, rescue medication use and triptan responder subgroup (good vs poor/nonresponder). Significance for interaction was defined as p<0.1.

Results: In combined analyses, there was no evidence that the benefit (on headache pain freedom, most bothersome symptom [MBS] freedom, headache pain relief) of lasmiditan 200mg versus placebo varied significantly between triptan responder subgroups. A significant differential benefit of lasmiditan 100mg over placebo favouring poor/nonresponders vs good responders was seen for headache pain freedom (odds ratio 4.5 vs 1.8, p=0.056) and MBS freedom (odds ratio 3.2 vs 1.5, p=0.042). Risk relative to placebo of experiencing a treatment-emergent adverse event was significantly lower for poor/nonresponders vs good responders for each lasmiditan dose. Significant differences between subgroups were not consistently seen in individual studies.

Conclusion: Therapeutic benefit of lasmiditan in patients with moderate/severe migraine disability was generally unaffected by prior triptan therapy response. Lasmiditan offers a possible alternative migraine therapy option for patients regardless of prior response to triptans.

References

1. Lipton RB, Buse DC, Serrano D, et al. Examination of unmet treatment needs among persons with episodic migraine: results of the American Migraine Prevalence and Prevention (AMPP) Study. Headache 2013;53:1300-11.

O31 Effect of galcanezumab on severity and symptoms of migraine in phase 3 trials in patients with episodic or chronic migraine

Kathleen A. Day1, Michael Ament2, Virginia L. Stauffer1, Vladimir Skljarevski1, Qi Zhang1, Eric M. Pearlman1, Sheena K Aurora1

1Eli Lilly and Company, Indianapolis, IN 46285 USA; 2Ament Headache Center, Denver, CO, 80206, USA
Correspondence: Virginia L. Stauffer (stauffer_virginia@lilly.com)

Objective: Galcanezumab, a humanized monoclonal antibody that binds CGRP, has demonstrated in multiple studies, a significant reduction in monthly migraine headache days compared to placebo. Here, we present data from 3 randomized clinical trials in patients with migraine showing that galcanezumab alleviates severity and symptoms of migraine.

Methods: EVOLVE-1 and EVOLVE-2 were 6-month double-blind studies conducted in North America and globally, respectively, in male and female patients 18–65 years of age with episodic migraine (i.e., 4–14 monthly migraine headache days [MHDs]). REGAIN was a global study with a 3-month double-blind phase in patients with chronic migraine (≥15 headache days [HDs] per month, where ≥8 met criteria for migraine). For the 3 studies, patients were randomized 2:1:1 to subcutaneous monthly injections of placebo, or 120 or 240 mg of galcanezumab. Patients randomized to the 120 mg galcanezumab group received a loading dose of 240 mg at randomization. Patients recorded headache characteristics, duration, and severity, as well as presence of nausea and vomiting, photophobia, phonophobia, and aura with each headache attack in an electronic patient-reported outcome (ePRO) diary. The reported parameters were changes from baseline in moderate to severe monthly HDs, mean severity of remaining MHDs, and monthly MHDs with nausea and/or vomiting, photophobia and phonophobia, aura, and prodromal symptoms other than aura. Rating for migraine severity was 1=mild, 2=moderate, and 3=severe. Analyses were conducted on the intent-to-treat population and those who had a non-missing baseline value and at least one post-baseline value. Change from baseline in severity and symptoms parameters were analyzed using a linear mixed model repeated measures approach.

Results: With the exception of “Mean severity of remaining MHDs” in EVOLVE-1 and “Monthly MHDs with aura” in REGAIN, both doses of galcanezumab were statistically significantly superior to placebo (p<.05) in reducing migraine symptoms and severity (Table 1).

Conclusions: Galcanezumab was superior to placebo in reducing the mean severity of remaining migraine headaches and in reducing the numbers of monthly moderate to severe headaches in patients with episodic or chronic migraine. Galcanezumab also reduced the frequency of associated symptoms of migraine, with the exception of aura, which was reduced in patients with episodic, but not chronic, migraine. Overall, along with the previously reported reductions in monthly MHDs, galcanezumab can alleviate potentially disabling symptoms in patients with migraine.

Trial registration: ClinicalTrials.gov identifiers NCT02614183 (EVOLVE-1), NCT02614196 (EVOLVE-2), and NCT02614261 (REGAIN)

Ethics approval

These studies were approved by the appropriate institutional review board for each of the study sites. They were all conducted according to Good Clinical Practice and the Declaration of Helsinki guidelines.

Table 1 (abstract O31).

Summary of overall results

Δ from BL in:

EVOLVE-1

Galcanezumab

EVOLVE-2

Galcanezumab

REGAIN

Galcanezumab

120 mg

(N=210)

240 mg

(N=208)

120 mg

(N=226)

240 mg

(N=220)

120 mg

(N=273)

240 mg

(N=274)

Moderate to severe monthly HDs

Δ (SE) vs. BL (PBO)

-2.89 (0.21)

-2.31 (0.18)

-2.92 (0.33)

Δ (SE) vs. BL

-4.24 (0.25)

-4.15 (0.25)

-3.90 (0.22)

-3.78 (0.22)

-4.90 (0.40)

-4.64 (0.39)

Δ (SE) vs. PBO

-1.35 (0.23)

-1.26 (0.24)

-1.59 (0.23)

-1.47 (0.24)

-1.98 (0.38)

-1.72 (0.38)

95% CI vs. PBO

(-1.81, -0.89)

(-1.72, -0.80)

(-2.05, -1.13)

(-1.93, -1.01)

(-2.73, -1.23)

(-2.47, -0.97)

p-value vs. PBO

<.001

<.001

<.001

<.001

<.001

<.001

Mean severity of remaining MHDs

Δ (SE) vs. BL (PBO)

-0.17 (0.02)

-0.15 (0.02)

-0.12 (0.02)

Δ (SE) vs. BL

-0.19 (0.03)

-0.22 (0.03)

-0.20 (0.03)

-0.22 (0.03)

-0.19 (0.02)

-0.19 (0.02)

Δ (SE) vs. PBO

-0.02 (0.03)

-0.05 (0.03)

-0.06 (0.03)

-0.08 (0.03)

-0.07 (0.02)

-0.07 (0.02)

95% CI vs. PBO

(-0.07, 0.03)

(-0.10, 0.01)

(-0.11, -0.01)

(-0.13, -0.03)

(-0.11, -0.03)

(-0.11, -0.03)

p-value vs. PBO

.447

.086

.031

.004

<.001

<.001

Monthly MHDs with nausea and/or vomiting

Δ (SE) vs. BL (PBO)

-1.17 (0.16)

-0.87 (0.13)

-1.92 (0.27)

Δ (SE) vs. BL

-1.91 (0.19)

-2.05 (0.19)

-2.02 (0.17)

-1.77 (0.17)

-3.13 (0.33)

-3.20 (0.33)

Δ (SE) vs. PBO

-0.74 (0.18)

-0.88 (0.18)

-1.14 (0.18)

-0.90 (0.18)

-1.21 (0.32)

-1.28 (0.31)

95% CL for Δ

(-1.10, -0.39)

(-1.23, -0.52)

-0.90 (0.18))

(-1.25, -0.55)

(-1.82, -0.59)

(-1.90, -0.66)

p-value vs. PBO

<.001

<.001

<.001

<.001

<.001

<.001

Monthly MHDs with photophobia and phonophobia

Δ (SE) vs. BL (PBO)

-2.10 (0.23)

-1.47 (0.19)

-2.25 (0.36)

Δ (SE) vs. BL

-3.50 (0.27)

-3.54 (0.27)

-3.22 (0.24)

-3.00 (0.24)

-3.81 (0.43)

-3.58 (0.43)

Δ (SE) vs. PBO

-1.39 (0.26)

-1.43 (0.26)

-1.76 (0.25)

-1.53 (0.25)

-1.56 (0.41)

-1.33 (0.41)

95% CI vs. PBO

(-1.90, -0.89)

(-1.94, -0.93)

(-2.25, -1.27)

(-2.02, -1.04)

(-2.37, -0.75)

(-2.14, -0.52)

p-value vs. PBO

<.001

<.001

<.001

<.001

<.001

.001

Monthly MHDs with aura

Δ (SE) vs. BL (PBO)

-0.96 (0.12)

-0.97 (0.12)

-1.42 (0.24)

Δ (SE) vs. BL

-1.39 (0.14)

-1.38 (0.15)

-1.45 (0.15)

-1.44 (0.16)

-1.40 (0.29)

-1.89 (0.29)

Δ (SE) vs. PBO

-0.43 (0.14)

-0.42 (0.14)

-0.48 (0.17)

-0.48 (0.17)

0.03 (0.28)

-0.47 (0.28)

95% CI vs. PBO

(-0.70, -0.16)

(-0.70, -0.15)

(-0.81, -0.16)

(-0.80, -0.15)

(-0.53, 0.58)

(-1.02, 0.09)

p-value vs. PBO

.002

.002

.004

.004

.922

.098

Monthly MHDs with prodromal symptoms other than aura

Δ (SE) vs. BL (PBO)

-1.23 (0.14)

-1.01 (0.14)

-1.15 (0.28)

Δ (SE) vs. BL

-1.83 (0.17)

-1.69 (0.17)

-1.84 (0.17)

-1.74 (0.17)

-1.81 (0.34)

-2.18 (0.33)

Δ (SE) vs. PBO

-0.61 (0.17)

-0.46 (0.17)

-0.83 (0.18)

-0.72 (0.18)

-0.66 (0.32)

-1.03 (0.32)

95% CI vs. PBO

(-0.93, -0.28)

(-0.79, -0.14)

(-1.18, -0.47)

(-1.08, -0.36)

(-1.29, -0.02)

(-1.67, -0.40)

p-value vs. PBO

<.001

. 006

<.001

<.001

.042

.001

Abbreviations: Δ change in least squares mean; BL baseline, CI confidence interval, HDs headache days, MHDs migraine headache days, N number of intent-to-treat patients who have non-missing baseline value and at least one post-baseline value; N’s differed slightly for mean severity of remaining MHDs. PBO placebo, SE standard error

Shaded cells represent change from baseline for placebo groups; N=425, 450, and 538 for EVOLVE-1, EVOLVE-2, and REGAIN, respectively

O32 Factors associated with significant reduction in migraine headache days: a post hoc analysis of phase 3 placebo-controlled trials of patients with episodic and chronic migraine treated with galcanezumab

Sheena K. Aurora, Dustin D. Ruff, Qi Zhang, Eric M. Pearlman

Lilly Corporate Center, Eli Lilly and Company, Indianapolis, IN, USA
Correspondence: Qi Zhang (zhang_qi_x1@lilly.com)

Background: Migraine remains undertreated with few approved preventive medications available. Galcanezumab, a humanized monoclonal antibody that binds to calcitonin gene-related peptide (CGRP), was developed for the prevention of migraine.

Objectives: To determine if previously seen galcanezumab response predictors are revalidated in phase III episodic and chronic migraine studies.

Methods: This post hoc analysis of 3 randomized, double-blind, placebo-controlled Phase 3 studies evaluated the effects of galcanezumab in patients aged 18-65 years. Results of two episodic migraine (EM) studies (NCT02614183, NCT02614196) that enrolled patients with a baseline of 4-14 migraine headache days (MHD) per month were pooled. One chronic migraine (CM) study (NCT02614261) enrolled patients with ≥15 headache days per month, of which 8 had migraine-like features. In all studies, patients were randomized 2:1:1 to placebo, galcanezumab 120 mg, or galcanezumab 240 mg given subcutaneously once monthly. Three possible predictors of clinical response – prior triptan use, migraine history ≥20 years, and history of failure to preventive treatments – were evaluated as subgroup analyses of 50% response rate (RR) (≥50% reduction in number of MHD). The overall treatment-by-subgroup interaction p-values for the double-blind phase (EM: 6 months; CM: 3 months) are reported with a 2-sided significance level of 0.10. The studies were approved by the appropriate Institutional Review Board for each study site.

Results: Baseline characteristics were generally consistent across the 3 studies, with the exception of mean headache days (EM: 10.67 (n=1773) vs. CM: 21.44 (n=1113)) and MHD (9.13 vs. 19.41). Both galcanezumab doses were associated with significantly higher 50% RRs than placebo in most of the examined subgroups for EM and CM. For the 120 mg dose vs. placebo in the EM and CM studies, a greater treatment effect was seen for those with vs. without history of failure of ≥1 preventive treatment (treatment-by-subgroup interaction EM: p=0.012; CM: p<0.001), and for those who used vs. did not use a triptan at baseline (EM: p<0.001; CM: p=0.062). Migraine diagnosis ≥20 years previously was predictive of response to the 120 mg dose for individuals with EM (p=0.056) but not for those with CM (p=0.206).

Conclusion: Analysis of this large data set expands previous findings and suggests that there may be some predictors of clinical response to galcanezumab compared with placebo in EM and CM, primarily driven by placebo response fluctuations, as the magnitude of 50% RR with galcanezumab was similar in all subgroups but was lower and varied with placebo.

O33 Effect of galcanezumab on possible menstrual-related migraine: exploratory analyses results from EVOLVE-1, EVOLVE-2 and REGAIN

Maria S. Fernandes,1 Holland C. Detke,1 Qi Zhang,1 Jelena M. Pavlovic,2 Sheena K. Aurora1

1Eli Lilly and Company, Indianapolis, IN 46285 USA; 2Albert Einstein College of Medicine, Montefiore Headache Center, Bronx, NY 10461USA
Correspondence: Sheena K. Aurora (sheena.aurora@lilly.com)

Background: Migraine is a common neurologic disease that affects more than 36 million people in the Unites States, being more prevalent in females of reproductive age. Attacks of migraine in more than 50% of women correlate with menstrual cycle hormonal fluctuations, and are typically more severe and difficult to manage with conventional therapies. Menstrual migraine attacks are defined as attacks occurring during the 5-day perimenstrual interval (-2 to +3, where first day of bleeding is defined as +1). These exploratory post-hoc analyses focus on the effect of galcanezumab, a Calcitonin gene-related peptide (CGRP) monoclonal antibody studied for the prevention of chronic and episodic migraine, on the incidence and severity of menstrual migraine attacks.

Methods: Post-hoc analyses were performed using data from 3 double-blind, placebo (PBO)-controlled, Phase 3 studies in patients aged 18-65 years with episodic (EVOLVE-1 & EVOLVE-2) or chronic migraine (REGAIN). A total of 2,886 patients (858 EVOLVE-1, 915 EVOLVE-2, 1113 REGAIN) randomly received 120mg (with 240mg loading dose at first month) or 240mg galcanezumab (GMB) or placebo (PBO), which was administered subcutaneously once/month for 6 months in EVOLVE-1&2 and for 3 months in REGAIN. Menstruation was assessed on a daily basis via self-reported diary, as well as headache characteristics, duration, and severity.

A menstrual-related migraine headache day (MRMHD) is defined as a headache with migraine characteristics (definition adapted from the standard IHS ICHD-3 beta definition) within the 5-day perimenstrual period (-2 to +3). Exploratory analyses included intent-to-treat (ITT) patients who had >0 MRMHD during a one-month baseline period and who were females with menstrual periods. Using a negative binomial repeated measures model, the number of MRMHDs per 30-day period was estimated each month and overall across 6 months for pooled EVOLVE-1 & EVOLVE-2 data, and across 3 months for REGAIN.

Results: For ITT patients with >0 MRMHD, baseline mean number of MRMHDs were 2.4, 2.4 and 2.6 for 120mg GMB, 240mg GMB, and PBO, respectively, for pooled EVOLVE-1 & EVOLVE-2 studies (n=650). Corresponding values were 4.0, 4.5, and 4.4 days, respectively, for REGAIN (n=407). Statistically significantly lower incidence of MRMHDs per 30-day period was observed for both GMB doses compared with PBO overall across 6 months for pooled EVOLVE-1 & EVOLVE-2 and across 3 months for REGAIN (Table 1).

Conclusion: Galcanezumab, given monthly, was effective in reducing migraine headache days during the perimenstrual period.

The studies were approved by a central Ethics Review Board and registered on ClinTrials.gov (NCT02614183, NCT02614196, and NCT02614261).

Table 1 (abstract O33).

Estimated Number of Menstrual-Related Migraine Headache Days

Period

Treatment

N

Estimated Number of MRMHDs per 30 day Period (SE)

95% CI

Rate Ratio per 30 day period

95% CI

P-value

ITT patients with baseline number of MRMHDs >0 for Episodic Migraine

 Average of Month 1 to 6

PBO

321

1.58 (0.13)

1.34, 1.86

   

120mg

170

1.16 (0.12)

0.96, 1.41

0.74

0.64, 0.85

<0.001

240mg

159

1.12 (0.12)

0.90, 1.38

0.71

0.60, 0.83

<0.001

ITT patients with baseline number of MRMHDs >0 for Chronic Migraine

 Average of Month 1 to 3

PBO

198

3.52 (0.18)

3.18, 3.90

   

120mg

112

2.58 (0.21)

2.58, 3.40

0.84

0.73, 0.97

0.015

240mg

97

3.01 (0.20)

2.64, 3.42

0.85

0.75, 0.98

0.021

MRMHD Menstrual-Related Migraine Headache Days, CI confidence interval, ITT intent-to-treat, MM menstrual migraine, PBO placebo, SE standard error

O34 Primary angiitis of the central nervous system and reversible cerebral vasoconstriction syndrome: a comparative study of two cohorts

Hubert de Boysson1, Jean-Jacques Parienti2, Jérôme Mawet3, Caroline Arquizan4, Grégoire Boulouis5, Cécilia Burcin3, Olivier Naggara6, Mathieu Zuber7, Emmanuel Touzé8, Achille Aouba1, Marie-Germaine Bousser9, Christian Pagnoux10, Anne Ducros5

1Internal Medicine, Caen University Hospital, Caen, France; 2Biostatistics, Caen University Hospital, France; 3Emergency Headache Centre, Lariboisière Hospital, APHP, Paris, France; 5Neurology, Montpellier University Hospital, Montpellier, France; 6Neuroradiology, Centre Hospitalier Sainte-Anne, Paris-Descartes University, Paris, France; 7Vascular Neurology - Saint Joseph Hospital, Paris, France; 8Neurology, Caen University Hospital, France; 9Neurology, Lariboisière Hospital, APHP, Paris, France; 10Rheumatology, Mount Sinai Hospital, Toronto, Canada
Correspondence: Anne Ducros (a-ducros@chu-montpellier.fr)

Distinguishing primary angiitis of the central nervous system (PACNS) and reversible cerebral vasoconstriction syndrome (RCVS) can remain a challenge in clinical practice.

We compared two large French cohorts of patients with biopsy or angiographically-proven PACNS (n=110) to patients with angiographically-proven RCVS (n=173) in order to better define differences at onset.

Patients with RCVS were more often women (71% versus 47% in PACNS, p<0.0001) and more often had a past history of migraine (32% versus 7%, p<0.0001). While headaches, especially thunderclap headaches, were more frequent in RCVS (99% versus 54% in PACNS and 94% versus 3% in PACNS, respectively, both p<0.0001), all other neurological symptoms (focal deficits, seizures, vigilance impairment) were more frequent in PACNS (all symptoms, p<0.0001), even when focusing only on angiography-diagnosed PACNS patients or on RCVS patients with abnormal brain imaging.

Brain MRI was abnormal in every PACNS patient, but only in 53 (31%) RCVS patients (p<0.0001). Acute ischemic stroke was more frequent in PACNS than in RCVS (76% versus 8%, p<0.0001). While intracerebral hemorrhage was more frequent in PACNS (20% versus 9% in RCVS, p=0.006), subarachnoid hemorrhage predominated in RCVS (27% versus 16% in PACNS, p=0.04). In a multivariate analysis, female sex and thunderclap headache were the two strongest variables associated with RCVS, whereas motor deficit and acute brain infarction were the two strongest variables associated with PACNS.

The clinical context (female sex, past history of migraine) and the characteristics of headache (thunderclap) combined with brain MRI features enable to distinguish RCVS from PACNS.

O35 VALIDATION OF THE ITALIAN VERSION OF THE “IDENTIFY CHRONIC MIGRAINE” SCREENING TOOL: THE IT-EC-ID

Simona Sacco1, Silvia Benemei2, Sabina Cevoli3,4, Gianluca Coppola5, Pietro Cortelli3,4, Francesco De Cesaris2, Roberto De Icco6, Cristiano De Marco7, Cherubino Di Lorenzo5, Luana Evangelista1, Pierangelo Geppetti2, Alessia Manni8, Andrea Negro7, Giulia Pierangeli3,4, Francesco Pierelli9, Lanfranco Pellesi10, Luigi Alberto Pini10, Francesca Pistoia1, Maria Pia Prudenzano8, Antonio Russo11, Grazia Sances6, Valentina Taranta1, Cristina Tassorelli6,12, Gioacchino Tedeschi11, Maria Trojano8, Paolo Martelletti7

1Department of Applied Clinical Sciences and Biotechnology, Section of Neurology, University of L’Aquila, L’Aquila, Italy; 2Department of Health Sciences, Section of Clinical Pharmacology and Oncology, University of Florence, Florence, Italy; 3IRCCS Institute of Neurological Science of Bologna, Bologna, Italy; 4Department of Biomedical and Neuromotor Sciences, University of Bologna, Bologna, Italy; 5Department of Medico-Surgical Sciences and Biotechnologies, Sapienza University Polo Pontino, Latina, Italy; 6Headache Science Center, IRCCS C. Mondino Foundation, Pavia, Italy; 7Department of Clinical and Molecular Medicine, Regional Referral Headache Centre, Sant'Andrea Hospital, Sapienza University, Rome, Italy; 8Department of Basic Medical Sciences, Neurosciences and Sense Organs, University of Bari, Italy; 9IRCCS NEUROMED, Pozzilli (IS), Italy; 10Headache and Drug Abuse Research Centre, Policlinico Hospital, University of Modena e Reggio Emilia, Modena, Italy; 11Department of Medical, Surgical, Neurological, Metabolic and Aging Sciences, Second University of Naples, Napoli, Italy; 12Department of Brain and Behavioral Sciences, University of Pavia, Pavia, Italy
Correspondence: Simona Sacco (simona.sacco@univaq.it)

Background

Chronic migraine (CM) is an underdiagnosed and undertreated condition. Tools to improve CM detection by health care professionals may enhance case finding and promote proper referral to dedicated care. Recently, the self-administered tool ‘Identify Chronic Migraine (ID-CM)’ proved to be a reliable instrument to identify patients likely to suffer from CM [1]. An Italian version of the ID-CM (IT-EC-CM) was developed according to a standardized methodology [2]. The aim of the present study was to validate IT-EC-ID on a sample of headache sufferers seeking consultation at tertiary headache centres in Italy.

Material and Methods

We included all consecutive patients, aged 18 years or older, consulting 9 selected tertiary Headache Centers for a first in-person visit for the presence of headache. We excluded patients who had language barrier, or any other condition, including cognitive disturbances that could affect the capability of filling the IT-EC-ID. Patients, self-filled the IT-EC-ID before the in-person visit. Thereafter, a clinical diagnosis, according to the International Classification of Headache Disorders (ICHD), III revision beta version, was assigned by a headache expert blinded to the IT-EC-ID results. This diagnosis was used as the gold standard for the validation of the diagnosis assigned by the IT-EC-ID. The study was approved by the local Ethic Committees of each of the participating centers.

Results

From November 2017 to April 2018, we included 532 subjects with headache (81% women, mean age 42.0±13.0). According to the clinical diagnosis, 209 (39.3%) of them suffered with CM. We excluded 39 patients (1 unwilling to complete the IT-EC-ID and 38 with incomplete IT-EC-ID). Among the 493 patients, eligible for the validation procedure, we had 185 patients diagnosed with CM according to ICHD-III and 218 patients with possible CM according to the IT-EC-ID. True positive cases were 150, true negative 240, false positive were 68, and false negative were 35. The sensitivity for the IT-ID-CM was 81.1% with a specificity was 77.8%, a negative predictive value of 86.0%, and a positive predictive value of 70.9%. Among the false positive, we found 73.7% of the patients with medication overuse without CM, 54.5% of patients with chronic tension type headache, 30.0% of patients with episodic tension type headache, and 14.3% of patients with migraine.

Conclusions

The sensitivity and specificity achieved by IT-EC-ID compares favorably with those achieved by the ID-CM, indicating that it is a reliable tool for identifying CM patients and for excluding patients with other headache forms. This study is still ongoing and an electronic version of the IT-EC-ID is being validated in the selected headache centers. The further step will be to test the reliability of the IT-ID-CM in the primary care setting and the feasibility of its use in the identification of subjects with CM for fast-track access to dedicated care.

Acknowledgements

This project was supported by an unconditional grant from Allergan Italy to the Fondazione Italiana per lo Studio delle Cefalee Onlus.

References

1. Lipton RB, Serrano D, Buse DW, Pavlovic JM, Blumenfeld AM, Dodick DW, Aurora SK, Becker WJ, Diener H-S, Wang S-J, Vincent MB, Hindiyeh NA, Starling AJ, Gillard PJ, Varon SF, Reed ML (2016) Improving the detection of chronic migraine: Development and validation of Identify Chronic Migraine (ID-CM). Cephalalgia 36:203–215.

2. Sacco S, Benemei S, Cevoli S, Coppola G, Cortelli P, De Cesaris F, De Marco C, Di Lorenzo C, Evangelista L, Geppetti P, Negro A, Pierangeli G, Pierelli F, Pini LA, Pistoia F, Russo A, Tassorelli C, Tedeschi G, Martelletti P. Development of the Italian version of the “identify chronic migraine” (IT-ID-CM). J Headache Pain 2017;18(Suppl 1):P43.

O36 Migraine progression in natural subgroups of migraine based on comorbidities and concomitant conditions: results of the Chronic Migraine Epidemiology and Outcomes (CaMEO) study

Richard B. Lipton1, Vincent T. Martin2, Michael L. Reed3, Kristina M. Fanning,3 Aubrey Manack Adams,4 Dawn C. Buse,1

1Department of Neurology, Albert Einstein College of Medicine, Bronx, NY, 10461, USA; 2University of Cincinnati Headache and Facial Pain Center, University of Cincinnati College of Medicine, Cincinnati, OH, 45267, USA; 3Vedanta Research, Chapel Hill, NC, 27517, USA; 4Allergan plc, Irvine, CA, 92612, USA
Correspondence: Richard B. Lipton (Richard.Lipton@einstein.yu.edu)

Background: Prior research has identified 8 natural subgroups of migraine based on profiles of comorbidities from the CaMEO Study. We tested the hypothesis that these subgroups differ in prognosis as measured by progression to chronic migraine (CM).

Methods: Participants from the prospective, web-based baseline CaMEO Study (ClinicalTrials.gov, NCT01648530) were identified using quota sampling. Episodic migraine (EM) and CM were distinguished. Based on respondents’ self-report, 8 subgroups were identified using latent class analysis: Most Comorbidities, Respiratory/Psychiatric (Resp/Psych), Respiratory/Pain (Resp/Pain), Respiratory, Psychiatric, Cardiovascular, Pain, and Fewest Comorbidities. Modelling approaches included forward stepwise analysis of time to CM onset in individuals with EM at baseline across 7 comorbid classes, using Fewest Comorbidities as reference. Covariates including age, gender, income, body mass index, race, Migraine Disability Assessment (MIDAS), Migraine Symptom Severity Scale (MSSS), allodynia, and medication overuse at baseline were added to the model starting with the variable providing the most significant improvement in model fit, and continuing until no further improvement was observed. The study received ethical approval from the Institutional Review Board of the Albert Einstein College of Medicine.

Results: In the analysis population (n=8658), MIDAS was the first variable added to the forward stepwise model, as it provided the most statistically significant improvement in fit. Medication overuse was included as step 2, followed by comorbid class variable, allodynia, income, age, gender and MSSS (Table 1). BMI and race did not further improve fit and were not added. In the final model, Most Comorbidities had the highest risk of progression to CM, 3 times higher than Fewest Comorbidities (HR, 3.01 [95% CI: 2.17, 4.18]). Addition of age tended to increase the HR for all comorbid classes; Most Comorbidities increased from 2.49 (95% CI: 1.83, 3.39) before addition of age to 3.02 after (95% CI: 2.17, 4.20).

Conclusions: Identified comorbid classes of migraine are associated with risk of progression from EM to CM. Understanding the biological differences among these subgroups may help minimize migraine disease progression and optimize management.

Table 1 (abstract O36).

Forward stepwise model* for the discrete time hazard to chronic migraine onset in comorbid classes of migraine in individuals with episodic migraine at baseline

 

Hazard Ratio (95% CI)*

LCA Class

Step 3 (Comorbid Class)

Step 4 (Allodynia)

Step 5 (Income ≥50k)

Step 6 (Age)

Step 7 (Gender)

Step 8 (MSSS)

Most Comorbidities

2.80 (2.06, 3.80)

2.59 (1.91, 3.53)

2.49 (1.83, 3.39)

3.02 (2.17, 4.20)

3.07 (2.21, 4.27)

3.01 (2.17, 4.18)

Resp/Psych

1.86 (1.39, 2.47)

1.75 (1.31, 2.33)

1.75 (1.32, 2.34)

1.87 (1.40, 2.49)

1.93 (1.44, 2.58)

1.87 (1.40, 2.50)

Resp/Pain

2.25 (1.68, 3.02)

2.13 (1.59, 2.86)

2.21 (1.64, 2.96)

2.61 (1.91, 3.57)

2.63 (1.92, 3.60)

2.57 (1.88, 3.51)

Respiratory

1.40 (1.07, 1.82)

1.33 (1.01, 1.74)

1.35 (1.03, 1.76)

1.40 (1.07, 1.83)

1.42 (1.09, 1.87)

1.41 (1.07, 1.84)

Psych

2.22 (1.63, 3.03)

2.15 (1.58, 2.94)

2.10 (1.54, 2.87)

2.09 (1.53, 2.85)

2.12 (1.55, 2.89)

2.07 (1.52, 2.83)

Cardiovascular

1.21 (0.84, 1.74)

1.21 (0.84, 1.74)

1.25 (0.87, 1.80)

1.46 (1.00, 2.13)

1.40 (0.96, 2.04)

1.41 (0.96, 2.05)

Pain

1.35 (0.93, 1.97)

1.30 (0.89, 1.90)

1.32 (0.91, 1.93)

1.48 (1.01, 2.17)

1.42 (0.96, 2.09)

1.41 (0.96, 2.07)

LCA latent class analysis, MSSS Migraine Symptom Severity Scale, Resp respiratory, Psych psychiatric

*Step 1 added MIDAS and Step 2 added medication overuse and are not included in this table as the comorbid class only enters at Step 3.

P≤0.05, compared with the “Fewest Comorbidities” class.

P≤0.001, compared with the “Fewest Comorbidities” class

O37 Complete detoxification is the most feasible treatment for medication-overuse headache: A randomized controlled open-label trial

Ida M. S. Engelstoft, Louise N. Carlsen, Signe B. Munksgaard, Mia Nielsen, Rigmor H. Jensen, Lars Bendtsen

Danish Headache Center, Neurological Clinic, Rigshospitalet, Glostrup, Denmark
Correspondence: Louise N. Carlsen (louise.ninett.carlsen@regionh.dk)

Background: Complete stop of acute medication and/or migraine medication for treatment of medication-overuse headache (MOH) has previously been reported more effective in reducing headache days and migraine days per month compared with restricted intake of acute medication. However, it is unknown whether complete stop or restricted intake is the most feasible treatment for patients.

Objective: To investigate if feasibility of detoxification in medication-overuse headache (MOH) is different between complete stop of acute medication and restricted intake, and if reductions in headache-related medication dependence, anxiety and depression differ between the treatments.

Methods: MOH patients were included in a prospective, outpatient study and randomized to two months detoxification with either no analgesics or acute migraine-medication (program A) or acute medication restricted to two days/week (program B). After 6 and 12 months of treatment, patients graded feasibility of detoxification. Psychological dependence was measured by Severity of Dependence Scale (SDS), while anxiety and depression were measured by Hospital Anxiety and Depression Scale (HADS).

Results: We included 72 MOH patients with primary migraine and/or tension-type headache. Forty-nine completed detoxification and the SDS-questionnaire at 12-months follow-up, and the feasibility of detoxification was significantly higher in program A compared to program B (p <0.001). At 12 months, the psychological dependence was reduced by 44% in program A compared to 26% in program B (p = 0.053), while anxiety score was reduced by 32% and 11%, respectively (p = 0.048).

Conclusion: Detoxification with complete stop of acute medication was more feasible and also the most effective in reducing headache-related anxiety.

Trial registration: Clinicaltrials.gov (NCT02903329)

Ethical approval

The study was approved by the Regional Ethical Committee in Denmark (H-1-2012- 105 116)

O38 Impact of fremanezumab on response rates, acute medication use, and disability in patients with episodic migraine who have failed at least one prior migraine preventive medication

Paul K. Winner1; Rashmi B. Halker Singh2; Joshua M. Cohen3; Ronghua Yang3; Paul P. Yeung3; Verena Ramirez Campos4

1Premiere Research Institute, West Palm Beach, Florida, USA; 2Mayo Clinic, Phoenix, Arizona, USA; 3Teva Pharmaceuticals, Frazer, Pennsylvania, USA; 4Teva Pharmaceuticals, Buenos Aires, Argentina
Correspondence: Paul K. Winner (khokenson@hcg-int.com)

BACKGROUND:

Preventive medication is recommended for episodic migraine (EM) patients with ≥4 headache days per month. Fremanezumab, a fully humanized monoclonal antibody (IgG2a) that selectively targets calcitonin gene-related peptide (CGRP), is efficacious in preventing EM, but its effectiveness in patients who failed previous preventive medications is unknown.

OBJECTIVE:

To assess the effects of fremanezumab on response rates, acute headache medication use, and disability in EM patients who failed at least one prior preventive migraine medication.

METHODS:

In this Phase 3, multicenter, randomized, double-blind, placebo-controlled study, patients were randomized 1:1:1 to receive subcutaneous injections of fremanezumab quarterly (675 mg at baseline and placebo at Weeks 4 and 8), fremanezumab monthly (225 mg at baseline, Weeks 4 and 8), or placebo (at baseline, Weeks 4 and 8) over a 12-week treatment period. Analyses were performed in patients who failed at least one prior preventive migraine medication (due to lack of efficacy or intolerability) using Cochran–Mantel–Haenszel test or an analysis of covariance model. Endpoints included the proportion of patients with ≥50% reduction in the monthly average number of migraine days, mean change from baseline in the monthly average number of days of acute headache medication use, and mean change from baseline in the Migraine Disability Assessment (MIDAS) score during the 12-week treatment period.

RESULTS:

The subgroup who failed at least one prior migraine preventive therapy included 58 fremanezumab quarterly, 65 fremanezumab monthly, and 63 placebo patients. A greater proportion of patients who received fremanezumab had a ≥50% reduction in the monthly average number of migraine days during the treatment period (quarterly: 38%, P=0.0100; monthly: 43%, P=0.0010) compared with placebo (17%). Fremanezumab significantly reduced from baseline the monthly average number of days of any acute headache medication use during the treatment period (quarterly [least-squares mean change ± standard error]: –3.1±0.5 days; monthly: –3.4±0.5 days) compared with placebo (–1.1±0.5 days; both, P<0.0001). Fremanezumab significantly improved disability from baseline, based on the change in MIDAS score during the treatment period (quarterly: –24.5±3.7, P=0.0006; monthly: –26.8±3.7, P<0.0001) compared with placebo (–11.1±3.4).

CONCLUSIONS:

Among EM patients who failed at least one prior preventive migraine medication, fremanezumab treatment was efficacious, reduced acute headache medication use, and improved disability, with effect sizes greater than those seen in the overall trial population.

TRIAL REGISTRATION: ClinicalTrials.gov, NCT02629861

ETHICS APPROVAL

The study was approved by relevant independent ethics committees or institutional review boards, according to national or local regulations.

O39 Impact of fremanezumab on response rates, migraine days, and acute medication use in patients with chronic migraine who have failed at least one prior migraine preventive medication

Stephen D. Silberstein1, Jessica Ailani2, Joshua M. Cohen3, Ronghua Yang3, Paul P. Yeung3, Verena Ramirez Campos4

1Jefferson Headache Center, Thomas Jefferson University, Philadelphia, Pennsylvania, USA; 2Medstar Georgetown University Hospital, Washington, District of Columbia, USA; 3Teva Pharmaceuticals, Frazer, Pennsylvania, USA; 4Teva Pharmaceuticals, Buenos Aires, Argentina

BACKGROUND:

Fremanezumab, a fully humanized monoclonal antibody (IgG2a) that selectively targets calcitonin gene-related peptide (CGRP), is efficacious in preventing chronic migraine (CM), but its effectiveness in patients who have failed previous preventive medications is unknown.

OBJECTIVE:

To assess the effects of fremanezumab on response rates, migraine days and acute headache medication use in patients with CM who failed one prior preventive migraine medication.

METHODS:

In this Phase 3, multicenter, randomized, double-blind, placebo-controlled study, patients were randomized 1:1:1 to receive subcutaneous injections of fremanezumab quarterly (675 mg at baseline and placebo at Weeks 4 and 8), fremanezumab monthly (675 mg at baseline and 225 mg at Weeks 4 and 8), or placebo (at Baseline, Weeks 4 and 8) over a 12-week treatment period. Analyses were performed in patients who failed at least one prior preventive migraine medication (due to lack of efficacy or intolerability) using a Cochran-Mantel-Haenszel test or an analysis of covariance model. Endpoints included the proportion of patients with a ≥50% reduction in headache days of at least moderate severity, mean change from baseline in the monthly average number of migraine days and mean change from baseline in the number of days of acute headache medication use during the 12-week treatment period.

RESULTS:

The subgroup of patients who failed at least one prior preventive migraine therapy included 130 fremanezumab quarterly, 141 fremanezumab monthly, and 136 placebo patients. More patients who received fremanezumab experienced a ≥50% reduction in headache days of at least moderate severity (quarterly: 28%, P<0.0001; monthly: 38%, P<0.0001) during the treatment period than did those given placebo (8%). Fremanezumab treatment reduced the monthly average number of migraine days during the 12-week treatment period ([least-squares mean change ± standard error]: fremanezumab quarterly, –4.2±0.6 days, P=0.0050; fremanezumab monthly, –4.8±0.5 days, P<0.0001) compared with placebo (–2.4±0.6 days). Fremanezumab significantly reduced the monthly average number of days from baseline of any acute headache medication use during the treatment period (fremanezumab quarterly, –3.4±0.5 days; fremanezumab monthly, –4.1±0.5 days; both, P<0.0001) compared with placebo (–1.2±0.5 days).

CONCLUSIONS:

Among patients with CM who have failed at least one prior preventive migraine medication, fremanezumab was efficacious, with effect sizes in excess of those seen in the overall trial population. Fremanezumab offers clinical benefits to these potentially difficult-to-treat patients.

TRIAL REGISTRATION: ClinicalTrials.gov, NCT02621931

ETHICS APPROVAL

The study was approved by relevant independent ethics committees or institutional review boards, according to national or local regulations.

O40 Efficacy of fremanezumab in migraine patients who have failed at least one prior migraine preventive medication

Peter McAllister1, David W. Dodick2, Joshua M. Cohen3, Ronghua Yang3, Paul P. Yeung3, Verena Ramirez Campos4

1New England Institute for Neurology and Headache, Stamford, Connecticut, USA; 2Department of Neurology, Mayo Clinic, Phoenix, Arizona, USA; 3Teva Pharmaceuticals, Frazer, Pennsylvania, USA; 4Teva Pharmaceuticals, Buenos Aires, Argentina
Correspondence: Peter McAllister (jpotuzak@hcg-int.com)

BACKGROUND:

Fremanezumab, a fully humanized monoclonal antibody (IgG2a) that selectively targets calcitonin gene-related peptide (CGRP), has been shown to be effective in the prevention of chronic migraine (CM) and episodic migraine (EM).

OBJECTIVE:

To assess the efficacy of fremanezumab in migraine patients who failed at least one prior preventive migraine medication.

METHODS:

Fremanezumab was studied in two Phase 3, multicenter, randomized, double-blind, placebo-controlled, parallel-group trials. Patients with CM or EM (confirmed during a 28-day pre-treatment baseline period) received subcutaneous injections of fremanezumab quarterly (675 mg at baseline and placebo at Weeks 4 and 8), monthly (CM: 675 mg at baseline and 225 mg at Weeks 4 and 8; EM: 225 mg at baseline and Weeks 4 and 8), or placebo (at baseline and Weeks 4 and 8) over a 12-week treatment period, with a final evaluation 4 weeks after the last dose of the study drug. Mean changes from baseline in the monthly average number of headache days of at least moderate severity or the monthly average number of migraine days during the 12-week treatment period were assessed in patients who failed at least one prior migraine preventive medication due to lack of efficacy or intolerability. Analyses were performed in the intent-to-treat population using an analysis of covariance (ANCOVA) model.

RESULTS:

In CM patients, fremanezumab yielded greater reductions in the monthly average number of headache days of at least moderate severity (quarterly [n=130] [least-squares mean change ± standard error]: –4.0±0.47, P<0.0001; monthly [n=141]: –4.6±0.46, P<0.0001) compared with placebo (n=136; –1.9±0.49). There were similar reductions in the monthly average number of migraine days (quarterly: –4.2±0.55, P=0.005; monthly: –4.8±0.53, P<0.0001) compared with placebo (–2.4±0.56).

In EM patients, fremanezumab yielded greater reductions in the monthly average number of headache days of at least moderate severity (quarterly [n=58]: –3.0±0.51, P<0.0001; monthly [n=65]: –3.2±0.49, P<0.0001) compared with placebo (n=63; –0.7±0.47). There were similar reductions in the monthly average number of migraine days (quarterly: –3.3±0.61, P=0.0015; monthly: –3.8±0.59, P<0.0001) compared with placebo (–1.3±0.57).P-values stated are compared with placebo.

CONCLUSIONS:

Fremanezumab was efficacious in migraine patients who failed at least one prior migraine preventive medication, a potentially difficult-to-treat population. Effect sizes in this subgroup were greater than those in the overall trial population.

TRIAL REGISTRATION: ClinicalTrials.gov NCT02621931 and NCT02629861

ETHICS APPROVAL

The study was approved by all relevant independent ethics committees or institutional review boards, according to national or local regulations.

O41 Cluster headache is not associated with sleep apnea or specific sleep stages

Nunu Lund1; Mads Barloese2; Agneta Snoer1; Anja Petersen1; Poul Jørgen Jennum3; Rigmor H. Jensen1

1Danish Headache Center, Department of Neurology, Rigshospitalet Glostrup, University of Copenhagen, Denmark; 2Department of Clinical Physiology, Nuclear Medicine and PET, Rigshospitalet Glostrup, University of Copenhagen, Denmark; 3Danish Center for Sleep Medicine, Dept. of Neurophysiology, Rigshospitalet – Glostrup, University of Copenhagen, Denmark
Correspondence: Nunu Lund (nunu.lund@regionh.dk)

Background and aim: Cluster headache (CH) is characterized by severe, unilateral attacks of pain and by a high nocturnal attack burden. Sleep quality remains significantly lower in patients more than one year after the last CH attack compared with healthy controls. Further, sleep parameters are shown to be altered in active CH patients. The primary aim of this study was to compare the macrostructure of sleep in eCH patients in both disease phases and to compare eCH patients with controls.

Method: ECH patients, aged 18-65 years, diagnosed according to the International Classification of Headache Disorders 2ndedition, were admitted for gold standard polysomnography at the Danish Center for Sleep Medicine, preferably both in bout and remission. The macrostructure of sleep including arousals, breathing parameters, limb movements (LMs) and periodic limb movements (PLMs) were compared with 25 age-, sex- and BMI-matched healthy controls. The study was approved by the ethics committee of the Capital Region of Denmark (H-7-2014-020) and the protocol was published at clinical trials.gov (NCT03439722).

Results: There were no differences in any of the sleep parameters for patients in bout (n=32) compared with patients in remission (n=23). Less than half of the patients in bout (14 out of 32 patients, 43.8%) suffered from 21 attacks in total during the polysomnography. Attacks were not related to specific sleep stages (N1: 2/21 attacks, N2: 6/21 attacks, N3: 5/21 attacks, REM: 7/10 attacks).

eCH patients had longer latency (18.9 vs. 11.7 minutes, p<0.05) and lower efficiency (84.4 vs. 86.5, p<0.05) compared with controls, but fewer PLMs (0.67 vs. 1.30 hour-1, p<0.05). Finally, the sleep apnea index was similar in both groups (9.63 vs. 7.76 hour-1, p=0.7674).

Conclusion: This is the first study that systematically investigates eCH patients with full polysomnography in both bout and remission and the largest study comparing eCH patients with controls. The observed sleep disturbances were not associated with the bout but rather seem to be the manifestation of a persisting, underlying pathology. Finally, the prevalence of sleep apnea was comparable in all groups and attacks were not related to specific sleep stages.

O42 Real-world preventative drug management of Chronic Migraine among Spanish Neurologists

D. García-Azorin1, S. Santos Lasaosa2, A. B. Gago-Veiga3, J. Viguera Romero4, A. L. Guerrero-Peral1, P. Pozo-Rosich5,6.

1Headache Unit, Neurology Department. Hospital Universitario Clínico de Valladolid. Valladolid, Spain; 2Headache monographic consult, Hospital Clínico Universitario Lozano Blesa, Zaragoza, Spain; 3Headache consult, Neurology Department. Hospital Universitario de la Princesa, Madrid, Spain; 4Headache consult. Neuroscience unit. Hospital Universitario Virgen Macarena, Seville, Spain; 1Headache Unit, Neurology Department. Hospital Universitario Clínico de Valladolid. Valladolid, Spain; 5Headache Unit. Neurology Department. Hospital Universitari Vall d’Hebron, Barcelona, Spain; 6Headache Research Group. Vall d’Hebron Institut de Recerca (VHIR), Barcelona, Spain
Correspondence: D. García-Azorin (davilink@hotmail.com)

Background:

In migraine, the therapeutic preventive drug arsenal is varied. When prescribing both Guidelines and patient characteristics are taken into account. In Spain, the use of preventive therapies seems to be heterogeneous.

The objective of this study was to evaluate real-life clinical prescribing practice amongst neurologists in Spain

Methods:

Observational descriptive study done with a survey by Neurologists of the Spanish Neurological Society (SEN). Neurologists who participated were divided into Headache Specialists or not. The following data was collected: socio-demographic data,; preventive treatment and choices different migraine sub-types, and their personal perception of efficacy and tolerability to different drugs.

Results:

We analyzed 152 surveys from neurologists around our country. From them: 43.4% were female, 53.3% <40 years, and 34.9% were interested in headache .

In regards to preventive treatment choice; in chronic migraine topiramate (57%) amytriptiline (17.9%) and beta-blockers (14.6%), whereas in episodic migraine the preferred drugs were beta-blockers (47.7%), topiramate (21.5%) and amytriptiline (13.4%).

Regarding perceived efficacy, topiramate was considered the best option in chronic migraine (42.7%) followed by onabotulinumtoxinA (25.5%) and amitryptiline (22.4%). In episodic migraine, neurologist preferred topiramate (43.7%) and beta-blockers (30.3%).

Regarding the duration of preventive therapy when improvement was achieved, when treating episodic migraine 43.5% of the surveyed neurologists recommended 3 months and 39.5% preferred 6 months. When they treated chronic migraine, 20.4% of neurologists recommended 3 months, 42.1% 6 months, 12.5% 9 months and 22.4% preferred to maintain treatment during 12 months.

When considering onabotulinumtoxinA treatment, the number of prior therapeutical failures was cero in 7.2% of surveyed, one in 5.9%, two in 44.1%, three in 30.9%, and four or more in 11.9%. The increase of OnabotulinumtoxinA dose up to 195 UI was considered by 51% of neurologists after a first ineffective procedure, by 42.2% after two injections, and by 83% after a third infiltration. Surveyed colleagues admitted to take into account in their decisions mainly patient comorbidities (70.2%) rather than guidelines (13.9%).

Conclusions:

Initial management of Migraine among Spanish Neurologists is made with the preventative drugs which are considered as first choices in most of the guidelines. Management of episodic migraine differed from chronic migraine, both in the order or drugs and the perception of the most effective therapy.

O43 Effect of the H1-antihistamine clemastine on PACAP38 induced migraine

Luise Haulund Vollesen1, Song Guo1, Malene Rohr Andersen2, Messoud Ashina1

1Danish Headache Centre and Department of Neurology, Rigshospitalet Glostrup, Faculty of Health and Medical Sciences, University of Copenhagen, Denmark; 2Department of Clinical Biochemistry, Herlev and Gentofte Hospital, Gentofte, Denmark

Correspondence: Messoud Ashina (ashina@dadlnet.dk)

Objective To investigate the effect of the H1-antihistamine clemastine on the migraine inducing abilities of pituitary adenylate cyclase activating peptide-38 (PACAP38).

Methods We conducted a double-blind, randomized, placebo controlled two-way cross-over study. Twenty migraine without aura patients were randomly allocated to receive bolus clemastine 2 mg (1 mg/ml) or bolus saline 2 ml intravenously over 2 min on two study days. Following each bolus injection 10 pmol/kg/min of PACAP38 was administered intravenously over 20 min. We recorded migraine/headache characteristics every 10 min until 90 min after infusion start and collected blood to investigate mast cell degranulation and the inflammation markers tryptase and tumor necrosis factor-alpha (TNF-alpha) before and after infusion of PACAP38.

Results After clemastine pretreatment 5/20 participants developed a migraine-like attack in response to a PACAP38 infusion compared to 9/20 after placebo pretreatment (P=0.288). Following clemastine pretreatment 15/20 participants reported headache in response to a PACAP38 infusion, whereas 19/20 participants did so following placebo pretreatment (P=0.221). We found no difference in area under the curve 12 h (AUC12h) for headache intensity between the two experimental days (P=0.481). We found no difference in AUC180min for tryptase (P = 0.525) or TNF-alpha (P = 0.487) between clemastine and placebo pretreatment days.

Conclusion H1-antihistamine, clemastine, failed to prevent migraine or headache after PACAP38 infusion thus making a role for histamine release or mast cell degranulation in PACAP38 induced migraine less likely.

O44 CSF pressure fluctuations as a marker of isolated CSF hypertension in headache sufferers

L. Rapisarda1,2, G. Demonte1, F. Tosto1, M. Curcio1, B. Vescio5, C. Bombardieri 3, D. Mangialavori4, U. Aguglia2, A. Gambardella2, F. Bono1,2

1Headache Center, and Institutes of Neurology2, Neuroradiology3, Ophthalmology4, Department of Medical and Surgical Sciences, Magna Græcia University of Catanzaro, Italy; 5Neuroimaging Research Unit, Institute of Bioimaging and Molecular Physiology, National Research Council, Catanzaro, Italy
Correspondence: G. Demonte (g.dem.1990@gmail.com)

Background

It is needed to identify the characteristics and the pressure-related features of isolated cerebrospinal fluid hypertension for differentiating headache sufferers with isolated cerebrospinal fluid hypertension from those with primary headache disorder.

Patients and Methods

In this prospective study patients with refractory chronic headaches suspected of having cerebrospinal fluid-pressure elevation without papilledema or sixth nerve palsy and non-headache controls underwent 1-hour lumbar cerebrospinal fluid pressure monitoring via a spinal puncture needle.

Results

We recruited 148 consecutive headache patients and 16 non-headache controls. Lumbar cerebrospinal fluid pressure monitoring showed high pressure and abnormal pressure fluctuations in 93 (63 %) patients with headache: 37 of these patients with the most abnormal pressure parameters (opening pressure above 250 mm H2O, mean pressure 301 mm H2O, mean peak pressure 398 mm H2O, and severe abnormal pressure fluctuations) had the most severe headaches and associated symptoms (nocturnal headache, postural headache, transient visual obscuration); 56 patients with the less abnormal pressure parameters (opening pressure between 200 and 250 mm H2O, mean pressure 228 mm H2O, mean peak pressure 316 mm H2O, and abnormal pressure fluctuations) had less severe headaches and associated symptoms.

Conclusions

Nocturnal headache and postural headache are the most common characteristics of isolated cerebrospinal fluid hypertension. Abnormal pressure fluctuations are associated with symptomatic high cerebrospinal fluid pressure, and they differentiate headache sufferers with isolated cerebrospinal fluid hypertension from those with primary headache disorder.

O45 The practical and clinical utility of non-invasive vagus nerve stimulation (nVNS) as an acute treatment for episodic migraine: a post hoc analysis of the randomised sham-controlled PRESTO trial

Licia Grazzi1; Cristina Tassorelli2,3; Marina de Tommaso4; Giulia Pierangeli5; Paolo Martelletti6; Innocenzo Rainero7; Pierangelo Geppetti8; Anna Ambrosini9; Paola Sarchielli10; Eric Liebler11; Piero Barbanti12

1Headache Center, Carlo Besta Neurological Institute and Foundation, Milano, Italy; 2Headache Science Centre, Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS) C. Mondino Foundation, Pavia, Italy; 3University of Pavia, Pavia, Italy; 4Neurophysiology and Pain Unit, University of Bari Aldo Moro, Bari, Italy; 5IRCCS Istituto delle Scienze Neurologiche di Bologna, Bologna, Italy; 6Department of Clinical and Molecular Medicine, Sapienza University, Rome, Italy; 7Department of Neuroscience, University of Turin, Turin, Italy; 8Headache Centre, University Hospital of Careggi, Florence, Italy; 9IRCCS Neuromed, Pozzilli (IS), Italy; 10Neurologic Clinic, Santa Maria della Misericordia Hospital, Perugia, Italy; 11electroCore, LLC, Basking Ridge, New Jersey, USA; 12Headache and Pain Unit, IRCCS San Raffaele Pisana, Rome, Italy
Correspondence: Licia Grazzi (licia.grazzi@istituto-besta.it)

Background: The multicentre, double-blind, randomised, sham-controlled PRESTO trial provided Class I evidence that for patients with an episodic migraine, non-invasive vagus nerve stimulation (nVNS; gammaCore®) significantly increases the probability of having mild pain or being pain-free 2 hours post‑stimulation [1]. Here, we aimed to reveal further insights into the practical and clinical utility of nVNS in PRESTO by evaluating the ability of this therapy to provide clinically meaningful reductions in pain while reducing the need for rescue medication.

Methods: The PRESTO study consisted of a 4‑week run-in period (individualised treatment regimens), a 4-week double-blind period of randomly assigned nVNS or sham treatment, and a 4-week open-label period wherein all patients received nVNS. In this post hoc analysis of PRESTO, the percentage of patients with a ≥1-point reduction in pain score (0, no pain; 1, mild pain; 2, moderate pain; 3, severe pain) for their first treated attack and the percentage of all treated attacks achieving this reduction were evaluated. Rescue medication use at any time point was also assessed for both the first attack and all attacks.

Results: The percentage of patients with a ≥1‑point decrease in pain was significantly higher with nVNS (n=120) than with sham (n=123) for the first attack at 30 minutes (nVNS, 32.2%; sham, 18.5%; p=0.020), 60 minutes (nVNS, 38.8%; sham, 24.0%; p=0.017), and 120 minutes (nVNS, 46.8%; sham, 26.2%; p=0.002). Results were similar when evaluating this end point as a percentage of all attacks. Rescue medication use was significantly lower in the nVNS group than in the sham group for both the first attack (nVNS, 40.7%; sham, 58.2%; p=0.013) and all attacks (nVNS, 47.7%; sham, 62.7%; p=0.008).

Conclusions: Findings from this post hoc analysis reinforce the practical and clinical utility of nVNS for episodic migraine. Patients using nVNS acutely benefited from consistent ≥1-point pain reductions and a decreased need for rescue medication. The flexibility of nVNS offers the ability to treat multiple attacks without increasing exposure to acute medications and pharmacologic adverse events.

Acknowledgements

PRESTO was sponsored by electroCore, LLC. We present this abstract on behalf of the PRESTO Study Group.

Trial registration: NCT02686034

Ethics approval

PRESTO was approved by the local ethics committee for each study site.

Reference

1. Tassorelli C, Grazzi L, de Tommaso M, et al. Non-invasive vagus nerve stimulation as acute therapy for migraine: the randomized PRESTO study. Neurology. In press.

Author Disclosures:

Dr. Grazzi has received consultancy and advisory fees from Allergan S.p.A. and electroCore, LLC.

Prof. Tassorelli has received consultancy fees from Allergan S.p.A.; electroCore, LLC; Eli Lilly and Company; and Novartis AG and research grants from the European Commission and the Italian Ministry of Health. She is also a principal investigator or collaborator for RCTs sponsored by Alder BioPharmaceuticals Inc.; Eli Lilly and Company; and Teva Pharmaceutical Industries Ltd.

Prof. de Tommaso has received advisory fees from Allergan S.p.A.; Neopharmed; and Pfizer Inc.

Dr. Pierangeli has nothing to disclose.

Prof. Martelletti has received research grants, advisory board fees, or travel fees from ACRAF; Allergan S.p.A.; Amgen Inc.; electroCore, LLC; Novartis AG; and Teva Pharmaceutical Industries Ltd.

Prof. Rainero has received consultancy fees from electroCore, LLC, and Mylan N.V. and research grants from the European Commission -- Horizon 2020. He is also a principal investigator for RCTs sponsored by Axovant Sciences Ltd. and TauRx Pharmaceuticals Ltd.

Prof. Geppetti has received consultancy fees from Allergan S.p.A.; electroCore, LLC; Evidera; Novartis AG; Pfizer Inc.; and Sanofi S.p.A. and research grants from Chiesi Farmaceutici S.p.A. He is also a principal investigator for RCTs sponsored by Eli Lilly and Company; Novartis AG; and Teva Pharmaceutical Industries Ltd.

Dr. Ambrosini has received consultancy fees from Almirall, S.A., and travel grants from Allergan S.p.A. and Almirall, S.A.

Prof. Sarchielli has received clinical study fees from Allergan S.p.A.

Mr. Liebler is an employee of electroCore, LLC, and receives stock ownership.

Prof. Barbanti has received consultancy fees from Allergan S.p.A.; electroCore, LLC; Janssen Pharmaceuticals, Inc.; Lusofarmaco; and Visufarma and advisory fees from Abbott Laboratories and Merck & Co., Inc.

SISC Oral Presentation

O46 Headache as presenting symptom of neurosarcoidosis

C. Lisotto1, L. Toma2, E. Mampreso3, G. Zanchin4

1Headache Centre, Department of Neurology, Pordenone, Italy, 2Department of Neurology, Ferrara, Italy, 3Headache Centre, Department of Neurology, Piove di Sacco, Italy 4Headache Centre, Department of Neurosciences, Padua, Italy
Correspondence: C. Lisotto (carlo.lisotto@aas5.sanita.fvg.it)

Objectives Sarcoidosis is a multi-organ granulomatous disease of unknown aetiology, characterized pathologically by multiple non-caseating granulomata in the absence of a defined infective or toxic trigger. Sarcoidosis involving the nervous system (the so-called neurosarcoidosis) is infrequent and headache may be the presenting symptom [1]. The diagnosis of headache attributed to neurosarcoidosis is challenging and requires particular attention from headache specialists.

Materials and methods The medical records of patients admitted in the past 15 years to our Department of Neurology for recent-onset headache with a final diagnosis of neurosarcoidosis were retrospectively reviewed. The diagnosis of headache attributed to neurosarcoidosis was made according to the International Classification of Headache Disorders, 3rd edition (ICHD-3) [2].

Results Four patients, two males and two females, mean age at observation 40 years (range 31-49), were included in our review. In all the subjects headache was the onset symptom, occurred acutely or subacutely. Two patients (one male and one female) reported headache as the only symptom; the pain was diffuse, severe, non-pulsating, with daily or nearly-daily occurrence, mimicking tension-type headache. In the remaining two cases the headache was unilateral, periorbital, intense and sharp, associated with third cranial nerve paralysis, resembling Tolosa-Hunt syndrome. All the patients underwent brain magnetic resonance imaging (MRI) and cerebrospinal fluid (CSF) examination. MRI showed non-enhancing periventricular white matter lesions, enhancement of the leptomeninges with predilection for suprasellar and frontal basal meninges and involvement of cavernous sinus ipsilateral to pain in the patients with third cranial nerve palsy. CSF examination revealed lymphocytic pleocytosis and elevated protein. All the patients were treated with oral prednisone, starting from 1 mg/kg daily, with rather rapid clinical improvement. In three patients chest radiography was abnormal, showing bihilar lymphadenopathy; on bronchoalveolar lavage CD4:CD8 lymphocyte ratio was more than 3:5:1.

Discussion The headache in our patients was clinically similar to tension-type headache in two cases and to Tolosa-Hunt syndrome in the other two. ICHD-3 criteria for headache attributed to neurosarcoidosis imply that the clinical features of this secondary headache have a wide range of presentations. As for differential diagnosis versus Tolosa-Hunt syndrome, our patients obtained a remission within 10-14 days, a longer time than 72 hours for pain and paresis resolution, as required by ICHD-3 diagnostic criteria for this syndrome.

Conclusions Headache may rarely herald the diagnosis of neurosarcoidosis. New case series continue to broaden the phenotype of neurosarcoidosis, reinforcing the need for a systematic approach to diagnosis and management.

References

1. Radwan W, Lucke-Wold B, Robadi IA, Gyure K, Roberts T, Bhatia S. Neurosarcoidosis: unusual presentations and consideration for diagnosis and management. Postgrad Med J 2017;93:401-5.

2. Headache Classification Committee of the International Headache Society (IHS). The International Classification of Headache Disorders, 3rd edition. Cephalalgia 2018;38:1-211.

3. Ibitoye RT, Wilkins A, Scolding NJ. Neurosarcoidosis: a clinical approach to diagnosis and management. J Neurol 2017;264:1023-8.

O47 Association of Tanacethum Parthenium, 5 - hydroxy tryptophan and magnesium ( Aurastop) versus Mg tablet impact on aura phenomena and its evolution : an observational study

Lidia Savi (lsavi@cittadellasalute.to.it)

Headache Center LBS, Lugano, Switzerland

BACKGROUND:

A new phytotherapic combination of Tanacethum Parthenium (150 mg), 5 - hydroxy tryptophan (20 mg) and magnesium (185 mg) (Aurastop ®) is now available for migraneous patients. The three components act on the four main mechanisms involved in the pathophysiology of migraine with aura: cortical Spreading Depression, sensitization of trigeminal vascular system, central sensitization and activation of “migraine generator” at the brainstem’s level. Since many years Magnesium is well known to interact with the aura phenomena and migraine itself.With this study we want to compare the efficacy on the aura phenomenon and its disability of the combination of Tanacethum Parthenium, 5 - hydroxy tryptophan and magnesium versus magnesium alone, when taken at the beginning of the aura.

MATERIALS AND METHODS: We selected from the Headache Center LBS of Lugano (CH) a population of 60 patients aged from 18 to 60 years (mean 32 years ), 31 women and 29 men, suffering from migraine with aura, not assuming migraine preventive therapy. They have to refer of an aura with a duration of at least 20 minutes to be included. We gave to the patients a form where they have to describe the aura features of the 4 aura episodes following the administration of 1 tablet of Aurastop at the beginning of the aura and 1 tablet at the beginning of the headache ( if present ) in the first 2 aura and 1 tablet of magnsium 2,25 gr in the same modality at the 3° and 4° episodes of aura. Patients were evaluated for duration and disability of the aura, need and response to their habitual analgesic drug

RESULTS: A reduction in duration greater than 50% in 54 patients versus 6 and of disability >50% in 52 patients against 8 were observed respectively after taking Aurastop or Magnesium alone

.Furthermore 30% of the aurastop group did not have to take pain reliever after the aura as the headache intensity was more tolerable, only 5% of the magnesium group. We also noted a marked improvement in the benefit of the usual pain killer in 30 patients that used aurastop .

CONCLUSIONS: By the fact that this combination pass very quickly the ematoencephalic barrier Aurastop has been shown to have a quick impact on the evolution of aura reducing the duration and disability of symptoms than the magnesium alone.

O48 Hemicrania continua-like headache revealed a subacute internal carotid artery dissection in patient with unrecognized connective tissue disorder

Silvia Ricci, Gaetano Salomone, Francesca Rossi, Alberto Polo

Neurology department- Mater Salutis Hospital- ULSS Scaligera, Verona, Italy
Correspondence: Silvia Ricci (silv.ricci@yahoo.it)

Background It is widely accepted that internal carotid (ICA) dissection could simulate a cluster headache attack. Conversely, clinical features resembling hemicrania continua (HC) occurring after cervical artery dissection have rarely been reported in the literature. We described the case of a patient who developed typical HC-like headache after carotid artery dissection.

Case-presentation On February 2018, a 43 year-old man presented to our emergency department because of the onset, four days before, of severe continuos right trigeminoautonomic cephalgia with Horner’s syndrome and elevated blood pressure. His familiar and personal medical history were unremarkable except for the cluster headache involving the left side few years ago. Neurological examination revealed acute headache fulfilling all IHS criteria for HC (apart from the time criterion) unresponsive to habitual medication for migraine associated with right tongue deviation. The routine laboratory test, CT brain scan and ultrasound examination of neck vessels were normal. Indomethacin 200mg i.v improved the headache but we decided to admit the patient to our department because of the continuity of pain. Over the next two days there was complete relief with oral indomethacin 200 mg per day and an improvement of the Horner’s syndrome, nevertheless the patient developed progressive dysphagia, dysphonia, and weak left-turning of the head suggesting 9th through 12th cranial nerve palsy. He underwent brain magnetic resonance imaging (MRI) with MR angiography of head and neck that showed a right ICA dissection with extension into the petrous segment and intramural hematoma causing mass effect upon the internal jugular vein; no hyperintensity was found in DWI sequences . The patient was started on acetylsalicylic acid 100 mg daily. An extended CT angiography showed extensive luminal irregularities in the main renal arteries, with aneurysm formations and irregularities of iliac vessels. Due to his new diagnosis of arterial hypertension and the other findings we assumed the possibility of a connective tissue disorder and we performed a genetic counseling with test for Ehlers-Danlos syndrome variants. So far, the results received were negative but other test are still ongoing and fibromuscolar dysplasia (FMD) is strongly considered.

Conclusion ICA dissection may result in an HC-like headache syndrome. The history of cluster headache, a specific response to indomethacin and the absence of neurological focal signs does not rule out dissection as underlying pathology. Screening for connective tissue disorder and extracranial manifestations of FMD should be considered even if the brain vasculature is normal.

Consent for publication: Informed consent was obtained from patient for publication.

References

1- Ashkenazi A, Abbas MA, Sharma DK, et al. Hemicrania continua-like headache associated with internal carotid artery dissection may respond to indomethacin. Headache 2007; 47: 127–130.

2- Headache Classification Committee of the International Headache Society (IHS). The International Classification of Headache Disorders, 3rd edition (beta version). Cephalalgia 2013; 33: 629–808.

3- O’Connor S, Poria N and Gornik H. Fibromuscular dysplasia: An update for the headache clinician. Headache 2015; 55: 748–755

O49 Neurophysiological correlates of clinical improvement after Greater Occipital Nerve (GON) Block in Chronic Migraine: relevance for chronic migraine pathophysiology

Alessandro Viganò1,2, Maria Claudia Torrieri3, Massimiliano Toscano1,4, Francesca Puledda5, Barbara Petolicchio1, Tullia Sasso D’Elia2, Angela Verzina6, Sonia Ruggiero1, Marta Altieri1, Edoardo Vicenzini1, Jean Schoenen7, Vittorio Di Piero1,8

1Headache Centre & Neurocritical Care Unit. Department of Human Neurosciences, Sapienza – University of Rome, Rome, Italy; 2Molecular and Cellular Networks Lab. Department of Anatomy, Histology, Forensic medicine and Orthopaedics, Sapienza – University of Rome, Rome, Italy; 3Rita Levi Montalcini Department of Neuroscience, Città della Salute e della Scienza, Turin, Italy; 4Department of Neurology – Fatebenefratelli Hospital – Rome, Italy; 5Headache Group, Department of Basic and Clinical Neuroscience, King's College London, and NIHR-Wellcome Trust King's Clinical Research Facility, Wellcome Foundation Building, King's College Hospital, London, SE5 9PJ, UK; 6Department of Neurology, University of Perugia, Perugia, Italy; 7Headache Research Unit. Department of Neurology, University of Liège, Citadelle Hospital, Liège, Belgium; 8University Consortium for Adaptive Disorders and Head pain – UCADH, Pavia, Italy
Correspondence: Alessandro Viganò (alessandro.vigano@uniroma1.it)

Background:

Therapeutic management of Chronic Migraine (CM), often associated with Medication Overuse Headache (MOH), is chiefly empirical, as no biomarker predicting or correlating with clinical efficacy is available to address therapeutic choices. The present study searched for neurophysiological correlates of Greater Occipital Nerve Block (GON-B) effects in CM.

Results:

We recruited 17 CM women, of whom 12 with MOH, and 19 female healthy volunteers (HV). Patients had no preventive treatment since at least 3 months. After a 30-day baseline, they received a bilateral betamethasone-lidocaine GON-B of which the therapeutic effect was assessed 1 month later. Habituation of visual evoked potentials (VEP) and intensity dependence of auditory evoked potentials (IDAP) were recorded before and 1 week after the GON-B. At baseline, CM patients had normal VEP habituation, but a steeper IDAP value than HV (p=0.009), suggestive of a lower serotonergic tone. GON-B significantly reduced the number of total headache days per month (-34.9%; p=0.003). Eight out 17CM patients reversed to episodic migraine and medication overuse resolved in 11 out of 12 patients. One week after the GON-B VEP habituation tended to be reduced (p=0.09) and became inferior to that of HV (p=0.03) like in episodic migraine, while the IDAP slope significantly flattened (p=0.008). GON-B-induced reduction in headache days positively correlated with IDAP slope decrease (rho=0.51, p=0.03).

Conclusions:

GON-B may be effective in the treatment of CM, with or without MOH. The pre-treatment IDAP increase is compatible with a weak central serotonergic tone, which is strengthened after GON-B, suggesting that serotonergic mechanisms may play a role in CM and its reversion to episodic migraine. Since the degree of posttreatment IDAP decrease is correlated with clinical improvement, IDAP might be potentially useful as an early predictor of GON-B efficacy.

O50 Short-Term Psychodynamic Psychotherapy versus OnabotulinumtoxinA as preventive therapy in Chronic Migraine: a real world study

M. Alessiani1, B. Petolicchio1,2, A. Viganò1, R. Di Giambattista3, M. Altieri1, E. Gilliéron3,V. Di Piero1,2

1Department of Human Neuroscience, Sapienza University of Rome, 00185 - Rome, Italy; 2 “Enzo Borzomati” Pain Medicine Unit – University Hospital Policlinico Umberto I, 00161-Rome, Italy; 3 Istituto Europeo di Psicoterapia Psicoanalitica (IREP), 00187 - Rome, Italy
Correspondence: B. Petolicchio (barbara.petolicchio@uniroma1.it)

Background

The preventive treatment for chronic migraine (CM) is difficult and often complicated by analgesics overuse and poor compliance.

Previously, we showed that short-term psychodynamic psychotherapy (STPP), alone or with pharmacological therapies, improved the clinical outcome, the analgesics overuse withdrawal and reduces long-term relapse rate of CM [1,2].

Since OnabotulinumtoxinA (BoNT-A) is one of the most effective options for CM [3,4], we investigated the effect of STPP versus BoNT-A as preventive treatment in a real world CM population, with and without medication overuse headache (MOH).

Results

We consecutively recruited, CM patients who underwent STPP or BoNT-A treatment according to clinical judgment of the attending headache specialist.

STPP consists of 4 exploratory meetings, followed by 8 meetings of freudian-inspired psychotherapy [5]. At the end of the STPP (90 days), if appropriate, a pharmacological therapy was added. BoNT-A was administered according to PREEMPT protocol [3,4]. No additional pharmacological therapies were allowed.

At 90, 180 and 270 days, evaluations were made on the treatment effectiveness by an investigator blinded of the assigned treatment. Ninthy-eight patients with CM (64% with MOH) were treated with STPP and 54 (59% with MOH) with BoNT-A. At baseline, BoNT-A patients had a significant (p <0.001) higher attack rates, more failed preventive therapies, more years of illness and chronicity, and were older.

The first appropriate follow-up to evaluate STPP efficacy is at 90d whereas for BoNT-A is after 180d. At these times, the episodic pattern remission rate was 53% (52/98) for STPP and 33% (18/54) for BoNT-A treatment. A pharmacological therapy was added in 27 patients of the STPP group.

With respect to baseline, at 270d STPP and BoNT-A groups showed a significant reduction of headache days (-14,9±0,3 vs –10,8±3,3) and analgesics intake (-12,2±10,3 vs –11,6±13,4, pills/month), respectively (Figs.1 and 2). In both groups, a high headache frequency at baseline (>25 days/month) was a significant negative prognostic factor for remission to an episodic pattern (p<0.05). Dropout rate was lower in BoNT-A group than STPP one (11% vs. 29%, p<0.05).

Conclusion

In the real world, both treatments with STPP, alone or combined with drug therapy, and BoNT-A were effective for treating patients with CM, with or without MOH. Treatment with BoNT-A is the physician preferred treatment for patients with more severe CM. Furthermore, the effectiveness of the STPP occurs earlier than BoNT-A but with a higher dropout rate.

Ethics approval

The study was approved by Policlinico Umberto I Ethical Board N°4604.

Reference

1. Altieri M, Di Giambattista R, Di Clemente L, Fagiolo D, Tarolla E, Mercurio A, Vicentini E, Tarsitani L, Lenzi GL, Biondi M, Di Piero V. Combined pharmacological and short term psychotherapy for probabile medication overuse headache: a pilot study. Cephalalgia 2009;29(3): 29-39

2. Petolicchio B, Viganò A, Di Giambattista R, Squitieri M, Zanoletti N, Tortora D’Amato P, Spensierato A, Baldassarre M, Di Piero V. Short-term psychodynamic psychotherapy versus pharmacological treatment in chronic headache: an observational study. J Headache Pain 2013; 14 (S13-S41): 31

3. Aurora SK, Dodick DW, Turkel CC, et al. OnabotulinumtoxinA for treatment of chronic migraine: results from the double-blind, randomized, placebo-controlled phase of the PREEMPT 1 trial. Cephalalgia. 2010;30(7):793–803. 57.

4. Diener HC, Dodick DW, Aurora SK, et al. OnabotulinumtoxinA for treatment of chronic migraine: results from the double-blind, randomized, placebo-controlled phase of the PREEMPT 2 trial. Cephalalgia. 2010;30(7):804–814

5. Gilliéron E. Setting and motivation in brief psychotherapy. PsychotherPsychosom 1987; 47:105–12

Fig. 1 (abstract O50).

Headache days per month analgesics (p<0.001)

Fig. 2 (abstract O50).

Monthly intake of (p<0.01)

O51 Resting-state between-networks functional connectivity is abnormal in chronic migraine patients

Gianluca Coppola1*, Barbara Petolicchio2, Antonio Di Renzo1, Emanuele Tinelli2, Cherubino Di Lorenzo3, Vincenzo Parisi1, Mariano Serrao4, Valentina Calistri2, Stefano Tardioli2, Gaia Cartocci2, Francesca Caramia2, Vittorio Di Piero2, and Francesco Pierelli4,5

1G.B. Bietti Foundation IRCCS, Research Unit of Neurophysiology of Vision and Neurophthalmology, Rome, Italy; 2Sapienza University of Rome, Department of Neurology and Psychiatry, Rome, Italy; 3Don Carlo Gnocchi Onlus Foundation, Milan, Italy; 4Sapienza University of Rome Polo Pontino, Department of Medico-Surgical Sciences and Biotechnologies, Latina, Italy; 5IRCCS-Neuromed, Pozzilli (IS), Italy
Correspondence: Gianluca Coppola (gianluca.coppola@gmail.com)

Background

The functional connectivity (FC) between default mode network (DMN), the executive control network (ECN), and the dorsal/ventral attention systems was found to be abnormal using resting state functional magnetic resonance imaging (RS-fMRI) in episodic migraine depending on migraine phase (ictal/interictal) and the frequency of the attacks. Here, we investigated RS between networks connectivity using independent component analysis (ICA) in chronic migraine (CM) patients.

Materials and methods

Twenty patients with untreated de-novo chronic migraine (CM) underwent 3T MRI scans and were compared to a group of 20 healthy controls (HC). We used MRI to collect RS data among three selected resting state networks, identified using group ICA: the DMN, the ECN, and the dorsal attention system (DAS).

Results

Compared to HCs, CM patients showed significant reduced functional connectivity between the DMN and the ECN. Moreover, in patients, the DAS showed significant stronger FC with the DMN and weaker FC with the ECN. The severity of headache attacks was correlated positively with the strength of DAS connectivity, and negatively with the strength of ECN connectivity.

Conclusions

These results suggest that the brain of CM patients is characterized by a large-scale reorganization at the level of the functional networks. Our data further suggest that the severity of migraine pain is associated with proportional inverse pattern of frontal executive and dorsal attentive networks connectivity.

O52 New daily persistent headache in a pediatric cohort

Laura Papetti, Barbara Battan, Romina Moavero, Giorgia Sforza, Samuela Tarantino, Massimiliano Valeriani

Headache Center Bambino Gesù Children Hospital, Rome Italy
Correspondence: Laura Papetti (laura.papetti@opbg.net)

Introduction

Primary new daily persistent headache (NDPH) is a rare disorder of children and adults defined by the onset of daily headaches with distinct and clearly-remembered onset, with pain becoming continuous and unremitting within 24 hours and present for >3 months. The pain lacks characteristic features, and may be migraine-like or tension-type-like, or have elements of both. Our aim was to investigate the clinical features of NDPH in a cohort of pediatric patients.

Methods

We retrospectively reviewed the charts of patients attending the Headache Centre of Bambino Gesú Children from the last ten years with history of persistent daily headache. The ICHD-III criteria were used for diagnosis. Statistical analysis was conducted by SPPS version 22.0 and χ2 test was used to study possible correlations between: - NDPH and population features (age and sex); - NDPH and headache qualitative features; - NDPH and response to prophylactic therapies.

Results

We included 377 patients with CPH (66.4% female, 33.6% male, age between 0 and 18 years). The frequency of NADPH was 13% (49/377). We did not find significant differences between the frequency of NADPH in males (42.9%) and females (57.1%). In relation to age we found that NDAPH is less common in the age group of 7-10 years (p<0.05).

Regarding the features of the pain we did not find significant differences compared to the other forms of chronic headache for the quality of pain (throbbing or gravating), and the presence of photophobia (59.2% vs 60.7%, p>0.05) and phonophobia (63.3% vs 70.1%, p>0.05). However we found a low frequency of nausea and vomiting in the NADPH population (28.6% vs 48.2%, p<0.05).

We found that 75% of patients have an onset of the symptoms in the winter months (November-February), respect the remaining months of the year when the incidence is very low (p<0.05).

Our results show that 29 (30.6%) out of 49 NADPH CPH received a prophylactic therapy. Among them, 26 patients received amitriptyline, 4 patients topiramate, one patient L-5 hydroxytryptophan, and one patient flunarizine. Positive response to therapy (reduction of attacks by at least 50% in a month) was detected in 30.6% of patients, while no outcome data were obtained from 63.3% of cases. Amitriptyline showed the highest efficacy (p<0.05).

Conclusions

Our results show that the incidence of NASDH in children with daily headache is 13%. In general, the onset occurs in the winter months and this is probably related to the increase in requests for school activities. Qualitative characteristics as for adults are variable, migrainous or tension type. The most effective drug is amitriptyline, although the number of patients who received other types of drugs is very low Furthermore, the number of patients for whom there is an absence of follow-up data is very high and for this reason the efficacy data are not conclusive.

O53 Clinical report of nineteen Italian patients with nummular headache

Lanfranco Pellesi1, Silvia Benemei2, Sabina Cevoli3, Valentina Favoni3, Chiara Lupi2, Edoardo Mampreso4, Antonio Russo5, Simona Guerzoni1

1Medical Toxicology, Headache and Drug Abuse Centre, University of Modena e Reggio Emilia, Modena, Italy; 2Headache Centre, Careggi University Hospital, Department of Health Sciences, University of Florence, Florence, Italy; 3IRCCS Institute of Neurological Sciences of Bologna, Bologna, Italy; 4Headache Centre, Headache Centre, Neurology - Euganea, Padova Health Unit, Padua, Italy; 5Headache Centre, Department of Medical, Surgical, Neurological, Metabolic and Ageing Sciences, University of Campania “Luigi Vanvitelli”, Naples, Italy
Correspondence: Lanfranco Pellesi (lanfranco.pellesi@gmail.com)

Background

Nummular headache, also known as coin-shaped headache, is a rare headache disorder described by a small circumscribed painful area of the scalp. In the last decades, the description of numerous case reports has motivated its inclusion among the primary headaches, in the International Classification of Headache Disorders [1]. Since its initial description, approximately 280 cases have been reported in literature. Here, we report a case series of 19 patients (10 men, 9 women), fifteen of which were retrospectively identified with the RegistRare Network, a collaborative group of seven Italian Headache Centres [2]. The remaining four patients were identified in a later period of time. Data are summarized in Table 1.

Results

Nummular headache was episodic (<15 days/month) in four patients and chronic (>15 days/month) in fifteen patients. Headache was appeared around 47 years (range, 18-63) and lasted approximately 11.8 years (range, 0.01-47). The pain was mainly unilateral (84% of cases). The temporal region was the most common location, followed by occipital and parietal areas. Pain is mostly described as stabbing (32%), pressing and tightening (32%) or throbbing (21%). Pain intensity can vary widely; the mean intensity, measured with Numerical Rating Scale, was 6.0 (range, 3-10). Nonsteroidal anti-inflammatory drugs (NSAIDs) were the most prescribed acute treatments, they were effective in 69% of patients. Pregabalin and amitriptyline were the most effective prophylaxis therapies (in 80% and 75% of patients, respectively).

Conclusions

Our series of cases reconfirm previous findings. Location, quality and intensity of pain are highly heterogeneous, whereas NSAIDs, pregabalin and amitriptyline were the most prescribed and effective therapies.

Ethics approval

Each participating centre received the approval of the competent Ethics Committee (for the Coordinating Centre, Careggi Hospital Headache Centre, Florence, approval #10976 of the Area Vasta Centro Section of the Tuscany Region Ethics Committee) before commencing any procedures.

References

1. Headache Classification Committee of the International Headache Society (IHS). The International Classification of Headache Disorders, 3rd edition. Cephalalgia 2018; 38 (1): 1-211.

2. Lupi C, Evangelista L, Favoni V, Granato A, Negro A, Pellesi L, Ornello R, Russo A, Cevoli S, Guerzoni S, Benemei S. Rare primary headaches in Italian tertiary Headache Centres: Three year nationwide retrospective data from the RegistRare Network. Cephalalgia. 2018 Jan 1: 333102418768824.

Table 1 (abstract O53).

Clinical profiles of nummular headache patients

Patient

Sex

Age (years)

Age of onset (years)

Duration (years)

Episodic

Chronic

Location

Accompanying symptoms

Quality of Pain

NRS

1

M

42

36

6

 

X

Right, P

Conjunctival lacrimation

Stabbing

3

2

M

63

20

43

 

X

Right, O

Confusion

Persistent

5

3

F

65

63

2

 

X

Left, V

Tinnitus and dizziness

Stabbing

8

4

M

52

52

0.01

X

 

V

Not present

Stinging and stabbing

4

5

F

33

33

0.25

 

X

Right, P

Photophobia and nausea

Throbbing

8

6

F

40

40

0.01

X

 

Left, O

Dizziness

Stabbing

8

7

M

39

39

0.01

X

 

O

Dizziness

Stabbing

9

8

M

55

52

3

 

X

Left, O

Not present

Stabbing

8

9

F

54

53

1

 

X

Left, T

Not present

Throbbing

5

10

F

58

57

1

 

X

V

Not present

Pressing and tightening

2

11

F

35

33

2

 

X

Right, T

Not present

Pressing and tightening

3

12

M

44

18

26

 

X

Left, P

Not present

Stinging

5

13

M

36

36

0.33

 

X

Right, O

Not present

Throbbing

7

14

M

30

18

12

 

X

Left, T

Conjunctival injection and ptosis

Pressing and tightening

5

15

F

40

40

0.17

X

 

Left, T

Not present

Throbbing

7

16

M

67

20

47

 

X

Right, V

Not present

Pressing and tightening

5

17

F

63

63

3

 

X

Left, T

Not present

Pressing and tightening

6

18

F

25

25

6

 

X

Right, T

Not present

Pressing and tightening

5

19

M

43

43

1

 

X

Right, T

Facial redness

Stinging

10

NRS Numerical Rating Scale

EHF Poster Presentation

P1 The cost of migraine in Greece: a half billion euros disease

Panagiotis Stafylas1, Marianthi Karaiskou2, Eirini Tsiamaki3, Maria Kalogeropoulou4, Dimos-Dimitrios Mitsikostas5

1HTA Consultant, HealThink, Thessaloniki, Greece; 2HTA Consultant, HealThink, Thessaloniki, Greece; 3Medical Advisor, Therapeutic Area Neuroscience, Novartis Hellas SACI, Athens, Greece; 4Health Economics Manager, Novartis Hellas SACI, Athens, Greece; 5Associate Professor of Neurology, National and Kapodistrian University of Athens, Athens, Greece
Correspondence: Maria Kalogeropoulou (maria.kalogeropoulou@novartis.com)

Background: Migraine is a common disabling disease that affects about one out of six to one out of five adults, most often female at productive age. The objective of this analysis is to approximate the economic burden of migraine in Greece.

Methods: A cost-of-Illness analysis was conducted to estimate direct and indirect costs for the management of migraine in Greece. Data on epidemiology and resource use were obtained from international literature and were validated by Greek clinical expert to cover evidence gaps. Unit costs were taken from officially published Greek sources (Ministry of Health, Social Insurance Funds -SIFs). Direct cost inputs included drug acquisition and other treatment related costs such as physician visits, hospitalization, lab and imaging tests. The results of a national survey of migraineurs in Greece reporting days absent from work (absenteeism) and days with reduced productivity (presenteeism) were used for the calculation of the indirect costs. The costs are estimated in euros with reference year 2017. The perspective of the analysis is societal.

Results: Assuming that the prevalence of migraine in Greek adults is 13.3%, it is estimated that about 1,208,210 adults suffer from migraine in Greece. Based on these data, the total direct cost for the management of migraine in Greece is €301,969,046. The total indirect costs due to lost productivity has been estimated at €145.085.134 (€22,919,208 and €122,165,926 due to absenteeism and presenteeism respectively). Concerning the direct costs, medications account for 12%, other therapeutic choices for 6%, physicians visits for 74%, hospitalization for 8%, other costs less than 1%. It is very interesting that from the total direct cost, about 83% represent out-of-pocket expenses. Consequently, the economic burden of migraine in Greece for the year 2017 (including both direct and indirect costs) was about €447,054,179.

Conclusion: The total economic burden of migraine in Greece has been estimated at about half billion euros for 2017. About one third is due to productivity loss mainly because of reduced productivity while symptomatic. About 74% of direct costs concern visits to primary care physicians and neurologists and 18% pharmaceutical or alternative treatments. It must be noticed that about 83% of the direct costs represent out-of-pocket expenses.

P2 Single-pulse transcranial magnetic stimulation (sTMS) for the treatment of migraine: a prospective real world experience

Lambru Giorgio1, Hill Bethany1, Lloyd Joseph2, Al-Kaisy Adnan3, Andreou Anna P1,2

1The Headache Centre, Guy’s and St Thomas’ NHS Foundation Trust, London, UK; 2Wolfson CARD, King’s College London, London, UK; 3Pain and Neuromodulation Academic Research Centre, Guy’s and St Thomas’ NHS Foundation Trust, London, UK
Correspondence: Lambru Giorgio (giorgiolambru@gmail.com)

Objectives: Single pulse transcranial magnetic stimulation (sTMS) is a non-invasive neuromodulation technique which has been approved in 2014 by the National Institute for Health and Care Excellence (NICE) for the acute and preventive treatment of migraine. However, its effectiveness in a real world NHS service has not been explored yet. The Headache Centre, Guy’s and St Thomas’ NHS Trust is currently the only NHS service commissioned to offer sTMS to migraine patients. Here we present our interim results.

Methods: This is an open-label prospective clinical audit. It aims to evaluate the effectiveness of sTMS as a non-pharmacological modality for the treatment of migraine with and without aura in a real world setting. The audit is ongoing. We present here the outcome of the first 44 consecutive treated patients with chronic or high frequency episodic migraine. Audit inclusion criteria were a documented diagnosis of chronic migraine documented in a headache diary and patients willingness in filling a headache diary and HIT-6 score, which were used to collect clinical outcomes. Change in headache days, migraine days and HIT-6 at 3 months of treatment compared to baseline were analysed. Adverse events and treatment compliance were also collected.

Results: Forty-two migraine patients (11 with aura, 31 without aura) treated with sTMS were analysed. Twenty patients (47.6%) received sTMS after failing Botox® therapy, hence were considered refractory to medical treatments. At baseline, patients displayed an average of 14.7 headache days (HD)/month, 11.1 migraine days (MD)/month and HIT-6 score of 63.3. Following 3-month trial, 28 patients (64%) obtained a clinically meaningful benefit (- 2.7 MD/month and -5.4 points on HIT-6 score) hence continued the treatment. Seventeen patients (36%) did not benefit from the therapy and discontinued the treatment. Of those, the majority were Botox non-responders. At 6 months 1 out of 28 responders stopped the treatment due to lack of effect durability. Amongst responders, five patients continued sTMS treatment for 12 months, 10 for nine months and 12 for six months. Treatment compliance was satisfactory with sTMS used up to eight pulses three times a day. Side effects were minor and include, worsening of the headache (n = 3), transient mild dizziness during the treatment (n = 1) and scalp tenderness (n = 2).

Conclusion: sTMS may constitute an effective and well tolerated preventive treatment option for difficult-to-treat high frequency/chronic migraine patients in a real world setting. Since sTMS is less costly than Botox® on the NHS, it could be included as one of the three preventive treatment to offer to chronic migraine patients prior to Botox®.

P3 The impact of fremanezumab on symptoms associated with migraine in patients with episodic migraine

Jan L. Brandes1; Paul P. Yeung2; Ernesto Aycardi2; Ronghua Yang2; Yuju Ma2; Joshua M. Cohen2

1Nashville Neuroscience Group, Vanderbilt University, Department of Neurology, Nashville, Tennessee, USA; 2Teva Pharmaceuticals, Frazer, Pennsylvania, USA
Correspondence: Jan L. Brandes (jtuck@hcg-int.com)

OBJECTIVES: Non–headache symptoms (nausea, vomiting, photophobia and phonophobia) are included in the International Classification of Headache Disorders, third edition (beta version) (ICHD-3 beta) criteria for migraine. Fremanezumab, a fully humanized monoclonal antibody (IgG2a) that selectively targets calcitonin gene-related peptide (CGRP), reduced the number of migraine days in EM patients. We assessed the effect of fremanezumab on nausea or vomiting, and photophobia and phonophobia in EM patients.

METHODS: In this multicenter, randomized, double-blind, placebo-controlled, Phase 3 study, patients with EM were randomized 1:1:1 to receive subcutaneous fremanezumab quarterly (675 mg at baseline, placebo at Weeks 4 and 8), fremanezumab monthly (225 mg at baseline, Weeks 4 and 8), or placebo over a 12-week treatment period. Exploratory endpoints included mean change from baseline in the monthly average number of days with nausea or vomiting, and days with photophobia and/or phonophobia during the 12-week period after the first dose of study drug. Analyses were performed in the full analysis set (all randomized patients who received ≥1 dose of study drug and had ≥10 days of post-baseline efficacy assessments on the primary endpoint). The data were analyzed using both the analysis of covariance approach, with baseline number of days with nausea or vomiting, or photophobia and phonophobia, and years since onset of migraines as covariates, and the Wilcoxon rank-sum test.

RESULTS: Fremanezumab treatment yielded greater reductions from baseline in the monthly number of days with nausea or vomiting during the 12-week treatment period (quarterly [least-squares mean ± standard error]: –1.9±0.19 days, P=0.0314; monthly: –2.1±0.19 days, P=0.0008) compared with placebo (–1.4±0.19 days). Reductions in nausea or vomiting were seen as early as Week 4 (quarterly: –1.7±0.21 days, P=0.0046; monthly: –1.9±0.21 days, P=0.0002) compared with placebo (–1.0±0.21 days). Fremanezumab treatment also yielded greater reductions from baseline in the number of days with photophobia and phonophobia during the 12-week treatment period (quarterly: –2.2±0.21 days, P=0.0038; monthly: –2.4±0.21 days, P=0.0001) compared with placebo (–1.5±0.21 days). Significant reductions in days with photophobia and phonophobia were seen as early as Week 4 (quarterly: –2.0±0.23 days, P=0.0003; monthly: –2.2±0.23 days, P<0.0001) compared with placebo (–1.0±0.23 days).

CONCLUSIONS: In patients with EM, fremanezumab treatment rapidly improved non–head pain symptoms associated with migraine, including nausea or vomiting, and photophobia and phonophobia.

TRIAL REGISTRATION: ClinicalTrials.gov, NCT02629861

ETHICS APPROVAL

The study was approved by all relevant independent ethics committees or institutional review boards, according to national or local regulations.

P4 The impact of fremanezumab on symptoms associated with migraine in patients with chronic migraine

Peter McAllister1, Paul P. Yeung2, Ernesto Aycardi2, Ronghua Yang2, Yuju Ma2, Joshua M. Cohen2

1New England Institute for Neurology and Headache, Stamford, Connecticut, USA; 2Teva Pharmaceuticals, Frazer, Pennsylvania, USA
Correspondence: Peter McAllister (pwong@hcg-int.com)

OBJECTIVES: The International Classification of Headache Disorders, third edition (beta version) (ICHD-3 beta) criteria for migraine include nausea, vomiting, photophobia, and phonophobia symptoms. Fremanezumab, a fully humanized monoclonal antibody (IgG2a) that selectively targets calcitonin gene-related peptide (CGRP), reduced the frequency and severity of headaches in patients with chronic migraine (CM). We assessed the effect of fremanezumab versus placebo on nausea or vomiting, and photophobia and phonophobia, in patients with CM.

METHODS: In this multicenter, randomized, double-blind, placebo-controlled, Phase 3 study, patients with CM were randomized 1:1:1 to receive subcutaneous injections of fremanezumab quarterly (675 mg at baseline, placebo at Weeks 4 and 8), fremanezumab monthly (675 mg at baseline, 225 mg at Weeks 4 and 8), or placebo (at baseline, Weeks 4 and 8) over a 12-week treatment period. Exploratory endpoints included the mean change from baseline in the monthly average number of days with nausea or vomiting, and days with photophobia and phonophobia during the 12-week period after the first dose of study drug. Analyses were performed in the full analysis set (all randomized patients who received ≥1 dose of study drug and had ≥10 days of post-baseline efficacy assessments on the primary endpoint) using analysis of covariance (with baseline number of days with the symptom, and years since onset of migraines as covariates) and the Wilcoxon rank-sum test.

RESULTS: Fremanezumab treatment yielded greater reductions from baseline in the monthly number of days with nausea or vomiting during the 12-week treatment period (quarterly [least-squares mean ± standard error]: –3.3±0.29 days, P=0.0009; monthly: –3.2±0.28 days, P=0.0019) compared with placebo (–2.2±0.29 days). Significant reductions in nausea or vomiting were seen as early as Week 4 (quarterly: –3.2±0.30 days, P<0.0001; monthly: –2.9±0.29 days, P=0.0014) versus placebo (–1.9±0.29 days). Fremanezumab treatment also yielded greater reductions from baseline in the number of days with photophobia and phonophobia during the 12-week treatment period (quarterly: –3.5±0.32 days, P=0.0025; monthly: –3.7±0.32 days, P=0.0001) versus placebo (–2.4±0.32 days). Reductions in days with photophobia and phonophobia were seen as early as Week 4 (quarterly: –3.5±0.33 days, P<0.0001; monthly: –3.5±0.32 days, P<0.0001) versus placebo (–2.1±0.33 days).

CONCLUSIONS: Fremanezumab treatment rapidly improved non–head pain symptoms associated with migraine, including nausea or vomiting, and photophobia and phonophobia, in patients with CM.

TRIAL REGISTRATION: ClinicalTrials.gov, NCT02638103

ETHICS APPROVAL

The study was approved by all relevant independent ethics committees or institutional review boards, according to national or local regulations.

P5 Long-term impact of fremanezumab on response rates, acute headache medication use, and disability in patients with episodic migraine: interim results of a 1-year study

Jan L. Brandes1*; Paul P. Yeung2; Joshua M. Cohen2; Sanjay K. Gandhi2; Timothy Fitzgerald2 ; Ronghua Yang,2; Yuju Ma2; Ernesto Aycardi2

1Nashville Neuroscience Group, Nashville, Tennessee; 2Teva Pharmaceuticals, Frazer, Pennsylvania, USA
Correspondence: Jan L. Brandes (MCoakley@hcg-int.com)

BACKGROUND: Fremanezumab, a fully humanized monoclonal antibody (IgG2a) that selectively targets calcitonin gene-related peptide (CGRP), has demonstrated efficacy in preventing episodic migraine (EM) in 3-month studies; this analysis evaluates its long-term effects.

OBJECTIVE: To investigate the long-term effect of fremanezumab on response, acute headache medication and disability in adults with EM.

METHODS: This 52-week, multicenter, randomized, double-blind, parallel-group study evaluated the long-term safety, tolerability and efficacy of fremanezumab in adults with migraine; disability was assessed using the Migraine Disability Assessment (MIDAS). Most patients rolled over from a pivotal EM study, but some patients enrolled directly into this long-term study. Patients were assigned to one of two subcutaneous dose groups: (1) monthly dosing: 225 mg doses of fremanezumab every month, or (2) quarterly dosing: 675 mg doses of fremanezumab every 3 months. Percentage of patients achieving ≥50% reduction in monthly average number of migraine days, the mean change from baseline in the monthly number of days of use of any acute headache medications, and the mean change from baseline in MIDAS score were assessed for both doses.

RESULTS: This study enrolled 780 EM patients. The mean change in monthly number of migraine days from baseline to Month 1 was –4.6 days for the monthly treatment group and –4.9 days for the quarterly group. The proportion of patients achieving ≥50% reduction in monthly average number of migraine days at Month 6 was 61% with monthly dosing, and 65% with quarterly dosing. The mean change in monthly number of days of use of any acute headache medications from baseline to Month 6 in patients with EM was –4.1 days in the monthly group and –4.3 days in the quarterly group. The change from baseline in the MIDAS disability score in patients with EM was similar in both treatment groups at Month 6; disability scores decreased by 27.1 and 27.3 at Month 6 in the monthly and quarterly treatment groups, respectively. For a subset of patients who completed the entire 12-month treatment period, data available at the cutoff date indicated that the response achieved at Month 6 was maintained throughout the treatment period.

CONCLUSION: Efficacy and disability data from this interim analysis indicated that the efficacy observed at Month 1 was maintained during the remainder of the study.

TRIAL REGISTRATION: ClinicalTrials.gov, NCT02638103

ETHICS APPROVAL

The study was approved by all relevant independent ethics committees or institutional review boards, according to national or local regulations.

P6 Overview of fremanezumab pooled safety data from placebo-controlled phase 2 and 3 studies

Stephen D. Silberstein1, Nicola Faulhaber2, Xiaoping Ning3, Paul P. Yeung3, Jimmy Schiemann3, Ronghua Yang3, Yuju Ma3, Ernesto Aycardi3

1Thomas Jefferson University, Philadelphia, Pennsylvania, USA; 2Teva Pharmaceuticals, Ulm, Germany; 3Teva Pharmaceuticals, Frazer, Pennsylvania, USA
Correspondence: Stephen D. Silberstein (abormes@hcg-int.com)

BACKGROUND: Fremanezumab, a fully humanized monoclonal antibody (IgG2a) that selectively targets calcitonin gene-related peptide (CGRP), has been shown to be effective in the prevention of episodic migraine (EM) or chronic migraine (CM).

OBJECTIVE: To summarize the safety profile of fremanezumab based on all placebo-controlled studies in patients with migraine.

METHODS: Fremanezumab has been studied in four placebo-controlled studies in patients with migraine, including two Phase 2 and two Phase 3 studies. Each study was a 16-week, multicenter, randomized, double-blind, placebo-controlled, parallel-group study to compare the efficacy, safety, and tolerability of fremanezumab and placebo in adults with EM or CM. The studies evaluated fremanezumab at the proposed subcutaneous doses of 225 mg monthly (CM patients received a starting dose of 675 mg), 675 mg quarterly, and at two higher doses (675 mg monthly and 900 mg monthly) for 3 months.

RESULTS: Most patients who received fremanezumab (N=1702) or placebo (N=861) were female (87%), with mean age of 41.4 years (range = 18 to 70 years), respectively. Serious adverse events (AEs) and AEs leading to discontinuation occurred infrequently, with similar incidences in patients who received fremanezumab (1% and 2%, respectively) versus patients who received placebo (2% for both subsets). The most common AEs in the placebo-controlled studies were injection-site reactions, including induration and erythema, which tended to be transient, mild and slightly more frequent in patients who received fremanezumab versus those given placebo. Upper respiratory tract infection and nasopharyngitis, both reported with similar incidence in patients who received either fremanezumab or placebo, were the next most frequently reported AEs. Cardiovascular AEs occurred infrequently and with a similar incidence in both fremanezumab and placebo groups. No signal for hepatoxicity was observed. No anaphylaxis or severe hypersensitivity occurred, and only three patients (two on placebo, and one on fremanezumab) had AEs of drug hypersensitivity of mild or moderate severity. None of these events was serious, and all resolved with steroid and/or antihistamine treatment. Incidence of antidrug antibody (ADA) formation was low, and there were no AEs related to ADA or neutralizing antibody development.

CONCLUSION: Four placebo-controlled studies demonstrate that fremanezumab, at the proposed monthly and quarterly dose regimens, is an efficacious and generally safe and well-tolerated preventive therapy.

TRIAL REGISTRATION: ClinicalTrials.gov, NCT02621931, NCT02629861, NCT02021773, NCT02025556

ETHICS APPROVAL

The study was approved by all relevant independent ethics committees or institutional review boards, according to national or local regulations.

P7 Reversion of patients with chronic migraine to an episodic migraine classification with fremanezumab treatment

Joshua M. Cohen1; Kristen Bibeau1; Maja Galic2; Michael J. Seminerio1; Verena Ramirez Campos3; Rashmi B. Halker Singh4; Jessica Ailani5

1Teva Pharmaceuticals, Frazer, Pennsylvania, USA; 2Teva Pharmaceuticals, Amsterdam, The Netherlands; 3Teva Pharmaceuticals, Buenos Aires, Argentina; 4Mayo Clinic, Phoenix, Arizona, USA; 5Medstar Georgetown University Hospital, Washington, District of Columbia, USA
Correspondence: Joshua M. Cohen (jbanigan@hcg-int.com)

OBJECTIVE: To evaluate the effect of fremanezumab on reversion from chronic migraine (CM) to episodic migraine (EM).

BACKGROUND: CM and EM are clinically, functionally, and anatomically differentiated, with evidence suggesting that they may be separate conditions. Furthermore, patients with CM usually have more comorbid conditions and more-frequent medication overuse, which complicates their clinical management. Fremanezumab, a fully humanized monoclonal antibody (IgG2a) that selectively targets calcitonin gene-related peptide (CGRP), has demonstrated efficacy in migraine prevention.

DESIGN/METHODS: In this Phase 3, multicenter, randomized, double-blind, placebo-controlled, parallel-group study, adults with prospectively confirmed CM (≥15 headache days and ≥8 migraine days per month) were randomized 1:1:1 to subcutaneous injections of fremanezumab quarterly (675 mg at baseline; placebo at Weeks 4 and 8), fremanezumab monthly (675 mg at baseline; 225 mg at Weeks 4 and 8), or matching placebo over a 12-week treatment period. Post hoc analyses evaluated the proportion of patients who reverted from CM to EM, defined as patients who had ≥15 headache days per month at baseline (28-day pre-treatment period) and then had <15 headache days per month in all 3 months of the treatment period.

RESULTS: In an analysis of the 1130 CM patients randomized in this trial (quarterly, N=376; monthly, N=379; placebo, N=375), significantly more fremanezumab-treated patients reverted from having ≥15 headache days per month at baseline to <15 headache days per month in Months 1, 2, and 3 (quarterly: 121 patients [32%]; monthly: 133 patients [35%]) than those who received placebo (86 patients [23%]; both, P≤0.002). On average, these fremanezumab-treated patients had 18–19 headache days per month at baseline and showed reductions to 6–9 headache days during any month in the treatment period, representing up to an approximately 70% reduction in headache days.

CONCLUSIONS: Along with its efficacy as a migraine preventive treatment, fremanezumab demonstrated the potential benefit for reversion from CM to EM.

TRIAL REGISTRATION: ClinicalTrials.gov, NCT02621931, NCT02629861

ETHICS APPROVAL

The study was approved by all relevant independent ethics committees or institutional review boards, according to national or local regulations.

Disclosures:

Joshua M. Cohen: Employee of Teva Pharmaceuticals.

Kristen Bibeau: Former employee of Teva Pharmaceuticals.

Maja Galic: Employee of Teva Pharmaceuticals.

Michael J. Seminerio: Employee of Teva Pharmaceuticals.

Verena Ramirez Campos: Employee of Teva Pharmaceuticals.

Rashmi B. Halker Singh: Received honoraria from Current Neurology and Neuroscience Reports, MedLink, and Amgen.

Jessica Ailani: Received honoraria from Allergan (speaking/consulting), Avanir (speaking), Eli Lilly (speaking/advisory board), Teva Pharmaceuticals (advisory board), Promius (speaking), Current Pain and Headache Reports (section editor), Theranica (clinical trials).

P8 Efficacy of fremanezumab in patients with chronic migraine with or without concomitant use of preventive medication

Peter J. Goadsby1*, David W. Dodick2, Stephen D. Silberstein3, Paul P. Yeung4, Tricia Blankenbiller4, Xiaoping Ning4, Ronghua Yang4, Yuju Ma4, Ernesto Aycardi4, Marcelo E. Bigal4

1NIHR-Wellcome Trust King’s Clinical Research Facility, King’s College, London, UK; 2Mayo Clinic, Phoenix, Arizona, USA; 3Jefferson Headache Center, Thomas Jefferson University, Philadelphia, Pennsylvania, USA; 4Teva Pharmaceuticals, Frazer, Pennsylvania, USA
Correspondence: Peter J. Goadsby (srieger@hcg-int.com)

OBJECTIVE: To investigate the efficacy of fremanezumab in chronic migraine (CM) patients with or without concomitant use of preventive medication.

BACKGROUND: Some patients with CM may take more than one preventive medication. Fremanezumab, a fully humanized monoclonal antibody (IgG2a) that selectively targets calcitonin gene-related peptide (CGRP), has demonstrated efficacy in migraine prevention.

DESIGN/METHODS: In this Phase 3, randomized, double-blind, placebo-controlled, parallel-group study, eligible patients with prospectively confirmed CM (≥15 headache days and ≥8 migraine days per month) were randomized 1:1:1 to receive subcutaneous injections of fremanezumab quarterly (675 mg at baseline; placebo at Weeks 4 and 8), fremanezumab monthly (675 mg at baseline; 225 mg at Weeks 4 and 8) or placebo at each time point over a 12-week treatment period. Changes from baseline were assessed in the monthly average number of headache days of at least moderate severity, and in migraine days in patients with or without concomitant preventive medication.

RESULTS: Analyses included 239 patients receiving one concomitant preventive medication (quarterly, N=77; monthly, N=85; placebo, N=77) and 882 patients receiving none (quarterly, N=298; monthly, N=290; placebo, N=294). During the 12-week treatment period, fremanezumab reduced from baseline the mean number of monthly headache days of at least moderate severity versus placebo in patients receiving concomitant preventive medication (quarterly: –3.8±0.61; monthly: –4.5±0.57; placebo: –2.5±0.61), reaching significance with monthly dosing (P=0.003). Reductions were also significant for fremanezumab quarterly and monthly in those not receiving concomitant preventive medication (quarterly: –4.6±0.33; monthly: –4.9±0.33; placebo: –2.7±0.33; both, P<0.0001). These reductions were observed as early as 4 weeks after initiation of fremanezumab monthly in patients receiving concomitant preventive medication (P=0.028); similarly early reductions occurred with fremanezumab monthly and quarterly in patients not receiving concomitant preventive medication (P<0.0001). There were also fewer migraine days with both fremanezumab regimens.

CONCLUSIONS: Fremanezumab demonstrated efficacy in patients with CM, regardless of concomitant preventive medication use.

TRIAL REGISTRATION: ClinicalTrials.gov, NCT02621931

ETHICS APPROVAL

The study was approved by all relevant independent ethics committees or institutional review boards, according to national or local regulations.

Disclosures:

Peter Goadsby: Personal fees from Teva Pharmaceuticals during the conduct of the study. He receives personal fees from Akita Biomedical, Alder Biopharmaceuticals, Avanir Pharma, Cipla Ltd, Dr. Reddy's Laboratories, ElectroCore LLC, Novartis, Pfizer Inc, Quest Diagnostics, Scion, MedicoLegal, UptoDate, and Oxford University Press. He receives grants and personal fees from Allergan, Amgen, Eli Lilly and Company, and eNeura Inc. He receives personal fees and other from Trigemina Inc. He reports work, personal fees from Journal Watch, and Massachusetts Medical Society, outside the submitted work. He has a patent on magnetic stimulation for headache licensed to eNeura.

David W. Dodick: Provides consultation to Acorda, Allergan, Amgen, Alder, Dr. Reddy’s, Merck, Promius, eNeura, Eli Lilly & Company, Insys, Autonomic Technologies, Teva, Xenon, Tonix, Trigemina, Boston Scientific, GBS, Colucid, Zosano, Laydenburg Thalmann, Biocentric, Biohaven, Magellan, Charleston Laboratories, Pfizer. Royalties: Oxford University Press and Cambridge University Press (Book Royalty). He receives editorial/honoraria from UpToDate. He receives honoraria/publishing or honoraria/royalties from Chameleon Communications, Medscape, WebMD, Academy for Continued Healthcare Learning, Haymarket Medical Education, Global Scientific Communications, HealthLogix, Academy for Continued Healthcare Learning, MeetingLogiX, Wiley Blackwell, Oxford University Press, Cambridge University Press. Stock/options: GBS/Nocira, Epien, and Mobile Health. He has a consulting use agreement with NAS. He has a board position at King-Devick Inc.

Stephen D. Silberstein: Provides consultation to Alder, Allergan, Amgen, Avanir, Curelater Inc., Depomed, Dr. Reddy’s Laboratories, Ensured Inc., ElectroCore Medical LLC, INSYS Therapeutics, Lilly USA LLC, Supernus Pharmaceuticals Inc., Teva Pharmaceuticals, Theranica, and Trigemina Inc.

Paul P. Yeung: Employee of Teva Pharmaceuticals.

Tricia Blankenbiller: Former employee of Teva Pharmaceuticals.

Xiaoping Ning: Employee of Teva Pharmaceuticals.

Ronghua Yang: Employee of Teva Pharmaceuticals.

Yuju Ma: Employee of Teva Pharmaceuticals.

Ernesto Aycardi: Former employee of Teva Pharmaceuticals.

Marcelo E. Bigal: Former employee of Teva Pharmaceuticals.

P9 The Effect of Cognitive Behavioural Therapy on Self-Efficacy and Headache Frequency, in Chronic Migraine

Ayhan Bingöl, Derya Uludüz, Özlem Mercan, Yasemin Akıncı, Duygu Deringöl, Sabahattin Saip, Aksel Siva

Department of Neurology, Istanbul University Cerrahpasa Faculty of Medicine, Istanbul, Turkey, 34096
Correspondence: Özlem Mercan (ozlemmercan3@gmail.com)

Background: Chronic migraine (CM) is still an underdiagnosed and undertreated headache disorder even though the incidence and prevalence of recurrent headaches have considerably increased over the last decades. CM patients suffer more prominent disease related decrease of quality of life, occupational and educational absenteeism. CM have also burden of disease with direct and indirect costs on population and healthcare systems. Treatment of CM is not only essential to recover quality of life of sufferers, but also could provide lessening of burden of disease and economical costs. Unfortunately refractory CM is much more disabling, debilitating and challenging. Psychosocial interventions such as cognitive-behavioral therapy can improve the pain, disability and impaired quality of life and can be as cost effective as medication in refractory CM. Patients with refractory CM with medication overuse headache were studied and the results of the CBT treatment were reported.

Methods: Fifty patients with refractory CM and medication overuse headache were included in the study. Patients with psychiatric comorbidity such as depression or anxiety were excluded and twenty patients out of fifty were received CBT treatment. CBT treatment consists four modules, patients underwent weekly CBT sessions lasting 45 minutes for 3 months. Headache spesific self efficacy scale and patient pain attitute and belief scale were administered before and after the CBT treatment.

Results: The mean age of the patients was 41±9.4 years and 13 patients were female (65%). Seventy-five percent had a history of trauma. %90 of the patients had an attitude of organic belief rather than psychological belief according to pain attitute and belief scale. Self efficacy scale mean score (SD) was 66.0±10.8 before CBT treatment and 104.9±9.2 after CBT. Headache frequency was 19.0±4.7 before CBT and 1.4±2.2 after the treatment. Decrease in the headache frequency was associated with the increase of self efficacy scores.

Conclusions: A well structured CBT treatment including life style changes in CM patients was found to be superior to medical treatment alone for improving pain frequency even in patients without psychiatric comorbidity. The efficacy is thought to be related with the increase of self efficacy scores.

P10 Efficacy of fremanezumab in patients with chronic migraine and comorbid moderate to moderately severe depression

Joshua M. Cohen1, Paul P. Yeung1, Ernesto Aycardi1, Marcelo E. Bigal1, Ronghua Yang1, Kristen Bibeau1, Maja Galic2, Michael J. Seminerio1, Richard B. Lipton3, Dawn C. Buse3

1Teva Pharmaceuticals, Frazer, Pennsylvania, USA; 2Teva Pharmaceuticals, Amsterdam, The Netherlands; 3Albert Einstein College of Medicine and Montefiore Medical Center, Bronx, New York, USA
Correspondence: Joshua M. Cohen (mmathew@hcg-int.com)

OBJECTIVE: To evaluate the efficacy of fremanezumab on migraine symptoms and depression in patients with chronic migraine (CM) and comorbid moderate to moderately severe depression.

BACKGROUND: Depression is common in CM and contributes to the already substantial burden of disease. Fremanezumab, a fully humanized monoclonal antibody (IgG2a) that selectively targets calcitonin gene-related peptide (CGRP), has demonstrated efficacy in migraine prevention.

DESIGN/METHODS: In this Phase 3, multicenter, randomized, double-blind, placebo-controlled, parallel-group study, eligible patients aged 18–70, with prospectively confirmed CM (≥15 headache days and ≥8 migraine days per month) were randomized 1:1:1 to receive subcutaneous injections of fremanezumab quarterly (675 mg at baseline; placebo at Weeks 4 and 8), fremanezumab monthly (675 mg at baseline; 225 mg at Weeks 4 and 8), or matching placebo over a 12-week treatment period. Post hoc analyses evaluated changes in headache and migraine frequency and depression in patients with moderate to moderately severe depression (score of 10–19 on the 9-item Patient Health Questionnaire [PHQ-9]) at baseline.

RESULTS: Almost 20% (219/1130) of randomized patients had moderate to moderately severe depression at baseline (quarterly, n=74; monthly, n=88; placebo, n=57). As in the overall study population, fremanezumab-treated patients in this subgroup had significant reductions from baseline in the mean number of monthly headache days of at least moderate severity (quarterly: –5.4±0.79; monthly: –5.6±0.75) versus those who received placebo (–2.2±0.84) during the 12-week treatment period (both, P<0.001), with effects observed as early as Week 4 (P<0.0001). Similar treatment differences were observed for change in the mean number of migraine days (P<0.001). Fremanezumab also reduced the mean PHQ-9 score from baseline to Week 12 (quarterly: –10.5±0.68; monthly: –9.5±0.63) versus placebo (–8.7±0.71); the quarterly group reached significance (P<0.05).

CONCLUSIONS: Fremanezumab demonstrated efficacy in preventive treatment of CM in patients with comorbid moderate to moderately severe depression, reducing migraine and headache frequency and improving depression.

TRIAL REGISTRATION: ClinicalTrials.gov, NCT02621931

ETHICS APPROVAL

The study was approved by all relevant independent ethics committees or institutional review boards, according to national or local regulations.

Disclosures:

Joshua M. Cohen: Employee of Teva Pharmaceuticals.

Paul P. Yeung: Employee of Teva Pharmaceuticals.

Ernesto Aycardi: Former employee of Teva Pharmaceuticals.

Marcelo E. Bigal: Former employee of Teva Pharmaceuticals.

Ronghua Yang: Employee of Teva Pharmaceuticals.

Kristen Bibeau: Former employee of Teva Pharmaceuticals.

Maja Galic: Employee of Teva Pharmaceuticals.

Michael J. Seminerio: Employee of Teva Pharmaceuticals.

Richard B. Lipton: Consultant to Teva Pharmaceuticals.

Dawn C. Buse: Consultant to Amgen, Allergan, Avanir, Biohaven, Eli Lilly and Promeius.

P11 Achievement of response over time with fremanezumab in the treatment of chronic and episodic migraine

Stephen D. Silberstein1, Richard B. Lipton2, Merle L. Diamond3, Joshua M. Cohen4, Ronghua Yang4, Bo Jiang4

1Jefferson Headache Center, Thomas Jefferson University, Philadelphia, Pennsylvania, USA; 2Albert Einstein College of Medicine, Bronx, New York, USA; 3Diamond Headache Clinic, Chicago, Illinois, USA; 4Teva Pharmaceuticals, Frazer, Pennsylvania, USA
Correspondence: Stephen D. Silberstein (jtuck@hcg-int.com)

OBJECTIVES: The long-term efficacy of monoclonal antibodies that selectively target calcitonin gene-related peptide (CGRP) in patients with early treatment failure is not well characterized. Based on data from Phase 3 trials in episodic (EM) and chronic migraine (CM) of fremanezumab, a fully humanized monoclonal antibody (IgG2a) that selectively targets CGRP, we assessed long-term treatment response rates in patients with early treatment failure.

METHODS: This multicenter, randomized, double-blind, parallel-group, long-term study, included patients who completed either 12-week Phase 3 study (HALO CM or HALO EM). Patients continued on treatment from the 12-week studies, receiving either subcutaneous fremanezumab quarterly (675 mg every 3 months), fremanezumab monthly (CM: 675 mg at baseline and 225 mg every month; EM: 225 mg every month) over a 12-month treatment period. The percentage of patients with a reduction in migraine days (response rates) >40% at Months 6 and 9 among patients with low response rates (<40%) at Month 1 was assessed in patients who received active treatment in the 12-week studies.

RESULTS: CM patients with <20% reduction in migraine days at Month 1 had >40% response rates of 29% (58/197) at Month 6 and 43% (35/81) at Month 9. Patients with <20% reduction at Month 3 had >40% response rates of 18% (32/176) at Month 6 and 30% (21/69) at Month 9. Patients with <40% reduction at Month 1 had >40% response rates of 36% (99/272) at Month 6 and 51% (55/108) at Month 9. Patients with <40% reduction at Month 3 had >40% response rates of 28% (72/253) at Month 6 and 41% (41/101) at Month 9.

EM patients with <20% reduction in migraine days at Month 1 had >40% response rates of 53% (53/100) at Month 6 and 62% (26/42) at Month 9. Patients with <20% reduction at Month 3 had >40% response rates of 41% (34/83) at Month 6 and 47% (15/32) at Month 9. Patients with <40% reduction at Month 1 had >40% response rates of 57% (92/162) at Month 6 and 63% (45/72) at Month 9. Patients with <40% reduction at Month 3 had >40% response rates of 46% (62/135) at Month 6 and 61% (33/54) at Month 9.

CONCLUSIONS: Failure to achieve an early response to fremanezumab does not predict failure at later time points.

TRIAL REGISTRATION: ClinicalTrials.gov, NCT02638103

ETHICS APPROVAL

The study was approved by all relevant independent ethics committees or institutional review boards, according to national or local regulations.

P12 The impact of fremanezumab on medication overuse in patients with chronic migraine

Stephen D. Silberstein1, Sait Ashina2, Zaza Katsarava3, Kristen Bibeau4, Michael J. Seminerio4, Danielle E. Harlow4, Joshua M. Cohen4

1Jefferson Headache Center, Thomas Jefferson University, Philadelphia, Pennsylvania, USA; 2Beth Israel Deaconess Medical Center Comprehensive Headache Center, Harvard Medical School, Boston, Massachusetts, USA; 3University of Essen, Unna, Germany; 4Teva Pharmaceuticals, Frazer, Pennsylvania, USA
Correspondence: Stephen D. Silberstein (khokenson@hcg-int.com)

OBJECTIVES: Overuse of acute or symptomatic headache medications (triptans, ergot derivatives, opioids, and combination analgesics) can cause medication overuse headache (MOH), which often accompanies chronic migraine (CM). Fremanezumab, a fully humanized monoclonal antibody (IgG2a) that selectively targets calcitonin gene-related peptide (CGRP), reduced the frequency and severity of headaches in CM patients. We assessed the effect of fremanezumab on medication overuse and acute headache medication use in CM patients.

METHODS: In this multicenter, randomized, double-blind, placebo-controlled, Phase 3 study, CM patients CM were randomized 1:1:1 to receive subcutaneous fremanezumab quarterly (675 mg at baseline, and placebo at Weeks 4 and 8), fremanezumab monthly (675 mg at baseline, and 225 mg at Weeks 4 and 8), or placebo over a 12-week treatment period. We assessed the proportion of patients who reverted from overusing medications at baseline (use of acute headache medication on ≥15 days, use of migraine-specific acute medication on ≥10 days, or use of combination medications for headache on ≥10 days during the 28-day baseline period) to not overusing medications at Week 12, and the change from baseline in the number of days of acute headache medication use among these patients. Analyses were performed in the full analysis set (all randomized patients who received ≥1 dose of study drug and had ≥10 days of post-baseline efficacy assessments on the primary endpoint).

RESULTS: Among patients with medication overuse at baseline (quarterly n=201; monthly n=198; placebo n=188), more fremanezumab-treated patients reported no medication overuse during the 12-week treatment period (quarterly: 111/201 patients [55%], P=0.0389; monthly: 120/198 patients [61%], P=0.0024) than those who received placebo (87/188 patients [46%]). This response was seen as early as Week 4 (quarterly: 102/201 patients [51%], P=0.0091; monthly: 107/198 patients [54%], P=0.0014; vs placebo: 73/188 patients [39%]). Among patients who responded (quarterly n=111; monthly n=120; placebo n=87), the baseline number of days with medication overuse was similar across treatment groups (quarterly [mean ± standard error]: 16.6±0.32 days; monthly: 16.7±0.33 days; placebo: 16.6±0.35). Within this population, fremanezumab treatment reduced the days of acute headache medication use over the treatment period (quarterly: –9.0±0.41 days, P=0.0017; monthly: –8.9±0.41 days, P=0.0040) versus those who received placebo (–7.1±0.46 days).

CONCLUSIONS: Fremanezumab treatment was associated with reduced overuse of acute medications and fewer days using acute medications.

TRIAL REGISTRATION: ClinicalTrials.gov, NCT02621931

ETHICS APPROVAL

The study was approved by all relevant independent ethics committees or institutional review boards, according to national or local regulations.

P13 Work productivity amongst those with migraine: results from the My Migraine Voice survey

Todd J. Schwedt1, Rebeca Quintana2, Veruska Carboni3, Paolo Martelletti4, 5, Michel Lanteri-Minet6, Hans-Christoph Diener7, Annik K.-Laflamme8, Elena Ruiz de la Torre9, Audrey Craven10, Annette Vangaa Rasmussen11, Donna Walsh12, Simon Evans13, Paula Dumas14, Rachel Fink8, Angela Fiorin8, Stephanie Ribbe8, Pamela Vo8

1Neurology Arizona, Mayo Clinic, Phoenix, United States; 2GFK, Madrid, Spain; 3GfK Health, Basel, Switzerland; 4Department of Clinical and Molecular Medicine, Sapienza University of Rome, Rome, Italy; 5EHF; 6Département d’Evaluation et Traitement de la Douleur, Centre Hospitalo-Universitaire de Nice, -, France; 7Department of Neurology and Headache Center, University Duisburg-Essen, -, Germany; 8ovartis Pharma AG, Basel, Switzerland; 9European Headache Alliance, Brussels, Belgium; 10Migraine Association Ireland, Dublin, Ireland 11Rigshospitalet Glostrup, Copenhagen, Denmark; 12European Federation of Neurological Associations, Brussels, Belgium; 13Migraine Action, Leicester, United Kingdom; 14Migraine Again, United States
Correspondence: Todd J. Schwedt (Schwedt.Todd@mayo.edu)

Objectives

Migraine-induced disability results in substantial economic and societal burden globally [1]. However, limited evidence exists for those with migraine who have used preventive medication. As part of the worldwide My Migraine Voice survey, this study aimed to describe the impact of migraine on work and activity impairment amongst migraine individuals who suffer from at least 4 monthly migraine days (MMDs) and reported use of preventive medication.

Methods

A cross-sectional study was conducted using an online worldwide survey of migraine patients from 31 countries across Africa, America, Asia, and Europe, recruited via online panels and patient organizations. Study participants were adult patients (≥18 years) who reported ≥4 MMDs over the 3 months preceding the time of the survey (September 2017- February 2018), with pre-specified 90% of them having reported having used preventive migraine treatments. The impact of migraine on work productivity and activities during the past seven days (prior to survey completion) was evaluated using the work productivity and activity impairment (WPAI) questionnaire and was compared among treatment naive, no prior treatment failure (TF), 1 TF, and ≥2 TF patient subgroups.

Results

A total of 11,266 migraine patients with at least 4MMDs responded to the survey (75% women, mean age: 39 years old). Migraine patients reported overall a reduction of 13% in their working time (absenteeism), 48% in productivity while working (presenteeism), and 52% in both overall work productivity (absenteeism and presenteeism combined) and daily activities due to migraine. Descriptive analysis of results by prior treatment showed that all WPAI outcomes are impacted by migraine especially in those who have failed 2 or more prior prophylactic treatments.

Conclusion

This large worldwide study shows that migraine is associated with work productivity and activity impairment especially in those patients who have experienced two or more treatment failures.

Ethics approval

Data was handled confidentially and anonymity of respondents was maintained throughout the study. Participants’ consent was obtained prior to participation in the survey.

Funding

This study was funded by Novartis Pharma AG, Basel, Switzerland

References

1. Steiner TJ, Stovner LJ, Vos T, Jensen R, Katsarava Z. Migraine is first cause of disability in under 50s: will health politicians now take notice? The Journal of Headache and Pain. 2018;19(1):17.

P14 Headache following mild traumatic brain injury (MTBI) in a population-based, controlled, longitudinal study

Lena H. Nordhaug1, Mattias Linde1, Turid Follestad2 Toril Skandsen1, Anne Vik1

1Department of Neuromedicine and Movement Science, Faculty of Medicine and Health Sciences, Norwegian University of Science and Technology, Postbox 8905, 7491 Trondheim, Norway; 2Department of Public Health and Nursing, Faculty of Medicine and Health Sciences, Norwegian University of Science and Technology, Trondheim, Norway
Correspondence: Lena H. Nordhaug (lena.h.nordhaug@ntnu.no)

Background

Headache is the most frequent symptom following mild traumatic brain injury (MTBI), but the majority of data published are from hospital admissions only. We explored both hospitalized and non-hospitalized subjects with MTBI and compared them to a healthy control group and a control group with orthopaedic injuries to examine whether the MTBI group had an increase in headache suffering following the head injury.

Methods

This was a population-based, controlled, longitudinal cohort study. Patients were recruited from the emergency departments at a level 1 trauma-center and a municipal outpatient-clinic. Information regarding the participants´ headache status was collected through questionnaires at baseline (with information on headache suffering during the last 12 months), 3 and 12 months after the MTBI. We used generalized linear mixed model to examine whether there was an interaction effect between the three groups over time regarding headache status (headache yes/no).

The Regional committee for research ethics approved the study. Participants, or parents of participants < 18 years, gave written consent.

Results

378 MTBI patients were included. The control groups consisted of 83 healthy controls and 82 orthopedic controls. Mean age in the MTBI group was 31.2 years (SD ±13.0). The majority of the participants was male (65%) and 69% were treated without hospital admittance. There was a significant interaction between time and participant group (p = 0.042). Figure 1 shows the trajectories of log odds for headache for the three participants groups as reported in the three questionnaires. The increase in odds of headache from pre-injury status to 3 months was significantly larger for the MTBI group than orthopedic controls (ratio of OR 4.25, 95% CI 1.46-12.40), and healthy controls (ratio of OR 3.53, 95% CI 1.08 – 11.59). The change in odds of headache from pre-injury status to 12 months, and from 3 months to 12 months, did however not differ between the groups. In the MTBI group the odds of headache increased significantly from pre-injury to 3 months (OR 8.62, 95% CI 4.90-15.17) and 12 months (OR 3.73, 95% CI 2.19 – 6.33), but a significant decrease in odds of headache from 3 months to 12 months was observed (OR 0.43, 95% CI 0.25-0.74).

Conclusions

There was a significantly larger increase in odds of headache from pre-injury status to 3 months for the MTBI group compared to orthopedic and healthy controls, but the change in odds of headache from pre-injury status to 12 months did not differ between the groups.

Fig. 1 (abstract P14).

Log odds with 95% CI for headache pre-injury, 3 months and 12 months for all three participant groups

P15 A randomised, double-blind, placebo-controlled study of erenumab safety in patients with stable angina

Christophe Depre1, Lubomir Antalik2, Amaal Starling3, Michael Koren4, Osaro Eisele1, Daniel D. Mikol1

1Amgen Inc., Thousand Oaks, CA, USA; 2Regional Hospital, Cardiological Department, Slovakia; 3Mayo Clinic, Scottsdale, AZ, USA; 4Jacksonville Center for Clinical Research, Jacksonville, FL, USA
Correspondence: Lubomir Antalik (antalik@nspbr.sk)

Background

During myocardial ischaemia, cardiac sensory nerves release a number of vasodilatory and cytoprotective mediators, including the calcitonin gene-related peptide (CGRP). Erenumab, a fully human anti-CGRP receptor antibody approved as a preventive treatment for migraine by the US FDA. We previously reported that erenumab did not adversely affect exercise time in an at-risk population of patients with stable angina. Here we provide additional analyses of erenumab effects on cardiovascular function and haemodynamics in a high-risk population of patients with stable angina.

Methods

In this double-blind, placebo-controlled study in patients with stable angina due to documented coronary artery disease (CAD), patients were randomised 1:1 to a single intravenous (IV) infusion of erenumab 140 mg or placebo, stratified based on baseline total exercise time average (<7 minutes or ≥7 minutes) of two qualifying exercise treadmill tests (ETTs) performed during screening. Following IV study drug administration, an ETT was conducted on Day 1. Safety follow-up visits occurred every 2–4 weeks for 12 weeks. The primary endpoint, previously reported, was change from baseline in exercise duration. Safety analyses included blood pressure (BP), heart rate (HR), laboratory assessments, vital signs, electrocardiograms, and monitoring of adverse events (AEs).

Results

Demographics and baseline disease characteristics of the 89 enrolled patients, balanced between treatment groups, were representative of a high-risk patient population: 100% had cardiovascular disease, ~40% had history of myocardial infarction, and 24% had history of cerebrovascular or peripheral arterial disease. At baseline, mean (standard deviation) systolic (SBP) and diastolic blood pressure (DBP; mmHg) was 132.1 (18.3) and 80.0 (11.8) in the placebo group and 129.3 (12.0) and 77.8 (13.6) in the erenumab group. Mean baseline heart rate (beats/min) was 70.5 (13.4) and 69.6 (10.0), respectively. ETT and last measured post-ETT SBP, DBP and HR are presented (Table 1). The mean changes from baseline in SBP, DBP and HR during the safety follow-up period were similar between the two groups.

Adverse events, reported by 32% and 27% of patients in placebo and erenumab groups, were mostly singularly reported. One serious AE (atrial fibrillation with placebo) was reported. No clinically significant changes in serum chemistry or haematology laboratory values were observed. No deaths occurred during the study.

Conclusions

These results demonstrate that erenumab has no adverse haemodynamic effects during exercise in patients with CAD and stable angina and does not impact functional recovery, providing reassurance that CGRP receptor blockade does not negatively impact cardiovascular function in patients with CAD.

Table 1 (abstract P15).

Outcome measures

Parameter

Erenumab 140 mg

Placebo

ETT

 Peak SBP

172.1 (22.9)

172.2 (22.4)

 Peak DBP

90.1 (15.1)

90.3 (15.4)

 Peak heart rate

122.2 (19.7)

122.6 (22.0)

Post-ETT

 SBP

134.5 (15.2)

135.0 (18.5)

 DBP

76.2 (9.3)

79.2 (11.6)

 Heart rate

73.3 (8.7)

78.8 (13.7)

ETT exercise treadmill tests, DBP diastolic blood pressure, SBP systolic blood pressure

P16 Burden and patient-reported outcomes of migraine patients with prior prophylactic treatment failure: Study design of the multinational BECOME study

Paolo Martelletti1, Christian Lucas2, Patricia Pozo-Rosich3, David Watson4, Charly Gaul5, Shannon Ritter6, Josefin Snellman6

1Department of Clinical and Molecular Medicine, Sapienza University of Rome, Sant'Andrea Hospital, Via di Grottarossa, Rome, Italy; 2Hopital Salengro, CHRU de Lille, Service de Neurochirurgie, Lille Cedex, France; 3Headache Unit, Neurology Department, Vall d'Hebron University Hospital, Barcelona, and Headache Research Group, Vall d’Hebron Institute of Research (VHIR), Universitat Autonoma of Barcelona, Spain; 4Hamilton Medical Group, Aberdeen, Scotland; 5Migraine and Headache Clinic Königstein, Königstein im Taunus, Germany; 6Novartis Pharma AG, Basel, Switzerland
Correspondence: Paolo Martelletti (paolo.martelletti@uniroma1.it)

Background

Migraine is the most prevalent primary headache disorder in tertiary care and can impair a patient’s quality of life. However, there is limited data available on the disease burden and quality of life in migraine patients with prior treatment failure from European countries.

Objectives

The primary objective of the BECOME study is to describe the proportion of migraine patients with at least one prior prophylactic treatment failure. Other objectives include assessment of impact of migraine on quality of life in this population and estimate the resulting healthcare resource utilisation (HRU).

Methods

BECOME is a multicentre, prospective, non-interventional study, being conducted simultaneously in two parts over three consecutive months in 167 headache clinics across 17 European countries and Israel in adult migraine patients (aged 18–65 years) who have failed more than one preventive treatment within the last 5 years. The study protocol was approved by the IRB/IEC and was in accordance with the Declaration of Helsiniki. In Part 1 of the study, the proportion of migraine patients is determined by weekly collection of site-specific data for a period of 3 months from patients visiting (Visit 0) the individual healthcare centres as an in- or out-patient (Fig. 1). For the cross-sectional Part 2, patients from Part 1, identified by investigators according to local routine clinical practice, who are willing to complete a set of questionnaires and provide study participation consent are invited for a subsequent study visit (Visit 1) within 14 days from Visit 0. A set of questionnaires are used to collect patient-specific data on disease characteristics, patient-reported outcomes, burden of disease, and HRU (Fig. 1). A sample size of 2462 patients will be included in Part 2 to give an overall error rate of 1.6% (half-width of 95% confidence interval), under the assumption that 80% of patients discontinue at least one therapy.

Conclusions

The outcome of the study will provide proportion of migraine patients with at least one prior treatment failure visiting the headache clinics in Europe and Israel, and describe patient characteristics and perspectives during disease management in real-life setting. This information can help in treatment decisions for patients with limited treatment options.

Fig. 1 (abstract P16).

BECOME study design and data collection during Parts 1 and 2

P17 My Migraine Voice: a worldwide survey of 11,266 migraine patients

Elena Ruiz de la Torre1, Rebeca Quintana2, Veruska Carboni3, Paolo Martelletti4,5, Todd J. Schwedt6, Michel Lanteri-Minet7, Hans-Christoph Diener8, Annik K.-Laflamme9, Annette Vangaa Rasmussen10, Donna Walsh11, Audrey Craven12, Simon Evans13, Paula Dumas14, Rachel Fink9, Angela Fiorin9, Stephanie Ribbe9, Pamela Vo9

1European Headache Alliance, Brussels, Belgium; 2GFK, Madrid, Spain; 3GfK Health, Basel, Switzerland; 4Department of Clinical and Molecular Medicine, Sapienza University of Rome, Rome, Italy; 5EHF; 6Neurology Arizona, Mayo Clinic, Phoenix, United States; 7Département d’Evaluation et Traitement de la Douleur, Centre Hospitalo-Universitaire de Nice, France,; 8Department of Neurology and Headache Center, University Duisburg-Essen, -, Germany; 9Novartis Pharma AG, Basel, Switzerland; 10Rigshospitalet Glostrup, Copenhagen, Denmark; 11European Federation of Neurological Associations, Brussels, Belgium; 12Migraine Association Ireland, Dublin, Ireland; 13Migraine Action, Leicester, United Kingdom; 14Migraine Again, United States
Correspondence: Elena Ruiz de la Torre (elena@europeanheadachealliance.org)

Introduction

The My Migraine Voice survey was conducted to assess migraine characteristics and describe the current real-world burden and impact of living with migraine from clinical, personal, and economic perspectives amongst those with at least 4 monthly migraine days (MMDs). This analysis reports on survey respondents’ demographics, migraine characteristics, use of migraine therapies, and association with other chronic conditions.

Methods

A worldwide cross-sectional study was conducted using a 30-minute online survey of adults with migraine recruited from 31 countries across Africa, America, Asia and Europe via online panels and patient organizations. To be included, participants had to report >=4 MMDs in the 3 months preceding survey administration (September 2017-February 2018). High-need patients were prioritized by ensuring 90% of patients had reported preventive migraine treatment use (pre-specified).

Results

A total of 11,266 individuals with migraine participated (75% female, mean age=39 years). Of all respondents, 47% were employed full-time, 56% married, 63% had children and 54% had migraine family history. Patients had had migraine for 11.6 years on average (27% for >20 years), 54% received a diagnosis within 6 months of consulting for their symptoms (19% within >=2 years), and 83% reported taking prescription medications for acute treatment (51% also take OTC drugs). Respondents reported 3.3 other chronic conditions on average (top 3: anxiety, insomnia/sleep disorders, and depression).

Conclusion

This large worldwide study constitutes a rich source of data to further describe this economically active population with prior treatment usage and with personal, social and professional commitments, and high healthcare use.

Ethics approval

Data was handled confidentially and anonymity of respondents was maintained throughout the study. Participants’ consent was obtained prior to participation in the survey.

Funding

This study was funded by Novartis Pharma AG, Basel Switzerland

P18 Economic burden of migraine: healthcare resource utilization in the My Migraine Voice survey

Paolo Martelletti1,2, Rebeca Quintana3, Veruska Carboni4, Todd J. Schwedt5, Michel Lanteri-Minet6, Hans- Christoph Diener7, Annik K.-Laflamme8, Elena Ruiz de la Torre9, Audrey Craven10, Simon Evans11, Donna Walsh12, Annette Vangaa Rasmussen13, Paula Dumas14, Rachel Fink8, Angela Fiorin8, Stephanie Ribbe8, Pamela Vo8

1Department of Clinical and Molecular Medicine, Sapienza University of Rome, Rome, Italy; 2EHF; 3GFK, Madrid, Spain; 4GfK Health, Basel, Switzerland; 5Neurology Arizona, Mayo Clinic, Phoenix, United States; 6Département d’Evaluation et Traitement de la Douleur, Centre Hospitalo-Universitaire de Nice, France; 7Department of Neurology and Headache Center, University Duisburg-Essen, Germany; 8Novartis Pharma AG, Basel, Switzerland 9European Headache Alliance, Brussels, Belgium; 10Migraine Association Ireland, Dublin, Ireland; 11Migraine Action, Leicester, United Kingdom; 12European Federation of Neurological Associations, Brussels, Belgium; 13Rigshospitalet Glostrup, Copenhagen, Denmark; 14Migraine Again, United States
Correspondence: Paolo Martelletti (paolo.martelletti@uniroma1.it)

Introduction

Migraine is a distinct neurological disease ranking among the top causes of disability globally [1]. This study aimed to evaluate the real-world healthcare resource utilization due to migraine, particularly among individuals who suffer from at least 4 monthly migraine days (MMDs).

Methods

A cross-sectional study was conducted using an online survey of migraine patients in 31 countries across Africa, America, Asia and Europe, recruited via online panels and patient organizations. Study participants were adults (>=18 years) who reported having >=4 MMDs over the 3 months preceding the time of the survey (September 2017-February 2018), with pre-specified 90% among those having reported having used preventive migraine treatment.

Results

A total of 11,266 migraine patients responded to the survey (75% women, mean age: 39 years old). Migraine patients with at least 4 MMDs reported visiting different healthcare professionals (HCP) in a 6- month period due to their migraine. In the previous 12 months, 38% of patients visited the Emergency room (ER) an average 3.3 times, and 23% stayed in hospital overnight for an average of 3.2 days. Brain scans were performed on 58% of patients on average 2.1 times. These proportions were both higher in Turkey, India, Brazil, Indonesia, Poland, USA, Portugal, Russia, and also for migraine patients who have failed >=2 prophylactic treatments (Table 1).

Conclusion

Migraine patients (>= 4MMD) reported a high rate of HCP, ER visits and overnight stays in the hospital due to migraine; results indicate that the burden is higher among those who have failed a prophylactic migraine treatment and this trend increased with the number of prophylactic treatment failures.

Ethics approval

Data was handled confidentially and anonymity of respondents was maintained throughout the study. Participants’ consent was obtained prior to participation in the survey.

Funding

This study was funded by Novartis Pharma AG, Basel, Switzerland

Table 1 (abstract P18).

Resource utilization in previous 12 months in migraine individuals

 

Overall (N=11266)

No prior prophylactic treatment

No prophylactic TF

1

prophylactic TF

2 or more prophylactic TFs

Brain scan

 Proportion of patients (%)

58%

29%

46%

56%

68%

 Average number of scans

2.1

1.7

1.8

1.7

2.3

ER visits

 Proportion of patients (%)

38%

17%

28%

28%

46%

 Average number of visits

3.3

2.9

2.5

2.7

3.5

Overnight hospital stay in past 12 months

 Proportion of patients (%)

23%

8%

14%

15%

29%

 Average nights of stay

3.2

2.6

2.6

2.3

3.4

ER emergency room, TF treatment failure; Data refer to 12 months prior to survey completion; survey took place between September 2017 and February 2018 in 31 countries

References:

1. Steiner TJ, Stovner LJ, Vos T, Jensen R, Katsarava Z. Migraine is first cause of disability in under 50s: will health politicians now take notice? The Journal of Headache and Pain. 2018;19(1):17.

P19 Effect of galcanezumab following double-blind treatment in patients with migraine: results from EVOLVE-1 and EVOLVE-2

Qi Zhang, Paula A. Morrow, Virginia L. Stauffer, Vladimir Skljarevski, Eric M. Pearlman, Sheena K Aurora

Eli Lilly and Company, Indianapolis, IN 46285 USA

Correspondence: Virginia L. Stauffer (stauffer_virginia@lilly.com)

Objective: Galcanezumab, a humanized monoclonal antibody that binds calcitonin gene-related peptide, has a half-life of 27 days so the effect can persist after the last injection. Here, we examine the efficacy and safety data from the post-treatment period of the phase 3 studies in patients with episodic migraine.

Methods: Patients aged 18-65 years with 4 to 14 baseline number of migraine headache days were enrolled into two double-blind, placebo-controlled, migraine prevention studies. The studies randomized 858 patients (EVOLVE-1) and 915 patients (EVOLVE-2) to receive galcanezumab 120mg (with 240mg loading dose at first month) or 240mg galcanezumab or placebo, which was administered subcutaneously once/month for 6 months. After completion or discontinuation of the 6-month treatment period, patients were to enter a 4-month post-treatment (PT) period without receiving galcanezumab or placebo. Efficacy (daily headache diary) and safety measures including post-treatment emergent adverse events (AEs) were collected. Change from baseline in number of migraine headache days (MHDs) over the 10 months of study were analyzed with mixed model repeated measures analysis. Time to first loss of 50% response were analyzed with Kaplan-Meier method with log rank test.

Results: Among 740 (EVOLVE-1) and 830 (EVOLVE-2) patients entered in the 4 month PT period, 95.1% (EVOLVE-1) and 96.0% (EVOLVE-2) completed the PT period. For change from baseline in monthly MHDs over the 10 months of study, the differences between each galcanezumab dose group and placebo were statistically significant at each month (smaller differences at months 7 to 10), with the exception of one galcanezumab dose group at month 10 for both studies (Figs. 1 and 2). There were not statistically significant differences between treatment groups for time to first loss of 50% response. By last month of PT period, about 50% patients across all treatment groups had first loss of 50% response in both studies. The only PT emergent AEs that were >1.0% were viral upper respiratory tract infection (URTI). There were no discontinuations due to AEs during the PT period for both studies.

Conclusion: Both treatment groups continued to have reduction in MHD frequency compared to baseline, but the treatment differences were lower once glacanezumab was stopped. No new safety signals emerged following cessation of treatment with galcanezumab.

Trial registration: ClinicalTrials.gov identifiers NCT02614183 (EVOLVE-1) and NCT02614196 (EVOLVE-2)

Ethics approval

These studies were approved by the appropriate institutional review board for each of the study sites. They were all conducted according to Good Clinical Practice and the Declaration of Helsinki guidelines.

Fig. 1 (abstract P19).

Change from baseline in the number of monthly migraine headache days during 6 months treatment and 4 month post-treatment period for EVOLVE-1

Fig. 2 (abstract P19).

Change from baseline in the number of monthly migraine headache days during 6 months treatment and 4 month post-treatment period for EVOLVE-2

P20 Sustained efficacy over 1 year of treatment with erenumab: results from the extension phase of the STRIVE study in episodic migraine

Peter J. Goadsby1, Uwe Reuter2, Yngve Hallström3, Gregor Broessner4, Jo H Bonner5, Feng Zhang6, Sandhya Sapra6, Denise E Chou6, Jan Klatt7, Hernan Picard6, Robert A Lenz6, Daniel D Mikol6

1NIHR-Wellcome Trust King’s Clinical Research Facility, King’s College Hospital, London, UK; 2Department of Neurology, Charité Universitätsmedizin Berlin, Berlin, Germany; 3Neuro Center, St Görans Hospital, Stockholm, Sweden; 4Department of Neurology, Headache Outpatient Clinic, Medical University of Innsbruck, Innsbruck, Austria; 5Mercy Research, Saint Louis, MO, USA; 6Amgen Inc., Thousand Oaks, CA, USA; 7Novartis Pharma AG., Basel, Switzerland
Correspondence: Peter J. Goadsby (peter.goadsby@kcl.ac.uk)

Background

To assess efficacy and safety of erenumab in the 28-week, dose-blinded, active treatment phase (ATP) of the Phase 3 STRIVE study (NCT02456740).

Methods

955 patients were randomised (1:1:1) during the 24-week double-blind treatment phase (DBTP) of the STRIVE study to placebo, erenumab 70mg or 140mg administered subcutaneously, once-monthly. At the end of 24 weeks DBTP, 845 patients were re-randomised (1:1) to receive erenumab 70mg or 140mg (during the 28-week dose-blinded ATP). Monthly migraine days (MMDs), monthly acute migraine-specific medication treatment days (MSMDs), >=50% responder rates in MMD, and safety were assessed.

Results

At Week 52, patients receiving 140mg or 70mg during the ATP showed changes from baseline/Week 24 in MMD of −4.64/−1.78 and −4.22/−1.10, respectively (Table 1). For patients switching from placebo to 140mg or 70mg, change from baseline/Week 24 in MMD was −4.50/−2.86 and −3.71/−2.18, recapitulating the numerically greater efficacy observed for 140mg vs 70mg in the DBTP. For patients increasing dose from 70mg to 140mg during the ATP, the change from Week 24 to 52 in MMD was −1.82; and −0.07 for patients decreasing dose from 140mg to 70mg. Overall, numerically greater efficacy was observed for patients receiving erenumab 140mg vs 70mg during the ATP. Safety of erenumab in the ATP was similar to that observed in the DBTP and in prior studies.

Conclusion

Over 52 weeks, erenumab provides sustained efficacy in prevention of episodic migraine and a safety profile comparable to placebo as observed in prior studies.

Table 1 (abstract P20).

Outcome measures

Outcome measures

Erenumab 140 mg (ATP)(N=424)

Erenumab 70 mg (ATP)(N=421)

MMD

 Baseline MMD, mean (SD)

8.23 (2.43)

8.34 (2.48)

 Change from baseline to Week 52

−4.64 (0.19)

−4.22 (0.22)

 Change from Week 24 to Week 52 (ATP)

−1.78 (0.19)

−1.10 (0.21)

Proportion of patients achieving >=50% reduction from baseline in MMD at Week 52, n/N1 (%)

239/368 (64.9)

225/369 (61.0)

MSMD

 Baseline MSMD, mean (SD)

3.49 (3.49)

3.60 (3.41)

 Change from baseline to Week 52

−2.00 (0.15)

−1.75 (0.14)

 Change from Week 24 to Week 52 (ATP)

−0.98 (0.13)

−0.72 (0.14)

Data are presented as mean (SE) unless specified

ATP active treatment phase, MMD monthly migraine days, MSMD monthly acute migraine-specific medication treatment days, SE standard error, SD standard deviation

N1, number of subjects with non-missing percentage change from baseline; % = n/N1 *100;

P21 Efficacy outcomes in responder and nonresponder patients with episodic migraine treated preventively with erenumab in the STRIVE study

Gregor Brössner1, Uwe Reuter2, Jo H Bonner3, David W Dodick4, Hernan Picard5, Shihua Wen6, Shannon Ritter6, Jan Klatt7, Daniel D Mikol5

1Headache Outpatient Clinic, Medizinische Universität Innsbruck, Innsbruck, Austria; 2Charité Universitätsmedizin Berlin, Berlin, Germany; 3Mercy Clinic Neurology and Headache Center, Saint Louis, MO, USA; 4Mayo Clinic, Scottsdale, AZ, USA; 5Amgen Inc., Thousand Oaks, CA, USA; 6Novartis Pharmaceuticals Corporation, East Hanover, NJ, USA; 7Novartis Pharma AG, Basel, Switzerland
Correspondence: Uwe Reuter (Uwe.Reuter@charite.de)

Background

Erenumab is a fully human anti-calcitonin gene-related peptide receptor antibody recently approved in the United States and recommended for approval in Europe as a preventive treatment for migraine. STRIVE study demonstrated safety and efficacy of erenumab (70 mg and 140 mg) in patients with episodic migraine (EM) [1]. In clinical practice, patients achieving/not achieving sufficient response to treatment are likely to continue/discontinue treatment; we sought to contextualise the actual treatment benefit among patients achieving (R subgroup) or not achieving (NR subgroup) response at the ≥50% threshold.To evaluate change from baseline in monthly migraine days (MMD), migraine-specific medication treatment days (MSMD), and Migraine Physical Function Impact Diary domain scores for everyday activity (MPFID-EA) and physical impact (MPFID-PI) in R and NR subgroups in STRIVE.

Methods

Patients (N=955; aged 18–65 years) with ≥4 and <15 migraine days per month were randomised (1:1:1) to receive subcutaneous erenumab 70 mg, 140 mg, or placebo once monthly for 6 months. The primary endpoint was change from baseline in MMD. The proportion of ≥50% Rs and change from baseline in MSMD, MPFID-EA, and MPFID-PI were prespecified secondary endpoints. All endpoints were evaluated by averaging the monthly treatment effect over Months 4, 5, and 6 of the double-blind treatment phase.

Results

In the overall study population, the odds of being a ≥50% R on erenumab were 2.13 (70 mg) and 2.81 (140 mg) compared with placebo. Baseline characteristics were similar in both subgroups (Table 1). In the R subgroup, there was a mean change of −6.0 to −6.1 MMD from a baseline of 8.2 to 8.3. For this, and for the efficacy measures MSMD, MPFID-EA, and MPFID-PI, change from baseline was 2.7- to 7.5-fold greater in Rs than in NRs and 1.4- to 1.9-fold greater in Rs than in the overall population (Table 1). Mean MPFID-EA and MPFID-PI domain scores were reduced by 7–10 points in Rs (differences of ≥3–5 points have been shown to be clinically meaningful).

Table 1 (abstract P21).

Primary and secondary outcome measures in erenumab-treated responder and nonresponder subgroups in STRIVE

Erenumab 70 mg

Responders (n=135),

baseline

Responders,

change

Non responders (n=161), baseline

Non responders change

Overall

(n=312),

baseline

Overall,

change (mean±SE)

MMD

8.3 ±2.5

−6.1 ±2.1

8.3 ±2.4

−1.1 ±2.8

8.3 ±2.5

−3.4 ±0.2

MSMD

2.9 ±3.3

−2.0 ±2.4

3.8 ±3.5

−0.4 ±2.0

3.2 ±3.4

−1.1 ±0.1

MPFID-EA

13.5 ±8.5

−9.9 ±6.8

14.1 ±8.9

−2.4 ±7.0

14.0 ±8.9

−5.8 ±0.5

MPFID-PI

11.8 ±9.3

−8.4 ±7.00

12.7 ±9.6

−1.1 ±7.7

12.6 ±9.7

−4.4 ±0.5

Erenumab 140 mg

Responders (n=159),

baseline

Responders,

change

Non responders (n=143), baseline

Non responders change

Overall

(n=318),

baseline

Overall,

Change (mean±SE)

MMD

8.2 ±2.4

−6.0 ±2.1

8.5 ±2.5

−1.4 ±2.3

8.3 ±2.5

−3.8 ±0.2

MSMD

3.2 ±3.4

−2.3 ±2.6

3.6 ±3.5

−0.9 ±1.7

3.4 ±3.5

−1.6 ±0.1

MPFID-EA

12.6 ±7.9

−8.9 ±6.8

13.6 ±8.6

−2.5 ±7.0

13.0 ±8.2

−5.8 ±0.4

MPFID-PI

11.5 ±8.3

−7.6 ±7.0

12.8 ±9.7

−1.8 ±8.00

12.0 ±9.0

−4.8 ±0.5

Data are mean ±standard deviation, except as indicated.

MMD monthly migraine days, MSMD migraine-specific medication treatment days, MPFID-EA Migraine Physical Function Impact Diary domain scores for everyday activity, MPFID-PI MPFID-physical impairment, SE standard error

Conclusion

Among patients with EM who achieved ≥50% reduction from baseline in MMD when treated with erenumab (70 mg, 43%; 140 mg, 50%), there were substantial, clinically relevant reductions in the frequency of MMD, MSMD and MPFID scores compared with NRs and the overall patient population. The odds of responding were numerically greater with the 140 mg dose than with the 70 mg dose.

P22 Efficacy of erenumab in patients with chronic migraine achieving ≥50% response: Subgroup analysis of a double-blind, randomised study

David Dolezil1, Jan Klatt2, Sunfa Cheng3, Feng Zhang3, Shihua Wen4, Shannon Ritter4, Daniel D Mikol3

1Prague Headache Center, DADO MEDICAL s.r.o., Prague, Czech Republic; 2Novartis Pharma AG, Basel, Switzerland; 3Amgen Inc., Thousand Oaks, CA, USA; 4Novartis Pharmaceuticals Corporation, East Hanover, NJ, USA
Correspondence: Jan Klatt (jan.klatt@novartis.com)

Background

Erenumab is a fully human anti-CGRP receptor antibody approved as a preventive treatment for migraine by the US FDA. A 12-week, randomised, double-blind, placebo-controlled study demonstrated efficacy of erenumab (70 mg and 140 mg) in patients with chronic migraine (CM). At Week 12, a greater proportion of patients treated with erenumab achieved ≥50% reduction in MMDs vs placebo (140 mg: 41.2%; 70 mg: 39.9%; placebo: 23.5%). Since in clinical practice, patients achieving/not achieving sufficient response to treatment are likely to continue/discontinue treatment, we sought to contextualise the actual treatment benefit among patients achieving (or not) response at the ≥50% threshold.

Methods

Patients (N=667; aged 18-65 years, inclusive) with CM (≥15 headache days/month; ≥8 migraine days/month) were randomised (2:2:3) to receive subcutaneous, once-monthly erenumab 70 mg, 140 mg or placebo. In this subgroup analysis, responders/non-responders were defined by the threshold of ≥50% reduction in MMD, and outcomes were change from baseline to Week 12 in: MMDs, migraine-specific medication treatment days (MSMD), the Headache Impact Test (HIT-6™) scores, Migraine Disability Assessment (MIDAS) scores, and Migraine-Specific Questionnaire (MSQ) scores.

Results

Mean (SD) baseline MMDs in the overall study population were 18.0 (4.6). The baseline MMDs in responders and non-responders were comparable. Greater reductions were observed in MMDs in responders (140 mg: −12.5; 70 mg: −12.2) vs non-responders (140 mg: −2.2; 70 mg: −2.6) at both erenumab doses. Similarly, both doses of erenumab showed greater improvements in terms of MSMDs, HIT-6, total MIDAS and MSQ scores in responders than the non-responders (Table 1). Across all outcome measures, change from baseline was 50-100% greater in responders than the overall population and 2-6 times (70 mg: 2-4 folds; 140 mg: 3-6 folds) greater in responders vs non-responders.

Conclusion

Among the 39.9%/41.2% of patients with CM treated with erenumab 70 mg/140 mg in this study who achieved ≥50% reduction MMD, there were substantial reductions in the frequency of migraines, the use of migraine-specific medication, and disability as assessed by the HIT-6, MIDAS and MSQ scores compared with non-responders and with the overall patient population. These findings may help to provide context for setting realistic patient expectations for response to treatment with erenumab.

Table 1 (abstract P22).

Effect of erenumab in patients achieving ≥50% response in MMDs vs non-responders and overall population

Outcome measures

Erenumab 70 mg

Erenumab 140 mg

≥50% Responders

(N=75)

Non-responders

(N=113)

Overall population

(N=188)

≥50% Responders

(N = 77)

Non-responders

(N =110)

Overall population

(N=187)

Change from baseline to Week 12

 MMD

−12.2 (2.9)

−2.6 (4.3)

−6.6 (6.1)

−12.5 (4.6)

−2.2 (4.4)

−6.5 (6.8)

 MSMD

−5.2 (5.2)

−1.8 (4.1)

−3.3 (4.9)

−6.9 (5.6)

−2.4 (3.9)

−4.3 (5.2)

 HIT-6

−10.0 (7.6)

−2.8 (5.1)

−5.7 (7.2)

−10.7 (8.0)

−1.7 (5.1)

−5.5 (7.9)

 MIDAS total score

−29.1 (45.4)

−12.6 (41.5)

−19.5 (43.8)

−35.0 (45.2)

−5.8 (38.4)

−18.1 (43.7)

 MSQ-RFP

23.0 (19.4)

6.0 (19.8)

13.0 (21.3)

25.7 (23.2)

4.8 (16.2)

13.7 (22.1)

 MSQ-RFR

29.7 (18.6)

9.4 (19.8)

17.7 (21.7)

32.7 (23.7)

8.2 (18.5)

18.7 (24.1)

 MSQ-EF

30.5 (25.4)

11.1 (26.7)

19.1 (27.8)

33.3 (27.2)

6.3 (19.9)

17.8 (26.8)

Data are expressed as mean (SD)

HIT-6 Headache Impact Test (higher score indicates worse outcome), MIDAS Migraine Disability Assessment (higher score indicates worse outcomes), MMD monthly migraine days, MSQ Migraine-Specific Quality-of-Life Questionnaire (higher scores indicate better outcomes), MSQ-RFR Migraine-Specific Quality-of-Life Questionnaire role function-restrictive, MSQ-RFP Migraine-Specific Quality-of-Life Questionnaire role function-preventive, MSQ-EF Migraine-Specific Quality-of-Life Questionnaire emotional functioning, SD standard deviation

P23 Long-term safety and tolerability of erenumab: Three-plus year results from an ongoing open-label extension study in episodic migraine

Messoud Ashina1*, Peter J. Goadsby2, Uwe Reuter3, Stephen Silberstein4, David Dodick5, Gregory A. Rippon6, Jan Klatt7, Feng Zhang6, Sunfa Cheng6, Daniel D. Mikol6

1Department of Neurology, Danish Headache Center, Rigshospitalet Glostrup, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark; 2NIHR-Wellcome Trust King’s Clinical Research Facility, King’s College London, UK; 3Department of Neurology, Charité Universitätsmedizin Berlin, Berlin, Germany; 4Jefferson Headache Center, Thomas Jefferson University, Philadelphia, PA, USA; 5Department of Neurology, Mayo Clinic, Scottsdale, AZ, USA; 6Amgen Inc., Thousand Oaks, CA, USA; 7Novartis Pharma AG, Basel, Switzerland
Correspondence: Messoud Ashina (ashina@dadlnet.dk)

Background: To assess long-term safety and tolerability of erenumab (human anti-CGRP receptor antibody) in patients with migraine after ≥3 years of treatment. Previously published 3-month placebo-controlled and 1-year open-label clinical trial data have provided information on efficacy and safety of erenumab.

Methods: Interim analysis from an ongoing 5-year open-label extension (OLE) after all patients completed ≥3 years in the OLE or discontinued the study. Following a 12-week double-blind, placebo-controlled study of erenumab (7 mg, 21 mg, or 70 mg) in adults with episodic migraine, patients could enroll in the OLE, initially receiving erenumab 70 mg monthly. A protocol amendment increased the dosage to 140 mg monthly to assess long-term safety of the higher dose. Safety and tolerability were assessed by monitoring adverse events (AEs), electrocardiograms, laboratory assessments, and vital signs.

Results: Of 383 patients enrolled in the OLE, at data cutoff 235 (61.3%) remained in study, all received 140-mg for ≥1 year. Median (Q1, Q3) exposure (70 mg or 140 mg) for all patients enrolled was 3.2 (1.3, 3.4) years. For those continuing in the study, exposure ranged from 3.0 to 3.9 years. Exposure-adjusted AE rate was 132.0/100-patient-years (142.0 prior to and 128.1 following dosage increase). Most frequent AEs (≥4.0/100-patient-years) were viral upper respiratory tract infection, upper respiratory tract infection, sinusitis, influenza, and back pain. Exposure-adjusted serious AE (SAE) rates were 4.2/100-patient-years. One death, which occurred during the first year of the OLE (prior to protocol amendment), was previously reported and was confounded by comorbidities. There was no increase in cardiovascular events over time and no meaningful changes in systolic/diastolic blood pressure or heart rate up to 3.3-years’ follow-up.

Conclusions: In this first, and so far only, long-term study of a CGRP-pathway antibody, erenumab was found to be safe and well tolerated with a spectrum and rate of AEs consistent with shorter-term placebo-controlled studies and no dose-dependent AEs.

P24 Assessment of the long-term safety and efficacy of erenumab during open-label treatment of subjects with chronic migraine

Stewart Tepper1, Messoud Ashina2, Uwe Reuter3, Jan L Brandes4, David Doležil5, Stephen Silberstein6, Paul Winner7, Feng Zhang8, Sunfa Cheng9, Daniel Mikol9

1Geisel School of Medicine at Dartmouth, Hanover, NH, USA; 2Department of Neurology, Danish Headache Center, Rigshospitalet Glostrup, University of Copenhagen, Copenhagen, Denmark; 3Department of Neurology, Charité Universitätsmedizin Berlin, Berlin, Germany; 4Nashville Neuroscience Group and Vanderbilt University Department of Neurology, Nashville, TN, USA; 5DADO MEDICAL sro, Prague Headache Center, Prague, Czech Republic; 6Jefferson Headache Center, Thomas Jefferson University, Philadelphia, PA, USA; 7Premiere Research Institute, Nova Southeastern University, West Palm Beach, FL, USA; 8Global Bio statistical Science, Amgen Inc, Thousand Oaks, CA, USA; 9Global Development, Amgen Inc, Thousand Oaks, CA, USA
Correspondence: Uwe Reuter (Uwe.Reuter@charite.de)

Background

Erenumab, fully human antibody, has demonstrated efficacy and safety in migraine prevention studies (NCT02066415, NCT02456740). Chronic migraine (CM), the most prevalent type of headache in tertiary care, may require long-term preventive therapy. Here, we report the results from a 1-year open-label extension (OLE) study (NCT02174861) of patients completing a 12-week, placebo-controlled study of erenumab for CM.

Methods

In the parent study, CM subjects were randomised (3:2:2) to placebo, erenumab 70 mg, and 140 mg for the 12-week double-blind treatment phase (DBTP), following which eligible subjects could enrol in the 52-week OLE, initially receiving erenumab 70 mg monthly. A protocol amendment increased dose to 140-mg for subjects who had not yet completed Week-28 visit, to assess long-term safety (primary endpoint) of higher dose. Safety was assessed by monitoring adverse events (AEs), electrocardiograms (ECG), laboratory assessments, and vital signs. Secondary endpoints were change from baseline to Week 52 in monthly migraine days (MMD), monthly acute migraine-specific medication days (MSMD), monthly cumulative hours of headache, and proportion of patients achieving ≥50% reduction in MMD. A post-hoc analysis on efficacy data, based on last dose received was conducted for subjects who completed the OLE treatment.

Results

Of the 609 subjects who were enrolled to OLE study 451 (74.1%) completed the study. Among these, 350 subjects received erenumab 70 mg; 60 received 140 mg; and 199 increased their dose from 70 mg to 140 mg by Week 28. Most subjects were women (83.6%); mean (range) age of patients was 42.5 (18–66) years. Overall, 398/609 (65.4%) subjects reported at least one AE during the OLE for an exposure-adjusted incidence rate of 126.3/100 subject-years. Most frequent AEs (>2.0/100-subject-years) were viral upper respiratory tract infection, upper respiratory tract infection, sinusitis, arthralgia, and migraine (Table 1). Exposure-adjusted treatment-related AE and SAE rates were 20.5 and 3.8/100-subject-years, respectively. There were no clinically meaningful changes from baseline in laboratory values, vital signs, ECG findings, blood pressure or heart rate at any post baseline time point, which appears to be consistent with the DBTP of the parent study. Sustained efficacy was noted for both erenumab doses. Based on the last dose received, a numerically greater benefit in terms of efficacy was observed with erenumab 140 mg compared with the 70 mg dose at both Weeks 40 and 52 in completers (Table 2).

Conclusions

Long-term safety data in CM was consistent with the known safety profile of erenumab. Efficacy was sustained throughout the study.

Table 1 (abstract P24).

Data on primary and secondary outcomes Safety: Exposure-adjusted Subject Incidence Rates of Treatment-emergent Adverse Events Occurring in > 2/100 subject-years for total erenumab (Safety Analysis Set)

Adverse event

Erenumab 70 mg/140 mg (N=609), n (%) / e [r]

Viral upper respiratory tract infection

96 (15.8) / 586.0 [16.4]

Upper respiratory tract infection

45 (7.4) / 624.5 [7.2]

Sinusitis

44 (7.2) / 620.4 [7.1]

Arthralgia

27 (4.4) / 636.7 [4.2]

Migraine

26 (4.3) / 638.5 [4.1]

% = n / N x 100; N = number of subjects exposed to erenumab in OLE; n = number of subjects reporting at least 1 occurrence of an adverse event; r = exposure-adjusted subject rate per 100 subject-years (n / e x 100)

e = sum across all subjects, the total time at risk in the study in years

Table 2 (abstract P24).

Efficacy ─ 52-week OLE completers

Outcome

Time-point

Erenumab 70-mg (OLE last dose received) (N=266)

Erenumab 140-mg (OLE last dose received) (N=203)

Change from baseline in MMD, mean (95% CI)

Baseline

17.92 (17.38, 18.45)

17.79 (17.16, 18.43)

Week 40

-7.81 (-8.64, -6.97 ) (n=228)

-9.96 (-10.91, -9.00 ) (n=187)

Week 52

-8.49 (-9.35, -7.63) (n=214)

-10.48 (-11.52, -9.43) (n=165)

Change from baseline in MSMD, mean (95% CI)

Baseline

10.22 (9.39, 11.06)

8.32 (7.28, 9.35)

Week 40

-4.68 (-5.33, -4.04) (n=228)

-4.59 (-5.32, -3.85) (n=187)

Week 52

-5.05 (-5.76, -4.34) (n=214)

-4.97 (-5.81, -4.13) (n=165)

Change from baseline in MSMD in subjects taking MSM, mean (95% CI)

Baseline

12.40 (11.67, 13.13)

11.35 (10.30, 12.40)

Week 40

-5.63 (-6.33, -4.93)

-6.15 (-7.00, -5.30)

Week 52

-6.16 (-6.93, -5.40)

-6.71 (-7.67, -5.75)

≥50% responder rate, N1(%)

Week 40

108 (47.4) (n=228)

126 (67.4) (n=187)

Week 52

114 (53.3) (n=214)

111 (67.3) (n=165)

CI confidence interval, OLE open label extension, MMD monthly migraine days, MSMD migraine-specific medication treatment days, N number of subjects in the analysis set, N1 number of responders at corresponding visit, n number of subjects with observed data

P25 Immunogenicity findings from Phase 3 galcanezumab trials in patients with episodic or chronic migraine

James M. Martinez, Sandra Garce, Greg Anglin, Michael Hodsdon, William Kielbasa, Brian A Moser, Eric Pearlman

Eli Lilly and Company, Indianapolis, IN, USA
Correspondence: James M. Martinez (martinez_james_michael@lilly.com)

Background: To evaluate the immunogenicity profile of galcanezumab, a humanized monoclonal antibody that selectively binds calcitonin gene-related peptide (CGRP) and inhibits its activity, in patients with episodic or chronic migraine.

Methods: The Phase 3 migraine program for galcanezumab consisted of 4 studies: the 6-month double-blind (DB), placebo (PBO)-controlled (DB/PC) EVOLVE-1 and EVOLVE-2 studies in episodic migraine, the 3-month DB/PC REGAIN study in chronic migraine (with optional 9-month open-label [OL] extension), and the 12-month OL Study CGAJ in chronic and episodic migraine. Immunogenicity was analyzed using data from the baseline and DB phases of EVOLVE-1, EVOLVE-2, and REGAIN, and from the baseline and OL phases of Study CGAJ. Analyses assessed the incidence of antidrug antibodies (ADA) at baseline, treatment-emergent ADA (TE ADA) and neutralizing ADA (NAb), as well as the time to first occurrence of TE ADA. The effect of ADA titer on both pharmacokinetics (PK) and pharmacodynamics (PD) was assessed from measurements of serum galcanezumab concentrations and plasma CGRP concentrations, respectively. The relationship between ADA status and efficacy was explored using average change in monthly migraine headache day (MHD) in galcanezumab-treated patients. Safety analyses assessed the potential relationship between TE ADA and hypersensitivity events or adverse events (AEs) related to injection sites.

Results: The percentage of patients with ADA present at baseline ranged from 6.20% - 11.21% in the galcanezumab group and 5.92% - 8.35% in the PBO group across the 4 studies. The incidence of TE ADA during the specified treatment periods across the 4 studies ranged from 2.57% - 12.40% in the galcanezumab group and 0.45% - 1.66% in the PBO group. The majority of TE ADA in galcanezumab-treated patients were detected approximately 3-6 months after the first dose of study drug. Overall, the observed ADA titer in patients did not impact galcanezumab concentrations, CGRP concentrations, or the efficacy profile of galcanezumab. Hypersensitivity events and AEs related to injection sites were examined in detail, and there was no evidence that such events were mediated by TE ADA.

Conclusion: These analyses from the Phase 3 migraine program characterize the immunogenicity profile of galcanezumab treatment in patients with episodic and chronic migraine. In these analyses, immunogenicity did not impact galcanezumab concentrations, CGRP concentrations, or the efficacy profile of galcanezumab. Additionally, TE ADA did not appear to mediate the occurrence of hypersensitivity events and AEs related to injection sites.

Ethics approval and consent to participate

Each study has been approved by the relevant institutional Ethics Board. Informed consent to publish has been obtained from all patients who participated in the above studies

Trial Registration: NCT02614183 (EVOLVE-1); NCT02614196 (EVOLVE-2); NCT02614261 (REGAIN); NCT02614287 (Study CGAJ).

P26 Lack of visual paired associative short-term plasticity in migraine patients between attacks

Gianluca Coppola1, Chiara Abagnale1, Federico Ranieri2, Clarissa Elizabeth Centurioni1, Gabriella Musumeci2, Fioravante Capone2, Giovanni Di Pino2, Vincenzo Parisi3, Vincenzo Di Lazzaro2, Francesco Pierelli1,4

1Sapienza University of Rome Polo Pontino, Department of medico-surgical sciences and biotechnologies, Latina, Italy; 2Research Unit of Neurology, Neurophysiology, Neurobiology, Department of Medicine, Università Campus Bio-Medico, Rome, Italy; 3G.B. Bietti Foundation IRCCS, Research Unit of Neurophysiology of Vision and Neurophthalmology, Rome, Italy; 4IRCCS Neuromed, Pozzilli (IS), Italy
Correspondence: Gianluca Coppola (gianluca.coppola@gmail.com)

Background

In healthy controls (HCs), we recently observed that the same time-dependent paired-associative plasticity rules found within the sensorimotor system are valid for the visual system. With the same paradigm of stimulation, here, we have verified whether dysfunctioning associative plasticity might characterize the visual system of episodic migraine without aura (MO) patients, where abnormalities in both inhibitory and excitatory paired-associative sensorimotor plasticity have been previously observed in between attacks (1).

Materials and methods

In 15 HCs and in 12 MO patients between attacks, we performed a visual paired associative stimulation (vPAS) protocol by coupling 90 black-and-white checkerboard pattern reversals with low-frequency TMS pulses over the occipital cortex at 2 interstimulus intervals in separate sessions by subtracting or adding 25ms to the visual evoked potential (VEP) P100 latency. We recorded VEPs (600 sweeps) before, after, and 10-min later each vPAS session. VEPs were partitioned in 6 blocks of 100 sweeps. We analysed VEP N1-P1 first block amplitude and delayed habituation.

Results

While vPAS-25 significantly enhanced and vPAS+25 reduced VEP amplitude habituation in HCs, they both did not significantly change VEP amplitude habituation in MO between attacks.

Conclusions

We provide for the first-time evidence for lack of excitability depressing and enhancing short-term associative plasticity mechanisms within the visual system in migraine between attacks.

References

1. Pierelli F, Iacovelli E, Bracaglia M, Serrao M, Coppola G. Abnormal sensorimotor plasticity in migraine without aura patients. Pain. 2013 Sep;154(9):1738-42.

P27 Effect of OnabotulinumtoxinA on the Frequency and Impact of Headaches in Patients with Chronic Migraine with or without a History of Acute Pain Medication Overuse: Results of the COMPEL Study

Stewart J. Tepper1* Maria-Carmen Wilson2 John F. Rothrock3 Amelia Orejudos4 Aubrey Manack Adams4 Andrew M. Blumenfeld5

1Neurology Department, Headache Center, Dartmouth-Hitchcock Medical Center, Lebanon, NH, 03748, USA; 2Ochsner Health System, Covington, LA, 70433, USA; 3Department of Neurology, George Washington School of Medicine, Washington, DC 20037, USA; 4Allergan plc, Irvine, CA, 92612, USA; 5Headache Center of Southern California, The Neurology Center, Carlsbad, CA, 92024, USA
Correspondence: Stewart J. Tepper (Stewart.J.Tepper@Dartmouth.edu)

Background: Overuse of acute pain medication by people with chronic migraine (CM) can increase the frequency and intensity of headache. This subanalysis of COMPEL Study data evaluates the relative effect of onabotulinumtoxinA on the frequency and impact of headaches in patients with CM based on history of acute pain medication overuse (MO).

Methods: The 108-wk, multicenter, open-label COMPEL Study (ClinicalTrials.gov, NCT01516892) enrolled adults with CM receiving onabotulinumtoxinA 155 U for 9 treatments. Patients completed a daily diary recording headache days for 28 days before the baseline visit and at intervals following treatments 2, 5, 7, and 9. A 6-item Headache Impact Test Questionnaire (HIT-6) was completed at every administration visit. History of MO was defined as use of acute pain medication ≥ 2 times/week in any week with diary data on ≥5 days during the 4-week screening period. Efficacy variables included mean change from baseline in overall number of headache days, number of moderate/severe headache days, and HIT-6 total score at weeks 60 (after 5 treatments) and 108 (after 9 treatments). Observed data are reported. The study received ethical approval from the Institutional Review Board or Independent Ethics Committee at each site.

Results: 716 patients were enrolled, 715 of whom had ≥ 1 efficacy analysis and comprised the intention-to-treat (ITT) population: 456 (63.7%) ITT patients had a history of acute MO, 259 (36.3%) did not. Throughout the study period onabotulinumtoxinA treatment showed similar efficacy in both groups, including similar reductions in headache frequency and number of moderate to severe headaches (Table 1). At week 60, 53.3% of patients with a history of MO had a ≥50% reduction in headache days from baseline, as did 55.5% of patients with no history of MO. Additional improvement was seen at week 108: ≥50% reductions were documented in 58.7% of patients with a history of MO and 69.1% of those without. Mean change from baseline (SD) in HIT-6 scores were similar for patients with and without a history of MO at week 60 (−6.8 [6.7] and –6.7 [6.2], respectively) and week 108 (–7.0 [7.19] and –7.2 [7.3], respectively).

Conclusions: These results suggest that onabotulinumtoxinA has similar efficacy in patients with or without a history of medication overuse, and that reductions in headache frequency are sustained over time.

Table 1 (abstract P27).

Mean change from baseline for headache day frequency and number of moderate/severe headaches in onabotulinumtoxinA-treated patients with and without a history of medication overuse

Variable

Medication Overuse (n=456)

No Medication Overuse (n=259)

Headache day frequency, d, mean (SD)

 Week 60

–10.1 (6.8)

–10.3 (7.6)

 Week 108

–11.4 (7.2)

–12.5 (7.5)

Moderate/severe headache days, d, mean (SD)

 Week 60

–8.8 (6.1)

–8.7 (6.2)

 Week 108

–10.1 (7.0)

–10.0 (7.2)

P28 Body Mass Index and its relationship with disability, severity, duration and frequency of headaches in female migraine patients

Mansouerh Togha, Faraidoon Haghdoost, Faezeh Khorsha, Soodeh Razeghi Jahromi, Zeinab Ghorbani

Headache Department, Iranian Center of neurological Research, Tehran University of Medical Sciences, Tehran, Iran
Correspondence: Faraidoon Haghdoost (faraidoon haghdoost)

Objectives: Migraine is a highly prevalent and debilitating neurological disorder. It is most common between the ages 20 and 45, with women predominantly. Several evidences have shown that increased Body Mass Index (BMI) is associated with increased frequency and severity of migraine headaches. The aims of the current study were to evaluate the relation of BMI with disability, severity, frequency and duration of headaches in female migraine patients.

Methods: This cross-sectional study evaluated the characteristics of migraine attacks and also MIDAS (Migraine Disability Assessment) score in female migrainures. The diagnosis of migraine was based on ICHD-3 beta criteria. The data on migraine attack characteristics; duration of each attack, frequency, and severity; was recorded on the patients’ diary form that designed by the senior investigator. Visual Analog Scale (VAS), a linear measure of zero without headache to 10 the severest attack, was used for headache severity. Also validated and translated Iranian version of MIDAS questionnaire, a valid and reliable short questionnaire for assessment of headache related disability, was fulfilled by the patients. Height and weight in order to calculate the BMI were measured. BMI was calculated as the weight in kilograms divided by the height in meters squared. Pearson correlation coefficient was used to assess the correlations. Informed consent to publish has been obtained from this patient.

Results: In the current study, 170 female migraine patients with the Mean (±SD) age of 34.03±8.03 were enrolled. Of the participants, 67.1% were married, 62.9% were educated at university level and 52.1% declared the association of headaches with menstruation. Mean (±SD) BMI, total MIDAS score, VAS and frequency of headaches were 25.40±4.30, 12.23±6.94, 5.82±2.15 and 9.94±0.64 respectively. BMI was significantly correlated with MIDAS total score (r=0.594, P<0.001), VAS (r=0.516, P<0.001) and frequency of headaches (r=0.500, P<0.001). The correlations remained significant after adjustment for age. No significant correlation was found between BMI and duration of each migraine attacks (r=0.093, P=0.229).

Conclusion: This study revealed an association between body mass index and disability, severity and frequency of headaches in female migraine patients. On the other hand, no association was found between headache durations and BMI.

Key words: Body mass index, Disability, Headache duration, Headache frequency, Migraine, Visual Analog Scale

P29 Effect of propranolol in a non-invasive human model of trigeminovascular activation

Eloísa Rubio-Beltran, Rianne M. Schoon, Jeffrey vd Berg, Jorie Versmissen, A.H. Jan Danser, Anton H. van den Meiracker, Antoinette MaassenVanDenBrink

Division of Pharmacology, Dept. of Internal Medicine, Erasmus University Medical Center, Rotterdam, The Netherlands
Correspondence: Eloísa Rubio-Beltran (a.rubiobeltran@erasmusmc.nl)

Propranolol is a β-adrenoceptor antagonist that is used for the prophylactic treatment of migraine since many years. However, the mechanism of action of propranolol in preventing migraine attacks has not yet been elucidated. Both a central action, as well as a vascular action (preventing β adrenoceptor‑mediated vasodilatation) have been suggested. In our study, we set out to assess whether propranolol has an inhibitory effect on the trigeminovascular system in our human forehead perfusion model.

We investigated the effect of propranolol (80 mg, 90 min after oral administration, corresponding to the Tmax) on the rise of dermal blood flow (DBF) of the forehead skin (innervated by the trigeminal nerve) by capsaicin application (0.6 mg/ml) and electrical stimulation(0.2-1.0 mA) before and after placebo (grapefruit juice) and propranolol (oral solution with tangerine taste, diluted in grapefruit juice) in a randomized, double-blind, placebo controlled cross-over study, including healthy males (n=11, age±SD: 28±10 yrs) and females (n=11, 25±3 yrs). In addition to the skin dermal blood flow, systolic (SBP) and diastolic blood pressure (DBP) and heart rate (HR) were recorded. As studies were performed in a double-blind manner, the investigator performing the blood flow studies was also blinded for the blood pressure and HR measurements. The study was approved by Medical Ethics Committee from Erasmus Medical Center (MEC 2016-196).

Preliminary results show a significant decrease in SBP (mean±SEM: 109±1 mm Hg vs. 105±2 mm Hg; p<0.001), DBP (mean±SEM: 63±1 mm Hg vs. 61±1 mm Hg; p<0.05) and HR (mean±SEM: 65±2 bpm vs. 58±2 bpm; p<0.001) after propranolol, but not after placebo (p>0.05). Furthermore, DBF responses to capsaicin (mean±SEM: 512.72±33.14 A.U.) were attenuated after propranolol (mean±SEM: 465.67±35.12 A.U., p<0.05) but no after placebo (mean±SEM: 504.8±40.46 A.U.). DBF responses to electrical stimulation were not modified by either placebo or propranolol. When sexes were analyzed separately, propranolol had no effect on the DBF responses to capsaicin in females (mean±SEM: 544.4±32.27 A.U. vs. 535.7±33.22 A.U.; p>0.05), whereas it significantly attenuated the response to capsaicin in males (mean±SEM: 472±54.57 A.U. vs. 394.7±51.09 A.U.; p<0.05).

In conclusion, propranolol 80 mg inhibits the capsaicin-induced increases in DBF, suggesting a modulation of the trigeminovascular system. Moreover, this effect seems to be independent from its direct cardiovascular effects, and was different between sexes, as significant changes were only observed in male subjects. More studies are required to elucidate the mechanism behind this modulation of the trigeminovascular system.

P30 Effects of subthreshold single pulse Transcranial Magnetic Stimulation (sTMS) on activity of hypothalamic A11 region

J. Lloyd1, M Jones2,3, S McMahon2, R Abuukar Abdullahi1,4, AP Andreou1,4

1Headache Research-Wolfson CARD, King’s College London, London, UK; 2Neurorestoration Department, Wolfson Centre for Age-Related Diseases, King’s College London, London, UK; 3Zenith Neuroteck Ltd, London, UK; 4Headache Centre, Guy’s and St Thomas’s NHS Trust, King’s Health Partners, London, UK
Correspondence: J. Lloyd (k1633995@kcl.ac.uk)

Objectives

Migraine pathophysiology has been shown to involve altered activity of hypothalamic region. The dopaminergic A11 nucleus appears to be of particular interest. Single-pulse transcranial magnetic stimulation (sTMS) is a non-invasive neuromodulation technique shown to be a successful acute preventative treatment for migraine patients. sTMS uses a single magnetic pulse of 170 μs duration to induce weak electrical currents to the cortex via electromagnetic induction. The aim of this experiment was to investigate if sTMS could affect the neuronal activity of dopaminergic cells in the A11 nucleus.

Methods

All procedures were performed under a UK Home Office Licence in accordance to the 1986 Animal (Scientific Procedures) Act in anaesthetised male adult Sprague-Dawley rats. Tungsten microelectrodes were used for extracellular recordings from the A11 nucleus. Spontaneous neuronal activity of the A11 nucleus was recorded following induction of a cortical spreading depression (CSD) induced by pinprick at the occipital cortex, or following application of sTMS pulses (~1.1T) applied to the visual cortex from a custom made sTMS coil (11 mm diameter; rise time 170 us). In the latter group, an sTMS pulse was applied every 10 min. Post-hoc spike analysis was used to isolate dopaminergic firing and data were compared to baseline spontaneous firing.

Results

A single 600 V sTMS pulse was found to have a significant effect on spontaneous dopaminergic firing of the A11 region. This effect was seen within a minute of application of the pulse (t (17) = 3.129, p<.05). In 50% of the cells recorded sTMS facilitated spontaneous firing and in the remaining it inhibited neuronal firing. In addition, repeating the sTMS pulse was found to have a cumulative effect on the firing of the A11 nucleus.

Likewise in the first minute following application of Cortical Spreading Depression there was a reduction in A11 nucleus activity (t (6) = 3.021, p<.5), which returned to baseline within 10 min.

Conclusions

CSD, as a vast cortical event, can alter the spontaneous neuronal firing in the A11 nucleus, suggesting at least an indirect cortical-subcortical networks communication. A single TMS pulse, as a cortical treatment, can alter the as well the firing rate of the dopaminergic A11 nucleus, suggesting that such a treatment could indirectly influence hypothalamic regions believed to be involved in the triggering of a migraine attack. Such alterations in the hypothalamic region be sTMS may be involved in the preventive mechanism of sTMS in migraine.

P31 Intracranial pressure: a comparison of the non-invasive HeadSense monitor vs. lumbar pressure measurement

Jeppe Hvedstrup1, Aleksandra Radojicic2,3, Walid Moudrou4, Martin W Herklots5, Anton Wert6, Manfred Holzgraefe6, Mark Obermann6,7, Guus G Schoonman5, Rigmor H Jensen2, Henrik W Schytz1

1Headache Diagnostic Laboratory, Danish Headache Center and Department of Neurology, Rigshospitalet-Glostrup, faculty of health and sciences, university of Copenhagen, Denmark; 2Danish Headache Center and Department of Neurology, Rigshospitalet-Glostrup, Faculty of Health and Medical Sciences, University of Copenhagen, Denmark; 3Neurology Clinic, Clinical Center of Serbia, Belgrade, Serbia; 4Department of Neurology, Maastad Hospital, Rotterdam, The Netherlands 5Department of Neurology, Elsabeth-Tweesteden Hospital, Tilburg, The Netherlands 6Center of Neurology, Asklepios Hospitals Schildautal, Seesen, Germany; 7Department of Neurology, university Hospital Essen, University of Duisburg-Essen, Germany
Correspondence: Jeppe Hvedstrup (jeppe.hvedstrup.mann@regionh.dk)

Background: Intracranial pressure (ICP) is essential in monitoring and as a tool to diagnose intracranial hypertension. A method for measuring non-invasive ICP (nICP) has been developed and showed promising results in intensive care patients when comparing the method to invasive ICP monitoring. The nICP uses mixed transcranial acoustic (TCA) signals generated via an acoustic signal transmitted through the cranium and detected in the opposite ear using an acoustic sensor.

Objective: To compare nICP with conventional lumbar puncture opening pressure (LP-ICP) in patients investigated at neurologic departments.

Hypothesis: nICP values using mixed TCA method correlate with LP-ICP values.

Design: A multicenter study of patients undergoing lumbar puncture for diagnostic purpose at neurological departments were included. Each patient underwent LP-ICP and nICP with HeadSense© equipment. The HeadSense nICP measurements were conducted with the patients’ head in a 30-degree tilt and in supine position right before and after the lumbar puncture. All the collectors of the mixed TCA nICP data were blinded to the LP-ICP data. The primary endpoint was the correlation between the nICP in the supine position before the lumbar puncture and the LP-ICP measurement.

Results: No correlation between the supine nICP before the lumbar puncture and the LP-ICP was found (r = -0.211 & P = 0.358). The nICP in 30-degree head-tilt correlated with the supine nICP before the lumbar puncture (r = 0.830 & P < 0.01). The supine nICP before and after the lumbar puncture did not correlate (r =0.056, P = 0.831). Furthermore, nICP showed values below 15 mmHg in the three patients with LP-ICP over 20 mmHg.

Conclusion: This is the first study to compare nICP using mixed TCA signals with LP-ICP in a neurological department setting. The nICP signals were not reliable and high ICP values were missed with the new nICP method. Thus, further development of the mixed TCA nICP is warranted.

P32 Triptans use in post-dural puncture headache

Federico Mainardi1, Giorgio Zanchin2, Carlo Lisotto3, Ferdinando Maggioni2

1Headache Centre, Neurological Division, SS Giovanni e Paolo Hospital, Venice, Italy; 2Headache Centre, Department of Neurosciences, Padua University, Padua, Italy; 3Headache Centre, San Vito al Tagliamento hospital, San Vito al Tagliamento, Italy
Correspondence: Federico Mainardi (fmainardi@iol.it)

Introduction: Post-dural puncture headache (PDH) is classified in chapter 7 - Headache attributed to non-vascular disorders as a subtype of Headache attributed to low cerebrospinal fluid pressure (code 7.2) in the current International Classification of Headache Disorders 3 ed (ICHD 3) [1]. The occurrence of PDH widely ranges from 1 to 40%, being linked to variable as needle gauge and orientation and operator skill level [2]. Accepted standard treatment for PDH is lacking. Albeit maintenance of the supine position as long as PDH lasts and mild analgesics when necessary are usually sufficient to control the pain, some patients require additional strategies. The use of triptans in treating PDH has been proposed without conclusive evidence of efficacy.

Material and methods: We reviewed the literature on the topic with the aim to assess the efficacy of triptans in the acute and prophylactic treatment of PDH. Triptans were used as abortive therapy in six papers [3-8], whereas two papers investigated their efficacy as a preventive option [9,10].

Results: Acute treatment: in a series of 30 patients, Zolmitritpan 2.5 mg resulted significatively superior versus placebo in relieving PDH at 6 (z:60%, p:36%;),12 (z:70%, p:46%) and 24 hours (z:86%, p:63%) [3]. Sumatriptan 6 mg sc was effective in 9 up to 14 patients who developed PLH [4-8]; in those with a positive response, headache recurred within 24 h in three cases. Prophylactic treatment: Frovatriptan 2.5 mg/die for 5 days was administrated in 50 patients after lumbar puncture; among them, a mild isolate headache episode was referred in five cases in the first day of treatment, while a persistent headache for the first 2 days was reported by two patients. In the second study, sumatriptan 25 mg 4 doses/day resulted superior to placebo in preventing the occurrence of PSD in the next 48 h from the induction of spinal anesthesia [10].

Conclusion: Albeit no definitive data are available, triptans appear to be more useful in the prophylaxis of PDH than in its acute treatment. More studies on the topic are needed.

References

1. Headache Classification Committee of the International Headache Society (IHS). The International Classification of Headache Disorders, 3rd edition. Cephalalgia 2018; 38: 1-211.

2. Basurto Ona X, Osorio D, Bonfill Cosp X. Drug therapy for treating post-dural puncture headache. Cochrane Database of Systematic Reviews 2015, Issue 7. Art. No.: CD007887. DOI:10.1002/14651858.CD007887.pub3.

3. Riaz A, Rao ASK, Sharif A. Zolmitriptan is effective in relieving post-dural puncture headache in young parturients. Anesth Pain & Intensive Care 2014; 18: 147-151.

4. Carp H, Singh PJ, Vadhera R, Jayaram A. Effects of the Serotonin-Receptor Agonist Sumatriptan on Postdural Puncture Headache: Report of Six Cases. Anesth Analg 1994; 79: 180-182.

5. Connelly NR, Parker RK, Rahimi A, Gibson CS. Sumatriptan in Patients with Postdural Pouncture Headache. Headache 2000; 40: 316-319.

6. Hodgson C, Roiberg-Henry A. The use of sumatriptan in the treatment of postdural headache. Anaesthesia 1997; 52: 808.

7. Lhuissier C, Mercier FJ, Dounas M, Benhamou D. Sumatriptan: an alternative to epidural blood patch? Anaesthesia 1996; 51: 1078.

8. Sprigge JS. The use of sumatriptan in the treatment of postdural puncture headache after accidental lumbar puncture complicated a blood patch procedure. Anaesthesia 1999; 54: 95-86.

9. Bussone G, Tullo V, d’Onofrio F, Petretta V, Curone M, Frediani F, Tonini C, Omboni S. Frovatriptan for the prevention of postdural puncture headache. Cephalalgia 2007; 27: 809-813.

10. Ghanei M, Rahmanian K, Jahromi AS, Sahraei R. Effect of Sumatriptan on Postdural Puncture Headache. Biomedical & Pharmacology Journal 2016; 9: 735-738.

P33 A case of autoimmune encephalitis preceded by posterior reversible encephalopathy syndrome and reversible cerebral vasoconstriction syndrome

Jaeho Kim, Mi Ji Lee

Department of Neurology, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Republic of Korea
Correspondence: Mi Ji Lee (mirony.lee@gmail.com)

Background & Significance: Posterior reversible encephalopathy syndrome (PRES) is typically characterized by headache, altered mental functioning, seizures, and visual loss associated with imaging findings of bilateral subcortical and cortical edema with a predominantly posterior distribution. We report a case of patient of Autoimmune encephalitis preceded by PRES and reversible cerebral vasoconstriction syndrome (RCVS).

Case: A 31-year-old woman presented with thunderclap headache after 1 week of paroxetine and alprazolam treatment due to new onset psychiatric symptoms. Brain MRI showed concomitant PRES and RCVS. After 1 week of admission, she developed repeated generalized tonic-clonic seizures. In addition to epileptic seizures, she had memory impairment, mood fluctuation, dullness, and psychiatric symptoms. Follow up brain MRI showed a marked improvement of PRES and RCVS, but persistent hyperintensities and swelling in the bilateral medial temporal areas. The patient underwent CSF autoimmune antibody test, which revealed anti-LGI1 antibody. Finally, she was diagnosed with LGI1 autoimmune encephalitis. After treated with steroid and antiepileptic drug, her symptoms have been improved, and she returned to work.

Conclusions: Autoimmune encephalitis can present with PRES and RCVS. Persistent encephalopathic symptoms, imaging abnormalities in medial temporal lobes, and autoantibody testing can serve as clues suggesting autoimmune encephalitis. Appropriate treatment such as immunotherapy and/or antiepileptic treatment can lead to excellent neurological recovery.

Consent for publication: Informed consent to publish has been obtained from this patient

Fig. 1 (abstract P33).

Brain MR findings show PRES (short arrows) and persistent high signal change in bilateral hippocampi and progressive atrophy in the right medial temporal structures (long arrows).

P34 New insights in post-traumatic cluster headache through a cohort study

Lou Grangeon1,2, Emer O’Connor1, Layan Akijian1, Thanh Mai Pham Ngoc3, Manjit Matharu1

1Headache Group, Institute of Neurology and The National Hospital for Neurology and Neurosurgery, Queen Square, London; 2Department of Neurology, Rouen University Hospital, 76031, Rouen, France; 3Mathematics Institute of Orsay, Paris Sud University, CNRS, 91405 Orsay, France
Correspondence: Manjit Matharu (m.matharu@uclmail.net)

Background: Very few cases of cluster headache (CH), one of the most painful conditions known to humans, have been reported following head injury, leading to loss of work capacity and significant fiscal consequences. This study attempts to investigate the characteristics of post-traumatic CH (PTCH) and to compare its severity to primary CH

Methods: A retrospective cohort study was conducted in a tertiary headache centre at the National Hospital for Neurology and Neurosurgery (Queen Square, London, UK) between 2007 and 2017. All consecutive patients diagnosed with chronic or episodic CH that developed within 7 days of head trauma were assessed. A control cohort of 553 CH patients

included all patients who attended the headache clinic during the same period and who fulfilled the criteria for primary CH without any previous history of head trauma. Demographics of PTCH patients, characteristics of PTCH attack, concomitant headache, response to treatment and cause and mechanism of head trauma. Multivariate analysis was performed using logistic regression and resorting to the powerful Elastic net algorithm for variable selection.

Results: 26 PTCH patients were identified. Approximately 84% were diagnosed with chronic CH and 55% responded poorly to preventive treatment. Five patients suffered from concomitant chronic migraine, four of whom developed it after head trauma as well. The CH attacks were ipsilateral to the injury in all patients. According to multivariate analyses, significant association was found between PTCH and familial history of CH (OR 2.32; 95% CI, 1.4 - 3.8), chronic form (OR 1.53; 95% CI, 1.0 – 2.2), parietal location (OR 3.9; 95% CI,

2.5 – 6.1), and presence of eye oedema during attacks (OR 1.53, 95% CI, 1.0 – 2.2). PTCH patients were at a higher risk of being intractable to acute (OR 2.1, 95% CI, 1.0 – 4.6) and preventive (OR 4.9, 95% CI, 3.0 – 8.2) treatment and of suffering from associated chronic migraine (OR 5.59; 95% CI, 3.0 - 10.4).

Conclusion: This largest series of PTCH defines it as a unique entity with specific evolutive profile. After comparison to a large cohort of primary CH, we demonstrated that PTCH is more severe with more chronic forms, marked autonomic features, higher risk of intractability to treatment and associated chronic migraine in patients with family history of CH. This highlights the requirement for individualized care.

Fig. 1 (abstract P34).

Estimate odds-ratio of each selected item entered into the logistic regression model (n=16)

Table 1 (abstract P34).

Characteristics of PTCH according to multivariate logistic regression model

Predictive factor

OR

95% CI

p value

Family History of CH

2.32

1.41 - 3.86

0.001

Chronic CH

1.53

1.04 - 2.26

0.032

Parietal location

3.96

2.57 - 6.17

<0.001

Presence of eye oedema

1.53

1.03 - 2.27

0.035

Associated Chronic Migraine

5.59

3.08 - 10.40

< 0.001

Associated Episodic Migraine

3.71

2.30 - 6.05

< 0.001

Intractable to Acute Treatment

2.16

1.03 - 4.61

0.043

Intractable to Preventive Treatment

4.97

3.03 - 8.28

< 0.001

CI Confidence interval, OR Odds-ratio

P35 The relevance of associated symptoms of migraine according to migraine subtypes: A Clinical study

Aynur Özge1, Osman Özgür Yalın2, Derya Uludüz3, Özlem Mercan3, Mehmet Ali Sungur4, Aksel Siva3

1Mersin University School of Medicine, Professor, Neurology Department, Mersin, Turkey; 2University of Health Sciences, Istanbul Training and Research Hospital, MD, Neurology Department, İstanbul, Turkey; 3Istanbul University Cerrahpasa School of Medicine, Associate Professor, Neurology Department,İstanbul, Turkey; 4Düzce University School of Medicine, Professor, Biostatistics Department, Düzce, Turkey
Correspondence: Osman Özgür Yalın (osmanozguryalin@yahoo.com)

Background: Migraine is a primary headache disorder with various associated symptoms. Nausea, vomiting, photophobia, phonophobia, osmophobia and allodynia can be present with different frequency in migraine subtypes. Clinical symptoms such as allodynia and osmophobia are not routinely evaluated during clinical visits even though their diagnostic and therapeutic implications are known. We aimed to observe the association with clinical symptoms and headace intensity and frequency in patients with migraine subtypes.

Methods: The study was based on the Turkish Headache Database Study group electronically recorded patient data. Database includes about 20.000 patient records from tertiary headache clinics since 20 years. Diagnosis of headache is based on the International Classification of Headache Disorders (ICHD) 3 beta. Patients were classified according to ICHD as; episodic migraine and chronic migrane with or without aura. Patients were asked if they experienced photophobia, phonophobia, osmophobia and allodynia during migraine attack. The results were compared within each subgroups.

Results: Totally 1935 patients were enrolled. Chronic migraine was diagnosed in 24.8%, episodic migraine in 75.2%, migraine without aura in %60.7 and migraine with aura in 39.3% of the patients. Osmophobia and allodynia were significantly more frequent among chronic migraine patients (p=0.001). The presence of photophobia and phonophobia were not differ in subgroups except photophobia was more frequent in patients with migraine with aura (p<0.001). We analyzed effects of associated symptoms within chronic migraine patients. Photophobia and phonophobia were positively correlated with the headache frequency, severity and headache duration within the group, whereas no correlation was found for osmophobia and allodynia.

Conclusions: We found an association between allodynia, osmophobia and headache chronicity. Awareness of those symptoms and understanding of revolution of migraine in the term of time will provide new insight for the management of disease. Future research should further elucidate these relationships and focus on prevention of migraine patients from chronification.

P36 Descriptive analysis of a population with chronic migraine in a tertiary Headache Center

Ana-Inês Martins, Joana Ramos-Lopes, Pedro Lopes, Bruno Silva, Sónia Batista, Lívia Sousa, Isabel Luzeiro

Neurology Department, Coimbra University and Hospital Centre, Coimbra, Portugal
Correspondence: Ana-Inês Martins (ana.inesm@hotmail.com)

Background: Chronic migraine (CM) is the 5th most prevalent disease and has a massive impact in individual quality-of-life and global economy. Although there are several international studies about this topic, in Portuguese population that analysis is scarce. We aim to describe a population of chronic migraine patients followed in a tertiary Headache Center.

Patients diagnosed with CM and followed in our tertiary hospital center were selected and posteriorly interviewed.

Results: A total of 201 patients were enrolled, mean age 44.98 (±13.20) years, 190 females (94.5%), mean BMI 24.30 (±3.59). Of those, 50.7% (N=102) lived in an urban area and 152 patients were professionally active. The mean age of symptoms onset was 22.71 (±9.82) years and the diagnosis of CM was made on average at 32.05 (±12.05) years, which was mainly established by a Neurologist (72.5%). At the time of diagnose, mean days of headache per month in the previous year was 17.82 (±4.73). After initiating preventing treatment mean days of headache per month decreased to 8.82 (±5.10). Phonophotophobia was the most common symptom accompanying migraine (90.2%). Moreover, in our sample there was a loss of 58 days from paid work in the preceding 3 months, a mean of 0.29 per person. Acute phase treatment comprised mainly non-steroidal inflammatory drugs, which are used for 82.6% of patients, followed by triptans (43.3%) and analgesics (32.3%). Regarding preventive treatment, the majority of patients are under two or more different pharmacological classes (57.2%, N=115). Most patients are under an anti-epileptic drug (50.7%,N=102). The second most used preventive drug class is beta-blockers (38.3%, N=77), closely followed by selective serotonin re-uptake inhibitors (35.3%, N=71). The least used classes are toxin botulinum (32.1%, N=64) and tricycle antidepressants (28.9%, N= 58).

Conclusions: Our work adds further evidence of epidemiological and clinical data about CM in Portugal. Prevention of migraine chronification is essential and requires adequate treatment of individual migraine attacks, early initiation of preventive medication and avoiding analgesic overuse.

Ethics Approval

The study was approved by Coimbra University and Hospital Centre Institutution‘s Ethics Board, approval number CHUC-106-17.

P37 WHITE MATTER LESIONS IN CHRONIC MIGRAINE ARE RELATED WITH MOLECULAR MARKERS OF INFLAMMATION AND BLOOD BRAIN BARRIER DISRUPTION

C. Dominguez1, M. Saavedra1, X. Rodríguez-Osorio1, T. Sobrino2, F Campos2, J. Castillo2, R. Leira1,2

1Servicio de Neurología, Hospital Clínico Universitario de Santiago de Compostela, Santiago de Compostela, 15706, Spain; 2Laboratorio de Investigación de Neurociencias Clínicas, Instituto de Investigación Sanitaria (IDIS). Santiago de Compostela, 15706, Spain
Correspondence: C. Dominguez (claravivero@hotmail.com)

Background: White matter lessions (WML) have been described in migraine patients, but their origin and role in migraine pathophysiology is still under discussion. In this study we aim to determine the relation between WML and levels of molecular markers of inflammation, endothelial dysfunction, blood brain barrier disruption and brain damage in chronic migraine (CM).

Methods: Prospective study including 62 patients with CM (IHS 2013) (41.4±11.1 years old; 89,5% women). The study was approved by the Galicia Autonomic Investigation Ethics Board (number 2016/079). All subjects underwent a clinical, molecular and neuroimaging protocol, including an 3T MRI study (T1,T2,T2* and FLAIR) . White matter hyperintensities were analysed and clasified in number (<3, 4-6, >6) and location (subcortical, periventricular or other). Plasma levels of biomarkers of inflammation: interleukin 6 (IL-6), interleukin 10 (IL-10), high-sensitivity C-reactive protein (hs-CRP), calcitonin gene-related peptide (CGRP); endothelial dysfunction: pentraxin 3 (PTX3), soluble TNF-like weak inducer of apoptosis (sTWEAK); blood-brain barrier disruption: cellular fibronectin

(cFN) and brain damage: s100 calcium binding protein (s100B) and neuron-specific enolase (SNE) were determined by ELISA in peripheral blood during interictal periods.

Results: 37 patients with CM (59.6%) showed WML in MRI. WML were related with higher levels of IL-6 (9.2±2.9 vs 7.5 ±2.8 pg/mL; p=0.001), cFN (17.4 ±6.2 vs 10.9 ±5.2 microgr/mL p=0.008 ) and SNE (18.7 ±5.1 vs 15.9 ±4.8 ng/mL). Logistic regression analysis showed an independent correlation between WML and levels of IL-6 (OR 1.2 95%CI 1.0-1.5; p=0.049) and cFN (OR 1.1, 95% CI 1.0-1,2; p=0.021).

Conclusions: High levels of biomarkers of inflammation and BBB disruption are associated with WML in patients with CM, suggesting a role of these mechanisms in white matter damage in CM.

Funding

This work was funded by project PI15/01578; from the State Plan of I+D+I 2013-2016 and co-funded by the ISCIII-Subdirección General de Evaluación y Fomento de la Investigación el Fondo Europeo de Desarrollo Regional (FEDER).

P38 IRON DEPOSITS IN PERIAQUEDUCTAL GRAY MATTER ARE RELATED WITH POOR RESPONSE TO ONABOTULINUMTOXIN A IN CHRONIC MIGRAINE

C. Dominguez1, M. Saavedra1, X. Rodríguez-Osorio1, C. Villalba2, P. Ramos-Cabrer3, T. Sobrino4, F Campos4, J. Castillo4, R. Leira1,4

1Servicio de Neurología, Hospital Clínico Universitario de Santiago de Compostela, Santiago de Compostela, 15706, Spain; 2Servicio de Radiología, Hospital Clínico Universitario de Santiago de Compostela, Santiago de Compostela, 15706, Spain; 3Molecular Imaging Unit. CIC biomaGUNE. Donostia. Ikerbasque, Basque Foundation for Science. Bilbao , Spain; 4Laboratorio de Investigación de Neurociencias Clínicas, Instituto de Investigación Sanitaria (IDIS). Santiago de Compostela, 15706, Spain
Correspondence: C. Dominguez (claravivero@hotmail.com)

Background: Response to treatment with Onabotulinumtoxin A (OnabotA) in chronic migraine (CM) has been related with several clinical features and molecular markers. Our aim is to determine if there is any relation between MRI evidence of iron deposits in deep brain nuclei and periaqueductal grey matter (PAG) and efficacy of treatment with OnabotA.

Methods: Prospective study including 62 patients with CM (IHS 2013) (41.4±11.1 years old; 89,5% women) that were treated with OnabotA ( PREEMPT protocol). The study was approved by the Galicia Autonomic Investigation Ethics Board (number 2016/085). All subjects underwent a 3T MRI (T1,T2,T2* and FLAIR) at baseline. Volume of hipointense areas in deep brain nuclei and PAG was measured. Patients were classified in responders (reduction of more than 50% in headache frequency) and non-responders (reduction of less than 50% in headache frequency) after one year of treatment.

Results: 47 patients (75.8%) responded to treatment with OnabotA. Non-responders showed larger volumes of iron in globus pallidus (GP) (2495,5 ± 1852,3 vs 1691,7±1000,3 microl; p=0.004) and PGA (405,7±55.1 vs 325,8±64.1 microl; p=0.001) when compared to responders. There was a negative correlation between volume of iron deposits in GP (r -0.270; p=0.040) and PGA (r -0..430; p<0.001) and response to OnabotA. After performing a logistic regression analysis, iron deposits in PGA were independently associated with poor response to OnabotA (OR 0.973 [0.955-0.991 95% IC; p=0.04).

Conclusions: Larger iron deposits in PGA are related with poor response to treatment with OnabotA in CM.

Funding

This work was funded by project PI15/01578; from the State Plan of I+D+I 2013-2016 and co-funded by the ISCIII-Subdirección General de Evaluación y Fomento de la Investigación el Fondo Europeo de Desarrollo Regional (FEDER).

P39 Economic impact of migraine in the EU5: a matched analysis of the NHWS 2017 data on work productivity and healthcare resource use

Michael J. Doane1, Pamela Vo2, Aikaterini Bilitou3, Juanzhi Fang4, Annik K-Laflamme2, Shaloo Gupta5

1Kantar Health, Horsham, Pennsylvania, USA, 19044; 2Novartis Pharma AG, Kohlenstrasse, Basel, Switzerland, 4056;3Novartis Global Services Centre, Dublin, Ireland, D04A9N6; 4Novartis Pharmaceuticals Corporation, East Hanover, New Jersey, USA, 07936; 5Kantar Health, Madison Ave, New York, USA, 10010
Correspondence: Pamela Vo (pamela.vo@novartis.com)

Introduction

Migraine is a distinct neurological disease ranking among the top causes of disability globally [1].

Objectives

This study aimed to describe the incremental burden of migraine on work productivity and healthcare resource utilization (HRU) in those suffering from ≥4 monthly headache days (HDs) in Europe.

Methods

A retrospective, cross-sectional analysis of the 2017 National Health and Wellness Survey (NHWS) data from the EU5 (France, Germany, Italy, Spain, and UK) was conducted. Outcomes from respondents who self-reported a doctor diagnosis of migraine, experienced at least one migraine during the prior month and overall ≥4 HDs during the prior month, were stratified by HD frequency (i.e., 4-7, 8-14 and ≥15 HDs) and matched by propensity scores within each subgroup and country using sociodemographic characteristics to respondents without migraine (controls). Work and activity impairment was assessed via Work Productivity and Activity Impairment Questionnaire – General Health version (WPAI-GH), and HRU via healthcare provider (HCP) visits, emergency room (ER) visits, and hospitalizations during the prior 6 months of survey completion. Mann-Whitney U tests were used for continuous and Chi-square tests were used for categorical variables to determine significant differences between subgroups.

Results

Analyses of the propensity score-matched sample of 1569 respondents with migraine (4-7, 8-14 and ≥15HDs/month) showed that a significantly higher proportion of patients reported at least one visit to a HCP, neurologist, ER or being hospitalized in the prior 6 months compared with matched controls (Table 1). WPAI outcomes were also significantly impacted across all migraine subgroups compared with controls.

Conclusions

Migraine patients across all migraine frequency subgroups reported significantly higher HRU and work impairment compared with matched non-migraine controls. This study highlights the economic implications of migraine to the healthcare system and society.

Ethics Approval

The NHWS received approval from the Pearl Institutional Review Board. All NHWS respondents provided informed consent prior to participating.

References

1. Steiner TJ, Stovner LJ, Vos T, Jensen R, Katsarava Z. Migraine is first cause of disability in under 50s: will health politicians now take notice? The Journal of Headache and Pain. 2018;19(1):17.

Table 1 (abstract P39).

HRU and WPAI outcomes after propensity score matched analysis*

 

Non-migraine (N=1,569)

4-7 HDs (N=783)

8-14 HDs (N=429)

>=15 HDs (N=357)

HRU in the past 6 months

% proportion of patients with at least 1 visit (N)

 Visited any HCP

85.1%a (1336)

96.0%b (752)

95.6%b (410)

94.1%b (336)

 Visited ER

11.9%a (187)

23.0%b,c (180)

21.7%b (93)

27.7%c (99)

 Visited Neurologist

4.2%a (66)

12.4%b (97)

14.5%b (62)

24.4%c (87)

 Hospitalized

7.8%a (123)

11.9%b (93)

14.9%b (64)

15.4%b (55)

WPAI outcome in the past 7 days

Average % work impairment* (N)

 Absenteeism

8.47%a (870)

11.28%b (447)

13.34%b,c (264)

19.13%c (166)

 Presenteeism

20.54%a (849)

32.11%b (431)

33.74%b (254)

43.51%c (154)

 Overall Work Impairment

22.62%a (841)

34.77%b (427)

36.95%b (251)

47.20%c (154)

*Propensity matching was conducted using patient demographic variables identified in pre-matched bivariate results (i.e., age, gender, employment status, marital status, income, education, smoking, alcohol use, body mass index, exercise and the Charlson comorbidity index). Subscripts refer to pairwise comparisons using chi-square tests for HRU and Mann-Whitney U tests for WPAI outcomes. If subscripts are different between categories, then statistical significance (p<.05) is indicated.

*These metrics are only reported of those currently employed; Non-Migraine (N=957), 4-7 HDs (N=481), 8-14 HDs (N=281) and

>=15 HDs (N=176)

P40 Humanistic burden of migraine in the EU5: a matched analysis of the NHWS 2017

Michael J. Doane1, Pamela Vo2, Aikaterini Bilitou3, Juanzhi Fang4, Annik K-Laflamme2, Shaloo Gupta5

1Kantar Health, Horsham, Pennsylvania, USA, 19044; 2Novartis Pharma AG, Kohlenstrasse, Basel, Switzerland, 4056; 3Novartis Global Services Centre, Dublin, Ireland, D04A9N6; 4Novartis Pharmaceuticals Corporation, East Hanover, New Jersey, USA, 07936; 5Kantar Health, Madison Ave, New York, USA, 10010
Correspondence: Pamela Vo (pamela.vo@novartis.com)

Introduction

Migraine is a distinct neurological disease ranking among the top causes of disability globally and affecting multiple domains of life for individuals [1].

Objectives

The purpose of this study was to describe the incremental burden of migraine on health- related quality of life (HRQoL) in those suffering from migraine of ≥4 monthly headache days (HDs) compared with matched controls in Europe (EU5; France, Germany, Italy, Spain, and UK).

Methods

A retrospective, cross-sectional analysis was conducted using patient-reported data from the 2017 EU5 National Health and Wellness Survey (NHWS). Outcomes from 1569 adult respondents, who self-reported a doctor diagnosis of migraine, experiencing at least one migraine in the prior month, and overall ≥4 HDs during the prior month, were stratified by HD frequency (i.e., 4-7, 8-14 and ≥15 HDs) and matched by propensity scores to 1569 respondents without migraine (controls) within each HD subgroup and country using sociodemographic characteristics. HRQoL was assessed via SF-36v2 and EQ-5D. Independent samples t-tests were used for the pairwise comparison of the outcomes across subgroups.

Results

All HRQoL outcomes assessed after propensity score matching in 783 respondents with 4-7 HDs, 429 respondents with 8-14 HDs and 357 respondents with ≥15 HDs were significantly lower compared with outcomes of 1569 control respondents without migraine (Table 1).

Conclusions

Individuals with migraine across migraine frequency subgroups report significantly worse HRQoL compared with those without migraine. Results highlight the burden that exists across the spectrum of migraine patients who may be eligible for preventive treatment.

Ethics Approval

The NHWS received approval from the Pearl Institutional Review Board. All NHWS respondents provided informed consent prior to participating.

Table 1 (abstract P40).

HRQoL outcomes in NHWS respondents with migraine versus matched controls*

 

Non-migraine controls (N=1,569)

4-7 HDs (N=783)

8-14 HDs (N=429)

≥15 HDs (N=357)

Mean (SD)

Mean (SD)

Mean (SD)

Mean (SD)

Mental Component Summary Score

45.17a

41.02b

40.03b

36.52c

Physical Component Summary Score

50.87a

48.11b

47.15b

42.69c

SF-6D Utility Score

0.70

0.64

0.63

0.58

EQ-5D Index

0.83

0.75

0.73

0.58c

Health Status, EQ VAS

74.22a

67.13b

64.24c

52.26d

*Propensity matching was conducted using patient demographic variables identified in pre-matched bivariate results (i.e., age, gender, employment status, marital status, income, education, smoking, alcohol use, body mass index, exercise and the Charlson comorbidity index). Subscripts refer to pairwise comparisons using independent samples t-tests between subgroups. Values in the same row that do not share the same subscript are significantly different at p<0 .05

References

1. Steiner TJ, Stovner LJ, Vos T, Jensen R, Katsarava Z. Migraine is first cause of disability in under 50s: will health politicians now take notice? The Journal of Headache and Pain. 2018;19(1):17.

P41 Phase 3 studies (SAMURAI, SPARTAN) of lasmiditan compared to placebo for acute treatment of migraine

Linda A. Wietecha1, Bernice Kuca2, Josephine Asafu-Adjei1, Sheena K. Aurora1

1Eli Lilly and Company, Indianapolis, IN; 2CoLucid Pharmaceuticals, Inc., a wholly owned subsidiary of Eli Lilly and Company
Correspondence: Linda A. Wietecha (wietecha_linda_a@lilly.com)

Background: Lasmiditan is a novel centrally acting serotonin (5-HT1F) agonist that lacks vasoconstrictive activity.

Objective: Efficacy and safety findings from two pivotal Phase 3 studies of lasmiditan for acute treatment of migraine are reported here.

Methods: SAMURAI (NCT02439320) and SPARTAN (NCT02605174) were Phase 3, randomized, double-blind, placebo-controlled studies. Inclusion criteria included Migraine Disability Assessment Score ≥11 (moderate disability) and 3–8 migraine attacks per month. Patients were randomized to a first dose of treatment (SAMURAI, 1:1:1 ratio of lasmiditan 200/100 mg or placebo, SPARTAN, 1:1:1:1 ratio of lasmiditan 200/100/50 mg or placebo) which was taken within 4 hours of migraine onset (moderate severity or worse and not improving). For rescue or recurrence, patients took a randomly assigned second dose of the previously assigned lasmiditan dose or placebo. The primary and key secondary analyses compared the proportions of patients in the lasmiditan 200-mg group with the placebo group who were headache pain-free and who were most bothersome symptom (MBS)-free at 2 hours post-first dose, respectively. Treatment-emergent adverse events (TEAEs) were used to assess safety. Logistic regression was used for comparisons. The studies were approved by the appropriate Institutional Review Board for each study site.

Results: At 2 hours post-first dose, significantly greater proportions of patients (p<0.001) were headache pain-free (lasmiditan 200 mg: SAMURAI 32.2%, SPARTAN 38.8%; placebo: SAMURAI 15.3%, SPARTAN 21.3%) and MBS-free (lasmiditan 200 mg: SAMURAI 40.7%, SPARTAN 48.7%; placebo: SAMURAI 29.5%, SPARTAN 33.5%) with lasmiditan 200 mg compared with placebo. For both endpoints, significance was also noted for other lasmiditan dose groups (100 mg, 50 mg) compared to placebo. The most frequently reported TEAEs with lasmiditan (≥2% and greater than placebo) after the first dose were dizziness, paresthesia, somnolence, fatigue, nausea, and lethargy, and most events were mild-to-moderate in severity.

Conclusion: The primary and key secondary endpoints were met and safety outcomes were consistent across the two Phase 3 studies.

P42 Conversion from chronic to episodic migraine with erenumab, a specific inhibitor of the calcitonin gene-related peptide receptor

Richard B. Lipton1, Stewart J. Tepper2, Stephen Silberstein3, David Kudrow4, Messoud Ashina5, Uwe Reuter6, David Dodick7, Feng Zhang8, Gregory A. Rippon8, Daniel D. Mikol8

1Department of Neurology, Albert Einstein College of Medicine and Montefiore Medical Center, Bronx, NY, USA; 2Geisel School of Medicine at Dartmouth, Hanover, NH, USA; 3Thomas Jefferson University, Philadelphia, PA, USA; 4California Medical Clinic for Headache, Santa Monica, CA, USA; 5Department of Neurology, Danish Headache Center, Rigshospitalet Glostrup, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark; 6Department of Neurology, Charité Universitätsmedizin Berlin, Berlin, Germany; 7Mayo Clinic, Phoenix, AZ, USA; 8Amgen Inc., Thousand Oaks, CA, USA
Correspondence: Richard B. Lipton (richard.lipton@einstein.yu.edu)

Background

Patients with migraine are classified into episodic migraine (EM: <15 headache days/month) and chronic migraine (CM: ≥15 headache days/month). Over time, migraine patients may move from EM to CM and from CM to EM. Erenumab is a fully human monoclonal antibody that specifically inhibits the canonical calcitonin gene-related peptide receptor and was developed as a preventive migraine therapy. Erenumab has been shown to significantly reduce the number of monthly migraine days versus placebo in patients with CM and EM. As conversion to EM is a treatment goal for patients with CM, this analysis of a pivotal CM study assessed the rate of conversion to EM during short-term erenumab treatment.

Methods

This is a post hoc analysis of a pivotal, randomised, double-blind, placebo-controlled trial of erenumab in CM. Patients aged 18–65 years with a history of CM were randomised 2:1:1 to receive placebo, erenumab 70 or 140 mg once every 4 weeks for 12 weeks. Migraine headache information was captured daily via an electronic diary throughout the double-blind phase. Numbers and percentages of erenumab-treated patients who converted to EM were calculated and compared with placebo within each 4-week period of the 12-week double-blind phase, as well as over the entire 12 weeks based on average monthly headache days. Adjusted odds ratios (ORs) and p values were obtained from a Cochran-Mantel-Haenszel test after missing data were imputed as nonresponse. Nominal statistical significance was determined when p<0.05 without adjustment for multiplicity.

Results

Demographics and baseline clinical characteristics were well balanced among groups. Based on average monthly headache days over the 12-week double-blind phase, patients receiving erenumab were significantly more likely to convert to EM than patients receiving placebo (OR: 2.31; 95% confidence interval [CI]: 1.57, 3.38; p<0.001 for 70 mg erenumab, and OR: 2.10; 95% CI: 1.44, 3.08; p<0.001 for 140 mg erenumab). Higher rates of conversion to EM were also observed at 4, 8, and 12 weeks (Fig. 1).

Conclusions

Conversion to EM is an important treatment goal for patients with CM. Over 12 weeks, erenumab significantly increased the odds of converting from CM to EM, with conversion to EM occurring early during treatment. Future studies should assess the rate and persistence of conversion of CM to EM over the long term.

Fig. 1 (abstract P42).

Conversion to episodic migraine during the 12-week double-blind phase. Odds ratio (OR) was obtained from a Cochran-Mantel-Haenszel test and stratified by region and medication overuse. Each erenumab dose group was compared with placebo. p<0.001, *p=0.003. CI, confidence interval.

P43 Erenumab impact on patient-reported outcomes in chronic migraine in the presence of acute medication overuse

Stewart J Tepper1, Messoud Ashina2, Jan Klatt3, Pooja Desai4, Feng Zhang4, Sunfa Cheng4, Daniel D Mikol4

1Geisel School of Medicine at Dartmouth, Hanover, NH, USA; 2Department of Neurology, Danish Headache Center, Rigshospitalet Glostrup, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark; 3Novartis Pharma AG, Basel, Switzerland; 4Amgen Inc., Thousand Oaks, CA, USA
Correspondence: Messoud Ashina (ashina@dadlnet.dk)

Background

Erenumab is a fully human anti-CGRP receptor monoclonal antibody approved as a preventive treatment for migraine by the US Food and Drug Administration. Erenumab has demonstrated clinically relevant efficacy in chronic migraine (CM), including in the presence of acute medication overuse (MO) at baseline (≥15 days/month on simple analgesics or ≥10 days/month on triptans, combination of therapies, or ergotamine derivatives). The objective of this study was to evaluate the efficacy of erenumab on patient-reported outcomes (PROs) in patients with CM in the presence of MO.

Methods

This was a subgroup analysis of data from a pivotal study of erenumab in patients with CM (≥15 headache days/month over 3 months with ≥8 migraine days/month). Patients were randomised to receive erenumab (70 or 140 mg once monthly) or placebo for 3 months, stratified by region and presence/absence of MO during the 4-week baseline period. Subgroups with MO were assessed for change from baseline at Month 3 on the Headache Impact Test (HIT-6), Migraine Disability Assessment (MIDAS), and Migraine-Specific Quality-of-Life Questionnaire (MSQ). No formal hypothesis was tested.

Results

Of 667 patients randomised, 41% (n=274) met MO criteria. Baseline PRO scores were similar among treatment arms. Erenumab 70 and 140 mg treatment showed greater reductions from baseline than placebo in HIT-6 total score at Month 3 in both MO and non-MO subgroups. The treatment differences (TD) exceeded the established group-level minimally important difference (MID) for HIT-6 total score (≥2.3 point reduction). Reductions from baseline to Month 3 in MIDAS total scores were greater with erenumab compared with placebo. The TD in MIDAS total score were >5 days of improvement over the last 3 months, a clinically meaningful change. At Month 3, changes from baseline were greater with erenumab treatment compared with placebo in each MSQ domain score in both subgroups. The observed differences between treatment groups exceeded the respective MIDs for the MSQ-RFR (≥3.2) and MSQ-EF (≥7.5) domain scores (Table 1).

Conclusions

Erenumab provided a consistent benefit across multiple measures of social and psychological impact, disability and health-related quality of life in the presence of MO in patients with CM. Change from baseline in all of the PROs studied showed clinically meaningful improvements. The observed improvement in quality of life is likely due to reduction of monthly migraine days and reduction of acute medication overuse. These data further support the use of erenumab in patients with CM, including those with MO.

Table 1 (abstract P43).

Patient-reported outcomes at Month 3 in patients with chronic migraine by baseline medication overuse status

 

Medication overuse

Without medication overuse

Placebo (N=113)

Erenumab 70 mg (N=77)

Erenumab 140 mg (N=78)

Placebo (N=168)

Erenumab 70 mg (N=111)

Erenumab 140 mg (N=109)

HIT-6 total score (range: 36–78)

 Baseline score, mean (SD)

63.8 (5.0)

63.9 (4.4)

63.3 (4.8)

63.0 (5.3)

63.0 (5.4)

62.2 (6.2)

 Change from baseline

−2.9 (−4.1, −1.7)

−5.2 (−6.7, −3.7)

−5.4 (−6.9, −3.9)

−3.4 (−4.4, −2.3)

−6.0 (−7.2, −4.6)

−5.8 (−7.1, −4.6)

 Difference from placebo

 

−2.3 (−4.2, −0.3)

−2.5 (−4.4, −0.6)

 

−2.6 (−4.2, −1.0)

−2.5 (−4.1, −0.8)

MIDAS total score

 Baseline score, mean (SD)

71.6 (52.7)

69.3 (43.4)

66.6 (55.7)

65.5 (58.2)

63.3 (47.5)

56.8 (49.4)

 Change from baseline

−3.6 (−12.0, 4.8)

−22.0 (−32.0, −12.1)

−16.1 (−26.1, −6.1)

−11.2 (−17.0, −5.5)

−18.40 (−25.2, 11.6)

−23.5 (−30.3, −16.6)

 Difference from placebo

 

−18.5 (−31.4, −5.5)

−12.5 (−25.4, 0.4)

 

−7.2 (−16.1, 1.7)

−12.2 (−21.1, −3.3)

MSQ-RFR (range: 0–100)

 Baseline score, mean (SD)

41.3 (17.4)

42.9 (16.5)

43.7 (17.3)

43.8 (17.7)

46.0 (19.4)

46.8 (20.3)

 Change from baseline

11.7 (8.0, 15.4)

17.1 (12.6, 21.5)

17.4 (13.0, 21.9)

12.0 (9.0, 15.1)

18.4 (14.7, 22.1)

20.6 (16.8, 24.3)

 Difference from placebo

 

5.4 (−0.4, 11.2)

5.7 (0.0, 11.51)

 

6.4 (1.6, 11.2)

8.5 (3.7, 13.3)

MSQ-RFP (range: 0–100)

 Baseline score, mean (SD)

60.8 (19.5)

63.8 (21.6)

61.1 (20.0)

59.9 (20.4)

60.6 (21.6)

64.2 (21.8)

 Change from baseline

7.7 (4.4, 11.1)

11.6 (7.6, 15.6)

10.5 (6.5, 14.4)

10.0 (7.3, 12.7)

14.2 (11.0, 17.5)

16.7 (13.4, 20.0)

 Difference from placebo

 

3.9 (−1.3, 9.0)

2.7 (−2.4, 7.9)

 

4.3 (0.0, 8.5)

6.8 (2.5, 11.0)

MSQ-EF (range: 0–100)

 Baseline score, mean (SD)

53.8 (24.3)

50.8 (23.9)

55.4 (24.8)

52.4 (26.7)

55.6 (26.1)

57.7 (27.9)

 Change from baseline

8.2 (4.2, 12.2)

17.1 (12.3, 21.9)

15.9 (11.1, 20.7)

11.3 (7.9, 14.8)

19.4 (15.3, 23.5)

21.2 (17.1, 25.4)

 Difference from placebo

 

8.9 (2.7, 15.1)

7.7 (1.5, 13.9)

 

8.1 (2.7, 13.4)

9.9 (4.5, 15.3)

Data represent LS mean (95% CI) unless otherwise indicated.

CI confidence interval, HIT-6 Headache Impact Test (higher score indicates worse outcome), LS least squares, MIDAS Migraine Disability Assessment (higher score indicates worse outcome), MSQ Migraine-Specific Quality-of-Life Questionnaire (higher score indicates better outcome), MSQ-EF Migraine-Specific Quality-of-Life Questionnaire emotional functioning, MSQ-RFP Migraine-Specific Quality-of-Life Questionnaire role function-preventive, MSQ-RFR Migraine-Specific Quality-of-Life Questionnaire role function-restrictive, N number of patients in the analysis set, SD standard deviation

P44 Long-term efficacy of erenumab in patients with chronic migraine who failed prior prophylactic treatment

Messoud Ashina1, Stewart J Tepper2, Jan L Brandes3, Uwe Reuter4, Guy Boudreau5, David Doležil6, Jan Klatt7, Feng Zhang8, Sunfa Cheng8, Daniel D Mikol8

1Department of Neurology, Danish Headache Center, Rigshospitalet Glostrup, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark; 2Geisel School of Medicine at Dartmouth, Hanover, NH, USA; 3Nashville Neuroscience Group, Nashville, TN, USA; 4Department of Neurology, Charité Universitätsmedizin Berlin, Berlin, Germany; 5Centre de Traitement Neurologique, Montreal, QC, Canada; 6Prague Headache Center, DADO MEDICAL s.r.o., Prague, Czech Republic; 7Novartis Pharma AG, Basel, Switzerland; 8Amgen Inc., Thousand Oaks, CA, USA
Correspondence: Messoud Ashina (ashina@dadlnet.dk)

Background

Erenumab is a fully human anti-CGRP receptor monoclonal antibody approved as a preventive treatment for migraine by the US Food and Drug Administration. In a pivotal placebo-controlled study of adults with chronic migraine (CM; NCT02066415), erenumab reduced the number of monthly migraine days (MMD) with a safety profile similar to placebo. A subsequent open-label extension (OLE) study (NCT02174861) characterised the long-term efficacy and safety of erenumab. We performed a subgroup analysis of patients in the OLE who had failed ≥1 prophylactic treatment due to lack of efficacy and/or poor tolerability.

Methods

The parent study enrolled 667 adult patients with CM. Efficacy endpoints were change from parent study baseline (BL) in MMD, monthly acute migraine-specific medication treatment days (MSMD), and proportion of patients with ≥50% response (≥50% reduction from parent study BL in MMD). Data were summarised by visit for the treatment failure (TF) subgroup and at Weeks 40 and 52 for patients who completed 52 weeks of erenumab treatment. Safety was summarised for the TF subgroup based on the dose received when adverse events (AEs) occurred.

Results

Of 416 TF patients who enrolled in the OLE with ≥1 measurement of MMD post-BL, 326 completed 52 weeks of the OLE. For the TF subgroup, the mean (standard deviation) BL MMD and MSMD were 18.4 (4.5) and 10.8 (7.1) days, respectively. Erenumab treatment in the OLE resulted in a sustained reduction in MMD and MSMD, and achievement of ≥50% response in most patients at Week 52 (Table 1). For patients who completed 52 weeks of erenumab, the BL MMD was 18.1 (4.3) and 18.2 (4.6), and the BL MSMD was 11.5 (6.5) and 9.6 (7.6) for the 70 and 140 mg dose groups, respectively. Reductions in MMD and MSMD and the percentage of patients who achieved a ≥50% response were greater with 140 versus 70 mg at Weeks 40 and 52 (Table 1). In the TF subgroup, the subject incidence of AEs was 60.3% (70 mg) and 66.7% (140 mg), and for serious AEs was 3.1% (70 mg) and 5.2% (140 mg), consistent with the overall study population.

Conclusions

In CM patients who had previously failed prophylactic treatment(s), erenumab 70 and 140 mg monthly led to a sustained reduction in MMD and MSMD, and more than half of patients achieved a ≥50% response. The therapeutic effect of erenumab was greater in the 140 mg dose group and after 52 weeks of treatment.

Table 1 (abstract P44).

Long-term efficacy with 52-week open-label erenumab treatment after 12-week double-blind treatment in patients with chronic migraine

 

Treatment failure subgroup

52-week OLE completers by last dose received

Erenumab 70 mg/140 mgN=416

Erenumab 70 mgN=189a

Erenumab 140 mgN=137a

OLE visit weeks

Week 12n=395

Week 40n=300

Week 52n=261

Week 40n=166

Week 52n=150

Week 40n=124

Week 52n=109

Change from BLb in MMD, mean (SE)

−6.84 (0.32)

−7.75 (0.38)

−8.58 (0.41)

−7.16 (0.48)

−7.86 (0.52)

−8.58 (0.62)

−9.66 (0.65)

Change from BLb in MSMD, mean (SE)

−4.17 (0.26)

−4.78 (0.29)

−5.56 (0.34)

−4.75 (0.38)

−5.47 (0.43)

−4.93 (0.47)

−5.75 (0.54)

Percentage of patients with ≥50% responsec(95% CI)

40 (35, 44)

50 (44, 56)

55 (49, 61)

43 (36, 51)

49 (41, 57)

60 (51, 68)

63 (54, 72)

aBased on the final dose of erenumab received. Patients in the erenumab 140 mg group received ≥3 months of erenumab 140 mg at Week 40 and ≥6 months of erenumab 140 mg at Week 52. bParent study baseline. c≥50% reduction in MMD from parent study baseline

BL, baseline; CI, confidence interval; MMD, monthly migraine days; MSMD, monthly acute migraine-specific medication treatment days; N, number of patients enrolled in the OLE and who failed ≥1 prophylactic treatment; n, number of patients with observed data at each time point; OLE, open-label extension; SE, standard error

P45 Changes in patient functioning and disability: results from two phase 3 double-blind placebo-controlled clinical trials evaluating galcanezumab for episodic migraine prevention (EVOLVE-1 and EVOLVE-2)

Janet H. Ford; David W. Ayer; Qi Zhang; Jeffrey N. Carter; Vladimir Skljarevski; Sheena K. Aurora

Eli Lilly and Company, Indianapolis, IN, USA
Correspondence: Jeffrey N. Carter (carter_jeffrey_n@lilly.com)

OBJECTIVE: To evaluate changes from baseline in migraine-specific patient-reported outcomes for measures of daily functioning and disability among patients treated with galcanezumab, a humanized monoclonal antibody that binds to CGRP, or placebo in two clinical studies (ClinicalTrials.gov NCT02614183 and NCT02614196).

METHODS: Patients with episodic migraine (4-14 monthly migraine headache days) were treated (monthly subcutaneous injections) with galcanezumab (EVOLVE-1: 120-mg N=210, 240-mg N=208; EVOLVE-2: 120-mg N=226, 240-mg N=220), or placebo (EVOLVE-1 N=425; EVOLVE-2 N=450) during six months of treatment. The Migraine-Specific Quality of Life Questionnaire v2.1 (MSQ; higher scores indicate better functioning) was used to measure the impact of migraine on daily functioning in three domains (Role Function-Restrictive [RFR], Role Function-Preventive [RFP], Emotional Function [EF]), and the Migraine Disability Assessment (MIDAS; lower scores indicate less disability) was used to quantify headache-related disability. Both were collected at baseline and during treatment (MSQ=monthly; MIDAS=Month 3 and 6). Changes from baseline in MSQ (Month 4-6 average) and MIDAS (Month 6) scores were analyzed with mixed models repeated measures. Both studies were approved by the appropriate Institutional Review Board for each study site.

RESULTS: No statistically significant differences between treatment groups were observed for most baseline scores, specifically MSQ Total score (EVOLVE-2: 120-mg=59.6; 240-mg=58.0; placebo=58.0), and MIDAS Total score (EVOLVE-1: 120-mg=32.9; 240-mg=36.1; placebo=31.8; EVOLVE-2: 120-mg=30.9; 240-mg=32.8; placebo=34.3). In EVOLVE-1, the mean baseline MSQ Total scores were statistically different among galcanezumab versus placebo (120-mg=56.7; 240-mg=54.6; placebo= 59.6 both P<.001); similar statistical differences were observed across the individual MSQ domains. Differences of least squares (LS) mean change from baseline for galcanezumab (120-mg, and 240-mg, respectively) compared with placebo in MSQ Total score were: EVOLVE-1=7.3 and 6.7 (both P<.001); EVOLVE-2=8.5 and 7.3 (both P<.001). Significant differences (P<.001 for both galcanezumab dose groups compared with placebo) were also observed at Month 1 in both studies, and across the three MSQ domains (RFR, RFP, EF). Differences of LS mean change from baseline for galcanezumab (120-mg and 240-mg, respectively) compared with placebo in MIDAS Total score were: EVOLVE-1=-6.3 (P<.001) and -5.2 (P=.002); EVOLVE-2=-9.2 and -8.2 (both P<.001). In EVOLVE-2, each individual item score of MIDAS overall achieved statistically significant improvement (P<.05) for both galcanezumab doses compared with placebo; statistically significant improvements were observed for most individual items in EVOLVE-1 for both doses compared with placebo.

CONCLUSIONS: Patients treated with galcanezumab reported statistically significant and clinically meaningful improvements in daily functioning, and decreased disability compared with those patients who received placebo.

P46 100% response rate to galcanezumab in patients with episodic migraine: randomized, double-blind, placebo-controlled studies

Abraham Jim Nagy1, Eric Pearlman2, Dustin Ruff2, Kathleen Day2, Noah Rosen3

1Nevada Headache Institute, Las Vegas, NV, 89113, USA; 2Eli Lilly and Company, and/or one of its subsidiaries, Indianapolis, IN, 46285, USA; 3Hofstra Northwell School of Medicine at Hofstra University, Department of Neurology, Hempstead, NY, 11549, USA
Correspondence: Eric Pearlman (eric.pearlman@lilly.com)

Objective: To characterize adult patients with episodic migraine headache who achieved 100% response to galcanezumab treatment.

Methods: The proportions of patients with 100% response (100% reduction from baseline in monthly MHD) were calculated for each month from 2 double-blind, 6‑month galcanezumab studies in patients with episodic migraine (4 to 14 MHD and ≥2 migraine attacks per month at baseline). Patients were randomized (1:1:2) to monthly subcutaneous galcanezumab 120 mg (after 240 mg initial loading dose) or 240 mg or placebo. A generalized linear mixed model with effects for baseline MHD, treatment, month, and treatment-by-month interaction was used to estimate the mean monthly response rate. The studies were approved by a central Ethics Review Board and registered with ClinicalTrials.gov (NCT02614183 and NCT02614196).

Results: The analysis included 1739 patients treated with galcanezumab 120 mg (n=436) or 240 mg (n=428) or placebo (n=875). The mean monthly 100% response rate on an average month in the 6-month double-blind phase was greater for galcanezumab 120 mg (13.5%) and 240 mg (14.3%) groups versus placebo (5.9%) with odds ratios of 2.5 (95% confidence interval [CI] 1.9, 3.2) and 2.6 (95% CI 2.0, 3.4), respectively (p<0.001). The rate of 100% monthly response increased at each month over the 6-month double-blind phase with higher rates for galcanezumab dose groups (9% to 21%) than placebo (2% to 10%) (p<0.001). Evaluation of 100% response by the number of months showed greater proportions of galcanezumab-treated patients in either dose group, compared to placebo, were able to achieve a 100% response (p<0.05) though few patients had ≥4 months of 100% response. The proportions of patients with 100% response were greater in the last 3 months of treatment. Considering the average number days between migraine attacks across the 6-month period (not just during the times of 100% response), the duration of migraine headache free periods in the galcanezumab groups was 29 days for those with at least 1 month of 100% response and 55 days for those with at least 3 months of 100% response– around 6 to 11 times the mean gap of 5 days observed at baseline.

Conclusion: More than a third of patients with episodic migraine headache treated with galcanezumab 120 mg or 240 mg achieved 100% response for at least 1 month. More patients had 100% monthly response in the last 3 months of the 6-month double-blind period. For those with 100% response of at least 1 month, the average time between attacks for the entire treatment period was nearly 1 month and approached 2 months for patients with 3 or more months of 100% response.

Trial Registration: ClinicalTrials.gov NCT02614183 and NCT02614196

P47 Diagnostic screeners for migraine: a methodological caveat

C. Ertsey1, É. Csépány2, M. Magyar1,2, T. Gyüre2, Bozsik Gy2, M. Tóth3

1Department of Neurology, Semmelweis University, Budapest, Hungary; 2János Szentágothai Doctoral School of Neurosciences, Semmelweis University, Budapest, Hungary; 3Department of Neurology, Vaszary Kolos Hospital, Esztergom, Hungary
Correspondence: C. Ertsey (konfreg1@bcdtravel.hu)

Introduction: Validated migraine screening tools are widely used for both research and clinical purposes. While evaluating the performance of two such instruments, the ID-Migraine (ID-M) and the Migraine Diagnostic (MDX) questionnaires in tertiary headache centres, we found a source of false positive cases.

Methods: Consecutive patients presenting at two Hungarian headache centres completed the questionnaires during their outpatient visits. The patients' results were confronted with the clinical diagnosis according to the ICHD-3beta diagnostic criteria. The questionnaires' sensitivity, specificity, positve and negative predictive value as well as their misclassification error were calculated.

Results: A total of 405 patients completed both questionnaires. 247 patients had only one type of headache, whereas 158 patients had at least 2 different headache diagnoses. The clinical diagnosis of migraine was made in 324 patients (200 had only migraine, and 124 had at least another type of headache beside migraine). Tension type headache (TTH) alone was diagnosed in 50 patients, cluster headache (CH) alone in 23, while 8 patients had other headaches (ICHD groups 4 and 11). Both questionnaires' performance was adequate: the sensitivity and specificity of the ID-M were 0.95 and 0.44, and those of the MDX were 0.95 and 0.57, respectively. Among the 23 CH patients 21 (91%) were false positive for migraine according to their ID-M scores and 20 (87%) according to their MDX scores. This corresponds to 5.9% and 5.8% of all positive ID-M and MDX cases, respectively.

Conclusion: In this study, the overwhelming majority of CH patients had positive ID-M and MDX scores. In tertiary centres, and also in special populations (such as headahce self-help groups) CH patients may be overrepresented and might be overlooked. In the case of non-representative sampling studies using migraine diagnostic screeners as the sole source of diagnosis may have a significant number of false positive patients.

P48 Comparison of personality traits and dependence behavior between MOH patients and illicit drug users

Baraldi Carlo, Pellesi Lanfranco, Guerzoni Simona, Cainazzo Maria Michela, Lo Castro Flavia, Pini Luigi Alberto

Medical Toxicology-Headache and Drug Abuse Centre, Department of Diagnostic Medicine, Clinical and Public Health, University of Modena and Reggio Emilia, Via del Pozzo 71, 41124, Modena, Italy.
Correspondence: Baraldi Carlo (infocarlo.baraldi@gmail.com)

Background

Chronic migraine usually leads to the excessive consumption of acute medications, generating a secondary headache called medication overuse headache (MOH). MOH pathogenesis has not been clarified yet, but personality traits seems to have a role in it. Moreover, illicit drug users have been compared with MOH patients, trying to find out clinical overlaps. Despite this, is also proved that the different the overused drug is and the different is the response to detoxification treatment, as well as the eventual relapse into it. The focus of this study is to explore the difference in the Leeds Dependence Questionnaire as well as personality traits between patients suffering for MOH and patients affected by illicit drug use.

Methods

A questionnaire containing the Leeds dependence questionnaire, the ‘International Personality Item Pool (IPIP) and the Symptom Checklist-90-R was filled out by patients enrolled during their recovery in Modena Headache and Drug Abuse Research Center- Medical Toxicology Unit, between 2015 and 2017. Mean values of the above-mentioned questionnaires were compared using a one-way analysis of variance followed by the Tuckey-Kramer post-hoc comparison test. These comparisons were made between illicit drug users and 4 categories defined by the overuse drug by headache people (triptans, NSAIDs, opioids and associations).

Results

The Leeds dependence questionnaire was significantly higher in illicit drug users compared with triptan users and NSAIDs ones (17±6.08 vs. 9.39±5.5 for triptans and vs. 10.9±7.08, respectively). Moreover, IPIP analysis showed that illicit drug users have a greater somatizations than triptan and NSAIDs users (1.03±0.08 vs. 0.56±0.4 for triptans and vs. 0.66±0.52, respectively). Furthermore, a greater mean of the sub-voice hostility of the IPIP was seen in illicit drug users rather than in triptan users. No other differences between illicit drug users and MOH patients were seen.

Conclusion

Personality differences are present especially for triptan overusers versus illicit drug users; in particular, illicit drug users showed a higher grade of dependence and higher depressive as well as hostility traits than triptan overuses. It should be highlighted that no differences were seen between other drugs’ users and illicit drug users. These observations can suggest that overuses of headache acute medications other than triptans have a higher degree of dependence towards their overuse drug, as they are psychologically more similar to illicit drug abusers than triptan overusers.

P49 VALIDITY AND RELIABILITY TURKISH HEADACHE IMPACT TEST (HIT-6) IN PATIENTS WITH EPISODIC AND CHRONIC MIGRAINE

P. Yalınay Dikmen1, M. Bozdag2, M. Gunes3, S. Kosak1, B. Tasdelen4, D. Uludüz3, A. Ozge2

1Acıbadem University, School of Medicine, Department of Neurology, Istanbul, Turkey; 2Mersin University, Faculty of Medicine, Department of Neurology, Mersin, Turkey; 3Istanbul University, Cerrahpasa Faculty of Medicine, Department of Neurology, Istanbul, Turkey; 4Mersin University, Faculty of Medicine, Department of Biostatistics and Medical Informatics, Mersin, Turkey
Correspondence: P. Yalınay Dikmen (pinar.yalinay@acibadem.com)

Background: The Headache Impact Test (HIT-6) is a self-report questionnaire designed to evaluate the impact of headache on quality of life in both clinical research and practice. The aim of this study is to assess the comprehensibility, internal consistency, patient-physician reliability and validity of Turkish version of HIT-6 questionnaire in patients with episodic and chronic migraine.

Methods: Migraine patients applying to three Neurology Clinics in Turkey were evaluated at the baseline (visit 1) and week 4 (visit 2). Patients were randomized 2:1 at the visit 1 as group A and group B. Patients in both group were asked to complete the HIT-6 questionnaire by themselves at the baseline and follow-up visits. Patients in group A were additionally assessed by the physicians who also applied the HIT-6 questionnaire. All patients were also asked to complete Comprehensibility Assessment Form (CAF) at visits 1 and 2. The physician also completed this form for the patients of group A at all visits. The correlation between the total patient-applied HIT-6 scores and the corresponding total physician-applied HIT-6 scores of group A was analyzed to evaluate the patient-physician reliability of the questionnaire.

Results: A total of 114 migraine patients (60.5 % female, mean age:35,8±9.2;77 episodic, 37 chronic) were enrolled into the study. Comprehensibility of HIT-6 was evaluated as good for each item. At least 95% of the patients stated that the items were comprehensible. The significant positive correlation (r=0.876; p<0.001) was detected between patient and physician HIT-6 assessments in Group A. Structural validity of HIT was firstly examined using exploratory factor analysis (EFA) and explained variance proportion was acceptable (> 0.60). Then, Confirmatory factor analysis (CFA) was employed in order to ensure consistency of HIT scores and model fit statistics were obtained as good (≥0.90). Internal consistency of HIT-6 was assessed using Cronbach’s alpha and was found at acceptable (>0.75) or excellent (>0.87) levels in both patients and physician applied HIT-6 scores at visits 1 and 2, respectively. Total HIT-6 score showed good test-retest reliability (r=0.68).

Conclusions: These results demonstrated that the Turkish translation is equivalent to English version of HIT-6 in terms of internal consistency, test-retest reliability and validity. The Turkish translation of HIT-6 could be reliably used by physicians in assessing the impact of headache in both episodic and chronic migraine patients.

Ethics approval

The study received approval by the Ethics Committee of the Acıbadem University, School of Medicine, approval number 2017-16/15.

P50 Retrospective analysis of peripheral nerve block for the treatment of headaches and cranial neuralgias in the neurology section of a general hospital

Vanesa Adell1, Jessica García-Alhama2, Sonia Jaraba2, Joan Prat3, Mariano Huerta2

1Neurology department, IDIBELL, Hospital de Viladecans, Barcelona, Spain; 2Neurology department, Hospital de Viladecans, Barcelona, Spain; 3Neurology department, Hospital Universitari de Bellvitge, Barcelona, Spain.
Correspondence: Vanesa Adell (vanesa.adell@bellvitgehospital.cat)

Purpose: Anaesthetic block (AB) is a diagnostic and mainly therapeutic technique increasingly used in the treatment of headaches.

Method: We conducted a retrospective observational study of activity registered and coded as "peripheral nerve or trigeminal branches block" in the neurology service of our hospital between May 2009 and March 2018. Anaesthetic blocks of cranial and / or facial nerves for the diagnosis or treatment of headache or neuralgia were included. Therapeutic response (TR) was defined as the improvement of pain frequency and / or intensity ≥ 7 days for preventive treatment and ≥ 24 hours for acute treatment.

Results: The total number of blocks was 224 carried out in 100 patients (73% women, with an average age of 57.3 ± 15. 2 years old) and 42% patients received > 1 block. The most commonly treated pathologies were: migraine with 75/224 blocks (33.5%, 51/224 episodic and 24/224 chronic migraine), cervicogenic headache 41/224 blocks (18%) and cluster headache 28/224 blocks (12.5%, 20/224 episodic and 8/224 chronic). A total of 168/224 (75%) blocks were performed on the great occipital nerve (GON) on one (30%) or both sides (45%), 34/224 (15%) were performed on GON in combination with other points and 24/224 (10.7%) on the supraorbital nerve (SON). Nerve block with anaesthesia alone was the most used treatment (114/224, 51%) followed by combination of anaesthesia with corticoids (96/224, 43%). Therapeutic response was obtained in 141/224 (62%) of the blocks performed: 29/41 (70%) in cervicogenic headache, 44/75 (58%) in migraine and 16/ 28 (57%) in cluster headache.

Conclusion: AB is a therapeutic support technique that can be performed safely in a neurology section of a general hospital as an adjuvant treatment with a high percentage of symptomatic improvement.

P51 RELATIONSHIP BETWEEN SEVERITY OF MIGRAINE AND VITAMIN D DEFICIENCY: A CASE CONTROL STUDY

L. Rapisarda1, A.D. Montisano1, A. Sarica2, G. Demonte1, F. Tosto1, A. Gambardella1,2, F. Bono1,2

1Headache Center, Institute of Neurology, Department of Medical and Surgical Sciences, Magna Graecia University of Catanzaro, Italy; 2Neuroscience Research Center, Department of Medical and Surgical Sciences, Magna Graecia University of Catanzaro, Italy
Correspondence: L. Rapisarda (laura_rapisarda90@yahoo.it)

Background

It is well recognized that vitamin D deficiency is involved in a number of neurological disorders. However, if the serum vitamin D levels correlate with severity of migraine remains uncertain [1].

Materials and methods

In this prospective study we enrolled 157 patients with primary headache and 62 healhty controls. Each patient underwent a careful neurological evaluation, recording the frequency of headache through a monthly headache diary; we also evaluated pain (VAS), disability (MIDAS, allodynia (ASC-12); depression and anxiety (BDI-II and HARS), and medical overuse. All participants underwent a venous blood sampling for 25-hydroxyvitamin D. It has been considered sufficient 25-hydroxyvitamin D ≥30 ng/ml; insufficient for values 20-30 ng/ml; deficient ˂20 ng/ml.

Results

Patients were grouped into 3 groups: Group 1 included 113 patients with chronic migraine (17 M, 96 F; age 41,5±13,4; BMI 25,5±4,2); Group 2 included 44 patients with episodic migraine (8 M, 36 F; age 39,9±12,8; BMI 22,7±2,9); control group included 62 patients (24 M, 38 F; age 40,8±14,6; BMI 24,1±3,7). Serum 25-hydroxyvitamin D deficiency has been reported in headache sufferers and less severely in control group (12,8±5,4; 18,6±6; 22±6; p<0,001). Chronic migraneurs had a higher percentage of medication overuse (68% and 27% respectively, p <0,001), higher disability (MIDAS: 36,5±17,2 vs 9,6±7 p<0,001) and greater psychiatric comorbility (BDI-II: 18,9±8,6 vs 16±7,4, p<0,001; HARS: 19±9 vs 16,2±9,3, p<0,001). No statistically relevant differences were reported among the other clinical parameters. Statistical analysis showed that serum 25-hydroxyvitamin D levels were negative related to headache frequency (Pearson correlation coefficient -0,636; p<0,001). Moreover there was a negative relation even between vitamin D levels and BMI, HARS, BDI-II, MIDAS, VAS (-0,315; -0,406; -0,471; -0,525, -0,4; p<0,001).

Discussion

As 25-hydroxyvitamin D receptors (VDR) and 1a-hydroxylase (1a-OHase), are expressed in neurons of dorsal ganglia[2], limbic system, basal ganglia, cerebellum, and cerebral cortex, particularly in prefrontal cortex, cingulate gyrus, hyppocampus, dentate gyrus, substantia nigra, lateral geniculate nuclei, supraoptic and paraventricular nuclei in hypotalamus [3]; recent studies showed that vitamin D is implicated in descending modulation of endogenous pain control. Indeed we speculated that vitamin D deficiency may facilitate headache attacks; moreover it has a role in peripheral and central sensitization which lead to migraine chronification and are responsible for other migraine related phenomena such as allodynia.

Conclusion

Our data indicate that severe vitamin D deficiency is associated with higher frequency of headache in migraine patients, suggesting that serum vitamin D levels correlate with severity of migraine.

REFERENCES:

1. Prakash et al. Vitamin D in chronic tension-type headache: a case control study. Headache. 2017 Jul;57(7):1096-1108.

2. Tague et al. Vitamin D receptor and enzyme expression in dorsal root ganglia of adult female rats: Modula/on by ovarian hormones. Journal of Chemical Neuroanatomy 41 (2011) 3. Eyles et al. Distribu/on of the Vitamin D receptor and 1a-hydroxylase in human brain. Journal of Chemical Neuroanatomy 29 (2005) 21–30.

P52 A case-control study of visual-vestibular mismatch in childhood with primary headaches

Daniele Monzani1, Pellesi Lanfranco2, Guerzoni Simona2, Cainazzo Maria Michela2, Lo Castro Flavia2, Baraldi Carlo2, Pini L Alberto2

1Otolaryngology Unit, Department of Diagnostic Medicine, Clinical and Public Health, University of Modena and Reggio Emilia, Via del Pozzo 71, 41124, Modena, Italy; 2 Medical Toxicology-Headache and Drug Abuse Centre, Department of Diagnostic Medicine, Clinical and Public Health, University of Modena and Reggio Emilia, Via del Pozzo 71, 41124, Modena, Italy
Correspondence: Baraldi Carlo (Carloinfocarlo.baraldi@gmail.com)

Background

Disorientation, nausea, imbalance, confusion, unsteadiness and dizziness are unpleasant mates of the 40% of migraineurs children. The abovementioned symptoms may be triggered by repetitive visual moving patterns (optic flow stimulation), even in inter-ictal phases and are called “visual vestibular mismatch” (VVM). Bronsky and coworkers found that there were no underlining neurologic or otolaryngology conditions in all children from a Pediatric Vestibular Clinic complaining vestibular symptoms associated with migraine. However, M is frequently triggered by specific visual stimuli such as repetitive patterns, suggesting a central relationships between pain and vestibular pathways. In this work the effect of optokinetic stimulation (OKS) on balance function in migraineurs children suffering for VVM and without vestibular abnormalities was explored to detect a possible central vestibular impairment..

Methods

A static posturography examination was performed on 30 children suffering for primary headaches and 22 healthy controls. Children were texted in three different conditions subsequently: with closed eyes (EC), with open eyes (EO) and under a condition of OKS- obtained with a vertical bar in front of their eyes. Posturogram length (L), surface (S) and the mean sway velocity of the center of pressure (V) were recorded under EO, EC and OKS conditions. The EC/EO ratio (Romberg index) was calculated regarding the value of S and the destabilization index (DI) with the values obtained under OKS. One way ANOVA followed by Tukey-Kramer post-hoc comparison test was performed to compare the mean values of the abovementioned parameters during the different conditions. The study was approved by the local Ethical Committee (protocol number: 1921, study code NOC09).

Results

S and L were significantly lower in the control group compared with headache sufferers, whilst V showed an opposite trend, both in Eo and EC conditions (all p<0.05). Under OKS a greater variability of explored parameter was seen, but the trend was the same as before, without differerences between the left and right OKS (all p<0.05). RI was not significantly different in any group, neither was the DI.

Conclusion

A vestibular impairment is present in children suffering for headaches, even in inter-critic phases. The vestibular frailty of those patients can be attributed to a central impairment of vestibular ways, connecting peripheral vestibular organs with the vestibular cortex. Maybe trigeminal connections with the vestibular ganglion as well as central vestibular pathways may play a role in it.

Table 1 (abstract P52).

See text for description

Stabilometric findings

Eyes Open

Parameter

C

TTH

M

p*

Ellipse Surface

20.134±13.203

339.181±223.8

339.745±195.423

<0.0001

Ellipse Lenght

22.596±10.623

530.733±195.997

548.924±164.403

<0.0001

Mean Sway Velocity

22.76±13.617

12.391±3.64

11.127±3.0396

0.0004

FFTx

24.269±11.488

0.071±0.084

0.047±0.04

<0.0001

FFTy

20.726±10.452

0.0455±0.038

0.0526±0.045

<0.0001

Eyes Closed

Parameter

C

TTH

M

P

Ellipse Surface

22.927±10.991

407.681±211.192

410.367±208.812

<0.0001

Ellipse Lenght

36.3±78.973

793.875±600.239

728.162±257.888

<0.0001

Mean Sway Velocity

26.292±11.498

17.793±10.976

14.171±5.635

0.01

FFTx

22.132±12.584

0.045±0.039

0.045±0.046

<0.0001

FFTy

20.884±8.691

0.049±0.054

0.038±0.031

<0.0001

Romberg Index

2.157±2.137

1.478±0.634

1.292±0.489

0.155

Destabilisation Index

5.295±4.964

4.119±3.071

2.641±1.067

0.0735

Stabilometric findings OKN Right and Left

OKN Right

    

Parameter

C

TTH

M

p*

Ellipse Surface

21.986±12.159

509.318±303.792

456.057±391.45

<0.0001

Ellipse Lenght

18.531±15.928

683.604±265.269

690.163±151.569

<0.0001

Mean Sway Velocity

22.409±11.745

15.643±4.279

14.046±2.87

0.0053

FFTx

23.562±9.849

0.065±0.092

0.033±0.021

<0.0001

FFTy

19.2102 11.78949

.0681818 .0972438

.0444298 .0327543

<0.0001

OKN Left

    

Parameter

C

TTH

M

P*

Ellipse Surface

29.778±13.215

527.543±291.058

436.288±340.867

<0.001

Ellipse Lenght

1252.205±5381.505

725.216±270.133

708.717±224.549

0.8630

Mean Sway Velocity

22.409±11.745

15.643±4.279

14.046±2.87

0.4209

FFTx

21.458±12.251

0.035±0.013

0.065±0.071

<0.0001

FFTy

24.837±13.58

0.068±0.072

0.042±0.031

<0.0001

*P refers to ANOVA followed by Tuckey-Kramer post-hoc test

P53 Primary headaches associated with physical exertion

Füsun Mayda Domaç, Sergül Zengin, Mehmet Fatih Demir

Health Sciences University, Erenköy Mental and Neurological Diseases Training and Research Hospital, Neurology Department, Istanbul, Turkey
Correspondence: Füsun Mayda Domaç (fusundomac@yahoo.com.tr)

OBJECTIVE:Headaches associated with physical exertion is rare and they can be primary or secondary and their etiologies may differ depending on the headache type. Primary headaches are less often seen and pathogenesis is poorly understood. Herein, we report the cases with primary physical exertion related headaches

MATERIAL AND METHODS: Headache classification of 473 patients followed up at the Headache outpatient clinic of Health Sciences University, Erenköy Mental and Neurological Diseases Training and Research Hospital were determined due to ICHD-3. Patients with physical exertion headache were investigated detailed neurologic examination, by cranial computerized tomography, cranial magnetic resonance (MR) imaging, cranial MR angiography and venography if necessary. Patients with any secondary reasons for headache were excluded.

RESULTS: Fifteen patients (%3.17) had primary headache associated with physical activity. Among these 4 male patients had primary cough headache with sudden onset and short lasting headache in association with coughing localized at occipital region. Primary exercise headache was diagnosed in 4 male patients with bilateral pulsatile headache. Headache has occurred while weight-lifting in 2 patients and in hot weather in 2 of them. Primary headache associated with sexual activity were diagnosed in 4 male and 1 female patients. Headache was usually bilateral, starting with a dull ache and abrupt explosive intensity in association with orgasm. One of the patients had a history of migraine. Two patients were diagnosed as primary thunderclap headache with abrupt onset high intensity headache.

CONCLUSION: Primary headaches associated with physical exertion have similar characteristics of secondary headaches. All may occur as a manifestation of a possible underlying, symptomatic etiology, and additional diagnostics should typically be pursued to rule out serious causes.

P54 Headache burden in the Emergency Room

A.Quka1,O. Cibuku1,2, I.Zekja1, I. Xhura1,2, J. Kruja1,2

1Neurology Department, UHC MotherTeresa, Tirana, 1000, Albania; 2Neurology, Faculty of Medicine, University of Medicine, Tirana, 1000, Albania
Correspondence: A.Quka (aidaquka@gmail.com)

Introduction: Headache remains an important symptom which leads the patients to the ER service. The aim of this study was to evaluate the burden of the patients presenting with this main symptom and try to evaluate their further management (diagnostic tests, hospitalization rate, causes and treatment) in the ER.

Methods: We prospectively collected the data of patients complaining of headache as the main symptom, admitted in the neurological ER unit, UHC Mother Teresa for three consecutive months,January,2018 –March 2018 and evaluated their further management in the ER.

Results: 2695 patients were admitted in the neurological ER service, and 22.15% (597) of them complained of headache as the main symptom, 374(62.6%)women and 223 (37.4%) males. Mean age was 49.1±13.4 years. Primary headache was observed in 285 (47.7%)pts: Migraine 151(25.3%)pts, Tension type headache 117 (19.5%)pts, Trigeminal neuralgia in 11(1.8%)pts with and 7(1.1%)other primary headaches . Secondary headaches were observed in 312 (52.3%)pts: Subarachnoidal hemorrhage 35 (5.9%)pts, Other types of stroke 78pts (13.1%), Infections 65(3.8%)pts, Primary brain tumors 15(2.5%)pts, Secondary brain tumors 19 (3.2%)pts, uncontrolled arterial hypertension 51 (8.5%)pts, Trauma and other types of secondary headache 49(8.2%)pts. Brain CT scan was performed in 411(68.8%)pts, brain CTA was performed in 153 (25.6%)pts. Hospitalization rate was 59.1%(353pts). Most pts were treated in the ER with NSAID (85.59%) combined with benzodiazepines (59.5%). Opioids and steroids were used less frequently.

Conclusions: Pts presenting with headache as the main primary symptom occupy an important part of the neurological care in the ER service and more than half of them in our study had primary headaches or uncontrolled arterial hypertension. A better identification and follow up of pts with primary headaches, infections and uncontrolled arterial hypertension, by the primary care physician or local neurologist, may lead to reduction in the number of pts presenting in the ER and thus avoid unnecessary tests and reduce the neurologist working time in the ER.

P55 Prevalence and risk factors of tension-type headache among adolescents in Kharkiv city (Ukraine)

Stepanchenko Kostiantyn (kosty0516@gmail.com)

Department of neurology and child neurology, Kharkiv Medical Academy of Postgraduate Education, Kharkiv, 61176, Ukraine

Background. The Worldwide prevalence of tension-type headache (TTH) an average of 42% in adults. In Ukraine the prevalence of TTH in adolescents is poor documented. Aim of this study – to determine the prevalence of TTH and identify the risk factors among adolescents in Kharkiv.

Methods. The scientific work is based on the results of the survey of 2342 adolescents aged 13-18 years in the period of preventive medical examinations in randomly selected secondary schools in Kharkiv. The analysis of the risk factors for the development of TTH was conducted by the questionnaire developed by us. Possible risk factors in the formation of TTH were divided into 4 groups: hereditary, biomedical, psychosocial and welfare.

Results. It was found that the prevalence of headache in adolescents in Kharkiv was 80,2%. Girls were more likely to suffer from headache (56,3%). Primary headache was the most common type of headache (72,2%). TTH has taken the main place among primary headaches (61,1%). We observed infrequent episodic TTH in 59,7% of adolescents with TTH, frequent episodic TTH – in 33,8% and chronic TTH – in 6,5% of adolescents with TTH.

The risk factors for development of TTH in adolescents were genetics factors for headache (59%), gastrointestinal (24%) and autonomic nervous system (46%) disorders; pathology of the ante-, intra- and postnatal periods: fetal pathology (51%) and newborn (55,8%); extragenital mother's pathology (27%) (especially for adolescents with chronic TTH (35,5%)), pathology of pregnancy and childbirth (50,5%); syndrome of increased neuro-reflex excitability (46%) and sleep disorders in early childhood; comorbidity (increased excitability (18%), sleep disturbance (27%), gastrointestinal tract diseases (24%)); unfavorable family factors (divorce (23%) and quarrel (27%) of parents); poor adaptation to pre-school (51%) and school education (40%); hypodynamics (prolonged work at the computer (1,4±0,2 hours), drop in visits of sports groups (27,3%), smoking (41%) and alcohol consumption (23%).

Conclusions. The frequency of TTH in adolescents in Kharkiv city is 61,1%. The most common form is infrequent episodic TTH. Chronic TTH is observed in 6,5%. It’s revealed that the main risk factors for the development of TTH in adolescents are genetic factors, pathology of the perinatal period, concomitant pathology, unfavorable family factors, hypodynamia, smoking and alcohol consumption. Prognostic tables have been developed for allocating risk groups for the formation and chronization of TTH for the timely administration of treatment and prophylactic measures.

Ethics approval

The study was approved by Kharkiv Medical Academy of Postgraduate Education`s Ethics Board, approval number 142.

P56 Pediatric migraine: A new pediatric migraine-spesific comorbidity index on prognosis

Didem Derici Yıldırım1, Bahar Taşdelen1, Derya Uludüz2, Aynur Özge3, Osman Özgür Yalın4, Saim Yoloğlu4

1Department of Biostatistics and Medical Informatics, Mersin University Faculty of Medicine, Mersin, Turkey; 2Istanbul University, Cerrahpasa School of Medicine, Neurology Department, İstanbul, Turkey; 3Mersin University, School of Medicine, Neurology Department, Mersin, Turkey; 4Health Sciences University, Istanbul Training and Research Hospital, İstanbul, Turkey
Correspondence: Osman Özgür Yalın (osmanozguryalin@yahoo.com)

Objective: We aimed to develop and validate a comorbidity index to predict prognosis of migraine, based to a longitudinally followed heterogeneous population.

Methods: The study has been conducted from a 15-year computer based follow up data as a part of Turkish Headache Database Study group. All patients selected from Mersin University School of Medicine and Cerrahpaşa School of Medicine Neurology department headache centers. First, the latent sub-groups were determined with Group-based trajectory modeling (GBTM) as outcome’s change in time was different for each patient. With the results of GBTM analysis we developed pediatric migraine specific comorbidity index.

Results: The study conducted with 481 pediatric migraine patients. Sub-group analysis performed to reveal effects of age, gender, headache attack severity, frequency and duration. Out of all weighting methods to evaluate co-morbidities, the three group model and quadratic form of all groups fitted the data best. After deciding the number of group and functional form, the information criteria and minimum group percentage of weighting methods were compared. The best method was the posterior probabilities obtained from latent class analysis (LCA) taken as weights. We found statistically significant difference in the term of age between subgroups. The third group-which involves more then three comorbidities were significantly older (p=0.004). Headache severity and attack duration did not differ between groups. Headache attack frequency differed between groups, third group headache frequency found significantly higher (p=0.018)

Conclusion: In this study we developed a pediatric migraine comorbidity index (p-MCI) to evaluate effect of covariates on migraine course. There are need to studies to predict course of migraine to classifify high risk patient groups.

Keywords: Migraine, group-based trajectory modeling, co-morbidity index, prognosis.

P57 Characteristics of Isolated Headache patients in Cerebral Venous Sinus Thrombosis (CVST): The Results of VENOST - national survey

Derya Uludüz1, Osman Özgür Yalın2, Taşkın Duman3, Füsun Mayda Domaç4, Şerefnur Öztürk5, Vildan Yayla6, Ali Yavuz Karahan7, Nazire Afşar8, Mehmet Ali Sungur9, VENOST Study Group

1Istanbul University Cerrahpasa School of Medicine, Professor, Neurology Department,İstanbul, Turkey; 2University of Health Sciences, Istanbul Training and Research Hospital, Associate Professor, Neurology Department, İstanbul, Turkey; 3Hatay Mustafa Kemal University School of Medicine, Professor, Neurology Department, Hatay, Turkey; 4University of Health Sciences, Erenköy Training and Research Hospital, Associate Professor, Neurology Department, İstanbul, Turkey; 5Selçuk University School of Medicine, Professor, Neurology Department, Konya, Turkey; 6University of Health Sciences, İstanbul Sadi Konuk Training and Research Hospital, Professor, Neurology Department, İstanbul, Turkey; 7Uşak University School of Medicine, Professor, Neurology Department, Uşak, Turkey; 8Acıbadem University School of Medicine, Professor, Neurology Department, İstanbul, Turkey; 9 University of Health Sciences, Bakırköy Training and Research Hospital, MD, Neurology Department, İstanbul, Turkey; 10Düzce University School of Medicine, Professor, Biostatistics Department, Düzce, Turkey
Correspondence: Osman Özgür Yalın (osmanozguryalin@yahoo.com)

Introduction: Cerebral Venous Sinus Thrombosis (CVST) is a rare cause of stroke in young age with a highly variable clinical presentation. The incidence of CVST was previously underestimated due to lack of detailed neuroimaging evaluation. With the developing radiological technology it’s estimated to account 3-5% of all strokes. Despite advances in the diagnosis of CVST in recent years, diagnosis can be challenging due to intensely variable clinical spectrum. Even worse CVST may present with solely headache. In this study we aimed to reveal characteristics of isolated headache patients diagnosed with CVST.

Methods: CVST study is a nationwide, multicenter study comprised 1144 patients, data obtained from the patient follow up files and 35 national stroke centers participated to this study. This study provides largest number of CVST patient data analysis until today to literature.

Results: Among 1144 CVST cohort isolated headache presented in 287 (25.1%) patients. Headache symptom onset was frequently acute and headache is severe in the isolated headache group (p<0.001). Transverse sinus thrombosis was more frequently involved (p<0.001) and parenchymal lesions were less common in the isolated headache group (p<0.001). MRI was normal in 79.8% of the patients. Modified Rankin Score on admission and first, second and third months of the follow up were more favorable in isolated headache patients.

Conclusion: CVST could present acute, subacute and chronic symptoms. Symptoms can be intracranial hypertension (headache, nausea, visual symptoms etc.), epileptic seizure or focal neurological findings. Various types of clinical presentation is the main cause of late diagnosis. We observed that one fourth of the patients were admitted with isolated headache without any neurological symptoms or findings even without any parenchymal lesions. CVST diagnosis is important in those patients. Prompt diagnosis of CVST is based to sufficient first evaluation of patients according to headache characteristics.

P58 One-year incidence of Chronic Migraine in Tertiary Headache Outpatient Clinics: A multi-center study

Aynur Özge1, Derya Uludüz2, Osman Özgür Yalın3, Seden Demirci4, Macit Selekler5, Ali Akyol6, Şebnem Bıçakçı7, Vesile Öztürk8, Musa Öztürk9, Betül Baykan10, Mehmet Ali Sungur11, Aksel Siva2

1Mersin University School of Medicine, Professor, Neurology Department, Mersin, Turkey; 2Istanbul University Cerrahpasa School of Medicine, Associate Professor, Neurology Department,İstanbul, Turkey; 3University of Health Sciences, Istanbul Training and Research Hospital, MD, Neurology Department, İstanbul, Turkey; 4Isparta Süleyman Demirel University School of Medicine, Assistant Professor, Neurology Department, Isparta, Turkey; 5Kocaeli University School of Medicine, Professor, Neurology Department, Kocaeli, Turkey; 6Aydın University School of Medicine, Professor, Neurology Department, Aydın, Turkey; 7Çukurova University School of Medicine, Professor, Neurology Department, Adana, Turkey; 8Dokuz Eylül University School of Medicine, Professor, Neurology Department, İzmir, Turkey; 9University of Health Sciences, Bakırköy Training and Research Hospital, MD, Neurology Department, İstanbul, Turkey; 10İstanbul University School of Medicine, Professor, Neurology Department, İstanbul, Turkey; 11Düzce University School of Medicine, Professor, Biostatistics Department, Düzce, Turkey
Correspondence: Osman Özgür Yalın (osmanozguryalin@yahoo.com)

Background: Chronic migraine is a disabling neurological disorder, affecting 0.5-2% of population. Exact understanding of pathophysiological mechanisms are lack and treatment options are limited. Chronic migraine is a disorder that affect individual quality of life, and also affect population with markedly disability at working. It’s also one of the important cause of analgesic overuse, and related with many other indirect costs.

Aims: This study is aimed to investigate burden of Chronic Migraine at tertiary Neurology clinics, specifically at headache outpatient clinics. Although there are studies investigating prevalence of migraine, this is the first study in our country investigating incidence of Chronic Migraine in tertiary headache centers.

Methods: Ten tertiary Neurology clinics included and 821 patients enrolled to study. Diagnosis based to International Classification of Headache Disorders- 3 beta (ICHD-3 beta). At each center, all consecutive patients of Headache outpatient clinics admitted to study for 1-year. To estimate Chronic Migraine incidence; only new diagnosed patients included to statistical analysis.

Results: Eight-hundred and twenty one-patient included to study. 733 patients (89.3%) diagnosed wtih primary headache disorder and 88 patients (10.3%) with secondary headache disorder. Totally study groups’ 66.4% have diagnosed migraine, %18 have tension type headache, and 1.7% have trigeminal autonomic cephalalgias. The Chronic Migraine incidence was estimated as 31.2% in 821 headache clinic patients. We compared clinical features of headache between primary and secondary headache groups. Primary headache disorders were more common at males (p<0.001), patients had longer headache history (years) (p<0.001), and attack duration (p=0.006). Headache days per month was higher at secondary headache disorders patients (p=0.049).

We compared features of chronic and episodic migraine patients. Chronic migraine patients were older (p=0.026). Disease duration was longer and allodynia was more common at chronic migraine group(p<0.001).

Expectantly headache frequency per month was higher in chronic migraine, aura was less commonly observed at chronic migraine patients (p<0.001).

Conclusion: This study is conducted with a large, nationally, multi center based headache clinics to evaluated incidence of Chronic Migraine. Our results is concordant with previous reports around the world and reflect high incidence of the disease. Chronic migraine is related with prominent occupational disability and medication overuse. Thus prompt action to diagnose and treat new patients to prevent complications is mandatory.

Key words: chronic migraine, incidence, burden, disability.

Fig. 1 (abstract P58).

See text for description

P59 Vestibular Migraine presenting as an acute peripheral vestibulopathy: clinical and vestibular function test profiles

Zeljka Calic1,2,3, Rachael L Taylor4, Allison Young4, Leigh M McGarvie4, Cecilia Cappelen-Smith1,2,3, Denis Cordato1,2,3, Miriam S Welgampola4,5

1Department of Neurophysiology, Liverpool Hospital, 2170, Australia; 2South Western Sydney Clinical School, University of New South Wales, Sydney, 2170, Australia; 3Ingham Institute for Applied Medical Research, Liverpool, 2170, Australia; 4Institute of Clinical Neurosciences, Royal Prince Alfred Hospital, Camperdown, 2006, Australia; 5Central Clinical School, Sydney Medical School, University of Sydney, Camperdown, 2006, Australia
Correspondence: Zeljka Calic (zcalic@hotmail.com)

Background

Migraine is considered the chameleon of neurology and can present with headache, vertigo, visual and other sensory symptoms. Vestibular migraine is a common cause of acute spontaneous vertigo lasting minutes to days. We report the clinical, oculographic and vestibular test characteristics of eight subjects who presented with prolonged spontaneous vertigo exceeding 24 hours, initially thought to represent peripheral vestibulopathy.

Methods

The diagnosis of vestibular migraine was made according to International Headache Society and the Bárány Society criteria. A history, neuro-otological bedside examination, video head impulse testing (vHIT), cervical and ocular VEMPs (cVEMP/oVEMP) to air-conducted clicks and bone-conducted vibration, subjective visual horizontal (SVH), audiometry and Magnetic Resonance Imaging (MRI) were undertaken.

Results

Six subjects presented to the Emergency Room and two to a rapid access neurology outpatient facility with vertigo that exceeded 24 hours in duration. All had a history of previous episodes of vertigo associated with headaches. None had tinnitus or hearing loss. All had primary position unidirectional horizontal spontaneous nystagmus in keeping with a unilateral vestibular dysfunction. All underwent video head impulse testing, and all had horizontal semi-circular canal dysfunction with reduced gain and catch up saccades. CVEMPs were normal in 75% and asymmetric in 25%. OVEMPs were normal in 75% and asymmetric in 25%. SVH showed an abnormal bias in 57% (range 3.3°-5.9°) and normal in 43%. Audiometry and MRI brain were normal in all. Subjects were followed up over 1-7 years with no change in the final diagnosis.

Summary

Vestibular Migraine can sometimes present as an acute peripheral vestibulopathy with findings that mimic vestibular neuritis and should be considered in the differential diagnosis of acute prolonged vertigo.

Ethics approval

The study was approved by Royal Prince Alfred Hospital Research Ethics and Governance Office, approval number HREC/13/RPAH/591.

P60 Headache in the Pediatric Emergency Department: proposal of diagnostic and therapeutic algorithm of management

Roberta Rossi1, Antonia Versace1, Barbara Lauria1, Giulia Grasso1, Emanuele Castagno1, Fulvio Ricceri2,3, Rosaura Pagliero1, Antonio Francesco Urbino1

1A.O.U. Città della Salute e della Scienza di Torino, Regina Margherita Children’s Hospital, Department of Pediatric Emergency, Pediatric Headache Centre, Turin, Italy; 2Unit of Cancer Epidemiology, Department of Medical Sciences, University of Turin, Turin, Italy; 3Unit of Epidemiology, Regional Health Service, ASL TO3, Grugliasco (TO), Italy.
Correspondence: Roberta Rossi (roberta.rossi15@gmail.com)

Background: headache is a very frequent cause of access to the Pediatric Emergency Department (ED). The vast majority of headaches referred to the Pediatric ED are benign, due to primary form or secondary to upper airway infections [1]. The main aim of ED pediatricians is to promptly recognize headache secondary to serious organic causes that need a rapid and appropriate treatment. We propose a diagnostic-therapeutic algorithm for the management of headache in a Pediatric ED.

Methods: we analyzed the Literature published about pediatric headache in the ED and we select 31 articles.

Results: a detailed personal history and an accurate neurological examination are crucial in the evaluation of a child with headache. The clinical red flags associated to major risk of “serious headache” are: visual disturbances, cranial nerve palsy, pupillary abnormalities, nystagmus, ataxia, hyposthenia, strabismus, drowsiness and meningismus [1-3]. Neuroimaging is recommended only in patients with altered neurological examination and it should be considered in presence of a chronic progressive headache [1, 4]. The evaluation and treatment of pain are also very important and they must begin during the triage. In presence of primary headaches it is also important to give specific information to refer to Pediatric Headache Centre (PHC) within few days for the follow-up; the collaboration between ED and PHC is crucial to limit repeated visits [1, 5] (Fig. 1).

Conclusions: in the evaluation of pediatric headaches personal history and neurologic examination are crucial and should guide pediatricians to prescription of any diagnostic test. The evaluation and treatment of pain are also essential and the collaboration with PHC allows to ensure the follow-up for these patients and their families.

References

[1] Headache in the pediatric emergency department: A 5-year retrospective study. R Rossi, A Versace, B Lauria, G Grasso, E Castagno, F Ricceri, R Pagliero, AF Urbino. Cephalalgia 2018 0(0) 1–8.

[2] Acute Headache in Children and Adolescents Presenting to the Emergency Department DW Lewis, F Qureshi. Headache 2000;40:200-203.

[3] Headache with Focal Neurologic Signs in Children at the Emergency Department. D Massano et al.

J Pediatr 2014;165:376-82.

[4] Management Of Headache In The Pediatric Emergency Department. MJ Alfonzo, K Bechtel, S Babineau. Pediatric Emergency Medicine Practice. 2013. Vol 10, N 7

[5] Clinic and Emergency Room Evaluation and Testing of Headache. BL Nye, TN Ward. Headache 2015

Fig. 1 (abstract P60).

diagnostic-therapeutic algorithm for the management of headache in a Pediatric ED

P61 Correlation between pediatric primary headache and specific learning disabilities: a case-control study

Ausilia Enea1, Antonia Versace1*, Barbara Lauria1, Giulia Grasso1, Roberta Rossi1, Emanuele Castagno1, Stefania Benetti1, Veronica Sciannameo2,3, Antonio Francesco Urbino1

1A.O.U. Città della Salute e della Scienza di Torino, Regina Margherita Children’s Hospital, Department of Pediatric Emergency, Pediatric Headache Centre, Turin, Italy; 2Unit of Cancer Epidemiology, Department of Medical Sciences, University of Turin, Turin, Italy; 3Unit of Epidemiology, Regional Health Service, ASL TO3, Grugliasco (TO), Italy
Correspondence: Antonia Versace (aversace@cittadellasalute.to.it)

Objective: to investigate the connection between primary headache and specific learning disabilities in a case-control study, comparing children respectively with and without primary headache.

Background: headache cause substantial impact on physical and mental health in childhood, as well as on school performance and quality of life. Moreover, recent findings underline the connection between recurrent and chronic headache and learning disabilities, which seem to have high prevalence among children with primary headache syndromes, especially migraine.

Methods: we studied 202 children aged 3-14 years with primary headache and 202 children aged 3-14 years without headache and/or neurological and chronic disorders. We described epidemiologic and clinical features of both the populations, including specific learning disabilities, their characteristics and their correlation to different kinds of headache and other clinical features.

Results: specific learning disabilities were well represented among patients with headache, in particular tension type headache (20%) compared to migraine with aura (7.69%), but their prevalence was not significantly different comparing the overall children with and without headache (5.94% vs 7.92%, p=0.94). Children with specific learning disabilities and headache were significantly older than those without headache (mean age: 11.40 ± 1.62 vs 8.70 ± 2.20 years, respectively; p=0.001) and were mostly males, regardless of headache. We also found a borderline significant correlation between headache and type of specific learning disabilities (p-value=0.05): among children with headache, reading disabilities were more frequent (45.5% vs 12.5%), while writing disabilities were more represented among patients without headache (25% vs 0%). Overall, combined disorders were the most frequent in the two populations (62.5% in patients without headache and 45.5% in others). Specific learning disabilities showed especially during school age (56.25%), but also before school age in a relevant way (25%), among patients with and without headache.

Conclusions: we found some connections about the type of headache, age and type of specific learning disabilities. The presence of specific learning disabilities is relevant among children with headache, in particular among children with tension type headache compared to migraine with aura, supporting “the continuum model” about tension type headache and migraine without aura (mixed headaches) as part of a continuum opposed to migraine with aura. Specific learning disabilities frequently show before school age and their early diagnosis can have beneficial effects on school performance as well as on headache attacks, improving the quality of life. Moreover, it is important to evaluate the presence and the type of headache among children with specific learning disabilities.

P62 Astrocytes contribute to the trigeminal central sensitization and cephalic cutaneous hypersensitivity in rat model of chronic migraine

M. Megemont, A. Descheemaeker, R. Dallel, L. Monconduit and P. Luccarini*

Université Clermont Auvergne, Inserm, Neuro-Dol, F-63000 Clermont-Ferrand, France
Correspondence: M. Megemont (philippe.luccarini@uca.fr)

Repeated migraine attacks are associated with maladaptive neural plasticity and lead to chronic headache. Sensitization of the pain pathways could play an important role in migraine’s pathophysiology and in the transition to the chronic forms of the disorder. In recent years, it is increasingly recognized that glial cells in the spinal and medullary dorsal horn (MDH), such as astrocytes, are activated in response to peripheral nerve injury or peripheral tissue injury and are involved in central sensitization of nociceptive neural networks (Ji et al., 2011, Lefevre et al., 2015). Combining behavioral and in vivo electrophysiological approaches, this study examined the contribution of astrocytes activity in trigeminal central sensitization and cephalic cutaneous hypersensitivity in a new model of chronic migraine (Dallel et al, 2018). We investigated the effect of intracisternal (i.c.) application of D-Amino-Acid-Oxidase (DAAO), a D-Serine degrading enzyme, on cephalic cutaneous sensitivity and on neuronal activation within the MDH in the rat evoked by recurrent administration of systemic administration of isosorbide dinitrate (ISDN), a nitric oxide donor (NO).

Recurrent ISDN injection (10 mg/kg, i.p., 5 injections, 1 per day) induced a persistent cephalic mechanical allodynia in vehicle-treated rats that peaked at 1 h. Conversely, DAAO-treated (0.17 UI in 5μl, i.c.) rats did not develop such cephalic mechanical allodynia. The anti-allodynia effect was significant at 30 min after ISDN administration and lasted at least 4 h (p< 0.0001). Using in vivo electrophysiological unitary extracellular recordings, we show that ISDN administration never affected the spontaneous activity of trigeminal wide dynamic range neurons, but facilitated C-fiber-evoked responses in 62% (18/29) of the neurons tested. The facilitation was significant from 30 min and still increased until 120 min (144 ± 3.4 % of baseline, n = 18, P < 0.001). Conversely, diffuse noxious inhibitory controls, quantified as an inhibitory effect on MDH neuronal firing during heterotopic immersion of one hindpaw in 49°C bath, remained unchanged. Interestingly, DAAO (0.17 UI in 5μl, i.c.) administration before the last ISDN injection prevented the facilitation by ISDN of C fiber-evoked activity of wide dynamic range neurons.

These results suggest that astrocytes contribute to the trigeminal central sensitization and cephalic cutaneous hypersensitivity that characterize the migraine progression.

P63 Withdrawn

P64 Сortical excitability in chronic migraine patients after OnabotulinumtoxinA preventive treatment

Vladlena Shevchenko1, Ada Artemenkoˡ, Mikhail Bzhiljanski2, Fedor Bushkov2, Nikolay Yahnoˡ, Alexey Kurenkov3

1Research Department of Neurology, Scientific-technological Park of biomedicine, I.M. Sechenov First Moscow State Medical University, Moscow, 119991, Russia; 2Rehabilitation centre «Preodolenie», Moscow, Russia, 127083; 3Scientific Centre of Children’s Health of the Ministry of Health of the Russian Federation, Moscow, 119991, Russian Federation
Correspondence: Vladlena Shevchenkoˡ (vladashevchenko@list.ru)

Background: Chronic migraine (CM) is a common and disabling disease from the primary headache group, one of the migraine (M) form, characterized by 15 headache days a month or more and at least eight days of them are represented by typical M attacks [1]. The leading role in the CM pathophysiology belongs to cortical hyperexcitability [2,3]. Transcranial magnetic stimulation (TMS) is the most informative and non-invasive tool to investigate the cortical excitability and cortical inhibition processes [4]. OnabotulinumtoxinA (Botox®) is the medication with proven efficacy (level A) in CM preventive therapy. The mechanism of OnabotulinumtoxinA (Botox®) analgesic effect is not fully understood, mainly associated with its peripheral action by blocking neurogenic inflammation and proinflammatory neuropeptides transmission in sensory nerves terminals of the trigemino-cervical system, but possible central effects have not been studied [5].

The aim of the study: to investigate the influence of OnabotulinumtoxinA on cortical excitability after CM preventive treatment using TMS.

Materials and methods: This open-label, prospective study included 36 patients with CM in the interictal period (mean age 41,9±10,6 years, female/ male 93,2%/6,8%) at the Moscow University neurological clinic. The diagnose of CM was established according to ICHD-III criteria, 2018. Clinical data were obtained from headache diaries: number of headache days per month; number of attacks per month, number of days with taking medications for acute migraine treatment. We determined neurophysiological parameters using diagnostic TMS («MagPro R30» (Medtronic, Copenhagen, Denmark) with figure-of-eight coil: motor cortex thresholds (MT r/l, % of maximal stimulator output) and the cortical silent period duration (CSP r/l, ms) were measured by stimulation of the motor cortex and recording responses from abductor digiti minimi muscles r/l, using electromyograph «Keypoint» (Medtronic, Copenhagen, Denmark). Also, phosphene threshold (PT, % maximal stimulator output) was assessed by visual cortex stimulation with the same coil before and 3 months after OnabotulinumtoxinA (Botox®) injections at a dose of 195 units, according the PREEMPT paradigm [5].

Results: Three month after OnabotulinumtoxinA (Botox®) treatment we found the reduction of headache frequency on 11 days (p<0,05), number of attacks per month on 7 days (p<0,05), number of days with taking medications for acute migraine treatment on 13 days (p<0,05). No significant differences were observed in MT r/l and PT (MTd: before treatment 43,5±10,1%, after 44,9±9,3%, p = 0.65, MTs: before 43,9±10,7%, after 44,76±7,63%, p=0,54; PT: before 71,1±17,2%, after 72,4±12,2%, p=0,62). The duration of the CSP r/l increased significantly (CSPd: from 99,1±28,7ms to 120±30,5ms, p ≤ 0.05, CSPs: from 98,8±28,5 to 126,4±36, р≤0,05).

Conclusion: The results of our study showed such changes in cortical excitability as an increasing duration of the cortical silent period for both brain hemispheres after Onabotulinumtoxin A treatment what was combined with the headache frequency reduction and improvement in the patients' condition.

References

1) Olesen J, et al., International Classification of Headache Disorders: 3rd Edition Lancet Neurol.2018 May; 17(5):396-397.

2) Aurora SK et al.: The brain is hyperexcitable in migraine. Celphalalgia. 2007 Dec;

3) Peter J. Goadsby Pathophysiology of migraine. Ann Indian Acad Neurol. 2012 Aug; 15(Suppl 1): S15–S22.

4) Barker AT, Shields K. Transcranial Magnetic Stimulation: Basic Principles and Clinical Applications in Migraine. Headache. 2017 Mar;

5) Dodick DW et al. PREEMPT Chronic Migraine Study Group. OnabotulinumtoxinA for treatment of chronic migraine: pooled results from the double-blind, randomized, placebo-controlled phases of the PREEMPT clinical program. Headache. 2010 Jun; 50(6):921-36.

P65 Beyond the headache phase of a migraine attack: closer look at the burden of migraine phases - results from the worldwide My Migraine Voice survey

Michel Lanteri-Minet1, Rebeca Quintana2, Veruska Carboni3, Paolo Martelletti4, 5, Todd J. Schwedt6, Hans- Christoph Diener7, Annik K.-Laflamme8, Elena Ruiz de la Torre9, Audrey Craven10, Simon Evans11, Donna Walsh12, Annette Vangaa Rasmussen13, Paula Dumas14, Rachel Fink8, Angela Fiorin8, Stephanie Ribbe8, Pamela Vo8

1Département d’Evaluation et Traitement de la Douleur, Centre Hospitalo-Universitaire de Nice, Nice, France; 2GFK, Madrid, Spain; 3GfK Health, Basel, Switzerland; 4Department of Clinical and Molecular Medicine, Sapienza University of Rome, Rome, Italy; 5EHF; 6Neurology Arizona, Mayo Clinic, Phoenix, United States; 7Department of Neurology and Headache Center, University Duisburg-Essen, Germany; 8Novartis Pharma AG, Basel, Switzerland; 9European Headache Alliance, Brussels, Belgium; 10Migraine Association Ireland, Dublin, Ireland; 11Migraine Action, Leicester, United Kingdom; 12European Federation of Neurological Associations, Brussels, Belgium; 13Rigshospitalet Glostrup, Copenhagen, Denmark; 14Migraine Again, United States
Correspondence: Michel Lanteri-Minet (lanteri-minet.m@chu-nice.fr)

Introduction

Limited evidence exists on the quantitative burden associated with premonitory and postdromal phases of the migraine attack. This study aimed to evaluate the burden of migraine as described by patients in these specific migraine phases: premonitory, headache, and postdromal.

Methods

My Migraine Voice is a cross-sectional study conducted using an online survey of 11,266 migraine patients (31 countries across Africa, America, Asia and Europe) recruited via online panels and patient organizations. Participants were adult migraine patients per ICHD-3 criteria, who reported having had >=4 migraine days/month in the 3 months preceding survey administration, with pre-specified 90% having reported having used preventive migraine treatment.

Results

A total of 11,266 migraine patients responded to the survey and reported that, over the last 3 months, they had on average 9.8 migraine days/month; 37% reported being affected by migraine for >15 years. 44% of respondents’ migraine attack lasted one day or more (19% reported longer than 3 days). Half of patients (49%) reported feeling limited throughout the 3 migraine phases. Almost 1/3 of patients (29%) reported feeling very to extremely limited during the premonitory phase, 71% during the headache phase and 30% in the postdromal phase (Table 1).

Conclusion

This study is the first to quantify the burden experienced by patients during the different phases of migraine. While the attack itself caused the highest degree of impairment, the findings demonstrate that the burden of migraine extends beyond the headache phase and is higher for patients who have failed >=1 preventive treatment.

Ethics approval:

Data was handled confidentially and anonymity of respondents was maintained throughout the study. Participants’ consent was obtained prior to participation in the survey.

Funding

This study was funded by Novartis Pharma AG, Basel Switzerland

Table 1 (abstract P65).

Description of the migraine phases

Proportion of respondents (%)

Premonitory phase

Headache phase

Postdromal phase

Duration of phase

 < 4 hours

51%

20%

30%

 4-24 hours

30%

45%

40%

 >24 hours

14%

34%

27%

Not experiencing this phase

6%

1%

3%

Duration of the phase >24 hours in migraine patients with:

 - no failure to migraine preventive treatment

11%

27%

20%

 - 1 failure to migraine preventive treatment

11%

29%

23%

 - ≥2 failures to migraine preventive treatment

17%

38%

30%

Feeling very to extremely limited during the phase

29%

71%

30%

P66 Withdrawn

P67 Carbon monoxide inhalation induces headache but no migraine in patients with migraine without aura

Hashmat Ghanizada1, Nanna Arngrim1, Henrik Winther Schytz1, Jes Olesen1, Messoud Ashina1

1Danish Headache Center and Department of Neurology, Rigshospitalet Glostrup, Faculty of Health and Medical Sciences, University of Copenhagen, Valdemar Hansens vej 5, DK-2600 Glostrup, Denmark
Correspondence: Messoud Ashina (ashina@dadlnet.dk)

This abstract was not included as it has been previously published [1].

Reference:

[1] Ghanizada H, Arngrim N, Schytz HW, Olesen J, Ashina M. Carbon monoxide inhalation induces headache but no migraine in patients with migraine without aura. Cephalagia. 2018: 333102418765771. doi: 10.1177/0333102418765771

P68 Demographic and clinical characteristics of patients with trigeminal neuralgia assisted by neurologists in an Emergency Department

Javier Camiña Muñiz, Germán Ferrer Juan, María Magdalena Rosselló Vadell, Antonio José Moreno Rojas, Francisco José Molina Martínez

Department of Neurology. Hospital Universitari Son Espases, Carretera de Valldemossa, 79. 07120, Palma, Illes Balears, Spain
Correspondence: Javier Camiña Muñiz (javier.camina.muniz@gmail.com)

Background: Trigeminal neuralgia is characterized by recurrent brief episodes of severe paroxysmal pain often needing medical treatment in Emergency Departments in cases of severe outbreaks of symptoms, with antiepileptic and non-antiepileptic drugs.

Objectives: To describe the demographic, clinical and therapeutical characteristics of 100 patients with acute exacerbations of trigeminal neuralgia treated in an Emergency Department. To analyze possible risk factors and predictors of these exacerbations.

Methods: We have retrospectively searched for patients with a diagnosis of trigeminal neuralgia by the clinical system of the Emergency Department (Firstnet® of Millennium). Demographic and clinical characteristics of the patients are collected from the clinical history by the Millennium Powerchart® clinical system.

Results: One hundred (100) patients with acute exacerbation of trigeminal neuralgia were treated in Emergency Department in 153 episodes between May 2016 and May 2018. They had an average age of 57 years, 64.60% were women and 34.68% needed more than 1 visit over this period. In 16.34% of the cases hospitalization was required for pain management.

Conclusion: Around 20% of patients with craniofacial pain assisted by Neurology in our Emergency Department have trigeminal neuralgia. One of the clinical objectives in trigeminal neuralgia patients should be to reduce the probability of admission by optimizing their outpatient treatment.

P69 Systematic review of the safety and efficacy of Occipital Nerve Stimulation for intractable chronic cluster headache

Iris Smet1, Jean-Pierre Van Buyten1, Michel Lanteri-Minet2, Denys Fontaine3, Jennifer Tinsley4, Brooke Kelley5

1 Multidisciplinary Pain Centre AZ Nikolaas, Sint -Niklaas, 9100, BE; 2 Pain Department CHU Nice, FHU INOVPAIN, Côte Azur University, 06001, Nice, FR; 3 Department of Neurosurgery, CHU de Nice, FHU INOVPAIN, University Cote d’Azur, 06001, Nice, FR; 4 Medtronic International Trading Sàrl, Clinical Research, Tolochenaz, 1131 CH; 5 Medtronic Plc, Clinical Research, Minneapolis, Minnesota, 55432, US
Correspondence: Jennifer Tinsley (jennifer.tinsley@medtronic.com)

Background: Occipital Nerve Stimulation (ONS) consists of applying mild electrical stimulation to the occipital nerves via leads implanted under the skin. An implanted battery generates the stimulation.

Methods: A literature search in MEDLINE and EMBASE was conducted to evaluate the safety of ONS (to treat any headache condition) and the performance of the therapy to treat Intractable Chronic Cluster Headache (iCCH). The search used a combination of peripheral nerve locations, and neurostimulation and headache key terms (timeframe 01-Jan-1990 through 30-AUG-2017).

Results: Of 820 results, 71 met selection criteria. Twenty-one publications described ONS for iCCH. There were 7 unique studies where performance outcome data could be pooled:
  • 61.8% of patients reduced attack frequency by ≥30% (5 studies; 110 patients) and 54.9% reduced by ≥50% (5 studies; 164 patients)

  • 39.3% of patients had reduced CH intensity score of ≥30% (5 studies; 56 patients)

  • mean 41.8% reduction in attack duration (2 studies; 78 patients)

  • 43.1% of patients reduced medications to some extent (7 studies; 188 patients)

Thirteen prospective studies comprising 575 unique patients with an average 37.5 months follow-up were included. A total of 469 adverse events (AEs) were reported with an AE rate (number of AEs/number of subjects) of 81.6% overall (range 12.5-130.6%). Most common events were lead migration (10.1%), persistent pain at device site (11.3%), undesirable change in stimulation (11.3%), infection (7.7%), wound complications (3.7%) and skin erosion (3.5%).

Conclusions: While efficacy of ONS for iCCH appears promising, the complication rate shows a need for improved technology and implant techniques.

P70 Safety data from phase 3 clinical studies comparing galcanezumab and placebo in patients with episodic and chronic migraine

Virginia L. Stauffer, Shufang Wang, Mark E. Bangs, Tina M. Oakes, Jeffrey N. Carter, Sheena K. Aurora

Lilly Research Laboratories, Indianapolis, IN, USA
Correspodence: Jeffrey N. Carter (carter_jeffrey_n@lilly.com)

OBJECTIVE: To evaluate the safety and tolerability of galcanezumab compared with placebo each given monthly (subcutaneous injection) for up to six months for prevention of migraine.

METHODS: Data were integrated from three double-blind clinical studies (EVOLVE-1=NCT02614183; EVOLVE-2=NCT02614196; REGAIN=NCT02614261); two galcanezumab dose-groups (120- and 240-mg) were pooled. Adverse events (AEs) that were treatment-emergent (TEAEs), discontinuation due to AEs (DCAEs), and serious AEs (SAEs) were analyzed. Laboratory results, vital signs, and ECG results were also assessed. Calcitonin gene-related peptide is a potent vasodilator and believed to play a protective role in cardiovascular (CV) health. People with migraine often have CV risk; therefore, patients with comorbid CV disease and risk based on medical history or pre-existing conditions were evaluated. The studies were approved by the appropriate Institutional Review Board for each study site.

RESULTS: A total of 1,435 patients were treated with galcanezumab and 1,451 with placebo. At baseline, 18.5% of placebo- and 17.2% of galcanezumab-treated patients reported CV risk factors. During the treatment period, TEAEs occurring in 1.5% or more of galcanezumab-treated patients, more frequently than among placebo-treated patients, and significantly different between galcanezumab and placebo included nasopharyngitis, injection site reaction, injection site erythema, injection site pruritus, and constipation (Table 1). The proportion of DCAEs among galcanezumab-treated patients was low (Table 2), and the proportion of patients who discontinued due to an injection-site related AE was less than 0.5%. None of the TEAEs related to injection site were reported as an SAE, and the majority of patients reported the events as mild or moderate in severity. Fewer than 2.0% of galcanezumab-treated patients reported an SAE (Table 2). There were no significant differences between galcanezumab- and placebo-treated patients in the frequency of serious CV TEAEs, or discontinuations due to CV TEAEs. There were no significant treatment-by-cardiovascular disease subgroup interactions for CV TEAEs. There were no clinically meaningful differences between galcanezumab- and placebo-treated patients in laboratory analytes, vital signs, ECGs, or cardiovascular-related TEAEs.

CONCLUSION:

Galcanezumab (120- and 240-mg monthly) demonstrated a favorable safety and tolerability profile for the prevention of episodic and chronic migraine.

Table 1 (abstract P70).

Treatment-emergent adverse events reported by 1.5% or more patients in any galcanezumab dose-group.

  

Galcanezumab

Event

Placebo

N=1451

n (%)

120-mg

N=705

n (%)

240-mg

N=730

n (%)

Combined N=1435

n (%)

Injection site pain

138 (9.5)

71 (10.1)

85 (11.6)

156 (10.9)

Nasopharyngitis

94 (6.5)

52 (7.4)

31 (4.3)

83 (5.8)

Upper respiratory tract infection

60 (4.1)

31 (4.4)

36 (4.9)

67 (4.7)

Injection site reaction

14 (1.0)

22 (3.1)

45 (6.2)

67 (4.7)

Dizziness

41 (2.8)

20 (2.8)

20 (2.7)

40 (2.8)

Injection site erythema

20 (1.4)

20 (2.8)

29 (4.0)

49 (3.4)

Sinusitis

31 (2.1)

20 (2.8)

19 (2.6)

39 (2.7)

Urinary tract infection

33 (2.3)

19 (2.7)

18 (2.5)

37 (2.6)

Fatigue

34 (2.4)

17 (2.4)

16 (2.2)

33 (2.3)

Injection site pruritus

2 (0.1)

15 (2.1)

24 (3.3)

39 (2.7)

Neck pain

21 (1.5)

15 (2.1)

6 (0.8)

21 (1.5)

Abdominal pain

24 (1.7)

13 (1.8)

6 (0.8)

19 (1.3)

Cough

19 (1.3)

12 (1.7)

13 (1.8)

25 (1.7)

Oropharyngeal pain

13 (0.9)

10 (1.4)

12 (1.6)

22 (1.5)

Bronchitis

17 (1.2)

9 (1.3)

11 (1.5)

20 (1.4)

Influenza

34 (2.3)

8 (1.1)

20 (2.7)

28 (2.0)

Constipation

8 (0.6)

7 (1.0)

11 (1.5)

18 (1.3)

Migraine

14 (1.0)

7 (1.0)

12 (1.6)

19 (1.3)

Indicates P < .05 compared with placebo

Indicates P < .001 compared with placebo

Table 2 (abstract P70).

Overview of adverse events.

  

Galcanezumab

Event

Placebo

N=1451

n (%)

120-mg

N=705

n (%)

240-mg

N=730

n (%)

Combined

N=1435

n (%)

Deaths

0

0

0

0

SAE

14 (1.0)

12 (1.7)

11 (1.5)

23 (1.6)

DCAE

24 (1.7)

13 (1.8)

22 (3.0)

35 (2.4)

TEAE

827 (57.0)

441 (62.6)

472 (64.7)

913 (63.6)

Abbreviations: SAE Serious adverse events, DCAE discontinuation due to an adverse event, TEAE Treatment-emergent adverse events

Indicates P < .05 compared with placebo

Indicates P < .001 compared with placebo

P71 OnabotulinumtoxinA: How and when do our patients improve?

A.Alpuente1,2, VJ. Gallardo2, M.Torres-Ferrús1,2, J.Álvarez-Sabín1, P.Pozo-Rosich1

1Headache Unit, Neurology Department, Hospital Universitari Vall d'Hebron, Barcelona, Spain; 2Headache Research Group, Vall d'Hebron Research Institute (VHIR), Universitat Autònoma de Barcelona, Barcelona, Spain
Correspondence: P.Pozo-Rosich (ppozorosich@yahoo.com)

Objective: To analyze the clinical characteristics of a long-term follow-up of patients with migraine in treatment with onabotulinumtoxinA.

Methods: A three-year prospective observational study. We included patients diagnosed with chronic migraine (CM) and high-frequency episodic migraine (HFEM) according to ICHD-3 beta. We collected clinical data. A comparative analysis was carried out at 6, 12, 18 and 24 months identifying response variables (frequency, intensity, analgesics intake) according to treatment and diagnosis time.

Results: Data was collected from 534 patients (84.6% women, mean age 46.9±12.8 years): 80.1% CM and 19.9% HFEM, 59.9% had medication-overuse (MOH) and 81.2% had severe disability (MIDAS). After 6 months (n=352), average headache frequency improved (-42.0%±39.1 in MC). In the following months, this reduction continued with a stepwise slope: -45.4% ± 34.2 (12 months), -48.6% ± 38.5 (18 months) and 59.4% ± 29.8 (24 months). Likewise, in CM patients, we observed and improvement in intensity greater than 50% during the follow-up (46.9% at 6 months, 50.0% at 12 months, 58.6% at 18 months, 63.9% at 24 months) and analgesics intake (81.7±59.3% at 6 months). There was also an statistically significant improvement in headache frequency, intensity and analgesics intake in HFEM patients.

An improvement in the anxiety and depression scales (HAD) at 6 months of treatment (19.0 ± 1.2 vs. 10.0 ± 5.0 with p-value <0.01, 15.8% ± 5.1% vs 7.8 ± 5.2 with p-value <0.05) was observed, and this remained stable during the rest of follow-up.

During the 24 months of follow-up, 23.2% discontinued treatment because of: clinical improvement (20.9%-CM vs. 34.2%-HFEM), lack of efficacy (46.5%-CM vs. 31.6%-HFEM) and other medical reasons (32.6%-CM vs. 34.2%-HFEM).

Conclusion: In our cohort, onabotulinumtoxinA efficacy is significant at 6 months, with further moderate progressive improvement at medium term.

The improvement in CM and HFEM is proportional and significant in terms of headache frequency, intensity, and analgesic intake.

This improvement is correlated with less anxiety and depression.

P72 The role of foods with a high glycemic index in migraine patients: a real life preliminary study

Gianluca Cecchi, Maria Bravo, Paola Di Caprio, Giorgia Botti, Nicoletta Brunelli, Matteo Paolucci, Manon Khazrai, Fabrizio Vernieri, Claudia Altamura

Headache and Neurosonology Unit, Neurology Unit, Università Campus Bio-Medico di Roma, Rome, Italy.
Correspondence: Gianluca Cecchi (gianlucacecchi250489@gmail.com)

Introduction

Migraine is one of the main causes of disability according to the WHO. [1] Numerous progresses have been accomplished in the individuation of the subtending pathogenetic mechanisms but there are still lands to be discovered. Different predisposing and trigger factors have been identified, among these an important role is played by an incorrect diet. [2]This study aimed at evaluating retrospectively the relationship between dietary habit, and migraine frequency and disability.

Methods

We enrolled 149 consecutive patients (mean age 41 ys SD 13.2, 86% female) affected by Migraine with or without Aura referring to our Headache Centre. All patients underwent anthropometric assessment and filled a Frequency Food Questionnaire (FFQ) to assess their dietary habit and clinical scales (BS11, PPI, BRS6, MIDAS e HIT-6) in the previous three months. All data were analysed with SPSS 25.0. The study was approved by our Local Ethical committee (prot 6.18TS CBM). Informed consent to publish has been obtained from patients.

Results

The analysis of baseline data showed average BMI 24.6 ± 4 kg/m2 and Waist Circumference 83 cm; mean headache days per month 9.3 ± 7, abortive drugs per month 9.2 ± 7, MIDAS TOT 25.6 ± 33, MIDAS-A TOT 20,7

± 18,6, MIDAS-B TOT 6.3 ± 1.9, HIT6 TOT 63.6 ± 7, BS-11 TOT 7.5 ± 1.9, PPI TOT 3.4 ± 1, BRS 6 TOT 3.7 ± 1.

We observed a correlation between sweet confectionery product (croiassant, biscuits, sweets and spreads) weekly intake and BS-11 (Spearman Rho= 0.178, p= 0.04), and PPI(Spearman Rho= 0.181, p= 0.037), MIDAS- tot (Spearman Rho= 0.189, p= 0.021) and HIT6 (Spearman Rho= 0.231, p= 0.005). Weekly rice consumption had a correlation with MIDAS-B (Spearman Rho=0.223, p=0.01). Likewise the consumption of potatoes had a correletion beetween MIDAS- B (Spearman Rho=0.216, p=0.022) and HIT6 (Spearman Rho=0.200, p=0.034). No other relation were observed between headache frequency and disability and all other foods and drinks.

Discussion and conclusion

Literature data hypothesize that changes of blood glucose values may play a role in the pathogenesis of fasting headaches. Martins-Oliveria et all highlighted that glycemic neuroendocrine signaling modulates specific neural networks can alter the transmission of trigeminal nociceptive inputs [3]. Our study supports this hypothesis: patients consuming more frequently high-glycemic foods tend to score higher on disability scales. We can speculate that high-glycemic foods amplify glucose and insulin blood oscillations, producing unstable neuroendocrine signalling.

References

1. Global, regional, and national incidence, prevalence, and years lived with disability for 301 acute and chronic diseases and injuries in 188 countries, 1990-2013: a systematic analysis fot the Global Burden of Disease Study 2013. 2015 Aug 22; 386 (9995):743-800.

2. Dalcara T. How does fasting trigger migraine? A hypothesis. Curr Pain Headache Rep. 2013;17(10):368)

3. Martins-Oliveira M, Akerman S, Holland PR, et al (2017) Neuroendocrine signaling modulates specific neural networks relevant to migraine. Neurobiol Dis 101:16–26 . doi: 10.1016/j.nbd.2017.01.005

P73 Do evidence-based practice guidelines exist to support physiotherapists in the approach of patients with episodic headache?

Sarah Mingels1,2, Marita Granitzer1

1REVAL Rehabilitation Research Centre, Biomedical Research Institute, Faculty of Medicine and Life Sciences, Hasselt University, Belgium; 2Musculoskeletal Research Unit, Department of Rehabilitation Sciences, Faculty of Kinesiology and Rehabilitation Sciences, Leuven University, Belgium
Correspondence: Sarah Mingels (sarah.mingels@uhasselt.be)

Background

The International Classification of Headache Disorders provides an extensive framework to classify headaches as primary or secondary. Physiotherapy is indicated if neuro-musculoskeletal dysfunctions are assumed to be related to the pathophysiological process. Mostly patients suffering from episodic migraine, cervicogenic and tension-type headache consult physiotherapists. Various interventions such as manual therapy, relaxation and exercise therapy are applied in such patients. Yet, clinical outcomes following physiotherapy tend to vary (Fig. 1).

Methods

National and international physiotherapy guidelines concerning the treatment of headache were searched in the databases Pubmed, Web of Science, Pedro and the Cochrane library from January to May 2017. The following Topics or Medical subject heading terms were combined: 'Headache', 'Adult', 'Physiotherapy or Physical Therapy', '(EBM/EBP) Guidelines' and 'Recommendations'. Guidelines as well as meta-analyses and (systematic) reviews in English and Dutch were included.

Results

Guidelines focus primarily on the pharmacological management of headache. From only two evidence-based physiotherapy guidelines it was concluded that effectiveness of interventions will depend on clinical reasoning since not all interventions are equally effective for all headache types (Fig. 2).

Fig. 1 (abstract P73).

Visualisation of the consequence of random physiotherapeutic interventions in patients with headache

Fig. 2 (abstract P73).

Visualisation of determinant-based physiotherapeutic interventions in patients with headache

P74 Efficacy and safety of a sequential surgical algorithm in 44 patients with refractory chronic cluster headache

Robert Belvís, Marina Guasch, Paula Marrero, Maria Jesus Alvarez, Rodrigo Rodriguez, Joan Molet, Carles Roig

Department of Neurology and Department of Neurosurgery. Hospital de la Santa Creu i Sant Pau. Barcelona. Spain
Correspondence: Robert Belvís (rbelvis@santpau.cat)

Several surgical procedures have been proposed when chronic cluster headache (CCH) becomes refractory (r). We usually perform in order of safety: ipsilateral sphenopalatine ganglion radiofrequencies (SPG-Rf), bilateral occipital nerve stimulation (NOM-S) and deep brain stimulation (DBS).

Patients.

We included patients with rCCH according to ICHD3 / EHF criteria between November 2003 - June2018 (mean follow-up: 87.4 months). End-point of efficacy: reduction superior to 50% of headache attacks / day.

Results.

We performed 74 SPG-Rf procedures in 44 patients (man: 70.4%, mean age: 41.2y). Average of headache attack / day: 4.4, and mean triptans / day consumption: 3.4. Efficacy of SPG-Rf: 33.3%. SPG-Rf reduced NRS score (10/10 points-to-7/10 points) and triptans consumption (20.5%). Safety: vaso-vagal syncope during the procedure (1) and palatal hypoaesthesia as a sequel (1).

We implanted bilateral NOM-S devices in 22 of the 29 SPG-Rf-refractory patients. Average of headache attack / day: 5.7, main sc sumatriptan / day consumption: 4.4. Efficacy of NOM-S: 50%. NOM-S reduced NRS score (10/10 points-to-6/10 points) and triptans consumption (50%). Three patients (13.6%) have been able to shut down the system. Complications: system infection-4, broken electrode-1, disconnected electrode-1.

Finally, 7 patients (man: 87.7%, mean age: 44.6y) were subjected to DBS (posterior hypothalamus), five of them due inefficacy of NOM-S and two more directly after SPG-Rf because NOM-S did not exist then. Average of headache attack / day: 6.5, mean sc sumatriptan / day consumption: 5.7. Efficacy: 85.7%. DBS reduced NRS score (10/10 points-to-4.5/10 points) and triptans consumption (74.5%). Only one patient (14.3%) has been able to shut down the system. Complications: broken electrode-1, relocation of electrode-1.

Conclusions.

The 86% of our refractory chronic cluster headache patients improved their quality of life, substantially and in a sustained way, after applying this surgical algorithm sequentially. We did not register serious adverse effects or relevant surgical complications.

P75 Spectral domain optical coherence tomography findings in RVCL-S, a monogenic vascular migraine model

Irene de Boer1, Sylvie R. Steenmeijer2, Nadine Pelzer1, Greet Dijkman2, Irene C. Notting2 , Gisela M. Terwindt1

1 Department of Neurology, Leiden University Medical Center, Leiden, 2300 WB, The Netherlands; 2 Department of Ophthalmology, Leiden University Medical Center, Leiden, 2300 WB, The Netherlands

Correspondence: Irene de Boer (ideboer@lumc.nl)

Background

Retinal Vasculopathy with Cerebral Leukoencephalopathy and Systemic manifestations (RVCL-S) is a monogenic small vessel disease caused by mutations in TREX1.[1] Several organs, including the brain and retina, are affected, most likely due to endothelial dysfunction.[2] One of the striking associated neurological symptoms is migraine. Migraine has a complex genetic background, but by using monogenic, homogenous, pathophysiological models we aim to increase our knowledge of migraine pathophysiology. One of such models for studying migraine is RVCL-S. Because the retina is a peripheral extension of the brain and shares a similar embryological origin, analyzing retinal anatomy is increasingly seen as a useful biomarker for multiple neurological disorders.[3-6] Optical coherence tomography (OCT) provides a non-invasive high-resolution visualization of the optic disc and retinal layers by creating cross-sectional images.[7] The aim of this study was to investigate retinal layer pathology as a possible biomarker for the migraine model RVCL-S.

Methods

Seventeen TREX1 mutation carriers and nine unrelated controls were included and examined by spectral domain optical coherence tomography (SD-OCT). Peripapillary retinal nerve fiber layer (pRNFL) thickness and total macular volume (TMV) were determined. Secondary outcomes were total macular thickness (TMT) and the thickness of individual retinal layers of the macula and peripapillary sectors of the pRNFL. SD-OCT measures of patients (n=34 eyes) and controls (n=18 eyes) were compared using generalized estimating equations (GEE) to account for intereye correlation.

Results

We found a decrease in pRNFL thickness (79.3 ±22.2 vs 99.5 ±11.8μm, p<0.001), and TMV (8.0 ±0.8 vs 8.6 ±0.4mm3, p=0.006) in TREX1 mutation carriers compared to controls (Fig. 1), which may occur at a relatively young age (Fig. 2). With the exception of the temporal sector, the thickness of all peripapillary sectors were decreased in TREX1 mutation carriers (Table 1). In TREX1 mutation carriers the TMT (292.0 ±32.1 vs 313.8 ±15.1μm, p=0.009) and individual layers in the macular area, ganglion cell layer (29.6 ±9.5 vs 38.3 ±3.2μm, p<0.001) and inner plexiform layer (27.9 ±6.2 vs 33.1 ±2.1 μm, p=0.001), were shown to be thinner than in controls (Table 2).

Conclusion

RVCL-S is associated with retinal thinning in the peripapillary and macular area. SD-OCT may serve as a mirror of the brain, therefore it will be interesting to see if these retinal changes mirror disease progression cerebrally. Furthermore, these retinal measurements might improve our understanding of several diseases for which RVCL-S serves as a model, including migraine.

Ethics Approval

The study was approved by Leiden University Medical Center Institution’s Ethics Board, approval number: P14-299.

Consent to publish

Informed consent to publish has been obtained from the patients

References

1. Stam AH, Kothari PH, Shaikh A, Gschwendter A, Jen JC, Hodgkinson S, et al. Retinal vasculopathy with cerebral leukoencephalopathy and systemic manifestations. Brain : a journal of neurology. 2016.

2. Pelzer N, Bijkerk R, Reinders MEJ, van Zonneveld AJ, Ferrari MD, van den Maagdenberg AMJM, Eikenboom J, Terwindt GM. Circulating Endothelial Markers in Retinal Vasculopathy With Cerebral Leukoencephalopathy and Systemic Manifestations. Stroke. 2017 Dec;48(12):3301-3307.

3. Cunha LP, Almeida AL, Costa-Cunha LV, Costa CF, Monteiro ML. The role of optical coherence tomography in Alzheimer's disease. International journal of retina and vitreous. 2016;2:24.

4. Alten F, Motte J, Ewering C, Osada N, Clemens CR, Kadas EM, et al. Multimodal retinal vessel analysis in CADASIL patients. PLoS One. 2014;9(11):e112311.

5. Talman LS, Bisker ER, Sackel DJ, Long DA, Jr., Galetta KM, Ratchford JN, et al. Longitudinal study of vision and retinal nerve fiber layer thickness in multiple sclerosis. Ann Neurol. 2010;67(6):749-60.

6. Iseri PK, Altinas O, Tokay T, Yuksel N. Relationship between cognitive impairment and retinal morphological and visual functional abnormalities in Alzheimer disease. J Neuroophthalmol. 2006;26(1):18-24.

7. Drexler W, Morgner U, Ghanta RK, Kartner FX, Schuman JS, Fujimoto JG. Ultrahigh-resolution ophthalmic optical coherence tomography. Nature medicine. 2001;7(4):502-7.

8. Feng YF, Guo H, Huang JH, Yu JG, Yuan F. Retinal Nerve Fiber Layer Thickness Changes in Migraine: A Meta-Analysis of Case-Control Studies. Curr Eye Res. 2016 Jun;41(6):814-22.

9. Tan FU, Akarsu C, Güllü R. Retinal nerve fiber layer thickness is unaffected in migraine patients. Acta Neurol Scand. 2005 Jul;112(1):19-23.

10. Reggio E, Chisari CG, Ferrigno G, Patti F, Donzuso G, Sciacca G, Avitabile T, Faro S, Zappia M. Migraine causes retinal and choroidal structural changes: evaluation with ocular coherence tomography. J Neurol. 2017 Mar;264(3):494-502.

Fig. 1 (abstract P75).

Peripapillary retinal nerve fiber layer thickness and total macular volume in TREX1 mutation carriers. Area of measurement peripapillary retinal nerve fiber layer (pRNFL) thickness (A) and total macular volume (TMV) (B). Mean pRNFL (C) and TMV (D) were reduced in TREX1 mutation carriers compared to controls.

Fig. 2 (abstract P75).

Distribution of peripapillary retinal nerve fiber layer thickness (A) and total macular volume (B) with age in TREX1 mutation carriers and controls. Mutation carriers (MC); Peripapillary retinal nerve fiber layer (pRNFL); total macular volume (TMV).

Table 1 (abstract P75).

Thickness of peripapillary sectors of the pRNFL in TREX1 mutation carriers and controls

 

TREX1 MC

mean ±SD (n=33a)

Controls

mean ±SD (n=18)

Estimate

CI

P-value

Nasal sup. (μm)

84.4 ±34.0

107.7 ±26.2

-23.3

-42.0;-4.7

0.014*

Nasal (μm)

61.2 ±21.4

87.7 ±25.4

-26.5

-42.8;-10.1

0.002*

Nasal inf. (μm)

84.7 ±34.6

118.7 ±30.6

-34.4

-56.6;-12.2

0.002*

Temporal inf. (μm)

102.1 ±37.9

133.8 ±20.0

-32.6

-52.7;-12.5

0.001*

Temporal (μm)

61.7 ±26.0

63.1 ±10.0

-1.5

-12.5;-9.5

0.79

Temporal sup. (μm)

109.7 ±37.4

131.1 ±16.6

-21.6

-39.1;-4.1

0.016*

Mutation carrier (MC); standard deviation (SD); confidence interval (CI); Peripapillary retinal nerve fiber layer (pRNFL). a In one patient measurements of one eye were not possible due to the patient’s inability to focus. * p <0.05 tested by GEE

Table 2 (abstract P75).

Thickness of the macula layers in TREX1 mutation carriers and controls.

 

TREX1 MC

mean ±SD (n=34)

Controls

mean ±SD (n=18)

Estimate

CI

P-value

TMT (μm)

292.0 ±32.1

313.8 ±15.1

-21.8

-38.1;-5.6

0.009*

mRNFL (μm)

23.0 ±6.3

25.7 ±2.2

-2.7

-5.6;-0.2

0.07

GCL (μm)

29.6 ±9.5

38.3 ±3.2

-8.7

-13.2;-4.2

<0.001*

IPL (μm)

27.9 ±6.2

33.1 ±2.1

-5.1

-8.1;-2.2

0.001*

INL (μm)

33.9 ±5.3

35.7 ±3.5

-1.8

-4.8;-1.3

0.25

OPL (μm)

28.6 ±2.8

28.9 ±2.2

-0.3

-1.8;-1.2

0.70

ONL (μm)

69.8 ±9.5

70.0 ±8.2

-0.2

-6.3;-6.0

0.96

RPE (μm)

13.8 ±1.5

14.0 ±1.3

-0.2

-1.2;-0.8

0.68

MC Mutation carrier, SD standard deviation, CI confidence interval, TMT total macular thickness, mRNFL macular retinal nerve fiber layer, GCL ganglion cell layer, IPL inner plexiform layer, INL inner nuclear layer, OPL outer plexiform layer, ONL outer nuclear layer; RPE retinal pigment epithelium. * p <0.05 tested by GEE

P76 Life traumatic experiences and stressful events as predictors of detoxification-therapy outcome at 6 months in chronic migraine with medication overuse

Bottiroli Sara1, Sances Grazia1, De Icco Roberto1,2, Vito Bitetto1, 2, Guaschino Elena1, Marta Allena1, Pazzi Stefania1, Giuseppe Nappi1, Tassorelli Cristina1,2

1Headache Science Center, Mondino Foundation, Pavia, Italy; 2Department of Brain and Behavioral Sciences, University of Pavia, Italy
Correspondence: Bottiroli Sara (sara.bottiroli@mondino.it)

Objectives. Withdrawal from overused drug is the treatment of choice for MOH, reverting the headache from chronic to episodic. Many factors are involved in MOH prognosis and outcome, becoming is a topic of interest. In this study we evaluated the association between early life traumatic experiences and recent stressful events with the outcome following detoxification therapy in a 6-month follow-up in 164 subjects with medication overuse headache (MOH).

Methods. This study was conducted at the Mondino Foundation in Pavia, Italy. All consecutive patients with MOH undergoing an inpatient detoxification program were enrolled and followed-up in a prospective study. Diagnosis was operationally defined according to ICHD-IIIβ. The study was approved by the Ethics Committee of San Raffaele Scientific Institute (Pavia, Italy) and written informed consent was obtained from all patients. The protocol consisted in an inpatients detoxification treatment and a 6-month follow-up. Data on early life traumatic experiences – distinguished in term of physical and emotional traumas – and recent stressful events were collected by means of self-report questionnaires. Data were analyzed with univariate and multivariate logistic regressions.

Results. Of the 164 patients who completed the 6-month follow-up, 111 (54%) stopped overuse and their headache reverted to an episodic pattern, whereas 53 (32%) had a negative outcome given that they stopped overuse without any benefit on headache frequency or failed to stop overuse. At the univariate analysis the following variables resulted associated to the negative outcome: having experienced emotional traumas (OR 3.409; p = 0.002), having had both traumas and stressful events (OR 12.429; p < 0.001), presence of mood disorders (OR 2.373; p = 0.014), higher MIDAS scores (OR 1.015; p < 0.001), higher number of days with medication intake (OR 2.373; p = 0.014) and higher number of days with headache (OR 1.193; p = 0.002). At the multivariate analyses, having experienced both childhood traumas and recent stressful events (OR 14.229; p = 0.002) together with higher MIDAS scores (OR 1.026; p = 0.004), and presence of mood disorders (OR 8.527; p = 0.009) were prognostic for the negative outcome.

Conclusions. Our data suggest the synergetic impact of both childhood traumas and recent stressful events, together with other psychological variables, in determining a negative outcome after detoxification in MOH. These findings have important practical implications on how to treat these patients.

Acknowledgements

This study was supported by a grant of the Italian Ministry of Health to C. Mondino Foundation (RC 2014-2016).

P77 Role of transient receptor potential (TRP) channels in a rat model of trigeminal neuropathic pain: focus on TRPA1 channels

Chiara Demartini1, Rosaria Greco1, Anna Maria Zanaboni1,2, Oscar Francesconi3, Cristina Nativi3, Cristina Tassorelli1,2, Kristof Deseure4

1Laboratory of Neurophysiology of Integrative Autonomic Systems, Headache Science Center, IRCCS Mondino Foundation, Pavia, Italy; 2Department of Brain and Behavioral Sciences, University of Pavia, Pavia, Italia; 3Department of Chemistry ‘Ugo Schiff’, University of Florence, Florence, Italy; 4Department of Medicine, Laboratory for Pain Research, University of Antwerp, Wilrijk, Belgium
Correspondence: Chiara Demartini (chiara.demartini@mondino.it)

The transient receptor potential ankyrin type-1 (TRPA1) channels are known to actively participate in different pain conditions including trigeminal neuropathic pain, whose clinical treatment is still unsatisfactory. The aim of this study was to evaluate the involvement of TRPA1 channels, by means of the antagonist ADM_12, in trigeminal neuropathic pain in order to identify possible therapeutic targets. Single treatment of ADM_12 in rats 4 weeks after the chronic constriction injury of the infraorbital nerve (IoN-CCI) significantly reduced the mechanical allodynia induced in the IoN-CCI rats. Additionally, ADM_12 was able to abolish the increased levels of TRPA1, calcitonin gene-related peptide (CGRP) and substance P (SP) gene expression in trigeminal ganglia, cervical spinal cord and medulla induced in the IoN-CCI rats. By contrast no significant differences between groups were seen as regards CGRP and SP protein expression in the nucleus trigeminalis caudalis. ADM_12 also reduced TRP vanilloid type-1 (TRPV1) gene expression in the same areas after IoN-CCI. These findings show the involvement of both TRPA1 and TRPV1 channels in trigeminal neuropathic pain and, more specifically, their role in trigeminal mechanical allodynia; moreover they suggest ADM_12 as a possible tool in trigeminal neuropathic pain management.

Ethics approval

The study was approved by Institution‘s Ethics Board (University of Antwerp, Belgium), approval number 2017-16.

P78 Meningeal contribution to migraine pain: a 3T magnetic resonance angiography study

Sabrina Khan1, Faisal Mohammad Amin1, Casper Emil Christensen1, Hashmat Ghanizada1, Samaira Younis1, Anne Christine Rye Andersen1, Patrick J H de Koning2, Henrik B W Larsson3, Messoud Ashina1

1 Danish Headache Center and Department of Neurology, Rigshospitalet Glostrup, Faculty of Health and Medical Sciences, University of Copenhagen, Denmark; 2 Division of Image Processing, Department of Radiology, Leiden University Medical Center, Leiden, Netherlands; 3 Functional Imaging Unit, Department of Clinical Physiology, Nuclear Medicine and PET, Rigshospitalet, Faculty of Health and Medical Sciences, University of Copenhagen, Denmark
Correspondence: Sabrina Khan (sksabrinakhan@gmail.com)

The origin of migraine pain is unknown but possibly implicates the dura mater, which is pain sensitive in proximity to the meningeal arteries. Therefore, subtle changes in vessel caliber on the head pain side could reflect activation of dural perivascular nociceptors that leads to migraine headache. To test this hypothesis, we measured circumference changes of cranial arteries in patients with cilostazol-induced unilateral migraine without aura using 3T high-resolution magnetic resonance angiography (MRA). The middle meningeal artery (MMA) was of key interest, as it is the main supply of the dura mater. We also measured the superficial temporal (STA) and external carotid (ECA) arteries as additional extracranial segments, and the middle cerebral (MCA), the cerebral and cavernous parts of the internal carotid (ICAcerebral and ICAcavernous), and the basilar (BA) arteries as intracranial arterial segments. MRA scans were performed at baseline, migraine onset, after sumatriptan, and ≥27 hours after migraine onset.A total of 30 patients underwent MRA scans, of which 26 patients developed unilateral attacks of migraine without aura and were included in the final analysis. Eleven patients treated their migraine with sumatriptan while the remaining 15 patients did not treat their attacks with analgesics or triptans.

At migraine onset, only MMA exhibited greater circumference increase on the pain side (0.24 ± 0.37 mm) compared to the non-pain side (0.06 ± 0.38 mm) (p=0.002). None of the remaining arteries revealed any pain-side specific changes in circumference (p>0.05), but exhibited bilateral dilation. Sumatriptan constricted all extra-cerebral arteries (p<0.05). In the late phase of migraine, we found sustained bilateral dilation of MMA.

In conclusion, onset of migraine is associated with increase in MMA circumference specific to the head pain side. Our findings suggest that vasodilation of MMA may be a surrogate marker for activation of dural perivascular nociceptors, indicating a meningeal site of migraine headache.

P79 Sex differences in vascular responses to CGRP

Alejandro Labastida-Ramírez1, Eloísa Rubio-Beltrán1, A. van den Bogaerdt2, J. Schouten3, A.H. Jan Danser1, Carlos M. Villalón4, Antoinette MaassenVanDenBrink1

1Division of Vascular Medicine and Pharmacology, Dept. of Internal Medicine, 2Heart Valve Bank Rotterdam, 3Deparment of Neurosurgery, Erasmus University Medical Center, P.O. Box 2040, 3000 CA Rotterdam, The Netherlands; 4Deparment of Pharmacobiology, Cinvestav-Coapa, Mexico City, Mexico
Correspondence: Alejandro Labastida-Ramírez (a.labastidaramirez@erasmusmc.nl)

Background and aim: Migraine is two to three times more prevalent in women than in men. The mechanisms underlying this high prevalence seem to be related with a cross-talk between (fluctuations of) ovarian steroid hormones and the CGRPergic system. The present study investigated the vasodilatory effects of CGRP in human isolated coronary and middle meningeal arteries of women in the pre- and postmenopausal age range and compared it to men of the same age category.

Methods: Human coronary arteries were obtained from “beating hearts” organ donors who died of non-cardiac disorders (females: n=19 <50 years, n=18 >50 years; males: n=15 <50 years, n=17 >50 years) and human middle meningeal arteries were obtained from dura mater of patients who underwent neurosurgery (females: n=8 <50 years, n=10 >50 years; males: n=7 <50 years, n=3 >50 years). In both arteries, concentration‑response curves to CGRP were constructed to obtain the pEC50 and maximum contractile response (Emax). Since we were not able to obtain the pre- or postmenopausal status of the women included because of ethical restrictions, we classified women into groups of below and above 50 years of age, approximately corresponding to pre- and postmenopausal women. Men were divided into the same age categories.

Results: In human isolated coronary arteries, CGRP induced concentration-dependent dilations that were not different between men and women, either in the younger (<50 years) and older (>50 years) age categories. In contrast, in middle meningeal arteries CGRP had a significantly (p=0.01) lower maximal response (but similar pEC50) in young (<50 years) women (Emax 61±9 %) when compared with men of the same age category (Emax 92±5), while there was no difference between responses to CGRP in arteries obtained from older women and men.

Conclusion: Relaxant responses to CGRP were diminished in dural arteries of women <50 years, as compared to those in dural arteries obtained in men from the same age group. Our results suggest that (fluctuations in) ovarian sex steroid hormones could desensitize the dural CGRP receptor, either directly, or via increased dural CGRP release. Further experiments are needed to determine the causal relationship between lower responses to CGRP and cycling steroid hormones in premenopausal women.

P80 Effect of onabotulinumtoxinA prevention on comorbidities of depression and anxiety in chronic migraine: Analysis in headache day frequency responders vs headache day frequency non-responders

Andrew M. Blumenfeld1 Stewart J. Tepper2 Lawrence D. Robbins3 Amelia Orejudos4 Aubrey Manack Adams4 Dawn C. Buse5 Stephen D. Silberstein6

1Headache Center of Southern California, The Neurology Center, Carlsbad, CA, 92024, USA; 2 Neurology Department, Headache Center, Dartmouth-Hitchcock Medical Center, Lebanon, NH, 03748, USA; 3Robbins Headache Clinic, Riverwoods, IL, 60015, USA; 4Allergan plc, Irvine, CA, 92612, USA; 5Department of Neurology, Albert Einstein College of Medicine, Bronx, NY, 10461, USA; 6Department of Neurology, Jefferson Headache Center, Philadelphia, PA, 19107, USA
Correspondence: Andrew M. Blumenfeld (blumenfeld@neurocenter.com)

Background: Chronic migraine (CM) is comorbid with anxiety and depression. This analysis of COMPEL Study data assessed the relationship between use of onabotulinumtoxinA and depression and anxiety in people with CM who had that comorbidity and also had a ≥25% reduction in headache day frequency at week 24.

Methods: The 108-week, multicenter, open-label COMPEL Study (ClinicalTrials.gov, NCT01516892) enrolled adults with CM receiving onabotulinumtoxinA 155 U. Changes in depression (Patient Health Questionnaire [PHQ-9]) and anxiety (Generalized Anxiety Disorder [GAD-7]) sum scores in those with clinically significant depression (PHQ-9 ≥5) and anxiety (GAD-7 ≥10) at baseline were analyzed in those with a ≥25% reduction in headache day frequency at week 24 (i.e., “headache day reduction responders”) vs those who did not (“non-responders”). A ≥1 severity category improvement in the PHQ-9 and/or GAD-7 was considered clinically meaningful. The study received ethical approval from the Institutional Review Board at each site.

Results: Patients (N=715) had a mean (range) age of 43 (18–73) years, were primarily women (84.8%; 606/715), and had on average mild or worse depressive symptoms (PHQ-9 ≥5; 74.5% [529/710]) or moderate or worse anxiety (GAD-7 ≥10; 24.6% [175/711]). Mean (SD) headache day frequency at week 108 significantly decreased from baseline: 22 (4.8) to 11.3 (7.4) days (P<0.0001). Depressive symptoms significantly (P<0.001) improved in people with mild or worse depression regardless of 25% headache day reduction response (Fig. 1A), as did anxiety symptoms in those with moderate or worse anxiety (P<0.001, Fig. 1B); 79.8% of headache day frequency responders and 53.2% of non-responders experienced a reduction of ≥1 severity category on the PHQ-9 (Fig. 1C). 82.2% and 70.4%, respectively, experienced a reduction of ≥1 severity category on the GAD-7 (Fig. 1D).

Conclusions: COMPEL study results demonstrate that onabotulinumtoxinA use is associated with a reduction in symptoms of depression and anxiety among people with CM, regardless of whether onabotulinumtoxinA treatment resulted in a ≥25% reduction in headache day frequency, although the change is less robust in the <25% responder group.

Fig. 1 (abstract P80).

Change from baseline in (A) PHQ-9 total scores and (B) GAD-7 total scores; proportion of patients experiencing 31 reduction in severity category for (C) PHQ-9 and (D) GAD-7 after treatment with onabotulinumtoxinA. GAD-7=7-item Generalized Anxiety Disorder Assessment; PHQ-9=9-item Patient Health Questionnaire. *Indicates P<0.0001 versus baseline. †Indicates P<0.001 for between group comparison

P81 Life with migraine, effect on relationships, career and finances, and overall health and well-being: Results of the Chronic Migraine Epidemiology and Outcomes (CaMEO) study

Dawn C. Buse1, Sharron Murray2, Paula K. Dumas3, Aubrey Manack Adams4, Michael L. Reed5, Kristina M. Fanning5, Richard B. Lipton1

1Department of Neurology, Albert Einstein College of Medicine, Bronx, NY, 10461, USA; 2Wenatchee, WA, 98801, USA; 3Migraine Again LLC, Alpharetta, GA, 30022, USA; 4Allergan plc, Irvine, CA, 92612, USA; 5Vedanta Research, Chapel Hill, NC, 27517, USA
Correspodence: Dawn C. Buse (dbuse@montefiore.org)

Background: Migraine can negatively affect many aspects of an individual’s life as well as the lives of people close to them. This analysis of CaMEO Study data evaluated and compared the effects of episodic (EM) and chronic migraine (CM) across a range of domains.

Methods: The CaMEO Study (ClinicalTrials.gov, NCT01648530) is a prospective, longitudinal, web-based survey study designed to characterize migraine impact, among other objectives, in a systematic US sample of people meeting modified ICHD-3 criteria: 19,891 respondents meeting said criteria were invited to complete the Family Burden Module. Answers by migraine respondents (probands) relating to the impact of migraine on family life, career and finances, and overall health—including how life would be without migraine—were recast as dichotomous variables for analysis. Descriptive analysis of items stratified by EM (<14 headache days/month) and CM (≥15 headache days/month) were reported. Comparative analyses utilized Chi-square and P values to indicate significant differences. The study received ethical approval from the Institutional Review Board of the Albert Einstein College of Medicine.

Results: 13,064 respondents (EM: 11,938 [91.4%]; CM: 1,126 [8.6%]) provided valid data. Approximately 20% of respondents not currently in a relationship (n=3,512) or in a relationship but not living together (n=1,393) indicated that headaches had contributed to relationship problems. Of those in a relationship and living together (n=8,154), 49.0% agreed somewhat/completely that they would be a better partner if they did not have headaches (EM: 46.2%; CM: 78.2%; P<0.001); 3.2% had delayed having children/had fewer children (EM: 2.6%; CM: 9.6%; P<0.001). Of 13,061 individuals responding to career items, 32.7% indicated that headaches had affected ≥1 item (EM: 30.0%; CM: 58.4%). Overall, 28.9% of respondents worried about covering household expenses (EM: 26.7%; CM: 52.9%), and 32.1% about long-term financial security (EM: 29.7%; CM: 57.4%). 16.4% reported poor or fair overall health (EM: 14.2%; CM: 40.5%). Across 9 “life-with-migraine” items, 69.6% of EM respondents (CM: 87.7%) reported ≥1 area that would be “better/a lot better” if they did not have headaches.

Conclusions: Migraine can negatively affect many aspects of life including relationships, career and financial outcomes, and overall health. People with migraine, particularly CM, feel that headaches affect many important areas of life and perceive that life would be better/a lot better without headache. Physicians managing migraine should consider the overall burden of disease.

P82 A multicenter, prospective, randomized, open-label study to compare onabotulinumtoxinA and topiramate for headache prevention in adults with chronic migraine: patient reported functional outcomes from the FORWARD study

Andrew M. Blumenfeld1, Atul T. Patel2, Aubrey Manack Adams3, John F. Rothrock4

1Headache Center of Southern California, The Neurology Center, Carlsbad, CA, 92024, USA; 2Department of Rehabilitation Medicine, Kansas City Bone and Joint Clinic, Overland Park, KS, 66211, USA; 3Allergan plc, Irvine, CA, 92612, USA; 4George Washington School of Medicine, Washington, DC, 20037, USA
Correspondence: Andrew M. Blumenfeld (blumenfeld@neurocenter.com)

Background: Patient-reported outcomes (PROs) can be important indicators of a migraine therapy’s real world effectiveness. Safety, tolerability, and PROs of onabotulinumtoxinA (onabotA) vs topiramate (TPM) for CM are presented.

Methods: FORWARD, a multicenter, randomized study (ClinicalTrials.gov, NCT02191579), compared onabotA 155U every 12 wks for 3 cycles with TPM 50-100 mg/day for up to 36 wks. The primary efficacy measure was proportion of patients with ≥50% reduction in headache (HA) days/mo vs baseline at wk 32. Adverse events (AEs) were recorded. PRO measures included: Controlled Oral Word Association Test (COWAT); 9-Item Patient Health questionnaire (PHQ-9); and the Work Productivity and Activity Impairment: Specific Health Problem (WPAI-SHP) questionnaire. The protocol was approved by the Institutional Review Board at each site.

Results: 282 patients enrolled (onabotA, n=140; TPM, n=142); 148 completed treatment (onabotA, 85.7%; TPM, 19.7%). Primary reasons for withdrawal were lack of efficacy (onabotA, 5.0%; TPM, 19.0%) and AEs (onabotA, 3.6%; TPM, 50.7%). Using baseline observation carried forward (BLOCF) imputation, more patients on onabotA had ≥50% reduction in HA frequency vs TPM (40.0% vs 12.0%; P<0.001). Treatment-related AEs (TRAEs) were reported by 17.3% of onabotA and 69.0% of TPM patients. TPM was associated with a reduction in mean [SD] COWAT scores at wk 12 (−2.8 [5.7]), suggesting early cognitive changes in TPM recipients. The effect of TPM was potentially obscured by BLOCF methodology due to the large proportion of TPM withdrawals. OnabotA resulted in a small increase in mean [SD] COWAT scores at wks 12 (1.2 [8.1]) and 36 (2.8 [.8]). At wk 36, onabotA had a significantly greater effect on mean [SD] PHQ-9 scores vs TPM (4.4 [4.2] vs 7.1 [5.8]; estimated mean difference: –1.86 [P<0.001]). Both treatments were associated with a slight reduction in WPAI-SHP Absenteeism and Presenteeism scores at week 36; onabotA significantly reduced mean Work Productivity Loss scores vs TPM.

Conclusions: Based on TRAEs and discontinuation rates, onabotA was associated with significantly better tolerability than TPM. PRO data suggest that changes in cognition may be seen as early as wk 12 in TPM recipients. OnabotA had a more favorable effect on depressive symptoms and improved work productivity loss and impairment in patients with CM vs TPM.

P83 Headache attributed to psychiatric disorder

Ana Lj Podgorac1, Goran Gajić 1, Bojana Pejušković 1,2, Ljubica Zamurović-Dunđerović 1, Vanja B Mandić-Maravić 1, Aleksandar Misojčić 1, Dušica M Lečić-Toševski 1,2,3

1 Institute of Mental Health, 37 Palmoticeva St, Belgrade, Serbia; 2 School of Medicine University of Belgrade, Belgrade, Serbia; 3 Serbian Academy of Sciences and Arts Belgrade, Serbia
Correspondence: Ana Lj Podgorac (anasundic@gmail.com)

Introduction: Contrary to numerous studies showing a high degree of comorbidity between psychitric disorders and primary headache disorders, pointing to psychiatric disorder as a risk factor for headache progression and chronification, the number of studies that put in the spotlight headache occurring only during the psychiatric disturbance, e.g. “headache attributed to psychiatric disorder” [1,2], is significantly smaller. Literature data, limitted to case reports and few retrospective studies, point out headache attributed to psychiatric disorders as an uncommon headache syndrome with wide area of clinical presentation, differential diagnosis, clinical implications and needs for future research [2,3].

Methods: Hereby, we present the sample of psychiatric patients, treated for a period of one year, from January to December 2016, at the Clinical Department for Psychotic Disorders of the Institute of Mental Health, who suffered from headache. The psychiatric disorder has been diagnosed according to diagnostic criteria given in the fifth edition of the Diagnostic and Statistical Manual of Mental Disorders (DSM-5) [4],, while the headache has been diagnosed according to diagnostic criteria given in the third edition of The International Classification of Headache Disorders (ICHD-3) [2],.

Results: Out of 427 patients that had been treated in this period, 25 of them had headache. Majority of patients with headache (19) had major depressive disorder , recurrent in 15 patients. One patient had bipolar affective disorder. Five patients had psychotic disorder, four of them schizophrenia, and one patient presented with acute polymorphic psychotic disorder with symptoms of schizophrenia. Primary headache was present in 19 patients (migraine without aura – 6, migraine with aura – 2, chronic migraine – 2, episodic tension type headache – 3, chronic tension type headache -5). One patient had medication overuse headache. The diagnosis of headache attributed to depressive disorder was established in three patients. One patient had headache attributed to somatization disorder, and one patient had headache attributed to psychotic disorder.

Discussion: This observation confirmes well-known high comorbidity of psychiatric disorders and primary headache disorders, especially the chronic forms and supports the current headache classification in which the headache attributed to somatization disorder and headache attributed to psychotic disorder had been recognized. As well, by this report authors support the opinion of other authors who suggested that the headache attributed to depressive disorder, as the most common type of headache attributed to psychiatric disorders, corresponding to the additional codes in the appendix of the classification (code 12.3) could be added to the classification itself.

Key words: headache, psychiatric disorder

References:

1. Smitherman TA, Baskin SM. Headache Secondary to Psychiatric Disorders. Current Pain and Headache Reports 2008; 12: 305 – 310.

2. Headache Classification Committee of the International Headache Society (IHS). The International Classification of Headache Disorders, 3rd edition (beta version). Cephalalgia 2013; 33(9): 629–808.

3. Radat F, Milowska D, Valade D. Headaches Secondary to Psychiatric Disorders (HSPD):A Retrospective Study of 87 Patients. Headache 2011;51:789-795.

4. American Psychiatric Association. (2013). Diagnostic and statistical manual of mental disorders (5th ed.). Arlington, VA: American Psychiatric Publishing.

P84 Healthcare expenditure: does society give migraine the focus and recognition patients deserve?

Leonhard Schaetz1, Parth Joshi2, Aoife Callan3, Vivek Khurana2, Jasper Huels1

1Global Patient Access, Novartis Pharma AG, Basel, CH-4002, Switzerland; 2Product Life Cycle Services, NBS, Novartis Healthcare Private Limited, Hyderabad, 500081, India; 3Novartis Global Services Centre, Patient Access Services, Dublin, D04 A9N6, Ireland
Correspondence: Leonhard Schaetz (Leonhard.schaetz@novartis.com)

Background

Migraine is a painful neurological disease that is under-recognized, under-diagnosed, and under-treated worldwide [1]. Indeed the scale of the under-treatment of headache disorders prompted the World Health Organization (WHO) in 2011 to write to the world’s Ministries of Health to “illuminate the worldwide neglect of a major public-health problem, and reveal the inadequacies of responses to it” [1, 2]. To understand investment in managing migraine, we analyzed and compared healthcare expenditure on diseases with high disability, including migraine, across four countries: the United States of America (USA), Canada, Germany, and the Netherlands.

Methods

Diseases associated with high disability, as measured by Years Lived with Disability (YLDs), were identified from the Global Burden of Disease 2016 study for each country [3]. The top 10 diseases with high disability where health expenditure data were also available, were included in this analysis. Direct annual healthcare expenditure data per disease was sourced from a published study for the USA and government websites for Canada, Germany, and the Netherlands [4-7]. All the cost estimates were adjusted to year 2016 using healthcare specific inflation rates and were converted to US dollars using purchase power parity conversion.

Results

Five diseases identified as high disability burden in all four countries, included osteoarthritis, diabetes mellitus, skin and subcutaneous diseases, anxiety disorders, and migraine. Of these, and despite high disability burden, health expenditure on migraine was consistently the lowest across all countries and constituted less than 0.5% of total direct annual healthcare expenditure. Comparatively, annual healthcare expenditure on osteoarthritis was 7-times as that of migraine in the USA, 4-times in Canada, 19-times in Germany, and 24-times in the Netherlands, though the disability associated with it was much lower than migraine (Fig. 1).

Discussion and conclusion

The study highlights the significant underinvestment in migraine despite its high burden and relative to other high disability diseases. Such underinvestment may be correlated with major gaps in migraine management including low diagnosis rates, delays and barriers in access to specialists, and under-treatment thus contributing to the overall burden of disease on individuals and society. Literature suggests that better-quality care leads to improved outcomes for patients with migraine [8-10]. Further research is needed to expand this analysis to other countries and to seek possible solutions on how improved care can be made accessible to broader patient populations.

Funding

This study was funded by Novartis AG, Basel, Switzerland.

References

1. Steiner TJ et al. Time to act on headache disorders. The Journal of Headache and Pain. 2011; 12: 501-3

2. Steiner TJ et al. Migraine is first cause of disability in under 50s: will health politicians now take notice? The Journal of Headache and Pain. 2018; 19: 17

3. Vos T et al. Global, regional, and national incidence, prevalence, and years lived with disability for 328 diseases and injuries for 195 countries, 1990–2016: a systematic analysis for the Global Burden of Disease Study 2016. The Lancet. 2017; 390: 1211-59

4. Dieleman et al. US Spending on Personal Health Care and Public Health, 1996-2013. JAMA. 2016; 316: 2627-46

5. EBIC. Economic Burden of Illness in Canada online tool 2008. Accessed on 17 May 2018. [Available from: http://cost-illness.canada.ca/index.php

6. GBE-BUND. Cost of illness in millions of Euro for Germany 2015. Accessed on 17 May 2018. [Available from: http://www.gbe-bund.de/gbe10/trecherche.prc_them_rech?tk=19200&tk2=19400&p_uid=gast&p_aid=64133544&p_sprache=E&cnt_ut=3&ut=19460

7. RIVM. Cost of Illness in the Netherlands 2015. Accessed on 17 May 2018. [Available from: https://statline.rivm.nl/#/RIVM/nl/dataset/50040NED/table?graphtype=Table&ts=1512975518824

8. Katsarava et al. Poor medical care for people with migraine in Europe – evidence from the Eurolight study. The Journal of Headache and Pain. 2018; 19: 10

9. Soon et al. Assessment of migraineurs referred to a specialist headache clinic in Singapore: diagnosis, treatment strategies, outcomes, knowledge of migraine treatments and satisfaction. Cephalalgia. 2005; 25: 1122–32

10. Hu et al. Survey of migraineurs referred to headache specialists: care, satisfaction, and outcomes. Neurology. 2000; 55: 141–143

Fig. 1 (abstract P84).

Annual direct healthcare expenditure for causes with high disability in the USA, Canada, Germany, and the Netherlands (Comparisons were made for 10 causes of high disability in each country. Data for the top five high disability diseases that were common across all four countries are presented). Abbreviations: Anxiety: Anxiety disorders; Diabetes: Diabetes mellitus; Skin and SC diseases: Skin and subcutaneous diseases; USA: United States of America; USDs: United States dollars; YLDs: Years lived with disability.

P85 Gender differences in clinical and pharmacological response to triptans

Daphne S. van Casteren1,2, Tobias Kurth3, Michel D. Ferrari2, Gisela M. Terwindt2,#, Antoinette Maassen van den Brink1,#

1Deparment Of Internal Medicine, Div. of Pharmacology, Erasmus Medical Center, P.O. Box 2040, 3000 CA Rotterdam, the Netherlands; 2Deparment Of Neurology, Leiden University Medical Center, P.O. Box 9600, 2300 RC Leiden, the Netherlands; 3Institute of Public Health, Charité – Universitätsmedizin Berlin, Berlin, Germany.
Correspondence: Daphne S. van Casteren (D.S.van_Casteren@lumc.nl)

# Shared last author

Objective

To examine the effect of gender on clinical response outcomes to triptans in migraine patients and to relate these gender differences to pharmacokinetic parameters of triptans in men and women.

Methods

In a systematic literature search of PubMed, MEDLINE, the Cochrane Library, Embase and Web of Science, we identified clinical trials distinguishing clinical response to or pharmacokinetic parameters of triptans between men and women. Male-to-female pooled risk ratios (RR) for each clinical outcome were calculated using random-effects models. For the investigation of gender differences in pharmacokinetic outcomes meta-analyses were conducted using pooled ratio of means (RoM) random-effects models.

Results

Over 1000 publications were found by searching for publications on clinical trials with triptans, of which 190 remained after adding sex and gender related search terms. Only in 19 publications data were presented in such a way that they could be included in the meta-analysis. No gender differences were revealed for headache response after 2 hours (9 studies, male-to-female RR 1.03, 95% CI: 0.99-1.08) and pain free response after 2 hours (6 studies, male-to-female RR 1.02, 95% CI: 0.98-1.07). In contrast, females had a higher risk for headache recurrence within 24 hours or 48 hours (4 studies, male-to-female RR 0.74, 95% CI: 0.56-0.97) and a higher adverse event (AE) frequency than males (6 studies, male-to-female RR 0.82, 95% CI: 0.76-0.89).Results for Area Under the plasma drug concentration-time Curve from time zero to infinite time (AUC 0-∞, ng/h/ml) and peak drug concentration (Cmax, ng/ml) were found only for frovatriptan, zolmitriptan and rizatriptan. Women appeared to have a higher AUC0-∞ (16 studies, RoM 0.64, 95% CI: 0.57-0.72) and Cmax (18 studies, RoM 0.70, 95% CI: 0.63-0.77) than men. No statistically significant gender differences were revealed on plasma half-life Times (T1/2) of frovatriptan (2 studies, RoM 0.90, CI: 0.70-1.14) and zolmitriptan (8 studies, RoM 0.93, CI: 0.85-1.01).

Conclusions

Given the widespread use of triptans and the large amount of literature on this topic, there are remarkably few publications about gender differences in response to triptans. Based on the limited data available, we conclude that the AUC0-∞ and Cmax are higher in women than in men for frovatriptan, zolmitriptan and rizatriptan, which may be an explanation for the higher AE frequency in women. This higher exposure in women (when extrapolated to the other triptans) is, however, not reflected by higher response rates to the triptans in women. Moreover, the headache recurrence rate is higher in women than in men, pointing to a potential discrepancy with the pharmacokinetic data. We hypothesise that the higher recurrence rate in women, despite their higher drug exposure, may be assigned to more persistent migraine attacks that are triggered by sex hormonal changes, such as menstrually-related migraine attacks and possibly attacks during perimenopause.

Fig. 1 (abstract P85).

Flowchart of publication selection process.

Fig. 2 (abstract P85).

Forest plots of headache recurrence rate after 24 hours or 48 hours and the incidence of at least one adverse event after the intake of a triptan in male and female migraine patients.

Fig. 3 (abstract P85).

Forest plots of AUC0-∞ and Cmax after the intake of frovatriptan, rizatriptan or zolmitriptan in male and female migraine patients.

P86 Migraine induction with calcitonin gene-related peptide in patients from erenumab trials

Casper Emil Christensen&; Samaira Younis&; Marie Deen; Sabrina Khan; Hashmat Ghanizada; Messoud Ashina

Danish Headache Center and Department of Neurology, Rigshospitalet Glostrup, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
Correspondence: Messoud Ashina (ashina@dadlnet.dk)

& These authors contributed equally to this work.

Background: Erenumab has recently been approved by the US Food and Drug Administration as a monoclonal antibody against the calcitonin gene-related peptide (CGRP) receptor for migraine-specific preventive treatment. Identifying those patients with the greatest potential to benefit from erenumab treatment could have a major impact on clinical practice. CGRP provokes migraine attacks and the question is whether hypersensitivity to CGRP infusion might be a predictor of erenumab efficacy, serving as a biomarker of treatment efficiency.

Objective: To explore a possible correlation between individual efficacy of anti-CGRP treatment and susceptibility to migraine induction by CGRP.

Methods: Thirteen migraine patients, previously enrolled in erenumab anti-CGRP receptor monoclonal antibody trials, received CGRP in a double-blind, placebo-controlled, randomized design to investigate their susceptibility to migraine induction. A standardized questionnaire was used to assess efficacy of antibody treatment. The patients were stratified into groups of high responders and poor responders.

Results: Ten high responders and three poor responders were included. CGRP induced migraine-like attacks in ten (77%) patients, whereof two were poor responders, compared to none after placebo (p=0.002). The area under the curve for headache intensity was greater after CGRP, compared to placebo, at 0–90 min (p=0.009), and 2–12 h (p=0.014). The median peak headache intensity score was 5 (5–9) after CGRP, compared to 2 (0–4) after placebo (p=0.004).

Conclusions: Patients with an excellent effect of erenumab are highly susceptible to CGRP provocation. A large-scale prospective CGRP provocation study in patients should confirm whether hypersensitivity to CGRP could be a biomarker for predicting antibody treatment efficacy.

Trials Registration: ClinicalTrials.gov identifier: NCT03481400.

Ethics approval and consent to participate

The study was approved by the Ethics Committee of the Capital Region of Denmark (H-16014580) and is registered at ClinicalTrials.gov (NCT03481400). All participants provided written informed consent to participate in accordance with the Declaration of Helsinki of 1964, with later revisions.

P87 Mitochondrial DNA and migraine

Sigrid Børte1,2, Bendik S. Winswold2,3, Lars G. Fritsche4,5, Ida Surakka6, Jonas B. Nielsen6, Wei Zhou7, Cristen J. Willer6,7,8, John-Anker Zwart1,2,3

1Research and Communication Unit for Musculoskeletal Health, Division of Clinical Neuroscience, Oslo University Hospital, Ullevål, Oslo, Norway; 2Institute of Clinical Medicine, Faculty of Medicine, University of Oslo, Oslo, Norway; 3Department of Neurology, Oslo University Hospital, Oslo, Norway; 4HUNT Research Centre, Department of Public Health and General Practice, Norwegian University of Science and Technology, 7600 Levanger, Norway; 5Department of Biostatistics, University of Michigan School of Public Health, Ann Arbor, MI 48109, USA; 6Department of Internal Medicine, Division of Cardiology, University of Michigan; Medical School, Ann Arbor, Michigan, 48109, USA; 7Department of Computational Medicine and Bioinformatics, University of Michigan, Ann Arbor, Michigan, 48109, USA; 8Department of Human Genetics, University of Michigan Medical School, Ann Arbor, Michigan, 48109, USA
Correspondence: Sigrid Børte (sigrid.borte@gmail.com)

Background: Mitochondria are the main source of energy for neuronal functioning, through oxidative phosphorylation. Mutations in mitochondrial DNA and mitochondrial dysfunction have been suggested to be involved in migraine pathogenesis, partly because migraine seems to be disproportion- ally transmitted through the maternal line. However, no mitochondrial-wide association analyses have been performed yet.

Methods: We used a sample of 57,924 genotyped individuals from the population-based Nord-Trøndelag Health Study (HUNT) from Norway. Mi- graine diagnoses were obtained by questionnaires. Samples were genotyped with the Illumina HumanCoreExome array,which included 369 mitochondrial variants. Variants were imputed using 2,202 sequenced individuals from the same HUNT population as reference panel, resulting in 858 mitochondrial variants for analysis. We also analysed 382,967 nuclear variants in and nearby genes coding for mitochondrial proteins. In addition, major European mito- chondrial haplogroups were assigned and analysed.

Results: No single mitochondrial variants or any of the mitochondrial haplogroups were associated with migraine. One nuclear variant was signifi- cantly associated with migraine, located in the ABCD2-gene. The ABCD2- gene encodes an ATP-dependent transporter, present in the organelle mem- branes (including the mitochondrial). It is involved in transporting very long chain fatty acids and probably plays a role in protecting against oxidative stress.

Conclusion: No mitochondrial single variants or haplogroups were as- sociated with migraine, indicating that inherited mutations in mitochondrial DNA does not explain the maternal-specific transmission of migraine. One significant variant in a nuclear encoded mitochondrial protein gene may sug- gest some degree of mitochondrial dysfunction in migraine, but the relevance of this variant is unclear.

P88 Headache in Call Center Employees: an Occupational Disease

Ilir Alimehmeti1, Xhovana Kane1, Jera Kruja2,3

1Department of Family and Occupational Health, Faculty of Medicine, University of Medicine, Tirana, Albania; 2Department of Neurosciences, Faculty of Medicine, University of Medicine, Tirana, Albania; 3Neurology Service, University Hospital Center “Mother Teresa”, Tirana, Albania
Correspondence: Jera Kruja (jkruja@gmail.com)

Background and Aim:

Headache is a common complaint, frequently referred as occupational. Call center employees face long hours in long and countless conversations, usually in sitting position in small personal spaces in large offices with numerous colleagues that produces additional stress and noise. Such an occupation is pursued by around 4.4% of the Albanian workforce. Thus, our aim was to assess headache severity among call center employees.

Methods:

During 2017, medical doctors visited a random sample of call center employees, which were invited online to answer to question pertaining to demographics, work conditions and health related issues. In detail, employees were asked about headache complaints and, if present, were invited to answer to the Migraine Disability Assessment test (MIDAS), in order to measure the impact of headache on their daily life. Moreover, data were obtained on education, marriage status, working hours, work experience, trouble with the supervisors, number of phone calls and contracts concluded, and achievement-related appraisal. In addition, depression was evaluated through the Beck’s Depression Inventory.

Results:

In total, 298 call center employees were enrolled, a sample composed of 183 females (61.4%) and 115 males (38.6%) with a mean age of 26.3 ± 5.6 years old, of which 255 (85.6%) were highly educated. Not surprisingly, all of them (100%) referred to suffer from some degree of headache. Mean working time was referred to be 7.74 ± 2.8 hours long. 35.9% of the sample was employed for less than a year in the call center industry, 40.6% for 1-5 years, and 21.8% for more than 5 years. Regarding to depression, 65.4% of the sample resulted in normal state, while 13.4% presented mild mood disturbance, 8.1% presented borderline clinical depression, 8.7% presented moderate depression, 2.3% presented severe depression, while 2.0% presented extreme depression. MIDAS test, headache-related disability was estimated as grade I in 16.8%, grade II in 19.1%, grade III in 30.5% and grade IV in 33.6% of the cases. In independent samples t-tests and chi-square tests, this distribution presented no statistically significant difference between age-groups, gender, education, marriage status, working hours and trouble with the supervisors. Nevertheless, more disability was positively associated with higher number of phone calls (Pearson chi-square 20.519, p 0.002). In regression analysis, higher MIDAS grade was positively correlate with depression (β 0.596, 95%CI 0.320-0.872, p <0.001) when adjusted for age, gender, working conditions and achievements.

Conclusions:

In our study resulted that all call center employees suffer from headache, paving the road towards regarding it as an occupational disease directly related to the number of phone calls. Moreover, 13% of the study group suffered from depression ranging from moderate to extreme, which significantly predicted higher grades of headache-related disability.

P89 Depression is not the only cause of cognitive impairment in chronic migraine

Nina Latysheva1,2*, Diana Osipova1, Elena Filatova1,2

1Department of Neurology, Institute for Professional Education, I.M. Sechenov First Moscow State Medical University, Moscow, Russia; 2Alexander Vein Headache Clinic, Moscow, Russia
Correspondence: Nina Latysheva (ninalat@gmail.com)

Background

Patients with various types of chronic pain frequently present with subjective cognitive complaints. Objective memory, attention and executive function deficits were demonstrated in 50–80% of patients with fibromyalgia.

This may be caused by the overlap in brain structures responsible for memory, attention, mood and chronic pain. New data is emerging on functional and structural changes in these brain areas, which may underlie cognitive impairment in depression and chronic pain. Cognitive deficits have been demonstrated in episodic migraine (EM) – both during attacks and interictally. Their severity correlated with headache frequency. The aim of this study was to evaluate subjective and objective cognitive impairment in patients with chronic migraine (CM).

Methods

We recruited 53 subjects with ICHD-3beta-defined CM and 22 gender- and age-matched controls with low-frequency EM (a maximum of 4 headache days per month), aged 18-59. All patients filled in the HADS anxiety and depression scale. Cognitive function was assessed with Montreal Cognitive Assessment (MoCA), Digital Symbol Substitution Test (DSST), Rey Auditory Verbal Learning Test (RAVLT) and the Perceived Deficits Questionnaire (PDQ-20). The study was approved by the Sechenov University’s Ethics Board.

Results

56% of CM and 9% of EM patients complained of memory impairment (p=0.00). Significant cognitive impairment was also demonstrated by PDQ-20 (24.4±12.4 vs. 18.2±7.6 in CM and EM, respectively, р=0.02). Objectively, we found a significant decrease in the 90-second DSST performance (41.6±10.0 vs. 50.6±8.9 in CM and EM, respectively, р=0.00), RAVLT total recall (32.4±12.1 vs. 38.5±12.2, respectively, р=0.04) and RAVLT learning rate (-0,7±1,6 vs. 0.14±1.0, p=0.01, respectively). 44% of CM subjects had MOCA-defined cognitive impairment, most often in attention (75%), memory/delayed recall (50%), and language (50%). Only 18% of EM patients scored lower than 26 points on the MoCA.

Depression correlated positively with RAVLT delayed recall only (r=0.78). Multiple linear regression showed that CM is an independent prognostic factor of lower DSST performance (р=0.03).

Conclusions

Subjective and objective memory and attention impairment is prevalent in the CM population.

As migraine becomes chronic, central sensitization and cognitive impairment become persistent and can be detected in the interictal period. Functional and structural changes in the brain observed in CM might underlie increasing cognitive impairment.

Even non-depressed CM patients need to be carefully screened for cognitive impairment.

P90 Psychosocial risk factors for headache

M Zaletel, L Zaletel-Kragelj, B Žvan

University Clinical Center of Ljubljana, Department for vascular Neurology, Ljubljana, Slovenia
Correspondence: M Zaletel (mzaletel34@gmail.com)

Background: Headache is a common disabling condition related to high health system burden. It can be deleterious for psychological and social well-being. In Slovenia psychosocial factor for headache are not well established. To identify population groups at very high risk for headache and thus enable more focused prevention actions in Slovenia.

Methods and subjects: Data originate from the national survey carried out in 2012 which was a part of the CINDI program. A self-administered postal questionnaire were used. Multiple logistic regression was used to determine the impact of gender, age, education, employment, self-assessed social class, type of residence community, stress perception, coffer drinking behaviour, sleep behaviour on headache.

Results: We noticed high odds for risky stress behaviour (OR yes vs. no =1.99; P<0.001), sleep behaviour (OR < 6 vs. 8 hours/day = 1.23; p P<0.001) and coffee drinking behaviour (OR > 1cups vs. no coups/day = 1.58; p P<0.001) in headache subjects. In addition, we found the highest odds in women (OR women vs. men=1.99, P<0.001), aged 25-29 years (OR 25-29 vs. 70-74 = 6.10, P<0.001), participants with the lowest (OR primary vs. postgraduate =1.34, P=0.082). Regarding kind of work we detected higher odds in intellectual/leading positions (OR intellectual/leading positions vs. pensioners =1.39, P=0.014), participants self-classified in the lowest social class (OR lower vs. upper-middle = 1.65, P= 0.005), and in persons under 18 in household (OR yes vs. no = 1.15, P=0.028).

Conclusions: In Slovenia, intellectual/leading position women, aged 25-29 years, were identified as the largest population sub-group at high risk for frequent headache disorders with stress behaviour.

P91 The prevalence and some risk factors chronic headache in Mongolia

Selenge Enkhtuya1, Otgonbayar Luvsannorov1, Byambasuren Tsenddorj2, Timothy J Steiner3

1Mongolian National University of Medical Sciences, Department of Neurology; 2Mungunguur hospital; 3Imperial College London, London, UK
Correspondence: Selenge Enkhtuya (selenge317@gmail.com)

Objective. The aim of this study was to determine the 1-year prevalence and clinical characteristics of chronic headache in adult Mongolian population.

Methods. A cross-sectional, population-based survey consisting of semi-structured questionnaires was administered to randomly selected population aged 18–65 years, living in five geographically different regions of Mongolia using stratified multistage cluster sampling during the period from June to November 2017. The prevalence of chronic headache was calculated in the sample representing 2 million Mongolian adults. The questionnaire of primary headache was based on International Classification of Headache Disorders-III criteria.

Results. The surveyed totally 2043 participants; the one-year prevalence of all types of headache was 66.1%. The one-year prevalence of chronic headache was 11.2% (n=229), and 20.5% (n=47) of chronic headache declared having headache 30 days per month. About 70% (n=152) those with chronic headache also had medication overuse. Chronic tension-type headache and chronic migraine had one-year prevalence 1.3% (n=26) and 2.2% (n=45), respectively. The risk of chronic headache increased more than one fold and half when the participants were elderly participants, females, personal situation, low income and in those with low education. The most commonly overused medication was multi-therapy (acetylsalicylic acid, acetaminophen and caffeine) among the population.

Conclusion. The prevalence of chronic headache in Mongolia is high compare to other countries worldwide. These patients require special attention and should be offered multidisciplinary medical support.

Keywords: Chronic headache, Probable Medication Overuse Headache, prevalence

P92 Symptoms of dependence in medication overuse headache: daily consumption versus days without consumption

J Azimova1, K Skorobogatykh1, A Amelin2

1University Headache Clinic, Moscow; 2Pavlov First Saint Petersburg State Medical University
Correspondence: J Azimova (azimova.j@mail.ru)

Objective: International Classification of Headache Disorders (ICHD) defines Medication Overuse Headache (MOH) as headache occurring ≥15 d/month in a patient with a preexisting headache disorder who has regularly exceeded specific thresholds of symptomatic medication use [1]. MOH is the result of: (1) headache frequency progression or/and (2)dependence-related behavior - craving, a deficit in controlling substance intake, which is associated to orbitofrontal cortex (OFC) dysfunction [2]. Typical manifestations of addiction - craving and euphoria, are not MOH characteristics. In the present study we investigated the prevalence of addiction disorder among the chronic migraine patients

Patients and methods. 75 patients with chronic migraine (CM) and MOH (ICHD-3) mean age 41,1±12,8y.o. (21-65), 9 men and 66 women. We assessed the mean amount of doses of acute migraine drugs (triptans, combined analgetics) during 3 months and addiction with Leeds Dependence Questionnaire (LDQ).

Results. The mean amount of acute migraine drugs per month was 31,6±23,2 (mean±SD) doses per month per patient (10-90). Mean LDQ score was 13,6±6,4 (3-26). We divided the patients into two groups: with daily consumption of acute migraine drugs (group 1) – 25 patients, and the group with consumption free days (group 2) – 50 patients. The subjects in the group 1 had 30,0±0 headache days per month, 18,9±3,9 migraine days per month and consumed 59,2±21,0 doses of acute medication per month. The subjects in the group 2 had 24,6±5,9 headache days per month, 16,6±4,5 migraine days per month and consumed 17,8±4.2 doses of acute medication per month. We found that LDQ score was 17,5±4,8 in daily consumption group (group 1) and 11,7±6,3 the group with consumption free days (group 2) (p<0.0001).

Conclusions. Patients with MOH are heterogeneous – some of them could be addicted to acute medication, some not. Daily consumption of acute migraine drugs may be a sign dependence.

References:
  1. 1.

    Headache Classification Committee of the International Headache Society (IHS). The International Classification of Headache Disorders, 3rd edition (beta version). Cephalalgia 2013;33:629–808.

     
  2. 2.

    Radat F, Chanraud S, Di Scala G, et al. Psychological and neuropsychological correlates of dependence-related behaviour in medication overuse headaches: a one year follow-up study. J Headache Pain. 2013;14:59.

     

P93 Effectiveness and safety of OnabotulinumtoxinA in the treatment of chronic migraine in patients older than 65

M. Castañón, E. Ameijide, J.M. Sánchez

Servicio de Neurología del Hospital Universitario Central de Asturias, Ausurias, Spain
Corresponence: M. Castañón (elenaviles90@hotmail.com)

BACKGROUND

Only two drugs have been approved for prophylactic treatment in chronic migraine, Topiramate and Onabotulinumtoxin A. Elderly population is increasing and this group is exposed to more drug interactions and greater risk of side effects. The PREEMPT study included patients aged 18-65 years old, but data are scarce in older than 65.

METHODS

We retrospectively reviewed medical records of patients with chronic migraine treated with Onabotulinumtoxin A. Patients older than 65 years old at first infiltration were selected. Responder was considered if reduction in headache days per month was greater than 50%.

RESULTS

Twelve patients (75% women), were indentified. Mean age at first infiltration was 70.08 year old (range 66-80). Infiltration was done according PREEMPT protocol and median dose was 192 u (105-240). Eight patients (66,6%), were considered responders. Nine patients (75%), reduced analgesics intake, although only one could reduced oral prophylactic treatment. Mild pain at the injection sites was the most common side effect.

CONCLUSIONS

Although a few patients, Onabolutinumtoxin A appears to be effective and safe also in patients older than 65 years old with chronic migraine.

P94 Headache education and management in a multi centric study Cameroon

García-Azorín D1, Kurtis Urra M2, Molina M3, Delgado-Suarez C4, Iglesias García P4, García-Morales I5, Gonzalez-Monje M6

1Hospital Clinico Universitario Valladolid, Headache Unit, Valladolid, Spain; 2Hospital Ruber Internacional, Movement Disorders Program, Department of Neurology, Madrid, Spain; 3 Hospital de Móstoles, Neurology department, Mostoles, Spain; 4Hospital Clinico San Carlos, Neurology, Madrid, Spain; 5Hospital Clínico San Carlos, Epilepsy Department, Madrid, Spain; 6Universidad Autónoma de Madrid, Neuroscience Department, Madrid, Spain
Correspondence: García-Azorín D (davilink@hotmail.com)

Background:

Headache is the main neurological condition in the high income countries, but prevalence of headache disorders is not well defined in low-income countries. In many hospitals, the absence of medical doctors obligate nurses to evaluate and treat patients. We aim to estimate the presence of headache in daily practice and evaluate education among the care providers.

Methods:

Observational analytic study conducted in a population of health care providers from the entire Cameroon. In October 2017, 7 Spanish neurologists organized a 4-day National Neurology Course, and one morning was dedicated to headache disorders. Before the course we performed a survey regarding sociodemographic and management variables and we evaluated the change after the course.

Results:

42 health care providers participated in the course. 52,4% were female with a mean age of 36,8 years. The mean number of patients consulted per week was referred of 64,3, among which, 21,1 complained of headache. The majority of participants mentioned headache as the most frequent neurological disorder in their clinics.

The concept of primary and secondary headaches was not clear: only 26,2% of participants considered migraine as a primary headache and only 12,2% tension type headache. 31,3% mentioned it specifically migraine as a secondary headache. Only 57% believed clinical history to be essential for the correct diagnosis and 40% recommended a cranial CT in every headache patient. When asked about basic headache signs and symptoms, 71,3% considered that an abnormal neurological examination could be seen in primary headaches while 50% thought fever could be a normal sign in migraine patients. Symptoms such as aggravation with movement, photophobia or nausea were considered as alarm symptoms of secondary headaches by 78,5%, 76,2% and 61,9% respectively.

Regarding etiology, 57,1% mentioned infections as the most frequent cause of headache, followed by head trauma (38,1%) and psychiatric disorders (31%). For the treatment of migraine the preferred option was paracetamol (47,6%) followed by NSAID (9,5%).

Conclusions:

Despite headache is the most frequent neurological condition in the Cameroonian clinical practice, many basic concepts about primary and secondary headaches are not properly understood. Identifying training gaps in developing countries is crucial in order to develop educational programs that could improve the management of those patients.

Ethics approval and consent to participate:

All the participants agreed to participate in the study.

P95 Non-compliance with follow-up: analysis of two years attendance to a second level headache centre in Italy

Teresa Catarci, Isabella Falomi and Roberto Batistoni

Azienda sanitaria locale Roma1, presidio Luzzatti headache centre, Rome, Italy.
Correspondence: Teresa Catarci (teresa.catarci@aslroma1.it)

The management of headache patients is a complex process where many factors play a crucial role, as, for example, patients’ compliance with follow-up. Previously, we had monitored the first 12 months of activity of our secondary headache outpatient clinic and found a total dropout rate of 45%, where 74% missed the first follow-up visit and 60% suffered from chronic headache. In order to further study this important aspect of headache care, we decided to verify the dropout rate, after the first visit, which occurred in the following two years and possibly ascertain the motivations.

We retrospectively analysed daily worksheets and case records of the 328 consecutive patients where follow-up had been scheduled between January 2016 and end of December 2017, the first visit had to be performed within the previous 6 months. The following data were gathered: diagnosis and headache attacks frequency, language barriers and nationality, date of first visit and missed follow-up, type of withdrawal (cancellation or missed attendance), time of scheduled follow-up, time of cancellation. Phone calls have been planned in order to inquire about motivations of dropout and will be done as soon as the local Health Authorities will provide permissions. The same neurologist (TC) visited all patients but 3, seen by other substitute colleagues.

Forty-five patients did not return for follow-up (13.7%), 11 males, 34 females mean age 39.2 ± 12.5 years, 57.8% was foreigner, language barriers were present in only two. Twenty-six did not return at scheduled follow-up, 19 cancelled. Another 3 patients cancelled but no data were available.

Our second level headache centre had a dropout rate, after the first visit, of 13.7 %, similar to what we had previously found (13.9%). More than half of the patients were not Italian, but since very few language barriers were found, it is possible that in those cases a more difficult patient-doctor relationship was to be taken into account (cultural barrier). Nevertheless, a previous study performed on 316 consecutive patients of a third level headache centre in Boston, reported "dislike of the clinician and seeking care elsewhere” the main reason for non-compliance. We believe that it is critical to keep dropout rates at follow-up low, particularly in second level headache centres; also, the reasons of dropout should be investigated in order to improve headache quality of care and be considered as an important indicator.

P96 A real-world analysis of global patient‑reported outcomes in patients with migraine

Janet H. Ford1, Sarah Cotton2, James Jackson2, Jeffrey S. Andrews1, Shonda A Foster1, Wenyu Ye, Russell M. Nichols1, Antje Tockhorn-Heidenreich3

1Eli Lilly and Company, Indianapolis, USA; 2Adelphi Real World, Bollington, UK; 3Eli Lilly and Company, Erl Wood Manor, UK
Correspondence: Janet H. Ford (ford_janet@lilly.com)

Background: Preventive treatment use has demonstrated improved health-related quality of life (HRQoL) in patients with migraine. Preventive treatment is recommended for patients with migraine who experience ≥4 migraine headache days (MHDs)/month; however, many are untreated. It is important to assess if the goal of achieving <4 MHDs/month leads to better outcomes on HRQoL measures.

Methods: The study used a cross-sectional survey of physicians (Adelphi Migraine Disease Specific Program, 2017) and their consulting patients with migraine in the United States (US) and in five European countries (5-EU: Germany, France, UK, Italy and Spain). Country‑specific and pooled information was captured for 5-EU. Objectives were to describe and compare patient-reported outcome (PRO) measures across two subpopulations by country. This included: 1) Patients with ≥4 MHDs/month versus <4 MHDs/month (reported here), and 2) patients with ≥3 lines of migraine preventives versus 0 to 2 lines. The PRO measures included Migraine-Specific Quality of Life Questionnaire Version 2.1 (MSQ), Migraine and Disability Assessment Scale (MIDAS), EuroQoL-5D-5L (EQ-5D-5L) and Work Productivity and Activity Impairment (WPAI). Higher MSQ scores indicate better functioning, lower MIDAS scores indicate less disability and higher EQ-5D-5L scores indicate better health utility. Demographic and treatment information were also captured.

Results: There were no significant differences between the two subpopulations (≥4 MHDs/month versus <4 MHDs/month) for age, gender or ethnicity in any country, with the exception of the ≥4‑MHDs/month population having significantly higher proportion of females in the US (77.6% vs. 72.5%, p<0.05). Significantly higher proportion of patients with ≥4 MHDs/month were on long-term sick leave/unemployed/retired due to migraine in 5-EU (pooled result: 5.1% vs. 1.7%; p<0.01); US trends were similar, but not significant (9.6% vs. 1.6%, p>0.05). A significantly higher proportion in the ≥4‑MHDs/month group was considered refractory to preventive treatment per clinician’s opinion (US: 8.2% vs. 1.5%, 5‑EU pooled: 9.3% vs. 3.6%; p<0.01). Table 1 lists HRQoL results. A significantly greater proportion of patients with ≥4 MHDs/month had the following outcomes: moderate-to-very severe disability (MIDAS), greater functional impairment (MSQ), worse health utility (EQ-5D-5L) and 1.5 to 2 times more work/activity impairment and work absenteeism (WPAI). Similar trends of differences between the two populations were seen in individual countries of 5-EU.

Conclusions: These results suggest that patients with migraine who experience <4 MHDs/month experience better outcomes on PRO measures versus patients with ≥4 MHDs/month. This suggests that goals of treatment regimens for migraine should be targeted towards reducing the frequency to <4 MHDs/month.

Ethics approval

The DSP was conducted as a survey adhering to market research guidelines and codes of conduct according to the International Chamber of Commerce/European Society for Opinion and Marketing Research international code on observational research. Before completing the voluntary patient self-completion (PSC) form, patients were asked to provide written consent. Physicians and patients provided anonymized data. The survey was submitted to the Freiburger Ethic-Kommission International (FEKI) where approval was granted on 24th October 2017 (FEKI Code 017/1763).

Table 1 (abstract P96).

Patient‑reported outcome (PRO) measures in patients with migraine who experience ≥4 migraine headache days/month and <4 migraine headache days/month in the US and in five European countries

 

US Population

5-EU Population

≥4 MHDs/ month

< 4 MHDs/ month

≥4 MHDs/ month

< 4 MHDs/ month

(n=584)

(n=789)

(n=1942)

(n=2147)

Disability Category by MIDAS Value, n (%)

 Little/No

102 (41.5)

291 (69.5)

247 (35.2)

477 (56.4)

 Mild

57 (23.2)

62 (14.8)

127 (18.1)

150 (17.8)

 Moderate

40 (16.3)

44 (10.5)

182 (26.0)

127 (15.0)

 Severe

30 (12.2)

18 ( 4.3)

101 (14.4)

77 ( 9.1)

 Very severe

17 ( 6.9)

4 ( 1.0)

44 ( 6.3)

14 ( 1.7)

MSQ Domain, Mean (SD)

 Total

67.6 (21.2)

78.8 (19.1)

67.7 (18.6)

76.1 (17.4)

 Role Function: Restrictive

63 (21.3)

75.6 (19.4)

64.2 (19.6)

72.4 (18.6)

 Role Function: Preventive

73.5 (21.9)

82.1 (20)

72.3 (19.8)

79.9 (17.9)

 Emotional

70.2 (24.9)

82 (22)

69.9 (21.8)

79.7 (19.8)

WPAI, Mean (SD)

 % work time missed due to problem

10.4 (22.8)

5.2 (18.1)

10 (21.4)

4 (13.7)

 % impairment while working due to problem

36.5 (28.3)

21.7 (24.1)

34.5 (22.5)

21.9 (22)

 % overall work impairment due to problem

40.3 (29.6)

22.7 (24.7)

39.7 (24.2)

23.4 (23.2)

 % activity impairment due to problem

38.6 (27.4)

25.3 (24.8)

39 (23.4)

27.7 (24)

EQ-5D-5L, Mean (SD)

 EQ5D Utility Score

0.9 (0.1)

0.9 (0.1)

0.8 (0.2)

0.9 (0.2)

 EQ5D Visual Analogue Scale

79.8 (14.7)

84.3 (13)

74.8 (15.8)

80.2 (15.4)

All comparisons between patients with ≥4 MHDs/month and <4 MHDs/month are statistically significant (p<0.01; Chi-square test for MIDAS value, t-test for all other comparisons). The 5-EU population consists of the combined populations from Germany, France, UK, Italy and Spain. Abbreviation: MHD migraine headache days.

P97 ONAMIG: Does onabotulinumtoxinA modulate cortical excitability in chronic migraine?

A.Alpuente1,2, N.Raguer3, M.Torres-Ferrús1,2; VJ.Gallardo2, J.Álvarez-Sabín1, P.Pozo- Rosich1

1Headache Unit, Neurology Department, Hospital Universitari Vall d'Hebron, Barcelona, Spain; 2Headache Research Group, Vall d'Hebron Research Institute (VHIR), Universitat Autònoma de Barcelona, Barcelona, Spain; 3Electromyography Unit, Neurophysiology Department, Vall d'Hebron University Hospital, Barcelona, Spain
Correspondence: P.Pozo- Rosich (ppozorosich@yahoo.com)

Background: Symptoms in migraine could be caused by changes in cortical excitability.

Objective: To analyze changes in cortical excitability in chronic migraine patients after onabotulinumtoxinA treatment.

Methods: We included patients diagnosed with CM with or without aura (ICHD-3 beta) without any preventive treatment and candidates for treatment with onabotulinumtoxinA, as well as patients with episodic migraine (EM) as controls.

We collected sociodemographic, clinical data, acute treatment intake, and disability scales. We evaluated cortical excitability using transcranial magnetic stimulation (TMS) parameters: resting motor threshold (RMT), cortical silent period (CSP) and shortinterval intracortical inhibition (SICI).

Using two-sided analysis and a level of 5% by means of t-test for independent samples and paired t-test for matched data, we analyzed clinical and neurophysiological data at baseline and after two cycles of onabotulinumtoxinA treatment (PREEMPT).

Results: Data was collected from 19 patients with CM and 16 controls (EM). We found a significant reduction in headache frequency after treatment with onabotulinumtoxinA (p-value=0.001). In TMS-measurements, after onabotulinumtoxinA treatment, RMT decreased (58.9±13.3% vs 55.1±11.9%, p-value=0.004), approaching control values (53.75±9.88%, p-value=0.019) and CSP increased (85.6±26.4ms vs 100.9±33.0ms, p-value=0.004) approaching control values (121.53±39.92, p=0.003). Measurements of greater inhibition in SICI predicted and improvement in frequency and intensity more than 50%.

Conclusion: In CM, after treatment with onabotulinumtoxinA cortical excitability changes which may indicate cortical modulation mechanisms.

Ethics Approval

The study was approved by CEIC institution with number MIG-ONA-2014-01.

P98 Effectiveness of OnabotulinumtoxinA in chronic migraine. If early introduction: faster, cheaper and more satisfactory

Robert Belvís, Noemí Morollón, Marina Guasch, Paula Marrero, Azahara Aceituno, Carles Roig

Headache Unit. Dexeus University Hospital and Headache Unit. Santa Creu i Sant Pau Hospital, Barcelona, Spain
Correspondence: Robert Belvís (rbelvis@santpau.cat)

Introduction

Only OnabotulinumtoxinA and Topiramate have evidence I and grade A of recommendation in the treatment of chronic migraine (CM). However, many patients receive other oral drugs before starting OnabotulinumtoxinA treatment, delaying the start of onabotulinumtoxinA months or years.

Objectives

The aim of this study was to demonstrate that the early administration of OnabotulinumtoxinA, in the course of CM, improves the speed of its effectiveness, and reduces the number of cycles, dose and cost.

Patients / methods

Patients with CM (ICHD3:1.3) treated with OnabotulinumtoxinA with the PREEMPT injection paradigm in two Headache Units. We classified two groups of patients: start of OnabotulinumtoxinA at 3-9 months of the evolution of CM (early group) and at >9months (late group). Main variable: response rate (decrease>50% of days of migraine/month at 16 weeks). Secondary variables: number of cycles and dose of OnabotulinumtoxinA, percentage of completion of treatment, cost in euros, triptans consumption, and Likert satisfaction scale.

Results

90 patients were treated with Botox: early group-18 (average 6.2 months) and late group-72 (average 57.8 months). Overall response rate 80%: 94.4% in the early group: 76.3% in the late group (p=0.07). Early response: excellent-61.1%, good-33.3%, non-response-5.5%; vs. late: 36.1%, 38.8%, 25% (p=0.05, 0.6, 0.07, respectively). Treatment completion rate: early-50% / late-23.6% (p= 0.02); need for more than 4 cycles: early-16.6% / late-37.5% (p=0.09); maximum dose rate: early-5% / late-31.9% (p=0.02); Botox spending 1st year: early-923€ / late-1,137€ (p=0.03); reduction in average consumption of triptans: early-66.6% / late-64.7% (p=0.8); Likert satisfaction scale: early-4.5 / late-3.3 (p =0.009).

Conclusion

The rate of OnabotulinumtoxinA responders seems independent of the time of the chronic migraine in which treatment is started. However, the time it takes to achieve effectiveness is lower the earlier you start, so the patient receives fewer sessions and lower doses increasing their satisfaction. Additionally, the final cost of the treatment is minor.

P99 Sickness absence and disability pension in cluster headache patients and in matched references: a population-based study

Anna Steinberg1, Pontus Josefsson2, Kristina Alexandersson2, Christina Sjöstrand1

1 Division of Neurology, Department of Clinical Neuroscience, Karolinska Institutet, SE 171 77 Stockholm, Sweden; 2 Division of Insurance Medicine, Department of Clinical Neuroscience, Karolinska Institutet, SE 171 77 Stockholm, Sweden
Correspondence: Anna Steinberg (anna.steinberg@sll.se)

Background: Cluster headache, a primary neurovascular headache syndrome, is considered one of the most severe pain conditions known to humans. Nevertheless, there is little knowledge about sickness absence and disability pension among cluster headache patients.

The aim was to estimate the prevalence of cluster headache among people of working ages and to compare their rates of sickness absence and disability pension with such rates among matched references and to explore whether sociodemographic factors were associated with these rates.

Methods: A population-based register study of all 3240 people aged 16-64 who lived in Sweden all of 2010 and who at least once during 2001-2010 had in- or specialized outpatient care with cluster headache (ICD10 code G44.0) as the main diagnosis. They were compared with a reference group (N=16,200) matched on age, sex, type of living area, and level of education from the total population aged 16-64 years (N=5,945,895) regarding their sickness absence and disability pension in 2010. Crude and adjusted prevalence rates with 95% confidence intervals (CI) of being on full-time disability pension all 2010, part of 2010, and for having had at least one sickness absence spell >14 days, were computed for all and by different sociodemographics.

Results: The prevalence of cluster headache among working-aged people in Sweden was 0.054%. In 2010, sickness absence rates were 17.30% (CI: 15.93-18.68) among cluster headache patients and 9.16% (8.70-9.61) among references. In the cluster headache group a much higher rate of women had sickness absence (25.31% (CI 22.56-28.07)) compared to among men (13.38% (CI 11.87-14.89)) or full-time disability pension (women 13.17% (CI 11.17-15.17) compared to men (8.79% (CI 7.59-9.99)). Cluster headache patients >35 years had a higher rate of sickness absence and disability pension compared to references in the same age group. The difference became even more obvious in patient ages 55-64; disability pension 21.77% (18.89-24.65) compared to 11.90% (10.89-12.91). A higher rate of cluster headache patients born outside Sweden were on full-time disability pension; 13.56% (CI 10.85-16.28) compared to cluster headache patients born in Sweden; 9.51% (CI 8.39-10.63). Level of education in the cluster headache group was not associated with disability pension as much as in the reference group.

In summary, this nationwide study of working-aged people showed that cluster headache patients had sickness absence or disability pension to a much higher degree than matched references. Moreover, this varied much by sociodemographics, which needs to be addressed.

Ethics approval

The project was approved by the Regional Ethical Review Board in Stockholm, Sweden

P100 Clinical features of pediatric medication overuse headache and applicability of new ICHD-3 criteria

Romina Moavero, Maddalena Stornelli, Laura Papetti, Barbara Battan, Samuela Tarantino, Federico Vigevano, Massimiliano Valeriani

Headache Center, Bambino Gesù Children’s Hospital, IRCCS, Rome, Italy
Correspondence: Romina Moavero (rominamoavero@hotmail.com)

Objectives. To describe the clinical phenotype of pediatric medication overuse headache (MOH) and to analyze the applicability of ICHD-3 criteria in comparison to the ICHD-2. MOH is characterized by headache occurring on ≥15 days/month in patients with pre-existing primary headache and developing as a consequence of regular overuse of symptomatic headache medication.

Materials and Methods. We conducted a retrospective analysis of clinical data of pediatric patients diagnosed with MOH in our Department. In all patients the clinical diagnosis of MOH was verified both according to ICHD-2 and ICHD-3 version criteria, to verify the degree of concordance.

Results. We identified 42 subjects diagnosed with MOH (31 F, 11 M), ranging between 8 and 17 years of age (mean 13.4 years). All patients presented with chronic migraine, with 9% fulfilling a diagnosis of migraine with aura. As for the clinical features of migraine, photo- and photophobia were both present in 81% of patients, nausea/vomiting in 30%, dizziness in 18%. Regarding the applicability of the ICHD-2 criteria, 21/42 (50%) fulfilled criterion A; 35/42 (83%) criterion B, 37/42 (88%) criterion C, and 23/42 (55%) criterion D. On the other hand, applying the criteria of ICHD-3, criterion A was fulfilled by 40/42 patients (95%), criterion B by 35/42 (83%), and criterion C by 40/42 (95%).

Discussion. Our data show that in comparison with ICHD-2, ICHD-3 criteria are satisfied by a higher rate of pediatric patients clinically diagnosed with MOH. The old criteria required a development or marked worsening of the headache during medication overuse, and a resolution within 2 months after medication withdrawal. Both these criteria disappeared in the new version of ICHD, being replaced by the requirement that the condition should be not better accounted by another ICHD-3 diagnosis. This means that now a diagnosis of MOH could be made in presence of a high frequency headache in a patient presenting a medication overuse, without the necessity of demonstrating a clear and direct correlation with abuse and discontinuation of symptomatic medications.

Conclusion. Our data show that ICHD-3 criteria allow a definite diagnosis of MOH in a higher rate of pediatric patients

P101 C-tactile touch perception and habituation in migraineurs

Hanna Sophie Lapp1, Ilona Croy2, Gudrun Gossrau1

1 Comprehensive Pain Center, Technische Universität Dresden, Dresden, Sachsen, 01307, Germany; 2 Department of Psychotherapy and Psychosomatic Medicine, Technische Universität Dresden, Dresden, Sachsen, 01307, Germany
Correspodence: Hanna Sophie Lapp (Hanna-Sophie.Lapp@uniklinikum-dresden.de)

Background: Migraine is characterized by sensory hypersensitivity and habituation deficits. Slow brushing over the skin activates c-tactile (CT) nerve fibres which mediate pleasant touch and analgesic effects in healthy subjects. As this function is altered in painful conditions, we aimed to examine whether the processing of CT fibres is also deranged in migraine.

Methods: Assessing c‐tactile function, we applied CT optimal (1cm/s, 3cm/s 10cm/s) and CT suboptimal (0,3cm/s, 30cm/s) brush stroking stimuli on both the dorsal forearm (body reference area) and the cheek as area with trigeminal sensory innervation of 53 interictal migraineurs and 53 matched healthy controls. For habituation testing, all subjects were presented 60 repeated CT optimal stimuli (3cm/s) in both test areas. The participants rated each stimulus on a 11-point visual analogue scale by intensity, pleasantness and painfulness. The study was approved by TU Dresden’s Ethics Board, approval number EK 412102017.

Results: Results showed no significant difference in pleasantness ratings between migraineurs and controls when assessing CT function. However, ratings decreased over time in both areas in migraineurs but not in controls during repeated stimulation (p<0.001). When comparing habituation of rarely and highly affected migraineurs, pleasantness ratings decreased in rarely affected subjects but remained stable in frequently affected subjects (p<0.001).

Conclusion: We conclude that there is no significant alteration of the c-tactile function in migraineurs. However, rarely affected migraineurs show a habituation deficit regarding CT processed touch whereas patients with frequent migraines show normal habituation. These findings correspond with previous research on habituation to other sensory stimuli.

P102 Endeavor to identify associations between vaping and primary headaches

Marge Vaikjärv1, Kati Toom2,3, Mark Braschinsky2,3

1Faculty of Medicine, University of Tartu; 2Headache Clinic, Tartu University Hospital 3Estonian Headache Society
Correspondence: Marge Vaikjärv (marge.vaikjarv@gmail.com)

Introduction

Smoking has been identified as one of the major risk and trigger factors of primary headaches. In recent years vaping as a socially more acceptable and presumably “healthier” form of nicotine consumption has increased in frequency. In recent studies vaping was associated with a lower and slower attainment of blood nicotine levels. The effects of vaping on human physiology, cognitive abilities and levels of different biomarkers are in the focus of many ongoing and completed studies. Although some of them bring out increase of headache frequency among vapers, associations between vaping and primary headache remains unknown.

Objectives

The objective of our study was to compare prevalence of primary headaches among vapers, non-smokers and smokers.

Methods

The data were derived from a population based survey conducted in Estonia form January 2016 till March 2017. The participants were asked about their age, sex, height and weight, daily coffee consumption, physical activity and occurrence, frequency and intensity of headaches. In order to specify the form of nicotine consumption respondents who agreed to give additional information after filling the survey, were contacted. Headache diagnoses based on given answers were determined according to ICHD-3 classification. Odd ratios (with 95% confidence interval) in all three groups for types of primary headaches (“migraine”, “tension type headache” and “others”) were calculated.

Results

Sample included 523 respondent, among whom 413 (79%) were non smokers, 101 (19%) smokers and 9 (2%) vapers. There was a statistically important difference in daily coffee consumption between non smokers and smokers as well as between non smokers and vapers but not between smokers and vapers. Primary headache prevalence was 82%, 77% and 78% among non smokers, smokers and vapers respectively.

Conclusions

The results indicated nicotine consumption to be a protective factor for primary headaches (ORs included 1) which differs from previous studies. While looking through our methodology we identified multiple probable biases which affected our results and made it impossible to give an adequate and reliable answer to the study objective. The most important ones being sampling and vaping as an form of nicotine consumption added to the original survey.

In order to study the possible connections between vaping and primary headaches data collection surveys should include vaping, and possible other nicotine consumption methods, separately from smoking.

Ethics Approval

The study was approved by Research Ethics Committee of the University of Tartu, approval number 252T-15.

P103 NDPH sub-categories and treatment in pediatrics patients

Priyanka Shekhawat, Alex S Silver, Jessica Oppenheimer, Robert Fryer

Department of Child Neurology, Columbia University Medical Center - New York, USA
Correspondence: Priyanka Shekhawat (ps2761@cumc.columbia.edu)

New Daily Persistent Headache (NDPH) is a chronic non-migrainous headache disorder. As defined by the International Classification of Headache Disorders (ICHD-3 beta), NDPH is a headache lacking the characteristic features and is continuous and unremitting from its onset. Most patients can recall the exact moment the headache began. Rather than being a distinct disease, some experts suspect that NDPH is a syndrome having multiple underlying causes. Little information is currently available about this form of headache in the pediatric population. We are looking at the charts of patients seen in the Division of Child Neurology at Columbia University, who are of ages 5-21 and who have been diagnosed with NDPH between 1/1/2012 and 1/1/2016. Our goal is to determine if there are possible sub-categories of this disorder. A secondary goal is to characterize the range of treatments for these patients and identify the successful treatments for NDPH in children. The chart review will be complete at the time of conference.

P104 Frequency, referral and demographic characteristics of patients with vestibular migraine from a tertiary centre

Isabel Luzeiro1, Isabel Pavão2

1Centro Hospitalar da Universidade de Coimbra; 2University of Lisbon and Santa Maria Hospital, Lisbon
Correspondence: Isabel Luzeiro (isabeluzeiro@gmail.com)

Background and goals. Vestibular migraine is a recently-described entity, still classified in the Appendix of the ICHD-3 beta and of the 2018 ICHD-3 final classification. The tertiary headache clinic of the Hospital and University Centre of Coimbra receives patients from the emergency department, from the general Neurology Department and from consultations of other specialties and primary health care. Taking into account the new classification, we proposed to describe how many patients were referred to our consultation, to characterize them in demographic terms and to identify their origin.

Patients and methodology. This is a descriptive study, including all patients that were referred to our Headache Clinic in the last year.

Results. In a universe of 400 patients referred, 27 had vestibular migraine. Their age varies between 19 and 57 years. All of them have, at least, a level of secondary education; about 40% have a university degree. The marital status is miscellaneous. Patients referred because of a clinical hypothesis of vestibular migraine were sent by otorhinolaryngologists, with a percentage of 30%. No patients from primary care had this clinical hypothesis established. However, all patients were referred because of migraine.

Discussion. The percentage of patients with vestibular migraine diagnosed at our tertiary center was 6.8%, slightly higher than the results reported in literature for the general population. Age did not allow to define preferential associations for this type of pathology. All levels of education were equally affected. The analysis of these data suggests a lack of knowledge of this entity by the primary health care system. Otorhinolaryngologists seem to be the most alert physicians for this clinical entity.

P105 Migraine comorbidity and cognitive performance in patients with focal epilepsy

Olivia AJ Begasse de Dhaem1, Chris Morrison2, Kimford J Meador3, Dale E Hesdorffer1, Sabrina Cristofaro2, Jacqueline French2, Mia T Minen2, on behalf of the HEP Investigators

1Department of Neurology, Columbia University – New York Presbyterian Hospital, New York, New York, 10023, USA; 2Department of Neurology, New York University, New York, New York, 10016, USA; 3Department of Neurology, Stanford University, Palo Alto, California, 94304, USA
Correspondence: Olivia AJ Begasse de Dhaem (oab2109@cumc.columbia.edu)

Background: Migraine and epilepsy are comorbid diseases that are both associated with cognitive impairments. [1,2,3,4,5] The presence of cognitive impairment in migraine patients is thought to be independent of migraine severity, duration, or medications. [1] Using prospective data from the Human Epilepsy Project (HEP) that follows patients with newly diagnosed focal epilepsy, we will assess whether the comorbid presence of migraine affects cognitive testing scores in epilepsy patients.

Methods: The primary outcomes are the total and subtest differences in initial cognitive performance between epilepsy patients with migraine and epilepsy patients without migraine. Cognitive function is assessed with the Wide Range Achievement Test 4 (WRAT4) and elements of the Cogstate test battery. Logistic regression will adjust for potential confounders such as depression, anxiety, age, cardiovascular protective medications, cardiovascular disease, and history of head trauma.

Impact: We hypothesize that there will be significant differences in cognition between epilepsy patients with migraine compared to epilepsy patients without migraine. If this is the case, future work could evaluate whether there is an association between new migraine diagnosis at the end of the study and change in Cogstate scores (between the initial and last score). Biomarker evaluation, brain MRI, and EEG could also be considered to assess for the etiology of such differences.

Ethics Approval

The study was approved by Columbia University Institutional Review Board, AAAL5255.

Consent to publish

Informed consent was obtained from subjects or legal guardians.

Disclosures

The HEP study is supported by the Epilepsy Study Consortium (ESCI), a non-profit organization dedicated to accelerating the development of new therapies in epilepsy to improve patient care. The funding provided to ESCI to support HEP comes from industry, philanthropy and foundations (UCB Pharma, Eisai, Pfizer, Lundbeck, Sunovion, The Andrews Foundation, The Vogelstein Foundation, Finding A Cure for Epilepsy and Seizures (FACES), Friends of Faces and others).

Dr. Meador has received research support from the National Institutes of Health, the Patient-Centered Outcomes Research Institute, UCB Pharma and Sunovion Pharmaceuticals, and travel support from UCB Pharma. The Epilepsy Study Consortium pays Dr. Meador’s university for his research consultant time related to Eisai, GW Pharmaceuticals, NeuroPace, Novartis, Supernus, Upsher-Smith Laboratories, UCB Pharma, and Vivus Pharmaceuticals.

Dr. Begasse de Dhaem, Dr. Morrison, Dr. French, and Dr. Minen do not have disclosures.

The abstract only describes the protocol. However, the data analysis will be performed by the time of the European Headache Federation meeting.

References

[1] Waldie KE, Hausmann M, Milne BJ, Poulton R. Migraine and cognitive function: a life-course study. Neurology. 2002 Sep 24;59(6):904-8.

[2] Precenzano F, Ruberto M, Parisi L, Salerno M, Maltese A, Gallai B, Marotta R, Lavano SM, Lavano F, Roccella M. Visual-spatial training efficacy in children affected by migraine without aura: a multicenter study. Neuropsychiatr Dis Treat. 2017 Jan 27;13:253-258.

[3] Pellegrino Baena C, Goulart AC, Santos IS, Suemoto CK, Lotufo PA, Bensenor IJ. Migraine and cognitive function: Baseline findings from the Brazilian Longitudinal Study of Adult Health: ELSA-Brasil. Cephalalgia. 2017 Jan 1:333102417737784.

[4] Haut SR, Bigal ME, Lipton RB. Chronic disorders with episodic manifestations: focus on epilepsy and migraine. Lancet Neurol. 2006 Feb;5(2):148-157.

[5] Smith DB, Craft BR, Collins J, Mattson RH, Cramer JA. Behavioral characteristics of epilepsy patients compared with normal controls. Epilepsia. 1986 Nov-Dec;27(6):760-8.

P106 Nosographic analysis of osmophobia and field testing of diagnostic criteria including osmophobia

Mona Ameri Chalmer, Thomas Folkmann Hansen, Jes Olesen, Professor

Department of Neurology, Danish Headache Center, Copenhagen University Hospital, Glostrup, Denmark
Correspondence: Mona Ameri Chalmer (mona.ameri.chalmer@regionh.dk)

Introduction

Omophobia has been suggested as an additional symptom of migraine without aura (MO) and high prevalence of osmophobia up to 50% has been reported in the literature. We conducted a nosographic study of osmophobia in all migraineurs and tension-type headache (TTH) patients and a field testing of suggested diagnostic criteria of osmophobia, presented in the appendix of the second edition of The International Classification of Headache Disorders (ICHD-2)[1] and suggested by Silva-Néto et al[2] and Wang et al[3], in MO and TTH patients (n=1,934).

Materials and methods

All patients were carefully phenotyped and fulfilled the ICHD-2 diagnostic criteria for migraine or TTH. Statistical analyses were performed using statistical software R. The statistical R package “Caret” was used to construct a confusion matrix and retrieve sensitivity, which was defined as the suggested criteria’s ability to correctly diagnose MO patients, and specificity, defined as the suggested criteria’s ability to not wrongly diagnose TTH patients.

Results

Osmophobia was present in 33.5% of patients with migraine with aura, in 36.0% of patients with MO, and in 1.2% of patients with TTH. All migraineurs with osmophobia also fulfilled the current criteria for migraine by having nausea or photophobia and phonophobia. The appendix criteria had a sensitivity of 0.96 and a specificity of 0.99 for MO, and a sensitivity of 0.65 and a specificity of 0.99 for probable MO (pMO). Both the criteria by Silva-Néto et al and Wang et al had a sensitivity of 0.98 and a specificity of 0.99 for MO, and a sensitivity of 0.66 and a specificity of 0.99 for pMO.

Discussion

This study demonstrates the remarkable specificity of osmophobia. The criteria by Silva-Néto et al and by Wang et al both had a higher sensitivity than the appendix criteria for MO; all three criteria had a low sensitivity for pMO. However, neither the appendix criteria nor the criteria by Silva-Néto et al or Wang et al added any extra patients that would not have been diagnosed by the current diagnostic criteria for migraine. Osmophobia is a valuable symptom that may be useful to differentiate between MO and TTH in difficult clinical cases.

Conclusion

Our results do not suggest that alterations of the current diagnostic criteria for MO are needed.

Ethics Approval

Our research group has permissions and approval from the Data Protection Agency (GLO-2010-10) and the Ethical Committee (H-2-2010-122).

References

1. International Headache Society (1997) The International Classification of Headache Disorders, 2nd edition. Cephalalgia 9–160 . doi: http://dx.doi.org/10.1016/B978-0-7506-3365-9.50006-7

2. Silva-Néto RP, Rodrigues ÂB, Cavalcante DC, et al (2017) Reply to the Letter to the Editor: “smell of migraine: Osmophobia as a clinical diagnostic marker.” Cephalalgia 37:907–908 . doi: 10.1177/0333102416658716

3. Wang Y-F, Fuh J-L, Chen S-P, et al (2012) Clinical correlates and diagnostic utility of osmophobia in migraine. Cephalalgia 32:1180–1188 . doi: 10.1177/0333102412461401

P107 Living with migraine: a report from the My Migraine Voice survey

Audrey Craven1, Rebeca Quintana2, Veruska Carboni3, Paolo Martelletti4,5, Michel Lanteri Minet6, Todd J. Schwedt7, Hans-Christoph Diener8, Annik K-Laflamme9, Annette Vangaa Rasmussen10, Elena Ruiz de la Torre11, Donna Walsh12, Simon Evans13, Paula Dumas14, Rachel Fink9, Angela Fiorin9, Stephanie Ribbe9, Pamela Vo9

1Migraine Association Ireland, Dublin, Ireland; 2GFK, Madrid, Spain; 3GfK Health, Basel, Switzerland; 4Department of Clinical and Molecular Medicine, Sapienza University of Rome, Rome, Italy; 5EHF; 6Département d’Evaluation et Traitement de la Douleur, Centre Hospitalo-Universitaire de Nice, France; 7Neurology Arizona, Mayo Clinic, Phoenix, USA; 8Department of Neurology and Headache Center, University Duisburg-Essen, Germany; 9Novartis Pharma AG, Basel, Switzerland; 10Rigshospitalet Glostrup, Copenhagen, Denmark; 11European Headache Alliance; 12European Federation of Neurological Associations, Brussels, Belgium; 13Migraine Action, Leicester, United Kingdom; 14Migraine Again, USA
Correspondence: Audrey Craven (audreycraven@migraine.ie)

Introduction

As a pilot to the My Migraine Voice study, online bulletin boards provided insights into the impact of migraine on the lives of those affected and the coping mechanisms used.

Objectives

The objective of this worldwide survey was to better understand what it is like to live with migraine, as directly reported from patients across the world.

Methods

My Migraine Voice is a worldwide cross-sectional online survey of 11,266 individuals (31 countries in Africa, America, Asia and Europe) recruited via online panels and patient organizations. Participants were adult migraine patients who reported ≥4 MMD in the 3 months preceding survey administration, with pre-specified 90% among those having reported having used preventive migraine treatment.

Results

A total of 11,266 migraine individuals participated (75% female, mean age 39 years); most were in employment/students (73%), with 9% receiving disability-related allowances due to migraines. 85% of participants reported negative aspects of living with migraine (feeling helpless, depressed, not understood), sleeping difficulties (83%); 55% lived in fear of the next attack. Migraines were associated with severe pain (85%), long-lasting headaches (lasting 4 to 72 hours) (83%), sound sensitivity (81%) light sensitivity (74%; mean=19 hours/month spent in darkness). Migraine impact on professional, private or social domains was reported by 87% of participants. Over the previous 3 months, 61% had relied on external support (family/friends/anyone else) to cope with daily tasks (mean=12.8 days). Despite the negative aspects, 57% of respondents indicated >=1 positive aspect, mainly relating to learning to cope with their disease (40%), or making them responsible for their disease (13%), and being stronger as a person (11%).

Conclusion

This study describes the daily reality of migraine individuals, especially those with frequent attacks and who have received migraine preventive treatments. While it highlights the significant challenges and unmet needs for these individuals suffering with migraine, the positive outlook on personal growth brought from coping with the disease highlights their resilience and strength.

Ethics approval

Data was handled confidentially and anonymity of respondents was maintained throughout the study. Participants’ consent was obtained prior to participation in the survey.

Funding

This study was funded by Novartis Pharma AG, Basel, Switzerland

P108 A model concept for assessing the cost-effectiveness of prophylactic migraine treatments

Ronan Mahon1*, Pamela Vo2, Philip Cooney1, Andrii Danyliv1, Aikaterini Bilitou1, Nagasuman Toram3, Sreelatha Vadapalle3, Jasper Huels2, Farooq Maniyar4, Peter J Goadsby5 Mark Sculpher6

1Novartis Global Services Centre, Patient Access Services, Dublin, Ireland; 2Novartis Pharma AG, Basel, Switzerland; 3Novartis Global Services Centre, Patient Access Services, Novartis Healthcare Pvt. Ltd., Hyderabad, India; 4Basildon and Thurrock University Hospitals and Queen Mary University, London, England; 5NIHR-Wellcome Trust, King’s Clinical Research Facility, King’s College London, UK; 6Centre for Health Economics, University of York, Heslington, Alcuin 'A' Block, York, YO10 5DD UK
Correspondence: Ronan Mahon (ronan.mahon@novartis.com)

Objectives

Migraine is a distinct neurological disease ranking among the top ten leading causes of disability [1]. Erenumab is a fully human monoclonal antibody (mAb) targeting the canonical calcitonin gene-related peptide (CGRP) receptor [2]. The objective of this research was to develop an economic model in order to assess the cost-effectiveness of erenumab as a migraine prophylactic treatment compared to relevant alternatives.

Methods

Relevant clinical guidelines (e.g. BASH and NICE) and previous economic evaluations were researched in order to understand clinical practice and previous modelling approaches in migraine prevention. Cost- effectiveness model concepts were devised and evaluated. Key opinion leaders, within both the medical and HE&OR fields, were consulted in order to select a model structure that is clinically and economically meaningful.

Results

A decision-tree plus Markov structure was developed as a cost-effectiveness model for erenumab in the preventive treatment of migraine. Reflecting clinical practice, the decision-tree component represents an assessment period, allowing for treatment discontinuation based on safety and clinically relevant response criteria. The Markov component represents a post-assessment period, where treatment responders and non-responders follow distinct treatment pathways. Responders, without safety or tolerability issues, continue treatment over the post-assessment with an optional re-evaluation period which may lead to positive discontinuation, while non-responders discontinue and do not reinitiate preventive treatment. The underlying assumption of the model is that both costs and quality-adjusted life-years (QALYs) can be estimated based on monthly migraine day (MMD) frequency. Thus, each health state in the model is associated with a patient distribution across MMD frequencies.

Conclusions

A decision-tree plus Markov model reflecting clinical practice was constructed to assess the cost- effectiveness of erenumab in the prophylactic treatment of migraine, estimating both, migraine patients’ MMD frequencies and their response to treatment.

Funding

This study was funded by Novartis Pharma AG, Basel, Switzerland

References
  1. 1.

    Vos, T. et al. Global, regional, and national incidence, prevalence, and years lived with disability for 328 diseases and injuries for 195 countries, 1990–2016: a systematic analysis for the Global Burden of Disease Study 2016, 2017; 390; 10100: 1211-1259.

     
  2. 2.

    Goadsby, P.J., Reuter, U., Hallstrom, Y., Broessner, G., Bonner, J.H., Zhang, F., Sapra, S., Picard, H., Mikol, D., Lenz, R.A. A Controlled Trial of Erenumab for Episodic Migraine, The New England Journal of Medicine, 2017; 377: 2123-32.

     

P109 Relative efficacy of outpatient infusion therapy on pediatric patients with post-concussive headaches

Sara J Gould1, Erin Mackenzie Katz2, Carly Ann Cignetti2

1University of Alabama at Birmingham; 2University of Alabama at Birmingham School of Medicine
Correspondence: Sara J Gould (sgould@uabmc.edu)

Background:

Concussion is an increasingly common diagnosis in the pediatric population. Our center has previously reported that among children who suffer from concussion symptoms longer than 10 days, over 98% report headache as a symptom.2 Standard practice in post-traumatic headache management dictates that prophylactic medications should not be started within 3 weeks of the injury, due to the rapid fluctuation and resolution in symptoms that often occurs following concussion. 3 However, the severity of the headaches can make activities of daily living difficult or impossible for the headache sufferers. Scholastic activities can suffer due to the inability to attend school or perform coursework. Intravenous therapy has been shown to be effective in the emergency department setting for post-traumatic headaches. 4 Therefore, we developed an infusion clinic to serve as an abortive therapy for intractable headache symptoms following concussion.

Methods: We administered an intravenous (IV) cocktail consisting of ketorolac, Compazine, diphenhydramine and 20mg/kg bolus of normal saline. The infusion was administered over. Patients followed up with their providers at an appointment following the infusion. Concussion Symptom Severity Scores were documented at physician visits before and after the infusion for each patient.

Results: We had a total of 27 pediatric patients, age 18 years or less who received an infusion from 2016-2018. 85% (23) of patients reported that the infusion helped diminish their headache. 4% (1) said that the infusion did not help at all. 11% (3) were not asked by their physician at the follow up visit about the infusion. Average symptom severity scores before the infusion were 57.5. Following infusion, the average symptom severity score decreased to 22. Headaches were rated on a scale of 0-6 on the symptom severity score. The average severity of the headache was rated at 4 prior to the infusion and rated at 2 following infusion.

Discussion: Following the infusion protocol, patients ranked their headaches an average of 2 points lower on the symptom severity score. Overall symptom burden decreased at follow up visit as well, from 57 at the initial visit to 22 following the infusion.

Conclusion: An outpatient infusion clinic may be an effective means to control subacute post-concussive headaches. Further research with randomized controlled trials should be conducted to determine efficacy of the protocol.

References
  1. 1.

    Nonfatal traumatic brain injuries related to sports and recreation activities among persons aged </=19 years--United States, 2001–2009. MMWR Morb Mortal Wkly Rep. 2011;60:1337–42.

     
  2. 2.

    Academic Difficulty and Vision Symptoms in Children with Concussion. Swanson MW, Weise KK, Dreer LE, Johnston J, Davis RD, Ferguson D, Hale MH, Gould SJ, Christy JB, Busettini C, Lee SD, Swanson E. Optom Vis Sci. 2017 Jan;94(1):60-67

     
  3. 3.

    Part II – Management of pediatric post-traumatic headaches. Pinchefsky E, Dubrovsky AS, Friedman D, Shevell M. Pediatr Neurol. 2015 Mar;52(3):270-80

     
  4. 4.

    Intravenous migraine therapy in children with posttraumatic headache in the ED. Chan S, Kurowski B, Byczkowski T, Timm N. Am J Emerg Med. 2015 May;33(5):635-9.

     

P110 Movement disorders as positive motor aura symptoms during hemiplegic migraine attacks

Elisa de la Cruz1, Geneviève Demarquay2, Caroline Roos3, Isabelle Sabatier4, Florence Riant5, Victoria Gonzàlez1, Anne Ducros1

1Service de Neurologie, CHU Gui de Chauliac, 34090 Montpellier, France; 2Service de Neurologie clinique et fonctionnelle, Hôpital Pierre Wertheimer, 69667 Bron, France; 3Centre d’Urgences Céphalées, Hôpital Lariboisière, 75010 Paris, France; 4Service de Neuropédiatrie, Hôpital Femme Mère Enfant, 69677 Bron, France; 5Laboratoire de Génétique moléculaire, Hôpital Lariboisière, 75010 Paris, France
Correspondence: Elisa de la Cruz (elisa@sdlc.ca)

Background: Migraine aura includes positive and negative symptoms. Positive motor symptoms (i.e movement disorders) have not been described so far during hemiplegic migraine (HM) attacks.

Methods: Patients were included if they had at least 2 attacks of hemiplegic migraine, and abnormal movements during the aura. After written informed consent, patients were interviewed and examined. Testing for FHM mutations in the CACNA1A, ATP1A2, SCN1A, PRRT2 genes or for a CADASIL mutation in the NOTCH3 gene has been done previously, for diagnostic purposes.

Results: Seven unrelated patients (2 males, 5 females) satisfied inclusion criteria. Five had familial HM (FHM), associated with a mutation in CACNA1A in 1 patient (a deletion without known pathological significance), ATP1A2 in 2 patients, and SCN1A in 1. Relatives with FHM had no movement disorders. Two patients had sporadic HM (1 with a S218L mutation on CACNA1A gene, and 1 without identified mutation). One patient had a secondary form of HM due to CADASIL with an archetypal NOTCH3 mutation. Seven patients had typical attacks with motor deficit (n = 7) associated with sensory (n = 6), language (n = 7) and visual symptoms (n = 5), that started at a mean of 8,3 (±3,6) years old. All 7 had movement disorders which appeared as a brief (mean duration 10,8 ± 5,3 minutes) and stereotyped component of their aura, with dystonic posturing in all and choreoathetosis in 4. The patient with the S218L mutation of CACNA1A had choreoathetosis during a prolonged severe HM attack with coma. Paroxysmal movements predominantly affected one upper limb and preceded the onset of ipsilateral paresis.

Discussion: Dystonia and dyskinesia may occur during the aura in any variety of familial or sporadic HM, either primary due to mutations of FHM genes or secondary to CADASIL. Cortical spreading depression might induce activation of different cerebral pathways generating movement disorders and then paresis. Functional imaging during attacks might help elucidate underlying mechanisms.

Consent for publication: Informed consent to publish was obtained from all patients or legal tutors.

P111 Long-term response to onabotulinumtoxin A in chronic migraine: analysis of efficacy and tolerability in a series of 40 patients

D García-Azorín, A Sierra, J Trigo, E Martínez-Pías, AL Guerrero

Headache Unit, Neurology Department. Hospital Clínico Universitario, Valladolid, Spain
Correspondence: García-Azorín D (davilink@hotmail.com)

BACKGROUND: The efficacy and safety of OnabotulinumtoxinA (OnabotA) in Chronic Migraine (CM) has been established both in clinical trials and in real-world setting. However, there is less information about tolerability and maintenance of efficacy in a long-term scenario. We aimed to analyze both efficacy and tolerability in a series of patients treated for a long time

PATIENTS AND METHODS: Patients with Chronic Migraine attended in a Headache Unit in a tertiary hospital. Treatment with OnabotA was recommended in patients non-responders to Topiramate and at least one other oral preventative, according to local guidelines. We prospectively collected demographic data and migraine characteristics from all the patients. We also recorded information about tolerability, headache days, migraine days, and the number of days on which patients used acute headache medications, in particular triptans. We specifically analyzed efficacy and tolerability in patients who had reached at least 10 OnabotA procedures according to PREEMPT protocol

RESULTS: We included 40 patients (34 female, 6 male), with 40.8 ± 12.3 years (16 - 69) at inclusion. Latency between migraine and CM onset and OnabotA therapy was respectively 22.7 ± 12.6 years and 26 ± 22.8 months. In 8 of these patients (20%), a decrease in the response time below 3 months was observed between the 5th and 8th procedures. This “wearing-off” response improved in most patients increasing OnabotA dose according to "follow the pain" protocol. In 12 cases (30%) an adverse effect appeared, mainly musculoskeletal pain or stiffness mainly in occipital location and, in one patient, fronto-temporal atrophy

CONCLUSION: Long-term decrease of efficacy and adverse effects were not rare in our series. We should be aware of this possibility after the third year of OnabotA treatment

P112 Acute and preventive treatment patterns and associated work productivity and activity impairment among patients with migraine in Germany

J. Scott Andrews1*, Janet Ford1, Grazia Dell’Agnello2, Sarah Cotton3, Antje Tockhorn-Heidenreich4, Louise Lombard1, Zoe Phillips3, James Jackson3

1Eli Lilly and Company, Indianapolis, IN, 46285, USA; 2Eli Lilly and Company, Florence, Italy; 3Adelphi Real World, Bollington, UK; 4 Eli Lilly and Company Limited, Windlesham, UK
Correspondence: Grazia Dell’Agnello (andrews_jeffrey_scott@lilly.com)

Background

Limited research exists on patients with migraine in Germany that addresses both acute and preventive treatment patterns and the productivity impact of migraine, which has been recognized as a significant contributor to societal burden. The objective of this study was to characterize treatment patterns, work productivity, and daily activity impairment associated with various levels of headache frequency among patients with migraine in Germany.

Methods

Data were taken from the 2017 Adelphi Real World Migraine Disease Specific Programme, a point-in-time survey of physicians and their patients with a diagnosis of migraine in Germany. Physicians (Primary care = 51, Neurologist = 40) completed patient record forms (n = 810) containing patient demographics, comorbidities, headache frequency, diagnosis, treatment practice, medication utilization, and unmet needs of current treatments. Productivity was captured via patient report on the Work Productivity and Activity Impairment Questionnaire (WPAI). Patients were stratified by the frequency of headache days (HD) experienced per month (0-3, 4-7, 8-14, 15+).

Results

Most patients with migraine experienced 0-3 (40%) or 4-7 (42%) HD/month. Mean duration from first migraine experienced to first diagnosis was 3.4 months. Mean duration from first diagnosis to first prescribed acute and preventive treatments was 2.2 months and 23.1 months, respectively. The majority of patients (70%, 0-3 HD; 68%, 4-7 HD; 55%, 8-14 HD; 63%, 15+HD) were prescribed acute treatment only, while 18% (0-3 HD), 25% (4-7 HD), 39% (8-14 HD), and 36% (15+HD) received preventive treatment. Sumatriptan and ibuprofen were the most commonly prescribed acute treatments across all headache frequency categories, while metoprolol and topiramate were the most frequently prescribed preventive treatments. Over the counter (OTC) medication use ranged from 17% in 0-3 HD group to 27% in 15+ HD group. Across all levels of headache frequency, at least 1 in 4 patients with migraine experienced impairment in work productivity and activity. The top physician-reported unmet needs with acute treatments included: speed of action / a faster acting drug needed, minimal / acceptable side effect profile, and minimal / no cardiovascular risk. Top unmet needs for preventives included: minimal side effects / acceptable side effect profile, effective medication, and tolerability.

Conclusions

Most patients in Germany are treated with acute medications only, although many experience headache frequencies indicating prevention eligibility. Notably, patients with chronic headache frequency (15+ HD) have low preventive treatment use and high combination OTC and acute prescription use. Considerable impairment in work productivity and daily activity was observed across all headache frequency groups.

P113 Baseline demographics and disease characteristics of patients with episodic cluster headache: results from a phase 3 clinical trial

James M. Martinez, Jennifer N. Bardos, Tina M. Myers Oakes, Chunmei Zhou

Eli Lilly and Company, Indianapolis, IN, 46285, USA
Correspondence: Jennifer N. Bardos (bardos_jennifer_n@lilly.com)

Background: Cluster headache (CH) is a disabling primary headache disorder characterized by episodic attacks of intense unilateral headache with autonomic symptoms and/or restlessness or agitation. Patients with episodic CH (approximately 85.0% of CH patients) have cluster periods typically lasting 2-12 weeks and differ diagnostically from chronic CH patients based on duration of remissions. Increased blood levels of calcitonin gene-related peptide (CGRP) have been associated with CH, making CGRP a potential therapeutic target. The objective of this study was to assess the efficacy and safety of galcanezumab, a CGRP monoclonal antibody, in patients with episodic CH. In this abstract, we report on baseline demographics and disease characteristics of these patients.

Methods: This phase 3, randomized, double-blind, placebo-controlled study enrolled patients aged 18-65 years who met International Classification of Headache Disorders, 3rd edition, beta version diagnostic criteria for episodic CH and had a prior history of a cluster period that lasted ≥6 weeks. During the prospective baseline, patients were required to have a total of ≥4 attacks, with an attack frequency of at least one attack every other day but ≤8 attacks/day. Certain concomitant abortive (but not preventive) treatments were allowed. Eligible patients were randomized to galcanezumab 300 mg or placebo administered subcutaneously once monthly for 2 months. Analyses were conducted on an intent-to-treat population.

Results: A total of 106 patients were randomized and treated with galcanezumab 300 mg (N=49) or placebo (N=57). Overall, the patient population was predominately male (83.0%) and white (84.9%), with a mean age of 46.4 years and the majority from Europe (66.0%). Mean duration of CH illness was 16.8 years. Lifetime suicidal ideation and suicidal behavior before screening was reported by 13.2% and 0.9% of patients, respectively. Current tobacco and nicotine combined use was reported by 53.8% of patients, while 26.4% reported prior use. The most common pre-existing conditions were insomnia (10.4%), gastroesophageal reflux disease (10.4%), and hypercholesterolemia (7.6%). During the prospective baseline period, patients had an average of 17.5 CH attacks per week. Average pain severity of the CH attack was 2.5 on a 5-point scale (moderate to severe). The average weekly total of CH attack duration was 15.5 hours. The proportion of patients using oxygen and/or subcutaneous sumatriptan during the prospective baseline period was 45.3% and 56.6%, respectively.

Conclusion: These data build upon the existing data to provide descriptive characteristics of the episodic CH population.

Ethics approval

The study was approved by a central Ethics Review Board and registered on ClinTrials.gov (NCT02397473).

P114 PrevenBox: Evaluation of concomitant use of preventive medications with OnabotulinumtoxinA in migraine

Marta Torres-Ferrus1,2; Sonia Santos Lasaosa3; Angel Guerrero Peral4; Jose M Laínez5; Javier Viguera Romero6; Ana B Gago Veiga7; Pablo Irimia8; Margarita Sanchez del Río9; Laila Asskour2; Victor J Gallardo2; Patricia Pozo-Rosich1,2

1Headache Unit, Neurology Department, Vall d’Hebron University Hospital, Barcelona, 08035, Spain; 2Headache Research Group, Vall d’Hebron Research Institute, Barcelona, 08035, Spain; 3 Neurology Department, Hospital Clínico Universitario Lozano Blesa, Zaragoza, 5009, Spain; 4 Headache Unit, Hospital Clínico Universitario de Valladolid, Valladolid, 47007, Spain; 5 Department of Neurology, Hospital Clinico Universitario de Valencia, Universidad Católica de Valencia, Valencia, 46010, Spain; 6 Department of Neurology, Hospital Virgen Macarena, Sevilla, 41009, Spain; 7 Department of Neurology, La Princesa Health Research Institute, La Princesa University Hospital, Madrid, 28006, Spain; 8 Department of Neurology, Clínica Universidad de Navarra, Pamplona, 31008, Spain; 9 Department of Neurology, Clínica Universidad de Navarra, Madrid, 28027, Spain
Correspondence: Patricia Pozo-Rosich (ppozo@vhebron.net)

Background: OnabotulinumtoxinA is an effective, tolerable and safe preventive treatment for chronic migraine (CM). Other than a reduction in headache frequency or disability, in CM the withdrawal of concomitant preventive medication indicates treatment effectiveness and quality of life improvement.

Objective: To characterize the change in the use of oral preventive medication after treatment with OnabotulinumtoxinA in patients with migraine.

Methods: This is a multicentre study. We consecutively included patients with migraine (ICHD-3) that were on preventive treatment with OnabotulinumtoxinA. We retrospectively collected demographic data, diagnosis of migraine, frequency and intensity changes, number of cycle and OnabotulinumtoxinA dose. In addition, we listed the initial and current preventive treatment (number of drugs and group) and the number and cycle of medications withdrawn. We performed a univariate and logistic regression analysis.

Results: We included 542 patients: 87.6% women, mean age 47.6 ± 11.7 years. A 89.3% had chronic migraine and 10.8% had high frequency episodic migraine. The mean reduction in frequency after treatment was 13.4±8.2 headache days/month. At baseline, a 91.3% took other preventives and during treatment with OnabotulinumtoxinA a 58.6% withdrew at least one drug, 25.8% stopped completely all oral preventive drugs. Factors associated with withdrawal were: being male, having >50% response in frequency and intensity, the number of infiltrations and a shorter chronification period until the first OnabotulinumtoxinA administration (p <0.05). The multivariate analysis showed that a better response in intensity (OR:1.8 [1.4-2.2], p<0.001), a greater number of infiltrations (OR:1.1 [1.0-1.2], p<0.001) and a shorter chronification period (OR:0.994 [0.992-0.997], p<0.001) were predictors of withdrawal. The ROC curve, showed that 6 OnabotulinumtoxinA cycles was the cut-off point that better predicted oral preventive medication withdrawal (p <0.001).

Conclusions: Treatment with OnabotulinumtoxinA reduces the use of other preventive medications for migraine. The highest probability of withdrawal occurs after 6 cycles of treatment.

P115 Onset of effect of onabotulinumtoxinA for chronic migraine treatment: analysis of PREEMPT data

David W. Dodick1* Stephen D. Silberstein2 Richard B. Lipton3 Ronald E. DeGryse4 Aubrey Manack Adams4 Hans-Christoph Diener5

1Department of Neurology, Mayo Clinic, Phoenix, AZ, 85054, USA; 2Department of Neurology, Jefferson Headache Center, Thomas Jefferson University, Philadelphia, PA, 19107, USA; 3Department of Neurology, Albert Einstein College of Medicine, Bronx, NY, 10461, USA; 4Allergan plc, Irvine, CA, 92612, USA; 5Department of Neurology, University of Duisbury-Essen, Essen, 45122, Germany

Correspondence: David W. Dodick (Dodick.David@mayo.edu)

Background: The PREEMPT trials (ClinicalTrials.gov, NCT00156910 and NCT00168428) demonstrated the efficacy and safety of onabotulinumtoxinA (onabotA) for the prevention of headache in adults with chronic migraine (CM). This analysis assessed the time to onset of treatment effects of onabotA relative to placebo (PBO) on reduction of headache days and migraine/probable migraine days per week from baseline.

Methods: Each PREEMPT trial included a 24-wk, double-blind, PBO-controlled phase followed by a 32-wk open-label phase. Patients were randomized to injections of onabotA (155 U to 195 U) or PBO every 12 wks for 2 cycles; followed by 3 open-label cycles of onabotA (155 U to 195 U). The primary efficacy variable for the pooled analysis was mean change from baseline in frequency of headache days per 28 days (primary endpoint, wk 24). Additional analyses included change in headache days and migraine/probable migraine days per wk vs baseline. Pooled analyses from the double-blind and open-label phases are presented. The studies were approved at each site by an institutional review board.

Results: 1384 adults were randomized to onabotA (n=688) or PBO (n=696). Baseline values (as assessed during wk 4 of the baseline period) were similar in both groups for mean (SD) headache days/wk (onabotA: 4.8 [1.6] days; PBO: 4.8 [1.6] days, P=0.70) and for migraine/probable migraine days per wk (onabotA: 4.6 [1.7]; PBO: 4.6 [1.7] days, P=0.72). Pooled analyses demonstrated a significant mean decrease from baseline in frequency of headache days per 28 days, favoring onabotA over PBO at the wk 24 primary endpoint (−8.4 vs −6.6; P<0.001) and at the end of the open label period (onabotA/onabotA: –11.7 vs PBO/onabotA: −10.8; P=0.02). One wk after the first treatment, onabotA reduced mean (SD) headache days by –0.9 (2.2) vs PBO (–0.7 [2.1]; P=0.046) and migraine/probable migraine days by –1.0 (2.4) vs PBO (0.7 [2.2]; P=0.031); the effect persisted from wk 3 of the first treatment cycle for both measures. OnabotA resulted in continued reduction in headache days (Fig. 1A) and migraine/probable migraine days (Fig. 1B) over 5 treatment cycles.

Conclusions: As early as wk 1 after the first treatment, onabotA treatment significantly reduced headache days/wk and migraine/probable migraine days/wk. This improvement persisted from wk 3 of the first treatment cycle compared with PBO. Treatment with onabotA resulted in a persistent and progressive reduction in headache days over the course of the 56-wk PREEMPT trials, indicating that peak benefit may require multiple treatments.

Fig. 1 (abstract P115).

Change from baseline in A) headache days/week and B) migraine/probable migraine days/week after treatment with onabotulinumtoxinA or placebo/onabotulinumtoxinA

P116 New daily persistent headache: A systematic review on an enigmatic disorder

Nooshin Yamani1, 2, Jes Olesen1

1Danish Headache Centre and Department of Neurology, University of Copenhagen, Rigshospitalet Glostrup, Copenhagen, Denmark; 2 Headache Department, Iranian Center of Neurological Research, Neuroscience Institute, Tehran University of Medical Sciences, Tehran, Iran
Correspondence: Nooshin Yamani (Jes.olesen@regionh.dk)

Background: New daily persistent headache (NDPH) is a recognized type of primary headache disorders. Although its prevalence is rare, NDPH is important because of its persistency, therapeutic refractoriness, associated disability and psychiatric comorbidity.

Objectives: To provide a structured systematic review to increase the understanding of new daily persistent headache.

Methods: PubMed and EMBASE search was performed for papers published or e-published before February 2018 using the terms “new daily persistent headache” and “NDPH”. We also searched for other useful sources in the reference lists of the selected articles.

Results: New daily persistent headache is heterogeneous in presentation and may resemble migraine or tension-type headache or both. Prevalence rate of NDPH has been estimated at 0.03% to 0.1% in the general population and may be higher in children and adolescents than in adults.

The underlying pathophysiology of NDPH is unknown, but since it was demonstrated that a number of factors such as infection, stressful event or extracranial surgery might precipitate NDPH, associations have been made with the role of pro-inflammatory cytokines and cervicogenic problems in its development.

There is no well-defined strategy for treatment of NDPH based on clinical evidence and it seems best to treat NDPH based upon the prominent headache phenotype. A few treatment regimens have been used in the literature with mixed results. However, even aggressive treatment is ineffective or only partially effective.

Conclusion: All aspects of NDPH discussed in this review need further study. NDPH remains poorly understood but very burdensome for the individual without any efficient therapy.

Keywords: New daily persistent headache, NDPH, Primary headache disorders, chronic daily headache

Table 1 (abstract P116).

Prevalence, age , sex and race distribution of NDPH in different studies.

Reference

Location

Definition criteria

Population surveyed

NDPH prevalence

Female

Male

F:M ratio

Age of onset

Race

Castillo-1995

Spain

S-L

1883 general population

22-73 yr

0.1%GP

     

Li & Rozen-2002

USA

S-L

56 NDPH cases

 

40(71%)

16(29%)

2.5

12-78

Caucasian:87%

Black:11%

Hispanic:2%

Bigal-2004

USA

S-L

170 adolescent 13-17 yr with CDH

638 adult with CDH

21% CDH

10.8% CDH

     

Takase- 2004

Japan

ICHD 2

30 NDPH cases of 1760 CDH

1.7% CDH

13(43%)

17(57%)

0.8

13-73

 

Meineri-2004

Italy

ICHD2,S-L

18 NDPH cases of 265 CDH

6.7% CDH

11(61%)

7(39%)

1.6

13-76

 

Mack-2004

USA

M-ICHD2

175 children <18 yr with CDH

23% CDH

27(67.5%)

13(32.5%)

2.1

  

Kung 2006

USA

M-ICHD 2

306 children and adolescents 6-18 yr in a tertiary headache center

28% CDH

34(64.2%)

19(35.8%)

1.7

  

Grande 2009

Norway

ICHD 2

30000 general population 30-44 yr

0.03% GP

     

Robbins 2010

USA

M-ICHD2

71 NDPH

 

51(72%)

20(28%)

2.5

8-76

Cacausian:80.3%

Black:5.6%

Hispanic:9.9%

Prakash 2012

India

M-ICHD2

63 NDPH

 

36(57%)

27(43%)

1.3

18-68

 

Rozen 2016

USA

ICHD-3β

97 NDPH

 

65(67%)

32(33%)

2

Mean:

F:32.4

M:35.8

Cacausian:98%

Black:1%

Hispanic:1%

Uniyal 2017

India

ICHD-3β

55 NDPH

 

45.5%

54.5%

0.8

Mean:28.4

 

S-L Silberstein-Lipton criteria, ICHD International classification of headache disorders, M-ICHD2 modified ICHD2(NDPH according to the criteria A and B of the ICHD-2 regardless of the presence of migraine features.), GP general population, CDH chronic daily headache

Table 2 (abstract P116).

ICHD-3 diagnostic criteria for NDPH

A. Persistent headache fulfilling criteria B and C

B. Distinct and clearly-remembered onset, with pain becoming continuous and unremitting within 24 hours

C. Present for >3 months

D. Not better accounted for by another ICHD-3 diagnosis

Table 3 (abstract P116).

Clinical characteristics of patients with NDPH in various published studies.

Study

Vanst

1986

Rozen

2002

Takase

2004

Meineri

2004

Kung

2008

Robins

2010

Peng

2011

Prakash

2012

Uniyal

2017

Definition criteria

 

S-L

ICHD-2

ICHD-2

M-ICHD2

M-ICHD2

M-ICHD2

M-ICHD2

ICHD3β

Number of NDPH cases

45

56

30

18

53

71

92

63

55

Mean age

 

F:3rd decade

M:5th decade

35

F:3rd decade

M:4th decade

14.2

(study of pediatrics)

 

5th decade

36.8

28.24

Female:male

1.4:1

2.5:1

0.8:1

1.6:1

1.7:1

 

1.3:1

1.3:1

0.8:1

Recalling time of onset

-

 

-