Open Access

11th European Headache Federation Congress jointly with 31st Congress of the Italian Society for the Study of Headaches

Rome, Italy. 01-03 December 2017
The Journal of Headache and PainOfficial Journal of the "European Headache Federation" and of "Lifting The Burden - The Global Campaign against Headache"201718(Suppl 1):111

https://doi.org/10.1186/s10194-017-0817-z

Published: 30 November 2017

EHF INVITED SPEAKERS

S1 Intracranial Hyper-and Hypotension

Jan Hoffmann

Headache is one of the most prominent symptoms during a change in intracranial pressure. As in these disorders headache is frequently unspecific, highly variable in its clinical presentation and may occasionally even mimic primary headaches including migraine, diagnosis may in some cases be challenging.

The clinical syndrome of idiopathic intracranial hypertension results from an increase in intracranial pressure without an identifiable cause. Patients suffer from an unspecific headache, which in most cases presents as a daily and bilateral headache without accompanying symptoms. However, an aggravation upon physical exercise, coughing and sneezing as well as nausea and photophobia may occur. In addition to the headache patients commonly suffer from a papilledema that leads to a progressive visual deficit which, if untreated, may results in a complete and irreversible visual loss. In addition patients may suffer from cranial nerve palsies, cognitive deficits, a pulsatile tinnitus and olfactory deficits adding to the significant loss in quality of life. Given the severity and potential irreversibility of these symptoms, a quick and accurate diagnosis as well as an early initiation of treatment is mandatory. Treatment usually consists of a combination of weight reduction and a pharmacological treatment with carbonic anhydrase inhibitors such as acetazolamide and topiramate. Invasive treatments should only be considered in exceptional therapy-resistant cases as long-term data regarding the safety and long-term benefit of these procedures is scarce.

In contrast to a chronic elevation in intracranial pressure which may be primary (idiopathic intracranial hypertension) or secondary, spontaneous intracranial hypotension is in almost all cases secondary to a meningeal rupture with a resulting leak of cerebrospinal fluid. The leaks are commonly localized in the cervicothoracic junction or along the thoracic spine. The clinical picture is dominated by an orthostatic headache which develops in temporal relation to a decrease in intracranial pressure. However, the time course of the orthostatic aggravation may vary substantially and with increasing disease duration may even disappear completely. The pain is thought to result from a slight downward displacement of the brain creating a painful traction of the dura mater. In many cases treatment is not necessary as the leak commonly heals within a few days or weeks causing a complete remission of the symptoms. If the leak persists and treatment becomes necessary an epidural blood patch should be the first step. If a spontaneous remission does not occur and repeated blood or fibrin sealant patches do not lead to a complete remission a surgical intervention may be considered.

S2 Emerging non CGRP drug targets

Messoud Ashina

There is a huge unmet need for new specific acute and preventive drugs in migraine. Development of therapies to treat migraine has previously been hampered by a lack of biomarkers and predictive animal models. This situation has dramatically changed over the last couple of decades, not least as a consequence of the increasing use of a human migraine provocation model that demonstrates the importance of naturally occurring signaling molecules in migraine. New highly specific mechanisms have been discovered and because of this progress, new drug targets are in different stages of clinical development.

S3 Emergency headaches

Luigi Titomanlio

Headache is one of the most common reasons for consultation in the pediatric emergency department (ED). Triage systems have been developed and adapted to the pediatric population to differentiate urgent from nonurgent patients, allowing appropriate and efficient management.In children with certain brain disorders, headache can be associated with focal neurologic signs or symptoms; these children represent a true diagnostic challenge to physicians, owing to the possibility of severe underlying disease. The differential diagnosis in children with headache and focal neurologic signs includes primary etiologies, such as migraine with aura, and secondary etiologies, such as trauma, infection, and vascular, neoplastic, and epileptic disorders. Achieving a diagnosis in children can be challenging at times; important reasons for this include poor description of pain by children and several childhood periodic syndromes that can be common precursors of migraine.

S4 Hypothalamic Regulation in Headache

Arne May (a.may@uke.de)

University Clinic of Hamburg, Dept. of Systems Neuroscience

Migraine is a multiphasic disorder and understanding of its pathophysiology starts with the acknowledgment that migraine is not simply a disease of intermittently occurring pain, but that it involves processes that affect the brain over time. If one wants to interpret the most recent findings in migraine pathophysiology it is important to again discuss the clinical presentation of all phases of a migraine attack. There are three clinical features of migraine which point towards the limbic system and hypothalamus as attack generating brain structures. The first one is that almost all symptoms of the premonitory phase including yawning, tiredness and mood changes already point towards hypothalamic involvement. Secondly, the circadian rhythmicity of attacks and thirdly the association of attacks with hormonal status and the menstrual cycle. The hypothalamus has various neuroanatomical connections to pain modulating systems and also to the spinal trigeminal nuclei. The orexinergic system, which is known to regulate arousal and nociceptive processing as well as thermoregulation and autonomic functions, has only recently become a site of interest in migraine research. Another neurotransmitter system involving the hypothalamus is the central dopaminergic system. Recent neuroimaging studies in migraine patients undermine hypothalamic involvement in the premonitory and acute pain phase of migraine. Most recently one migraine patient went into the scanner daily over a whole month which included 3 spontaneous untreated headache attacks. Increased hypothalamic activation was seen in the prodromal phase (within the last 24 h before migraine headache onset) as compared to the interictal state. More importantly, the pain-related hypothalamic functional connectivity between the hypothalamus and the spinal trigeminal nuclei was significantly increased during the preictal phase as compared to the interictal phase. These data strongly suggest that the hypothalamus plays a crucial role in generating premonitory symptoms but also the migraine attack itself. Moreover, using a recently developed protocol for high resolution brainstem imaging of standardized trigeminal nociceptive stimulation, the anterior right hypothalamus (HT) was significantly stronger activated in CM as compared to healthy controls. These data corroborate a crucial role of the HT for migraine chronification but also as for the sustainment of acute migraine pain.

References

1. Schulte LH, Sprenger C, May A. Physiological brainstem mechanisms of trigeminal nociception: An fMRI study at 3T. NeuroImage 2015; 124: 518–525.

2. Schulte LH, Allers A, and May A. The hypothalamus as a mediator of chronic migraine: Evidence from high resolution fMRI. Neurology 2017 88:2011–2016

3. May A. Understanding migraine as a cycling brain syndrome: reviewing the evidence from functional imaging. Neurol Sci 2017; 38: 125–130

4. Holland PR, Goadsby PJ. Cluster headache, hypothalamus, and orexin. Curr Pain Headache Rep 2009; 13: 147–54

5. Alstadhaug KB. Migraine and the hypothalamus. Cephalalgia 2009; 29: 809–17.

S5 CGRP CNS models in headache

U. Reuter

Charité Universitätsmedizin Berlin, Department of Neurology, Charitéplatz 1, 10117 Berlin, Germany

Immunohistological studies show widespread distribution of CGRP within the CNS, but the role and function of this neuropeptides in the brain and spinal cord are largely unknown. There is also increasing interest whether CGRP antagonists penetrate the blood brain barrier and abort migraine headaches in part via central mechanisms. As migraine is a CNS disorder a central abortive or preventative mechanisms is suspected for several years. In this lecture, we will evaluate the information derived from experimental CGRP studies within the CNS. We will analyze the role of CGRP in central sensitization as CGRP most likely facilitates nociceptive transmission. The contribution of CGRP to vasodilation in the CNS will also be discussed, and we look into imaging data of CGRP receptor antagonists in humans. Finally, we will illustrate the contribution of CGRP in an animal model of photophobia.

S6 The classification of headache disorders has improved over the years

Henrik Schytz

The classification of headache disorders has improved over the years, but further work is needed to develop and improve headache diagnosis within headache subtypes. The lecture presents laboratory tests that might be useful in phenotyping and/or diagnosis of long-lasting headache disorders such as migraine, tension-type headache, trigeminal autonomic cephalalgias, trigeminal neuralgia and persisting secondary headaches.

S7 CGRP PNS models in headache

A. Maassen van den Brink

Div. of Pharmacology, Dept. of Internal Medicine, Erasmus MC Rotterdam, The Netherlands

Calcitonin gene-related peptide (CGRP) is considered to be one of the main molecules in the pathophysiology of migraine. Currently, several drugs that target either the CGRP peptide or its receptor are in clinical studies for the prophylactic as well as the acute treatment of migraine. While CGRP is expressed abundantly in the central nervous system, it also plays an important role in the peripheral nervous system. Most antimigraine drugs that are currently in clinical development and target CGRP or its receptor (for example, the monoclonal antibodies) are not able to cross the blood brain barrier and thus do not reach the central nervous system, highlighting the importance of CGRP and its receptors at sites not protected by the blood brain barrier. These sites include the trigeminal ganglion, but also perivascular sensory afferents that may be involved in the pathophysiology of migraine as well as in the development of potential side effects. During the lecture, models and mechanisms important for the understanding of the role of CGRP in the peripheral nervous system will be discussed.

S8 Understanding the non-pain phases of migraine: premonitory and postdromal

Peter J Goadsby

NIHR-Wellcome Trust King’s Clinical Research Facility, King’s College London, UK

Migraine is the most common cause of neurological disability worldwide [1]; it is a disorder of the brain with pan-sensory dysfunction [2]. Migraine has, in essence, three phases, prior to the canonical attack- the premonitory or prodromal phase, the attack itself, headache with or without aura, and the period after canonical attack, the postdrome.

The premonitory phase can occur from hours to days before the canonical attack. The symptoms include: neck discomfort, yawning, tiredness, concentration impairment, mood change, polyuria/polydipsia, or food cravings [3]. The symptoms can be seen in children, as they are in adults [4]. Moreover, there is evidence from functional imaging of activation in the region of the hypothalamus during the premonitory phase [5].

The postdrome phase occurs after the headache phase of the canonical attack is settling; it is typically settled in about half of patients in six hours. The most common symptoms are: feeling tired/weary, concentration impairment and neck discomfort [6]. Remarkably there is widespread reduction in brain blood flow in the postdrome [7], which reflects the phenotype well.

Understanding the non-pain phases of migraine will lead to be a better formulation of the pathophysiology of migraine and eventually to better treatment.

References

1. Disease GBD, Injury I, Prevalence C. Global, regional, and national incidence, prevalence, and years lived with disability for 310 diseases and injuries, 1990-2015: a systematic analysis for the Global Burden of Disease Study 2015. Lancet. 2016;388(10053):1545-602.

2. Goadsby PJ, Holland PR, Martins-Oliveira M, Hoffmann J, Schankin C, Akerman S. Pathophysiology of Migraine- A disorder of sensory processing. Physiological Reviews. 2017;97:553-622.

3. Giffin NJ, Ruggiero L, Lipton RB, Silberstein S, Tvedskov JF, Olesen J, et al. Premonitory symptoms in migraine: an electronic diary study. Neurology. 2003;60:935-40.

4. Karsan N, Prabakhar P, Goadsby PJ. Premonitory symptoms of migraine in childhood and adolescence. Current Pain and Headache Reports. 2017;21:34.

5. Maniyar FH, Sprenger T, Monteith T, Schankin C, Goadsby PJ. Brain activations in the premonitory phase of nitroglycerin triggered migraine attacks. Brain. 2014;137:232-42.

6. Giffin NJ, Lipton RB, Silberstein SD, Olesen J, Goadsby PJ. The migraine postdrome. An electronic diary study. Neurology (Minneap). 2016;87:1-5.

7. Bose P, Karsan N, O'Daly O, Zelaya F, Goadsby PJ. ALTERATIONS IN CEREBRAL BLOOD FLOW DURING THE POSTDROME PHASE OF A MIGRAINE ATTACK CAPTURED WITH ARTERIAL SPIN LABELLED (ASL) MRI. Cephalalgia. 2017;37:in press.

S9 The Eurolight Project 2017

Christian Lampl

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

The Eurolight project, supported by the EC European Agency for Health and Consumers of the European Commission, was a data-gathering exercise undertaken primarily to inform health policy on headache disorders in the European Union (EU). This very large and complex study involved multiple collaborating partners (academic and lay) in ten countries, representing 60% of the adult population of the EU. The project took the form of surveys by structured questionnaire, conducted from November 2008 to August 2009. Questionnaires were analysed from 8,271 participants (58% female, mean age 43.4 y). Unadjusted lifetime prevalence of any headache was 91.3%. Gender-adjusted 1-year prevalences were 35.3% for migraine, 38.2% for TTH and 7.2% for headache on ≥ 15 d/mo. Personal impact was high, and included ictal symptom burden, interictal burden, cumulative burden and impact on others (partners and children). Mean per-person annual costs were €1,222 for migraine, €303 for tension-type headache. We confirmed that depression and especially anxiety are comorbid more than by chance with migraine. The level of this impact and its pervasiveness taken together with estimates of huge financial cost, have important implications for health policy in Europe. Eurolight 2017 should proceed with focusing on cluster headache and headache in the elderly.

S10 Multidisciplinary approach to head pain

Rigmor Hoejland Jensen

Danish Headache Center, Rigshospitalet-Glostrup, University of Copenhagen, Denmark

Background : Despite the very high prevalence of headaches, multidisciplinary headache clinics are still few and better documentation of their content and efficacy is needed.

Objective : To describe the structure of a multidisciplinary approach and to characterize the patients and treatment results from existing centres. Further to describe the proposed organization of headache care in Europe.

The collaboration between European Headache Federation and Lifting The Burden has proposed a three-tiered structure for Headache Care in Europe. It is organised with the majority of patients (90%) treated in primary care, the more complex migraine and tension-type headache patients (7-8%) in secondary care with a headache specialist and a nurse whereas the most complex patients i.e. medication overuse headache, comorbidity, chronicity or rare headache disorders(2-3%) should be referred to a tertiary headache centre. At this level headache specialists and a multidisciplinary team should conduct more complex treatment, initiate research and education. The composition of the multidisciplinary team may vary, however and here there is no international consensus. Most centres include nurses, psychologists and in some countries also sports-therapists or physiotherapists.

A systematic review of 1300 patients from the tertiary Danish Headache Centre revealed that patients had a mean age of 43.7 years and the male/female ratio was 3/7. In total, headache frequency was reduced from 20 to 11 days (p<0.001) and the absence rate 5 to 2 days/month (p<000.1) after treatment. Predictors for good outcome was female gender, migraine, triptan overuse and a mean headache frequency of 10 days/month. In recent years more evidence from other centres has been provided and the positive outcome was confirmed, also in so called refractory patients.

Conclusion : Treatments strategies to the complicated headache patients need individualization but the present evidence provide hope for the patients and a strong support for a multidisciplinary approach in a tertiary headache centre. The existing treatment strategies will be presented. Further discussion and evaluation of the elements and the outcome predictors are important for future planning.

S11 GWAS studies in migraine

Arn M.J.M. van den Maagdenberg

Departments of Human Genetics & Neurology, Leiden University Medical Center, Leiden, The Netherlands

Migraine is a common debilitating brain disorder characterized by severe headache attacks with various associated neurological symptoms. About one-third of migraine patients experience an aura preceding the headache phase: hence migraine with and without aura. Many migraine patients also suffer from comorbid neurological disorders, such as epilepsy, depression and stroke. Migraine is a genetic disease with both environmental and genetic factors determining the susceptibility to attacks. Recent technological advances in genetic analysis, which allowed simultaneous testing of hundreds of thousands of single nucleotide polymorphisms (SNPs) in tens of thousands of migraine patients in genome-wide association studies (GWAS), made it feasible to identify robust gene variants for the common forms of migraine. Whereas GWAS performed in various migraine subtypes yielded different top hits for the different subtypes, additional analyses seem to point to a shared genetic underpinning in migraine. Identified gene variants point towards various molecular pathways, e.g. neuronal dysfunction, vascular integrity and function, and pain signaling. GWAS data sets, to some extent, can also been used to identify the type of brain cell involved in pathology. GWAS also enable the identification of (shared) genetic factors for diseases comorbid with migraine. Unlike gene mutations in monogenic migraine subtypes, the effect size of gene variants in common migraine is small, thus complicating direct translation to diagnostic tests, pathogenetic mechanisms, and treatment targets. In fact, strategies to properly address the biological role of these variants are still being developed. Further technological advances in genetic research, commonly labelled by “next generation sequencing” (NGS), make it feasible to identify gene variants/mutations at the DNA level at an unprecedented scale. The coming years will show the true impact of these combined genetic approaches on the identification of genes, pathological mechanisms, and diagnosis of patients in migraine.

S12 Diagnostic tests for assessing patients with neuropathic pain

A Truini

Department of Neurology and Psychiatry, University Sapienza, Rome, Italy

Research has devised various techniques for investigating nociceptive and non-nociceptive somatosensory pathways in patients with neuropathic pain. The most widely agreed tools in use today include neurophysiological techniques and skin biopsy.

The standard neurophysiological techniques such as nerve conduction studies, trigeminal reflexes and somatosensory evoked potentials are mediated by large non-nociceptive afferent fibres (Aβ-fibres), and are widely used for assessing peripheral and central nervous system diseases.

Laser Evoked Potentials (LEPs) are the easiest and most reliable neurophysiological technique for assessing nociceptive pathway function. Laser-generated radiant heat pulses selectively excite free nerve endings in the superficial skin layers and activate Aδ and C nociceptors and evoke scalp potentials. In diseases associated with nociceptive-pathway damage, LEPs can be absent, reduced in amplitude or delayed in latency.

Skin biopsy is a reliable and minimally invasive tool for investigation of nociceptive fibres in human epidermis and dermis. Researchers have used this technique for assessing epidermal nerve fibres qualitatively and quantitatively. Skin biopsy can be done at any site of the body, with a disposable punch, using a sterile technique, and under local anaesthesia. Many investigators have used skin biopsy to investigate epidermal nerve fibres in various peripheral nerve diseases, such as diabetic neuropathy, infectious and inflammatory neuropathies and neuropathies associated with systemic diseases. In all studies, epidermal nerve fibre density was significantly lower in patients with neuropathy than in controls.

S13 Neuromodulation and Headache. Future perspectives

Massimo Leone (Massimo.Leone@istituto-besta.it)

Neuroalgology Department, Fondazione I.R.C.C.S. Istituto Neurologico Carlo Besta, Milan, 20133, Italy

Patients suffering from chronic headaches challange health care systems. They are estimated to affect 3% of general population and carry a considerable disease burden. A proportion of chronic headache patients does not properly respond to prophylactic treatments or shows low tolerability profile and remains in need for alternative therapeutic strategies and options.

The improved understanding of head pain pathophysiology has focused attention on the role of neural structures both at peripheral and central nervous system level. Thus in the attempt to improve chronic intractable neurovascular headache (migraine and cluster headache) patients a number of neuromodulation procedures targeting peripheral and central nervous system structures have been tried.

So far, efficacy and safety of various non-invasive and invasive stimulation procedures and devices have been investigated. Vagus nerve stimulation, supraorbital stimulation and single-pulse transcranial magnetic stimulation are considered non invasive neurostimulation options. While invasive procedures are occipital nerve stimulation, sphenopalatine ganglion stimulation and hypothalamic deep brain stimulation. Years after their introduction there is still debate about their use and place in clinical practice.

Results from open label series and few controlled trials suggest the need of further investigations.

Criteria employed to define intractable headaches were given more than ten years ago (1). An ad hoc European Headache Federation expert board has reviewed these aspects (2). A still unsolved issue is the lack of adequate placebo to properly design randomized controlled trials in neurostimulation studies. In patients with chronic pain conditions interpretation of placebo effect is a challange particularly for headache specialists.In chronic migraine and chronic cluster headache patients occurrence of psychiatric comorbidities is frequently encountered. Also, occurrence of medication overuse headache – seen as an addiction behavior - is frequently observed both in chronic migraine and chronic cluster headache. The role of psychosocial factors driving drug overuse/addiction behavior in chronic headaches is undisputable. These factors are often a barrier when selecting patients for neurostimulation procedures.

Long term experience with deep brain stimulation of the posterior hypothalamic area in chronic cluster headache has suggested that the generator of the attacks is not there (3). Similarly other neurostimulation procedures tried in migraine and cluster headache have shown poor, unsatisfactory ability to stop ongoing attacks. These observations suggest either that these stimulation procedures are not able to switch off the attack generator or that there are multiple migraine/cluster pain generators.

References

1. Goadsby PJ, Schoenen J, Ferrari MD, Silberstein SD, Dodick D. Towards a definition of intractable headache for use in clinical practice and trials. Cephalalgia 2006; 26:1168–70

2. Martelletti P, Jensen RH, Antal A, Arcioni R, Brighina F, de Tommaso M, Franzini A, Fontaine D, Heiland M, Jürgens TP, Leone M, Magis D, Paemeleire K, Palmisani S, Paulus W, May A. Neuromodulation of chronic headaches: position statement from the European Headache Federation. J Headache Pain. 2013 Oct 21;14(1):86.

3. Leone M, Franzini A, Proietti Cecchini A, Bussone G. Success, failure and putative mechanisms in hypothalamic stimulation for drug resistant chronic cluster headache. Pain 2013; 154 (1): 89-94

S14 What we should in the future

T.J. Nurmikko

The Walton Centre NHS Foundation trust

An underlying concept in the new ICHD-3 classification of trigeminal neuralgia is the postulation that clinical presentations matter because they reflect distinct pathophysiological mechanisms. Previous attempts to establish the connection between the two have yielded uncertain results as the authors have paid limited attention to individual clinical symptoms and signs. Yet, the relatively strict criteria for trigeminal neuralgia and its subgroups yield homogenous populations that allow advantage to be taken of the advances in neurophysiological and imaging methods. It is now possible to conduct subgroup-specific pathophysiological studies aimed at biomarkers that pave the way for precision diagnosis of TN and individualised therapy. An example of how this might be done comes from recent studies based on sensory profiling of peripheral neuropathic pain. In a large group of patients with three different diagnoses, cluster analysis of detailed sensory testing revealed three main sensory phenotypes [1], with the potential to allocate individual patients to these sensory groups [2]. For TN, a stratification based on the new classification and linked to patients’ symptoms, somatosensory profiles, and neurophysiological and neuroimaging data provides a unique opportunity to explore clinical questions that are even more ambitious than those for other neuropathic pains. In my presentation I will suggest a pathway as to how to accomplish this. I will start by arguing that the existing data are sufficient to recommend preferred treatment in selected cases. I will then highlight a number of clinically relevant research questions that can be answered by large-population multi-centre studies applying established methods ranging from QST and evoked potentials to structural and functional neuroimaging of the trigeminal system and linking them with clinical signs and symptoms. Alongside this, I will discuss the challenges of phenotype profiling that could guide pharmacotherapy with, e.g., Nav 1.7 channel blockers or identifying genes that could make a subject susceptible to the development of TN.

References

1. Baron R, Maier C, Attal N, et al. Peripheral neuropathic pain: a mechanism-related organizing principle based on sensory profiles. Pain 2017;158:261-272.

2. Vollert J, Maier C, Attal N, et al. Stratifying patients with peripheral neuropathic pain based on sensory profiles: algorithm and sample size recommendations. Pain 2017158;14461455.

S15 Posttraumatic headache in children and adolescents

Ishaq Abu-Arafeh

Consultant in paediatric Neurology, Royal Hospital for Children, Glasgow, UK

Headache is a common problem in children and adolescents with a prevalence of about 60%. Head injuries are also relatively common with an estimated incidence of 3/1000 children per year with 80-90% of cases are considered as minor injuries (Glasgow Coma Score 13-15). Mild head injury is associated with good recovery in most patients, but with a small risk of poor outcomes. Headache is the most common complication that occurs as an isolated symptom or can be a part of the post-concussion syndrome which can also include dizziness, fatigue, reduced ability to concentrate, psychomotor slowing, mild memory problems, insomnia, anxiety, personality changes and irritability Following head injuries, children may develop headache for the first time or have their previously experienced headache getting worse in severity or frequency. Post head injury headache is referred to as acute posttraumatic headache if it evolves within one week of the injury and resolves within 3 months and it is called chronic posttraumatic headache (CPTH) if it persisted for over 3 months.

Systematic review of the occurrence of headache after head injury shows that up to 40% of children complain of any type of headache following head injury and around 7% have CPTH as defined by the ICHD-2 and 3beta.

The pathophysiology of posttraumatic headache is not well understood, but likely to involve several mechanisms and factors. It is suggested that even minor head injury may cause a widespread stretching or shearing injuries to the axonal network. Psychosocial factors may also play a role in the pathogenesis of CPTH.

The clinical features of CPTH are similar to primary headache disorders phenotypes with the majority of children presenting with migraine-like headache and probable tension-type headache. Some children may have mixed or unclassified headache disorders. In the majority of children no investigations are necessary. However, neuroimaging and other investigations may be necessary in children with red flags or abnormal findings on neurological examination.

The management of children with CPTH should include reassurances, adequate pain relief and preventative treatment as appropriate. Multidisciplinary approach is necessary and should include support from clinical psychology and education to help the child achieve normal school attendance and education.

The prognosis of CPTH is generally good, but long term data are needed.

S16 Contraception in Women with Seizure Disorder

György Bártfai

Department of Gynaecology and Obstetrics, University of Szeged

One third of women with epilepsy (WWE) are in reproductive age, and nearly 50% of their pregnancy are unplanned because of using an inappropriate method or failure of combined oral hormonal contraceptives (COCs). The interaction between enzyme inductive antiepileptics (EiAED) like carbamazepine, phenytoin, primidone, phenobarbitone, rufinamide, lamotrigine, topiramate and COCs is well-known. Therefore, while taking this medication, the risk of contraceptive failure is quite high.

The mechanism of action of enzyme-inductors is to modify the metabolism of the sexual steroids in the liver. Moreover, ethinylestradiol (EE) might modify the metabolism of certain antiepileptic drugs (glucuronization of lamotrigine). Therefore, the gynaecologist has to be careful when prescribing the pill or administering other types of hormonal contraceptives for WWE.

Knowing the interaction between antiepileptics and contraceptives is important to find the most effective medication with fewer side effects. The consequence of interaction between EiAED and COC as well as EE and AED (lamotrigine) may be: a) unwanted pregnancy; b) teratogenicity; negative effect on the cognitive and psychomotor functions of the child; and/or c) changes in seizure activity.

Nowadays, women with epilepsy do not always get the right information; thus, it is necessary to improve the cooperation and consultation between the epileptologist and the gynaecologist. The first meeting with the epileptologist or gynaecologist is equally important in choosing the right antiepileptic drugs and/or contraceptive method. The information is also needed even if the patient is sexually inactive.

S17 CSD evolution in 2017

H. Bolay

Migraine is a complex neuronal disorder where the cortex has a key importance and characteristic headache attack is associated with multiple sensorial disturbances. A cerebral cortical phenomenon known as cortical spreading depression (CSD) was linked to lateralized headache. CSD is an intrinsic brain phenomenon to a noxious stimulus such as high potassium or trauma, and manifests as an extreme excitability state of the gray matter with massive depolarization of neuronal and glial membranes and redistribution of ions. Initial depolarization is replaced by a long-term depression in the neuronal activity which traverses whole hemisphere in case of lissencephalic brain with a rate at 3–6 mm/min. Propagating depolarization in the brain parenchyma leads to a release of various vasoactive and nociceptive ions and molecules. Vascular compartment reacts with initial hyperemia followed by long-term oligemia. It occurs in many species from rodents to primates, though it is hard to initiate and sustain its propagation in gyrencephalic brains. Spreading depression wave involves neuronal, glial and vascular cells, and leads remarkable effects on those compartments and overlying meningeal membranes with capability of triggering peripheral trigeminal fibers and second order trigeminal neurons in the brainstem nucleus, though its effect on subcortical structures are less known. CSD is implicated in the development of inflammatory response and releasing CGRP and nitric oxide from trigeminal nerve endings.

Animal studies investigating the mechanisms of migraine and CSD are usually conducted under anesthesia, despite the fact that pain is a conscious experience. Anesthesia have profound effects on the mechanisms by which CSD is initiated and propagated, and clearly prevents observation of any associated behavioral response. Therefore CSD studies in awake animals are crucial for translational migraine research. CSD in freely moving lissencephalic animals, led to reduced locomotor activity, freezing & grooming episodes and pain calls (Akcali et al, 2010).

Cerebral cortex and thalamus are inseparable in sensory processing and thalamic reticular nucleus (TRN) is the gatekeeper of sensory outflow to the cortex. CSD was shown to activate thalamic reticular nucleus (TRN) only in awake animals (Tepe et al, 2015). Electrocorticographic recordings demonstrated the direct propagation of CSD waves in to thalamic reticular nucleus. Activation of TRN was unilateral and ipsilateral to CSD and TNC. It was dependent on full conscious experience and highly vulnerable to anesthetics. CSD selectively activated visual sector of TRN, though other six TRN sectors of auditory, gustatory, visceral, somatosensoriyal, motor and limbic TRN were not affected by CSD. CGRP receptor antagonist MK-8825, reversed CSD induced freezing, grooming, wet dog shake behavior, reductions in von Frey thresholds and c-fos induction in TNC and TRN. However, MK-8825 did not block CSD waves and accompanied rCBF response (Filiz et al, 2017). MK-8825 did not exert any effect on CSD induced amygdala activation and anxiety behavior.

TRN is also involved in discrimination of sensory stimulus and transient disruption of sensorial perception during migraine headache attacks was reported (Boran et al, 2016). Disruption of temporal discrimination of two consecutive sensorial stimuli seems specific to migraine headache attacks (Vurallı et al, 2016, Vurallı et al, 2017).

Involvement of a strategic subcortical thalamic structure by a cortical event is important to explain several clinical features of migraine such as 1) Dysfunction of the GABAergic neurons in TRN would result in enhanced transmission of sensory information to the cortex and disruption of sensory discrimination 2) Photophobia and visual hallucinations of aura may reflect dysregulation of visual stimuli by the TRN, 3) TRN could play a role in either termination or initiation of an attack as sleep is closely related with migraine, attacks are often associated with the circadian cycle and are typically relieved by sleep, 4) Thalamo-cortical gating could be a novel target in migraine as valproate, triptans and CGRP antagonists MK-8825 suppressed CSD induced TRN activation.

S18 Trigeminal Neuralgia and other facial pains

R. Benoliel

In this discussion, we will review the differential diagnosis of Trigeminal Neuralgia (TN) vis-à-vis other facial pains that may mimic TN’s features. Common misdiagnoses for TN include dental pathology, other regional neuralgias, short-lasting neuralgiform headaches with autonomic signs (SUNHA), cluster headache and theoretically an atypical (shorter) cluster-tic syndrome (CTS). More rarely there may be more sinister underlying disorders (tumors, multiple sclerosis) that induce TN-like syndromes. We will outline and highlight the salient features across disorders that will ensure correct diagnosis.

S19 The concept of trigeminal neuralgia

Giorgio Cruccu

Trigeminal neuralgia (TN) is a neurological disease which is peculiar under several respects. The diagnosis of TN, in its typical presentation, in unmistakable on clinical grounds alone. Pain manifests with intense bursts that occur and end abruptly and usually last few seconds only. This type of pain is paradigmatic of what pain scholars call paroxysmal pain. The most common verbal descriptors are electric-shock like or stabbing. Unique to TN is the trigger mechanism. The attacks are evoked by innocuous stimuli in tiny zones of the extra- or intraoral trigeminal territories. The most frequent trigger maneuvers include activities of the daily life such as washing, cleaning, brushing the teeth or talking. Although the trigger zones shared by most patients are confined between the nostril and the lateral perioral region, any area innervated by the trigeminal nerve may do.

One aspect of pathophysiology is supported by established neurophysiologic, neuroimaging, and histologic evidence: the primary mechanism is focal demyelination of primary afferents near the entry (extra- or intra-axial) of the trigeminal root into the pons. A second pathophysiologic theory, admittedly more debatable, is that hyperexcitable primary afferents, in the area of focal demyelination, become a source of ectopic generation of impulses and ephaptic transmission (cross talk) from close, healthy nerve fibers. More supported by evidence from animal models is the generation of high-frequency discharges. A third potential step, with so far almost no sound evidence at all, is that the hyperactivity of primary afferents secondarily induces central sensitization of wide dynamic range neurons in the spinal trigeminal nucleus or even more central changes.

Finally, TN is unique also for its pharmacological and surgical treatment. TN is highly sensitive to voltage-gated, frequency-dependent sodium-channels blockers (and almost nothing else), and is the neuropathic pain condition that respond best to surgical lesions of the postganglionic primary sensory afferents.

S20 The HUNT Studies

Mattias Linde

The Nord-Trøndelag Health study (HUNT), ongoing in Norway since 1984, is one of the worlds’ largest longitudinal epidemiological studies collecting comprehensive data on headache disorders. The speaker will present an overview of the methodological potentials and challenges of the HUNT survey. Results will be displayed regarding prevalences of the common headache disorders and their trends over time.

Most importantly, the HUNT-survey enables risk factor analyses. Findings will be reviewed for factors of life such as physical activity, substance use, head traumas, insomnia, and mortality. Also, associations between headache and women’s issues such as contraceptives, hormone replacement, pregnancy, and menarche have been studied and will be discussed. Finally, associations between intracranial abnormalities and headache disorders are now beginning to be published from a neuroimaging sub-study (HUNT MRI).

S21 CSD in primary and secondary headaches

Cenk Ayata

Spreading depression (SD) is a wave of simultaneous and near-complete depolarization of virtually all cells in brain tissue associated with a transient “depression” of all spontaneous or evoked electrical activity in the brain. SD is widely accepted as the pathophysiological event underlying migraine aura, and may play a role in headache pathogenesis in secondary headache disorders such as ischemic stroke, subarachnoid or intracerebral hemorrhage, traumatic brain injury, and epilepsy. Here, we provide an overview of the pathogenic mechanisms and propose plausible hypotheses on the involvement of SD in primary and secondary headache disorders. SD can activate downstream trigeminovascular nociceptive pathways to explain the cephalgia in migraine, and possibly in secondary headache disorders as well. In healthy, well-nourished tissue (such as migraine), the intense transmembrane ionic shifts, the cell swelling, and the metabolic and hemodynamic responses associated with SD do not cause tissue injury; however, when SD occurs in metabolically compromised tissue (e.g. in ischemic stroke, intracranial hemorrhage, or traumatic brain injury), it can lead to irreversible depolarization, injury and neuronal death. Recent non-invasive technologies to detect SDs in human brain injury may aid in the investigation of SD in headache disorders in which invasive recordings are not possible. SD explains migraine aura and progression of neurological deficits associated with other neurological disorders. Studying the nature of SD in headache disorders might provide pathophysiological insights for disease and lead to targeted therapies in the era of precision medicine.

S22 Headache in the Emergency Room

Anne Ducros

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

The proportion of adult patients reporting non-traumatic headache as their major complaint at ER access ranges from 0.5 to 4.5%.The main objective is to identify the patients who require urgent investigations besause of a suspected serious secondary cause. Serious conditions are disclosed in 5-10% of the cases; the remaining patients have benign secondary headaches, or more frequently, primary headaches.

The crucial step in the diagnosis is the initial interview. Most patients presenting with headache as the chief complaint have a primary headache disorder, such as migraine or tension-type headache, the diagnosis of which relies on strict diagnostic criteria in the absence of any objective marker. Secondary headache disorders manifest as new-onset headaches that arise in close temporal association with the underlying cause.Secondary headache should be suspected in any patient without a history of primary headache who reports a new onset headache and in any patient with a new unusual headache that is clearly distinct from their usual primary headache attacks. Since many serious disorders, such as subarachnoid haemorrhage, can present with isolated headache and a normal clinical examination, diagnosis is reliant on clinical investigation.

Subarachnoid hemorrhage should be suspected in anyone with a sudden or a thunderclap headache. Diagnosis is based on plain brain computed tomography and, if tomogram is normal, on lumbar puncture. Reversible cerebral vasoconstriction syndrome should be suspected in anyone with recurrent thunderclap headaches over a few days. Cervical artery dissection, cerebral venous thrombosis, reversible cerebral vasoconstriction syndrome and pituitary apoplexy may present with isolated headache and normal physical examination, normal cerebral computed tomography and normal cerebrospinal fluid. When computed tomography and lumbar puncture are normal, other investigations are needed, including cervical and cerebral vascular imaging and brain magnetic resonance imaging.

Treatment of headaches in the ER should be based on the etiology. A severe migraine attack can be treated by SC sumatriptan, intravenous non-steroidal anti-inflammatory drugs and/or dopamine antagonists. The treatment of secondary headaches requires the treatment of the underlying cause and a symptomatic treatment based on intravenous acetaminophen or on opiates depending on the pain intensity.

S23 Progestin-only contraception and beneficial effects on migraine

Gabriele S. Merki-Feld

In women migraine prevalence peaks during reproductive years. Menstruation is a significant risk factor for migraine with attacks most likely to occur between 2 days before the onset of menstruation and the first three days of bleeding. The pathophysiology of menstrual attacks involves estrogen withdrawal and potentially abnormal release of prostaglandins triggered by the end-cycle drop in estrogen level. Reproductive year are the life span during which many women require effective contraception.

Migraine with aura (MA) and to a lesser extent migraine without aura (MO) increase the risk for cardiovascular events, especially for stroke. There is a substantial elevation of these risks in migraineurs using combined contraceptive pills (COC). In additon it has been shown that COC can initiate migraine, worsen the course of migraine and induce a change from MO to MA. Several clinical trials report improvements in migraine frequency and intensity in users of the progestin-only pill (POP) with desogestrel 75microgram. Both, inhibition of ovulation and ist continous use contribute to reduce hormone flucutations during ist use. In contrast to COC, POP are not associated with an increased risk for stroke. The positive impact of this pill has been shown in MA and MO patients. In women with chronic migraine, the reduction in pain medications used contributes to prevent medication overuse headaches.

S24 Current Consensus on Classification of the Trigeminal Neuralgia

Zaza Katsarava

Unna/Essen, Germany

Chapter 13 sets out a classification system for painful lesions of the cranial nerves and other facial pains based on a consensus between the International Headache Society (IHS) and the International Association for the Study of Pain (IASP).

The existing nosology of cranial-nerve pains does not fully portray the subtle differences between various conditions. However, rather than abandoning many long-established diagnostic terms, this classification retains them, providing detailed definitions for differential diagnoses and their types, subtypes and subforms.

There are several axes of classification: a) syndomology (neuralgia vs. neuropathy), b) location (central vs. peripheral neuropathic pain) and c) aethiology (classical, idiopathic or secondary).

The authors of the classification tried to incorporate the existing literature into the IHS classification system.

The current version defines the trigeminal neuralgia and trigeminal neuropathy. Trigeminal neuralgia is subdivided into classical (due to nerve-vascular compression, not purely a nerve vascular contact), idiopathic (unknown cause or nerve vascular contact, because the value of a nerve vascualr contact is unclear) and secondary (due to other disease). Base don the clinical presentation it is further characterised as TN with and without concomitant facial pain indicating pure response to treatment.

S25 Traumas and headache

Mark Braschinsky (mark.braschinsky@kliinikum.ee)

Department of Neurology, Tartu University Clinics, Tartu 51014, Estonia

Headache following the trauma or so called post-traumatic headache is on of if not the most common secondary headache disorder, reaching approximately 4 % of all secondary headaches. According to the International Classification of Headache Disorders, 3rd edition (beta version) headache attributed to trauma or injury to the head and/or neck is divided into acute and persistent headache for each separate trauma mechanism – injury to the head, whiplash or craniotomy (performed for reasons other than traumatic head injury) [1]. The cut-line for distinguishing between an acute and persistent headache is defined to be 3 months: resolution of headache within this period complies with an acute, persistence for the longer time – with a persistent headache. Headache attributed to the injury to the head is further subclassified based on the severity of preceding trauma. Probably one of the most debated diagnostic criterions of this chapter is the time of onset of headache after a traumatic event. For the main classification it is agreed that causative relation between trauma and development of headache should be within 7 days after the trauma. However based on a data derived from reports of everyday clinical practice alternative criteria published under the Appendix allow the delayed onset of headache, reaching up to 30 days following the injury. Clinical phenotypes of post-traumatic headache are varying from mild tension-type-like to severe migrainous. Pathophysiological mechanisms of post-traumatic headaches remain largely unclear as a reason to the epidemiological data suggesting, that mild injury to the head represents a greater risk of developing persistent headache. The latter one causes a considerable reduction of health related quality of life and frequently is challenging in terms of treatment, requiring pharmacological (preventative medications) and non-pharmacological (cognitive behavioural treatment, physical therapy, counselling etc) approaches. For treatment resistant cases interventional procedures, usage of onabotulinum toxin A and neurostimulation have been reported to be potentially effective.

S26 Within person variation in headache days in persons with migraine

Richard Lipton

Objective

To determine persistence of and transitions between episodic migraine (EM) and chronic migraine (CM) and to describe and model the natural variability of self-reported frequency of headache days

Background

Relatively little is known about the stability of headache days per month in persons with EM or CM over time. Within person variability in headache day frequency has implications for the diagnosis of CM, assessing treatment in clinical practice and for the design and interpretation of clinical trials.

Methods

The Chronic Migraine Epidemiology and Outcomes (CaMEO) Study is a longitudinal survey of a systematic sample of US adults with EM and CM identified by a web-questionnaire. A validated questionnaire was used to classify respondents with EM (<15 headache days/month) or CM (≥15 headache days/month) every 3 months for a total of 5 assessments. We modelled longitudinal transitions between EM and CM and, separately, headache day frequency per month using negative binomial repeated measures regression models (NBRMR). The NBRMR was parameterized using polynomial mixed effects to better account for cyclic variation.

Results

Among the 5,464 respondents with EM at baseline providing 4 or 5 waves of data, 5,048 (92.4%) had EM in all waves and 416 (7.6%) had CM in at least one wave. Among 526 respondents with CM at baseline providing 4 or 5 waves of data, 140 had CM in every wave (26.6%) and 386 (73.4%) had EM for at least one wave. Individual plots revealed striking within-person variations in headache days per month. The polynomial mixed effect NBRMR model revealed that the rate of headache days increased across waves of observation 19% more per wave for CM compared to EM (rate ratio [RR], 1.19; 95% CI, 1.13 – 1.26). The inclusion of a comprehensive covariate pool in the fully adjusted model increased this difference to a 26% increase per wave (RR, 1.26; 95% CI, 1.2 – 1.33).

Conclusions

Follow-up at 3 month intervals reveals a high level of short-term variability in headache days per month. As a consequence many individuals cross the arbitrary CM diagnostic boundary of ≥15 headache days per month over the course of one year. Nearly three forths of persons with CM at baseline drop below this diagnostic boundary at least once over the course of a year. These findings my influence case definitions of migraine subtypes, the design and interpretation of epidemiologic studies and clinical trials as well as the interpretation of change in headache days in clinical practice.

S27 Migraine and the Glymphatic System

Rami Burstein and Aaron Schain

Department of Anesthesia, Critical Care and Pain Medicine, Beth Israel Deaconess Medical Center, Boston MA 02115 and Harvard Medical School, Boston, MA 02215, USA

Impairment of brain solute clearance through the recently described glymphatic system has been linked with traumatic brain injury, sleep deprivation, and aging. This lecture will summarize new data showing that cortical spreading depression (CSD), the neural correlate of migraine aura, closes the paravascular space and impairs glymphatic flow. This closure holds the potential to define a novel mechanism for regulation of glymphatic flow. It also implicates the glymphatic system in altered cortical and endothelial functioning of the migraine brain, which can explain the increased risk of stroke among migraine aura patients.

S28 Photophobia and Hypothalamus

Rami Burstein, Rodrigo Noseda

Department of Anesthesia, Critical Care and Pain Medicine, Beth Israel Deaconess Medical Center, Boston MA 02115 and Harvard Medical School, Boston, MA 02215, USA

Many patients report that their need to avoid light is driven mainly by how unpleasant it makes them feel. This lecture will attempt to explain why is light unpleasant. The data presented will show that during migraine, light can trigger the perception of (a) hypothalamic-mediated autonomic responses such as chest tightness, throat tightness, shortness of breath, fast breathing, faster than usual heart rate, light-headedness, dizziness, nausea, vomiting, dry mouth, salivation, rhinorrhea, stuffy sinuses and lacrimation; (b) hypothalamic mediated non-autonomic responses such as thirst, hunger drowsiness, tiredness, sleepiness, fatigue, and yawning; (c) negative emotions such as intense, irritable, angry, nervous, hopeless, needy, agitated, sad, scared, cranky, upset, depressed, disappointed, jittery, worried, stressed, anxious, panic and fear; and (d) positive emotions such as happy, relaxing, soothing, and calming. The data presented will also show that retinal axons converge on dopaminergic/noradrenergic, histaminergic, orexinergic, MCHergic, oxytocinergic and vasopressinergic hypothalamic neurons that regulate autonomic functions and emotions. By defining better the aversive nature of light, the findings suggest that the retina and hypothalamus play a critical role in migraine-type photophobia and that photophobia may not depend on hyperexcitable visual cortex, as traditionally thought.

S29 The Gymphatic System

Maiken Nedergaard

We have recently described a macroscopic pathway in the central nervous system – the glymphatic system that facilitates the clearance of interstitial waste products from neuronal metabolism. Glymphatic clearance of macromolecules is driven by cerebrospinal fluid (CSF) that flows in along para-arterial spaces and through the brain parenchyma via support from astroglial aquaporin-4 water channels. The glymphatic circulation constitutes a complete anatomical pathway; para-arterial CSF exchanges with the interstitial fluid, solutes collect along para-venous spaces, then drain into the vessels of the lymphatic system for ultimate excretion from the kidney or degradation in the liver. As such, this may after circulation represent a novel and unexplored target for prevention and treatment of neurodegenerative diseases.

S30 A population based survey for headaches in greece

Dimos D. Mitsikostas1, Chrisanthy Arvanity2, Theodoros Constantinidis3, Manolis Dermitzakis4, Nikolaos Fakas5, Jobst Rudolf6, Michail Vikelis7, on behalf of the Hellenic Headache Society

1First Neurology Department, Aeginition Hospital, School of Medicine, National & Kapodistrian University of Athens, Athens, Greece; 2Second Neurology Department, Attikon Hospital, School of Medicine, National & Kapodistrian University of Athens, Athens, Greece; 3Private Headache Clinic, Korinthos, Greece; 4Department of Neurology, “Geniki Kliniki” Euromedica, Thessaloniki, Greece; 5401 Army General Hospital of Athens, Neurology Department, Athens, Greece; 6Neurology Department, Papageorgiou Hospital, Thessaloniki, Greece; 7Headache Clinic, Mediterraneo Hospital, Glyfada, Greece

We aimed to investigate the prevalence of headache in General Population (adults 18-70 years old) in Greece. A quantitative study, using the form of computer-assisted telephone interviews (C.A.T.I.) was designed. A draft questionnaire consisting of 37 questions was delivered in 145 headache sufferers in a pre-study work to evaluate the diagnosis of the primary headache disorder according to ICH-3beta diagnostic criteria. After the analysis of this questionnaire the specific 37-item questionnaire was decided. In total, N=10,008 interviews, representative of the population of Greece in terms of gender, age, and area, based on the most recent census (ELSTAT, 2011) were performed using the structured evaluated questionnaire. Based on the above contacts, n=1,197 respondents (12% of the sample) were found to suffer from headaches that reduce their performance. The one-year prevalence of Migraine that reduces activity was 8.2% (n=0.6m population) of Tension-Type Headache (TTH) 3.8% (n=0.28m of population) and of Cluster Headache 0.01% (n=0.74K of population). Chronic migraine one-year prevalence was 1% (n=0.7K of population). Females tend to suffer more from migraines and TTH as well as ages 35-54. The average patients has been suffering from headaches for 12 years. Headaches typically occur once a month or more frequently, 8 days per month on average. Although patients rarely misss work due to headaches, they do report headache-induced reductions in performance around 3 days per month. Slighly less than half patients have felt bad/ humiliated because of headaches, while social/family obligations are affected 3 days per month on average. About one fifth of patients seek professional treatment for headaches, most of them in the private sector. The most popular specialty for headache treatment is neurologist, followed by internist. Regarding both prophylactic and acute treatment, patients prefer oral medication to injection, even if the former is administered more frequently. They also prefer oral medication/ injection to a stimulation device. The stimulation device seems to be more attractive to males. Painkillers also are by far the most common acute treatment for headaches and the vast majority of patients have never taken prophylaxis for headaches. Only a small fraction have stopped taking a prophylactic treatment due to adverse effects. Interstingly, patients would be willing to spend 20€ on average per month for headache treatment, on average.

S31 The big CGRP flood - sources, sinks and signalling sites in the trigeminovascular system

Karl Messlinger

Institute of Physiology and Pathophysiology, Friedrich-Alexander-University of Erlangen-Nürnberg, 91054 Erlangen, Germany

Calcitonin gene-related peptide (CGRP), a neuropeptide previously known only by specialists interested in neurogenic inflammation, is now discussed throughout the communities of migraine researchers, headache therapists and even migraine patients. The reason for this surprising career of CGRP awareness is evident. CGRP is the main neuropeptide of a major part of nociceptive trigeminal afferents and is released upon their activation. Thus CGRP release is characteristic, though in no way specific, for the trigeminovascular system, which is regarded as the structural basis for headache generation. In fact, CGRP has been found at elevated concentrations in the cranial outflow during attacks of migraine and some trigemino-autonomic headaches; infusion of CGRP into patients suffering from primary headaches can cause head pain mimicking their spontaneous headache attacks; inhibiting CGRP or its receptors or its release can be preventive or therapeutic in those types of primary headaches. However, looking behind the curtain of impressive significance of this biomarker, broad gaps in our knowledge are visible concerning the sites of CGRP release, its flow through the meningeal compartments, the sites and mechanisms of actions and its elimination. With preclinical experiments we are only at the beginning to study these issues, which are increasingly important in the light of new pharmacological developments targeting CGRP and its receptors by antagonists or monoclonal antibodies, and keeping in mind possible risks of a long-term treatment with these substances. Trigeminal activity controlled by CGRP receptor activation could indeed be a pivot point in headache generation and therapy. However, measurable circulating concentrations of CGRP are far too low to explain any receptor effects, while it is difficult to assess its real concentrations near the likely release sites, namely the meningeal terminals of trigeminal afferents, the trigeminal ganglion and the central terminals in the trigemino-cervical brainstem complex. The central effects of CGRP as a synaptic neuromodulator could explain neuronal CGRP effects to some extent but big molecules like monoclonal antibodies are unlikely to pass the blood-brain barrier and may not be able to act there. Peripheral effects of CGRP are largely confined to its well-known vascular functions, while fast neuronal effects are not established so far in the trigeminal system. The trigeminal ganglion is a possible point of CGRP action but only few experiments have shown an impact on the signalling or metabolic changes of ganglion neurons. Therefore new experimental approaches are needed to uncover the secrets of the nociceptive CGRP signalling system and its therapeutic control.

S32 EHF-LTB Aids to management of headache disorders in primary care (2nd edition)

TJ Steiner1,2, R Jensen3, Z Katsarava4,5, M Linde1,6, EA MacGregor7, P Martelletti8,9, V Osipova10,11 and K Paemeleire12, on behalf of Lifting The Burden: The Global Campaign against Headache and the European Headache Federation

1Department of Neuroscience, Norwegian University of Science and Technology (NTNU), Trondheim, Norway; 2Division of Brain Sciences, Imperial College London, London, UK; 3Danish Headache Centre, Department of Neurology, University of Copenhagen, Glostrup Hospital, Glostrup, Denmark; 4Department of Neurology, Evangelical Hospital Unna, Unna, Germany; 5Medical Faculty, University of Duisburg-Essen, Essen, Germany; 6Norwegian Advisory Unit on Headache, St Olavs Hospital, Trondheim, Norway; 7Centre for Neuroscience and Trauma, Blizard Institute of Cell and Molecular Science, Barts and the London School of Medicine and Dentistry, London, UK; 8Department of Clinical and Molecular Medicine, Sapienza University, Rome, Italy; 9Regional Referral Headache Centre, Sant’Andrea Hospital, Rome, Italy; 10Research Department of Neurology, First “I. Sechenov” Moscow State Medical University, Moscow, Russian Federation; 11 Research Center for Neuropsychiatry, Moscow, Russian Federation; 12 Department of Neurology, Ghent University Hospital, Ghent, Belgium
Correspondence: P Martelletti (paolo.martelletti@uniroma1.it)

Medical management of headache disorders, for the vast majority of people affected by them, can and should be carried out in primary care. It does not require specialist skills. Nonetheless, it is recognised that non-specialists throughout Europe may have received limited training in the diagnosis and treatment of headache.

This publication, in the Journal of Headache and Pain, provides a combination of educational materials and practical management aids. It is a product of the Global Campaign against Headache, a programme of action for the benefit of people with headache conducted by the UK-registered non-governmental organization Lifting The Burden (LTB) in official relations with the World Health Organization. It updates the first edition [1], published 10 years ago.

The content has been put together by a writing group of experts convened by Lifting The Burden in collaboration with the European Headache Federation (EHF). It has undergone review by a wider consultation group of headache experts, including representatives of the member national societies of EHF, primary-care physicians from eight countries of Europe, and lay advocates from the European Headache Alliance. While the focus is Europe, the inclusion in the consultation group of members from all six world regions has aimed for cross-cultural relevance of all content so that it is useful to a much wider population.

The European principles of management of headache disorders in primary care, laid out in 11 sections, are the core of the content. Each of these is more-or-less stand-alone, in order to act as practical management aids as well as educational resources. There is a set of additional practical management aids. An abbreviated version of the International Classification of Headache Disorders, 3rd edition (ICHD-3), provides diagnostic criteria for the few headache disorders relevant to primary care. A headache diary further assists diagnosis and a headache calendar assists follow-up. A measure of headache impact (the HALT-90 index) can be employed in pre-treatment assessment of illness severity, and an outcome measure (the HURT questionnaire) is a guide to follow-up and need for treatment-review. Five patient information leaflets are included, which may be offered to patients to improve their understanding of their headache disorders and their management.

LTB and EHF offer these aids freely available for use without restriction. We hope for benefits for both physicians and patients.

S33 Combined hormonal contraception and migraine, WHO and EHF/ESCRH criteria and balancing risks and benefit

Simona Sacco (simona.sacco@univaq.it)

Neurology section, Department of Applied Clinical Science and Biotechnology, University of L’Aquila, L’Aquila, Italy

Several data indicate that migraine, especially migraine with aura, is associated with an increased risk of ischemic stroke and other vascular events. Of concern is whether the risk of ischemic stroke in migraineurs is magnified by the use of hormonal contraceptives (HCs). As migraine prevalence is high in women of reproductive age, it is common to face the issue of migraine and HC use in clinical practice.

To improve decision-making on the use of HCs in women with migraine, a selected group of representatives from the European Headache Federation (EHF) and the European Society of Contraception and Reproductive Health (ESC) developed a Consensus Statement on this topic. The document pointed out that evidence addressing the risk of ischemic stroke associated with the use of HCs is generally poor. All information relies on observational data, which may carry the risk of potential bias. Available studies had different settings and used different groups for comparing risks, limiting reliable comparison of studies as a pooled analysis of data. Most of the available studies were published several years ago and used compounds which are different from those available today. Additionally, in most studies not enough information is available regarding the type of HC considered and in most cases results are not provided according to migraine type. Despite those limitations, available data pointed toward an increased risk of ischemic stroke associated with the use of HCs in women with migraine. Literature indicated that, whereas combined HCs carry a certain risk of arterial ischemic events this does not happen for progestogens-only HCs which are considered safe in terms of cardiovascular risk even in the presence of associated risk factors. Considering those data, and unless studies will prove safety of the use of combined HCs in women with migraine, the recommendations from the Consensus Group gave priority to safety and suggested several limitations in the use of combined HCs in women with migraine. There are alternative methods to combined HCs which provide similar contraceptive benefits but that are much safer in terms of risks. Further research is need to address safety of newer compounds in women with migraine.

References

Sacco S, Merki-Feld GS, Ægidius KL, Bitzer J, Canonico M, Kurth T, Lampl C, Lidegaard Ø, MacGregor EA, MaassenVanDenBrink A, Mitsikostas D, Nappi RE, Ntaios G, Sandset PM, Martelletti P; on behalf of the European Headache Federation (EHF) and the European Society of Contraception and Reproductive Health (ESC). Hormonal contraceptives 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 2017;in press.

S34 Neuropathic pain: basic concepts

Rolf-Detlef Treede

Department of Neurophysiology, Center for Biomedicine and Medical Technology Mannheim, Heidelberg University, Germany

Neuropathic pain is pain caused by a lesion or disease of the somatosensory nervous system. The term lesion is refers to nervous system damage demonstrated by imaging, neurophysiology, biopsies or surgical evidence. The term disease is used when the nervous system damage is due to a neurological disorder such as stroke or peripheral diabetes neuropathy. In peripheral neuropathic pain there is usually a mixture of damaged and undamaged axons within the peripheral nerve, leading to the clinical presentation with ongoing pain, sensory loss and sensory gain (hyperalgesia, allodynia). The clinical presentation in central neuropathic pain is similar, but the mechanisms are less well understood. Mechanisms of peripheral neuropathic pain include ectopic impulse generation, peripheral sensitization of undamaged nerve fibers, and central sensitization; the latter includes altered signal processing in the CNS due to changes in descending pain modulation. Neuropathic pain is included in the upcoming ICD-11 coding system, but not in the currently used classifications ICD-10 and ICD-9. For this reason the exact prevalence of neuropathic pain is not yet known, but is expected to be high due to the high prevalence of the underlying neurological disorders.

S35 Migraine and cerebellum

Koppen Hille

A range of clinical neurophysiological and functional imaging studies have suggested that migraine might be associated with cerebellar dysfunction. These studies all had methodological short-comings to a greater or lesser extent. Therefore, it is still uncertain whether migraine is associated with cerebellar dysfunction, and, if so, to what extent and why. Is this presumed cerebellar dysfunction due to the increased prevalence of cerebellar ischemic lesions in migraine patients or is there a more functional explanation similar to what’s seen in familial hemiplegic migraine type 1 (FHM1)? Recent anatomical studies demonstrated that the output of the cerebellum targets multiple non-motor areas in the prefrontal and posterior parietal cortex. Neuro-anatomy and functions of the cerebellum will be reviewed as well as the evidence of cerebellar infarcts in migraineurs. In detail results of the population-based CAMERA II (Cerebral Abnormalities in Migraine, an Epidemiological Risk Analysis Cohort) study specific on cerebellar ischemia and cerebellar function will be discussed.

S36 Neurophysiology of Headaches

Gianluca Coppola

G.B. Bietti Foundation-IRCCS, Research Unit of Neurophysiology of Vision and Neurophthalmology, Rome, Italy

During the last decades, the methods of neurophysiology proved to be very effective in disclosing subtle functional abnormalities of the brain of patients affected by primary headache disorders. These methods received several refinements during the last years, further improving our understanding of headaches pathophysiology. Abnormal increased responsivity was several times revealed with almost all the sensory modalities of stimulation in migraine between attacks, with its normalization during the attacks. Recently, authors observed that the degree of some neurophysiological abnormalities might depends on the distance from the last attack, i.e. on the point where the patient is recorded during the migraine cycle. Thalamic/thalamocortical drives were found to be less active interictally, but normally active ictally. Somatosensory cortex lateral inhibition, gating, and interhemispheric inhibition were altered in migraine, and may contribute to cortical hyperresponsivity and clinical features.

Cluster headache patients are characterized by a deficient habituation of the brainstem blink reflex during the bout, outside of attacks, on the affected side. Evidence for sensitization of pain processing was disclosed by studying temporal summation threshold of the nociceptive withdrawal reflex, which was less modulated by supraspinal descending inhibitory controls.

In conclusion, much has been discovered and much more needs to be investigated to better understand what causes, how it triggers, keeps and runs out recurrent primary headaches. Clarifying some of these mechanisms might help in the identification of new therapeutic targets.

S37 Mechanisms of Photophobia

Andrew Russo

In this rejoinder to “Photophobia and Hypothalamus”, I will speculate on how the diverse collection of neuropeptides, including CGRP, in the hypothalamus might increase sensitivity to light. Within the brain, neuropeptides can modulate the strength of synaptic signaling even at a relatively large distance from their site of release. Given the evidence for CGRP in migraine and potential roles for other hypothalamic peptides, it seems likely that altered neuropeptide actions may be a general theme underlying the heightened sensory state of migraine. Towards this point, I will briefly discuss our preclinical CGRP and optogenetic studies using light aversive behavior in mouse models as a surrogate for migraine-associated photophobia. I will describe how both the brain and the periphery are susceptible to elevated CGRP and how CGRP appears to act by distinct mechanisms in these sites. In the CNS, we have identified the posterior thalamus as a likely site of CGRP action, which is in agreement with Burstein’s evidence that this region is a convergent relay point from the retina and dura. These ideas will be tied together in a speculative model that integrates peripheral and central CGRP actions in photophobia.

S38 Classical trigeminal neuralgia – clinical and MRI findings

Stine Maarbjerg

Department of Neurology, Helse Fonna, Haugesund, Norway

Background

Classical trigeminal neuralgia (TN) is a unique neuropathic facial pain disorder. As there are no diagnostic tests to confirm the diagnosis, it relies on a thorough history and exam. MRI is used to exclude symptomatic trigeminal neuralgia, not to confirm the diagnosis of TN. Knowing how to interpret MRI findings is of importance with respect to surgical treatment options and their expected chance of a successful outcome.

Results

TN is characterized by paroxysms of unilateral intense pain usually in the 2nd and 3rd trigeminal branch. The pain quality is stabbing and the pain is typically evoked by sensory stimuli like light touch, brushing teeth, cold wind or eating. Up to half of the patients also have concomitant persistent pain. A smaller proportion of patients may have sporadic autonomic symptoms. The average age of disease onset is in the early fifties and TN is slightly more prevalent in women than in men.

As a general rule, the neurological exam is normal in TN patients. As objective signs of TN, patients may wince at pain paroxysms and may avoid shaving or brushing their teeth on the affected side. Some studies argue that a proportion of TN patients have subtle sensory abnormalities at bedside exam, primarily hypoesthesia. Studies using quantitative sensory testing also documented sensory changes in TN. Rather than indicating nerve damage, the findings may be explained by functional changes of the nervous system in response to severe pain.

There is widespread consensus that TN is associated to a neurovascular contact between the trigeminal nerve and a blood vessel in the prepontine course of the nerve. Emerging advanced imaging studies confirms that at the site of a neurovascular contact on the ipsilateral side of pain, there is of demyelination – a process that seems to be reversible in some patients after successful surgery. Imaging studies also consistently show that TN is strongly associated to a neurovascular contact with morphological changes of the trigeminal nerve, i.e. dislocation, distortion or atrophy of the trigeminal nerve. Meanwhile, only half of TN patients have morphological changes of the trigeminal nerve and there may be other unknown etiological factors causing TN.

Conclusions

The talk discusses the clinical features and the clinical and MRI findings of TN. The pearls and pitfalls of TN diagnosis and neuroimaging is discussed from both a clinical and a scientific perspective.

S39 PACAP in migraine

László Vécsei1,2, Délia Szok1, János Tajti1

1Department of Neurology, Faculty of Medicine, Albert Szent-Györgyi Clinical Center University of Szeged, H-6725 Szeged, Semmelweis u. 6, Hungary; 2MTA-SZTE Neuroscience Research Group, University of Szeged, H-6725 Szeged, Semmelweis u. 6, Hungary
Correspondence: László Vécsei (vecsei.laszlo@med.u-szeged.hu)

Background

Pituitary adenylate cyclase-activating polypeptide (PACAP) is a member of the vasoactive intestinal polypeptide (VIP)/secretin/growth hormone-releasing hormone/glucagon neuropeptide superfamily, widely expressed in vertebrate tissues [1]. The first evidence for potential role of PACAP in pathomechanism of migraine was the intravenous administration of PACAP-38 caused headache and vasodilatation in healthy subjects as well as in migraineurs, and lead to delayed-type migraine-like attacks [2]

Materials and methods

A systematic literature search was conducted to identify preclinical and clinical publications in the field of PACAP and migraine in the database of MEDLINE/PubMed up to 31 May 2017.

Results

Preclinical experiments revealed that both PACAP-27 and PACAP-38 were found elevated in the trigeminal nucleus caudalis of rats following electrical stimulation of the trigeminal ganglion or chemical stimulation by nitroglycerin of the trigeminovascular system [3]. A magnetic resonance imaging (MRI) angiographic study demonstrated that PACAP-38-induced headache was associated with prolonged dilatation of the middle meningeal arteries, but not of the middle cerebral arteries in healthy volunteers [4]. Another MRI trial concluded that PACAP-38-induced vasodilatation was longer lasting compared to VIP in migraineurs [5]. The recent functional imaging study pointed that intravenous PACAP-38-induced migraine attacks was associated with alterations in brain network connectivity [6]

Clinical investigation provided evidence of a clear association between migraine phases (during a spontaneous migraine attack versus pain-free period) and the alteration of plasma PACAP-38 level [7].

Conclusions

The activation and sensitization of the trigeminovascular system by vasoactive neuropeptides might be crucial factors of the migraine pathogenesis [8]. The recent preclinical and clinical studies suggest the importance of PACAP as a future biomarker of migraine headache.

Acknowledgements

This work was supported by the projects EUROHEADPAIN FP7-Health 2013-Innovation; Grant No. 602633; GINOP-2.3.2-15-2016-00034, KTIA_NAP_13-2014-0022.

References

1. Arimura A. PACAP: the road to discovery. Peptides. 2007; 28:1617-1619.

2. Schytz, H.W., Birk, S., Wienecke, T., Kruuse, C., Olesen, J., Ashina, M. PACAP38 induces migraine-like attacks in patients with migraine without aura. Brain. 2009; 132:16-25.

3. Tuka, B., Helyes, Z., Markovics, A., Bagoly, T., Nemeth, J., Mark, L., Brubel, R., Reglodi, D., Pardutz, A., Szolcsanyi, J., Vecsei, L., Tajti, J. Peripheral and central alterations of pituitary adenylate cyclase activating polypeptide-like immunoreactivity in the rat in response to activation of the trigeminovascular system. Peptides 2012; 33:307-316.

4. Amin, F.M., Asghar, M.S., Guo, S., Hougaard, A., Hansen, A.E., Schytz, H.W., van der Geest, R.J., de Koning, P.J., Larsson, H.B., Olesen, J., Ashina, M. Headache and prolonged dilatation of the middle meningeal artery by PACAP38 in healthy volunteers. Cephalalgia 2012;32: 140-149.

5. Amin, F.M., Hougaard, A., Schytz, H.W., Asghar, M.S., Lundholm, E., Parvaiz, A.I., de Koning, P.J., Andersen, M.R., Larsson, H.B., Fahrenkrug, J., Olesen, J., Ashina, M. Investigation of the pathophysiological mechanisms of migraine attacks induced by pituitary adenylate cyclase-activating polypeptide-38. Brain 2014; 137:779-794.

6. Amin, F.M., Hougaard, A., Magon, S., Asghar, M.S., Ahmad, N.N., Rostrup, E., Sprenger, T., Ashina, M. Change in brain network connectivity during PACAP38-induced migraine attacks: A resting-state functional MRI study. Neurology 2016; 86:180-187.

7. Tuka, B., Helyes, Z., Markovics, A., Bagoly, T., Szolcsanyi, J., Szabo, N., Toth, E., Kincses, Z.T., Vecsei, L., Tajti, J. Alterations in PACAP-38-like immunoreactivity in the plasma during ictal and interictal periods of migraine patients. Cephalalgia 2013; 33:1085-1095.

8. Vécsei L, Tuka B, Tajti J. Role of PACAP in migraine headaches. Brain 2014; 137:650-651.

S40 Comorbidity Grounds

Noemi Faedda1, Vincenzo Guidetti2, Giulia Natalucci2

1PhD program in Behavioural Neuroscience, Department of Paediatrics and Child and Adolescent Neuropsychiatry, Sapienza University of Rome; 2Department of Paediatrics and Child and Adolescent Neuropsychiatry, Sapienza University of Rome
Correspondence: Vincenzo Guidetti (vincenzo.guidetti@uniroma1.it)

Several studies are found a relationship between headache and psychiatric comorbidity in both children and adolescents [1-3]. The most frequently described comorbidities include anxiety, mood disorders [1], sleep disorder [2] and attention hyperactive disorder [3]. The association between headache and comorbidities has been interpreted in the light of different possible causal pathways. Psychiatric comorbidity may represent the consequence of a link between neurotransmitter systems involved in migraine and psychiatric disorder, such as depression and anxiety [4]. A central role is thought to be played by serotonergic receptors, adrenergic and dopaminergic D2 receptor genotype, that seem to be associated with migraine, major depression, generalized anxiety disorder, panic attacks and phobia [5]. It has been suggested that the patient's vulnerability to anxiety disorders and affective disorders as well as migraine might be attributed to the dysregulation of the serotonergic system [6]. Furthermore, it is possible that each disorder increases the risk of the other [4;7]. Twin studies have shown that the genetic liability related to migraine amounts to 40-60%, while the contribution of non-shared environmental factors has to be weighed in a range between 35 and 55% [8]. Therefore, the relevance of other mediating factors for the co-occurrence of headache and psychiatric comorbidity has to be taken into consideration. Recent research found that an insecure attachment may be a risk factor for an outcome of poor adaptation that includes chronic pain [9] and that pain perception may change in relation with specific attachment styles.

The ambivalent attachment seems to be the most common style among patients reporting high attack frequency and severe pain intensity and in children with this attachment style there is a relationship between high attack frequency and high anxiety levels [10]. Barone et al. [11] showed that higher is the attachment security, lower is the association between maternal stress and children’s behavioural problems in children and adolescents with headache. Although more studies are needed in order to detect the biological, genetic and environmental mechanisms underlying the relationship between headache and comorbidities, attachment styles can be regarded as one of the factors mediating this association [12].

References

1. Blaauw BA, Dyb G, Hagen K, Holmen TL, Linde M, Wentzel-Larsen T, Zwart JA. Anxiety, depression and behavioral problems among adolescents with recurrent headache: the Young-HUNT study. J Headache Pain. 2014;15:38.

2. Guidetti V, Dosi C, Bruni O. The relationship between sleep and headache in children: implications for treatment. Cephalalgia. 2014 Sep;34(10):767-76.

3. Parisi P, Verrotti A, Paolino MC, Ferretti A, Raucci U, Moavero R, Villa MP, Curatolo P. Headache and attention deficit and hyperactivity disorder in children: common condition with complex relation and disabling consequences. Epilepsy Behav. 2014;32:72-5

4. Antonaci F, Nappi G, Galli F, Manzoni GC, Calabresi P, Costa A. Migraine and psychiatric comorbidity: a review of clinical findings. J Headache Pain. 2011;12(2):115-25.

5. Peroutka SJ, Price SC, Wilhoit TL, Jones KW. Comorbid migraine with aura, anxiety, and depression is associated with dopamine D2 receptor (DRD2) NcoI alleles. Mol Med. 1998;4:14–21.

6. Liu H, Liu M, Wang Y, et al. Association of 5-HTT gene polymorphisms with migraine: a systematic review and meta-analysis. J Neurol Sci 2011; 305(1-2): 57-66.

7. Bellini B, Arruda M, Cescut A, Saulle C, Persico A, Carotenuto M, Gatta M, Nacinovich R, Piazza FP, Termine C, Tozzi E, Lucchese F, Guidetti V. Headache and comorbidity in children and adolescents. J Headache Pain 2013; 14:79.

8. Mulder EJ1, Van Baal C, Gaist D, Kallela M, Kaprio J, Svensson DA, Nyholt DR, Martin NG, MacGregor AJ, Cherkas LF, Boomsma DI, Palotie A. Genetic and environmental influences on migraine: a twin study across six countries. Twin Res. 2003 Oct;6(5):422-31.

9. Lumley MA, Cohen JL, Borszcz GS, Cano A, Radcliffe AM, Porter LS, Schubiner H, Keefe FJ. Pain and emotion: a biopsychological review of recent research. J Clin Psychol 2011; 67 (9): 942-968).

10. Esposito M, Parisi L, Gallai B, Marotta R, Di Dona A, Lavano SM, Roccella M, Carotenuto M. Attachment styles in children affected by migraine without aura. Neuropsychiatr Dis Treat. 2013;9:1513-9.

11. Barone L, Lionetti F, Dellagiulia A, Galli F, Molteni S, Balottin U. Behavioural problems in children with headache and maternal stress: is children's attachment security a protective factor? Inf. Child. Dev 2015; DOI: 10.1002/icd.1950.

12. Williams R, Leone L, Faedda N, Natalucci G, Bellini B, Salvi E, Verdecchia P, Cerutti R, Arruda MA, Guidetti V. The role of attachment insecurity in the emergence of anxiety symptoms in children and adolescents with migraine: an empirical study. J Headache Pain (In Press)

SISC INVITED SPEAKERS

S41 Application of “very low-calorie ketogenic diet” in migraine treatment

Cherubino Di Lorenzo1, Roberta Ienca2, Simona Sodano2, Gianluca Coppola3, Francesco Pierelli4,5

1Don Carlo Gnocchi Onlus Foundation, Milan, Italy; 2Department of Experimental Medicine-Medical Physiopathology, Food Science and Endocrinology Section, Sapienza University, Rome, Italy; 3G.B. Bietti Foundation – IRCCS, Department of Neurophysiology of Vision and Neurophthalmology, Rome, Italy; 4Department of Medico-Surgical Sciences and Biotechnologies, Sapienza University of Rome, Rome, Italy; 5IRCCS – Neuromed, Pozzilli (IS), Italy
Correspondence: Cherubino Di Lorenzo (cherub@inwind.it)

Background. Metabolic syndrome and overweight are highly prevalent among migraineurs and the weight-loss was suggested as a useful strategy to improve both migraine and metabolic syndrome. Among different approaches to achieve a rapid weight loss, in the last years the very low-calorie diets (VLCDs), characterized by a dramatic caloric restriction (<800 Kcal/day), are gaining large dietician approval. Recently, we have observed that a particular version of VLCD characterized by very low-carbohydrate intake and Ketone bodies (KBs) production, named very low-calorie ketogenic diet (VLCKD), was able to induce a rapid improvement of headache in migraineurs. To assess if the favorable outcome on migraine was due to the caloric restriction, instead of KBs, we performed a double blind crossover study to compare headache modifications during a VLCD and a VLCKD in a population of overweighed and obese migraineurs.

Methods. Among patients referred to the Sapienza University Obesity Clinic, a neurologist specializing in headache recruited 35 migraineurs. After one month of headache diary recording, they started a 4-month weight-loss program characterized by the alternation of two VLCD protocols named “red” and “blue”; one of them was a VLCKD, the other a non-ketogenic VLCD. Randomly patients started with one of the two diets according to the following scheme: first VLCD, transition diet (progressive increase of calorie, up to 1200 Kcal/day), the other VLCD, and the second transition diet (Fig. 1). To verify variations in headache frequency, we used as baseline the month before the first VLCD and the first transition diet.

Results. Out 35 enrolled patients, six dropped at the first month of diet: all followed the “blue” diet; 29 completed the study. The primary endpoint was the responder rate (number of patients with a headache frequency reduction ≤50%): 26 of 29 patients (74.28% of intention to treat (ITT) patients) responded to the “red diet”, only 2 (5.7% of ITT patients) responded to the “blue diet”. When the blind was broken, we found out that the “red diet” was the ketogenic diet and the “blue diet” was the non-ketogenic.

Conclusions. Our results are suggestive for an outstanding protective effect of VLCKD in migraineurs. This positive outcome could be due to the KBs GABAergic, anti-inflammatory, and energetic properties. The 17% of dropout rate is in line with other similar studies and it is interesting to highlight that all the patients that drops did it during the first month of non-ketogenic VLCKD.
Fig. 1 (abstract S41).

See text for description

S42 Real Clinical Practice: Physiotherapy Evaluation of Disorders cranial-cervical-mandibular headaches in ebm

Riccardo Rosa (clinicadelmalditesta@gmail.com)

1La Sapienza University of Roma, Italy; 2CLINICADELMALDITESTA, 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 side- locked 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]. 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 [8, 9]. In this presentation, an evidence based physical protocol of specific tests it will be provided by a physiotherapist to assess musculoskeletal disorders in the most common primary headaches as Migraine and Tension Type Headache. Moreover, the integration of this examination in a multidisciplinary team it will be discussed.

References

1. Stovner LJ. Migraine prophylaxis with drugs influencing the renin- angiotensin system. 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 doi:10.1186/s10194-016-0687-9

6. 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.

7. Luedtke K, Starke W, May A. Musculoskeletal dysfunction in migraine patients. Cephalalgia. 2017; Jan 1:333102417716934. doi: 10.1177/0333102417716934.

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.

S43 Pediatric Hedache

Massimiliano Valeriani (m.valeriani@tiscali.it)

Centro per lo Studio e la Cura delle Cefalee in Età Evolutiva, UO Neurologia, Ospedale Pediatrico Bambino Gesù, Rome, Italy; Center for Sensory-Motor Interaction, Aalborg University, Aalborg, Denmark

Headache represents the most common neurological symptom in pediatric age. Among the primary headaches, migraine is far more prevalent than tension-type headache and cluster headache. Though extremely rare at this age, also trigeminal autonomic cephalgias have been reported. The most frequent causes of pediatric secondary headaches are represented by respiratory tract infections, while potentially life-threatening diseases, such as brain tumors, are less common. However, especially in the emergency setting, the possibility that a headache attack is due to a brain tumor must be always considered. To avoid missing these cases, some headache characteristics (red flags) have been identified [1]. In pediatric age, as in adulthood, the diagnosis of primary headache is based on the International Classification of Headache Disorders III-beta version (ICHD-IIIb). However, while the most recent ICHD criteria improved the possibility to classify some patients, such as children with migraine with aura [2], they turned out to be unsuitable for others, such as young patients with primary headache. In particular, we have showed that more than 50% of children up to 6 years of age have a headache duration shorter than 30 minutes, thus they could not be classified either in migraine or in tension-type headache [3]. Several studies have shown the primary role played by psychological factors in determining the severity of migraine in children [4]. Therefore, a psychological examination is often mandatory, as part of the initial assessment of the patient. Lastly, when assessing a child with primary headache, possible comorbidities should be never forgotten, since addressing them can represent a crucial point for the treatment [5].

References

1. Papetti L, Capuano A, Tarantino S, Vigevano F, Valeriani M. Headache as an emergency in children and adolescents. Curr Pain Headache Rep 2015;19:3.

2. Balestri M, Papetti L, Maiorani D, Capuano A, Tarantino S, Battan B, Vigevano F, Valeriani M. Features of aura in paediatric migraine diagnosed using the and ICHD 3III beta criteria. Cephalalgia, submitted.

3. Torriero R, Capuano A, Mariani R, Frusciante R, Tarantino S, Papetti L, Vigevano F, Valeriani M. Diagnosis of primary headache in children younger than 6 years: A clinical challenge. Cephalalgia 2017;37:947-954.

4. Özge A, Yalin OÖ. Chronic Migraine in Children and Adolescents. Curr Pain Headache Rep 2016;20:14.

5. Guidetti V, Arruda M, Özge A. Headache and comorbidities in childhood and adolescence. Springer, 2017

S44 Overuse of Headache Medications: from Neurochemistry to Pathophysiology. Clinical and Preclinical Clues

Alberto Chiarugi

Department of Health Sciences, Section of Clinical Pharmacology and Oncology, University of Florence, and Headache Center University Hospital, Italy

Whether medication-overuse headache (MOH) represents a distinct biological entity within the concept of chronic daily headache with specific neurobiological and genetic background is still a matter of debate. A great deal of interest has been directed at understanding the neurophysiological mechanisms that underlie MOH pathogenesis. Currently, two main, non-mutually exclusive hypotheses have been proposed. The first, stems from the apparent compulsive use of headache medications by MOH patients, and considers this disorder a sort of addiction to symptomatic remedies. The second shifts the focus from drug addiction to neural sensitization, claiming that triptan overuse triggers adaptations of the trigeminovascular system, thereby facilitating pain transmission and leading to a state of latent sensitization. However, whether the effects of triptans are shared by all symptomatic headache medications as a sort of signature of the complex neurophysiologic rearrangements occurring in MOH is still unknown, as well as the extent of neurotransmitter/neuromodulators involved. Answering these questions might be relevant to better understand the neurochemical mechanisms prompted by acute headache medications that underlie the pathophysiology of MOH and of chronic headache in general.

In this presentation, preclinical data will be presented showing that chronic exposure to eletriptan or indomethacin alter trigeminal ganglion gene expression patterns broadly and to a similar extend. Remarkably, qualitative transcriptomic analysis reveals that prolonged exposure to the two different symptomatic drugs triggers almost identical, increased expression of various genes coding for proteins involved in headache pathogenesis such as neuropeptides, their cognate receptors, TRP channels, prostanoid and NO synthesizing enzymes. These findings will be correlated with the clinical aspects of MOH.

S45 The very low calorie ketogenic diet in the clinical practice

Roberta Ienca, Simona Sodano

1Department of Experimental Medicine, Medical Pathophysiology, food science and endocrinology section, Sapienza University, Rome, 00100, Italy
Correspondence: Roberta Ienca (roberta.ienca@libero.it)

Background

The very low calorie diet (VLCD) is a dietetic regimen characterized by a daily energetic intake < 800 Kcal/day, also called “simulated fasting”. The dramatic caloric restriction promotes the fat metabolism, mimicking the starvation, even if meals replacements ad hoc developed accounts for essential nutrients, avoiding the malnutrition. Because of the extreme caloric restriction, this type of diet is very effective in weight loss, however, that characteristic also is the main limit of VLCD, since it is possible to follow this kind of dietetic regimen for a very limited period (usually 3-12 weeks).

Materials and methods

According to macronutrients intake, it is possible to divide all the VLCDs in two sub-groups: ketogenic (VLCKD) and non-ketogenic diets. The VLCKD is characterized by low-carbohydrate (about 30 g/day carbohydrates), low-fat (fixed 15 g lipids), and slightly high-protein (1.0–1.4 g/kg of ideal body weight), divided in four daily meals consisting of dietary products developed ad hoc and nutraceutical integrators (Table 1). Salads are allowed ad libitum dressed with a spoonful of olive oil. The non-ketogenic VLCD is characterized by a slightly limited carbohydrate intake (100 g/day carbohydrates), low-fat (10 g lipids), and normal-protein (0.8 g/kg of ideal body weight). Also in this kind of diet, there are 4-5 meals per day, mainly consisting in meal replacement products. Both in VLCD and VLCKD lipids are usually provided by olive oil or omega-3.

Results

There is a growing interest in the ketogenic form of the VLCD because several studies have shown a higher compliance of patients with this diet. The reason of this higher adherence to the diet is still under scrutiny but several reasons are called in cause: an appetite suppression induced by proteins and (maybe) by ketone bodies (KBs), or a modification in hormone secretion (insulin, glucagon, ghrelin, adipokines).

Conclusion

The real impact of ketogenic diets in weight loss is still disputed; in fact, on the long period there are not differences between low-carb and low-fat diets in terms of weight reduction and regain of lost weight after the diet. However, thanks to the higher compliance and the drastic caloric restriction, the VLCKDs seem to be a promising approach in the early management of obesity and in the preparation phase for patients that must undergo to bariatric or other types of surgical procedures.
Table 1 (abstract S45).

See text for description

 

Daily dose

RDA

Vit A

800 mcg

100% RDA

Vit B1

1.4 mg

100% RDA

Vit B2

1.6 mg

100% RDA

Vit B3

18 mg

100% RDA

Vit B5

6 mg

100% RDA

Vit B6

2 mg

100% RDA

Vit B8

150 mcg

100% RDA

Vit B9

200 mcg

100% RDA

Vit B12

1 mcg

100% RDA

Vit C

60 mg

100% RDA

Vit D

5 mcg

100% RDA

Vit E

10 mg

100% RDA

Ca

800 mg

100% RDA

Cr

7.5 mcg

15% RDA

Cu

0.6 mg

50% RDA

Mg

90 mg

30% RDA

Mn

1.75 mg

RDA 1-10 mg

Zn

7.5 mg

50% RDA

S46 Headache and temporomandibular disorders: association or causality? The bio-psychosocial model applied to the clinical reasoning

Marco Testa

Department of Neuroscience, Rehabilitation, Ophthalmology, Genetics, Maternal and Child Health, University of Genova – Campus of Savona, 17100 Savona - Italy

Temporomandibular disorders (TMD) represent the main cause of orofacial pain of non-dental origin and comprehend several disturbances of the masticatory system characterized by myofascial pain of masticatory muscles or articular pain localized in the pre-auricular area. Moreover, TMD patients show temporomandibular joint sounds and deviation or limitation of the opening of the mouth.

Myofascial pain is a probable consequence of central nervous system mechanisms of convergence and activation of second order neurons with enlargement of the receptive field, reduced pain threshold and allodinia. Often there are accompanying symptoms like facial pain and headaches.

Headache is the most prevalent neurologic disorder, third most diffused health disturbance and the seventh cause of disability in the world. It can be primary, without apparent organic cause, or secondary to other pathologies.

Some epidemiological studies indicates that headache is more prevalent in TMD patients and TMD is more prevalent in subjects affected by headache. A stronger association exists between TMD and chronic migraine in comparison with other types of headache. Myofascial TMD is more frequently associated to headache than articular TMD. Nevertheless the methodological quality of the available studies is not optimal and many of them classify patients with anamnestic questionnaire that tend to overestimate the values of prevalence.

A growing body of literature suggests that the association between headache and TMD may be a manifestation of a central sensitization mechanism. Temporomandibular joint and muscles receive the sensitive innervation of the trigeminal nerve that supply also the cranial vascular structures likely involved in the etiology of the headache. The sensitization of the trigeminal caudate nucleus by the TMD symptoms can favor the triggering of migraine episode.

Beside the epidemiological studies and the neurophysiologic hypothesis, there are some initial clinical evidence that show how severity of TMD symptoms parallels an increase of frequency and intensity of migraine and the simultaneous treatment of both conditions results in better outcomes.

From a clinical perspective, a comprehensive assessment based on a biopsychosocial approach can provide relevant information to plan a contemporaneous treatment of TMD and headache, together with an intervention targeted to the reduction of psychosocial conditions that can elicit and maintain mechanisms of central sensitization likely responsible of the comorbidity of TMD and headache.

S47 Tension-Type Headache and Central Sensitization: the Role of Physical Therapy According to EBM

Matteo Castaldo1,2,3 (matteo.castaldo@poliambulatoriofisiocenter.com)

1Department of Health Science and Technology. Aalborg University, Aalborg, Denmark; 2Siena University, Siena, Italy; 3Poliambulatorio Fisiocenter, private practice, Parma, Italy

Tension-type headache (TTH) is the most common headache, with a lifetime prevalence ranging between 30% and 78% in the general population, and with a high socio-economic impact [1].

The exact pathophysiology is still unknown, but evidence supporting both peripheral and central mechanisms (i.e. central sensitization) is increasing [2,3].

In fact, the frequency of headache attacks has found to be related to the level of central sensitization [4].

However, not all TTH patients present with the same level of central sensitization and clinical presentation, but subgroups need to be identified in order to offer specific therapeutic programs [5].

Prolonged peripheral nociceptive input from the pericranial, neck, and shoulder regions (e.g. trigger points (TrPs), zygoapophyseal joints) may over time sensitize the central nervous system, transmitting nociceptive input to the trigemino-cervical nucleus caudalis [6].

In fact, it has been found that sustained stimulation of TrPs may induce central sensitization in healthy participants [7].

There is evidence supporting the role of TrPs as contributor to TTH, and that the referred pain elicited by TrPs stimulation reproduces the headache pattern in TTH patients [8].

The number of TrPs seems to be associated with the degree of widespread pressure pain hypersensitivity in TTH patients, supporting the role of TrPs on central sensitization: however the cross-sectional nature of the study does not allow to establish a cause and effect relationship between TrPs and central sensitization, as other variables may influence this association [9].

Physical therapy may be helpful for the management of TTH patients [10,11], as it may decrese the peripheral nociceptive input.

However, to nowdays, studies on treatment of TrPs in TTH are still few and more evidence is needed.

References

1. Stovner L, Hagen K, Jensen R, et al. The global burden of headache: a documentation of headache prevalence and disability worldwide. Cephalalgia 2007;27:193–210.

2. De Tommaso M and Fernández-de-Las-Peñas C. Tension type headache. Curr Rheumatol Rev 2016; 12: 127–139.

3. Andersen S, Petersen MW, Svendsen AS, et al. Pressure pain thresholds assessed over temporalis, masseter, and frontalis muscles in healthy individuals, patients with tension- type headache, and those with migraine: A systematic review. Pain 2015; 156: 1409–1423

4. Buchgreitz L, Lyngberg AC, Bendtsen L, et al. Frequency of headache is related to sensitization: a population study. Pain 2006; 123(1-2):19-27.

5. Fernández-de-Las-Peñas C, Benito-González E, Palacios-Ceña M, et al. Identification of subgroups of patients with tension type headache with higher widespread pressure pain hyperalgesia. J Headache Pain 2017; 18(1):43.

6. Bendtsen L, Fernandez-de-Las-Penas C. The role of muscles in tension-type headache. Curr Pain Headache Rep. 2011;15:451–458.

7. Xu YM, Ge HY, Arendt-Nielsen L. Sustained nociceptive mechanical stimulation of latent myofascial trigger point induces central sensitization in healthy subjects. J Pain. 2010;11:1348–1355.

8. Fernández-de-Las-Peñas C, Cuadrado ML, Arendt-Nielsen L, et al. Myofascial trigger points and sensitization: An updated pain model for tension-type headache. Cephalalgia 2007; 27: 383–393.

9. Palacios-Ceña M, Wang K, Castaldo M, et al. Trigger Points are associated with widespread pressure pain sensitivity in people with tension-type headache. Cephalalgia 2016 [Epub ahead of print].

10. Alonso-Blanco C, de-la-Llave-Rincón AI, Fernández-de-las-Peñas C. Muscle trigger point therapy in tension-type headache. Expert Rev Neurother 2012; 12(3):315-22.

11. Espí-López GV, Arnal-Gómez A, Arbós-Berenguer T,et al. Effectiveneess of physical therapy in patients with tension-type headache: literature review. J Jpn Phys Ther Assoc 2014; 17(1):31-38.

S48 The use of nutraceuticals in migraine

Cherubino Di Lorenzo (cherub@inwind.it)

Don Carlo Gnocchi Onlus Foundation, Milan, Italy

Background

Migraine is related to the highest disability among headaches. Great efforts are faced to improve the outcome of forthcoming treatments. However, still now, many patients regard as unsatisfactory the low responder rate (about the half of patients) and adverse effects that current treatments account. Therefore, waiting for innovative, more tolerated and effective treatments, there is a large request for non-pharmacological approaches that in many cases have specific pathophysiological targets. Among these treatments, nutraceuticals has a leading role. The term “nutraceuticals” indicates any product derived from food or herbal sources, administrated at a specific dose, adequate to obtain some health benefits. Several nutraceutical products are proposed for migraine and sold around the world, but researchers adequately study only few compounds

Methods

Among studied nutraceuticals compounds, only few of them have studies of good quality in support. Moreover, also interactions among different molecules are not studied. We have reviewed literature data in order to find researches that support the use of nutraceutical molecules in migraine management.

Results

Available good quality data support the use of certain nutraceuticals, in particular riboflavin, coenzyme Q10, magnesium, butterbur, feverfew, and omega-3 polyunsaturated fatty acids. Even if not supported by double blind studies, recently some prospective observational studies about fixed combination of nutraceuticals were performed. For instance, it is the case of a combination of coenzyme Q10, feverfew and magnesium for migraine prophylaxis: a prospective observational study. A double blind versus placebo study about the effect of a fixed combination of riboflavin, coenzyme Q10, feverfew, andrographis and magnesium for migraine prophylaxis is currently in progress.

Conclusions

Usually patients appreciate nutraceuticals more than traditional drugs, since they are regarded as safe and of efficacy not inferior to other pharmacological products. Available data seem to support this widespread belief, but some concerns about the regulation of nutraceuticals and quality of some products, still remain.

S49 Headaches and Algology (Pain Therapy)

M. Evangelista (maurizio.evangelista@unicatt.it)

Istituto di Anestesiologia, Rianimazione e Terapia del Dolore, Università Cattolica del Sacro Cuore, Roma, Italia

Contrary to what is generally thought of, headaches and algology (pain therapy) share many aspects.The first, and perhaps most important, aspect of sharing between headaches and chronic pain is the fact that both cause a negative impact on “quoad valetudinem” rather than “quoad vitam” [1]; in both cases it is possible to talk about under-sized and under-diagnosed diseases as well as primary health illnesses for the nation's health policy [2].Headaches and chronic non-oncological pain are two paradigms of chronic illness capable of generating enormous individual and social impact by disabling the sick person not only in the biological, but also in the psychological, professional, social and relational spheres. Both cause alterations in psychological equilibrium, secondary depression, loss of social and professional roles, which, in the most serious cases, can cause loss of work. Literature documents in both cases, headaches and chronic pain, a rise in direct costs but above all of the indirect ones with a huge burden of disease. Both are capable of generating a marked drop in the quality of life associated with a serious bio-psycho-social disability. Headaches and chronic pain, although distinct according to a topographical criterion, share many mechanisms and physiopathogenetic steps. One of the most current fields in which neurologists and pain therapists converge is the focus on neuroinflammation [3] and central sensitization[4], two key mechanism for triggering, maintaining, and subsequent perpetuation of pain: the pain as a symptom, filogenetically responsible for maintaining homeostasis of the organism against actual or potential damage, becomes unnecessary illness without any protective meaning. Another important shared pathogenetic passage is that of neuroimmune mechanisms, which interlink the immune system with the central nervous system[4]. Furthermore, numerous contribution to the scientific international literature highlight the need to modify the therapeutic approach, directing it towards a semeiotic criterion (pain phenothype: specific sign and symptoms of a certain type of pain in a specific moment), which is an epiphenomenon of underlyng pathogenetic mechanism, instead of basing it on a etiologic criterion[5]. This would enable a more appropriate prescription and greater efficiency, taking into primary consideration the possibility of getting back to everyday life rather than obtaining complete analgesia. In both cases, headaches and chronic pain, a therapeutic protocol should be effective as well as sustainable in terms of both biologic aspect (effectiveness/safety ratio) and acceptability (minimum interference with professional, relational and social life). All the above mentioned aspects are equally important but one of them can prevail over the others depending on patient characteristics and background. From that derives another shared aspect: the concept of personalized “dynamic” therapy, where the physician (neurologist or pain physician), once identified realistic objectives that the patient wants to achieve, has to define the best possible protocol basing on his expertise and on the avalaible treatments, as well as periodically re-evaluate the clinical trend in order to provide modifications or integrations to the therapy, if necessary [5]. In conclusion it can be stated that the aspects of sharing between headaches and chronic non-oncological pain are significantly greater than those that clearly divide them. this must therefore be an area where researchers’ efforts must converge to achieve the primary goal of recovering pain-related disability.

References

1. World Health Organization. International classification of functioning, disability and health (ICF). Geneva, World Health Organization, 2001

2. Steiner T.J Lifting the burden: The global campaign against headache. (2004) Lancet Neurology, 3 (4), pp. 204-205

3. Ru-Rong Ji Emerging targets in neuroinflammation-driven chronic pain. Nat Rev Drug Discov. 2014 Jul; 13(7)

4. Baron R Neuropathic pain: diagnosis, pathophysiological mechanisms, and treatment. Lancet Neurol. 2010 Aug;9(8):807-19. doi: 10.1016/S1474-4422(10)70143-5

5. Edwards RR Patient phenotyping in clinical trials of chronic pain treatments: IMMPACT recommendations. Pain. 2016 Sep;157(9):1851-71.

S50 Neuroimaging and headaches

Paola Sarchielli, Laura Bernetti

Headache Center, Neurologic Clinic, Ospedale Santa Maria della Misericordia, University of Perugia Perugia Italy

Headache is a common clinical feature in neurological patients .Usually, neuroimaging is unnecessary in patients with episodic migraine or tension type headache with typical headache features and with a normal neurological examination. These patients do not have a higher probability of a relevant brain pathology compared to the general population.

A recent study, however, reported that neuroimaging is routinely ordered in outpatient headache even if guidelines specifically recommend against their use. In the same study, after 5 years, a patient with a new migraine has a 40% chance of receiving a neuroimaging examination[1].

Brain MRI with detailed study of the pituitary area and cavernous sinus, is recommended for all trigeminal autonomic cephalalgias TACs. Sometimes additional scanning of intracranial/cervical vasculature and/or the sellar/orbital/(para)nasal region are needed to exclude underlying pathological conditions [2].

Neuroimaging should be considered in patients presenting with atypical headache features, a new onset headache, change in previously headache pattern, headache abruptly reaching the peak level, headache changing with posture, headache awakening the patient, or precipitated by physical activity or Valsalva manoeuvre and abnormal neurological examination. Other condition for which MRI is recommended are: first onset of headache ≥50 years of age, trauma, fever, seizures, history of malignancy, history of HIV or active infections, and prior history of stroke or intracranial bleeding [2, 3].

A recent consensus recommends brain MRI for the case of migraine with aura that persists on one side or in brainstem aura. Persistent aura without infarction and migrainous infarction also require brain MRI, MRA and MRV. According the same consensus, fFor primary cough headache, exercise headache, headache associated with sexual activity, thunderclap headache and hypnic headache apart from brain MRI additional tests may be required [3].

Particularly in emergency room it is mandatory to exclude a secondary headache that requires special attention and further diagnostic workup. A careful patient history should be collected and additional ‘red flags’ should be detected at the physical examination to identify patients which can benefit of a MRI or CT scan to detect significant brain pathology. and make a correct diagnosis and receive an adequate and prompt therapeutic intervention.

CT scan is the first line neuroimaging examination. MRI offers a greater resolution and discrimination and might therefore be the preferred method of choice in non acute headache. In addition, radiation due to CT scanning may be avoided

Neuroimaging non conventional techniques are of little or no value in the clinical setting .but may contribute greatly to increasing understanding of the pathogenesis of primary headaches.

References

1. Callaghan BC, Kerber KA, Pace RJ, Skolarus L,Cooper W, Burke JF.Headache neuroimaging: Routine testing when guidelines recommend against them. Cephalalgia. 2015 Nov;35; 1144-52.

2. Sandrini G, Friberg L, Coppola G, Janig W, Jensen R, Kruit M, et al. europhysiological tests and neuroimaging procedures in non-acute headache (2nd edition) Eur J Neurol. 2011;18(3):373–81.

3. Mitsikostas DD, Ashina M, Craven A, Diener HC, Goadsby PJ, Ferrari MD et al.; EHF committee. European Headache Federation consensus on technical investigation for primary headachedisorders. J Headache Pain. 2015;17:5.

S51 Risk factors for chronic migraine

Cristina Tassorelli1,2, Grazia Sances1, Sara Bottiroli1, Michele Viana1, Natascia Ghiotto1, Marta Allena1, Giorgio Sandrini1,2, Giuseppe Nappi1

1Headache Science Center (HSC), C. Mondino National Institute of Neurology Foundation, Pavia, Italy; 2Dept of Brain and Behavioural Sciences, University of Pavia, Italy
Correspondence: Cristina Tassorelli (cristina.tassorelli@unipv.it)

Migraine frequency fluctuates over time. Chronic migraine is defined by the occurrence of headache on more than 15 days/month for at least 3 months. Chronic migraine affects 1–2% of the general population, and about 8% of patients with migraine, with an annual conversion rate of about 3%. In the literature, the most important recognized factors associated to chronic migraine are overuse of acute migraine medication, ineffective acute treatment, obesity, depression, presence of allodynia and stressful life events. These latter seem in particular relevant not only incidentally, as a precipitating/aggravating factor in the short term, but, most importantly and interestingly, as potential epigenetic modulators of disease severity over time. Other factors reported in studies are age, female sex and low educational status. Very recently, a large population study suggested that the presence of additional noncephalic pain site is a risk factor for migraine chronification.

For many of these factors the relationship with migraine chronification may however be bi-directional. For instance, in the case of depression, it is possible that depression may negatively affect the response of migraine to acute and prophylactic treatments, but it is also true the opposite: i.e. the recurrence of disabling headache attacks may alter the psychological well-being of a normothymic subject, thus leading to mood alterations. In the case of obesity, the association with chronic migraine may simply be ascribed to the effect of fat tissue in drug distribution.

Beside and beyond the putative biological factors that may cause a worsening of disease, several lines of evidence suggest that the progression from episodic to chronic migraine is associated to a progressive increase and stabilization of functional and anatomical changes associated to chronic sensitization. In this frame, it appears obvious that an additional cause for chronic migraine is quite likely represented by the low rate of prescription of preventive medications. According to the American Migraine Prevalence and Prevention Study, nearly 40% of migraine sufferers should be considered for preventive migraine therapy, while only 13% of all patients with migraine currently use preventive therapy to control their attacks. The underutilization of preventive drugs has several explanations ranging from drug-associated issues (limited efficacy, poor tolerability profile) to education of practitioners, pharmacists and patients, and it also involve the limited access to qualified care. Underutilization of preventative drugs also translate into a higher recourse to acute drugs, thus feeding on a vicious cycle that leads to negative consequences.

Conflicts of interests

CT has participated in advisory boards for Allergan and electroCore; she has lectured at symposia sponsored by Allergan; she is PI or collaborator in clinical trials sponsored by Alder, electroCore, Eli-Lilly and Teva. She has received grants from the European Commission, the Italian Ministry of Health and the Italian Ministry of University

References

Scher AI, Buse DC, Fanning KM, Kelly AM, Franznick DA, Adams AM, Lipton RB. Comorbid pain and migraine chronicity: The Chronic Migraine Epidemiology and Outcomes Study. Neurology. 2017 Aug 1;89(5):461-468. 1.

Silberstein SD, Diamond S, Loder E, et al. Prevalence of migraine sufferers who are candidates for preventive therapy: results from the American migraine study (AMPP) study. Headache 2005; 45: 770– 771.

Tassorelli C, Jensen R, Allena M, De Icco R, Katsarava Z, Miguel Lainez J, Leston JA, Fadic R, Spadafora S, Pagani M, Nappi G; COMOESTAS Consortium. The added value of an electronic monitoring and alerting system in the management of medication-overuse headache: A controlled multicentre study. Cephalalgia. 2016 [Epub ahead of print]

S52 Comorbidities in primary headaches

Antonio Carolei1,2, Cindy Tiseo1, Diana Degan1

1 Institute of Neurology, Department of Applied Clinical Sciences and Biotechnology, University of L’Aquila, via Vetoio, 67100 L’Aquila, Italy; 2 Department of Neurology and Stroke Unit, Avezzano Hospital, 67051, Avezzano, Italy
Correspondence: Antonio Carolei (antonio.carolei@univaq.it)

According to the International Classification of Headache Disorders, 3rd edition (beta version) [1], primary headaches are classified as “migraine”, “tension-type headache”, “trigeminal autonomic cephalalgia”, and “other primary headache disorders”. To date, the majority of clinical studies concerning primary headaches and their comorbidities are focused on migraine. Comorbidities of migraine may include neurological and psychiatric conditions, as mood disorders (depression, mania, anxiety, panic attacks), epilepsy, essential tremor, stroke, and the presence of white matter abnormalities [2]. Particularly, a complex and bidirectional relation between migraine and stroke has been described, including migraine as a risk factor for cerebral ischemia, migraine caused by cerebral ischemia, migraine mimicking cerebral ischemia, migraine and cerebral ischemia sharing a common cause, and migraine associated with subclinical vascular brain lesions [2]. A recent meta-analysis pointed out that migraine is associated with increased ischemic stroke risk [3], and according to a systematic review and meta-analysis [4] the risk of hemorrhagic stroke in migraineurs is increased with respect to non-migraineurs. Besides, the risk of transient ischemic attack seems to be increased in migraineurs, although this issue has not been extensively investigated [5]. A recent systematic review and meta-analysis also describes an increased risk of myocardial infarction and angina in migraineurs compared to non-migraineurs [6]. Concerning the association between migraine and vascular risk factors (arterial hypertension, diabetes mellitus, dyslipidemia, obesity, alcohol consumption, family history of cardiovascular disease), a recent review [7] showed no solid evidence of an increased burden of conventional vascular risk factors in migraineurs, with the only exceptions of dyslipidemia and cigarette smoking, while a systematic review and meta-analysis regarding migraine and body mass index categories [8] found an increased risk of having migraine in underweight subjects and in obese women as compared with normal-weight subjects. Few studies investigated the comorbidities of tension-type headache (TTH), despite the fact that tension-type headache (TTH) is highly prevalent, and may be as debilitating as migraine [9]. It is noteworthy that, according to a review, TTH is associated with increased rate of affective distress [9]. Furthermore, some medical disorders may worsen a preexisting TTH, and it has been described the comorbidity of TTH with psychiatric disorders and fibromyalgia [10].

References

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. Sacco S, Olivieri L, Bastianello S, Carolei A. Comorbid neuropathologies in migraine. J Headache Pain. 2006;7:222-230.

3. Spector JT, Kahn SR, Jones MR, Jayakumar M, Dalal D, Nazarian S. Migraine headache and ischemic stroke risk: an updated meta-analysis. Am J Med. 2010; 123:612-624.

4. Sacco S, Ornello R, Ripa P, Pistoia F, Carolei A. Migraine and hemorrhagic stroke: a meta-analysis. Stroke. 2013; 44:3032-3038.

5. Sacco S, Kurth T. Migraine and the risk for stroke and cardiovascular disease. Curr Cardiol Rep. 2014;16:524.

6. Sacco S, Ornello R, Ripa p, Tiseo C, Degan D, Pistoia F, Carolei A. Migraine and risk of ischaemic heart disease: a systematic review and meta-analysis of observational studies. Eur J Neurol. 2015; 22:1001-1011.

7. Sacco S, Degan D, Carolei A. Conventional vascular risk factors: Their role in the association between migraine and cardiovascular diseases. Cephalalgia. 2015; 35:146-164.

8. Ornello R, Ripa P, Pistoia F, Degan D, Tiseo C, Carolei A, Sacco S. Migraine and body mass index categories: a systematic review and meta-analysis of observational studies. J Headache Pain. 2015;16:27.

9. Heckman BD, Holroyd KA. Tension-type headache and psychiatric comorbidity. Curr Pain Headache Rep. 2006;10:439-447.

10. Sacco S, Ricci S, Carolei A. Tension-type headache and systemic medical disorders. Curr Pain Headache Rep. 2011;15:438-443.

S53 Headeache in the Emergency Department

Vittorio Di Piero (vittorio.dipiero@uniroma1.it)

Department of Neurology and Psychiatry, “Sapienza” - University of Rome, Rome, Italy

Differentiating patients with life-threatening headaches from the overwhelming majority with primary headaches (eg migraine, tension or cluster headache) is an important issue in emergency department (ED). Patients with non-traumatic headaches are up to 4.5 per cent of adults looking for emergency visits (Torelli, 2010). Of these patients, only 20% had a secondary headache requiring diagnosis and hospitalization (Pari, 2015). On the other hand, 80% of these patients have a primary form, requiring evaluation and outpatient treatment. These numbers seem to remain constant in Western countries (Ramirez-Lassepas, 1997; Kowalski, 2004; Cvetkovic, 2007; Gaughran, 2014).

Primary headaches still pose an open challenge in the ED because the failure to recognize a secondary headache could cause potentially fatal consequences. Unfortunately, to date, there is still no a standard diagnostic procedure for headache in emergency conditions; although according to the diagnostic guidelines there are red flags that could help in the process, the positive predictive value of each severity indicator is not yet determined.

The problem of poor diagnostic sensitivity was attributed to IHCD-3 criteria rigidity in relation to primary headache diagnosis in emergency setting (Dutto, 2009, Swadron, 2010). Attempting to overcome the primary headache diagnostic problem in ED, the Canadian Emergency Association proposed simplified IHS criteria to be easily implemented in the ED environment (Ducharme, 1999). Alternatively, a different standardized work-up has been proposed for the most frequent headache scenarios in ED (Cortelli, 2004; Dutto, 2009).

A careful history and physical examination remain the most important part of the assessment of the headache patient; they enable the clinician to determine whether the patient is at significant risk for a dangerous cause of their symptoms and what additional workup is necessary. This presentation will discuss how to approach adults with headache in ED with an emphasis on those features that characterize high-risk headaches.

S54 Migraine without aura, arthrogenic and myofascial cervical afferents: role of EBM physiotherapy

Firas Mourad1,2,3(firas.mourad@me.com)

1“Tor Vergata” Roma University, Roma, Italy; 2Alumno de Doctorado, Escuela Internacional de Doctorado, Universidad Rey Juan Carlos, Alcorcon, Madrid, Spain; 3PHYSIOPOWER, viale Duca degli Abruzzi 107, Brescia, 25124, Italy

Headaches are one of the most disabling disorders [1]. That is, 50% of general population suffer from headache (HA) during any given year; moreover, 90% report a lifetime history of HA [1, 2].

Migraine is one of the most common type of headache with an estimated prevalence of 10% [3] of the general population.

The International Headache Society (IHS) classify Migraine as a primary headache. That is, the 3rd edition of the International Classification of Headache Disorders (ICHD-III) describes also the diagnostic criteria of each headache disorder types. Interestingly, Migraine and Cervicogenic Headache (CGH) share similarities in these criteria and clinical presentation. Moreover, Neck Pain associated disorders (NAD) is a very common presentation in Migraine population [4]. Thus, the muscolokeletal contribution in Primary Headaches is still debate in the literature [5]. Moreover, recent knowledge suggests that different clinical headache phenotypes arising from a common pathophysiology rather than an independent disorder [6]. That is, in the most prevalent headaches disorders (i.e. TTH, Migraine, CGH) the ascending pathway of trigeminovascular system and Trigemino Cervical Nucleus (TCN) play a primary role in the head | face pain etiopathogenesis [7, 8]. In this presentation, the role of the musculoskeletal inputs in primary headaches it will be provided. Moreover, evidences of the effectiveness of a manual therapy management provided by a physiotherapist and its integration in a multidisciplinary team it will be discussed.

References

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

2. Steiner TJ, Stovner LJ, Katsarava Z, Lainez JM, Lampl C, Lanteri-Minet M et al. The impact of headache in Europe: principal results of the Eurolight project. J Headache Pain. 2014;15:31. doi:10.1186/1129-2377-15-31.

3. Pietrobon D, Striessnig J. Neurobiology of migraine. Nat Rev Neurosci. 2003;4(5):386-98. doi:10.1038/nrn1102.

4. 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.

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. Cady RK. The convergence hypothesis. Headache. 2007;47 Suppl 1:S44-51. doi:10.1111/j.1526- 4610.2007.00676.x.

7. Noseda R, Burstein R. Migraine pathophysiology: anatomy of the trigeminovascular pathway and associated neurological symptoms, CSD, sensitization and modulation of pain. Pain. 2013;154 Suppl 1. doi:10.1016/j.pain.2013.07.021.

8. Noseda R, Burstein R. Migraine pathophysiology: anatomy of the trigeminovascular pathway and associated neurological symptoms, cortical spreading depression, sensitization, and modulation of pain. Pain. 2013;154 Suppl 1:S44-53. doi:10.1016/j.pain.2013.07.021.

S55 OnabotulinumtoxinA for migraine treatment

Andrea Negro1,2 (andrea.negro@uniroma1.it)

1Regional Referral Headache Centre, Sant'Andrea Hospital, Via di Grottarossa 1035-1039, 00191; 2Department of Clinical and Molecular Medicine, Sapienza University of Rome, Italy

Since 2010 the armamentarium of preventative drugs for chronic migraine (CM) has become wider with the introduction of OnabotulinumtoxinA (Botox®). The European Headache Federation recognized the value of OnabotulinumtoxinA suggesting that, before labeling a patient as affected by refractory CM, a proper treatment with this drug needs to be completed [1]. In the last years several real-life prospective studies provided further evidence in clinical setting of OnabotulinumtoxinA 155-195 U efficacy for the headache prophylaxis in CM complicated by medication overuse headache (MOH) [2]. Recently we published the results of a prospective study on the long-term (2 years) efficacy and safety of a single dose of OnabotulinumtoxinA (155 or 195 U) in patients with CM plus MOH had failed previous preventative drugs and detoxification attempts [3]. Both the doses were effective and equally safe, but 195 U was more effective than 155 U in reducing headache days, migraine days, pain medication intake days and Headache Impact Test (HIT)-6 score. Even more, the 195 U dose superior efficacy was evident since the first injection and maintained over all the study period of 24 months. Interestingly we observed a progressive improvement in all the efficacy measures during the 2 years of follow-up with both the doses and significantly more with 195 U. Sometime a response appears only after the second or third injections. For this reason in selected cases can be useful to temporarily continue an oral preventative agent. CM patients close to developing MOH, patients with high frequency episodic migraine (HFEM), and those already abusing of drugs require special attention and maybe an be an “early treatment”. The NICE guidelines recommend OnabotulinumtoxinA only for patients who have already tried at least three different preventative drug treatments that have not worked. The chance to use it as first-line preventative treatment may shorten the period of chronicity and eventually prevent the developing of MOH. Another early use of OnabotulinumtoxinA could be in patients with HFEM. Several studies conducted before OnabotulinumtoxinA approval shown that it is ineffective in patients with episodic migraine [4]. Those studies had important limitations as range doses and injection paradigm. Furthermore, the population enrolled was represented in the majority by patients with low frequency episodic migraine (an average of 6-7 attacks per month). Interestingly post hoc analyses including episodic migraine patients with a greater mean frequency of headache days (≥12 and ≤15) suggested that they have a more robust response to OnabotulinumtoxinA [4].

References

1. Martelletti P, Katsarava Z, Lampl C, Magis D, Bendtsen L, Negro A, Russell MB, Mitsikostas DD, Jensen RH. Refractory chronic migraine: a consensus statement on clinical definition from the European headache federation. J Headache Pain 2014;28;15:47.

2. Negro A, Curto M, Lionetto L, Guerzoni S, Pini LA, Martelletti P. A critical evaluation on MOH current treatments. Curr Treat Options Neurol. 15;19(9):32.

3. Negro A, Curto M, Lionetto L, Martelletti P. A two years open-label prospective study of OnabotulinumtoxinA 195 U in medication overuse headache: a real-world experience. J Headache Pain 2015;17:1.

4. Shuhendler AJ, Lee S, Siu M, Ondovcik S, Lam K, Alabdullatif A, Zhang X, Machado M, Einarson TR. Efficacy of botulinum toxin type A for the prophylaxis of episodic migraine headaches: a meta-analysis of randomized, double-blind, placebo-controlled trials. Pharmacotherapy 2009;29:784–91.

S56 Trigeminal autonomic cephalalgias (TACs)

Ferdinando Maggioni (ferdinando.maggioni@unipd.it)

Headache Centre, Department of Neurosciences, University of Padua, Italy

Trigeminal autonomic cephalalgias (TACs) are a group of primary headaches comprehending the following syndromes: episodic and chronic cluster headache (CH), episodic and chronic paroxysmal hemicrania (PH), short-lasting unilateral neuralgiform headache attacks, and hemicrania continua(HC) [1]. Their phenotypes are similar and attack duration is the main feature distinguishing the first three TACs. An accurate diagnosis is important because of their different response to treatments. Among TACs, CH is most common; however TACs are approximately at least 100 times less common than migraine. CH prevalence in adults is < 1% and interests specially the male population. CH typically occurs at the same time of the day, from once to eight times per day, and in the same period of the year. CH is featured by severe unilateral peri-orbital and/ or temporal pain lasting from 15 to 180 minutes if untreated, associated with at least one autonomic symptom (conjunctival injection, lacrimation, nasal congestion, rhinorrhea, facial sweating, miosis, ptosis and eyelid edema). Trigger factors can include alcohol, volatile chemicals or a warm environment (3). Acute therapy includes the use of oxygen at a rate of 12-15L/min for at least 15 minutes and triptans. Controlled trials have investigated the efficacy of subcutaneous sumatriptan, nasal sumatriptan, and nasal zolmitriptan. When a preventive medication is required, verapamil is the reference treatment. PH attack features are characterized by unilateral, often stabbing, headaches, shorter and more frequent than in cluster headaches. PH is responsive to treatment with indomethacin. Indomethacin dosages ranges from 25 to 75 mg, three times a day. SUNCT-SUNA attacks are very short in duration (seconds to minutes), triggered by touching the face or chewing, with associated autonomic features and occur up to hundreds of times per day. SUNCT-SUNA most often responds to lamotrigine, limited the evidences for topiramate, gabapentin, carbamazepine, duloxetine and oxcarbazepine. In HC, clinical attack features have been reported as unilateral, side-locked continuous pain (although interrupted by frequent severe exacerbations), associated with autonomic symptoms and responsive to indomethacin.

Therapeutic options in TACs are limited. In many patients the preventive treatment does not help to control attack frequency, or the acute drugs are not well tolerated or are contraindicated. For these reasons, after the discovery of the central role of the hypothalamus in TACs pathogenesis, neuromodulation techniques started. After the results obtained with hypothalamic deep brain stimulation in CH, other peripheral neuromodulation targets (occipital nerves, spinal cord, sphenopalatine ganglion, vagus nerve) were tried in the management of refractory CH and other TACs.

References

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

2. Nesbitt AD, Goadsby PJ: Cluster Headache. Br Med J 2012 344:e2407.

3. Lainez M, Guillam_E. Cluster Headache and Other TACs: Pathophysiology and Neurostimulation Options. Headache 2017; 327-334.

S57 Chronic Headaches Cefalee Croniche

Grazia Sances1, Sara Bottiroli1, Michele Viana1, Natascia Ghiotto1, Elena Guaschino1, Marta Allena1, Cristina Tassorelli1-2

1Headache Science Center (HSC), C. Mondino National Institute of Neurology Foundation, Pavia, Italy; 2Dept of Brain and Behavioural Sciences, University of Pavia, Italy
Correspondence: Grazia Sances (grazia.sances@mondino.it)

Chronic headaches are a relevant health problem characterized by significant disability, poor quality of life and high economic burden (1). The most common forms include chronic migraine (CM) and medication overuse headache (MOH), which are frequently associated, given that the majority of CM sufferers do overuse acute medications (CM with MO). Chronic headaches represent a challenge for physicians, given their frequent resistance to therapies, risk of relapse and associated comorbidities. Their management includes several steps aimed to: 1) make a proper diagnosis excluding secondary forms; 2) identify exacerbating factors; 3) treat comorbidities; 4) identify and address medication overuse; 5) establish a therapeutic agreement with patient; 6) define an integrated care approach. Patient-history collection is crucial for defining headache onset and its life-long course, chronicization factors, and outcomes of previous therapies (acute and prophylactic).

Overused drug discontinuation is the first approach for MOH and it can be achieved via multiple modalities - in-patient or out-patient withdrawal procedures, advice alone – depending on several headache-associated or patient-associated factors. During withdrawal, adequate care is required to help the patient to go through the treatment phases, given the frequent occurrence of headache recrudescence.

Headache diaries represent useful tools in monitoring attacks frequency, detecting medication overuse, checking therapies outcomes, and assessing disability improvements. A relevant problem in MOH is the risk of relapse into overuse after successful withdrawal. There are only few controlled pharmacological trials on the management of MO in CM, which does not allow to derive precise figures on the risk of relapse into MO associated to specific therapies. Furthermore, the relapse risk is also influenced by psychological and clinical comorbidities. For instance, mood and personality disorders (e.g., anxiety, depression, obsessive-compulsive personality, or addictive behavior) are very common in patients with CM with MO. Psychological factors indeed seem to play a crucial role in predicting the outcome (e.g., reduction in headache attacks and medication intake or relapse into overuse) of detoxification and should be considered when treating these patients (2,3). The presence of other pain-syndrome comorbidities (e.g., fibromyalgia) can further adversely affect treatment response.

The pivotal role in the management of CM with MO is the “physician-patient alliance” deriving from the active involvement of the patient in all phases of her/his health-care management through a comprehensive rehabilitation counseling. Such a management is not limited to the earliest stages of treatment (diagnosis, therapies, detoxification), being very important also when the patients resume their everyday life (4). It is important to prevent unrealistic expectations (e.g., complete healing) and identify intermediate steps. In conclusion, the complete management of CM and MOH patients derives from an array of synergistic and multidisciplinary interventions aimed to improve patient’s quality of life, response to treatments and clinical outcome.

Conflicts of interests

None

References

1. Linde M, Gustavsson A, Stovner LJ, Steiner TJ, Barré J, Katsarava Z, Lainez JM, Lampl C, Lantéri-Minet M, Rastenyte D, Ruiz de la Torre E, Tassorelli C, Andrée C. The cost of headache disorders in Europe: the Eurolight project. Eur J Neurol. 2012 May;19(5):703-11.

2. Bottiroli S, Allena M, Sances G, De Icco R, Avenali M, Fadic R, Katsarava Z, Lainez MJ, Goicochea MT, Jensen RH, Nappi G, Tassorelli C; Comoestas Consortium. Changes in anxiety and depression symptoms associated to the outcome of MOH: A post-hoc analysis of the Comoestas Project. Cephalalgia. 2017 Jan [Epub ahead of print]

3. Bottiroli S, Viana M, Sances G, et al. Psychological factors associated to failure of detoxification treatment in chronic headache associated with medication overuse. Cephalalgia 2016; 36: 1356-1365.

4. Tassorelli C, Jensen R, Allena M, De Icco R, Sances G, Katsarava Z, Lainez M, Leston J, Fadic R, Spadafora S, Pagani M, Nappi G; the COMOESTAS Consortium. A consensus protocol for the management of medication-overuse headache: Evaluation in a multicentric, multinational study. Cephalalgia. 2014 Aug; 34(9):645-655.

S58 Headache in the elderly

Carlo Lisotto

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

Background

Headache prevalence is age-dependent and decreases progressively over time, especially starting from the age of 55-60. The incidence of primary headaches declines, whereas secondary headaches tend to occur more frequently with increasing age [1]. Although the prevalence of headache in the elderly is relevant, few studies have been conducted in patients over 65 so far.

Materials and Methods

The clinical records of 9075 consecutive outpatients aged over 18 referred to our Headache Centre from 2000 to 2015 were reviewed. Patients were diagnosed based on The International Classification of Headache Disorders, 3rd edition (beta version) criteria [2].

Results

Out of 9075 patients, a total of 469 (5.2%) were over 65 at their first observation. Primary headaches were diagnosed in 365 patients (80.5%, mean age 70.1 ± 4.7), secondary headaches in 64 cases (11.2%, mean age 74.1 ± 6.1), whereas painful cranial neuropathies and other facial pains were identified in 40 subjects (8.3%, mean age 77.1 ± 5.9). In the primary headache group the most common disorders were migraine without aura (26.0%), chronic tension-type headache (23.0%) and chronic migraine (20.3%). As for patients with migraine and chronic tension-type headache, the onset of headache occurred in most cases before 45, in particular in chronic migraine (89.2%), while in migraine with aura patients the headache started over 45 in 55.6% of cases. Secondary headaches were represented above all by cervicogenic headache, frequently associated with tension-type headache. Among cranial neuropathies, trigeminal neuralgia was by far the most commonly diagnosed headache.

Conclusions

In our population of elderly headache patients, migraine without aura, chronic tension-type headache and chronic migraine accounted for 61.3% of the total cases. There was a large majority of females in all the subgroups of headaches. In cluster headache, considered as a typical disorder of young men, we found indeed a slight preponderance of females. Migraine with aura not infrequently occurs in the elderly; this headache, as well as cluster headache, can even start, even rarely, over 65 and in such cases a differential diagnosis with a possible secondary disorder is mandatory. Among patients with chronic headaches, a medication overuse was found more frequently in chronic migraine (71.6%), than in chronic tension-type headache (33.3%). The choice of headache treatment is challenging, since specific guidelines are lacking and also because elderly patients commonly present with comorbidities. Further clinic-based studies should be carried out, with the aim to define possible therapeutic guidelines for these patients.

References

1. Schwaiger J, Kiechl S, Seppi K, Sawires M, Stockner H, Erlacher T, Mairhofer ML, Niederkofler H, Rungger G, Gasperi A, Poewe W, Willeit J. Prevalence of primary headaches and cranial neuralgias in men and women aged 55-94 years (Bruneck Study). Cephalalgia 2009;29: 179-187.

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. Lisotto C, Mainardi F, Maggioni F, Dainese F, Zanchin G. Headache in the elderly: a clinical study. J Headache Pain. 2004; 5:36-41.

EHF POSTER PRESENTATIONS

P1 Anti-CGRP monoclonal antibodies for the treatment of chronic migraine: an overview of available results and comparison with the currently used prophylactics

Fenne Vandervorst, Laura Van Deun, Jacques De Keyser, Jan Versijpt

Department of Neurology, University Hospital Brussels, Brussels, Belgium
Correspondence: Fenne Vandervorst

Treatment of patients with chronic migraine remains challenging in daily clinical practice due to several factors: variable tolerability of the currently available medical treatments, frequent co-existence of medication overuse and lack of disease specific treatment strategies.

At this stage, Topiramate and OnabotulinumtoxinA are the only evidence based treatments for chronic migraine, of which only OnabotulinumtoxinA is FDA-approved.

Therefore, anti-CGRP monoclonal antibodies are considered an attractive treatment option for this patient population. Multiple studies with anti-CGRP monoclonal antibodies for the treatment of chronic migraine were conducted and some are still ongoing.

Here, we present an early overview on currently available efficacy results of anti-CGRP monoclonal antibodies in the treatment of chronic migraine. Secondly, these results are compared to the results of the currently used prophylactics for chronic migraine.

At present results from two phase 2 and two phase 3 trials are available.

In order to analyse these early results next to the efficacy results of established prophylactics for chronic migraine the ‘change in monthly migraine days compared to placebo’ of each agent will be presented.

Results from 1863 patients with chronic migraine, treated with anti-CGRP monoclonal antibodies are now available, compared to 688 patients treated with OnabotulinumtoxinA and 185 patients treated with Topiramate.

The overall mean reduction of monthly migraine days (compared to placebo) for the anti-CGRP monoclonal antibodies is -2,05 days. For Topiramate and OnabotulinumtoxinA these values are respectively -1,79 and -2 days.

In conclusion, the first efficacy results of anti-CGRP monoclonal antibodies in the treatment of chronic migraine are promising and at least comparable with the effect sizes of both Topiramate and OnabotulinumtoxinA. Combined with the fact that the anti-CGRP monoclonal antibodies have, already at this stage with several trials still ongoing, the highest number of patients studied ánd given their excellent tolerability, these new agents are emerging, from a clinical point of view, as a promising treatment for chronic migraine.

P2 Biomarkers of inflammation in patients with Chronic Migraine after withdrawal from Medication Overuse: longitudinal changes and comparison with healthy subjects

Licia Grazzi1, Emanuela Sansone1, Alberto Raggi2, Matilde Leonardi2, Emilio Ciusani3, Elena Corsini3, Giovanni D’Andrea4, Andrea Bolner4, Francisco Salgado-García5, Frank Andrasik5, Domenico D’Amico1

1Headache and Neuroalgology Unit; Neurological Institute “C. Besta” IRCCS Foundation; Milan; 20133; Italy; 2Neurology, Public Health and Disability Unit; Neurological Institute “C. Besta” IRCCS Foundation; Milan; 20133; Italy; 3Laboratory of Clinical Pathology and Medical Genetic; Neurological Institute “C. Besta” IRCCS Foundation; Milan; 20133; Italy; 4Research & Innovation (R&I); Padua; 35121; Italy; 5Department of Psychology; University of Memphis; Memphis, TN; 38152; USA
Correspondence: Domenico D’Amico

Background

Chronic Migraine (CM) is characterized by more than 15 days/month for more than three months, and is frequently associated to the overuse of acute medications. In recent years, non-pharmacological treatments have been proposed and, among them, Mindfulness is one of the most promising1 and showed to be comparable to pharmacological prophylaxis2. It was also shown that patients undergoing pharmacological prophylaxis and Mindfulness sessions had similar baseline levels for biomarkers and in part underwent significant improvement3. Here we aim to address improvement in biomarkers by comparing results on patients with those of healthy controls.

Materials and methods

Two group of patients, one receiving pharmacological prophylaxis alone and one treated with six group session of Mindfulness-based training, were followed-up at 3, 6 and 12 months. We compared patients and control for white blood cell (WBC) count, neutrophils, total lymphocytes and lymphocyte subsets CD3, CD4, CD8, CD19 at each point with Mann-Whitney test.

Results

Data were available for 34 patients (17 per group: no differences were found cross-sectionally, and the longitudinal course was similar) and 34 controls. Compared to controls, patients reported higher baseline levels for WBC, neutrophils and lymphocyte subsets CD4. All levels, except lymphocyte subsets CD4, became similar to that of controls from the third month, and CD4 became comparable at six months from withdrawal.

Conclusions

Some biomarkers of inflammation were altered in patients with CM associated to medication overuse: from the third month after withdrawal patients show a reduction of inflammation that is maintained at 12 months. Pharmacological prophylaxis and Mindfulness showed comparable results.
Fig. 1 (abstract P2).

WBC Count (mean and 95% CI)

Fig. 2 (abstract P2).

Neutrophils (mean and 95% CI)

Fig. 3 (abstract P2).

CD4 Lymphocyte subset (mean and 95% CI)

Table 1 (abstract P2).

See text for description

 

WBC

Neutrophils

Lymphocytes

CD3

CD4

CD8

CD19

Healthy Controls

5732 [5299-6165]

3674 [3233-4010]

1836 [1703-1971]

1366 [1259-1473]

766 [703-829]

559 [486-632]

196 [171-222]

Patients-T0

7322 [6489-8156]

4801 [4120-5482]

2019 [1773-2265]

1577 [1364-1790]

1027 [869-1185]

568 [491-645]

219 [186-253]

P-value

.003

.006

.611

.362

.014

.949

.627

Patients-3M

6185 [5681-6690]

3639 [3263-4016]

1899 [1730-2267]

1475 [1332-1617]

933 [841-1026]

550 [481-619]

196 [166-226]

P-value

.197

.950

.677

.253

.009

.827

.663

Patients-6M

6226 [5544-6908]

3762 [3226-4297]

1829 [1659-1998]

1399 [1263-1535]

890 [779-1001]

525 [475-576]

190 [156-224]

P-value

.517

.885

.820

.969

.112

.748

.264

Patients-12M

6182 [5601-6763]

3758 [3266-4250]

1802 [1639-1965]

1367 [1230-1504]

875 [781-969]

515 [461-570]

186 [157-214]

P-value

.373

.890

.598

.729

.101

.480

.278

References

1) Andrasik F, et al. Mindfulness and headache: A “new” old treatment, with new findings. Cephalalgia. 2016;36(12):1192-1205.

2) Grazzi L, et al. Mindfulness and pharmacological prophylaxis after withdrawal from medication overuse in patients with Chronic Migraine: an effectiveness trial with a one-year follow-up. J Headache Pain. 2017;18(1):15.

3) Grazzi L, et al. Mindfulness and pharmacological prophylaxis have comparable effect on biomarkers of inflammation and clinical indexes in chronic migraine with medication overuse: results at 12 months after withdrawal. Neurol Sci 2017;38(Suppl 1):173-175.

P3 Outcome of microvascular decompression in trigeminal neuralgia is highly dependent on sex and degree of neurovascular contact – A prospective systematic study using independent assessors

Tone B. Heinskou1, Per Rochat2, Stine Maarbjerg1, Frauke Wolfram3, Jannick Brennum2, Jes Olesen1, Lars Bendtsen1

1Danish Headache Center, Department of Neurology, Rigshospitalet. Faculty of Health and Medical Sciences, University of Copenhagen., Glostrup; 2Department of Neurosurgery, Rigshospitalet. Faculty of Health and Medical Sciences, University of Copenhagen., Copenhagen; 3Department of Diagnostics, Rigshospitalet. Faculty of Health and Medical Sciences, University of Copenhagen., Glostrup, Denmark
Correspondence: Tone B. Heinskou

Objectives: Microvascular decompression (MVD) is first choice neurosurgical treatment option in medically refractory trigeminal neuralgia patients with an MRI verified neurovascular contact (NVC). There is a lack of high-quality prospective, systematic studies, using independent assessors of outcome of the procedure. Here we aimed to evaluate whether sex and degree of NVC can predict outcome of MVD.

Methods: Clinical characteristics and outcome data were systematically recorded prospectively from consecutive trigeminal neuralgia patients, using standardized semi-structured interviews and schemes. A pre-surgical 3.0 Tesla MRI was performed to evaluate the degree of NVC blinded to symptomatic side. The patients were assessed before and 3, 6 and 12 months after MVD by a neurologist at the Danish Headache Center. Department of Neurosurgery had no influence on recording or evaluation of data. Data from a self-completed 12 months post-surgical questionnaire including items on pain intensity, complications and satisfaction, were also recorded. The primary outcome was pain relief according to the Barrow Neurological Institute pain score (BNI I-VB), Table 1. Secondary outcome was patient satisfaction.

Results: From May 2012 to February 2016, 27 men and 33 women had completed one year follow- up. Mean age at operation was 59.9 years (range 28-80 years). Mean duration of disease was 6.6 years (range 1-40 years). Thirty-three patients (55%) had NVC with morphological changes.

Forty-three (72%) patients had an excellent outcome defined as ‘no pain, no medication’ (BNI I). Nine (15%) patients had a good outcome, while eight patients (13%) had poor outcome.

At multiple logistic regression the odds ratio between NVC with displacement or atrophy of the trigeminal nerve and excellent outcome was 5.2 (95% CI 1.3 – 20.1, P = 0.0183) and the odds ratio between sex (male vs. female) and excellent outcome was 10.6 (95% CI 2.0 – 56.1, P = 0.0057). There was no significant interaction between sex and severe NVC (p = 0.56).

Conclusion: These high-quality prospective data using independent assessors demonstrate that patients with morphological changes of the trigeminal nerve and male sex have a considerably better chance of an excellent outcome of MVD. These data should guide patients and physicians in decision-making before neurosurgery.

P4 Headache Clinical Refractoriness

Christian Lampl

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

In the past years a unifying definition of refractory headache (rH) has been extensively discussed but, to date, has not been agreed upon. It is widely agreed, that refractoriness, for whatever category and disease, implies a high burden with tremendous impact in health related quality of life (HRQoL). Despite that fact, an overall accepted definition of rH would be more than important for managing and triaging patients to an appropriate level of care and for determining eligibility for epidemiological and clinical studies. What are the critical issues so far: (i) there is no standardized definition of rH; (ii) at the time of first diagnosis headache patients do not necessarily become refractory immediately, nor do they mandatorily remain refractory throughout the course of their disease; (iii) due to the necessity that most patients should be treated rapidly after diagnosis response to medication often is assessed without a pretreatment baseline and it remains unclear whether or not so-called refractory patients have had a substantial response to treatment; (iv) headache pain and associated symptoms are frequently intermittent, making this disease different from others that have been examined for treatment resistance; (v) the natural history is not known. For all these purposes the Board of the European Headache Federation (EHF) felt the need to develop new consensus criteria that define refractory chronic migraine (rCM) and refractory chronic cluster headache (rCCH). These new definitions of rCM and rCCH, which were agreed upon within the EHF, allows us to separate patients into categories of refractory and non-refractory, being important for clinicians, clinical and epidemiological trials.

References

1. Silberstein S, Dodick D, Pearlman S (2010) Defining the pharmacologically intractable headache for clinical trials and clinical practice. Headache 50:1499–1506

2. Schulman E, Lake A, Goadsby P, Peterlin BL, Siegel SE, Markley HG, Lipton RB (2008) Defining refractory migraine and refractory chronic migraine: proposed criteria. Headache 48:778–782

3. Stovner LJ, Hagen K, Jensen R, Katsarava Z, Lipton R, Scher A, Steiner T, Zwart JA (2007) The global burden of headache: a documentation of headache prevalence and disability worldwide. Cephalalgia 27:193–210

4. Goadsby PJ, Zanchin G, Geraud G, de Klippel N, Diaz-Insa S, Gobel H, Cunha L, Ivanoff N, Falques M, Fortea J (2008) Early vs. non-early intervention in acute migraine- ‘Act when Mild (AwM)’. A double-blind, placebo-controlled trial of almotriptan. Cephalalgia 28:383–391

P5 Sphenopalatine ganglion block using Tx360 device. First results in refractory chronic migraine in Spain

Jose M Sanchez, Maria Rico, Elena Ameijide, Maria Castanon

Hospital Universitario Central de Asturias, Neurology, Oviedo, Spain
Correspondence: Jose M Sanchez (jmsancheza@gmail.com)

Background

Despite current treatments 2-4 % of migraneurs become chronic (1). This is a very disabling condition leading to a high suffering and low quality of life (2). Inhibiting sphenopalatine ganglion (SPG) could reduce the frequency of the crisis (3), but its access is quite difficult requiring aggressive methods (4). Tx360 device is a nasal applicator made of plastic material easing the access to the SPG and the application of local anaesthetic in its vicinity with minor inconveniencies (5).

Materials and methods

Twelve blocks (three each week during four weeks), were done with Bupivacaine 0,5% (0,3 cc each nostril), using the Tx360 device. We evaluate at the end of the 12th block (four weeks), efficacy parameters (mean reduction of headache days and pain intensity in a visual analogue scale), impact (Headache Impact Test [HIT-6]), and quality of life (Migraine-Specific Quality of Life Questionary [MSQ]), tools. We also analysed 30% and 50% response rates.

Results

Nine patients refractories to habitual treatments were treated (2 M, 7 F; mean age 48,1 ± 16). There was analgesic abuse in 8. At the 12th block there were a significant reduction of mean headache days (17,6 vs. 25,8, p 0,034), pain intensity (5,4 vs. 8,1, p <0,001), and mean analgesic consumption (13,6 vs. 54,6, p <0,000002). There were also a significant reduction in mean HIT6 (57,85 vs. 66,9), and MSQ (40,14 vs. 57,22). Forty five per cent had a reduction ≥50% of headache days. There were no significant adverse events but minor and transient local discomfort.

Conclusions

Repetitive blocks of the SPG with the Tx360 device seem to be an effective treatment in chronic migraine, even with analgesic abuse, with only minor adverse events. These benefits were evident both in headache days and in quality of life measures. Although encouraging these results must be confirmed in a greater number of patients, and know how long they will last.

References

1. Buse DC, Manack AN, Fanning KM, Serrano D, Reed ML, Turkel CC, Lipton RB. (2012) Chronic migraine prevalence, disability, and sociodemographic factors: results from the American Migraine Prevalence and Prevention Study. Headache. 2012;52:1456–1470

2. Steiner TJ, Birbeck GL, Jensen RH, Katsarava Z, Stovner LJ, Martelletti P. Headache disorders are third cause of disability worldwide. J Headache Pain. 2015;16:58.

3. Narouze S, Kapural L, Casanova J, et al. Sphenopalatine ganglion radiofrequency ablation for the management of chronic cluster headache. Headache. 2009;49:571–577.

4. Candido KD, Massey ST, Sauer R, Darabad RR, Knezevic NN. A novel revisión to the classical transnasal topical sphenopalatine ganglion block for the treatment of headache and facial pain. Pain Physician. 2013;16:E769-78

5. Cady RK, Saper J, Dexter K, Cady RJ, Manley HR. Long-term efficacy of a double-blind, placebo-contolled, randomized study for repetitive sphenopalatine blockade with bupivacaine vs. saline with the Tx360 device for treatment of chronic migraine. Headache. 2015;55:529-42.

P6 Efficacy of erenumab (AMG 334) in chronic migraine patients with prior prophylactic treatment failure: Subgroup analysis of the phase 2, randomised, double-blind, placebo-controlled study

Messoud Ashina1, Stewart J Tepper2, Jan Lewis Brandes3, Uwe Reuter4, Guy P Boudreau5, David Dolezil6, Sunfa Cheng7, Dean Leonardi7, Robert A Lenz7, Jan Klatt8, Daniel D Mikol7

1Danish Headache Center and Department of Neurology, Rigshospitalet Glostrup, Faculty of Medical and Health Sciences, University of Copenhagen, Copenhagen, Denmark; 2Geisel School of Medicine at Dartmouth, Hanover, NH; 3Nashville Neuroscience Group and Vanderbilt University School of Neurology, Nashville, TN; 4Department of Neurology, Charité Universitätsmedizin Berlin, Berlin, Germany; 5Headache unit Neurology department University Hospital Center of Montreal Qc. Canada; 6DADO MEDICAL s.r.o., Prague Headache Center, Czech Republic; 7Amgen Inc., Thousand Oaks, CA; 8Novartis Pharma AG, Basel, Switzerland
Correspondence: Messoud Ashina (ashina@dadlnet.dk)

Background

Erenumab, a fully human monoclonal antibody, selectively targets the CGRP receptor. A phase 2, 12-week randomised, double-blind, placebo-controlled study demonstrated efficacy of erenumab (70 mg and 140 mg) in patients with chronic migraine (CM), with a safety profile comparable to placebo. We report a prespecified subgroup analysis on prior prophylactic treatment failure (≥1, ≥2 and never failed) due to lack of efficacy and/or poor tolerability.

Methods

Patients (N=667; aged ≥18–65 years) with CM (≥15 headache days/month; ≥8 migraine days) were randomised (2:2:3) to once-monthly subcutaneous erenumab 70 mg, 140 mg or placebo. Efficacy endpoints were change in monthly migraine days (MMD), achievement of ≥50% reduction in MMD, change in monthly acute migraine-specific medication treatment days, and change in cumulative monthly headache hours. Assessments compared weeks 9–12 to baseline. No correction for multiple comparisons was performed.

Results

With erenumab 70 mg and 140 mg, there were greater reductions at week 12 in MMD and more patients achieved ≥50% reduction in MMD versus placebo in all three subgroups. Moreover, greater reduction in monthly acute migraine-specific medication treatment days was observed with erenumab 70 mg and 140 mg in patients who previously failed prophylactic medications versus placebo. Cumulative monthly headache hours reduced with erenumab 140 mg versus placebo in patients who failed prophylactic medications. Notably, placebo effect was greatest in patients who had never failed a prophylactic medication. Across endpoints, reductions were greater with erenumab 140 mg than 70 mg.

Conclusion

Numerically, erenumab 140 mg showed better efficacy in patients with CM who previously failed ≥1 or ≥2 current standard of care prophylactic medication(s).

P7 Sequential presentation of ipsilateral supraorbital and lacrimal neuralgias in a patient

Chavarría Miranda, A.; Talavera De la Esperanza, B.; Martínez Pías, E.; Trigo López, J.; Gómez López de San Román, C.; Ruiz Piñero, M.; Pedraza Hueso, M.I.; Guerrero Peral, Á.L.; García Azorín, D

OBJECTIVE:

The first trigeminal nerve branch is divided in three main branches: lacrimal nerve (LN), frontal nerve, which divides into supraorbital (SON) and supratrochlear nerves and nasociliar nerve. We describe the case of a patient diagnosed of supraorbital nerve neuralgia who developed an ipsilateral lacrimal neuralgia.

PATIENT AND METHODS:

47-year-old woman with prior medical history of Crohn disease treated with Adalimumab and Azatioprine. She complained about a oppressive continuous pain, of 5/10 intensity according to Analogic Visual Scale circumscribed to the left supraciliar region, with 2-3 seconds length superimposed paroxysms of 8/10 intensity. In the physical examination we detected tenderness at the palpation of the supraorbital notch. She was treated by anesthetic lidocaine blockade successfully and was managed during 6 years with blockades every 3-10 months.

RESULTS:

In a regular consult she complained of a new oppressive pain of 6/10 intensity in the left superoexternal periorbital region, with 3 seconds stabbing paroxisms of 8/10 intensity. In the exam she presented pain at the palpation of lacrimal nerve and circumscribed hypoesthesia in the lacrimal nerve territory. We only performed SON blockade first but the superoexternal pain persisted, so we performed a specific lacrimal nerve blockade with pain cessation, confirming the diagnosis of Lacrimal Neuralgia. A facial, orbital and cranial CT did not show any abnormality.

CONCLUSSION:

Sequential presentation of pain in contiguous nervous branches in the absence of structural lesions supports the epicranial nature of the trigeminal terminal branches neuralgias.

Consent for publication: The authors declare that written informed consent was obtained for publication.

P8 Cognitive impairment in episodic and chronic migraineurs and tension-type headache suffers

A. Bianchi, R. Monastero, M. Davì, F. Brighina, C. Camarda

Department of Experimental Biomedicine and Clinical Neurosciences, University of Palermo, Italy
Correspondence: A. Bianchi (alessia.bianchi@unipa.it)

Background. Migraine and tension-type headache are highly prevalent brain disorders characterized by recurrent painful attacks that lead to a highly disabling condition, particularly when chronic. Headache suffers frequently reported cognitive deficits, nonetheless previously data regarding cognitive impairment are inconclusive. The aim of this hospital-based study was to compare cognitive performance in subjects affected by different headache types including: migraine without aura (MWA), chronic migraine (CM), tension type headache (TTH) and chronic tension type headache (CTTH).

Materials and methods. We studied 307 patients, 246 woman and 61 male consecutively referred to the Adult Headache Centre, Neurological Unit of the University of Palermo during a 2-year period. Headache diagnoses were established according to the ICHD-III criteria. Each patient carried out a comprehensive neuropsychological evaluation including: MiniMental – State Examination (MMSE), Rey Auditory Verbal Learning Test (episodic memory), Token Test (verbal comprehension), Frontal Assessment Battery (executive functioning), and Visual Search (selective attention). Impaired cognitive domains were computed according to age- and education Italian normative data (dichotomised variable of impaired versus not impaired). The presence of co-existing anxiety and depression was evaluated with the Hospital Anxiety and Depression Scale.

Results. In our sample mean age was 49,9±12,7 years for women (80%) and 50,8 ±14,07 years for men (20%) (Table 1). Mean age was higher in CTTH (55,8 ±13,7; p≤.0001). The most frequent form of headache was MWA (45%) followed by TTH (27,7%), CM (14%) and CTTH (13,7). The mean MMSE score was 28,2 ± 1,6 with no statistical difference between sex and headache types. Depression and anxiety were more frequent in female [HAD-A: 9,9 ± 4,5 versus 7,5 ± 4,4; p≤.0001) HAD-D (7,5 ± 3,9 versus 6,1 ± 3,9; p≤.0001)]. Sixty-one (19.9%) patients reported impairment in at least one cognitive domain; CTTH suffers reported the highest prevalence of cognitive deficits (28,6%), even it did not reach statistically significance (Table 2). Just one patient reported a praxis deficit. In our sample, after multiple logistic regression analysis, cognitive impairment seems not to be influenced by headache type even when data are adjusted by age and educational status.

Conclusion. Cognitive impairment is rather frequent in our hospital-based cohort. It was reported in about 20% of the population study, while the prevalence estimated in general population is about 5-6%. In our sample, cognitive deficits were more frequent in CTTH. Future research on bigger sample will evaluate cognitive performance in different headache types versus controls.
Table 1 (abstract P8).

Characteristics of study population

Study population n: 307

 

Number:

Percent

Sex

  

 Male

61

19,9%

 Female

246

80,1%

Age group (year-old)

 <21

5

1,6

 21 – 30

20

6,5

 31 – 40

38

12,4

 41 – 50

94

30,6

 51 – 60

86

28,0

 61 – 70

48

15,6

 ≥71

16

5,2

Headache type

 Migraine without aura

138

45

 Chronic Migrain

43

14,0

 Tension type headache

84

27,7

 Chronic tension type headache

42

13,7

Education (years of school

 0

3

1,0

 1– 5

85

27,7

 6– 8

104

33,9

 9– 13

79

25,7

 >13

36

11,7

Marital status

 Unmarried

44

14,3

 Married

234

76,2

 Divorced

29

9,4

Mean ± DS

 MMSE

28,2 ± 1,6

 HAD_A

9,4 ± 4,6

 HAD_D

7,2 ± 4,0

Table 2 (abstract P8).

Prevalence of impairment in different cognitive domains stratified by headache type

Prevalence of cognitive deficit n = 61

 

Prevalence of attentive deficit

Prevalence of esecutive deficit

Prevalence of language deficit

Prevalence of memory deficit

Prevalence of praxis deficit

Prevalence of cognitive deficit in ≥1 domain

Migraine without aura

11 (8%)

8 (5,8%)

2 (1.4%)

18 (13%)

0 (0,0%)

29 (21.0%)

Chronic Migrain

4 (9,3%)

2 (4,7%)

0 (0,0%)

4 (9,3%)

1 (2,3%)

6 (14.0%)

Tension type headache

7 (8,3%)

4 (8%)

2 (2,4%)

7 (8,3%)

0 (0,0%)

14 (16.7%)

Chronic tension type headache

5 (11,9%)

6 (14,3%)

2 (4.8%)

6 (14,3%)

0 (0,0%)

12 (28.6%)

Acknowledgements

Financial support: no specific financial support was received for this study.

References

1) Rist PM, Kurth T. Migraine and cognitive decline: a topical review. Headache. 2013 Apr; 53(4):589-98.

2) Gil-Gouveia R, Oliveira AG, Martins IP. Assessment of cognitive dysfunction during migraine attacks: a systematic review. J Neurol. 2015 Mar;262(3):654-65.

P9 A multicenter, prospective, randomized, open-label study to compare the efficacy, safety, and tolerability of onabotulinumtoxinA and topiramate for headache prophylaxis in adults with chronic migraine: the FORWARD study

John F. Rothrock1, Aubrey Manack Adams2, Esther Jo3, Xiang Zhao4, Andrew M. Blumenfeld5

1George Washington School of Medicine, Washington, DC, 20037, USA; 2Global Medical Affairs, Allergan plc, Irvine, CA, 92623-9534, USA; 3Bioststistics, Allergan plc, Irvine, CA, 92623-9534, USA; 4Statistics, Pharmaceutical Product Development, LLC, Austin TX, 78744, USA; 5Headache Center of Southern California, The Neurology Center, Carlsbad, CA, 92024, USA
Correspondence: John F. Rothrock (jrothrock@mfa.gwu.edu)

Background

To compare the efficacy, safety, and tolerability of onabotulinumtoxinA and topiramate for preventive treatment of chronic migraine (CM) in adults.

Materials and Methods

The FORWARD Study randomized adults with CM (1:1) to receive 155 U onabotulinumtoxinA every 12 weeks (±7 days) for 3 treatment cycles or topiramate 50-100 mg/day administered up to week 36. Patients who discontinued topiramate at any time were allowed the option of crossing-over to receive onabotulinumtoxinA at the next scheduled office visit (week 12 up to week 36; Fig. 1). The primary efficacy measure was a dichotomous variable (responder/nonresponder) defined as the proportion of patients with ≥50% reduction in headache days during the 28-day period before week 32 (weeks 29-32). A baseline last observation carried forward imputation method was utilized to impute missing data replacing the missing value with the baseline value if the responder rate was missing at week 32 for any reason. Adverse events (AEs) were monitored. Safety data include AEs from randomization and cross-over phases.

Results

282 patients were enrolled (onabotulinumtoxinA, n=140; topiramate, n=142) at 35 US sites. Patients were primarily female (n=239, 84.8%); mean (SD) baseline headache days (onabotulinumtoxinA, 22.1 [4.6]; topiramate, 21.8 [4.8]) were similar across treatment groups. 148 patients completed treatment as randomized (onabotulinumtoxinA, n=120 [85.7%]; topiramate, n=28 [19.7%]) through week 32. Primary reasons for withdrawal were ineffective treatment (onabotulinumtoxinA, n=7 [5.0%]; topiramate, n=28 [19.7%]) and AEs (onabotulinumtoxinA, n=5 [3.6%]; topiramate, n=72 [50.7%]). 80 topiramate patients crossed-over to onabotulinumtoxinA.

OnabotulinumtoxinA demonstrated significantly higher proportion of patients with ≥50% reduction in headache frequency compared to baseline vs topiramate (40.0% vs 12.0%, respectively; adjusted OR, 5.0 [95% CI, 2.7-9.2]; P<0.001) at the week-32 assessment.

AEs were reported by 45.5% of onabotulinumtoxinA and 76.8% of topiramate patients; serious AEs by 1.4% and 4.2%, respectively. Only sinusitis was reported in ≥5% of 220 patients receiving onabotulinumtoxinA at any time; a number of individual AEs were reported in ≥5% receiving topiramate (Table 1). Treatment-related AEs were reported by 17.3% of onabotulinumtoxinA and 69.0% of topiramate patients. One serious AE (nephrolithiasis) was reported as related to topiramate.

Conclusions

In this open-label study, preventive treatment of adults with CM with onabotulinumtoxinA demonstrated a more favorable tolerability profile than topiramate. When using imputation methods accounting for differences in discontinuation rates, onabotulinumtoxinA was more effective than topiramate based on ≥50% responder rates and headache day reduction.
Fig. 1 (abstract P9).

FORWARD Study methodology

Table 1 (abstract P9).

Adverse events in ≥5% of Patients in Any Treatment Group

Patients with Adverse Event (AE), % (n)

OnabotulinumtoxinA (n=220)

Topiramate

(n=142)

Total

(N=282)

Switched to OnabotulinumtoxinA

(n=80)

Any AE

45.5 (100)

76.8 (109)

62.4 (176)

41.3 (33)

 Cognitive disorder

0.5 (1)

12.7 (18)

6.4 (18)

1.3 (1)

 Disturbance in attention

0

7.7 (11)

3.9 (11)

0

 Dizziness

2.7 (6)

12.7 (18)

8.2 (23)

1.3 (1)

 Migraine

2.7 (6)

2.1 (3)

2.5 (7)

5.0 (4)

 Paraesthesia

0.5 (1)

31.0 (44)

16.0 (45)

0

 Sinusitis

5.5 (12)

6.3 (9)

5.7 (16)

6.3 (5)

 Nausea

0.5 (1)

13.4 (19)

7.1 (20)

0

 Neck pain

4.5 (10)

2.1 (3)

4.3 (12)

6.3 (5)

 Fatigue

0.5 (1)

13.4 (19)

7.1 (20)

0

 Depression

1.8 (4)

5.6 (8)

3.5 (10)

2.5 (2)

 Vision blurred

2.7 (6)

7.0 (10)

5.0 (14)

3.8 (3)

 Decreased appetite

0

10.6 (15)

5.3 (15)

0

Funding

Allergan plc

Trial Registration

ClinicalTrials.gov, NCT02191579

P10 Chronic migraine treatment with erenumab: Responder rates

Hans-Christoph Diener1, Jan Brandes2, David Dolezil3, Marshall C Freeman4, Peter J McAllister5, Paul Winner6, Sunfa Cheng7, Dean K Leonardi7, Robert A Lenz7, Daniel D Mikol7

1University Duisburg-Essen, Essen, Germany; 2Nashville Neuroscience Group, Nashville, TN, USA; 3Prague Headache Center, DADO MEDICAL s.r.o., Prague, Czech Republic; 4Headache Wellness Center, Greensboro, NC, USA; 5New England Institute for Neurology and Headache, Stamford, CT, USA; 6Palm Beach Headache Center, West Palm Beach, FL, USA; 7Amgen Inc., Thousand Oaks, CA, USA
Correspondence: Hans-Christoph Diener (Hans.Diener@uk-essen.de)

Background

Erenumab (AMG 334) is a human anti-calcitonin gene-related peptide (CGRP) receptor antibody being evaluated as preventive treatment for chronic migraine (CM). When assessing efficacy of CM treatments by responder rates, there is an unmet need for more effective treatments.

Methods

In a prospective exploratory analysis of data from a phase 2 study (NCT02066415) in patients with CM (≥15 headache days/month over 3 months with ≥8 migraine days), patients (N=667) were randomised to erenumab (70 mg or 140 mg once monthly) or placebo. This analysis included calculation of proportions of patients with ≥50%, ≥75%, or 100% reduction in monthly migraine days (MMD) from baseline to last 4 weeks of a 12-week double-blind phase. P-values are based on odds ratios (ORs) from placebo and are not adjusted for multiple comparisons.

Results

Mean (SD) baseline MMD were 18.0 (4.6). Significantly higher proportions of patients treated with erenumab 70 mg or 140 mg experienced a ≥50% reduction from baseline in MMD compared with placebo at Week 12 (39.9% and 41.2%, vs 23.5%; OR: 2.2 [p<0.001] and 2.3 [p<0.001]). The ≥75% responder rates were higher for patients treated with erenumab 70 mg or 140 mg compared with placebo (17.0% and 20.9%, vs 7.8%; OR: 2.4 [p=0.002] and 3.1 [p<0.001]). Likewise, the 100% responder rates were higher for patients treated with erenumab 70 mg or 140 mg compared with placebo (4.3% and 2.7%, vs 0.4%; OR: 12.6 [p=0.002] and 8.1 [p=0.026]).

Conclusions

Erenumab treatment resulted in higher proportions of patients with CM experiencing ≥50%, ≥75%, and 100% reduction in MMD as compared with placebo.

P11 Systematic Cochrane review of botulinum toxins for the prevention of migraine in adults

Alexandra Sinclair1, Clare P Herd2, Claire L Tomlinson3, Caroline Rick3, WJ Scotton1, Julie Edwards4, Natalie Ives3, Carl E Clarke2

1Institute of Metabolism and Systems Research, University of Birmingham, Birmingham, UK; 2Institute of Applied Health Research, University of Birmingham, Birmingham, UK; 3Birmingham Clinical Trials Unit, University of Birmingham, Birmingham, UK; 5Department of Neurology, Sandwell and West Birmingham Hospitals NHS Trust, Birmingham, UK

Objectives

To assess the effects of botulinum toxins versus placebo, active treatment or different dose for prevention of episodic or chronic migraine in adults.

Background

Many migraine patients suffer prolonged and frequent migraine attacks despite optimised acute and prophylactic treatments. Botulinum toxin type A has been licensed for use in chronic migraine in some countries, based largely on two commercially sponsored trials.

Methods

Relevant trials were identified through electronic searches of Cochrane Central Register of Controlled Trials, Medline, Embase, and trials registries, handsearching reference lists and citation searches on key publications, and correspondence with manufacturers. We included randomised, double-blind, controlled trials. Twelve week time-point data following final round of treatment was analysed.

Results

Twenty-eight trials (N=4192) were eligible for inclusion. No trial carried out long term follow up. All larger trials (N>100) were at high risk commercial sponsorship bias, otherwise trial quality was mixed. Botulinum toxin was compared with placebo in 23 trials. Four trials (N=1497) of botulinum toxin in chronic migraineurs showed a reduced frequency of -3.1 migraine days/month (95% confidence interval (CI) -4.73 to -1.41) compared with placebo. Addition of one trial (418 participants) in episodic migraine lowered this pooled estimate of effect to -2.39 days/month (95% CI -4.02 to -0.76), still in favour of botulinum toxin. Secondary efficacy measures were inconsistent. Data for number of migraine attacks from six trials including chronic and episodic migraineurs showed no significant between group difference (P=0.30), but severity of migraine (10 cm visual analogue scale), was improved by -3.30 points (95% CI -4.16 to -2.45) more with active treatment. Global assessment and quality of life measures were poorly reported. Botulinum toxin had a relative risk of treatment related adverse events of twice that seen for placebo (2.18, 95% CI 1.73 to 2.75). Insufficient data was available to establish any dose-response relationship for any outcome measure. Three trials of comparisons with oral prophylactic agents independently reported no significant between group differences for a variety of diary data outcomes but meta-analysis was not possible. Compared with oral treatments, botulinum toxin showed a reduced relative risk of treatment-related adverse events of 0.76 (95% CI 0.59 to 0.98).

Conclusions

In chronic migraine, botulinum toxin type A reduces frequency of migraine by three days/month, reduces migraine severity by 30% and has a favourable safety profile compared with other preventative drugs. Evidence to support or refute the efficacy of botulinum toxin in episodic migraine was not identified.

P12 Complete detoxification is the most effective treatment of medication-overuse headache: A randomized controlled open-label trial

Louise N Carlsen, Signe B Munksgaard, Rigmor H Jensen, Lars Bendtsen

Danish Headache Center, Department of Neurology, Rigshospitalet-Glostrup, Lars Bendtsen; Ndr. Ringvej 69, 2600 Glostrup, Denmark
Correspondence: Lars Bendtsen (lars.bendtsen@regionh.dk)

Background: There is lack of evidence on how to detoxify medication-overuse headache (MOH).

The aim was to compare the effect of complete stop of acute medication with restricted intake.

Methods: MOH-patients were included in a prospective, outpatient study and randomized to two-month detoxification with either A) no analgesics or acute migraine-medication, or B) acute medication restricted to two days/week. Detoxification was followed by preventives if indicated. Patients were followed-up at 2, 6 and 12 months. Percentage reduction in headache-days/month after 6 months was the primary outcome.

Results: We included 72 MOH-patients with a primary migraine and/or tension-type headache diagnosis. Fifty-nine completed detoxification, 58 (81%) were followed-up at month 6 and 53 (74%) at month 12. At month 6, program-A reduced headache-days/month by 46% (95% CI 34–58) compared with 22% (95% CI 11–34) in program-B (p=0.005), and 70% in program-A versus 42% in program-B were reverted to episodic headache (p=0.04). Migraine-days/month were reduced by 7.2 in program-A (p<0.001) and 3.6 in program-B (p=0.002) after 6 months.

Conclusion: Both detoxification programs were very effective. Detoxification without analgesics or acute migraine-medication was the most effective program.

Trial registration: Clinicaltrials.gov (NCT02903329).

P13 Sphenopalatine ganglion block using Tx360 device. First results in refractory chronic cluster headache in Spain

Jose M Sanchez, Maria Rico, Maria Castanon, Elena Ameijide

Hospital Universitario Central de Asturias, Neurology, Oviedo, Spain
Correspondence: Jose M Sanchez (jmsancheza@gmail.com)

Background

Despite current preventive treatments almost 20% of patients with cluster headache become chronic [1], with severe repercussion in his/her daily activities and poor quality of life. Inhibiting sphenopalatine ganglion (SPG) could suppress the crisis [2], but its access is quite difficult requiring aggressive methods [3]. Tx360 device is a nasal applicator made of plastic material easing the access to the SPG and the application of local anaesthetic in its vicinity with minor inconveniencies [4].

Materials and methods

Twelve blocks (three each week during four weeks), of the SPG were done with Bupivacaine 0,5% (0,3 cc each nostril), using the Tx360 device. We evaluate at the end of the 12th block (four weeks), efficacy parameters (mean reduction of attack frequency and headache days), impact (Headache Impact Test [HIT-6]), and quality of life (Migraine-Specific Quality of Life Questionary [MSQ]), tools. We also analysed 30% and 50% response rates.

Results

Five patients refractories to standard oral therapies were treated (4 M, 1 F; mean age 41,6 ± 11,8). At the 12th block there was a significant reduction in mean attack frequency (6 vs. 15, p < 0,00002), and mean pain intensity (7 vs. 9,6, p< 0,005), not in mean headache days (18,6 vs 26, p 0,15). There was a significant reduction in mean HIT-6 (63 vs. 71), and MSQ (57 vs. 68). Four patients (80%), had a 50% or greater reduction in attack frequency, and two (20%), in headache days. There were no significant adverse events but minor and transient local discomfort; only one patient suffer a syncope two hours after the second block, probably not related to the procedure.

Conclusions

Repetitive blocks of the SPG with the Tx360 device seem to be an effective treatment in chronic cluster headache, with minor adverse events. These benefits were evident both in attack frequency and in quality of life measures. Although encouraging these results must be confirmed in a greater number of patients, and know how long they will last. This therapy probably should be tried before invasive treatments, with more serious adverse events.

References

1. Goadsby PJ. Pathophysiology of cluster headache: A trigeminal autonomic cephalalgia. Lancet Neurol. 2002;1:251-257.

2. Tepper SJ, Caparso A. Sphenopalatine Ganglion (SPG): Stimulation, Mechanism, Safety, and Efficacy. Headache. 2017;57:14-28.

3. Narouze S, Kapural L, Casanova J, et al. Sphenopalatine ganglion radiofrequency ablation for the management of chronic cluster headache. Headache. 2009;49:571–577.

4. Candido KD, Massey ST, Sauer R, Darabad RR, Knezevic NN. A novel revisión to the classical transnasal topical sphenopalatine ganglion block for the treatment of headache and facial pain. Pain Physician. 2013;16:E769-78.

P14 Are there gender differences related to cost of disease in patients with Medication Overuse Headache receiving structured withdrawal?

Grazzi Licia1, D’Amico Domenico1, Emanuela Sansone1, Matilde Leonardi2, Raggi Alberto2

1Headache and Neuroalgology Unit; Neurological Institute “C. Besta” IRCCS Foundation; Milan; 20133; Italy; 2Neurology, Public Health and Disability Unit; Neurological Institute “C. Besta” IRCCS Foundation; Milan; 20133; Italy
Correspondence: Grazzi Licia

Background

Medication Overuse Headache (MOH) impacts on patients’ daily life and is associated to increased burden and cost1. Our aim is to explore gender differences with regard to cost and treatments.

Materials and methods

Direct (medical and non-medical) and indirect cost were directly gathered from patients and referred to the previous three months. Direct cost included medications for acute treatment and prophylaxis, diagnostic procedures, visits, complementary treatments and informal care. Indirect costs were referred to missed workdays and workdays with headache, and we relied on patients’ report on their salaries and judgement on their overall level of performance for days worked with headache.

Results

A total of 159 patients (25 males – 15.7%) were included.

With regard to indirect costs, males had higher salaries (202 Vs. 103 €/day; P<.001) and were less frequently unemployed (9.5% Vs. 27%). Despite there were no differences on lost workdays and of days worked with headache, indirect costs were higher among males (2998 Vs. 1321 €/3-months; P=.022).

With regard to direct costs, there were no differences connected to the overall amount and cost of drugs for prophylaxis and for acute management, despite males consumed more triptans (89 Vs. 61 over 3 months; P=.019). Direct medical cost were comparable across gender, while non-medical cost were mostly reported and were higher for females (177 Vs. 19 €/3-months; P=.012). Taken as a whole, direct costs were higher among females (1359 Vs. 794 €/3-months; P=.046).

Total cost were higher for males, but not to a significant extent (3792€ Vs. 2680€ over three months).

Conclusions

Cost of MOH at the time point of withdrawal are high and widespread. Males reported higher indirect cost, likely due to higher salaries, while females reported higher direct cost, likely due to higher non-medical ones. However, overall costs were similar across gender. Taken as a whole, our data indicate that the annual cost per case of non-treated MOH might be approximately 11400€: considering that MOH prevalence is 2.1% among people aged 18-652 (i.e. around 39 millions), the global annual cost would be 9336.6 million €.

References

1) Steiner TJ, et al GBD 2015: migraine is the third cause of disability in under 50s. J Headache Pain. 2016;17:104.

2) Allena M, et al. Impact of headache disorders in Italy and the public-health and policy implications: a population-based study within the Eurolight Project. J Headache Pain. 2015;16:100.

P15 Optimal response to onabotulinumtoxina in chronic migraine: evaluation in a series of 124 patients

D García-Azorín, M Ruiz, Mi Pedraza, Al Guerrero

Background: OnabotulinumtoxinA (OnabotA) is considered a safe and effective preventive therapy in Chronic Migraine patients, as has been shown in the PREEMPT clinical program and in real-life setting. Though previously mentioned in literature, a possible excellent response to this therapy has not been previously assessed in clinical practice. We aimed to analyze the response to OnabotA, including characteristics of optimal responders in a series of CM patients.

Materials and Methods: We included 124 CM patients (108 females, 16 males) treated with OnabotA according to the PREEMPT paradigm in a headache unit. They had been previously treated with topiramate and at least one other medication from beta-blocker and flunarizine for at least three month, as recommended in local guidelines. Monthly headache and migraine days before and after OnabotA injections were recorded in a diary. Patients were considered as responders when a reduction of monthly headache days by at least 50% was achieved, and, among them, as optimal responders if the reduction obtained was over 75%.

Results: Mean age at first procedure was 41.8 ± 11.4 years (18-71). Latency between migraine onset and inclusion was 24 ± 12.9 years (2-61), and between CM onset and inclusion 39.7 ± 44.2 months (6-240). We classified 99 patients (79.8%) as responders and, among them, 30 (30.3) were considered as optimal responders. Among responders group, both age at inclusion (40.5±11 vs 47±12, p:0.02) and latency between migraine onset and OnabotA therapy (22.3±11.71 vs 20.4±15.4 years, p:0.021) were significantly decreased. Nevertheless, when comparing optimal responders with rest of responders we found no differences.

Conclusion: An optimal response to the first procedures of OnabotA is not exceptional in CM patients. It is advisable to consider this type of response in order to look for its predictors.

P16 N=1 statistical approaches to examine within-individual risk factor profiles of ICHD-3beta classified migraines versus non-migraine headaches

Ty Ridenour1, Francesc Peris2, Gabriel Boucher2, Alec Mian2, Stephen Donoghue2, Andrew Hershey3

1Behavioral and Urban Health, RTI International, Research Triangle Park, NC, 27709, USA; 2Curelator, Inc., Cambridge, MA, 02142, USA; 3Cincinnati Children’s Hospital Medical Center, Cincinnati, 45229, USA

Background

To what extent do migraines differ from non-migraine headaches (per ICHD-3beta criteria) in underlying pathophysiology? This study examined risk factors associated with (a) occurrence and (b) severity of both migraine vs non-migraine headaches. Because profiles of headache triggers / protectors vary greatly among patients, analyses were conducted at the individual level and their results then used to draw sample aggregate conclusions. For example, among participants who experienced a trigger, the proportion for whom the trigger was associated with only migraines, only non-migraine headaches, or both, was evaluated.

Materials and methods

Participants were 479 individuals with both migraines and non-migraine headaches identified by clinician referral or via the internet and registered to use a novel digital platform (Curelator HeadacheTM). Participants completed baseline questionnaires and entered daily data on headache occurrence, severity (level of pain), ICHD-3beta migraine symptom criteria, and exposure to 70 migraine risk factors. Nearly 88% of participants were female, 41% were US residents and 40% were UK residents. Cox regression tested associations between binomial occurrence of a (non)migraine headache and risk factors. Hierarchical linear modeling that was tailored for N=1 analysis (mixed model trajectory analysis or MMTA) tested associations between risk factors and pain severity of (non)migraine headaches. MMTA controlled for patient-specific time-related trends in pain severity (mild – moderate – severe), autocorrelation, and used conservative statistical tests for N=1 analyses.

Results

Regarding headache severity, 50% of risk factors were statistically associated with both migraine and non-migraine headaches whereas the other half were unique to one form of headache. However, within individuals, the particular risk factors that were associated with either form of headache varied greatly. Moreover, regarding specific risk factors, few individuals’ triggers / protectors were associated with both forms of headache. To illustrate, Fig. 1 presents the proportion of participants whose protector was associated with both forms of headache (rather than only one form).

Conclusions

Results suggest that risk factors associated with occurrence of migraines both overlap and differ from the factors of migraine severity. Moreover, these two sets of associations differ between migraine and non-migraine headaches. These observations imply that etiological factors differ between types of headaches. Results further suggest that treatment of migraines could aim to not only prevent attacks, but also reduce the pain (and thus impairment) that patients experience during a migraine headache, a strategy that could be particularly important for patients with chronic migraines.
Fig. 1 (abstract P16).

Proportion of Participants Whose Occurence Protector Affects both Headache Types

P17 N=1 statistical approaches to examine risk factor profiles of ICHD-3beta classified migraines within individuals

Ty Ridenour1, Francesc Peris2, Gabriel Boucher2, Alec Mian2, Stephen Donoghue2, Andrew Hershey3

1Behavioral and Urban Health, RTI International, Research Triangle Park, NC, 27709, USA; 2Curelator, Inc., Cambridge, MA, 02142, USA; 3Cincinnati Children’s Hospital Medical Center, Cincinnati, 45229, USA

Background

This investigation compared two within-individual analytic approaches to understand daily migraine occurrence and severity patterns in relation to a spectrum of suspected risk factors. Cox regression modelled migraine occurrence whereas headache severity was modelled using a form of hierarchical linear modeling tailored for intensive within-person analyses. These two techniques were compared in terms of which risk factors were identified as possible “triggers” of migraine occurrence versus possibly contributing to severity of a migraine.

Materials and methods

Participants were 479 individuals with migraines identified by clinician referral or via the internet and registered to use a novel digital platform (Curelator HeadacheTM). Participants completed baseline questionnaires and then entered daily data on headache occurrence and severity (level of pain), ICHD- 3beta migraine criteria, and exposure to 70 migraine risk factors. Nearly 88% of participants were female, 41% were US residents and 40% were UK residents. Risk factors spanned emotions, sleep qualities, environment and weather, lifestyle, diet, substance use, and travel. Cox regression modelled the binomial occurrence of migraine attacks per individual participant; hazard ratios quantified their strength of association with suspected triggers. The continuous measure of severity of migraine headache was modelled using mixed model trajectory analysis (MMTA), a form of hierarchical linear modeling. MMTA statistically controlled for patient-specific time-related trends in pain severity, autocorrelation, and used statistical tests that generate conservative estimates for N=1 analyses.

Results

Numerous risk factors were associated with occurrence and severity of migraine headaches. Cox regression detected potential triggers that were associated only with occurrence (not severity) of migraine attacks. Consistent with past evidence, the profile of risk factors that were associated with occurrence and severity of migraines varied considerably among patients, demonstrating that comprehensive clinical research on migraines requires analytics at the N=1 level. Moreover, “profiles” of triggers and protectors varied considerably among individuals (Fig. 1), suggesting that studies which only consider sample-aggregate results do not generalize to many migraine patients.

Conclusions

Cox regression and MMTA each provide unique insights regarding within-person patterns and correlates of migraine occurrence and severity, respectively. Cox regression’s detection of unique risk factors for occurrence of migraine headaches suggests that different risk factors are associated with occurrence of migraine attacks versus severity of migraine pain. Moreover, treatment of migraine headaches could aim to not only prevent occurrence of attacks, but also reduce pain level (and thus impairment) during a migraine headache, which could be especially important for patients with chronic migraines.
Fig. 1 (abstract P17).

See text for description

P18 Reliability and validity of a questionnaire for detecting cluster headache among headache patients

Pil-Wook Chung1, Soo-Jin Cho2, Kwang-Yeol Park3, Mi-Ji Lee4, Chin-Sang Chung4, Byung-Su Kim5, and Korean Cluster Headache Registry Group

1Department of Neurology, Kangbuk Samsung Hospital, Sungkyunkwan University School of Medicine, Seoul; 2Department of Neurology, Dongtan Sacred Heart Hospital, Hallym University College of Medicine, Hwaseong; 3Department of Neurology, Chung-Ang University Hospital, Chung-Ang University, Seoul; 4Department of Neurology, Neuroscience Center, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul; 5Department of Neurology, Bundang Jesaeng Hospital, Seoul, Republic of Korea
Correspondence: Pil-Wook Chung

Background

Cluster headache is a severe debilitating primary headache disorder. Because cluster headache is very rare compared with migraine, cluster headache is frequently misdiagnosed and neglected. We developed an 8-item self-administered questionnaire tool for detecting cluster headache among patients with primary headache disorder, and test its reliability and validity compared with neurologist’s diagnosis.

Materials and Methods

The candidate items were developed based on the diagnostic criteria of cluster headache from the international classification of headache disorder 3rd edition beta version and expert opinions. The total score was calculated from the sum of positive response to each items (ranging 0 to 8). The questionnaire was self-administered during the first visit to headache clinic before neurologist’s diagnosis. The reliability and validity were tested among patients with various primary headache disorders

Results

In total, 342 patients were enrolled: 28 with cluster headache, 254 with migraine, 44 with tension-type headache, and 16 with primary stabbing headache. Cronbach alpha was 0.619 and the areas under the curve were 0.922 in receiver operating characteristic curves for all 8 items. Using the total score of 5 as cut-value, sensitivity and specificity were 83.3% and 90.9% for definite episodic cluster headache among 342 patients. The validity was similar for differentiating cluster headache from migraine. Remission or cluster period did not influence the detection rate.

Conclusions

This preliminary self-administered questionnaire for cluster headache is reliable and useful tool. It may be suitable for detecting cluster headache among primary headache disorders.

P19 Postdural Puncture Headache after Cervical Medial Branch Block

Young In Lee1, Donggyu Han2, Yoo Jung Rark2, Eung Don Kim1

1Department of Anesthesiology and Pain Medicine, Daejeon St. Mary’s Hospital, College of Medicine, The Catholic University of Korea ; 2Department of Anesthesiology and Pain Medicine, Saint Vincent’s Hospital, College of Medicine, The Catholic University of Korea
Correspondence: Young In Lee (ehs99@catholic.ac.kr)
Cervical medial branch block (MBB) is a frequently performed procedure for management of neck pain that rarely has complications [1]. With fluoroscopic guidance, the procedure is considered a relatively safer procedure than epidural block [2,3]. We report a case of a 27-year-old woman presenting with postural headache after cervical MBB. Although no specific evidence of dural injury was found in her cervical MRI (Fig. 1), dural penetration by inappropriate needle placement was suspected after reviewing fluoroscopic images of the procedure (Fig. 2). After conservative treatment, including bed rest and analgesic treatment, the patient completely recovered without any neurological complications. Complications associated with MBB are rare and previous case reports have focused only on infection or vascular injection as etiologies. This is the first report of complications related to dural puncture after cervical MBB. Our findings suggest that misplacement of the block needle by inaccurate alignment of both sides of the cervical articular pillar, assessed by fluoroscopic view during the procedure, can result in dural injury.
Fig. 1 (abstract P19).

Cervical MRI of the patient

Fig. 2 (abstract P19).

Fluoroscopic lateral view during cervical medial branch block

Consent for publication: The authors declare that written informed consent was obtained for publication.

References

1. Bogduk N, Marsland A. The cervical zygapophysial joints as a source of neck pain. Spine 1988; 13:610-7.

2. Barnsley L, Lord S, Bogduk N. Comparative local anaesthetic blocks in the diagnosis of cervical zygapophysial joint pain. Pain 1993; 55:99–106.

3. Verrills P, Mitchell B, Vivian D, Nowesenitz G, Lovell B, Sinclair C. The incidence of intravascular penetration in medial branch blocks: cervical, thoracic, and lumbar spines. Spine 2008; 33:E174–7.

P20 Cervical Medial Branch Block using Botulinum Toxin Type A in Patient with Cervicogenic Headache

Young In Lee1, Donggyu Han2, Eung Don Kim1, Yoo Jung Rark2

1Department of Anesthesiology and Pain Medicine, Daejeon St. Mary’s Hospital, College of Medicine, The Catholic University of Korea; 2Department of Anesthesiology and Pain Medicine, Saint Vincent’s Hospital, College of Medicine, The Catholic University of Korea
Correspondence: Young In Lee (genial7@naver.com); Yoo Jung Rark (genial7@naver.com)

Background

Cervicogenic headache (CGH) is defined as headache originating from various neck conditions. Transcutaneous electrical nerve stimulation, nerve block, botulinum toxin (BoNT) injection and radiofrequency neurotomy have been recommended for treatment of medically intractable CGH [1]. A few theories have been proposed to explain the analgesic effect of BoNT. Some clinical trials of injecting BoNT near the targeted nerves have shown its effectiveness in pain relief [2,3].

However up to this point, there is no report regarding the effectiveness of BoNT when used in middle cervical medial branch block (MBB) for the treatment of CGH. We hereby report a case where BoNT was used in cervical MBB to treat cervicogenic headache.

Case Report

A 54 year-old male patient visited our pain clinic, complaining cervicogenic headache and neck pain. The C-spine MRI revealed the osteoarthritis at the facet joints of left C 3-4, 4-5 and 5-6. The MBB was performed at left C3, 4 and 5 under fluoroscopy (Figs.1, 2 and 3). 1.2 ml of 1% lidocaine was injected at each medial branch of C 3 to 5. The NRS for cervicogenic headache decreased from 6 to 3 after the block but without long lasting effect. After another trial of MBB with similar result, we decided to use botulinum toxin under the hypothesis that it would provide longer pain relief than diagnostic local anesthetics. 1.8ml of 1% lidocaine and BoNT (BOTOX® Type A, Allergan Inc., Irvine, CA, USA) 50 U were mixed to 1.8ml of normal saline, and 1.2ml of the mixture was injected at each level. The patient’s pain immediately decreased from NRS 6 to 3, and the effect lasted even after 3 months.

Conclusion

The use of botulinum toxin in middle cervical MBB may be effective in treating cervicogenic headache.

Consent for publication: The authors declare that written informed consent was obtained for publication.
Fig. 1 (abstract P20).

Fluoroscopic lateral view during cervical medial branch block at left C3, 4 and 5

Fig. 2 (abstract P20).

Fluoroscopic lateral view during cervical medial branch block at left C3, 4 and 5

Fig. 3 (abstract P20).

Fluoroscopic lateral view during cervical medial branch block at left C3, 4 and 5

References

1. Park SW, Park YS, Nam TK, Cho TG. The effect of radiofrequency neurotomy of lower cervical medial branches on cervicogenic headache. J Korean Neurosurg Soc. 2011; 50: 507-11.

2. Park JH, Park HJ. Botulinum toxin for the treatment of neuropathic pain. Toxins 2017; 9 : 260.

3. Kapural L, Stillman M, Kapural M, McIntyre P, Guirgius M, Mekhail N. Botulinum toxin occipital nerve block for the treatment of severe occipital neuralgia: a case series. Pain pract. 2007; 7: 337-40.

P21 Chronic Migraine Treatment and Work Productivity

Valeria Canzonetta1, Valerio De Angelis2, Elena Rogante1, Eleonora Sabatelli2, Salvatore Sarubbi1, Alice Sparagna1, Denise Erbuto1, Marco Innamorati1, Maurizio Pompili1, Paolo Martelletti2

1Department NESMOS, Sapienza Univeristy of Rome, Italy; 2Department of Clincal and Molecular Medicine, Sapienza University of Rome, Italy
Correspondence: Valeria Canzonetta

Background

Migraine is one of the most frequent neurological diseases. Specific features of migraine are moderate to severe pain associated with photophobia, phonophobia, nausea and/or vomit and it is worsened by physical activity. It lasts 4 to 72 hours [1]. Several studies showed that 2,5% of Episodic Migraines (EM) can evolve in Chronic Migraine (CM), characterized by high frequency of attacks (≥ 15days/month for more than 3 months with at least 8 attacks having the features of migraine headache) [2]. The pain intensity and the frequency may cause a chronic excessive intake of medication for acute or symptomatic treatment of migraine (triptans, AINS drugs, analgesics) leading to Medication Overuse Headache (MOH) [1].

Chronic migraine condition has a negative influence on many aspects of life, particularly on productivity at work. The American Migraine Prevalence and Prevention Study (AMPP) showed that migraine has a role both on absenteeism and presenteeism (reduced performance while at work) [3].

The present study is a preliminary analysis on a sample with CM treated with OnabotulinumtoxinA to examine work productivity in association with sociodemographic and psychosocial variables.

Materials and methods

104 patients with a diagnosis of chronic migraine, undergoing OnabotulinumtoxinA treatment (13 males; 91 females; mean age = 48,38 ± 9,85) have been enrolled in the Regional Referral Headache Centre of Sant'Andrea Hospital in Rome. Sample healthy control has been matched for age and sex.

All participants signed a consent form.

For this study the following tests have been used: Endicott Work Productivity Scale (EWPS, Endicott J., 1997) is a self-report questionnaire to evaluate work productivity through behaviours and feelings that are likely to reduce efficiency; Quality of Life Enjoyment and Satisfaction Questionnaire (Q-LES-Q, Endicott et al., 1993), Beck Depression Inventory (BDI, Beck AT, 1961), State and Trait Anxiety Inventory (Spielberger C, 1970); IPDQ (Innamorati et al., 2009).

Data have been analyzed using correlations and mean comparisons.

Results

There is no significant difference in work productivity between the clinical group (M = 17,22; ± 12,31) and healthy controls (M = 17,98; ± 11,7).

In the clinical sample there is a strong negative correlation among EWPS and Q-LES-Q scores (-,490: p<.000). Furthermore, there is a strong correlation between less work productivity and high scores in BDI (,445; p< .000), STAI (.499; p< .000), and IPDQ (.532; p< .000).

Conclusions

CM condition in patients undergoing treatment with OnabotulinumtoxinA is not associated to decreasing work productivity and efficiency.

References

1. Headache Classification Commitee of the International Headache Society (IHS). The International Classification of Headache Disorders 3rd edition (β version). Cephalalgia. 2013;33:629-808.

2. Negro A, Curto M, Lionetto L, Guerzoni S, Pini LA, Martelletti P. A Critical Evaluation on MOH Current Treatments. Current Treatment Options in Neurology. 2017;19:32.

3. Stewart WF, Wood GC, Manack A, Varon SF, Buse DC, Lipton RB. Employment and work impact of chronic migraine and episodic migraine. Journal of occupational and environmental medicine. 2010;52:8-14.

P22 A systematic literature review and meta-analysis of prevalence estimates in migraine

Akaterini Bilitou1, Pamela Vo2, Sandra Lopez-Leon3, Sneha Kelkar4, Claudia Cheung4, Emily Gao5, Keith A. Betts6, Zhou Zhou5

1 Novartis Global Services Centre, Patient Access Services, Dublin; 2 Novartis Pharma AG, Basel, Switzerland; 3 Novartis Pharmaceuticals Corporation, East Hanover, NJ, USA; 4 Analysis Group, New York/USA; 5 Analysis Group, Boston/USA; 6 Analysis Group, Los Angeles/USA
Correspondence: Akaterini Bilitou (katerina.bilitou@novartis.com)

Introduction

Reported epidemiological estimates in migraine vary widely across studies, mainly because of geographic variations, differences in study characteristics and diagnostic criteria used over time. This study aimed to identify and summarize population-based prevalence estimates of migraine in the last decade, after the revised International Classification of Headache Disorders (ICHD)-II definition.

Methods

A systematic literature review (SLR) of epidemiological studies in migraine published from 2006 until October 2016 from MEDLINE and EMBASE was conducted according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. In addition, conference abstracts published in the past 3 years (2014-2016) and references of most recent SLRs published were also reviewed. The quality of the extracted articles was evaluated using the modified Newcastle-Ottawa Scale for cohort studies. Random-effect models based on the DerSimonian and Laird method were used for meta-analysis of selected studies upon feasibility and quality assessment. The results were reported as forest plots displaying prevalence estimates and corresponding 95% confidence intervals (CI).

Results

A total of 1,133 records were identified and screened, and 77 publications reporting results for 51 unique studies met study criteria for data extraction (Fig. 1). In total 31 studies reported 1- year migraine prevalence, while 7 studies reported lifetime prevalence. Significant variation was observed between studies; ICHD-II was the most commonly used diagnostic criteria, while 25 out of 77 publications did not report the diagnostic criteria used. The estimated migraine prevalence by any definition was 14.2% (n=19, range 5.7% to 25.6%, 95% CI 13%-15.5%). The prevalence of migraine was higher among studies based on ICHD-II or later definitions (15.1%, 95% CI 13.6%-16.6%) than those using other migraine definitions (11.4%, 95% CI 10.4%-12.5%). The prevalence of episodic and chronic migraine were 13.6% (95%CI 10.4%-16.7%) and 0.9% (95%CI 0.32%-1.39%), respectively.

Conclusion

Despite marked heterogeneity of epidemiological studies across the literature, this study provided an updated systematic summary and evidence synthesis of the available prevalence estimates in migraine during the last decade.
Fig. 1 (abstract P22.)

PRISMA diagram for the SLR of epidemiologic studies in migraine

Competing interest

This study was funded by Novartis AG, Switzerland.

P23 Anxiety and Depression in Patients with Cluster Headache

Kwang-Yeol Park1; Soo-Jin Cho2; Byung-Kun Kim3; Pil-Wook Chung4; and Korean Cluster Headache Registry Group

1Department of Neurolgy, Chung-Ang University, Seoul, Korea; 2Department of Neurology, Dongtan Sacred Heart Hospital, Hallym University, Hwaseong, Korea; 3Department of Neurolgy, Seoul Eulji Hospital, Eulji University, Seoul, Korea; 4Department of Neurology, Kangbuk Samsung Hospital, Sungkyunkwan University, Seoul, Korea

Background: While cluster headache is one of the most disabling pain, it has been less well studied compared with migraine. We hypothesized that, considering its severity and chronicity, cluster headache could bring about anxiety or depression, but the degree of psychological symptoms might be different between active attack period and remission period. Our aim was to investigate the association between cluster headache and anxiety or depression during with or without headache period.

Methods: This is a preliminary analysis of ongoing prospective registry enrolling patients with cluster headache from 17 clinics in South Korea since June 2016. The diagnosis of cluster headache was made according to the ICHD-III beta criteria. We assessed anxiety and depression using the Generalized Anxiety Disorder 7 (GAD-7) and Patient Health Questionnaire 9 (PHQ-9) scales. Control subjects without cluster headache were recruited from 3 outpatient clinics. Linear regression was performed to compare the GAD-7 and PHQ-9 scores between groups.

Results: A total of 78 patients (male 61, 78%) with cluster headache and 72 controls (male 60, 83%) were enrolled. Mean ages are 37 ± 11 years in cases and 37 ± 9.2 years in controls. GAD-7 scores were 7.9 ± 6.0 in cases during active attack period, 2.8 ± 3.4 in cases during remission period, and 3.4 ± 3.8 in controls. PHQ-9 scores were 7.7 ± 6.6 in cases during active attack period, 3.3 ± 4.4 in cases during remission period, and 3.7 ± 4.1 in controls. On multivariable analysis, compared with control, cluster headache was significantly associated with GAD-7 (beta 4.4; 95% confidence interval 2.7 to 6.0; p value < 0.001) and PHQ-9 (3.9; 2.1 to 5.6; <0.001). Also, compared with remission, active cluster headache was significantly associated with GAD-7 (4.7; 1.4 to 8.1), but if was marginally associated with PHQ-9 (3.2; -0.3 to 6.8; 0.07). However, compared with control, remission status of cluster headache was not associated with GAD-7 (-0.88; -3.1 to 1.3; 0.43) and PHQ-9 (-0.80; -3.2 to 1.7; 0.52).

Conclusion: Our study suggests that active attack of cluster headache is associated with increased anxiety and depression compared with remission status or control. However, remission period is not associated with anxiety or depression.

P24 Benefit-Risk Assessment of Migraine Prophylaxis Treatments Using Likelihood of Being Helped or Harmed (LHH)

Pamela Vo1, Shihua Wen1, Marie-Josee Martel2, Dimos Mitsikostas3, Uwe Reuter4, Jan Klatt1

1Novartis Pharma AG, Switzerland; 2Xcenda, UK; 31st Neurology Department, Aeginition Hospital, National and Kapodistrian University of Athens, Greece; 4Department of Neurology, Charité Universitätsmedizin Berlin, Germany
Correspondence: Pamela Vo (pamela.vo@novartis.com)

Background

A key measure of successful therapy in migraine is the ability to sustain efficacy. Numerous prophylactic medications are available for this chronic disorder; however most of them have major shortcomings primarily due to variable efficacy and poor tolerability due to side effects. This study aimed to evaluate the benefit-risk of novel CGRP receptor antagonist erenumab, relative to other approved prophylactic migraine therapies.

Materials and Methods

Potential trials for inclusion were identified via a published systematic literature review [1] updated up to November 2016 using MEDLINE. As at the time of evaluation erenumab’s complete pivotal trial results were unpublished, clinical study reports were used (NCT02066415, NCT02456740). The ≥50% responder rates and discontinuations due to adverse events were defined as primary efficacy and tolerability variables to generate numbers needed to treat (NNT) and harm (NNH). The LHH as a quantitative benefit-risk measure was computed based on the ratio of NNH/NNT. Sensitivity analyses were conducted using alternative efficacy and tolerability data.

Results

Of 146 articles assessed, 9 RCTs (11 articles) met inclusion/exclusion criteria and were deemed of high quality per the Jadad score. Propranolol, topiramate, and onabotulinumtoxinA (the latter approved for CM only) were retained as comparators as they are approved for migraine prophylaxis and available in the majority of European countries. Table 1 shows an NNT of around 6 in both CM and EM for erenumab. This low NNT is numerically comparable to topiramate and onabotulinumtoxinA and show the strong treatment benefit of erenumab. NNH showed substantial differences among treatments, with higher numbers indicating better tolerability for erenumab. A favorable relative benefit-risk was seen for erenumab with LHHs of 41.7 and 166.7 for CM and EM respectively. In comparison, LHHs were lower in CM for topiramate (1.6 and 3.3) and onabotulinumtoxinA (4.3), and in EM, for topiramate (1.6) and propranolol (2.2). Sensitivity analyses showed results’ robustness despite residual variations and overall magnitude of LHH consistently favored erenumab.

Conclusions

While all prophylactic migraine treatments were more likely to help than harm (LHH > 1), erenumab showed LHHs of high magnitude, providing additional evidence to support the favorable benefit-risk profile of erenumab to patients across the entire spectrum of migraine compared with other migraine prophylactic treatments available in Europe.
Table 1 (abstract P24).

NNT, NNH and LHH for CM and EM prophylactic treatments

 

Chronic migraine (CM)

Episodic migraine (EM)

Erenumab 140 mg

Topiramate 100 mg

Onabotulinum-toxin A

Erenumab 140 mg

Topiramate 100 mg

Propranolol 160 mg

Data source :

NCT 02066415

Silberstein et al 2007 & 2009

Diener et al 2007

Dodick et al 2010

NCT 02456740

Bussone et al 2005

Diener et al 2004

NNT

≥50% RR (95%CI)

6 (4,12)

13 (NE, NE)

4 (3, 10)

9 (6, 15)

6 (4, 9)

5 (4, 6)

5 (4, 10)

NNH

% d/c due to AEs (95%CI)

250 (NE, NE)

21 (NE, NE)

13 (NE, NE)

39 (23, 100)

1000a (NE, NE)

8 (6, 13)

11 (6, 72)

LHH

NNH/NNT (95%CI)

41.7 (5.3, 301.8)

1.6 (0.0, 112.8)

3.3 (0.7, 364.9)

4.3 (1.9, 11.4)

166.7 (9.0, 299.3)

1.6 (1.1, 3.1)

2.2 (0.8, 14.5)

CI confidence interval, 50% RR 50% responder rate, NE not estimable (risk difference CI overlaps zero)

aDiscontinuation rate (d/c) for erenumab was lower than placebo, yielding a negative absolute risk reduction. Conservative imputation of 0.1% absolute difference used to calculate erenumab’s NNH (otherwise not evaluable)

References

1. Jackson JL, Cogbill E, Santana-Davila R, Eldredge C, Collier W, Gradall A, et al. A Comparative Effectiveness Meta-Analysis of Drugs for the Prophylaxis of Migraine Headache. PLoS ONE. 2015; 10(7): e0130733.

Funding: This study was funded by Novartis AG, Switzerland.

Acknowledgements

This poster has been previously presented at the 18th Congress of the International Headache Society, 7-10th September 2017, Vancouver, Canada.

P25 Healthcare resource utilization among migraine sufferers in the EU5 from the patient perspective

Pamela Vo1, Aikaterini Bilitou2, Juanzhi Fang3, Annik Laflamme1, Shaloo Gupta4

1Novartis Pharma AG, Switzerland; 2Novartis Global Services Centre, Ireland; 3Novartis Pharma, USA; 4Kantar Health, USA
Correspondence: Pamela Vo (pamela.vo@novartis.com)

Objectives

Migraine is a disabling neurological condition. The purpose of this study was to understand the incremental burden of migraine on healthcare resource utilization (HRU) in adults in Europe from the National Health and Wellness Survey (NHWS), a self-administered, internet-based questionnaire.

Methods

A retrospective, cross-sectional analysis of NHWS responses collected in 2016 from the EU5 (France, Germany, Italy, Spain, and UK) was performed. Adult (≥18 years old) respondents with a self-reported migraine diagnosis who completed the migraine module and with migraine experienced for ≥4 headache days in the past month were matched by propensity scores using sociodemographic characteristics to respondents without migraine (controls). HRU was evaluated via the number of healthcare provider (HCP) visits, emergency department (ED) visits and hospitalizations in the past six months. Mann-Whitney and Chi-square tests were used to determine significant differences between groups.

Results

Among respondents with migraine (≥4 headache days/month; n=218), 79.4% were female, the mean age was 43.25 years (SD = 13.48), and 60.1% were married or living with partner. Furthermore, 39.9% completed a university education and 62.4% were employed. Analysis of the propensity score-matched sample of 218 migraineurs and 218 controls showed that in the 6 months prior to questionnaire completion, the mean number of HCP visits (8.48 vs. 5.13, p<0.001) and ED visits (0.46 vs. 0.21, p=0.011) were significantly higher for migraine patients than those without migraine. The number of hospitalizations was higher among migraine patients (0.18 vs. 0.11, p=0.056) but marginally significant. Compared with matched controls, a significantly higher proportion of migraine respondents had ≥1 visits to a general/family practitioner (77.1% vs. 67.4%, p=0.025), neurologist (13.8% vs. 3.7%, p<0.001), and psychiatrist (13.3% vs. 3.2%, p<0.001) in the prior 6 months. The proportion of individuals with ≥1 ED visit was significantly higher for migraine patients than those without migraine (20.6% vs. 12.4%, p=0.02) whereas the proportion hospitalized (12.8% vs. 7.3% p=0.056) was slightly higher, but marginally significant.

Conclusions

Results demonstrated a statistically significant increase in HRU in terms of HCPs, neurologists, psychiatrists, and ED visits for migraine patients compared with non-migraine controls. To help reduce the burden of migraine on the European healthcare system better treatment options for migraineurs should be investigated.
Table 1 (abstract P25).

Results on HRU after propensity score matched analysis with non-migraine controls across EU5

 

Non-migraine controls

(N=218)

Migraine

(N=218)

p-value

Number of HCP visits in the past 6 months (mean, SD)

5.13 (6.86)

8.48 (10.89)

<0.001a

Number of ED visits in the past 6 months (mean, SD)

0.21 (0.79)

0.46 (1.20)

0.011a

Number of hospitalizations in the past 6 months (mean, SD)

0.11 (0.53)

0.18 (0.54)

0.056a

Visited General Practitioner/Family Practitioner in the past 6 months (n, %)

147 (67.4%)

168 (77.1%)

0.025b

Visited Neurologist in past 6 months (n, %)

8 (3.7%)

30 (13.8%)

< 0.001b

Visited Psychiatrist in past 6 months (n, %)

7 (3.2%)

29 (13.3%)

< 0.001b

Visited ED in the past 6 months (n, %)

27 (12.4%)

45 (20.6%)

0.020b

Hospitalized in the past 6 months (n, %)

16 (7.3%)

28 (12.8%)

0.056b

aMann-Whitney test

bChi-square test

Funding: This study was funded by Novartis AG, Switzerland.

Acknowledgements

This poster has been previously presented at the 18th Congress of the International Headache Society, 7-10th September 2017, Vancouver, Canada.

P26 Burden of migraine in the 5EU from the patient perspective: A cross-sectional analysis of National Health and Wellness Survey (NHWS) data

Pamela Vo1, Juanzhi Fang2, Aikaterini Bilitou3, Annik K. Laflamme1, Shaloo Gupta4

1Novartis Pharma AG, Basel/Switzerland; 2Novartis Pharmaceuticals Corporation, NJ/USA; 3Novartis Global Services Centre, Patient Access Services, Dublin/Ireland; 4Kantarhealth, Princeton NJ/USA
Correspondence: Pamela Vo (pamela.vo@novartis.com)

Introduction

Migraine is one of the most disabling neurological conditions worldwide. The purpose of this study was to characterize the incremental burden of migraine on quality of life (QoL), productivity, and healthcare resource utilization (HRU) by the frequency of migraine in adults using European data from the National Health and Wellness Survey (NHWS), a self-administered, internet-based questionnaire.

Methods

A retrospective, cross-sectional analysis of responses from the 2016 NHWS was performed using data from the France, Germany, Italy, Spain, and UK (5EU). Adult NHWS respondents with a self-reported migraine diagnosis who completed the migraine module were matched by propensity scores to those without migraines (controls) using sociodemographic characteristics. Outcomes of interest analyzed were from EQ-5D, SF-36v2, HRU and the Work Productivity and Activity Impairment (WPAI) questionnaires. Migraine respondents were stratified by frequency of migraines (headache days/month): 4-7 episodic migraine (EM), 8-14 EM, and chronic migraine (≥15; CM). Independent sample t-tests were used to determine significant differences between controls and the frequency of migraine groups.

Results

Results from the propensity score matched analysis demonstrated that migraineurs reported statistically significant lower QoL and higher HRU as compared to their matched controls. Impairment while at work and total activity impairment was statistically significant higher among all migraineurs compared to matched controls (Table 1).

Conclusion

Migraine is a chronic disorder negatively affecting multiple domains of individuals’ lives. This study demonstrated that there is a statistically significant incremental burden due to migraine on QoL, HRU and work productivity amongst the migraineurs in comparison to matched controls.

P27 Understanding the impact of migraine on work productivity using self-reported migraine diary data using the Migraine Buddy application in Europe

Nicolas Paris1, Pamela Vo2, Tomas Valena3, Aikaterini Bilitou4, Frederic de Reydet de Vulpillieres2, Juanzhi Fang5, Christel Naujoks2, Francois Everhard2, Francois Cadiou1

1Healint Pte. Ltd, Singapore 118520; 2Novartis Pharma AG, Switzerland; 3Novartis s.r.o., Czech Republic; 4Novartis Global Services Center Dublin, Ireland; 5 Novartis Pharmaceuticals Corporation, East Hanover, NJ 07936-1080, USA
Correspondence: Aikaterini Bilitou (katerina.bilitou@novartis.com)

Introduction

The purpose of the study was to evaluate the impact of migraine on work productivity as perceived by individuals suffering from migraine in the real world using a self-reported smartphone application called Migraine-Buddy©.

Methods

A retrospective, cross-sectional analysis was conducted using data captured through Migraine-Buddy© from adult, self-diagnosed migraineurs in 17 European countries. Data were analyzed for the most recent 28-day period reported by migraineurs during the study period June 2015-July 2016. Data from chronic migraine (CM: ≥15 headache days/month, N=900), 4-7 episodic migraine (EM) (n=1500) and 8-14 EM (n=1500) individuals were randomly selected based on data completeness (fill rate >70%). Descriptive analysis was performed.

Results

A total of 10,347, 11,301 and 6,504 migraine records were retrieved from CM, 8-14 EM and 4-7 EM individuals, respectively corresponding to a total of 16,815, 14,398, and 7,693 migraine days. Among employed migraineurs (n=3,106) who declared ‘work’ either as their migraine location or in ‘affected activities’ at least once, an average of 57.4, 27.7 and 15.5 work days missed per year were estimated as reported by CM (n=730), 8-14 EM (n=1237) and 4-7 EM (n=1139) sufferers, respectively. The most commonly reported triggers of absenteeism-related migraines were psychological (38%), sleep (34%), nutrition (25%) and/or menstruation (23%). Employed sufferers reporting absenteeism recorded symptoms relating to pain/body, mood/cognition disturbances, environmental handicap and depression among others (Table 1).

Conclusion

Migraine is reported to have a considerable impact in the lives of affected individuals with symptoms impacting the work productivity of employed migraineurs irrespective of migraine frequency.
Table 1 (abstract P27).

Symptoms reported by working migraineurs at least once in absenteeism-related migraine records. Number and proportion of users reporting each of the symptoms are shown (n=3106)

Symptoms

CM (n=730)

8-14EM (n=1237)

4-7EM (n=1139)

Total (n=3106)

Pain/Body

684 (94%)

1145 (93%)

1024 (90%)

2853 (92%)

Mood and cognition

661 (91%)

1114 (90%)

972 (85%)

2747 (88%)

Environmental handicap

643 (88%)

1073 (87%)

944 (83%)

2660 (86%)

Depression

436 (60%)

590 (48%)

435 (38%)

1461 (47%)

Sleep alterations

296 (41%)

435 (35%)

256 (22%)

987 (32%)

Others

271 (37%)

296 (24%)

213 (19%)

780 (25%)

No symptoms

126 (17%)

274 (22%)

161 (14%)

561 (18%)

Note: each user could specify more than one symptom per record and therefore numbers do not add up to 100%. Environmental handicap includes ringing in ears (tinnitus), sensitivity to light, noise or smell; mood and cognition symptoms include nausea, anxiety, confusion, blurred vision, moodiness, or giddiness. Analysis of record-level data showed consistent results with the user-level data analysis.

CM chronic migraine, EM episodic migraine

Funding: This study was funded by Novartis AG, Switzerland.

Acknowledgements

This poster has been previously presented at the 3rd Congress of the European Academy of Neurology in Amsterdam, June 24-27, 2017.

P28 A descriptive analysis of the burden of migraine based on self-reported migraine diary data using the Migraine Buddy application in Europe

Nicolas Paris1, Pamela Vo2, Tomas Valena3, Aikaterini Bilitou4, Frederic de Reydet de Vulpillieres2, Juanzhi Fang5, Christel Naujoks2, Francois Everhard2, Francois Cadiou1

1Healint Pte. Ltd, Singapore 118520; 2Novartis Pharma AG, Switzerland; 3Novartis s.r.o., Czech Republic; 4Novartis Global Services Center Dublin, Ireland; 5Novartis Pharmaceuticals Corporation, East Hanover, NJ 07936-1080, USA
Correspondence: Aikaterini Bilitou (katerina.bilitou@novartis.com)

Introduction

Migraine is a neurological disorder that can cause severe disabling pain. The purpose of the study was to describe the burden of migraine on health-related quality of life (HRQOL) as perceived by individuals suffering from migraine in the real world using a self-reported mobile application.

Methods

A retrospective, cross-sectional analysis was conducted using data captured through the Migraine-Buddy© smartphone application from adult, self-diagnosed migraineurs in several European countries including the UK, France, and Spain. Data were analyzed for the most recent 28-day period reported by migraineurs during the study period (June 2015-July 2016). Migraine respondents (n=3900) were randomly selected based on data completeness (fill rates >70%) and stratified by migraine headache days/month: 4-7 episodic migraine (EM) (n=1500), 8-14EM (n=1500), and chronic migraine (≥15; CM) (n=900). Descriptive analysis was performed.

Results

More than 95% of 3900 self-reported migraineurs reported that migraine negatively impacted their daily activities in at least one migraine attack. Attacks were estimated to affect 50.5% (184.4 days/year), 26.9% (98 days/year) and 14.5% (53 days/year) of their calendar year among CM, 8-14EM, and 4-7EM groups, respectively. On average, 44.8% CM, 40.9% 8-14EM and 34.7% of 4-7EM sufferers respectively reported anxiety and/or depression symptoms during migraine attacks. Social or home activities, productivity, or sleep were highly impacted in migraineurs (Table 1). Triptans (31.9%), nonsteroidal anti-inflammatory drugs (28.7%), acetaminophen (18.9%) and opioids (8.4%), and were self-reported as the most common medicines used by migraineurs across migraine records (n=28152).

Conclusion

This study highlights the high burden of migraine on HRQOL and overall well-being of individuals suffering from migraines irrespective of migraine frequency.

Funding: This study was funded by Novartis AG, Switzerland.
Table 1 (abstract P28).

Impact of migraine on daily activities as reported by migraineurs in at least one of their migraine records. Number and proportion of users, by migraine frequency and overall, reporting type of activity affected is shown

Type of activity affected

CM (n=900)

8-14 EM (n=1500)

4-7 EM (n=1500)

Total (n=3900)

Home activities

520 (58%)

985 (66%)

933 (62%)

2438 (63%)

Productivity

590 (66%)

993 (66%)

841 (56%)

2424 (62%)

Social activities

553 (61%)

882 (59%)

736 (49%)

2171 (56%)

Sleep

470 (52%)

827 (55%)

676 (45%)

1973 (51%)

Others

268 (30%)

298 (20%)

204 (14%)

770 (20%)

Any activity

855 (95%)

1447 (96%)

1430 (95%)

3732 (96%)

Others include affected activities that do not fit in the displayed categories. Migraine Buddy users could specify more than one activity affected in their records; pooled results across all migraine records are presented for the most recent 28-day period reported by migraine patients during the study (June 2015-July 2016)

CM Chronic Migraine, EM Episodic Migraine

Acknowledgements

This poster has been previously presented at the 3rd Congress of the European Academy of Neurology in Amsterdam, June 24-27, 2017.

P29 Evaluating clinically meaningful within-subject change in functioning associated with migraine prevention using the Migraine Physical Function Impact Diary (MPFID)

Ariane K Kawata1, Asha Hareendran2, Jiat-Ling Poon1, Andrew Thach3, Pooja Desai3, Yumi Kubo3, Daniel D Mikol3, David W Dodick4, Richard B Lipton5, Stewart J Tepper6

1Evidera, Bethesda, MD, USA; 2Evidera London, UK; 3Amgen Inc., Thousand Oaks, CA, USA; 4Department of Neurology, Mayo Clinic Arizona, Phoenix, AZ, USA; 5Montefiore Medical Center, Albert Einstein College of Medicine, Bronx, NY, USA; 6Geisel School of Medicine at Dartmouth, Department of Neurology, Dartmouth-Hitchcock Medical Center, Lebanon, NH, USA
Correspondence: Ariane K Kawata (ariane.kawata@evidera.com)

Background

Monthly Migraine Physical Function Impact Diary (MPFID) domain scores (Impact on Everyday Activities [EA, 7 items] and Physical Impairment [PI, 5 items]) range from 0–100 (higher score=greater impact). A Global Impact on Everyday Activities score (G-EA) is generated from a single item. We report a clinically meaningful within-patient change (CMWPC) in migraine impact scores and evaluation of CMWPCs in the STRIVE study (NCT02456740) in subjects with episodic migraine (EM).

Methods

CMWPCs for MPFID were developed using anchor- and distribution-based methods using data pooled across treatment groups from the ARISE study (NCT02483585) and an observational study of patients who recently initiated or changed their migraine preventive regimen. Clinically relevant anchor variables (≥30% and ≥50% reduction in monthly migraine days [MMD] and ≥20% and ≥50% reduction in MPFID G-EA) were used to estimate average within-subject point change from baseline in MPFID domain scores; distribution-based estimates based on variability were considered supportive. These CMWPCs were used to examine the proportion of responders to treatment in a post-hoc analysis of the STRIVE study. Cumulative distribution function (CDF) plots demonstrated percentage of subjects within each treatment group achieving the range of CMWPCs from baseline in MPFID domain scores.

Results

Estimates from the ARISE study and observational study suggested that CMWPCs starting at 3-point change in MPFID EA and PI domains represented CMWPC. In the STRIVE study, larger proportions of erenumab-treated subjects than placebo achieved a ≥5-point reduction (pre-specified endpoint) from baseline to mean of weeks 13–24 in PI (140mg: 42.5%; 70mg: 39.1% vs placebo: 30.1%, both p<0.05) and EA domain scores (140mg: 50.3%; 70mg: 49.0% vs placebo: 34.5%, both p<0.001). The CDF plots showed that more subjects in 140mg and 70mg erenumab groups than placebo had greater reductions in EA and PI domain scores. The erenumab groups had consistently larger proportions of responders than placebo starting as low as a 3-point change from baseline score and across a range of CMWPCs.

Conclusion

Reductions starting at 3 points in MPFID domains are representative of CMWPCs. Treatment with erenumab 140mg and 70mg in the STRIVE study was related to clinically meaningful reductions in the impact of migraine on physical functioning versus placebo, based on greater proportions on erenumab experiencing within-subject change ≥5 points. This supports the utility of MPFID as a marker for migraine clinical benefit and demonstrates the value of erenumab as a preventive therapy to improve functioning in subjects with EM.

P30 The Trigger Avoidance Model of Headaches and Learning to Cope with Triggers: An update

Paul R Martin (paul.martin@griffith.edu.au)

School of Applied Psychology and Menzies Health Institute Queensland, Griffith University, Mount Gravatt, Queensland, Australia, 4122

The Trigger Avoidance Model of Headaches

The Trigger Avoidance Model of Headaches (TAMH) has been proposed to explain how triggers acquire the capacity to precipitate headaches [1,2,3]. The Model is based on the theory that a critical process in the development of a headache disorder may be trying to avoid the triggers resulting in a sensitisation process such that tolerance for triggers diminishes. The conceptual underpinning of the TAMH comes from cognate literatures such as the anxiety literature as there is much evidence that efforts to avoid stimuli/situations that elicit anxiety resulting in short exposure to those stimuli, will lead to those stimuli eliciting more anxiety in the future. Treatment of anxiety disorders is based on the reverse principle of prolonged exposure to anxiety-eliciting situations, leading to desensitisation. The TAMH has received support in a series of laboratory investigations that demonstrate short exposure to headache triggers results in sensitisation, whilst prolonged exposure leads to desensitisation [4,5,6,7].

Learning to Cope with Triggers

Advice to avoid triggers as a means of preventing headaches, has been the standard for decades. The implication of the TAMH is that such advice may be counterproductive for some triggers as it could lead to reduced tolerance for those triggers. Based on the TAMH, it has been argued that counselling avoidance should be replaced with a philosophy of Learning to Cope with Triggers (LCT) [1,2,3]. LCT specifies use of exposure-based strategies for triggers such as stress, negative affect, and sensory triggers (visual disturbance, noise); and avoidance strategies for triggers that are not consistent with a healthy lifestyle (e.g., hunger, dehydration, lack of sleep). LCT has been evaluated in a randomised controlled trial with the following outcomes [8]. Changes in headaches and medication consumption (in parentheses) from pre- to post-treatment were (a minus sign indicates improvement): Waiting-list, +11.0% (+15.4%); Avoidance, -13.2% (-9.0%); and LCT, -35.9% (-27.9%). Avoidance did not differ significantly from Waiting-list for headaches or medication use, but LCT differed significantly from Waiting-list for both measures. Three illustrative case studies of LCT have since been published describing the use of exposure techniques with the triggers of stress/anger, tiredness and heat [9]. Coping with triggers is now beginning to achieve recognition in the literature. For example, the European Federation of Neurological Societies guidelines on treatment of tension-type headache include “Identification of trigger factors should be performed, as coping with trigger factors may be of value (Martin & MacLeod, 2009)” [10].

References

1. Martin PR, MacLeod C. Behavioral management of headache triggers: Avoidance of triggers is an inadequate strategy. Clinical Psychology Review. 2009; 29:483-495.

2. Martin PR. Managing headache triggers: Think ‘coping’ not ‘avoidance’. Cephalalgia. 2010; 30:634-637.

3. Martin PR. Behavioral management of migraine headache triggers: Learning to cope with triggers. Current Pain and Headache Reports. 2010; 14:221-227.

4. Martin PR. How do trigger factors acquire the capacity to precipitate headaches? Behaviour Research and Therapy. 2001; 39:545-554.

5. Martin PR, Reece J, Fordyce M. Noise as a trigger for headaches: Relationship between exposure and sensitivity. Headache. 2006; 46:962-972.

6. Martin PR, Lae L, Reece J. Stress as a trigger for headaches: Relationship between exposure and sensitivity. Anxiety, Stress and Coping. 2007; 20:393-407.

7. Martin PR. Headache triggers: to avoid or not to avoid, that is the question. Psychology and Health. 2000; 15:801-809.

8. Martin PR, Callan M, Reece J, MacLeod C, Kaur A, Gregg K, Goadsby PJ. Behavioral management of the triggers of recurrent headache: A randomized controlled trial. Behaviour Research and Therapy. 2014; 61:1-11.

9. Martin PR, Callan M, Kaur A, Gregg K. Behavioral management of headache triggers: Three case examples illustrating a new effective approach (Learning to Cope with Triggers). Behaviour Change. 2015; 32:202-208.

10. Bendtsen L et al. EFNS guideline on the treatment of tension-type headache – Report of an EFNS task force. European Journal of Neurology. 2010; 17:1318-1325.

P31 The intermediary relationship between analgesic/abortive medication use, sleep quality, and headache frequency: A potential new partial mechanism contributing to medication overuse headache

Daniel P Sullivan, Paul R Martin

School of Applied Psychology and Menzies Health Institute Queensland, Griffith University, Mount Gravatt, Queensland, Australia, 4122
Correspondence: Daniel P Sullivan (daniel.sullivan5@griffithuni.edu.au)

Background

Evidence that sleep dysfunction can play a role in headaches has been well established. We have previously reported various sleep factors are correlates of headaches, particularly sleep quality [1]. Medication overuse headache develops when acute or symptomatic headache medications are used too frequently. Given commonly used medications such as NSAIDs and opioids disrupt sleep architecture [2, 3], we sought to test the hypothesis that greater use of acute medications would be associated with more frequent headaches, as mediated by sleep quality.

Method

Participants (n = 370, 85% female) were recruited through headache and pain websites, and University recruitment channels. Utilising a cross-sectional design, participants completed a battery of online measures including headache type/frequency and use of headache analgesic/abortive medications, and sleep variables such as sleep quality and duration.

Results

Regression models found medication use (MU) and sleep quality (SQ) to be significant predictors of migraine frequency, F (2, 367) = 78.21, p < .001, R 2 = .3; and non-migraine headache frequency, F (2, 367) = 98.67, p < .001, R 2 = .35. Mediation analysis revealed MU had a significant direct effect on migraine (Predictor coefficient = .417, p < .001), which was mediated by SQ (Mediator coefficient =.048, 95%CI .023, .083, κ2 = .061). A significant direct effect for MU was found for non-migraine headaches (PC = .524, p < .001), and that effect was also mediated by SQ (MC = .03, 95%CI .006, .06, κ2 = .039).

Conclusions

This paper provides a foundation for future investigations using stronger prospective designs to examine if medication overuse headache is partly mediated by the deleterious effect some medications may have on sleep architecture and quality. Such studies may employ prospective designs and sophisticated laboratory measurements rather than self-report. Another avenue for investigation is whether the effect of headache relieving medications can be augmented with adjunctive therapy for sleep (e.g., Melatonin).
Fig. 1 (abstract P31).

Graphical representation of the mediatory relationship between medication and sleep quality, and headache

References

1. Sullivan DP, Martin PR: Sleep and headaches: Relationships between migraine and non-migraine headaches and sleep duration, sleep quality, chronotype, and obstructive sleep apnoea risk. Australian Journal of Psychology. 2017; 69:210-217.

2. Murphy PJ, Badia P, Myers BL, Boecker MR, Wright KP, Jr.: Nonsteroidal anti-inflammatory drugs affect normal sleep patterns in humans. Physiol Behav. 1994; 55:1063-1066.

3. Dimsdale JE, Norman D, DeJardin D, Wallace MS: The effect of opioids on sleep architecture. J Clin Sleep Med. 2007; 3:33-36.

P32 State and Trait anger and its expression in migraine and cluster headache

Marialuisa Rausa1,3, Sabina Cevoli2, Giulia Giannini1, Valentina Favoni1, Sara A Contin3,Donatella Ballardini3, Pietro Cortelli1,2, Giulia Pierangeli1,2,3

1Department of Biomedical and Neuromotor Sciences DIBINEM, University of Bologna, Bologna,40100, Italy; 2IRCCS Istituto delle Scienze Neurologiche di Bologna, 40100, Italy; 3Centro Gruber. Service for the Diagnosis and Treatment of Eating Disorders. Service for the Diagnosis and Treatment of Anxiety and Psychosomatic Disorders, Bologna,40100, Italy
Correspondence: Marialuisa Rausa (m.rausa@gmail.com)

Background:

Negative affective states, like anger and fear, are deeply involved in the emotional experience of pain [1]. It is reported that individuals with migraine and tension type headache are more likely to hold their anger-in than controls. One study showed that headache patients hold their anger-in more than controls, even after controlling for depression and anxiety [2]. However, no study evaluated anger in cluster headache (CH) and differences between migraine (M) and CH patients. The objective is to evaluate differences between M and CH patients in anger levels and in anger expression.

Materials and Methods:

134 M patients and 105 CH patients were administered the State Trait Anger Expression Inventory (STAXI-2, 56 items), composed by seven subscales. State Anger refers to the intensity of the individual’s angry feelings at the time of testing. Trait Anger evaluates person’s general predisposition to become angry. Anger expression is measured by: Anger Expression Out (the extent to which anger could be expressed in an outwardly manner), Anger Expression In (the extent to which anger is suppressed), Anger Control Out (prevent explosive manifestations of anger), Anger Control In (try to relax and reduce angry feelings) and Anger Expression index (an overall index of the individual tendencies to express anger).

Results:

CH patients have higher scores than M patients (p<0.05) in State Anger. Moreover CH patients have higher scores in Anger Expression-Out (p<0.05). No differences were found in trait anger subscales (tab.1). In particular, in sub-group analysis, patients with CH during cluster period have higher state anger than chronic migraine patients, while CH patients in headache free period did not differ from M patients.

Conclusions:

The results indicate that M and CH patients differ in state anger, but not in trait anger, suggesting that there are no dispositional differences in anger feeling. In CH, especially during cluster period, was detected higher intensity of anger feeling during the time of testing. This data support the bio-behavioral hypothesis of different behavioral response to pain in M and CH patients (sickness behavior vs defense reaction) [3], and add new information about emotional regulation involved during headache’s attack.
Table 1 (abstract P32).

Mean scores at Staxi-2

STAXI-2

Migraine patients (n=134)

Cluster headache patients (n=105)

p

State Anger

17,51

20,11

P<0.05

Trait Anger

5,42

6,15

ns

Anger Expression index

46,27

47,29

ns

Anger Expression in

20,25

19,76

ns

Anger Expression out

16,99

18,32

P<0.05

Anger Control in

18,48

18,79

ns

Anger Control out

20,48

20,00

ns

References

1. Venable VL, Carlson CR, Wilson J. The role of anger and depression in recurrent headache. Headache 2001;41:21–30.

2. Nicholson RA, Gramling SE, Ong JC, Buenevar L: Differences in anger expression between individuals with and without headache after controlling for depression and anxiety. Headache 2003;43:651-663.

3. Montagna P, Pierangeli G, Cortelli P.The primary headaches as a reflection of genetic darwinian adaptive behavioral responses. Headache. 2010 Feb;50(2):273-89. Epub 2009 Dec 21.

P33 A Phase 1 Study to Assess the Pharmacokinetics, Safety, Tolerability and immunogenicity of Fremanezumab doses (225 mg, 675 mg and 900 mg) in Japanese and Caucasian Healthy Subjects

Orit Cohen-Barak1, Xiaojun Hu1, Michele Rasamoelisolo1, Nicola Faulhaber1, Paul Yeung1, Esther Yoon2, Mohit Gandhi 3, Ernesto Aycardi1

1Global Research and Development, Teva Pharmaceutical Industries, Netanya, Israel; 2PAREXEL International, Los Angeles; 3PRA Health Sciences, Lenexa, United States
Correspondence: Orit Cohen-Barak

Objectives

Fremanezumab is a fully humanized IgG2Δa monoclonal antibody that selectively blocks CGRP isoforms (α- and β) from binding to the CGRP receptor. Fremanezumab was effective and well-tolerated as a preventive treatment of episodic migraine and chronic migraine in phase 2 and phase 3 trials. The present study evaluated the pharmacokinetic profile, safety, and immunogenicity of fremanezumab doses tested in the phase 2 and 3 trials (225mg, 675mg and 900mg) following single administration in Japanese (n=32) and Caucasian (n=32) healthy subjects.

Methods

Japanese and Caucasian healthy subjects were enrolled into 1 of 4 cohorts: cohorts 1 and 3 were Japanese and cohorts 2 and 4 were Caucasians. Subjects in each cohort were randomly assigned to 1 of 4 treatments: 225, 675, or 900 mg fremanezumab, or placebo. In the first cohort only, a dose escalation scheme was applied where study drug was not escalated to the next dose level unless the safety and tolerability of the previous doses were acceptable by sponsor and clinical team. Caucasian subjects were matched to Japanese subjects based on gender, age (± 10 year) and BMI (±20%). PK and immunogenicity sampling and safety & tolerability assessments occurred during 13 clinic visits including 1 inpatient visit from day -1 to day 6 and 12 ambulatory visits between post treatment days 8-225.

Results

Sixty-two subjects out of 64 completed the study; 2 Japanese subjects (1 225mg and 1 900mg fremanezumab) withdrew consent because of family emergencies. Overall median Tmax was similar across doses and ranged from 5 to 7 days. Mean half-lives were similar across doses (range 32.23 to 36.15 days). No differences due to race/ethnicity. Increases in Cmax and AUCs were slightly greater than dose proportional for both Japanese and Caucasian subjects. Fremanezumab exposures were generally higher with lower body weights. No deaths or SAEs; most frequently occurring AEs (≥2 subjects) were injection site reactions, abdominal pain, headache, upper respiratory tract infection, constipation and nasopharyngitis. Local tolerability of the SC fremanezumab injection was comparable between Japanese and Caucasian subjects. No treatment-induced anti-drug-antibodies occurred and there were no clinically meaningful changes in laboratory findings.

Conclusion

Overall fremanezumab was safe and well tolerated following SC single doses (225, 675, or 900mg). Pharmacokinetic exposure parameters per dose were similar for Japanese and Caucasians. Half-life following SC injections support the once monthly SC injections of 225mg and quarterly SC injections of 675mg as a treatment doses.

Trial registration

Clinicaltrials.gov NCT02673567

Competing Interest

O. Cohen-Barak Conflict with: Teva Pharmaceutical Industries, Conflict with: Teva Pharmaceutical Industries, X. Hu Conflict with: Teva Pharmaceutical Industries, M. Rasamoelisolo Conflict with: Teva Pharmaceutical Industries, N. Faulhaber Conflict with: Teva Pharmaceutical Industries, P. Yeung Conflict with: Teva Pharmaceutical Industries, Conflict with: Teva Pharmaceutical Industries, E. Yoon Conflict with: PAREXEL International, M. Gandhi Conflict with: PRA Health Sciences, E. Aycardi Conflict with: Teva Pharmaceutical Industries, Conflict with: Teva Pharmaceutical Industries

P34 Fremanezumab increases the maximum number of consecutive headache free days for patients with high frequency episodic migraine

Robert Noble, Ernesto Aycardi, Marcelo Bigal, Mirna McDonald, Pippa Loupe, Investigators of the EM study

1Statistics, Teva Global Medical Affairs, Hamilton; 2Global Clinical Development; 3Clinical Development, Teva Global Research and Development, Frazer; 4Academic Affairs and Network, Teva Global Research and Development, Overland Park , United States

Background

Fremanezumab is a fully humanized IgG2Δa monoclonal antibody found to be effective and well-tolerated as a preventive treatment for migraine in phase 2 and 3 studies. Previously reported data has shown that on headache free days, patients on fremanezumab treatment had greater number of days in which they were able to work/study normally, less time with difficulty in concentration, and more time engaged and interested in daily activities. The present report describes a Bayesian model performed to evaluate the number of consecutive headache free days in the high frequency episodic migraine (HFEM) study.

Methods

This was a randomized 3-month phase 2 study comparing two doses of fremanezumab (225 mg and 675 mg) with placebo. During a 28 day run-in period, patients were screened and trained to capture daily headache information using an electronic headache diary. Following the run-in period, patients who were 80% compliant in diary entry and had migraine headaches at least 8 but less than 14 days per 28 days were randomized and treated subcutaneously once every 28 days with either 225 mg or 675 mg fremanezumab or placebo. Compared to placebo, both doses of fremanezumab significantly reduced the primary endpoint of the HFEM study, change in the number of migraine days at month 3 relative to baseline; herein we assessed in a post-hoc analysis whether there were differences in the maximum number of consecutive headache free days among the treatment arms. Due to the skewed nature of the distribution of maximum headache free days, the data were modeled assuming a geometric likelihood. Bayesian model using non-informative priors on the headache rate was used.

Results

In the posterior distributions for the maximum number of consecutive headache free days (Fig. 1), there is a separation between the curves for participants taking fremanezumab 225mg (n=96) and 675mg (n=97) compared to those taking placebo (n=104). Posterior probabilities and 90% credible intervals for the differences between the fremanezumab 225 mg arm and placebo were 0.965 [0.316,6.709] and for fremanezumab 675 mg arm vs placebo 0.993 [1.553,8.322]. Patients in the fremanezumab 225 mg group had mean(SD) maximum number of consecutive headache free days of 14.5(15.0), 675 mg group experienced 15.9(14.8) days and the placebo group 11.12(10.6) days.

Conclusion

The results of this post-hoc analysis suggest that HFEM patients taking fremanezumab at doses of 225mg and 675mg can expect to have a greater maximum number of consecutive headache free days than patients on placebo.

Trial registration

Clinicaltrials.gov NCT02025556

Competing Interest

Fremanezumab HFEM Study supported by Teva Pharmaceutical Industries Global Research and Development, Netanya Israel. RN, EA, MEB, and PL are employees of Teva Pharmaceutical Industries, Israel.

P35 A Phase 1 Study to Assess the Pharmacokinetics, Safety, Tolerability and immunogenicity of Fremanezumab doses (225 mg, 675 mg and 900 mg) in Japanese and Caucasian Healthy Subjects

Orit Cohen-Barak, Xiaojun Hu, Michele Rasamoelisolo, Nicola Faulhaber, Paul Yeung, Esther Yoon, Mohith Gandhi and Ernesto Aycardi

Background. Fremanezumab (formerly TEV-48125) is a fully humanized IgG2Δa monoclonal antibody that selectively blocks both CGRP isoforms (α- and β) from binding to the CGRP receptor. Fremanezumab was effective and well-tolerated as a preventive treatment of episodic migraine and chronic migraine in phase 2 and phase 3 trials. The present study evaluated the pharmacokinetic profile, safety, and immunogenicity of fremanezumab doses tested in the phase 2 and 3 trials (225mg, 675mg and 900mg) following single administration in Japanese (n=32) and Caucasian (n=32) healthy subjects.

Methods. Japanese and Caucasian healthy subjects were enrolled into 1 of 4 cohorts: cohorts 1 and 3 were Japanese and cohorts 2 and 4 were Caucasians. Subjects in each cohort were randomly assigned to 1 of 4 treatments: 225, 675, or 900 mg fremanezumab, or placebo. In the first cohort only, a dose escalation scheme was applied where study drug was not escalated to the next dose level unless the safety and tolerability of the previous doses were acceptable by sponsor and clinical team. Caucasian subjects were matched to Japanese subjects based on gender, age (± 10 year) and BMI (±20%). PK and immunogenicity sampling and safety & tolerability assessments occurred during 13 clinic visits including 1 inpatient visit from day -1 to day 6 and 12 ambulatory visits between post treatment days 8-225.

Results: Sixty-two subjects out of 64 completed the study; 2 Japanese subjects (1 225mg and 1 900mg fremanezumab) withdrew consent because of family emergencies. Overall median Tmax was similar across doses and ranged from 5 to 7 days. Mean half-lives were similar across doses (range 32.23 to 36.15 days). No differences due to race/ethnicity. Increases in Cmax and AUCs were slightly greater than dose proportional for both Japanese and Caucasian subjects. Fremanezumab exposures were generally higher with lower body weights. No deaths or SAEs; most frequently occurring AEs (≥2 subjects) were injection site reactions, abdominal pain, headache, upper respiratory tract infection, constipation and nasopharyngitis. Local tolerability of the SC fremanezumab injection was comparable between Japanese and Caucasian subjects. No treatment-induced anti-drug-antibodies occurred and there were no clinically meaningful changes in laboratory findings.

Conclusions. Overall fremanezumab was safe and well tolerated following SC single doses (225, 675, or 900mg). Pharmacokinetic exposure parameters per dose were similar for Japanese and Caucasians. Half-life following SC injections support the once monthly SC injections of 225mg and quarterly SC injections of 675mg as a treatment doses.
Fig. 1 (abstract P35).

Posterior Mean Maximum Headache Free Day Distrivutions

P36 Analysis of injection site reactions across four placebo controlled trials of erenumab for migraine prevention

Julio Pascual1, David Doležil2, Brendan Davies3, Hernan Picard4, Frank Hong5, Feng Zhang4, Fei Xue4, Dan Mikol4, Jan Klatt5

1Service of Neurology, University Hospital Marqués de Valdecilla and IDIVAL, Santander, Spain; 2DADO MEDICAL sro, Prague Headache Center, Prague, Czech Republic; 3Department of Neurology, Royal Stoke University Hospital, Stoke-on-Trent, UK; 4Amgen Inc., Thousand Oaks, CA, USA; 5Novartis Pharma AG, Basel, Switzerland
Correspondence: Julio Pascual (juliopascual@telefonica.net)

Background

Erenumab is a fully human monoclonal antibody that selectively inhibits the calcitonin gene-related peptide (CGRP) receptor under investigation for migraine prevention. Erenumab is administered monthly by subcutaneous injection. Here we report the incidence of injection site reaction-related adverse events (ISR-AEs) observed in erenumab clinical trials in subjects with episodic or chronic migraine.

Methods

Data were obtained from four placebo-controlled clinical trials (clinicaltrials.gov NCT01952574, NCT02066415/NCT02174861, NCT02456740, NCT02483585). Analysis was performed for two periods: the 12-week double-blind placebo-controlled treatment period (DBTP; erenumab and placebo) and the entire erenumab exposure period (EEP), including the open-label extension phase (erenumab only). AEs were graded according to Common Terminology Criteria Version 4.03.

Results

Over the 12-week DBTP, incidence of ISR-AEs was 3.2%, 5.6%, and 4.5% in the placebo, erenumab 70 mg, and erenumab 140 mg groups, respectively (Table 1).

Over the EEP, which extended erenumab exposure to median 46 weeks (mean 47, range 0–159), incidence of ISR-AEs was 6.1% and 4.2% in the erenumab 70 mg and 140 mg groups, respectively (Table 2)

Over the EEP across both doses, most ISR-AEs were mild (Grade 1). Moderate ISR-AEs (Grade 2) were injection site erythema (four subjects, 0.2%), injection site pain (three subjects, 0.1%), and injection site reaction, injection site induration, and injection site urticaria (one subject each, <0.1%). There were no ISR-AEs of Grade >2, and no serious ISR-AEs. Across 2519 subject years of erenumab exposure, one subject (<0.1%) discontinued due to injection site pain, one due to injection site rash, and one due to injection site urticaria.

Conclusion

ISR-AEs occurred in a small proportion of subjects treated with either dose of erenumab, with little change over time. Most ISR-AEs were mild and did not require discontinuation.
Table 1 (abstract P36).

ISR-AEs over the 12-week DBTP, n (%)

 

Erenumab, mg

Placebo

(N=1043)

70

(N=893)

140

(N=507)

Any ISR-AE

33 (3.2)

50 (5.6)

23 (4.5)

ISR-AEs with >0.5% frequency in any group

 Injection site pain

18 (1.7)

33 (3.7)

8 (1.6)

 Injection site erythema

2 (0.2)

9 (1.0)

10 (2.0)

 Injection site pruritus

3 (0.3)

4 (0.4)

4 (0.8)

Table 2 (abstract P36).

ISR-AEs over the EEP

 

Erenumab, mg

70 (N=2128)a

140 (N=1198)a

Subjects who experienced an ISR-AE, n (%)

130 (6.1)

50 (4.2)

Total time at risk summed across subjects, years

1738

649

Exposure-adjusted subject incidence rate per 100 subject-years

7.5

7.7

aSubjects who received >1 dose level were counted in both dose levels

P37 Ipoglycemia a trigger factor for migraine chronification in migraineurs: diagnosis with glycemic load

Claudio Mostardini

Headache Center, Ospedale G.B. Grassi, ASL Roma 3

Chronification of migraine has many known factors and many others under study, like psychological, psychiatric, metabolic factors, metabolic poor management of therapy, etc.

Simple and cost-effective parameters, to identify target for new therapy have always been the target of research. Careful observation of headache diaries shows sometimes that some migraine attacks may be recurrent and methodically after 2-3h after meals, especially if carbohydrates rich, such as breakfast and lunch in the Mediterranean diet.

The fact that nutritional and metabolic factors can worse and chronify migraine is well known, but body weight and body mass index (BMI) are probably not the only elements to evaluate in these patients.

We therefore identify patients with chronic migraine diagnosis in which a diary with a methodically post-prandial attack, we performed a glycemic and insulin-like curve of with a load of 75g glucose and subsequent withdrawals at 0-60-120-180 minutes. We collected also data on headache/day frequency per month, BMI, anamnestic presence of polycystic ovary in the woman.

We currently recruited 28 subjects, 24 women, 4 men 32.6 years of age, BMIs between 34 and 18 with an average of 26.9, mean headache days per month of 18,2.

Comparing the glycemic curves of these patients it is noted that baseline blood glucose was for everyone within the norm parameters, but in 24 of 28 patients between 2 and 3 hours the blood glucose decreased below baseline and in 20 below normal values, (hypoglycaemia), no patient has exceeded 200mg /dl.

For insulinemic values, all patients showed normal baseline values that increase after 60 minutes reaching > 10 times of baseline, with gradual reduction over the next 3h.

Based on the data obtained, we have diagnosed metabolic syndrome in 6 patients, for the correlation between hyperinsulinaemia and high BMI, and insulin resistance related to polycystic ovary syndrome in 22 patients with hypoglicemya and PCOS history.

Both group of patients with metabolic syndrome and insulin resistance, were then subjected low charb diet. Preliminary data show that there is a rapid reduction in body weight and the reduction/ansence of post meal migraine attack with a mean reduction of more than 50% on headache days.

References

Barbanti P, Fofi L, Aurilia C, Egeo G, Caprio M. Ketogenic diet in migraine: rationale, findings and perspectives. Neurol Sci. 2017 May;38(Suppl 1):111-115

P38 Peripheral Vagal Nerve Stimulation attenuates migraine aura: a case report

Grazia Sances1, Vito Bitetto1, Eric J Liebler2, Roberto De Icco1, Michele Viana1, Cristina Tassorelli1,3

1Headache Science Center (HSC), C. Mondino National Institute of Neurology Foundation, Pavia, 27100, Italy; 2Electrocore LLC, Basking Ridge, NJ, 07920, USA; 3 Dept of Brain and Behavioural Sciences, University of Pavia, 27100, Italy
Correspondence: Grazia Sances (grazia.sances@mondino.it)

Background

Noninvasive neuromodulation techniques promise efficacy in the treatment of migraine [1]. Interestingly, Ayata et al. have recently reported that noninvasive direct vagus nerve stimulation (nVNS) significantly suppresses spreading depression susceptibility in the occipital cortex in rats [2]. Here we describe a case of a female patient whose aura was repeatedly and consistently shortened by peripheral vagal nerve stimulation using the gammaCore device.

Case report

The subject is a 38-year-old female patient with both migraine with (MA) and without aura (MwA), diagnosed according to the ICHD-3 beta criteria [3] The reported mean frequency of MwA days per month was 7-8, while the frequency of MA attacks was 4-5 per year. Usual aura consisted in monolateral negative scotoma with gradual onset, progressively evolving in homonymous hemianopia (either left or right) and followed by unilateral paresthesias with a progressive involvement of the arm and hemiface. The full aura duration was 1-2 hours, being followed almost immediately by severe unilateral migraine (either left or right) resistant to triptans. MRI and angio-MRI showed a paraphysiological vascular variation of the anterior communicating artery which devoid of clinical relevance. The patient was taking cinnarizine, 25 mg daily, for migraine prevention. She was also on combined oral contraception since 2013, without any worsening effect of hormonal treatment on either MA or MwA. Medical history showed only an asymptomatic iron deficient anemia.

The patient first used the gammaCore device during a clinical study for the acute treatment of migraine attacks. She was trained to deliver one 120” stimulation per side of the neck at the beginning of the attack, regardless of the location of the pain.

During the open label phase of the study, the patient had the possibility to treat multiple migraine attacks. During the 3 treated MA attacks, the patient recorded on the electronic diary a consistent effect of nVNS in terms of: reduction of the duration of the visual symptoms (from the usual 60-120 minutes to 1-2 minutes), the complete prevention of the somatosensory aura and the prevention and/or reduction of the painful phase.

Conclusions

Previous data from the literature clearly show that, in animal studies, nVNS modulates multiple pain pathways and decreases cortical spreading depression. VNS activates nucleus tractus solitarius, locus ceruleus and dorsal raphe nuclei, all of which can modulate CSD susceptibility [2]. To the best of our knowledge this is the first documented report on the effectiveness of nVNS using gammaCore on aura symptoms and, together with the experimental data cited above, it provides a rationale for assessing the potential effect of nVNS in the acute treatment of MA.

Conflicts of interests

CT advisory board fees from Allergan S.p.A. and electroCore, LLC

EL electroCore, LLC

Consent to publish

The patient signs a consent form and she gives consent for information about herself to be published.

References

1. Puledda F, Goadsby P.J. An Update on Non-Pharmacological Neuromodulation for the Acute and Preventive Treatment of Migraine. Headache. 2017; 57(4):685-691.

2. Chen SP et al. Vagus Nerve Stimulation Inhibits Cortical Spreading Depression. Pain. 2016; 157(4): 797–805.

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

P39 Cortical laminar necrosis in a 14-year old patient with status migrainosus

L. M. Messina, C. Gallo, V. Raieli, E. Correnti, F. Vanadia

Cortical laminar necrosis (CLN) is a permanent brain injury radiologically with gyriform distribution. CLN is caused by cerebral energy depletion and it is characterised by high-intensity cortical lesions on T1-weighted MRI images which follow the gyral anatomy of the cerebral cortex. In children, cortical laminar necrosis is usually seen in the subacute or chronic phase of brain damage in hypoxic-ischemic encephalopathy. Other possible etiologies are metabolic disorders, hypoglycemia, renal and hepatic dysfunction and immunosuppressive chemotherapy. CLN may also be seen in patients with encephalitis, but it's an uncommon finding in migraine and status migrainosus with or without aura.

We present the case of a 14-year old male patient, without known history of migraine or neurologic issues, who came to our attention for the manifestation of an acute and long persistent (>72h) symptomatology characterized by headache, confusional state, dysarthria, aphasia and visual disturbances. Clinical evaluation, laboratory tests and instrumental examinations were performed during the hospitalization. Submitted to a first emergency RMN, a localized edema in the supramarginal gyrus in left brain hemisfere has been identified as a possible vascular etiology. Supramargynal gyrus (Broadmann's area 40), a portion of the parietal lobe, is considered to be part of Wernicke's area and it is probably involved with language perception and processing. At a RMN control, it was possible to highlight a laminar necrosis of the cortical-pial zone in that area. This case appears to be interesting for the uncommon correlation between cortical laminar necrosis and status migrainosus with aura as well as for the site of the hypoperfusion revealed through RMN and for the atypical progression of the aura.

Consent for publication: The authors declare that written informed consent was obtained for publication.

References

- Adrià Arboix, Sebastià González-Peris, Elisenda Grivé, María-José Sánchez, Emili Comes. Cortical laminar necrosis related to migrainous cerebral infarction. World Journal of Clinical Cases 2013 November 16; 1(8): 256-259

- Migraine and ischaemic vascular events. Cephalalgia 2007; 27: 965-975

- Tietjen EG. Migraine and ischaemic heart disease and stroke: potential mechanisms and treatment implications. Cephalalgia 2007; 27: 981-987

- Bousser MG, Welch KM. Relation between migraine and stroke. Lancet Neurol 2005; 4: 533-542

- Komiyama M, Nakajima H, Nishikawa M, Yasui T. Serial MR observation of cortical laminar necrosis caused by brain infarction. Neuroradiology 1998; 40

- Headache Classfication Subcommittee of the International Headache Society. The International Classification of Headache Disorders: 2nd edition. Cephalalgia 2004; 24 Suppl 1: 9-160

- A Donaire, M Carreno, B Go’mez, P Fossas, N Bargallo’, R Agudo, M Falip, X Setoaı’n, T Boget, T Raspall, V Obach, J Rumia. Cortical laminar necrosis related to prolonged focal status epilepticus. J Neurol Neurosurg Psychiatry 2006;77:104–106.

- Alexander M. McKinney, Mehmet Teksam, Ross Felice, Sean O. Casey, Ronald Cranford, Charles

- L. Truwit, and Stephen Kieffe. Diffusion-Weighted Imaging in the Setting of Diffuse Cortical Laminar Necrosis and HypoxicIschemic Encephalopathy. AJNR Am J Neuroradiol 25:1659–1665, November/December 2004

- T. Niwa N. Aida A. Shishikura K. Fujita T. Inoue. Susceptibility-Weighted Imaging Findings of Cortical Laminar Necrosis in Pediatric Patients. AJNR 29 Oct 2008

- Sethi N K, Torgovnick J, Macaluso C, Arsura E. Cortical laminar necrosis following anoxic encephalopathy. Neurol India 2006;54:327

P40 Visual snow in a patient with occipital stroke: do we have to rethink migrainous infarction pathophysiology?

Teresa Catarci (teresa.catarci@aslroma2.it)

Headache Centre, Azienda Sanitaria Locale Roma 1-2, Rome, Italy

Background

Visual snow (VS) has recently been described as a distinct event from persistent migraine aura and classification criteria have been proposed [1]. The latest classification of headache disorders of 2015 [2] describes migrainous infarction (MI) as a typical aura that persists and neuroimaging shows an ischaemic lesion in the contralateral cortex.

We describe the case of a patient who reported short-lasting daily symptoms of VN in his entire visual field, for about 40 years, until the day where he woke up with a continuous right sided visual snow phenomenon and was later diagnosed a left occipital stroke.

Case report

On January 2017 a 74 years-old male was referred to our headache outpatient clinic with the diagnosis of cerebral ischaemia and migraine aura. Nine months before he was admitted to the emergency department due to persistent visual symptoms started 8 hours before: at neurological examination he had a left visual field impairment, therefore he was admitted to the neurological ward with the diagnosis of possible protracted migraine aura. He was discharged 6 days later, with the diagnosis of cerebral ischaemia due to occlusion of right posterior inferior cerebral artery. Few weeks after the discharge, a paroxysmal atrial fibrillation was detected on 24-hours ECG and a treatment with novel anticoagulants started. One month later a visual field detected superior right homonymous quadrantopia.

When we first visited the patient, he referred that, prior to the stroke, he had been suffering over the last 40 years, of sudden impairment of vision, lasting for about 5 minutes, similar to a badly-tuned tv channel, with little spots moving in the entire visual field, with little if no disability. He also referred no significant headache ever. After the occurrence of the stroke the same symptoms became persistent and localised at his left visual field. Neurological examination disclosed, in addition to the known visual field impairment, bilateral hypoacusia with left tinnitus. Therefore, a diagnosis of persistent partial VN phenomenon secondary to occipital stroke was done and Magnetic Resonance Imaging (MRI) prescribed together with a visual field: no changes were later reported in the follow-up visit in both exams.

Conclusions

We report, for the first time, the case of a patient whose temporary daily VN phenomenon reversed to a persistent one, in the visual field affected by ischaemic occipital stroke, as typically happens in migraine stroke. This fact may open a new scenario in the pathophysiogenesis of MI that is believed to be due to either vasoconstriction or protracted oligoemia after an aura [3], while visual snow phenomenon has been associated to an increase of blood flow [4]. We hypothesise that, in our patient, the occipital lesion disrupted inhibitory circuits producing quadrantopic persistent VN. The same mechanism could be hypothesised for MI, where the aura could be the result rather then the actual cause of the stroke itself.

Consent for publication: Written informed consent was obtained

References

1. Shankin CJ, Maniyar FH, Digre KB and Goadsby P. ‘Visual snow’ – a disorder distinct from persistent migraine aura. Brain 2017:137; 1419-1428

2. Olesen J. 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. Gryglas A, Smigiel R. Migraine and stroke: What’s the link? What to do? Curr Neurol Neurosci Rep. 2017;17-22.

4. Schankin CJ, Manyiar FH, Sprenger T et al. Brain structural and neurometabolic correlates of visual snow disorder. Neurology 2015;84 (Supplement) P1.291

P41 Treatment patterns and medication use among migraine patients in Finland

Timo Purmonen, Hanna Wahlman, Minna Korolainen

Novartis Finland Oy, Espoo, 02130, Finland
Correspondence: Timo Purmonen

Background

Migraine is a disabling neurological disease. While it is most common among working-age population, it presents significant indirect costs to society, especially when migraine attacks are frequent. The aim of this study was to assess the prevalence of migraine, and proportion of patients needing prophylactic treatment in different age-groups. In addition, we aimed to define the current primary care migraine treatment patterns in Finland.

Materials and methods

We conducted a retrospective register-based study based on prescription data from primary healthcare electronic medical records. The data set covers an overall population of 2,1M inhabitants. Patients were included in the study cohort if they had ≥ 1 prescription for an acute or prophylactic migraine medication during 1.1.2012-30.9.2016. Patients of all ages were included in the cohort. An open text search was combined to search based on ICD-10 and ATC-codes, in order to confirm the accuracy of migraine-related use.

Results

Altogether 61,077 migraine patients were identified. Among these patients 94% were receiving at least one acute treatment (n=57,186), and 20% at least one prophylactic treatment (n=12,082). The prevalence of migraine was 2,9% in the overall population, and 4,2%-5,3% among age-groups between 15-55 years. The most commonly prescribed treatments for acute events were triptans (56%) and NSAIDs (38%). Among the prescribed prophylactic treatments, the most common were beta-blockers (48%), tricyclic antidepressants (24%), angiotensin-receptor-blockers (14%), and anti-epileptics (7%). The most common combination of two acute treatments (NSAID and triptan) were prescribed to 19% of the patients (n=11,625). Prophylaxis was mainly based on monotherapy, but it was often combined with an acute treatment. The most common combination of acute and prophylactic treatment was triptans and beta-blockers. This combination was prescribed for 32% (n=3,832) of patients on prophylactic treatment.

Conclusions

Medical treatment of migraine in Finnish primary care is based on combinations of various substances. Migraine was most common among ages between 15-55 years. Among all patients, 20% received prophylactic treatment.

P42 The impact of fremanezumab on headache-related disability in patients with chronic migraine using the Headache Impact Test

Paul K Winner1, Timothy Fitzgerald2, Sanjay K Gandhi2, Paul P Yeung2, Joshua M Cohen2, Yuju Ma2, Ernesto Aycardi2

1Palm Beach Neurology, West Palm Beach, Florida, 33407, USA; 2Teva Pharmaceutical Industries, Frazer, Pennsylvania, 19355, USA
Correspondence: Paul K Winner

Background

Patients with chronic migraine (CM) experience substantially impaired daily functioning and reduced quality of life, with daily or near-daily headache attacks. In clinical trials, fremanezumab, a fully humanized monoclonal antibody that selectively targets calcitonin gene-related peptide, reduced the frequency, severity, and duration of headaches in patients with CM. The impact of migraine cannot be fully understood only by assessment of headache frequency; the validated 6-item Headache Impact Test (HIT-6) was used to assess the effect of fremanezumab versus placebo on headache-related disability.

Methods

In this multicenter, randomized, double-blind, placebo-controlled, Phase III study, eligible patients with CM were randomized 1:1:1 to receive subcutaneous injections of fremanezumab quarterly dosing (675 mg at baseline and placebo at Weeks 4 and 8), fremanezumab monthly dosing (675 mg at baseline and 225 mg at Weeks 4 and 8), or placebo at each time point over a 12-week treatment period. As a secondary endpoint, change in HIT-6 score was evaluated from baseline to 4 weeks after administration of the last dose of study drug. HIT-6 scores range from 36 to 78, with higher scores indicating a greater impact of headache on daily life. Efficacy analyses were performed in the full analysis set (FAS; all randomized patients who received at least one dose of study drug and had at least 10 days of post-baseline efficacy assessments on the primary endpoint) and repeated for the per-protocol analysis set (PPS). The data were analyzed using the analysis of covariance approach, with baseline HIT-6 score and years since onset of migraine used as covariates. P-values for treatment comparisons were based on the Wilcoxon rank-sum test.

Results

Treatment with both fremanezumab dose regimens yielded significant improvements in disability, as measured by the reductions in HIT-6 scores from baseline to 4 weeks after administration of the last study dose. In the FAS, the least-squares mean ± standard error changes from baseline with fremanezumab quarterly dosing (–6.4±0.45 points) and monthly dosing (–6.8±0.44 points) were greater than with placebo (–4.5±0.45 points); resulting in significant treatment differences (relative to placebo) in HIT-6 score change for fremanezumab-treated patients (quarterly: –1.9±0.49 points, P=0.0004; monthly: –2.4±0.49 points, P<0.0001). Similar treatment differences were observed in the PPS (quarterly: –2.1±0.51 points, P=0.0001; monthly: –2.3±0.51 points, P<0.0001).

Conclusions

In this Phase III study, fremanezumab treatment demonstrated a significant improvement in headache-related disability in patients with CM.

Trial registration

ClinicalTrials.gov NCT02621931

Competing Interest

Paul K Winner has been an investigator in clinical trials sponsored by Teva, Amgen, Genetech, Novartis, Allergan, AstraZeneca, Biogen Idec, and Ipsen. He has participated in advisory boards for Teva, Amgen, Avinar, Novartis, and Allergan, and has been on a speaker’s bureau for Allergan, Avinar and Teva.

All other authors are employees of Teva Pharmaceutical Industries.

P43 Development of the Italian version of the “identify chronic migraine” (IT-ID-CM)

Simona Sacco1, Silvia Benemei2, Sabina Cevoli3, Gianluca Coppola4, Pietro Cortelli3, Francesco De Cesaris2, Cristiano De Marco5, Cherubino Di Lorenzo4, Luana Evangelista1, Pierangelo Geppetti2, Andrea Negro5, Giulia Pierangeli3, Francesco Pierelli4, Luigi Alberto Pini6, Francesca Pistoia1, Antonio Russo8, Cristina Tassorelli7, Gioacchino Tedeschi8, Paolo Martelletti5

1Department of Applied Clinical Sciences and Biotechnology, Section of Neurology, University of L’Aquila, L’Aquila, Italy; 2 Department of Health Sciences, Section of Clinical Pharmacology and Oncology, University of Florence, Florence, Italy; 3 Department of Biomedical and Neuromotor Sciences, University of Bologna, Bologna, Italy; 4 Department of Medico-Surgical Sciences and Biotechnologies, Sapienza University Polo Pontino, Latina, Italy; 5 Department of Clinical and Molecular Medicine, Regional Referral Headache Centre, Sant'Andrea Hospital, Sapienza University, Rome, Italy; 6 Headache and Drug Abuse Research Centre, Policlinico Hospital, University of Modena e Reggio Emilia, Modena, Italy; 7 Headache Science Center, C. Mondino National Neurological Institute, Pavia, Italy Dept. of Brain and Behavioral Sciences, University of Pavia, Italy; 8 Department of Medical, Surgical, Neurological, Metabolic and Aging Sciences, Second University of Naples, Naples, Italy

Background

Chronic migraine is an underdiagnosed and undertreated condition. Tools to improve chronic migraine detection by health care professionals may promote proper referral to dedicated care. Recently, the self-administered tool ‘Identify Chronic Migraine (ID-CM)’ was developed and validated to help clinicians to identify patients likely to suffer from CM. The aim of the present study was to develop the Italian version of the ID-CM (IT-ID-CM).

Material and Methods

One participant in the study translated the original version of the ID-CM into Italian. Then, a meeting was held to share the draft of the IT-ID-CM among study participants and discuss possible issues related to the translation and future validation. After the meeting, each study participant was asked to compare the draft of the IT-ID-CM with the original version and provide comments and suggestions. The suggestions were reviewed by two study participants, and a revised draft was developed. The draft was back-translated into English and compared with the original version to develop the final IT-ID-CM.

Results

We developed a fully comprehensible and accurate Italian translation of the ID-CM consistent with the original English text (Figure).

Conclusions

The IT-ID-CM is now available for evaluation in the clinical setting. The next steps foresee the validation of the tool in specialized and primary care settings, and the creation of an application for smartphones, tablets and desktop computers, which will help to promote the diffusion of the IT-ID-CM.

Acknowledgements

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

References

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.

P44 Importance of Anatomical Diagnostic Approach for Migraine and Tension type headache using Acupuncture and Meridian of Korean Hand Therapy

SoonWon Park1, Kyuhyun Park2, Taewoo Yoo3

1Dept. of Neurology, Bongseng Memorial Hospital, Busan, Korea; 2Emeritus Prof. Pusan National University, Busan, Korea; Dept. of Neurology, Jungang Nara Hospital, Busan, Korea; 3Korean Hand Acupuncture Therapy Institute, Seoul, Korea
Correspondence: Kyuhyun Park (qhynbak@pusan.ac.kr)

Background

The current diagnosis of primary headache has not been sufficient for appropriate treatment. We used to make diagnosis based on the history taking and criteria of International Headache Classification. One of criteria is location such as unilateral or bilateral. Correct anatomical diagnosis might be a clue to the problem. There are no standardized methods to decide the location (side and sites) in practice. Traditional Acupuncture and Meridian System has been used for long in oriental medicine. It is well described, but it is complicated to use easily. It is difficult to resolve the underdiagnosis and undertreatment of headache. Therefore, we propose the Acupuncture and Meridian of Korean Hand Therapy (KHT) as a tool for diagnosis of migraine and tension type headache.

Subjects and methods

This procedure was performed during physical examination based on history taking including detailed palpation on the affected regions at Department of Neurology, Pusan National University Hospital from March, 2009 to February, 2012. The 200 primary headache patients who had no other neurological or systemic diseases were included. We checked pain sites or tender points on both sides of head using Acupuncture points and Meridian of Gallbladder (CM1-12) and Urinary Bladder (CI1-8) of KHT.

Results

We identified several tender points, which were connected to each other. The points were closely related with the Acupuncture and Meridian of KHT, which were different from depending on the type of headache. The pain sites and tender points of primary headache presented as Gallbladder and Urinary Bladder Meridian of KHT. The migraine belonged to Gallbladder and tension-type headache belonged to Urinary Bladder Meridian, respectively. Also mixed type headache belonged to various combined Gallbladder and Urinary Bladder Meridian. The pure migraine groups are divided into three, pure tension type headache groups are three and mixed form headache group are nine, respectively.

Conclusion

The pain location of primary headache patients is closely related with Acupuncture and Meridian System of KHT. Application of this method might improve the diagnostic accuracy of primary headache such as migraine and tension-type headache.

P45 Use of nutraceutical Clevia, in Pure Menstrual Migraine

Claudio Mostardini

Headache Center, Ospedale G.B. Grassi, ASL Roma 3

The use of nutraceuticals in the prevention of migraine is increasingly spreading, both for a more holistic approach to pathology and for a patient’s specific request to use less “traditional drugs” and ultimately for their effectiveness, which it is proving to be higher than expectations.

In this sense, Clevia combines the analgesic activity of the three major furanodienes of Commirhora myrrha (MyrLiq), the activity of compensating metabolic mytocondrial deficits of riboflavin, the effect of coenzyme Q10 (CoQ10) that improves energy metabolism neuronal, and last vasoactive and scavenger activity of Gingko Biloba and its derivatives.We decided to test this nutraceutical medicine in one of the most difficult forms of migraine, that is pure menstrual migraine, consisting of migraine attacks closely related to the menstrual cycle.

We selected 7 women with age between 25 and 46 with migraine attacks exclusively during the menstrual phase, with the possibility of using estroprogestin therapy. Patients were given a headache diary that monitored the last three menstrual cycles.Patients had an average of 3.8 days headache per period with an average pain intensity evaluated with a numerical rating scale (NRS) of 8.5 and a use of about 6.2 pain killer / menstrual cycle. Patients were then treated with Clevia 1 cp for about 15 days a month starting 10 days before the menstrual cycle covering the whole cycle for 3 months. Therefore, the previously monitored parameters, headache days, mean pain intensity, number of killer pain per menstrual cycle were compared with those of patients without clevia.

The results have shown that although there was no significant reduction in the number of headache days per period, with a 3.8 to 3 day variation, a marked reduction in pain intensity was observed, which was more manageable with the usual pain killer and consequently even less use of the same, thus resulting in an average pain intensity of NRS of 8.8 to 5.5 with a reduction of Pain Killer from 7.8 to 4 per period.Finally, NRS evaluated the degree of satisfaction of patients with clevia therapy on various parameters (ease of use, side effects, clinical improvement, costs, etc.) compared to non-use with a mean satisfaction value of 7, 8 ie medium / high.This study highlights how the use of nutraceuticals such as Clevia can be useful in the management of migraine patients and in particular of once with pure menstrual migraine.

References

4. I-H-S Classificazione Internazionale delle Cefalee III beta Cephalalgia. 2013 Jul;33(9):629-808

5. Germano A, Occhipinti A, Barbero F, Maffei ME. A Pilot Study on Bioactive Constituents and Analgesic Effects of MyrLiq®, a Commiphora myrrha Extract with a High Furanodiene Content.Biomed Res Int. 2017;2017:3804356.

6. Thompson DF, Saluja HS. Prophylaxis of migraine headaches with riboflavin: A systematic review. J Clin Pharm Ther. 2017 Aug;42(4):394-403.

P46 Maternal alexithymia and attachment style: which relationship with their children's headache features and psychological profile?

Samuela Tarantino1, Laura Papetti1, Cristiana De Ranieri2, Angela Rocco2, Valeria Valeriano2, Francesca Boldrini2, Barbara Battan1, Maria Francesca Paniccia2, Federico Vigevano1, Simonetta Gentile2, Massimiliano Valeriani1,3

1Headache Center, Division of Neurology; 2Unit of Clinical Psychology, Ospedale Pediatrico Bambino Gesù, IRCCS, Piazza Sant’Onofrio 4, Rome, Italy; 3Center for Sensory-Motor Interaction, Aalborg University, Aalborg, Denmark
Correspondence: Samuela Tarantino

Background. A growing body of literature has showed a relationship between insecure “attachment style” and somatic symptoms. In a recent study, we found an association between ambivalent attachment style, migraine severity and psychological symptoms in children/adolescents. There is evidence that caregivers’ attachment styles and their way of management/expression of emotions can influence children’s psychological profile and pain expression. To date, data dealing with headache are scarce. We aimed to study the role of maternal alexithymia and attachment style on their children’s migraine severity (intensity and frequency) and psychological profile (anxiety, depression, somatization and attachment style).

Materials and methods. We enrolled 84 consecutive patients suffering from migraine without aura (female: 45, male: 39; age range 8-18 years; mean age 11.8 ± 2.4 years). Patients were divided into two groups according to frequency of the migraine episodes (high or low). According to headache attack intensity, patients were classified into two groups (mild and severe pain). Children’s psychological profile was assessed by SAFA Anxiety, Depression and Somatization scales. Attachment style was measured by the semi-projective test SAT for patients and ASQ questionnaire for mothers. Maternal alexithymia levels were evaluated by TAS-20.

Results. We found a significant higher score in maternal alexithymia levels in children classified as “ambivalent”, compared to those classified as “avoiding” (Total scale: p= 0.011). Alexithymia levels also correlated with children’s psychological profile. A positive correlation has been identified between mothers’ TAS-20 Total score and the children's SAFA-A Total Score (p=0.026). In particular, positive correlations were found between maternal alexithymia and children’s “separation anxiety” subscale (p=0.009) and “school anxiety” (p=0.015). Maternal “externally oriented thinking” subscale correlated with SAFA-A “school anxiety” subscale (p=0.050). Moreover, we found a correlation between TAS-20 Total score and SAFA-D “Feeling of guilt” subscale (p=0.014). Our data did not show any relationship between TAS-20 and ASQ questionnaires and children’s migraine intensity and frequency.

Conclusions. Maternal alexithymia and attachment style have no impact on children's migraine frequency and intensity. However, our results suggest that, although maternal alexithymic traits don’t play a causative role on children’s migraine severity, they show a relationship with patients’ attachment style and psychological symptoms, which in turn may impact on migraine severity.

P47 Post accidental dural puncture headache: 3 years of obstetric experience using conservative treatment

Paolo Diamanti1, Laura Toscani1, Luigi Farina1, Maurizio Evangelista2

1Cristo Re Hospital, U.O.C Anestesia e Rianimazione,Via delle Calasanziane 25, 00167 Rome, Italy; 2Università Cattolica del Sacro Cuore, Istituto di Anestesiologia, Rianimazione e Terapia del Dolore,Largo Francesco Vito, 1, 00168 Rome, Italy
Correspondence: Paolo Diamanti (diamantipaolo1@tin.it)

Background

Accidental dural puncture represents the most frequent complication of peridural analgesic techniques.

It can cause headache variable in terms of intensity and duration, sometimes requiring invasive treatments.

Accidental dural puncture headache treatment can be either conservative or interventional.

The first one only include prophylactic measures ( bed rest, fluid therapy, analgesia) while the second envisages the epidural blood patch execution.

In our birth centre (2000 deliveries for year) epidural technique is adopted for both labour analgesia and anaesthesia for cesarian section.

The aim of this observational study is to evaluate the effectiveness of preventive/conservative treatment of women affected by post dural puncture haedache in the obstetrics setting.

Material and Methods

We collected data from January 2014 to December 2016.

Primary end point was headache development, secondary the duration of in hospital stay.

The diagnosis of accidental dural puncture headache was carried out following the criteria of The International Classification of Headache Disorders 3rd edition.

All the patients who experienced dural puncture during the procedure received preventive/conservative treatment for headache development.

Treatment consisted in 48 hours bed rest, oral or ev fluid therapy (at least 2000ml/day), and 1g paracetamol PRN up to a maximum of 3g.

Results

On a total of 5898 delivery we practiced epidural analgesia/anaesthesia on 4128 women with an incidence of accidental dural puncture of 0.43 % (18 patients).

Anthropometric data of the included patients are reported in Table 1.

Among the treated patients only 2 (11%) women developed headache requiring analgesics administration.

These patients were discharged from the hospital in 4.18 days on average.

None experienced headache for longer than two days and in none of the selected cases epidural blood patch was required.

Conclusion

In our experience preventive/conservative treatment has proven to be effective on obstetrics patient with dural puncture. The complication prolonged patients hospital stay only in two cases and for three and four days only.
Table 1 (abstract P47).

See text for description

Age

Weight

Height

BMI

33.7

73.6

164.8

27.09

References

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

2. Sprigge J. S., Harper S. J. Accidental dural puncture and post dural puncture headache in obstetric anaesthesia: presentation and management: A 23-year survey in a district general hospital Anaesthesia, 2008, 63, pages 36–43

P48 Pediatric use of Tanacetum Parthenium, Griffonia Simplicifolia an Magnesium in the prophylaxis and symptomatic treatment of headache attacks

Anna Rita Bellomo1, Federica Di Ruscio2, Lorenzo Toni3 (tonilor@tin.it)

1G.B.Grassi Hospital,Rome,Italy,00122; 2Medical and Surgery School Campus Bio-medico University, Rome Italy,00128; 3Department of Mental Health ASL RM/3, Rome,Italy,00125
Correspondence: Anna Rita Bellomo1 (annaritabellomo62@gmail.com); Federica Di Ruscio (federica.diruscio@gmail.com)

Aim: The purpose of this study is to evaluate the use and the self-perceived efficacy and tolerability of three nutraceutical components - Tanacetum parteninum, Griffonia simpliciofila and Magnesium - in children and adolescents with primary headaches without other comorbidities.

Background: Although pharmacological treatments are the first choice for migraine, adverse effects and contraindications limit the use of drugs in children. There is increasing evidence for the efficacy and tolerability of some complementary approaches as nutraceuticals in the management of headache disorders. Nutriceuticals are complementary therapies that include dietary supplements in form of vitamins and minerals. In the last few years, some nutraceutical preparations as magnesium, CoQ10, vitamin D, melatonin and others have been proposed as potential treatment for headache also in childhood. Triptans could be used more frequently as first or almost second choice for treating migraine attack in adolescents. [5]

Methods: 20 children (age 5 – 16 years) with ≥ three migraine attacks per month are treated with Aurastop. The treatment period was 3 months following a 4 week baseline period without prophylactic treatment. Patients were assessed before treatment and at the end of the 3-month-treatment-phase for days with migraine, migraine pain, burden of disease (HIT-6) and subjective evaluation of efficacy.

Discussion: Feverfew (Tanacetum parteninum) has potential function in reducing aura duration and complexity [1] through Parthenolide inhibition of nitroglycerin-induced neuronal activation in specific brain nuclei, as dorsal root ganglia. Griffonia simpliciofila has a role in reducing NMDA-receptors aberrant activity in trigeminal-vascular system, as well as in cortical spreading depression, (CSD) developing. The activity of its precursor (kynurenic acid) acting as an endogenous NMDA receptor antagonist [2]; Magnesium, is involved in numerous enzyme reactions and important for energy metabolism. Deficiencies in magnesium may lead to neuronal dysfunction and are found in individuals with headache attacks; it has been associated with CSD, neurotransmitter release, platelet aggregation and vasoconstriction all of which are important aspects of pathophysiology [3].

Conclusion: All these observations are aimed at testing the synergistic effect of AurastopR as symptomatic treatment of migraine aura and related symptoms in childhood and prophylaxis of headache attacks too, as a already been done in adults[4]. The preliminary results of the study, that are still ongoing, are encouraging, and Tanaceutum partenum, Magnesium and 5HTP with their joint action would seem to have important impact in reducing the pain intensity and the frequency of headache.

References

1) Tassorelli, C., Greco, R., Morazzoni, P., Riva, A., Sandrini, G. and Nappi, G. (2005) Parthenolide Is the Component of Tanacetum parthenium That Inhibits Nitroglycerin-Induced Fos Activation: Studies in an Animal Model of Migraine. Cephalalgia: An International Journal of Headache, 25, 612-621. https://doi.org/10.1111/j.1468-2982.2005.00915.x

2) Chauvel, V., Vamos, E., Pardutz, A., Vecsei, L., Schoenen, J. and Multon, S. (2012) Effect of Systemic Kynurenine on Cortical Spreading Depression and Its Modulationby Sex Hormones in Rat. Experimental Neurology, 236, 207-214. https://doi.org/10.1016/j.expneurol.2012.05.002

3) Sun-Edelstein C., Mauskopm A. (2011) Alternative Headache Treatments: Nutraceuticals, Behavioral in Headache Current, American Headache Society, Willey Blackwell and Physical Treatments

4) Zavarise P., Dalla Volta G. (2017) A Combination of Tanacetum parthenium,Griffonia simplicifolia and Magnesium(Aurastop®) as Symptomatic AcuteTreatment for Migraine Aura:A Retrospective Cohort Study. In Open Access Library Journal, Volume 4, e3660, ISSN Online: 2333-9721, ISSN Print: 2333-9705

5) Toldo I., Rattin M., Perissinotto E., Survey on treatments for primary headaches in 13 specialized juvenile Headache Centers: The first multicenter Italian study, European Journal of Paediatric Neurology

P49 The impact of fremanezumab on migraine-specific health-related quality of life and overall health status in chronic migraine

Richard B Lipton1, Sanjay K Gandhi2, Timothy Fitzgerald2, Paul P Yeung2, Joshua M Cohen2, Yuju Ma2, Ernesto Aycardi2

1Albert Einstein College of Medicine, Bronx, New York, 10461, USA; 2Teva Pharmaceutical Industries, Frazer, Pennsylvania, 19355, USA
Correspondence: Richard B Lipton

Background

Chronic migraine (CM) is characterized by frequent attacks, which adversely affect health-related quality of life (HRQoL). In clinical trials, fremanezumab, a fully humanized monoclonal antibody that selectively targets calcitonin gene-related peptide, reduced the frequency, severity, and duration of headaches in patients with CM. This study measured HRQoL using the Migraine-Specific Quality of Life (MSQoL) questionnaire and health status using the EuroQol 5-dimension 5 response level (EQ-5D-5L) questionnaire in patients treated with fremanezumab versus placebo.

Methods

In this multicenter, randomized, double-blind, placebo-controlled study, patients with CM were randomized 1:1:1 to receive subcutaneous injections of fremanezumab quarterly dosing (675 mg at baseline and placebo at Weeks 4 and 8), fremanezumab monthly dosing (675 mg at baseline and 225 mg at Weeks 4 and 8), or placebo at each time point over a 12-week treatment period. The MSQoL questionnaire (version 2.1) assessed the role function-restrictive (RR), role function-preventive (RP), and emotional function (EF) domains (range 0–100; higher scores indicate better HRQoL). The EQ-5D-5L questionnaire allowed patients to report their general health status on a visual analog scale (VAS, range 0–100; higher scores indicate better health). MSQoL domains were analyzed using a mixed-effects repeated-measures model (with years since onset of migraine and baseline MSQoL domain score as covariates). EQ-5D-5L analyses were conducted using an analysis of covariance approach (with years since onset of migraine and baseline EQ-5D-5L score as covariates).

Results

The study included 375 patients in each fremanezumab treatment group and 371 patients in the placebo group. Compared with placebo, fremanezumab treatment resulted in significant improvements in MSQoL scores from baseline to Week 12. For the RR domain of MSQoL, there were significant treatment differences with each fremanezumab group relative to placebo (quarterly: 5.6±1.4, P<0.0001; monthly: 6.3±1.4, P<0.0001). The RP and EF domains also showed significant treatment differences (P<0.05). Significant improvements with fremanezumab were observed as early as 4 weeks after the first dose and were sustained at all pre-defined assessments. As measured by the EQ-5D-5L VAS, fremanezumab-treated patients reported larger improvements in overall health status than those given placebo (4.6±1.1 [quarterly] and 4.8±1.1 [monthly] versus 2.2±1.1 [placebo]), resulting in significant treatment differences (quarterly: 2.4±1.2, P=0.0402; monthly: 2.6±1.2, P=0.0291).

Conclusions

These results indicate that fremanezumab improves migraine-specific QoL and overall health status of patients with CM, highlighting the positive impact of fremanezumab on CM patients’ ability to engage in and perform work and daily activities.

Trial registration

ClinicalTrials.gov NCT02621931

Competing Interest

Richard B Lipton is a consultant to Teva Pharmaceutical Industries.

All other authors are employees of Teva Pharmaceutical Industries.

P50 Clinical presentation and diagnostic evaluation of idiopathic intracranial hypertension in children and adolescents

Barbara Battan, Laura Papetti, Irene Salfa, Federico Vigevano, Massimiliano Valeriani

1Headache Center, Child Neurology Unit, Bambino Gesu’ Children’s Hospital, Rome, Italy
Correspondence: Barbara Battan (barbara.battan@opbg.net)

Background

Idiopathic intracranial hypertension (IIH) or pseudotumor cerebri is a syndrome characterized by signs and symptoms of increased intracranial pressure in the absence of a secondary cause. The aim of the study is to report the IIH clinical presentation in children and adolescents presenting to our hospital during a 10-year period.

Materials and methods

Retrospective study, between January 2007 and January 2017, of IIH patients, younger than 15 years, was conducted. Modified Dandy criteria were used for IIH diagnosis. The patients were analysed according to age (≤10 and 11-15 years).

Results

Thirty-four patients, ranging from 3.8 to 15 years, were included. Thirteen patients were younger than 11 years (38.2%), while twenty-one patients were 11-15 years old (61.7%). Twenty-nine patients (85.2%) were obese (weight centile ≥ 90%). Mean cerebrospinal fluid opening pressure was 422 mm H2O (260-890 mmH2O). The most common presenting symptoms were headache (94.1%), vomiting (29.4%), dizziness (11.76%), blurred vision or diplopia (67.6%). Sixth nerve palsy occurred in 11 children (32.3%). In general, headache did not respond to pain medication. All our patients showed papilledema. Diagnostic evaluation included neuroimaging studies and ultrasound-based optic nerve sheath diameter (ONSD) measurement. In 6 patients (15%), MRI or CT showed signs of empty sella syndrome, while in 9 patients (26.4%) ultrasound ONSD measurement showed optic nerve sheath distension. There were no significant differences between the age groups in both clinical presentation and instrumental findings. Treatment included weight loss and acetazolamide (maximum 5mg/kg/die) in 28 patients (82.3%). Furosemide was added to acetazolamide in 2 patients (5.8%) and in 2 other patients was necessary added Delatcortene (5.8%). All patients fully recovered and none of them complained visual loss in the follow-up.

Conclusion

IIH should be considered in children with new-onset headache. Clinical headache presentation can be variable, although vomiting and visual symptoms are frequently associated. To exclude a secondary cause, neuroimaging should be performed. ONSD measurement may be useful as an additional tool to identify patients with IIH. Early diagnosis and treatment for IIH can prevent potential visual loss that remains the major morbidity. Acetazolamide and weight loss remain the most effective treatments in children.

P51 Onabotulinumtoxin A in a patient with ileointestinal bypass and chronic migraine: a case report

Ottavio Di Marco, Stefania Di Mauro, Fernando Ferrauti

ASL Frosinone

Background

Migraine is a common, chronic, incapaciting disorder, characterized by attacks of severe headache. Episodic migraine can progress to chronic migraine, which is defined as headache on ≥15 days/month for ≥3 months of which ≥8 days [1]. Onabotulinumtoxin A was approved in Italy in 2013 for symptom relief in patients with chronic migraine who have failed, or do not tolerate, oral prophylactic treatments [2].

Case Report

We describe the clinical case of a 36-year-old female patient who refers to the onset of cefalalgic pain at puberty, described with compression-type pain, diffused, with intolerance to light, hight intensity that prevented her from studying and lasted about 1-3 days. In the following years there was a further worsening of the frequency and intensity of the crisis. During the same period she began to take on weight, until serious obesity. She therefore carried out many hospital admissions, with the assumption of various anti-inflammatory therapies, until morphine. At 23 years she has been submitted to intestinal bypass surgery. Approximately 4-5 years ago, there were a re-onset of migraine, which gradually increased in intensity, not including anti-inflammatory therapies, with many accesses to Emergency Unit and use of opioid. Becouse of the ileointestinal bypass, shehad poor absorption with no repetition to prophylactic medical therapy. In September 2016 she was included in botulinum toxin treatment, meeting the criteria for chronic treatment-resistant migraine. Already after the second application, there was a regression of symptoms, a reduction of intensity and frequency of attacks and recovery of daily life activities.

Conclusion

There is good clinical evidence that treatment with onabotulinumtoxinA leads to a reduction of monthly headache days and improves quality of life [3], also in this case report in which other treatment were no possible and not efficacy due to ileointestinal bypass, with secondary malabsorption.

Consent for publication: The authors declare that written informed consent was obtained for publication.

References

1. Headache Classification Committee of the International Headache Society (IHS) (2013) International classification of headache disorders, 3rd edition (beta version). Cephalalgia 33:629–808

2. Russo A, Silvestro M, Tessitore A, Tedeschi G. The “Ram’s Horns Sign”: A Case Report of an Unusual Side Effect of OnabotulinumtoxinA in a Chronic Migraine Patient. Headache. 2016;56(10):1656-1658

3. Claus M Escher, Lejla Paracka, Dirk Dressler, and Katja Kollewe. Botulinum toxin in the management of chronic migraine: clinical evidence and experience. Ther Adv Neurol Disord. 2017 Feb; 10(2): 127–135.

P52 The impact of headache free days on headache-related disability and productivity among people with migraine with ≥4 headache days in the past month

Lulu Lee1, Jvawnna Bell2, Timothy Fitzgerald2, Joshua M. Cohen2

1Kantar Health, 1810 Gateway Drive, Suite 120, San Mateo, CA, 94404, USA; 2Teva Pharmaceutical Industries, Frazer, Pennsylvania, 19355, USA
Correspondence: Lulu Lee

Objectives: Determine the relationship between headache-related quality of life measures and headache free days (HFDs) among patients with ≥4 headache days in the past month.

Methods: The 2016 US National Health and Wellness Survey (NHWS; N=97,503) is a self-administered, sample of adults (≥18 years). Patients with a migraine diagnosis and reported experiencing ≥4 headache days a month were considered at risk for disease progression. Primary independent variable was the number of HFDs as both a continuous (30-number of HFDs in the past 30 days) and categorical (0-10;11-20;21-26 HFDs) measure. HFDs was used as a predictor in separate generalized linear models (GLMs).

Outcomes included patient reported number of days absent from work and days of household activities missed due to migraine, estimated annual indirect costs due to work productivity loss (assessed via Work Productivity and Activity Impairment Questionnaire). Headache-related disability was measured via the Headache Impact Test (HIT-6).

Results: Using HFDs as a continuous variable in the multivariable regression, each HFD was found to be associated with a 0.15 (regression coefficient) point reduction in HIT-6 scores. As a categorical variable, each 10 day increase in HFDs was associated with significantly lower HIT-6 total scores (adjusted means=66.59 [0-10 HFDs], 65.66 [11-20], 63.91 [21-30], all p<0.02).

Each HFD associated with 0.95 (Rate Ratio [RR]) times days of work missed due to migraines and 0.95 (RR) times days of household activities missed due to migraines. Thus, each HFD reduces both number of work days missed and number of days of household activities missed by 5%.

Increasing the number of HFDs from 0-10 to 21-26 (adjusted means=4.44 vs. 1.46, p=0.002) and from 11-20 to 21-26 (3.36 vs 1.46, p=0.009) categories was associated with significantly fewer work days missed due to migraine. Similarly, increasing the number of HFDs from 0-10 to 11-20 (adjusted means = 22.99 vs. 9.72, p<0.001) and from 0-10 to 21-26 (22.99 vs. 7.34, p=0.001) categories was associated with significantly fewer days of household activity missed due to migraine.

Increasing the number of HFDs from 0-10 to 21-26 per month was associated with significantly lower indirect costs.

Conclusions: Increasing the number of HFDs is associated with a decrease in headache-related disability among those with migraine who are at risk for disease progression. Migraine places a substantial indirect cost burden on this patient population and increasing total HFDs may help to reduce this burden.

P53 Early Onset of Action with Fremanezumab Versus Placebo for the Preventive Treatment of Chronic Migraine

Paul Yeung1, Ernesto Aycardi1, Marcelo Bigal1, Tricia Blankenbiller1, Melissa Grozinski-Wolff1, Ronghua Yang1, Yuju Ma1, Jan Brandes2

1Teva Pharmaceutical Industries, Frazer, Pennsylvania, 19355, USA; 2Nashville Neuroscience Group, Nashville, TN 37203, USA
Correspondence: Paul Yeung

Background: Migraine prevention is intended to reduce the frequency, severity, and disability associated with migraine attacks, and faster onset of action could increase benefit to patients with migraine. Fremanezumab is a fully humanized monoclonal antibody targeting the calcitonin gene-related peptide (CGRP) ligand, a preventive treatment designed to specifically target a pathophysiologic mechanism of migraine. This analysis assesses the early onset of action of fremanezumab in the prevention of chronic migraine.

Methods: A 16-week, multicenter, randomized, double-blind, placebo-controlled, parallel-group study comparing the efficacy, safety, and tolerability of 2 subcutaneous dose regimens of fremanezumab and placebo (PBO) in adults with Chronic Migraine (CM). Patients maintained a 28-day daily diary during baseline period, and throughout treatment period. Patients were assigned randomly to 1:1:1 ratio to 1 of 3 treatment groups: (1)monthly dosing: 675 mg of fremanuzemab followed by 225 mg of fremanezumab at months 2 and 3, (2)quarterly dosing: 675 mg of fremanuzemab at month 1, followed by placebo injections at months 2 and 3, and (3)monthly administration of matching placebo. The secondary endpoint, the mean change from baseline (28-day run-in period) to the 12-week randomization period in the monthly average number of migraine days, and results at Weeks 1, 2, 3 and 4 were also assessed using a mixed-effect model for repeated measures.

Results: Statistically significant reduction in the number of monthly headache days of at least moderate severity was experienced during the 12-week period after 1st dose for both fremanezumab dosing regimens [monthly (-4.6 days);quarterly (-4.3 days); p<0.0001] vs. placebo (-2.5 days), and during the 4-week period after 1st dose, for both dosing regimens (p<0.0001). Fremanezumab resulted in significant reduction in the weekly number of headache days of at least moderate severity:
  • At Week 1, (-1.1 days; p<0.0001) versus placebo (-0.5 days)

  • At Week 2, (-1.2 days; p<0.0001) versus placebo (-0.5 days)

  • At Week 3, (-1.2 days; p<0.0001) versus placebo (-0.6 days)

  • At Week 4, (-1.1 days; p=0.0006) versus placebo (-0.7 days)

Posthoc analysis indicated that more patients reported no headache of at least moderate severity with fremanezumab (69%; p=0.0036) versus placebo (61%) by the next day following first injection.

Conclusion: Onset of action with fremanezumab occurred rapidly for preventive treatment of migraine. Significant improvement was maintained for both monthly and quarterly subcutaneous injections.

P54 Burden of illness among treated migraine patients with ≥4 headache days in the past month

Jvawnna Bell1, Lulu Lee 2,Timothy Fitzgerald1, Joshua M. Cohen1

1Teva Pharmaceutical Industries, Frazer, Pennsylvania, 19355, USA; 2 Kantar Health, 1810 Gateway Drive, Suite 120, San Mateo, CA, USA 94404
Correspondence: Jvawnna Bell

Objectives: To determine the burden of illness among patients treated for migraine with ≥4 headache days in the past month.

Methods: The data source was the 2016 US National Health and Wellness Survey (NHWS; N=97,503), a self-administered, nationally representative sample of adults (≥18 years). Respondents were included in this analysis if they self-reported a diagnosis of migraine, experienced ≥ 4 headache days in the past 30 days, and were currently using a prescription treatment for migraine. Using propensity score matching to reduce bias, respondents meeting the above criteria were matched with people without migraine on age, gender, comorbidities (Charlson Comorbidity Index), annual household income, education, insurance status, body mass index (BMI), and smoking status. Outcomes included mental health comorbidities, work productivity and activity impairment as measured by the Work Productivity and Activity Impairment Questionnaire (WPAI), health utilization in the past 6 months (i.e., healthcare provider (HCP) visits, emergency room visits, and hospitalizations), and estimated annual indirect and direct costs. Post-match, groups were compared using One-Way ANOVAs and chi-square tests on outcomes.

Results: There were 197 respondents in each cohort. A statistically significantly greater proportion of treated migraine patients reported being diagnosed with depression than non-migraine controls (58.4% vs. 27.9%, p<0.001). A greater portion of treated patients also reported being on long-term disability compared to non-migraine controls (13.7% vs. 5.6%,p<0.003). Treated migraine patients reported greater losses in work productivity and increases in activity impairment. Compared to non-migraine controls, treated patients experienced greater absenteeism (11.8% vs. 6.3%, p=0.03), presenteeism (36.0% vs. 17.5%, p<0.001), overall work impairment (40.9% vs. 20.9%, p<0.001), and activity impairment (45.4% vs. 25.4%, p<0.001). These patients also reported more HCP visits (7.55 vs. 4.43, p<0.001) and ER visits (0.48 vs. 0.25, p=0.030) compared to non-migraine controls in the previous 6 months. Greater work productivity loss among treated migraine patients resulted in higher estimated annual indirect costs ($14,770.57 vs. $5,764.93, p<0.001) compared to non-migraine patient controls. Treated migraine patients utilized more healthcare services than non-migraine patients ($24,499.90 vs. $15,318.91, p=0.013).

Conclusions: The overall burden associated with migraine is substantial despite the availability of treatment options. Migraine patients in this survey reported a higher percentage of depression, long-term disability, work productivity loss, absenteeism, presenteeism, activity impairment, and use more health care services compared to people without migraine. As a result, patients treated for migraine incurred substantially greater direct and indirect costs compared to non-migraine controls.

P55 Efficacy and Safety of Motilitone in Migraine Patients with Gastrointestinal Symptoms

Dong Wook Kim1 and Kwang Ki Kim2

1Department of Neurology, Konkuk University School of medicine, Seoul, Korea; 2Department of Neurology, Dongguk University Ilsan Hospital, Ilsan, Korea

Background: Nausea and vomiting are a frequent accompaniment of migraine and prokinetic medications are frequently used in its management. Most prokinetic medications that are used in migraine are dopamine antagonists and therefore have the potential to cause drug-induced extrapyramidal symptoms. We evaluate the efficacy and safety of motilitone, a recently developed prokinetic drug, in migraine patients with gastrointestinal symptoms.

Materials and Methods: From two outpatient neurological clinics, we prospectively included 100 migraine patients with nausea and vomiting and treated them with medications including motilitone. For the evaluation of safety, we used drug-induced extrapyramidal symptoms (DIEPS) questionnaire, and the clinical improvement was assessed with clinical global clinical impression of change (C-GIC) and patients’ global clinical impression of change (P-GIC).

Results: Among the 100 patients, only two patients described the presence of mild extrapyramidal symptoms (one with difficulty in standing up from chair and the other with difficulty in find movements), but it was not certain that these extrapyramidal symptoms were associated with motiltione treatment and both patients refused to discontinue motiltione with the clinical improvement. The mean values of C-GIC and P-GIC were 3.26±0.8 and 3.19±1.1 respectively, which indicate mild improvement with the treatment.

Conclusions: Our study shows that medication including motiltione for migraine patients with gastrointestinal symptoms is effective and there is low risk of clinically significant extrapyramidal symptoms. Further studies are necessary to accurately evaluate the risk of extrapyramidal symptoms with motilitone treatment in patients with migraine.

P56 Topiramate is more effective than acetazolamide at lowering intracranial pressure in healthy rodents

Hannah Botfield1,2†, William J Scotton1,2,3†, Maria Uldall4, Connar Westgate1,2, James Mitchell1,2,3, Rigmor Jensen4, Alex Sinclair1,2,3

1Institute of Metabolism and Systems Research, University of Birmingham, Edgbaston, B15 2TT, UK; Centre for Endocrinology, Diabetes and Metabolism, Birmingham Health Partners, B15 2TH, UK; 3Department of Neurology, University Hospitals Birmingham NHS Foundation Trust, B15 2TH, UK; 4Danish Headache Center, Clinic of Neurology, Rigshospitalet-Glostrup, University of Copenhagen, Nordre Ringvej 69, 2600 Glostrup, Denmark
Correspondence: Alex Sinclair (a.b.sinclair@bham.ac.uk)

Joint first author

Background

Management of Idiopathic Intracranial Hypertension (IIH) aims to reduce intracranial pressure (ICP). Acetazolamide is the most commonly used drug, with class 1 evidence demonstrating modest improvement in patients with mild visual loss. Other drugs used include topiramate, furosemide, amiloride and octreotide, despite there being little mechanistic or clinical evidence to support their use. The aim of this study was to ascertain which of these drugs has the greatest effect on lowering ICP in vivo.

Materials and methods

Using a validated epidural ICP recording method, we measured changes in ICP in conscious female rodents after subcutaneous administration of clinical and high doses of drug over 2 hours (the time to peak serum concentration). Drugs evaluated, with clinical and high doses, were: acetazolamide (1g and 4g), topiramate (50mg and 200mg), furosemide (40mg and 240mg), amiloride (5mg and 20mg) and octreotide (350μg and 2mg). In addition, we measured ICP for 12 hours after oral administration of equivalent high doses of acetazolamide and topiramate. Dose conversion between rodents and humans followed the US Food and Drug Administration (FDA) guidance.

Results

At clinical doses, subcutaneous administration of topiramate lowered ICP by 32% (p=0.0009). There was no significant reduction in ICP noted with acetazolamide (-19%), amiloride (-11%), furosemide (-1%) or octreotide (-1%). At high doses, subcutaneous administration of topiramate lowered ICP by 21% (p=0.015) whilst there was no significant reduction in ICP noted with high subcutaneous doses of acetazolamide (-20%), furosemide (-13%), amiloride (-27%) and octreotide (-18%). Oral administration of equivalent high doses of topiramate lowered ICP by 22% (p=0.018), compared to only a 5% reduction with acetazolamide (p=>0.999).

Conclusions

Our in-vivo studies have demonstrated that, at both clinical and high subcutaneous doses, as well as high oral doses, administration of topiramate significantly lowers ICP. Other drugs tested, including the acetazolamide the current first line oral therapy in IIH, did not significantly reduce ICP. In the clinical setting topiramate may have additional advantages in IIH due to migraine prevention and weight loss effects, though the potential for negative impact on mood and cognition must also be considered. Future clinical trials evaluating efficacy and side effects of topiramate in IIH would be of interest.

P57 National awareness campaign to prevent medication-overuse headache in Denmark

Louise Ninett Carlsen1, Maria Lurenda Westergaard1, Mette Bisgaard1, Julie Brogaard Schytz2, Rigmor Højland Jensen1

1Danish Headache Center, Neurology Department, Rigshospitalet, Ndr. Ringvej 69, 2600 Glostrup, Copenhagen, Denmark; 2Association of Danish Pharmacies, Copenhagen, Denmark
Correspondence: Rigmor Højland Jensen (rigmor.jensen@regionh.dk, +45 38 63 30 59)

Background: Medication-overuse headache (MOH) is prevalent but in principle preventable. The objective is to describe the Danish national awareness campaign for MOH.

Methods: The Danish Headache Center, the Association of Danish Pharmacies, and headache patient organizations implemented a four-month MOH awareness campaign in 2016. Target groups were the general public, general practitioners, and pharmacists. Key-messages were: overuse of pain-medication can worsen headaches; pain-medication should be used rationally; and MOH is treatable. A range of communication technologies was used. A survey on the public’s awareness of MOH was conducted.

Results: The Danish adult population is 4.2 million. Online videos were viewed 297,000 times in three weeks. All 400 pharmacies received campaign materials. Over 28,000 leaflets were distributed. Two radio interviews were conducted. A television broadcast about headache reached an audience of 520,000. Forty articles were published in print media. Information was accessible at 32 reputable websites and 5 online news-agencies. Three scientific papers were published. Information was available at an annual conference of general practitioners including a headache lecture. The survey showed an increase in percentage of the public who knew about MOH (from 31% to 38%).

Conclusion: A concerted campaign to prevent MOH can be implemented through involvement of key stakeholders.

P58 Alcohol as a risk factor for migraine attacks: an exploration

Pablo Prieto1, Gabriel Boucher1, Stephen Donoghue1, Alec Mian1, Noah Rosen2

1Curelator Inc., Cambridge; 2Northwell Health, New York, United States
Correspondence: Pablo Prieto

Background

Alcohol has long been suspected as a migraine trigger commonly resulting in avoidance and possible impact on quality of life, but numerous studies have been inconclusive [1]. To explore this question we statistically compare intake of alcohol and occurrence of migraine.

Methods

Individuals with migraine registered to use Curelator Headache (1) through a physician ‘coupon referral’ program, (2) via the Curelator website or (3) the iOS App Store and answered questions about personal suspected triggers, including alcohol, and their importance (0=none; 10=maximal). Curelator Headache was used daily for at least 90 days, entering details about headaches and tracking factors that may affect migraine occurrence. Alcohol consumption was recorded daily as ‘YES/NO’ and if YES by type and units. After 90 days all factors were analyzed and for each individual the association of alcohol intake with attacks was determined [2].

Results

Of 531 individuals with migraine (Table 1), alcohol was suspected as a risk factor by 304 (57%).

Consumption of alcohol was significantly different between those who did and those who did not suspect it. A quarter of users never consumed alcohol and 32% of those who did had inadequate data for analysis (e.g. avoidance of alcohol or regular consumption so insufficient variability). In alcohol consumers, comparisons between those who did not vs those who did suspect alcohol as a trigger showed no association with migraine in the majority in both groups; alcohol as a potential trigger in 6% vs 8%; and as a potential protector in a 4% vs 7%.

No association was found between degree of suspicion of alcohol and the percentage of individuals with a confirmed association (Table 2).

Previous day analysis (Table 3) found association in different proportions.

Conclusions

Despite the belief that alcohol is a common risk factor for migraine, in the majority of users no association was found. Alcohol intake was less frequent in people not suspecting alcohol, possibly because abstainers would also not suspect alcohol as risk factor. Irrespective of the degree to which a user suspected alcohol as a trigger, more than 80% of users showed no association between alcohol and migraine. Same day intake was as often found to be associated with risk reduction (potential protector) as with risk increase (potential trigger) (7% each), but delayed association was mostly found as a potential trigger (17%). Our data do not support the hypothesis that alcohol is a common trigger for migraine.
Table 1 (abstract P58).

User characteristics and risk factor associations in those suspecting alcohol as a risk factor, those who did not and all users

 

Total

Did not consume alcohol

Consumed Alcohol

Adequate data for analysis

Potential trigger

Potential protector

No Association

Suspected

304 (57.3%)

23 (8%)

281 (92%)

198 (72%)

16 (8%)

14 (7%)

168 (75%)

Not suspected

227 (42.7%)

110 (48%)

117 (52%)

74 (64%)

4 (5.5%)

4 (5.5%)

66 (89%)

Totals

531

133 (25%)

398 (75%)

272 (68.3%)

20 (7%)

18 (7%)

234 (86%)

Table 2 (abstract P58).

Association analysis by degree of suspicion

 

Total

Potential trigger

Potential protector

No Association

Mildly suspected

75

4 (8%)

11 (21%)

35 (71%)

Moderately suspected

99

8 (11%)

10 (14%)

76 (75%)

Highly suspected

154

5 (5%)

16 (18%)

57 (77%)

Table 3 (abstract P58).

Association by timing of alcohol intake

 

Lagged analysis (previous day)

Same-day analysis

 

Potential trigger

Potential protector

No Association

Potential trigger

Potential protector

No Association

Suspected

34 (16.1%)

1 (0.5%)

176 (83.4%)

16 (8%)

14 (7%)

168 (75%)

Not suspected

15 (20.6%)

2 (2.7%)

56 (76.7%)

4 (6%)

4 (4%)

66 (89%)

Totals

49 (17%)

3 (1%)

232 (82%)

20 (7%)

18 (7%)

234 (86%)

References

[1] Panconesi A. Alcohol and migraine: trigger factor, consumption, mechanisms. A review. J Headache Pain (2008) 9:19–27

[2] Peris F, Donoghue S, Torres F, Mian A, Wöber C. Towards improved migraine management: Determining potential trigger factors in individual patients. Cephalalgia. 2017 Apr;37(5):452-463

P59 Medication use and overuse patterns in a cohort of US and UK individuals with migraine using a digital platform

Pablo Prieto1, Gabriel Boucher1, Stephen Donoghue1, Stephen D. Silberstein2

1Curelator Inc., Cambridge, United States; 2Jefferson Headache Center, Thomas Jefferson University, Philadelphia, United States
Correspondence: Pablo Prieto

Background

Overuse of acute medications may worsen migraine and lead to medication overuse headache (MOH) [1]. Here we describe medication use and identification of overuse (MO) in users of a digital platform for migraine (Curelator HeadacheTM). The objective is to compare medication use and possible overuse patterns in individuals’ with both chronic (CM) and episodic (EM) migraine from the US and the UK.

Methods

Individuals with migraine registered to use Curelator Headache (1) through a physician ‘coupon referral’ program, (2) via the Curelator website or (3) the iOS App Store and and was used daily for at least 90 days entering details about headaches and medications used acutely and chronically. Acute medication use was analyzed at the level of individual drug names and MO was defined according to ICHD-3 beta criteria; other reported medication was not included in the analysis.

Results

Individuals from the USA (n = 261) and the UK (n = 216) entered 20,353 (USA) and 17,965 (UK) headache instances. Only 6 (2.3%) US and 4 (1.8%) UK users did not use any acute medication for their headaches.

The average number of medications per user was significantly higher for CM than EM but significantly higher in EM than in CM group in both countries on a per headache basis (Table 1).

MO was significantly higher in the US EM (21%) than the UK EM group (12%). MO groups have similar usage of medication, but CM & no MO users typically use much less medication per headache than their EM & no MO peers.

Triptans and NSAIDs are most frequently used by EM users in both countries and significantly more frequently than in CM cohorts. NSAIDs are most frequently used by CM users in both countries. While usage of analgesic combinations by CM users is similar in both countries, UK CM users use triptans more frequently than in the US. Opioids were used more frequently by US CM users than UK CM users.

Conclusion

Curelator Headache identified MO in 29% of individuals in a predominantly physician referred group (US) and in 19% in a predominantly population recruited group (UK). CM and EM users showed different frequency of medication use and overuse, similar to previously reported [2]. The higher ratio of medication use in the EM MO subgroup compared to the CM MO subgroup indicates that a MO pattern may be identifiable in EM individuals.
Table 1 (abstract P59).

Medication use description

Variable / Cohort

US

UK

 

CM

EM

CM+MO

CM+nMO

EM+MO

EM+nMO

CM

EM

CM+MO

CM+nMO

EM+MO

EM+nMO

Average medication classes per user

2.45

2.19

2.80

1.89

2.53

2.10

2.82

2.45

3.11

2.53

2.48

2.45

Average medications per user

3.55

2.81

4.13

2.63

3.33

2.67

3.58

2.91

4.26

2.89

2.95

2.90

Average medications classes per headache

0.81

0.94

1.16

0.24

1.19

0.83

0.72

1.01

1.04

0.37

1.25

0.96

Average medications per headache

0.86

0.97

1.23

0.24

1.22

0.84

0.74

1.02

1.07

0.38

1.28

0.97

References

[1] Tassorelli C, et al. The added value of an electronic monitoring and alerting system in the management of medication-overuse headache: A controlled multicentre study. Cephalalgia. 2016 Jul 20

[2] Scher AI et al. Patterns of medication use by chronic and episodic headache sufferers in the general population: results from the frequent headache epidemiology study. Cephalalgia. 2010 Mar;30(3):321-8

P60 Individual self-prediction of migraine attacks: longitudinal analysis of cohort of migraine patients using a digital platform

Pablo Prieto1, Gabriel Boucher1, Alec Mian1, Noah Rosen2

1Curelator Inc., Cambridge; 2Northwell Health, New York, United States
Correspondence: Pablo Prieto

Background: As a critical component towards self-management of their condition we examine the individual ability of patients to predict their attacks 24 hrs in advance. Prediction of attacks might be expected to be difficult as migraine premonitory symptoms, and the potential risk factors that trigger them, show significant inter-individual variation [1] and possibly also intra-individual variation.

Accurate prediction may impact quality of life, allow optimal timing of medication dosing and may also lead to understanding of the profiles and “best practice” of good predictors. Thus, the objective is to understand and compare ability of episodic migraineurs to self-predict attacks on an individual level.

Methods: Individuals with migraine registered to use a digital platform (Curelator Headache™) via website or the App Store (iOS only) and on a daily basis for at least 90 days entered about lifestyle factors, possible headaches, and medications as well as migraine expectation for the next 24 hours (low/moderate/high). Patients with at least 10 low and 10 high expectations instances of migraine were included in the analysis. Prediction was considered successful when 24hr expectation of migraine was high and an attack occurred on the next day; or 24 hr expectation was low and was followed by a migraine free day.

Results: Of 497 episodic migraineurs examined in the study, 146 met the criteria for analysis. Good predictors were defined as having an accuracy of ≥75% at predicting an attack or a migraine-free day; bad predictors were defined as those with ≤25% accuracy predicting a migraine or a migraine-free day.

In this study we found 9% (n= 13) were good migraine predictors and 27% (n=40) were defined as bad migraine predictors (Table 1), and both groups stood up as different from the rest of the sample with statistical significance (p<0.001). Only 5% (n=7) were good migraine and migraine-free predictors.

Conclusion: A substantial proportion (64%, n= 93) of users predict their migraine with only moderate accuracy (>25% but <75%). A small group (27%, n=40), were considered bad predictors with ≤25% accuracy. A smaller group (9%, n=13) were found to be good predictors with ≥75% accuracy and just 5% (n=7) were able to accurately predict migraine or migraine-free days. A next step would be to understand the in possible differences risk factors and premonitory symptoms that these two groups may exhibit and are possibly using for prediction of their attacks.
Table 1 (abstract P60).

Ability to predict migraine or a migraine-free day

 

Good predictors

(≥75% accuracy)

Rest

Bad predictors

(≤25% accuracy)

Migraine prediction

9%

64%

27%

Migraine free prediction

71%

28.3%

0.7%

Both

5%

95%

0%

References

[1] Peris F, Donoghue S, Torres F, Mian A, Wöber C. Towards improved migraine management: Determining potential trigger factors in individual patients. Cephalalgia. 2017 Apr;37(5):452-463

P61

Withdrawn

P62 A rapidly progressive cerebral hematoma secondary to cerebral venous sinus thrombosis (CVST) - A Case Report

Andrea Giorgetti (andrea.giorgetti@asst-ovestmi.it), Elena P. Verrengia, Patrizia Perrone

Department of Neuroscience, Neurology and Stroke Unit, Legnano Hospital, Italy

Background

Intracranial hemorrhage (ICH) accounts for up then 15% of strokes. When hemorrhage is secondary to cerebral venous sinus thrombosis (CVST) the diagnosis is sometimes difficult to establish. The early diagnosis of CVST is important to ensure best management including best medical treatment, mechanical trombectomy or surgical interventions.

Case Report

A 51 year-old woman was admitted in Emergency Room with unusual acute severe headache and seizure involving left-side limbs. Recent past medical history was significant for ulcerative colitis with ongoing steroid and anti-inflammatory therapy. Neurological evaluation revealed facial left nerve palsy and mild left upper limb weakness without Brudzinski and Kernig’s signs and no papilledema on clinical examination. A cerebral computed tomography (CT) scan showed hyperdensity of parietal right lobe such as intraparenchymal hemorrhage with surrounding large hypodensity area. The day after a cerebral magnetic resonance imaging (MRI) revealed a large parenchymal hematoma of right parietal-occipital lobe and surrounding hypodense ischemic injury with initial “mass effect”; a magnetic resonance imaging with angiovenous sequences showed a filling defect of transverse and sigmoid right sinuses.. The patient was clinically unchanged with persistent headache (VAS 8/10) but alert, oriented with slight life-sided deficits. Suddenly she was treated with low-molecular-weight heparin (LMWH) high dose therapy. After 48 hours of hospitalization, she developed hyperpyrexia, hemiplegia of left limbs and became comatose due to a “mass effect” produced by unilateral edematous venous infarction and parenchymal hemorrhage detected by cerebral CT. Decompressive surgery with hematoma evacuation was performed with good outcome. Medical treatment after surgery included steroid, anticonvulsants, anticoagulation. 3 months later the patient presented a nearly complete recovery (median Rankin Scale score 1): she was able to walk and to perfom basic daily activities.

Conclusions

CVST is a possible cause of cerebral venous infarct or parenchymal hematoma. Headache represents the most common symptoms of this condition (80-90% of patients); underlyng risk factors to develop CVST could be inflammatory bowel disease such as ulcerative colitis and treatment like corticosteroids. The use of MRI is essential for identify CVST and understand the location, volume and severity of hemorrhage. When CVST is suspected, is important to avoid a delay in diagnosis and treatment. Mortality in untreated cases ranges from 13 to 48%of patients and is due to large parenchymal lesions causing herniation. Decompressive surgery in these cases is lifesaving and related to good functional outcome even in patients with severe clinical conditions.

References

1. Heit Jeremy J, Iv Michael, Wntermark Max. Journal of Stroke. 2017;19(1):11-27

2. Ferro Jose’ M, Crassard Isabelle, Coutinho Jonathan M, Canha˜ Patrícia, Barinagarrementeria Fernando, Cucchiara Brett, Derex Laurent, Lichy Christoph, Masjuan Jaime, Massaro Ayrton, Matamala Gonzalo, Poli Sven, Saadatnia Mohammad, Stolz Erwin, Viana-Baptista Miguel, Stam Jan, Bousser Marie-Germaine. Second International Study on Cerebral Vein and Dural Sinus Thrombosis (ISCVT 2) Investigators. Stroke. 2011;42:2825-2831.

P63 Benign intracranial hypertension in children can be due to hypoparathyroidism: a case-report

Giorgia Sforza1,3, Annalisa Deodati2, Laura Papetti1, Barbara Battan1, Paolo Curatolo3, Federico Vigevano1, Massimiliano Valeriani1

1Headache Center, Child Neurology Unit, Bambino Gesu’ Children’s Hospital, Rome, Italy; 2Child Endocrinology Unit, Bambino Gesu’ Children’s Hospital, Rome, Italy; 3Child Neurology and Psychiatry Unit, Tor Vergata University of Rome, Italy
Correspondence: Giorgia Sforza (sforzagiorgia@gmail.com)

BACKGROUND

To present the rare case of a 9-year-old girl with idiopathic intracranial hypertension (IIH) secondary to hypoparathyroidism (HPTH) and our work-up, including physical examination, blood tests, diagnostic imaging, and lumbar puncture.

CASE REPORT:

We present a 9-year old female patient who was hospitalized for headache associated with nausea and vomiting for 3 weeks. She underwent ophthalmologic examination which showed papilledema. She had never had cramps, paraesthesias or tetany. Lumbar puncture (LP) revealed an opening pressure of 65 cm H2O. CSF analysis and brain CT scan were normal. The patient was started on acetazolamide 375 mg/die. However, a low serum calcium level (6.3 mg/dL) was found, thus leading us to suspect HPTH. Indeed, phosphorus was 10.2 mg/dL, parathormone was very low (3 pg/mL). Chvostek and Trousseau signs scored positive. Neck ultrasonography showed normal thyroid, while parathyroids were not viewable. Oral supplementation with calcitriol (0.50 mcg/day) and calcium (500 mg/day) was started.

CONCLUSIONS

IIH is defined as an elevated intracranial pressure (>25 cmH2O) without clinical, laboratory or radiological evidence of hydrocephalus, infection, tumor or vascular abnormality. Annual incidence is 1-2 per 100,000. Several hypotheses have been proposed for the IIH pathophysiology, but none of them has reached a general consensus. Rare cases of IIH secondary to HPTH have been described [1]. It is supposed that hypocalcemia causes a decrease in the CSF absorption at level of the arachnoidal granulations [2]. Interestingly, our patient did not present with the typical neurological HPTH symptoms, such as tetany, cramps, paraesthesias, seizures, behavioral disorders, and intracranial calcifications. Only the serum calcium dosage led us to suspect this condition. Therefore, we recommend that possible HPTH should be always checked in children with clinical findings of benign intracranial hypertension.

Consent to publish

Written informed consent has been obtained from the parents

References

1. Aragones JM, Alonso-Valdés F. Hipertensiòn intracraneal benigna secundaria a hipoparatiroidismo. Rev Neurology 2014; 58: 94.

2. Sambrook MA, Hill LF. Cerebrospinal fluid absorption in primary hypoparathyroidism. J Neurol Neurosurg Psychiatry 1977; 40:1015-7.

P64 Headache following head injury: A population-based longitudinal cohort study (HUNT)

Lena Hoem Nordhaug1; Knut Hagen1, 2; Anne Vik1, 3; Lars Jacob Stovner1, 2; Turid Follestad4, Torunn Pedersen5; Gøril Bruvik Gravdahl2, Mattias Linde1, 2

1Department of Neuromedicine and Movement Science (INB), Faculty of Medicine and Health Sciences, Norwegian University of Science and Technology, Trondheim, Norway; 2Norwegian Advisory Unit on Headaches, St. Olavs University Hospital, Trondheim, Norway; 3Department of Neurosurgery, St. Olavs University Hospital, Trondheim, Norway; 4Department of Public Health and Nursing, Faculty of Medicine and Health Sciences, Norwegian University of Science and Technology, Trondheim, Norway; 5Division of Mental Health and Addiction, Oslo University Hospital, Oslo, Norway
Correspondence: Lena Hoem Nordhaug (lena.h.nordhaug@ntnu.no)

Objective

To explore whether subjects exposed to head injury more often developed a new headache or experienced exacerbation of previously reported headache compared to non-exposed.

Methods

This population-based historical cohort study included headache data from two large epidemiological surveys performed with an 11-year interval. This was linked with data from hospital records on exposure to head injury occurring between the health surveys. Participants in the surveys who had not been hospitalized because of a head injury comprised the control group. The head injuries were classified according to the Head Injury Severity Scale (HISS). Multinomial logistic regression was performed to investigate the association between head injury and new headache or exacerbation of pre-existing headache in a population with known pre-injury headache status, controlling for potential confounders.

Results

The exposed group consisted of 294 individuals and the control group of 25,662 individuals. In multivariate analyses, adjusting for age, sex, anxiety, depression, education level, smoking and alcohol use, mild head injury increased the risk of new onset headache suffering (OR 1.74, 95% CI 1.05 – 2.87), stable headache suffering (OR 1.70, 95% CI 1.15 – 2.50) and exacerbation of previously reported headache (OR 1.93, 95% CI 1.24 – 3.02). The reference category was participants without headache in both surveys.

Conclusion

Individuals exposed to a head injury were more likely to have new onset and worsening of pre-existing headache and persistent headache, compared to the surrounding general population. The results support the entity of the ICHD-3 beta diagnosis “persistent headache attributed to traumatic injury to the head”.

P65 Pediatric headache clinics: toward in-pediatric emergency department models

Laurence Geffroy1, Silvana De Lucia1, Luigi Titomanlio1,2

1APHP-Hospital Robert Debré, Department of Pediatric Emergency Care, APHP-Hospital Robert Debré, Paris, France; 2APHP-Hospital Robert Debré, Pediatric Migraine and Neurovascular Diseases Unit, Paris, France
Correspondence: Laurence Geffroy

BACKGROUND: Headache is a frequent pediatric complaint in the emergency department (ED). Although medical protocols are available at the ED, diagnosis and therapy of children with headache are challenging, due to wide spectrum of headache aetiologies. Aim of the study was to analyze the impact of the creation of a Headache Clinic in our pediatric university hospital.

METHODS: Review of all medical records of children 3-18 years consulting at the PED for headache as the main complaint, starting from Jan 2011, when the Headache Clinic was created, until Dec 2016. Statistical analysis was performed by GraphPad Instat 3.10.

RESULTS: Over the study period, 502,456 patients consulted our PED, of whom 5,185 for headache (1%). Characteristics of these patients and results of statistical analysis are summarized in Table 1.

CONCLUSIONS: The creation of a Headache Clinic in our hospital allowed an improvement of the quality of care in our region, reducing the delay of specialist assessment. On the other hand, although the number of headache patients consulting at the PED did not significantly increase, we observed a significant temporal trend in terms of headache severity at triage, an increased length of stay, more complementary investigations, and increased admission rate. So, the positive effects of the creation of the Headache Clinic are actually counterbalanced by PED overload.

To continue caring headache children with high standards, the next step would be the implementation of the Headache Clinic in the PED. Although this may require some structural costs to provide a dedicated area, health benefits would be huge. The presence of a headache team at the PED (doctors, nurses, psychologists) would result in an important gain of time for emergency physicians, in the reduction of the length of stay at the PED (less waiting time for specialists, reduction of unuseful tests), in a better multidisciplinary care, and in the reduction of parental stress (with reduction of return visits and medical shopping). Prospective analysis at both short- and long- term is required before concluding about the usefulness of this approach and of its generalisability to other PEDs.
Table 1 (abstract P65).

See text for description

 

2011

2012

2013

2014

2015

2016

p

PED consultants for headache (% on total)

647 (0.8%)

829 (1%)

824 (1%)

955 (1.1%)

933 (1.1%)

997 (1.1%)

-

Male gender

360 (55.6%)

453 (54.6%)

440 (53.4%)

490 (52.1%)

498 (53.4%)

527 (52.9%)

-

Age (mean, years)

8.9

9

9.2

9.3

9.3

9.8

<.001

Arrival during night shift

273 (42.1%)

298 (35.9%)

266 (32.3%)

318 (33.2%)

312 (33.4%)

318 (31.8%)

-

Arrival during weekend shift

153 (23.6%)

210 (25.3%)

219 (26.5%)

248 (25.9%)

233 (25%)

244 (24.5%)

-

Triage severity

      

-

Low

309 (47.8%)

404 (48.8%)

394 (47.8%)

430 (45%)

404 (43.3%)

429 (43.1%)

 

Intermediate

272 (42 %)

326 (39.3%)

322 (39%)

385 (40.3%)

383 (41.1%)

397 (39.8%)

 

Urgent

66 (10.2%)

99 (11.9%)

108 (13.2%)

40 (14.7%)

146 (15.6%)

171 (17.1%)

<.05

Context of head trauma

122 (18.9%)

198 (23.9%)

193 (23.4%)

224 (23.5%)

184 (19.7%)

193 (19.7%)

 

Dismissed without investigations

392 (60.6%)

411 (49.6%)

400 (48.6%)

387 (40.5%)

417 (44.7%)

382 (38.3%)

<.05

Head CT scans at PED (% on all headaches)

29 (4.5%)

14 (1.7%)

25 (3%)

23 (2.4%)

16 (1.7%)

39 (3.9%)

 

Admission following PED (% on all headaches)

40 (6.2%)

48 (5.8%)

52 (6.3%)

58 (6.1%)

91 (9.8%)

100 (10%)

<.05

Length of stay at the PED (mean, min)

197

193

205

203.5

211.4

230.2

<.0001

P66 Individual identification of factors associated with reduced risk of migraine attacks: potential ‘protectors’

Stephen Donoghue1, Francesc Peris1, Gabriel Boucher1, Alec Mian1, Christian Wöber2

1Curelator Inc, suite 4503, 5th floor, 195 Binney, Cambridge, MA, USA 02142; 2Headache Group, Department of Neurology, Medical University of Vienna, Vienna Austria
Correspondence: Stephen Donoghue

Background

Curelator Headache™ is a digital platform that collects daily data about an individual’s migraine attacks and up to 80 factors (mood, stress, diet, activity, weather etc.) which may affect their occurrence and then statistically identifies factor-attack associations. Hence we identify potential triggers (both “true” triggers and premonitory symptoms) [1]. Our analysis also identifies factors associated with reduced risk of attack occurrence: we call these potential ‘protectors’ [2]. Here we compare potential protectors in individuals with episodic (EM) or chronic (CM) migraine.

Methods

Individuals with migraine registered to use Curelator Headache via 1) a physician ‘coupon referral’ program, 2) the Curelator website or 3) the App Store (currently iOS only). They used Curelator Headache daily for 90 days, entering details about headaches and tracking factors that may affect migraine attack occurrence, after which factor-attack associations were analyzed for each individual [1].

Results

557 individuals were included: demographic data are shown in Table 1:

Overall, potential protectors were found in 471 (84.4%) individuals: on average individuals had 3.0 (CI 0.20) such associations; range 0 - 16. The factors most commonly found (>5% individuals) were physical activity, happiness, being relaxed, sleep quality, sleep duration, sleep quality, waking refreshed, caffeine, mean outside temperature and humidity, time outdoors.

In general the same factors appeared as ‘protectors’ in both groups, although for some there was a higher proportion of EM individuals, possibly reflecting real differences or increased difficulty of identifying risk factors in individuals with frequent attacks.

Conclusions:

Identifying ‘protectors’ may be clinically useful for people with migraine. However it is important to guide each individual to think about their behaviours and self-analyse the context in which ‘protectors’ appear to affect their condition. For example, apparent ‘protectors’ may be due to avoidance immediately before/during attacks (e.g. nicotine, physical activity) or to actions taken to mitigate a factor effect (e.g. avoiding going out on hot days).

Our data support what many clinicians and people with migraine believe intuitively, i.e that moderate activity, staying relaxed, and trying to maintain good sleep hygiene reduce risk of attacks. In addition warm weather may have a protective role. Caffeine appears protective for some people (but can be a trigger for others).
Fig. 1 (abstract P66).

Shows the proportion of individuals in each group for whom the most common ‘protectors’ were identified

Table 1 (abstract P66).

Demographics

 

All

EM

CM

Total number in population

557

473

84

Mean Age (years) (SD)

42.9 (13.4)

43.5 (13.2)

39.4 (14.2)

Age range (years)

11 - 75

11 -75

15 - 69

No. Females (%)

488 (87.6%)

409 (86.5%)

79 (94%)

Female - menstrual cycles (%)

292 (52.4%)

240 (50.7%)

52 (61.9%)

Female - menopausal (%)

90 (16.2%)

80 (16.9%)

10 (11.9%)

Female - non-menstrual or menopausal (%)

106 (19.0%)

89 (18.8%)

17 (20.2%)

References

1. Peris F et al. Towards improved migraine management: determining potential trigger factors in individual patients. Cephalalgia 2016; 37(5): 452-463

2. Donoghue S et al. Identification of ‘protectors’ - factors associated with reduced risk of migraine attacks: some surprising observations and interpretations. Headache 2016; 56 Suppl.1: 36.

P67 Self-reported triggers vs prospectively statistically determined factors associated with attacks in individuals with episodic and chronic migraine

Stephen Donoghue1, Gabriel Boucher1, Francesc Peris1, Alec Mian1 and Paul R. Martinl2

1Curelator Inc., Cambridge, MA, USA; 2School of Applied Psychology, Griffith University, Queensland, Australia
Correspondence: Stephen Donoghue

Background

In this study we compare in individuals with episodic (EM) or chronic (CM) migraine their suspected, self-reported triggers versus risk factors identified statistically. Migraine attacks may be triggered by combinations of internal and external factors which differ markedly between individuals [1]. Most migraineurs suspect a range of triggers, usually based on a combination of popular literature and (unreliable) retrospective recall which is subject to misinterpretation and recall bias. Few have been tested for causality but, when done, triggering of attacks has usually been inconsistent and avoidance has had limited effect [2]. Previously we reported that less than 20% of suspected self-reported triggers were shown to be statistically associated with attacks when using individuals’ prospective data collected using a digital platform (Curelator Headache™) [3].

Methods

Individuals with migraine registered to use Curelator Headache via 1) a physician ‘coupon referral’ program, 2) the Curelator website or 3) the App store (currently iOS only) and completed a questionnaire about personal suspected triggers and their importance (1=low; 10=maximal). They used Curelator Headache daily for 90 days, entering details about headaches and tracking factors that may affect migraine attack occurrence. After 90 days factors were analyzed for each individual [4] and those significantly associated with attacks were compared with self-reported triggers.

Results

488 individuals were included: demographic data are shown in Table 1:

Overall, individuals each suspected between 3 and 44 different triggers; mean (SD) = 23.2 (12.4). Most frequently, and often most strongly, suspected were: menstruation, stress, anxiety, irritability, angriness, sleep quality and duration, neck pain, eye strain, bright lights, odors, loud noise, fatigue, activity, travel, weather, dehydration, missed meals, alcohol.

Table 2 shows how many suspected triggers were confirmed statistically or shown to have no association with migraine attack risk.

The CM group overall suspected more triggers per person but fewer of these were statistically associated with migraine attacks (p = 0.008). In the EM group stress, anxiety, sadness, tiredness/fatigue, neck pain/tension, eye strain head/neck skin sensitivity and menstruation were more commonly confirmed as potential triggers.

Conclusions

EM and CM groups differ in the proportion of suspected risk factors (potential triggers) confirmed statistically. This may represent real differences between the groups, i.e ability to self-recognise triggers correctly, or difficulty in detecting some associations in the CM group. Nevertheless, the difference contrasts with the lack of differences in self-reported suspected triggers between EM and CM groups.
Table 1 (abstract P67).

Demographics

 

All

EM

CM

Total number in sample

488

391

97

Mean Age (years) (SD)

43.0 (13.4)

43.7 (13.2)

40.3 (14.0)

Age range (years)

11 - 75

11 -75

15 - 69

No. Females (%)

440 (90.2%)

348 (89.0%)

92 (94.8%)

Female - menstrual cycles (%)

275 (56.4%)

215 (55.0%)

60 (61.9%)

Female - menopausal (%)

87 (17.8%)

72 (18.4%)

15 (15.5%)

Female - non-menstrual or menopausal (%)

78 (16.0%)

61 (15.6%)

22 (22.7%)

Table 2 (abstract P67).

See text for description

 

All

(N = 488)

EM

(N = 391)

CM

(N = 97)

Mean no. suspected per individual

(95% CI) (range)

23.2

(1.1) (3 - 44)

22.9

(1.2) (3 - 44)

24.3

(2.4) (5 - 43)

% of total suspected triggers identified statistically

11.5

12.2

8.9

Mean no. of previously suspected

triggers statistically identified

(95% CI) (range)

2.7

(0.21) (0 - 12)

2.8

(0.24) (0 -12)

2.2

(0.39) (0 - 8 )

Mean no. of previously suspected

triggers with no association with attacks (95% CI) (range)

14.2

(0.74) (0 - 33)

13.8

(0.81) (0 - 33)

15.5

(0.74) (1 - 33)

Mean no. previously suspected

triggers with insufficient data to determine statistical association

(95% CI) (range)

5.1

(0.37) (0 - 23)

5.0

(0.42) (0 - 23)

5.4

(0.74) (0 - 18)

Mean no. of unsuspected triggers statistically identified

(95% CI) (range)

1.3

(0.15) (0 -9)

1.4

(0.17) (0 - 9)

1.1

(0.30) (0 - 9)

References

1. Spierings EL et al. Sufficiency and necessity in migraine: how do we figure out if triggers are absolute or partial and, if partial, additive or potentiating? Curr Pain Headache Rep 2014; 18: 455-461.

2. Martin PR. Behavioural management of migraine headache triggers: learning to cope with triggers. Curr Pain Headache Rep 2010; 14: 221-227.

3. Donoghue S et al. Migraineurs’ suspected triggers compared with scientifically determined associations using a daily diary and statistical analysis platform. Headache 2016; 56 (Supp 1): 35.

4. Peris F et al. Towards improved migraine management: determining potential trigger factors in individual patients. Cephalagia 2016; 37(5): 452-463

P68 Vertigo and Migraine

Elena Filatova, Tatiana Ivanova

Institute of Professional Education, Chair of Neurology. I.M. Sechenov First Moscow State Medical University 8-2 Trubetskaya st., Moscow 119991, Russia
Correspondence: Tatiana Ivanova (itamail@mail.ru)

Vestibular migraine (VM) is the most common cause of episodic vertigo in adults as well as in children. (1).The exact neural mechanisms of vestibular migraine are still unknown. Vestibular migraine often begins several years after typical migraine and has a variable clinical presentation. The neurological and otoneurological examination of patients with vestibular migraine is mostly normal and diagnosis are usually based on clinical history. Treatment trials of vestibular migraine are scarce and therapeutic recommendations are based on migraine guidelines.

Objective: The aim of study is to determine the mechanisms of vertigo and dizziness in migraine patients

Methods: This study recruited 152 patients with migraine with aura and migraine without aura as defined by ICHD-3. VM was diagnosed by (ICHD-3) Diagnostic criteria.(2) We analyzed the medical history of migraine patients with vertigo and dizziness, all patients had a neurological examination, and questionnaire survey by scales: Dizziness Handicap Inventory (DHI) scale (3)), HADS , HIT-6. Patients with vertigo additionally had an otoneurological examination for excluding peripheral vestibulopathy.

Results: The main study group consisted of patients with vestibular migraine (VM) – 13,8% (n=21), and controls were patients with dizziness - 42,2% (n=64) . There were no significant differences in sex, age, VAS, HADS , HIT-6 in main and control group . Chronic migraine and migraine without aura was more prevalent in patients with VM ( СМ: 88.8%, n=16 vs. 36.4%, n=12, respectively). DHI-positional scale in VM was higher, then in dizziness patients (15,43±5,9 vs 12,28±6,9,p<0,05) Vertigo manifest during migraine attack and dizziness was permanent. VM patients have more often motion sickness , subjective hearing loss, although otoneurologist found no current disease. More then 50% of VM patients had family history of hearing loss or dizziness.

Conclusion: VM is mostly observed in patients with chronic migraine and migraine without aura. Our study suggests the role of central sensitization of the vestibular nuclei in the patients with preexisting pathology of the vestibular system in VM pathogenesis. The leading part, of central sensitization in the genesis of vertigo in migraine patients are warranted to pave the way to potential new therapies for this condition.

References

1. Stolte B., Holle D., Naegel S., Diener H.C., Obermann M. Vestibular migraine. Cephalalgia. 2014

2. The International Classification of Headache Disorders, 3rd edition (beta version).Cephalalgia. 2013;33(9):629-808.

3. Jacobson GP, Newman CW. The development of the Dizziness Handycap Inventory. Arch Otolaryngol Head Neck Surg. 1990, 116(4): 424-7.

P69 Characterising the effect of lumbar puncture on headache in idiopathic intracranial hypertension

Andreas Yiangou1,2, James Mitchell1,3, Keira Annie Markey1,2, William Scotton1,2, Peter Nightingale5, Ryan Ottridge6, Susan Mollan1,4, Alexandra Sinclair1,3

1Institute of Metabolism and Systems Research, University of Birmingham, Edgbaston, B15 2TT, UK; 2Centre for Endocrinology, Diabetes and Metabolism, Birmingham Health Partners, B15 2TH, UK; 3Department of Neurology, University Hospitals Birmingham NHS Foundation Trust, B15 2TH, Birmingham, UK; 4Birmingham Neuro-Ophthalmology Unit, Ophthalmology Department, University Hospitals Birmingham NHS Foundation Trust, B15 2TH, Birmingham, UK; 5Wellcome Trust Clinical Research Facility, Queen Elizabeth Hospital, Birmingham, UK; 6Birmingham Clinical Trials Unit, School of Cancer Sciences, Robert Aitken Institute, University of Birmingham, Birmingham, UK
Correspondence: Andreas Yiangou (a.yiangou@bham.ac.uk)

Introduction

Headache is the most prevalent symptom in idiopathic intracranial hypertension (IIH). This study aimed to evaluate the temporal change in headache severity in the week following lumbar puncture (LP) in patients with active IIH.

Methods

Headache severity was prospectively recorded using the numeric rating scale (NRS) 0 (no pain) to 10 (most severe pain) immediately prior to and following LP (1,4 and 6 hours and then daily to 7 days). Demographic data and variables hypothesised to impact on the post-LP headache severity were recorded.

Results

52 IIH patients were recruited with mean BMI 41 ± 10 Kgm-2, LP opening pressure 33.2 ± 6.1 cmCSF and headache severity 3.6 ± 2.8. Exacerbation of headache was noted in 64% with 30% experiencing an exacerbation ≥4 NRS. In the whole cohort, a small improvement in headache severity was noted 1 hour in 58% (-1.1 ± 2.6 NRS (p<0.001)) and this was maintained at 7 days in 47% (-1.0 ± 2.7 NRS (p=0.004)). In those with severe headaches pre-LP (NRS 7-10), 75% improve at 1 hour (-3 ± 3.7 NRS, p=0.024) and 67% improved at 7 days (-3.0 ± 2.8 NRS, p=0.012) whilst deterioration was uncommon (8% at 1 hour and zero at 7 days). In those with moderate headaches pre-LP (NRS 4-6), 91% improve at 1 hour (-2.2 ± 1.6 NRS, p<0.001) and 61% improved at 7 days (-1.7 ± 2.3 NRS, p=0.007) and deterioration was uncommon (4% at 1 hour and 22% at 7 days). Amongst, those with mild headaches pre-LP (NRS 1-3), no significant improvement was noted and the likelihood of deterioration was higher (50% at 1 hour and 19% at 7 days). In those with no headache pre-LP, 20% will experience deterioration at 1 hour and 27% at 7 days. There was no relationship between the response of the headache severity post-LP and BMI, height, skin to dura depth, LP opening or closing pressure, CSF volume withdrawn, number of LP attempts, CSF red blood cell count, acute analgesics, acetazolamide use and Frisén papilloedema grade.

Conclusion

The majority of IIH patients will experience deterioration in headache at some point during the week post-LP. Headache severity pre-LP significantly influenced the likelihood of improving or deteriorating after LP. Additionally, we noted that the improvement at 1 hour post-LP was maintained at 7 days. Characterisation of headache outcomes post-LP in IIH has relevance when counselling patients about the procedure.

Trial registration

ClinicalTrials.gov Unique identifying numbers: NCT02017444, NCT02124486.

P70 Effectiveness of a digital platform for headache training of specialists

Edvige Correnti1, Filippo Brighina2, Antonino Sandullo3, Marcello Romano4, Francesca Marchese1, Carmela Loiacono1, Luca Messina11, Vincenzo Raieli5

1Child Neuropsychiatry School – University of Palermo –Italy 90100; 2Department of Experimental Biomedicine and Clinical Neurosciences - University of Palermo-Italy 90100; 3Primary Care Dept. –ASP 1 Agrigento- Italy 92100; 4Neurology Dept.- Cervello-Villa Sofia Ospedali Riuniti –Palermo –Italy 90100; 5UO NPI- P.O. Cristina - ARNAS Civico Palermo –Italy 90100
Corrispondence: Vincenzo Raieli (v.raieli@alice.it)

Background. Headache represents a peculiar condition, that is often underdiagnosed and undertreated, with remarkable dissatisfaction of the patients. An adequate training is crucial for all the headache specialists[1,2]. Considering the unsatisfying results obtained with standard updating courses and the rising need of a continuous training, a digital platform was developed in the last two years as a tool of update.

Methods. A digital platform, has been activated since the 1st October 2014. The platform is easily accessible to doctors by free membership, validated by the administrators of the group. Repeatedly in two years Administrators invited to subscription members of scientific societies potentially interested to headache. The users have access to the platform’s whole material, that includes scientific articles, e-books, presentations and images. They can directly share their material, discuss on clinical cases and submit new ones. The system allows to monitor the participation of members in terms of platform access, resource upload and / or download, introduction of cases and participation in their discussion. Finally, we sent a questionnaire to understand the reasons of use or not use of platform by registered members.

Results .The platform currently boasts 39 members. The resources in the platform consist of many different materials concerning headache ( more than 100 articles dedicated to migraine aura, several books, many slide libraries on different headache topics, collections of artistic or neuroimaging images related to headaches etc...). In the last year 316 files have been downloaded, 5 discussions have been started with 22 contributors. 15 of 37 members have never carried out any action. The last year number of uploaded files amounts to 74, but 90% of the contributions is due to a restricted group. There were no significant differences in use of platform between members of society for study of headache and other specialists (see Table 1). The results of questionnaire show summarily that first reason of non-use of platform is the lack of time.

Conclusions. After 2 years of activity, a the data show that about 40% of the members have never carry out any operation and the remaining mainly used the platform in a passive way, through the resources downloading. Even if the platform appears to be an easily accessible, interactive and not expensive instrument, the passive use suggests that a critical aspect for medical education on the diagnosis and treatment of headaches lies more in the doctors’ ability to invest themselves emotionally on these issues.
Table 1 (abstract P70).

Utilization of Headache digital platform by members

Academic groups

members

Members with no actions performed

Login

Downloaded files

Uploaded files

Clinical cases submitted

Contribution on clinical cases

Sisc (Italian society for the study of headache) members

18

5

112

146

68

4

20

SINPIA (Italian society of neuropsychiatry for childhood and adolescence) members

11

6

28

139

3

1

2

Other specialists

8

4

7

31

3

0

0

Total

37

15

147

316

74

5

22

References

1. Raieli V. ,Compagno A., Puma D., La Vecchia M., Pandolfi E., La Franca G., Ragusa D. Headache: What do children and mothers expect from paeditricians? Headache, 2010, 50: 2, 290-300;

2. Brighina F., Raieli V., La Pegna G., Lanaia F.. Disability and social impact of headaches and migraine. The role of information and cooperation among patient, general practitioner and specialist: A project of the SISC Sicilia. Giornale delle Cefalee.2006; 2:10-12.

P71 Tanacethum Parthenium , 5 - hydroxy tryptophan and magnesium (Aurastop©) efficacy in episodic migraine prevention. A multicentric observational study

Federico Mainardi1, Paola Merlo2, Ferdinando Maggioni3, Giorgio Zanchin3, Giorgio Dalla Volta4

1Headache Centre, Neurological Division, SS Giovanni e Paolo Hospital, Venice; 2Headache Centre of Neurological Division of Gavazzeni Hospital, Bergamo; 3Headache Centre, Department of Neurosciences, Padua University, Padua; 4Headache Center of Neurological Unit of Istituto Clinico Citta’ di Brescia, Brescia
Correspondence: Giorgio Dalla Volta (dalla@numerica.it)

Background: Each component of the novel phytotherapic combination of Tanacethum Parthenium (150 mg), 5-hydroxy tryptophan (20 mg) and magnesium (185 mg) (Aurastop©) acts on a different target among the main mechanisms involved in the pathophysiology of migraine: sensitization of trigeminal vascular system, central sensitization and activation of the “migraine generator” located in the brainstem, through glutammate and kynurenine pathway. Aim of this study is to test the effectiveness of Aurastop© in the prophylaxis of migraine without aura.

Materials and methods: Sixty consecutive patients (F: n=37, M: n=23, mean age: 37.5±17.1) presenting with an ICHD-3 beta diagnosis of migraine without aura (MO) were enrolled in the survey and treated with Aurastop© twice a day for a period of 3 months. Diary cards were filled in during a 3-months period prior the beginning of the survey and during the 3-months duration of the study. A preventative treatment had been started previously and continued during the study in 5 cases (propranolol: n=2; amitriptyline: n=2; onabotulinumtoxin A: n=1).The reduction of MO attacks per month was assessed as the primary end-point; the reduction of headache days per month, the intensity of the pain and the patient’s satisfaction were considered as secondary end-points.

Results: A statistically significant reduction of both MO attacks and number of headache days per month was observed. Moreover, a sensible reduction of the intensity of the pain was reported. The secondary end-point regarding the satisfaction of the patients was achieved, as participants agreed when a new cycle of Aurastop© was proposed. No side effects were reported. The effectiveness appeared since the first month of intake and was maintained during the three months of therapy .

Conclusion: In this observational open study, Aurastop© appears to be effective and safe in the preventive treatment of MO.

References

Curto M, Lionetto L, Negro A, Capi M, Fazio F, Giamberardino MA, Simmaco M, Nicoletti F, Martelletti P. Altered kynurenine pathway metabolites in serum of chronic migraine patients. J Headache Pain. 2015; 17: 47.

Geppetti P, Bernabei S, De Cesaris F. CGRP receptors and TRP channels in migraine. J Headache Pain. 2015; 16(Suppl 1): A21.

Diener HC, Pfaffenrath V, Schnitker J, Friede M, Henneicke-von Zeppelin HH. Efficacy and safety of 6,25 mg t.i.d feverfew CO2-extract ( MIG-99) in migraine prevention – a randomized, double blind, multicenter, placebo controlled study. Cephalalgia. 2005; 25: 1031-41.

P72 Association of Tanacethum Parthenium, 5-Hydroxytryptophan and Magnesium (Aurastop®) in the treatment of migraine aura: an observational study

F. Antonaci1-3, V.Rebecchi4, G. Sances1, P.Merlo5, A.Giorgetti6, F. Di Palma7, E. Matta8, C.Dall’ Occhio9, C.Tassorelli1-3, G.Dalla Volta10, On behalf of Società Italiana per lo Studio delle Cefalee (SISC–Lombardia) - Italia

1Headache Science Centre, Istituto Neurologico Nazionale Mondino, Pavia; 2 UC Neurologia Speciale d'Urgenza, Istituto Neurologico Nazionale, Pavia; 3 Dipartimento di Scienze del Sistema Nervoso e del Comportamento Università di Pavia; 4 Centro Cefalee UOC Neurologia -Varese- ASST Settelaghi – Univ. Insubria; 5 U.O.Neurologia- Centro Cefalee, Humanitas Gavazzeni, Bergamo; 6 Centro Cefalee, Dipartimento di Neuroscienze H di Legnano ASST Ovest milanese; 7 Centro Cefalee UOC Neurologia della ASST Lariana-Ospedale S. Anna di Como; 8 Centro Cefalee UOC neurologia ASST Bergamo ovest; 9 UO Neurologia, ASST Pavia. Ospedale Civile, Voghera; 10 Centro Cefalee U.O Neurologia - Istituto Clinico Citta’ di Brescia - Brescia
Correspondence: G.Dalla Volta (dalla@numerica.it)

INTRODUCTION: A new phytotherapic combination of Tanacethum Parthenium (150 mg), 5 - Hydroxy tryptophan (20 mg) and Magnesium (185 mg) (Aurastop®) is now available for migraine patients. The three components may tackle the main mechanisms involved in the pathophysiology of migraine with aura: Cortical Spreading Depression, sensitization of trigeminal vascular system, central sensitization

AIM: The purpose of this open study was to evaluate the efficacy of the combined action of Tanacethum Parthenium, 5-Hydroxy tryptophan and magnesium in the reduction/disappearance of the aura phenomenon and reduction of its disability when taken at the aura onset.

MATERIALS AND METHODS: Study of a population of 200 patients aged between 18 and 65 years (mean age: 33.00 yrs ), 117 F and 83 M, suffering from migraine with aura referred to 8 Lombardia Headache Centers. Patients were either without preventive therapy or without changing the prophylaxis during the aura treatment. Inclusion criteria: suffering of aura with at least 20 minutes duration. Patients retrospectively filled a aura diary for the description of the aura features in the past 3 episodes. Then they treated 3 consecutive aura attacks with a tablet of Aurastop® at the onset of the aura. In case of headache they were instructed to take another 1 tablet at the headache onset. The effect of the Aurastop® was prospectively recorded using the aura diary in order to evaluate: duration of the aura, disability caused by the aura, number/efficacy of habitual symptomatic treatment

RESULTS: We recorded a total of 600 aura episodes from a total of 200 subjects: Aurastop® produced more than 50% reduction in duration in 180 patients ( 90%of the total ) and disability in 185 patients( 92,5%). Notably 35% of the patients did not use other symptomatic treatment due to the fact that headache intensity was less severe after Aurastop®.

DISCUSSION AND CONCLUSIONS: The combination of tanacethum partenum, Mg and 5-HTP, (Aurastop®), could be an effective symptomatic treatment for migraine aura. Randomised controlled trials are still required to confirm these results .

References

- Curto M, Lionetto L, Negro A, Capi M, Fazio F, Giamberardino MA, Simmaco M, Nicoletti F, Martelletti P. Altered kynurenine pathway metabolites in serum of chronic migraine patients. Journal of Headache pain 2015 Dec; 17(1):47.

- Geppetti et al.: CGRP receptors and TRP channels in migraine. The Journal of Headache and Pain 2015 16(Suppl 1):A21

- Pietrobon D, Moskowitz MA. Chaos and commotion in the wake of cortical spreading depression and spreading depolarizations. Nat Rev Neurosci. 2014;15:379–93.

P73 Medical (respiratory, sleep, cardiovascular and gastrointestinal) comorbidities of migraine: Results from the Chronic Migraine Epidemiology and Outcomes (CaMEO) study

Richard B. Lipton1, Vincent T. Martin2, Michael L. Reed3, Kristina M. Fanning3, Aubrey Manack Adams4, Dawn C. Buse5

1The Saul R. Korey Department of Neurology, Albert Einstein College of Medicine, Bronx, NY, USA; 2University of Cincinnati Headache and Facial Pain Center, University of Cincinnati College of Medicine, Cincinnati, OH, USA; 3Vedanta Research, Chapel Hill, NC, USA; 4Global Medical Affairs, Allergan plc, Irvine, CA, USA; 5Montefiore Headache Center, Bronx, NY, USA
Correspondence: Richard B. Lipton (Richard.Lipton@einstein.yu.edu)

Background

Many comorbidities associated with migraine have a higher relative frequency in chronic migraine (CM) than episodic migraine (EM). The objective of this study was to replicate and extend work on comorbid medical conditions in a systematically recruited sample of people with migraine.

Materials and Methods

Data from the prospective web-based baseline survey of the Chronic Migraine Epidemiology and Outcomes (CaMEO) Study were used to identify people, recruited from an online panel using quota sampling, with EM and CM based on criteria modified from the International Classification of Headache Disorders, third edition, beta version. Participants completed a Comorbidities/Endophenotypes module that assessed 64 symptoms and conditions. Respondents were asked (1) if they ever had a specific symptom (“Self-Reported [SR]”) and, if present, (2) if the SR symptom or condition had been confirmed/diagnosed by a “doctor” (“SR-physician diagnosis [SR-PD]”). Chi-square analysis was used to compare the proportion of people with each symptom or condition among respondents with EM vs. CM. This report presents data on the Respiratory, Sleep Disorder, Cardiovascular, and Gastrointestinal comorbidity categories.

Results

Available CaMEO respondents with migraine (16,763) were sent the Comorbidities/Endophenotype module and 12,810 (76.4%) provided valid responses: 11,699 with EM; 1,111 with CM. Compared with the EM group, the CM group had a similar mean age (EM, 41.3 years; CM, 41.9 years), was more likely to be female (EM, 74.2%; CM, 81.5%; P<0.001) and white (EM, 84.0%; CM, 88.7%; P<0.001), and had a mean higher body mass index (EM, 27.7 kg/m2; CM, 28.7 kg/m2; P<0.001). The relative frequencies were significantly higher for 29 (93.5%) of the 31 SR symptoms and SR-PD conditions assessed. Conditions or groups of conditions with relative frequencies >10% higher in CM than EM included allergies/hay fever/allergic rhinitis (EM, 37.4%; CM, 51.0%), sinusitis/sinus infection (EM, 47.3%; CM, 58.8%), insomnia (EM, 35.6%; CM, 50.2%), vertigo/dizziness/balance problems (EM, 17.8%; CM, 29.7%), and gastroesophageal reflux disease (EM, 14.3%; CM, 24.4%; Fig. 1).

Conclusions

Overall, significantly more respondents with CM vs. EM reported medical comorbidities. Mechanisms explaining this association might include manifestations of migraine, direct causality (e.g., CM causes the comorbidity), reverse causality (e.g., the condition increases the risk of CM), and shared genetic or environmental risk factors. Confounding or detection bias (i.e., “Berkson’s Bias”) could also contribute. Future analyses will address naturally occurring subgroups (taxa) defined by migraine phenotypes and comorbidities and assess the relationships of these groups to external validators such as treatment response and clinical course.
Fig. 1 (abstract P73).

EM and CM respondents self-reporting (SR) an assessed symptom or a physician diagnosis (SR-PD) of a condition

Acknowledgments

Editorial support for development of this abstract was provided by Lee B. Hohaia, PharmD, at Complete Healthcare Communications, LLC (Chadds Ford, PA), a CHC Group company, and funded by Allergan, plc (Dublin, Ireland).

P74 Development of a claims-based algorithm for use in patients with migraine to identify potentially undiagnosed chronic migraine patients

Jelena M. Pavlovic1, Justin S. Yu2, Stephen D. Silberstein3, Michael L. Reed4, Steve H. Kawahara5, Robert P. Cowan6, Firas Dabbous7, Karen L. Campbell2, Anand S. Shewale2, Riya Pulicharam5, Jonathan W. Kowalski2, Hema N. Viswanathan2, Richard B. Lipton1

1Montefiore Medical Center, Bronx, NY, USA; 2Health Economics and Outcomes Research, Allergan plc, Irvine, CA, 92612, USA; 3Jefferson Medical Center, Philadelphia, PA, USA; 4Vedanta Research, Chapel Hill, NC, USA; 5DaVita Medical Group, El Segundo, CA, USA; 6Stanford University School of Medicine, Stanford, CA, USA; 7Independent Consultant, La Jolla, CA, USA
Correspondence: Justin S. Yu (Justin.Yu@Allergan.com)

Background

Published surveys have demonstrated that 75-80% of persons meeting the criteria for chronic migraine (CM) do not report having received an accurate diagnosis [1,2]. The primary objective of this study was to develop a claims-based algorithm for use in patients with migraine to identify potentially undiagnosed CM patients.

Materials and Methods

An observational study using claims data and survey data was conducted in a large United States medical group. Eligible patients had continuous enrollment and a migraine diagnosis (ICD-9/10 code of 346.xx/G43.xxx) in the 12-months prior to the screening date. Patients were excluded if they had a prior CM diagnosis (346.7x/G43.7xx) or migraine-related onabotulinumtoxinA claim. The Semi-structured Diagnostic Interview (SSDI) served as the gold standard for identifying CM and was administered to a convenience sample by trained clinicians. The SSDI included 31 questions related to headache frequency, symptoms, disability, medication use, and diagnosis.

A multivariate logistic regression model was used to identify potential predictors of CM based on claims data obtained in the 12 months prior to the screening date. Over 40 potential predictors for CM, identified from the literature and headache expert input, were evaluated for model inclusion. Variables that were significantly different in bi-variate analyses (p<0.05) between SSDI+ (CM) and SSDI- (non-CM) patients were included; each variable was categorized based on the data distribution and clinical relevance. The c-statistic, sensitivity, and specificity were calculated.

Results

Of the 108 patients who were included, 64 were SSDI+ and 44 were SSDI- for CM. Four statistically significant predictors of CM status were identified. Patients with ≥15 claims for acute treatment of migraine (including opioids) were nearly six times as likely to have CM as those with <15 claims (OR=5.87, 95% CI=1.34, 25.63); patients with ≥24 visits of any type (outpatient, inpatient, and emergency room visits) were nearly three times as likely to have CM as those with <24 visits (OR=2.80, 95% CI=1.08-7.26); females were 9 times as likely to have CM (OR=9.17, 95% CI=1.26-66.51); patients with claims for ≥2 unique migraine preventive classes were more than 4 times as likely to have CM as those without claims for preventive treatments (OR=4.40, 95% CI=1.19, 16.22). The c-statistic, sensitivity, and specificity for the model were 0.80, 78%, and 73%, respectively.

Conclusions

The claims-based algorithm for identification of undiagnosed CM patients demonstrated acceptable sensitivity and specificity, and can be used in health care settings to optimize the diagnosis and management of CM patients who may not be otherwise detected.

Trial registration

Not applicable

Consent to publish

Not applicable

References

1. Dodick D, Loder E, Manack Adams A, Buse D, Fanning K, Reed M, Lipton R. Assessing Barriers to Chronic Migraine Consultation, Diagnosis, and Treatment: Results from the Chronic Migraine Epidemiology and Outcomes (CaMEO) Study. Headache. 2016;56(5):821-834.

2. Bigal M, Serrano D, Reed M, Lipton R. Chronic migraine in the population. Neurology. 2008;71:559-566.

P75 The relationship between pain, psychiatric, and endocrine/neurological comorbidities of migraine: Results from the Chronic Migraine Epidemiology and Outcomes (CaMEO) study

Richard B. Lipton1, Vincent T. Martin2, Michael L. Reed3, Kristina M. Fanning3, Aubrey Manack Adams4, Dawn C. Buse1

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

Background

Migraine is comorbid with various conditions, many with a greater relative frequency in chronic migraine (CM) versus episodic migraine (EM). The objective of this study was to replicate and extend work on the comorbidity of pain, psychiatric, and endocrine/neurological symptoms and conditions in a systematically recruited sample of people with EM and CM.

Materials and Methods

Data from the prospective web-based baseline survey of the Chronic Migraine Epidemiology and Outcomes (CaMEO) Study were used to identify people, recruited from an online panel using quota sampling, with EM and CM based on criteria modified from the International Classification of Headache Disorders, third edition, beta version. Participants completed a Comorbidities/Endophenotypes module that assessed 64 symptoms (e.g., neck pain) and conditions (e.g., rheumatoid arthritis). Respondents were asked (1) if they ever had a specific symptom (“Self-Reported [SR]”) and, if present, (2) if the SR symptom or condition had been confirmed/diagnosed by a “doctor” (“SR-physician diagnosis [SR-PD]”). Chi-square analysis was used to compare the relative frequency of symptoms and conditions in respondents with EM versus CM. This report presents data on symptoms and conditions from the Pain, Psychiatric, and Endocrine/Neurological comorbidity categories.

Results

Available CaMEO respondents with migraine (16,763) were sent the Comorbidities/Endophenotype module and 12,810 (76.4%: EM, 11,699; CM, 1,111) provided valid responses. Compared with the EM group, the CM group had a similar mean age (EM, 41.3 years; CM, 41.9 years), was more likely to be female (EM, 74.2%; CM, 81.5%; P<0.001) and white (EM, 84.0%; CM, 88.7%; P<0.001), and had a mean higher body mass index (EM, 27.7 kg/m2; CM, 28.7 kg/m2; P<0.001). The relative frequencies were significantly higher for 24 (85.7%) of the 28 SR symptoms and SR-PD conditions assessed (Fig. 1). 5 of these conditions had relative frequencies >10% higher in CM than EM: chronic back pain (EM, 22.5%; CM, 37.6%), chronic pain (EM, 7.4%; CM, 22.2%), neck pain (EM, 38.1%; CM, 55.3%), anxiety (EM, 25.7%; CM, 42.2%), and depression (EM, 28.1%; CM, 45.6%).

Conclusions

Overall, significantly more respondents with CM versus EM reported having specific symptoms or conditions. Mechanisms explaining this association might include direct causality (e.g., CM causes the comorbidity), reverse causality (e.g., the condition increases CM risk), and shared genetic or environmental risk factors. Confounding, or detection bias (i.e., “Berkson’s Bias”) could also contribute.
Fig. 1 (abstract P75).

EM and CM respondents self-reporting (SR) an assessed symptom or a physician diagnosis (SR-PD) of a condition

Acknowledgments

Editorial support for development of this abstract was provided by Lee B. Hohaia, PharmD, and Dana Franznick, PharmD, at Complete Healthcare Communications, LLC (Chadds Ford, PA), a CHC Group company, and funded by Allergan, plc (Dublin, Ireland).

P76 Are there sex differences among self-report pain features in patients with migraine? A pilot study

Lidiane L. Florencio1, Gabriela F. Carvalho1, Carina F. Pinheiro1, Marcela B. Mendes1, Mariana T. Benato1, Samuel S. Lodovichi1, Fabiola Dach2, Débora. Bevilaqua-Grossi1

1 Department of Biomechanics, Medicine and Locomotor Apparatus Rehabilitation –Ribeirão Preto Medical School, University of São Paulo, Ribeirão Preto-SP, Brazil; 2 Department of Neurosciences and Behavioral Sciences – Ribeirão Preto Medical School, University of São Paulo, Ribeirão Preto-SP, Brazil
Correspondence: Lidiane L. Florencio

Background: Greater prevalence of migraine in women and the fact that women seek out medical advice more often than men have lead to a presumption that migraine is a female disorder. Possibly, this influenced to the actual under-diagnosis of migraine and to the suboptimal headache management in men. Therefore, clinicians and researchers are being encouraged to enhance the knowledge among possible sex differences in migraine clinical profile and comorbidities. Accordingly, the aim of the present study is to explore the self-related pain features, regarding migraine and neck pain, among patients with migraine of both sexes.

Materials and Methods: Patients with migraine, aging between 18 and 55 years old, were trialed in the university-based headache center from November 2015 to July 2017. Migraine diagnosis was provided by an expert neurologist according to the beta version of third edition of International Headache Disorders Classification. Exclusion criteria were other concomitant headache, fibromialgia, history of neck or head trauma. A structured questionnaire was applied to verify migraine and neck pain characteristics. The outcomes of interest were frequency of migraine, years living with pain conditions and its intensity. Severity of the disabilities related to migraine and to neck pain were respectively assessed by the Migraine Disability Assessment and the Neck Disability Index. Additionally, presence and severity of cutaneous allodynia was verified by 12 item Allodynia Symptom Checklist. Groups were compared using t test for independent samples and distribution among questionnaires classifications were tested by the Fisher’s exact test. All statistical analysis was performed by SPSS 20.0 adopting a level of significance of 0.05.

Results: Groups did not differ regarding migraine features and migraine related disability (p>0.05) (Table 1). Neck pain was reported by 83% of women group (n=10) and by 42% of men group (n=5) (p=0.09). Women presented more intense neck pain (p=0.045) and greater neck related disability (p=0.002) than men (Table 1). They also reported more symptoms of allodynia (Table 1; p=0.005). The prevalence of cutaneous allodynia was 92% (n=11) in the women’s group and 77% (n=8) in the men’s group; severe and mild allodynia were the most frequent classification respectively (Fig. 1). No difference could be evidenced among severity distribution of cutaneous allodynia, migraine- and neck-related disability (Fig. 1).

Conclusion: For instance, findings suggest that female sex may be associated with a higher frequency of cutaneous allodynia symptoms and worse severity of neck pain and neck related disability in migraineurs.
Fig. 1 (abstract P76).

Prevalence of the severity classifications of cutaneous allodynia measured by the 12 item Allodynia Symptom Checklist (ASC-12); migraine related disability assessed using the Migraine Disability Assessment (MIDAS) and; neck related disability assessed by the Neck Disability Index (NDI)

Table 1 (abstract P76).

Sample characteristics considering self-report pain features and disability related to migraine and neck pain

 

Men with migraine

(n=12)

Women with migraine

(n=12)

Age (years)

34.2 (8.1)

34.3 (10.6)

ASC-12

4.2 (3.3)*

9.1(4.5)

Migraine

 Frequency (days/moth)

16.3 (9.8)

15.4 (8.5)

 Intensity (0-10)

8.3 (1.4)

7.9 (2.3)

 Onset (years)

15.2 (13.0)

19.6 (18.7)

 MIDAS

19.3 (14.1)

34.1 (32.5)

Neck pain

 Intensity (0-10)

2.7 (3.7)*

5.7 (3.0)

 Onset (years)

2.8 (6.0)

6.6 (5.8)

 NDI

6.7 (6.5)*

12.6 (5.6)

Abbreviations: ASC-12 12 item Allodynia Symptom Checklist, MIDAS Migraine Disability Assessment, NDI Neck Disability Index

*P<0.05

P77 Analysis of endurance capacity of cervical extensors and flexors muscles in individuals with migraine and controls: a pilot study

Iuri V De Oliveira1, Samuel S Lodovichi1, Lidiane L Florencio1, Carina Pinheiro1, Fabiola Dach1, Debora Bevilaqua Grossi1

1 Department of Biomechanics, Medicine and Rehabilitation of Locomotor Apparatus, Ribeirão Preto Medical School, University of São Paulo, Ribeirão Preto, São Paulo, 14049-900, Brazil
Correspondence: Iuri V De Oliveira (iurivaloti@gmail.com)

BACKGROUND

Patients with migraine often present neck pain. Additionally, migraine has been associated to an altered neck muscle performance characterized by increased activity of the superficial cervical extensor muscles and decreased cervical extensor strength. [1,2] Despite the evidences of the impaired endurance capacity in neck pain sufferers [3,4], neck muscles endurance has never been reported in subjects with migraine. Accordingly, our aim was to evaluate the endurance capacity of neck muscles in individuals with migraine and controls.

MATERIALS AND METHODS

Fifteen subjects with migraine were screened from a headache tertiary clinic and fifteen headache-free controls from general population. The participants responded to a previously structured questionnaire containing general information, such as sex, age, weight, and height (Table 1). Endurance test of flexors and extensors was held by a blind evaluator. The flexor endurance was performed with the patient lying in the supine position and positioning the head and neck in slight flexion. The examiner placed the hand under the head, and the test was terminated if the head touched the hand of the examiner or if the subject cannot sustain the position. The extensor endurance test was performed with the patient lying prone. A cervical range-of-motion device was placed on the head to maintain the head's alignment with the horizontal plane. A Velcro band was fixed at the head of the patient and a 2-kg weight was attached to the Velcro band, placed around the participants’ head. The test was terminated when the subject was no longer able to hold the position, or if the head position changed more than 5° from the starting position[5]. Holding time (s) of both positions were recorded with a chronometer. Approval for the study was obtained from the Human Ethics Committee of the University of Sao Paulo (6861/2016), and each subject gave informed consent before testing. Groups were compared using Independent-samples t tests adopting a level of significance of 0,05).

RESULTS

Migraine group presented lower holding time in the flexor endurance test when compared to the control group. At the extensor endurance test there was no significant difference (Table 2).

CONCLUSIONS

Preliminary findings suggest that subjects with migraine present worse performance of neck flexor endurance characterized by a decreased holding time when compared to controls.
Table 1 (abstract P77).

Sample characterization

 

Control (n=15)

Migraine (n=15)

Age (y)

25,06(4,07)

29,93 (7,17)

Weight(kg)

64,38(11,35)

68,4 (11,28)

Height (cm)

164(8)

165 (7)

Data are expressed by mean (standard deviation)

Table 2 (abstract P77).

Holding time of endurance tests

Endurance

Control (n=15)

Migraine (n=15))

p

Flexion (s)

81,33(51,06)

46,73(31,34)

0,03

Extension (s)

351(138,42)

242,20(169,24)

0,07

Data are expressed by mean (standard deviation)

References

1. Florencio LL, de Oliveira AS, Carvalho GF, et al. Cervical Muscle Strength and Muscle Coactivation During Isometric Contractions in Patients With Migraine: A Cross-Sectional Study. Headache. 2015; 55(10): 1312-1322

2. Florencio LL, de Oliveira AS, Lemos TW, Carvalho GF, Dach F, Bigal ME, Falla D, Fernández-de-las-Peñas C, Grossi DB. Patients With Chronic, but not Episodic, Migraine Display Altered Activity of Their Neck Extensor Muscles. J Electromyogr Kinesiol. 2016; (30): 66–72

3. Falla D, Lindstrom R, Rechter L, Boudreau S, Petzke F. Effectiveness of an 8-week exercise programme on pain and specificity of neck muscle activity in patients with chronic neck pain: A randomized controlled study. Eur J Pain, 2013. (17): 1517-1528

4. Jull GA, Falla D, Vicenzino B, Hodges PW. The effect of therapeutic exercise on activation of the deep cervical flexor muscles in people with chronic neck pain. Man Ther 2009;14(6):696-7

5. Edmondston SJ, Wallumrød ME, MacLéid F, Kvamme LS, Joebges S, Brabham GC. Reliability of isometric muscle endurance tests in subjects with postural neck pain. J Manipulative Physiol Ther 2008; (31):348-354

P78 Light-induced discomfort changes semi-static posture control of migraine patients

Carina F Pinheiro1, Renato Moraes2, Lais Sestari1, Gabriela F Carvalho1, Anamaria S Oliveira1, Fabiola Dach1, Débora B Grossi1

1Department of Biomechanics, Medicine and Rehabilitation of Locomotor Apparatus, Ribeirão Preto Medical School, University of São Paulo, Ribeirão Preto, São Paulo, 14049-900, Brazil; 2School of Physical Education and Sports of Ribeirão Preto, University of São Paulo, Ribeirão Preto, São Paulo, 14049-900, Brazil
Correspondence: Carina F Pinheiro (carinafp@hotmail.com)

Background: Patients with migraine have showed balance deficits with increased postural oscillation during quiet stance, alterations in gait mobility, reaction time, and movement velocity in comparison to control subjects [1,2]. Light sensibility is a migraine feature that happens mostly during headache attacks, but also can be present in lower intensity during the interictal period, contributing to migraine disability [3]. However, it has not been established if the exposition to different light intensities modifies the semi-static posture control of migraine patients in the interictal period. Our purpose was to investigate bipedal postural control of migraine women under different light intensities.

Materials and Methods: Fourteen woman with migraine [4] were selected from a headache tertiary clinic and from general population. All participants aged between 18 and 55 years-old (mean 29.3, 95% CI 23.6 to 35.0) with body mass index lower than 30 kg/cm2 (mean 23.6, 95%CI 23.2 to 24.0). The exclusion criteria were: volunteers affected by vascular and/or neurological systemic conditions, presence of other concomitant headache, movement coordination impairment or any musculoskeletal disability that could interfere in the test performance. Participants were exposed to gradual light increase from 300 to a maximum of 2000 lux, and were asked about the visual discomfort intensity (VAS) induced by the light. For balance assessment, participants stood upright in a bipedal position on a force platform for 30 seconds in the following light conditions: 1) visual threshold, in which light induce the minimal visual discomfort; 2) visual discomfort, in which light induce moderate-to-intense visual discomfort; and 3) control, with only ceiling light room (270 lux). Participants performed three trials for each condition. Light intensity was measured by a digital luximeter positioned at participant’s eye level. All participants were assessed during the interictal period.

A repeated measures ANOVA with LSD post-hoc (p<0.05) was used to compare the center of pressure (CoP) ellipse area and the CoP speed among the three light conditions.

Results: We found a median visual threshold equal to 450 lux (IQR 400 to 600) and a median visual discomfort of 2000 lux (IQR 1900 to 2000). Migraineurs showed larger CoP area at the visual discomfort condition compared to the visual threshold and control conditions (p<0.05). CoP speed at the visual discomfort condition was higher than the other conditions tested, but with no statistical difference (Table 1).

Conclusion: Visual discomfort induced by light intensity manipulation increased the CoP area of migraineurs patients in bipedal quiet stance.
Table 1 (abstract P78).

CoP area and CoP speed at three light conditions - mean and 95% confidence interval

 

Visual threshold

Visual discomfort

Control

CoP area (cm2)

3.54 (0.87 to 6.20)a

5.03 (1.82 to 8.25)

1.52 (0.99 to 2.06)a

CoP speed (cm/sec2)

1.74 (1.35 to 2.14)

1.78 (1.45 to 2.10)

1.49 (1.39 to 1.59)

adifferent from the visual discomfort condition (p<0.05)

References

1. Carvalho GF, Chaves TC, Dach F, Pinheiro CF, Gonçalves MC, Florencio LL, et al. Influence of migraine and of migraine aura on balance and mobility - A controlled study. Headache. 2013;53(7):1116–22.

2. Carvalho GF, Bonato P, Florencio LL, Pinheiro CF, Dach F, Bigal ME, et al. Balance Impairments in Different Subgroups of Patients With Migraine. Headache J Head Face Pain. 2017; Mar;57(3):363-374

3. Harriott AM, Schwedt TJ. Migraine is Associated With Altered Processing of Sensory Stimuli. Curr Pain Headache Rep. 2014;18(11).

4. Olesen J. The International Classification of Headache Disorders, 3rd edition. Cephalagia. 2013;33(9):629–808.

P79 Poor sleep quality in probable migraine: a population-based study

Tae-Jin Song1, Soo-Jin Cho2, Won-Joo Kim3, Kwang Ik Yang4, Chang-Ho Yun5, Min Kyung Chu6

1Department of Neurology, Ewha Womans University School of Medicine, Seoul, Korea; 2Department of Neurology, Dongtan Sacred Heart Hospital, Hallym University College of Medicine, Hwaseong, Korea; 3Department of Neurology, Gangnam Severance Hospital, Yonsei University, College of Medicine, Seoul, Korea; 4Department of Neurology, Soonchunhyang University College of Medicine, Cheonan Hospital, Cheonan, Korea; 5Clinical Neuroscience Center, Department of Neurology, Seoul National University Bundang Hospital, Seongnam, Korea; 6Department of Neurology, Kangnam Sacred Heart Hospital, Hallym University College of Medicine, Seoul, Korea
Correspondence: Min Kyung Chu (chumk@hallym.ac.kr)

Background: Although sleep problems are common among headache sufferers,[1] there is little knowledge of the association of poor sleep quality with probable migraine (PM) in general population. In the present study, we aimed to 1) describe the prevalence of poor sleep quality in PM in a general population-based sample; 2) compare the prevalence of poor sleep quality and components of Pittsburgh Sleep Quality Index (PSQI) score among migraineurs, participants with PM, and non-headache individuals and 3) assesse the clinical impact of poor sleep quality among participants with PM.

Materials and methods: We used the data of Korean Headache-Sleep Study (KHSS) in the present study.[2] The KHSS is nation-wide population-based survey regarding headache and sleep for adults aged 19 – 69 years. The KHSS used 2-stage clustered random sampling method which was proportional to population distribution in all Korean territories. Diagnoses of migraine and PM were based on criteria A to D for migraine without aura (code 1.1) in the International Classification of Headache Disorders-3 beta.[3] We investigated the components of PSQI and defined poor sleep quality as PSQI score > 5.[4]

Results: In a representative sample of 2,695 individuals, 143 (5.3%), 379 (14.1%) and 715 (26.5 %) had migraine, PM, and poor sleep quality, respectively (Table 1). The PM participants with poor sleep quality were noted in 134 (35.4%). The prevalence of poor sleep quality was lower among individuals with PM compared to those with migraine (35.4% vs. 47.6%, p = 0.011) but higher than those with non-headache (17.9%, p < 0.001). Among components of PSQI, sleep latency (p < 0.001), sleep duration (p < 0.001), sleep disturbance (p < 0.001), daytime functioning (p < 0.001), and use of sleeping medication (p < 0.001) scores were higher in participants with PM compared to non-headache participants (Table 2). The PM participants with poor sleep quality had more frequent headache (median [interquartile range]) (2.0 [0.3 – 4.0/month] vs. 1.0 [0.3 – 2.0]/month, p = 0.001), visual analogue scale score for headache intensity (6.0 [4.0 – 7.0] vs. 5.0 [3.5 – 6.0], p = 0.003), and headache impact test-6 score (50.0 [44.0 – 58.0] vs. 44.0 [40.0 – 50.0], p < 0.001) than those who without poor sleep quality.

Conclusions: Approximately 35% of participants with PM had poor sleep quality. Poor sleep quality was associated with increased headache frequency, intensity and impact of headache among PM in general population setting.
Fig. 1 (abstract P80).

Pearson’s correlation between TAMPA with FES and with MIDAS among migraineurs, p<0.05

Table 1 (abstract P79).

Sociodemographic characteristics of survey participants; the total Korean population; and cases identified as migraine, probable migraine and poor sleep quality

 

Survey participants

N (%)

Total population

N (%)

p

Migraine

N, % (95% CI)

PM

N, % (95% CI)

Poor sleep quality

N, % (95% CI)

(PSQI> 5)

Sex

 Men

1,345 (49.3)

17,584,365 (50.6)

0.854a

36, 2.7 (1.8-3.5)

136, 10.1 (8.5-11.8)

334, 24.8 (22.5-27.1)

 Women

1,350 (50.7)

17,198,350 (49.4)

107, 7.9 (6.5-9.4)

243, 17.9 (15.8-19.9)

381, 28.2 (25.8-30.6)

Age

 19–29

542 (20.5)

7,717,947 (22.2)

0.917a

25, 4.5 (2.7-6.2)

69, 12.6 (9.8-15.4)

153, 28.3 (24.4-32.0)

 30–39

604 (21.9)

8,349,487 (24.0)

42, 7.0 (4.9-9.1)

102, 16.8 (13.7-19.8)

136, 22.5 (19.2-25.9)

 40–49

611 (23.1)

8,613,110 (24.8)

39, 6.5 (4.5-8.4)

102, 16.8 (13.9-19.8)

167, 27.3 (23.8-30.9)

 50–59

529 (18.9)

6,167,505 (17.7)

22, 4.1 (2.4-5.9)

62, 11.6 (8.8-14.4)

160, 30.2 (26.3-34.2)

 60–69

409 (15.6)

3,934,666 (11.3)

15, 3.9 (2.0-5.7)

44, 11.2 (8.1-14.2)

99, 24.2 (20.0-28.4)

Size of residential area

 Large city

1,248 (46.3)

16,776,771 (48.2)

0.921a

76, 6.1 (4.8-7.5)

180, 14.4 (12.4-16.3)

338, 27.1 (24.6-29.6)

 Medium-to-small city

1186 (44.0)

15,164,345 (43.6)

48, 4.0 (2.9-5.2)

174, 14.7 (12.7-16.7)

303, 25.5 (23.1-28.0)

 Rural area

261 (9.7)

2,841,599 (8.2)

19, 7.4 (4.2-10.6)

25, 9.7 (6.1-13.3)

74, 28.4 (22.8-33.9)

Education level

 Middle school or less

393 (14.9)

6,608,716 (19.0)

0.752a

22, 5.5 (4.2-7.7)

44, 11.5 (8.4-14.7)

110, 28.0 (23.5-32.4)

 High school

1,208 (44.5)

15,234,829 (43.8)

60, 5.0 (3.8-6.3)

178, 14.7 (12.7-16.7)

317, 26.2 (23.8-28.7)

 College or more

1,068 (39.6)

12,939,170 (37.2)

60, 5.6 (4.3-7.0)

155, 14.4 (12.3-16.5)

281, 26.3 (23.7-29.0)

 Not responded

26 (9.6)

  

1, 3.8 (0.0-11.8)

2, 7.7 (0.0-18.7)

7, 26.9 (8.7-45.2)

Total

2695 (100.0)

34,782,715 (100.0)

 

143, 5.3 (4.5-6.2)

379, 14.1 (12.7-15.4)

715, 26.5 (24.9-28.2)

N number, CI 95% confidence interval, PM probable migraine, PSQI Pittsburgh Sleep Quality Index, Variables are presented as number (%) or number, % (95% confidence interval)

aCompared gender, age group, size of residential area, and education level between the sample of the present study and the total population of Korea

Table 2 (abstract P79).

Total and subcomponents score of PSQI of individual with non-headache, PM and migraine

 

Non-headache individuals

N = 1,422 (52.8%)

PM

N = 379 (14.1%)

Migraine individuals

N = 143 (5.3%)

p value

Subjective sleep quality

2.0 (2.0-2.0)

2 (2.0-2.0)

2.0 (2.0-2.0)

0.879

Sleep latency

1.0 (0.0-1.0)

1.0 (0.0-2.0)a

1.0 (0.0-2.0)a

<0.001

Sleep duration

0.0 (0.0-1.0)

0.0 (0.0-1.0)a

0.0 (0.0-1.0)

<0.001

Habitual sleep efficacy

0.0 (0.0-0.0)

0.0 (0.0-0.0)

0.0 (0.0-0.0)

0.244

Sleep disturbance

1.0 (0.0-1.0)

1.0 (1.0-1.0)ab

1.0 (1.0-2.0)a

<0.001

Use of sleeping medication

0.0 (0.0-0.0)

0.00 (0.0-0.0)a

1.0 (0.0-1.0)a

<0.001

Daytime functioning

0.0 (0.0-1.0)

1.0 (0.0-1.0)a

1.0 (0.0-1.0)a

<0.001

Total

4.0 (3.0-5.0)

5.0 (4.0-6.0)a

5.0 (4.0-7.0)a

<0.001

PSQI Pittsburgh Sleep Quality Index, PM probable migraine, Variables are presented as median (interquartile range)

aSignificantly different compared to individuals with non-headache

bSignificantly different compared to individuals with migraine

References

1. Rains JC, Poceta JS, Penzien DB. Sleep and headaches. Curr Neurol Neurosci Rep. 2008;8(2):167-75.

2. Song TJ, Cho SJ, Kim WJ, Yang KI, Yun CH, Chu MK. Anxiety and depression in probable migraine: A population-based study. Cephalalgia. 2016 Jun 1. pii: 0333102416653235

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

4. Buysse DJ, Reynolds CF, 3rd, Monk TH, Berman SR, Kupfer DJ. The Pittsburgh Sleep Quality Index: a new instrument for psychiatric practice and research. Psychiatry Res. 1989;28(2):193-213.

P80 Correlation and differences between kinesiophobia, fear of falling and disability among women and men with migraine

Gabriela Ferreira Carvalho1; Lidiane L Florêncio1, Carina Ferreira Pinheiro1, Marcela B. Mendes1, Mariana T. Benato1, Samuel S. Lodovichi1, Fabiola Dach2, Débora Bevilaqua-Grossi1

1Department of Biomechanics, Medicine and Locomotor Apparatus Rehabilitation – Ribeirão Preto Medical School, University of São Paulo, Ribeirão Preto-SP, Brazil. 2Department of Neurosciences and Behavioral Sciences – Ribeirão Preto Medical School, University of São Paulo, Ribeirão Preto-SP, Brazil
Correspondence: Gabriela Ferreira Carvalho

Background: Migraine could be associated to balance changes and self-report of falls due malfunctioning of the cerebellum and inner ear. Further knowledge regarding features related to balance such as kinesiophobia, fear of falling, dizziness handicap and migraine disability are important for proper management among migraineurs.

Objective: To investigate the presence of kinesiophobia, fear of falling, dizziness handicap and migraine disability and its correlation among women and men with migraine.

Methods: Patients diagnosed with migraine according with the ICHD-III were screened from a tertiary headache center and sorted in two groups: women (n=38) and men (n=17). Subjects with systemic diseases, vestibular disease history, presence of other headache diagnosis or any musculoskeletal impairment were excluded. A structured interview was conducted in order to obtain information regarding demographics including age, BMI, presence of dizziness, physical activity level and headache features. Subsequently it was applied the following questionnaires: Tampa Kinesophobia Scale, Falls Efficacy Scale (FES), Dizziness Handicap Inventory (DHI) and Migraine Disability Assessment (MIDAS). Demographics were contrasted using a one-tailed t-test, questionnaires scores were compared with a Mann-Whitney for independent samples and its classifications among groups with Fisher’s Exact Test. Pearson’s correlation between the questionnaires was calculated based on Cohen classification (0.1-0.3: weak, 0.3-0.5: moderate and >0.5 large correlation). The analysis was performed in the SPSS 21.0 software with a fixed significant level at 5%.

Results: Women and men group of migraineurs did differ in the following outcomes: age (p=0.12), BMI (p=0.13), migraine frequency, intensity and headache onset (p>0.09). However, the level of physical activity was different between women and men (p=0.04). No differences according with the sex was found in the FES, TAMPA and MIDAS questionnaires, and scores for most of them were considered moderated-to-high, even though presence of kinesiophobia was identified just in man (DHI=0.08, FES=0.17, MIDAS=0.06, TAMPA=0.08), Presence and handicap due dizziness were higher in women than men (p<0.05) (Table 1). Moderate significant correlations were found between TAMPA and FES (r=34), and for TAMPA and MIDAS (r=41) (Fig. 1).

Conclusion: Few studies address men with migraine and these results highlight the absence of significant differences in headache disability, kinesiophobia, fear of falling, according with sex, with found scores moderate-to-high for all migraineurs. Dizziness handicap Kinesiophobia is correlated to headache disability and fear of falling in migraineurs. Those aspects are related to migraineurs’ quality of life and might be addressed during clinical assessment.
Fig. 1 (abstract P96).

Change from baseline in AHM days/month

Table 1 (abstract P80).

Average and 95%CI of sample characteristics and questionnaires scores among men and women with migraine.

 

Men with migraine

(n=17)

Women with migraine

(n=38)

Age (years)

33.8 (7.3)

34.2 (11.3)

BMI

27.2 (4.7)

27.2 (5.8)

Migraine

 Frequency (days/month)

17.0 (9.0)

17.3 (10.7)

 Intensity (0-10)

8.5 (1.4)

7.9 (2.2)

 Onset (years)

14.0 (12.6)

14.1 (10.0)

Level of physical activity*

 Inactive

11%

12%

 Minimally active

27%

47%

 Active

51%

29%

 Hepa active

11%

12%

MIDAS

17.3 (13.7)*

32.0 (37.7)

FES

22.2 (11.9)

24.8 (8.7)

Tampa

39.2 (8.1)

35.3 (8.7)

Dizziness

 Self-report

24%*

63%

 DHI

34.5 (16.1)*

47.4 (20.5)

Abbreviations: BMI Body Mass Index, MIDAS Migraine Disability Assessment, FES Falls Efficacy Scale, DHI Dizziness Handicap Inventory

*p<0.05

P81 Handl syndrome in pediatric age

Irene Salfa, Laura Papetti, Barbara Battan, Romina Moavero, Massimiliano Valeriani

Pediatric Headache Center, Children Hospital Bambino Gesù of Rome, Italy

OBJECTIVES

The syndrome of transient headache and neurologic deficits with cerebrospinal fluid lymphocytosis (HaNDL) is a rare syndrome of unclear pathogenesis characterized by one or more episodes of severe headache, transient neurologic deficits and lymphocytic pleocytosis in the cerebrospinal fluid, seldom reported in paediatric age. In most cases it is a benign and self limited disorder, although it may mimic various serious, including life-threatening, diseases, such as stroke and meningoencephalitis, which is why vigorous tests should be sought before this diagnosis of exclusion can be reached.

METHODS/RESULTS

We report three cases of HaNDL occurred in 2 boys (14 years and 10 years old) and in a 17 years old girl. Each patient presented with headache, altered conscious state and papilledema associated with different neurological symptoms such as dysarthria, hemiplegia, pernicious vomiting, ideomotor slowing and psychomotorr agitation. None of them had fever and there was no evidence of meningeal irritation.

They received Ceftriaxone, Aciclovir, and Dexamethasone for possible encephalitis and/ or autoimmune disorders. Clinical manifestations were compatible with a variety of disorders including structural brain lesions, meningitis, seizures, autoimmune, vasculitic and paraneoplastic disorders. We performed neuroimaging examinations (CT scan and MRI of the brain), EEG and serum/CSF studies for infectious, autoimmune and vasculitic diseases. All of these aetiologies were ruled out. In one case, a complete tox screen was added and it resulted negative. The laboratory finding common to all three cases was a clear CSF lymphocytic pleocytosis and an elevated opening pressure during lumbar puncture. The intracranial hypertension treated in all three cases with acetazolamide per os with complete remission. In one case, it was necessary the admission in the intensive care unit because of the worsening of psychomotorr agitation of the patient, requiring sedation and endotracheal intubation. All three patients recovered without any neurological sequelae during the follow up.

CONCLUSION

The possibility of HANDL should be considered in patients presenting with unusual patterns of headache and transient neurological symptoms. It is most commonly diagnosed in the third or fourth decades of life and is rare in the paediatric population. However, awareness of HANDL existence also in children and adolescents can avoid unnecessary and potentially harmful investigations and therapies.

P82 Usage of Quetiapine in Profilactic Treatment of Chronic Migraine

Tetiana Maikova, Sergiy Lukashov, Ekaterina Dzevitskaya, Mariya Kuts

Headache Center, Kyiv, Ukraine, 04070
Correspondence: Tetiana Maikova (maykova@headache.com.ua)

Background. The treatment and prevention of migraine attacks has for long yielded insufficient results. A usual level of result achieved (using standard treatment methods) (i.e. 50% reduction in frequency of attacks) [1] does not produce satisfactory quality of life for the patients. Neither does it reduce the problem of resistant attacks.

We conducted the current study with the goal of increasing efficacy of the prevention of migraine attacks using quetiapine as an additional (supplementary) medicine in patients suffering from Chronic Migraine [2] and already taking anticonvulsants.

Materials and methods. 118 male and female patients from 18 to 50 y.o., suffering from Chronic Migraine were included in this study. Pregnant and nursing mothers and any patient suffering from somatic illnesses were excluded from the sample.

Patients were prescribed topiromat (up to 300 mg/per day) for a 6-month period, but were transferred to sodium valproat (up to 30 mg/kg of weight) in cases of non-response. In cases of response to treatment quetiapine was added as a supplementary (secondary) medicine after 6-month treatment with sodium valproat. A single dose of quetiapine was prescribed at night. The dosage was titrated from 25 mg to 400 mg for a period of 1-1.5 months until a therapeutic effect was attained . The treatment using topiromat+quetiapine or sodium valproat+ quetiapin lasted for a period of 6 months.

Results. We observed in 68.5% of patients complete absence of attacks as result of supplementing quetiapine to the achieved existing level of their individual therapeutic dosage. In 32.5% of cases frequency of attacks was no more than 2 per month. In 1%, frequency of attacks were remained up to 4 per month. All observed attacks were relieved rapidly by NSID or triptans.

Conclusions. Quetiapine shows a high efficacy as a supplementary (secondary) medicine when insufficient results were achieved over a 6 months period when prescribing topiromat or sodium valproat respectively.

The following side-effects were observed when dosage of quetiapine was rapidly increased (up to 100mg per 1-1.5 months): daytime drowsiness for the first 10 days of medication in doses up to 100 mg/per day. This side-effect disappeared when the pain subsided. In 3 patients, congestion of nasal passages was observed before sleep, which was also reduced with increased dosage.

In addition to the pain relief achieved, the following concomitant disorders were reduced: anxiety and asthenia, insomnia, hiperalgomenorroea. The total effect was a general enhancement of the patients’ quality of life.

We suggest that increased level of transmissions of serotonin may be underlying reason basis of high efficacy of quetiapine in resistant and chronic forms of migraine (with and without aura).

Referenses

1. Martelletti P., Katsarava Z., Lampe C., et al (2014) Refractory chronic migraine: a consensus statement of clinical definition from the European Headache Federation. J. Headache Pain 28: 15-47 (PubMed).

2. Headache Classification Committe of the Internationa lHeadache Society (2013). The International Classification of Headache Disorders, 3rd edition. Cephalalgia 33: 629-808 (PubMed).

P83 Ice cream headache and rock and roll

Federico Mainardi1, Giorgio Zanchin2, Ferdinando Maggioni2

1Headache Centre, Neurological Division, SS Giovanni e Paolo Hospital, Venice, Italy; 2Headache Centre, Department of Neurosciences, Padua University, Padua, Italy
Correspondence: Federico Mainardi (fmainardi@iol.it)

Background: Headache attributed to ingestion or inhalation of a cold stimulus is currently codified in Chapter 4 of the International Classification of Headache Disorders 3 beta (ICHD 3 beta) [1] at the first sub-digit of 4.5 Cold stimulus headache (CSH). Although the exact prevalence of CSH in the general population has not been assessed, it appears to be not so uncommon: a 15% lifetime prevalence was found in the general population aged 25-64 [2], raising to 41% in 13-15 years old adolescent [3].

Case report: The renowned journal Billboard published the comment of a live performance of the American rocker Bruce Springsteen, held at the Metlife Stadium (East Rutherford, New Jersey) on August 30, 2016. During the show, the rocker swallowed a cold beverage and, immediately after, turned to the public, saying that he had got an ice cream headache: “In a comical moment, Springsteen put the song on pause for a moment when he stopped to enjoy a cold drink from the audience. “I’ll be with you in a minute,” he said, later taking another swig and chugging it like a teenager. “I got an ice cream headache”” [4]. From this brief comment, we can infer that criteria B and C for 4.5.1 Headache attributed to ingestion or inhalation of a cold stimulus are satisfied, but not criterion A. Therefore, a diagnosis of 4.5.3.2 Probable headache attributed to ingestion or inhalation of a cold stimulus could be proposed.

Discussion: CSH, as well as External pressure headache (EPH), previously considered as secondary headaches and codified in chapter 13, have been moved in Chapter 4 of the current classification, within Chapter 4. Other primary headaches. The reason of this modification is justified by the fact that “they are brought on by physiological (non-damaging) stimuli” [1]. However, both of these forms of headache are strictly related to the application of recognizable factors, fulfilling criterion C of general diagnostic criteria for secondary headache.

Conclusion: This curious anecdote testifies that the intensity of CSH may be so severe to induce a temporary interruption of a concert held in front of a crowd of enthusiast fans. In general terms, a causative factor, independently from its nature, is clearly recognizable for inducing both CSH and EPH. Therefore, the primary or secondary nature of these forms of headache and their classification will be discussed on the basis of the literature on this subject.

References

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

2. Rasmussen BK, Olesen J. Symptomatic and nonsymptomatic headaches in a general population. Neurology. 1992; 42: 1225-1231.

3. Fuh JL, Wang SJ, Lu SR, Juang KD. Ice-cream headache--a large survey of 8359 adolescents. Cephalalgia. 2003; 23: 977-981.

4. http://www.billboard.com/articles/news/7494667/bruce-springsteen-record-metlife-stadum (visited 6.8.2017).

P84 Implementation of improved working practices in a chronic migraine Botox® clinic has increased treatment capacity by up to 60% with the same resources

Rebecca Stuckey, 1 April Bostock, 1 Stuart Weatherby, 1 Gemma Taylor, 1 Donna Clewer, 1 Paul Button, 2 Julie Button2

1Neurology Department, Plymouth Hospitals NHS Trust, UK; 2ProcEx Solutions Ltd., Wales, UK

Objective: Chronic migraine is defined as headaches occurring on 15 or more days each month, at least half of which have migraine symptoms. Botox® (onabotulinum toxin A) is used extensively in the UK National Health Service for the treatment of chronic migraine. We provide this treatment regimen to our patients in a nurse-led clinical service. The demand for the treatment is increasing and we needed to find more efficient ways of running the service to meet the increasing demands. In 2016 we had a waiting list for treatment with a number of patients breaching the 18 week ‘treat-by-date’. Our main objective was to eliminate the waiting list by treating substantially more patients in each clinic session and avoiding any further breaches of the 18 week guideline. To do this we needed to develop an efficient and standardised process without adding additional resources into the service.

Method: We undertook a structured work improvement program partnering with a company called ProcEx Solutions Ltd. We utilised the model of firstly measuring our current process (assessment) and then secondly implementing standardised improvements (kaizen) as identified in the measurement phase. Measurements were made of nurse walking distances due to clinic room set-up, time taken to reconstitute and draw up Botox and we also assessed the amount of ‘down-time’ in the clinics. Different categories of patients were assessed and we observed that certain patients would require significantly more clinic time than others. We were allocating 30 minute time slots to all patients but we realised that we could segregate the patients into categories of 15 and 30 minute time slots. The table below illustrates the increase in annual capacity by using this approach.

Clinics

Clinic Times

Frequency

Current Annual Capacity

New Annual Capacity

Tuesday AM

09:00-12:30

Weekly

336

546

Wednesday AM

09:00-12:30

Monthly

96

156

Wednesday PM

13:30-16:30

Monthly

84

132

Thursday PM

13:30-16:30

Monthly

84

132

Friday PM

13:30-16:30

Fortnightly

168

264

   

768

1230

   

% Increase

60%

Results: We realised additional clinic capacity of 462 treatments per year, an increase of 60%. We observed actual increases from 292 treatments in the second half of 2016 to 395 treatments in the first half of 2017, an actual increase of 35%, with the same number of staff.

Conclusion: The assessment of our working practices has identified opportunities to improve our efficiencies. The subsequent implementation of an improved process has enabled us to treat significantly more patients without increasing the number of clinical staff. We continue to see further increases in the number of patients we are able to treat.

P85 Zonisamide for headache prophylaxis in dementia

Yunju Choi1, Seung H. Lee2, Myeong K. Kim2, Kyung W. Kang2

1Department of neurology, Presbyterian Medical Center, Jeonju, Republic of Korea, 54987; 2Department of neurology, Chonnam National University Hospital, Gwangju, Republic of Korea, 61469
Correspondence: Yunju Choi (neurologist16@gmail.com)

Background

Zonisamide is an antiepileptic drug that shows broad spectrum of anticonvulsant activity. Furthermore, recent studies have demonstrated additional therapeutic use in migraine prophylaxis [1]. Zonisamide, a sulfonamide analog, is a drug with mechanisms of action similar to topiramate. Also these two drugs have similar adverse effects, such as weight loss, ureteric stone. In contrast with topiramate, zonisamide has no cognitive impairment or learning difficulty [2]. Therefore zonisamide could be one of the therapies for prevention of headache in patients with dementia.

Materials and Methods

We enrolled 10 Alzheimer’s disease patients with migraine headache, retrospectively. For headache, we investigated headache frequency with severity by using their headache diary and visual analog scales (VAS). Mini-mental status examination (MMSE), clinical dementia rating (CDR) was checked on visit and 3 months later.

Results

8 patients were male. The average add-on dose of zonisamide was 230 (range: 200-300). Frequency and severity of headache was also improved. The baseline average VAS was 6.9 (range: 6-8) and follow-up VAS was 3.8. The headache frequency declined from 16.4 times per month to 8.3. There is no significant change on MMSE and CDR.

Conclusions

Our findings support the use of zonisamide and an effective therapy for headache prophylaxis in patients with dementia.

References

1. Assarzadegan F, Tabesh H, Hosseini-Zijoud SM, Beale AD, Shoghli A, Ghafoori Yazdi M, et al. Comparing Zonisamide With Sodium Valproate in the Management of Migraine Headaches: Double-Blind Randomized Clinical Trial of Efficacy and Safety. Iran Red Crescent Med. J. 2016;18:e23768.

2. Lee HJ, Son JM, Mun J, Kim DW. Safety and Efficacy of Zonisamide in Patients with Epilepsy: A Post-Marketing Surveillance Study. J Epilepsy Res. 2015;5:89-95.

P86 Postural headache and spontaneous intracranial hypotension: clinical features, neuroimaging and quality of life improvements in patients treated with blind epidural blood patch: a case series

Marco Mercieri1, Riccardo Chierichini1, Barbara Silvestri2, Roberto Arcioni1

1 Department of Medical and Surgical Science and Translational Medicine, Sapienza University of Rome and Pain Therapy Unit, Sant'Andrea Hospital, Rome, IT; 2 Unit of Anaesthesia, Intensive Care and Pain Management, Campus Bio-Medico University, Rome, Italy
Correspondence: Marco Mercieri (marco.mercieri@uniroma1.it)

Spontaneous Intracranial Hypotension (SIH) is a rare syndrome (incidence: 5/100.000) [1] reportedly described over the past years [1,2]. Although SIH can produce a broad spectrum of clinical presentations, most patients experience postural headache. A conservative treatment is advocated as first-line therapy for patients with SIH, but in refractory cases an epidural blood patch (EBP) may be attempted [3,4]. We aimed to assess the efficacy of blind lumbar EBP in a case series of patients with postural headache and spontaneous intracranial hypotension.

Methods. We retrospectively analysed patients with SIH treated with EBP in our Centre. Information regarding demographics, radiology and clinic follow up was extracted from an electronic patient record system. The patients were asked to answer questions regarding their daily life activities using the 12-Items Short Form Survey (SF-12) questionnaire before and after 1 month from the procedure (following our Pain Unit protocols). Data regarding their global impression of change 1-week after treatment were collected. All patients underwent Brain MRI after 6-month from BP to evaluate radiologic resolution and the data were compared to the clinical evolution.

Results. Five patients who underwent lumbar epidural blood patching were analysed (3 female; mean age 41 years). The site of Cerebrospinal Fluid leak was evident in 4 patients (3 through spinal MRI, 1 through Cisternography) (Tab. 1). Three patients reported instantaneous headache resolution, 2 responded only partially, having symptoms persisting for 1-2 weeks before recovering and developed a chronic headache without postural component. All patients reported improvements in Physical Component Summary and Mental Component summary after the procedure (p<0,02), and all patients had impression of benefit 1-week after treatment. MRI showed normal findings at 6-month follow-up.

Conclusions. A blind blood patch procedure can provide complete resolution in headache symptoms in selected patients. Our patients who did not achieve instantaneous complete symptoms resolution after the procedure, still showed improvements in their quality of life and reported a noticeable change after the procedure, showing that EBP might be beneficial also for those cases in which complete relief is not instantaneous.
Table 1 (abstract P86).

See text for description

Case n.

Sex

Age

Spine NMR

Cisternography

Leakage

Blood administered (ml)

n° of Blood Patches

1

F

35

+

 

T2-T3

20

1

2

M

57

-

+

L2-L3

20

1

3

M

43

+

 

C7-T1

20

1

4

F

45

+

 

T12-L1

20

2

5

F

27

-

 

/

20

1

Note: + = evidence of liquor leakage, - = not evidence of liquor leakage

References

1 Kranz, Peter G., Michael D. Malinzak, Timothy J. Amrhein, and Linda Gray. “Update on the Diagnosis and Treatment of Spontaneous Intracranial Hypotension.” Current Pain and Headache Reports 21, no. 8 (August 2017): 37. doi:10.1007/s11916-017-0639-3.

2 Limaye, Kaustubh, Rohan Samant, and Ricky W. Lee. “Spontaneous Intracranial Hypotension: Diagnosis to Management.” Acta Neurologica Belgica 116, no. 2 (June 2016): 119–25. doi:10.1007/s13760-015-0577-y.

3 Davidson, Benjamin, Farshad Nassiri, Alireza Mansouri, Jetan H. Badhiwala, Christopher D. Witiw, Mohammed F. Shamji, Philip W. Peng, Richard I. Farb, and Mark Bernstein. “Spontaneous Intracranial Hypotension: A Review and Introduction of an Algorithm For Management.” World Neurosurgery 101 (May 2017): 343–49. doi:10.1016/j.wneu.2017.01.123.

4 Mokri, B., D. G. Piepgras, and G. M. Miller. “Syndrome of Orthostatic Headaches and Diffuse Pachymeningeal Gadolinium Enhancement.” Mayo Clinic Proceedings 72, no. 5 (May 1997): 400–413. doi:10.1016/S0025-6196(11)64858-1.

P87 Retinal migraine: three case reports

Vlasta Vukovic Cvetkovic, Lars Bendtsen, Jes Olesen

Danish Headache Center, Rigshospitalet-Glostrup, Copenhagen, Denmark
Correspondence: Vlasta Vukovic Cvetkovic (vlasta.vukovic@uclmail.net)

Background: Retinal migraine is a rare form of migraine. According to the ICHD-3 beta criteria the diagnosis requires an aura consisting of fully reversible monocular positive and/or negative visual phenomena (e.g., scintillations, scotomata or blindness) confirmed during an attack by 1. clinical visual field examination and/or 2. the patient’s drawing of a monocular field defect and at least two of the following three characteristics: 1. the aura spreads gradually over ≥5 min, 2. aura symptoms last 5-60 min, 3. aura is accompanied, or followed within 60 min, by headache.

Case reports: We present three cases of patients with retinal migraine, they all fulfill ICHD criteria but have some “case specific” interesting features:
  1. 1.

    A 29-year old woman with aura always on her left eye. The patient experiences first a slight pressure beyond her eye, followed by an aura described as slowly blackening of her visual field in all 4 quadrants, or scintillating scotoma, lasting 3-5 minutes, followed by complete normalization of her visual field. In 50% of attacks she has a subsequent mild headache lasting 10-30 minutes. She has 1-2 attacks per month. Case specific: headache is present in only 50% of attacks.

     
  2. 2.

    A 40-year old woman with aura always on her left eye, beginning with palpitation, sense of fear, followed by grey scintillating scotoma, followed by complete blindness, with complete resolution after 10 minutes. Aura is followed by a mild headache lasting couple of hours to several days. She has 1 attack per month. Case specific: has additional “autonomic aura symptoms”.

     
  3. 3.

    A 69-year old man, with migraine without aura and separately sudden attacks of complete visual loss lasting from 10 seconds to 10 minutes on right or left eye, rarely both. Simultaneously pressing headache behind the affected eye, duration 5 minutes to 6 hours with foto-and fonofobia, slight nausea and aggravation by physical activity. He has 3 attacks per month. Case specific: pt. experiences sudden visual loss, not march, symptoms are always reversible.

     

Common to all cases: never typical (hemianoptic) visual aura, sensory, speech or motor aura; accompanying headache is of mild intensity, in 2 cases not migrainous; in 2 cases aspirin had no effect on migraine.

Conclusion: Although rare, retinal migraine should not be misdiagnosed as amaurosis fugax, papilledema or optic disc disease, transient visual obscuration or Uhthoffs phenomenon.

Consent for publication: The authors declare that written informed consent was obtained for publication.

P88 Changes in grey matter volume and functional connectivity in cluster headache versus migraine

Silvia Benemei1, Antonio Giorgio2, Jian Zhang2, Chiara Lupi1, Marzia Mortilla3, Antonio Federico2, Pierangelo Geppetti1, Francesco De Cesaris1, Nicola De Stefano2

1Department of Health Sciences, University of Florence, Florence, Italy; 2Department of Medicine, Surgery and Neuroscience, University of Siena, Siena, Italy; 3Anna Meyer Children’s University Hospital, Florence, Italy
Correspondence: Silvia Benemei

Background

Recent MRI studies have shown structural and functional abnormalities in the brain of cluster headache (CH) and migraine (M) patients. However, no between-group comparison of MRI measure has been performed.

Materials and methods

Multimodal MRI was acquired on a 3T MR scanner in age-matched patients with CH (n=12), M without aura (n=13), both during attack-free period, and normal controls (NC, n=13). MRI processing was performed with FSL. Voxelwise analyses of variance were done with nonparametric permutation testing (p<= 0.05, corrected).

Results

Compared to NC, higher grey matter volume (GMV) occurred in CH in the cerebellum and occipital fusiform gyrus and in M in the lateral occipital cortex (LOC). GMV was lower than in NC in the inferior frontal gyrus of CH and in the lingual gyrus of M. Compared to M, GMV of CH was higher in the cerebellum and lower in the frontal pole and LOC. Functional connectivity (FC) was, compared to NC, higher in CH in the default mode, working memory and executive networks (DMN, WMN, EN) and altered in DMN of M, with lateral increase and medial decrease. FC in WMN and EN of CH was also higher than M. FC between cerebellar and temporo-insular networks was higher in CH than M.

Conclusions

The brain of attack-free CH seems to be characterized, compared to M, by (i) GMV changes, with decrease in a classical pain processing region (frontal cortex) and increase in an atypical region (cerebellum) and (ii) increased FC in key cognitive networks, with a possible maladaptive role.

P89 Intercepting migraine in its path towards chronicity

Angela Koverech, Paolo Martelletti1,2

1Department of Clinical and Molecular Medicine, Sapienza University, Rome Italy; 2Regional Referral Headache Centre, Sant’Andrea Hospital, Via di Grottarossa 1035, 00189 Rome, Italy
Correspondence: Paolo Martelletti (paolo.martelletti@uniroma1.it)

Today there is the need of analysis of individual monoclonal antibody studies for CGRP or CGRPr in migraine, and also on the future role of these drugs in a disease with such a large impact on the general population. Fourteen percent of the global population suffers from migraine, and we now have to imagine how to proceed in the dissemination of these new drugs. Excluding the prophylaxis of the episodic form of migraine, we will have to postpone for ethical and pharmacoeconomic reasons the choice to treat with CGRP(r) mAbs the very low frequency migraine subpopulation (4-6 migraine days per month). Unfortunately, the tight application of existing guideline-recommended drugs could make this choice difficult. We must instead focus attention towards the highly disabling and costly forms; otherwise we would hypothesize treating almost one billion people with migraine. However, only 2% of the world's population suffers from chronic migraine (with or without pharmacological abuse of acute drugs – analgesics, non-steroidal anti-inflammatory drugs, triptans, opioids, ergot derivatives, barbiturates, caffeine, etc. and their various combinations) and this chronic form is the current true challenge in headache management. We should attempt to prevent the chronicization of these patients, who constitute the core group with personal-social-working burden, and who fluctuate in a pre-chronic phase with high-frequency migraine crisis but who are not yet chronic. Only in this way will we reduce the huge number of chronic migraine patients, who stray towards medication overuse headache (MOH) and are at risk of refractoriness. And only in this way will we reduce the cascade of multi-systemic pathologies (gastrointestinal, renal, cardiovascular, cerebral, psychiatric, etc.) originating from acute drug abuse, which are often not recognized or directly correlated with it. This is a top priority, because we know that the rehabilitation procedures for chronic migraine complicated by MOH present with relapse in 50% of patients within the first 12 months. Another priority area of intervention is refractory migraine, as clinically defined by the European Headache Federation. Refractory migraine is very hard to treat and has been the target for a number of ineffective invasive techniques. These priority areas could represent immediate targets for the application of the new CGRP mAbs.

Reference

Martelletti P. The application of CGRP(r) monoclonal antibodies in migraine spectrum: needs and priorities. Biodrugs 2017 in press.

P90 Induction of migraine-like photophobia by PACAP-38: A potential target in migraine treatment

Adisa Kuburas1, Bianca N. Mason2, Maria-Christina M. Loomis4, Leon F. Garcia-Martinez4, Andrew F. Russo1,2,3

1Department of Molecular Physiology and Biophysics; 2Molecular and Cellular Biology Program, 3Veterans Affairs Medical Center; University of Iowa, Iowa City, Iowa 52242; 4Alder Biopharmaceuticals; Bothell, Washington 98011
Correspondence: Andrew F. Russo

Migraine is a disabling neurological disorder and a significant public health problem. The pathophysiology of migraine is not well understood, but studies have shown that calcitonin gene-related peptide (CGRP) plays a strong role. Recently there has been a significant interest for role of pituitary adenylate cyclase-activating polypeptide-38 (PACAP38) in migraine. We have previously shown that administration of PACAP38 induces photophobia similar to CGRP-induced photophobia in wild-type CD1 mice. As a surrogate to photophobia, we measured light aversion behavior. The objective of this study is to determine if pretreatment with anti-PACAP antibodies will inhibit the PACAP-induce light aversion. We have also used anti-PACAP and anti-CGRP antibodies to better understand the relationship between PACAP and CGRP in their involvement in migraine.

Our results show that intraperitoneal (ip) injection of anti-PACAP38 antibody was able to inhibit PACAP-induced light-aversive response in CD1 mice compared to mice treated with control antibody. In addition, PACAP38-induced increase in resting time in the dark, reflecting pain as experienced during migraine, was inhibited by anti-PACAP antibody. Our results also suggest that PACAP and CGRP may work through different pathways as the cross antibody treatment was not able to inhibit PACAP or CGRP-induce light aversion. Future work will attempt to understand more about PACAP38 in migraine and to explore PACAP as a potential novel target in migraine therapy.

P91 Burden and impact of migraine: a caregiver’s perspective

Elena Ruiz de la Torre1, Paolo Martelletti2,3, Audrey Craven1,4, Donna Walsh4, Simon Evans5, Paula Dumas6, Hans-Christoph Diener7, Michel Lanteri-Minet8, Todd J. Schwedt9, Jean-Pierre Malkowski10, Monisha Sodha11, Susann Walda11, Anne Aronsson11, Annik Laflamme10, Pamela Vo10

1European Headache Alliance, Brussels, Belgium; 2European Headache Federation, Rome, Italy; 3Department of Clinical and Molecular Medicine, Sapienza University of Rome, Rome, Italy; 4European Federation of Neurological Associations; 5Migraine Action, Leicester, LE1 6NB, UK; 6Migraine Again, USA; 7Department of Neurology and Headache Center, University of Duisburg-Essen, Essen, Germany; 8Département d’Evaluation et Traitement de la Douleur, Centre Hospitalo-Universitaire de Nice, Hôpital de Cimiez, 06300 Nice, France; 9Department of Neurology, Mayo Clinic, USA; 10Novartis Pharma AG, 4002 Basel, Switzerland; 11GfK Switzerland, 4058 Basel, Switzerland
Correspondence: Pamela Vo (pamela.vo@novartis.com)

Background

Migraine has far-reaching impacts on the family of individuals with migraine but limited evidence is available to describe this reality. To better understand the full burden of migraine, this study sought to describe the impact of migraine from the caregiver’s perspective.

Materials and Methods

This cross-sectional study was conducted using Online Bulletin Boards (OBB), an interface developed for online survey, discussions and interactions led by a trained facilitator over 4 consecutive days. Caregivers aged ≥25 years who were caring for an adult migraine patient in their household were recruited to participate in 3 OBBs in Germany, Italy and USA (1/country). Participants were blinded to each other and agreed to partake daily for ≥30 minutes in the OBBs, where they were asked to respond to specific questions on migraine and provide their perspectives on statements and other participants’ blinded responses. All responses were aggregated by country and qualitatively analyzed.

Results

A total of 30 caregivers participated in this pilot phase of a large global study (10/country). All caregivers reported that they were highly involved in the management of migraine and that they spent an average of 15 hours/month supporting their family member suffering from migraine. 83% of respondents (n=25/30) reported feeling stressed, exhausted and overwhelmed with the amount of work resulting from their caregiving activities. They described themselves as powerless witnesses of the frequent and intense suffering of their loved ones, wanting to be helpful while knowing the limits of what they could do. 60% of caregivers (n=18/30) reported a worsening of personal relationships over time due to migraines. Regardless of whether they were employed, unemployed or retired, 83% of caregivers (n=25/30) reported that their caregiver role affected their lives due to the significant changes it imposed on their own daily routines/schedules. This affected private life, social engagements, relationships, and professional obligations, including fear of losing employment. Most caregivers (87%, n=26/30) reported ambivalent feelings, being torn between commitment, self-sacrifice and resentment. All agreed that migraine patients were thankful for their help and assistance.

Conclusions

Caregiving has a major impact on the lives of close relatives supporting migraine patients. This study highlights how the burden of migraine extends beyond the patients, with substantial functional and emotional impacts of the disease on caregivers. This pilot confirmed the unique opportunity that this type of study provides for insights into the caregivers’ experience and unmet needs in the current treatments available to migraine patients.

Funding

This study was funded by Novartis AG, Switzerland.

Acknowledgements

This poster has been previously presented at the 18th Congress of the International Headache Society, 7-10th September 2017, Vancouver, Canada.

P92

Withdrawn

P93 Real-world patient perspective on the burden and impact of migraine

Elena Ruiz de la Torre1, Paolo Martelletti2,3, Audrey Craven1,4, Donna Walsh4, Simon Evans5, Paula Dumas6, Hans-Christoph Diener7, Michel Lanteri-Minet8, Todd J. Schwedt9, Jean-Pierre Malkowski10, Monisha Sodha11, Susann Walda11, Anne Aronsson11, Annik Laflamme10, Pamela Vo10

1 European Headache Alliance, Brussels, Belgium; 2 European Headache Federation, Rome, Italy; 3 Department of Clinical and Molecular Medicine, Sapienza University of Rome, Rome, Italy; 4 European Federation of Neurological Associations; 5 Migraine Action, Leicester, LE1 6NB, UK; 6 Migraine Again, USA; 7 Department of Neurology and Headache Center, University of Duisburg-Essen, Essen, Germany; 8 Département d’Evaluation et Traitement de la Douleur, Centre Hospitalo-Universitaire de Nice, Hôpital de Cimiez, 06300 Nice, France; 9 Department of Neurology, Mayo Clinic, USA; 10Novartis Pharma AG, 4002 Basel, Switzerland; 11 GfK Switzerland, 4058 Basel, Switzerland
Correspondence: Pamela Vo (pamela.vo@novartis.com)

Background

Migraine is a prevalent condition affecting about 11% of the adult population. It has debilitating symptoms and affects patient functioning. The present study was undertaken to understand the full burden and impact of migraine in everyday life from the patient’s point of view.

Materials and Methods

This cross-sectional study was conducted using Online Bulletin Boards (OBB). This interface was developed for online survey, discussions and interactions led by a trained facilitator over a period of 4 consecutive days. Adults with chronic and episodic migraine aged between 25 and 60 years old were recruited to participate in 6 OBBs established in Germany, Italy and USA (2 per country). Participants were blinded to each other and agreed to partake for at least 30 minutes each day in the OBBs, where they were asked to respond to specific questions on migraine and to provide their perspective on statements and other participants’ blinded responses. All responses were aggregated by country and qualitatively analyzed.

Results

A total of 60 migraine patients participated in this pilot phase of a large global study (20 per country). About half (47%, n=28) reported having been diagnosed with migraine, either by a general practitioner (GP) or neurologist within the year following the date of their 1st symptoms. Table 1 summarizes the 3 most common migraine attack triggers, symptoms, and coping mechanisms reported by patients. All respondents reported important limitations resulting from migraines in private, professional and social aspects of life, mainly the disruption of daily routines, significant strain on personal relationships, difficulty caring for children, and missed days of work, deadlines, or social events. Anxiety and frustration were most frequently reported as emotional consequences of migraine in private/social life (92% and 72%) and work (97% and 88%). 87% of patients (n=52) had seen a physician for migraine management but many (85%, n=51) did not consult regularly, especially if their diagnosis had occurred long ago. Two thirds (n=38 / 63%) of respondents reported getting functional and emotional support from family and friends, but wished for improved understanding/compassion from others and more efficacious medications.

Conclusions

This study highlights the substantial functional and emotional burden migraine exerts on individuals, as well as the significant unmet needs that remain for these patients despite currently available care and treatment options.
Table 1 (abstract P93).

Main Migraine Triggers, Symptoms, and Coping Mechanisms

 

3 Most Common per Category

Migraine attack triggers

Bright light

Loud/repetitive sounds

Stress

97%(n=58)

93%(n=56)

93%(n=56)

Migraine symptoms

Pounding/throbbing

Photophobia

Sensitivity to sound and noise

97%(n=58)

97%(n=58)

93%(n=56)

Coping mechanisms

Lying down in a darkened room

Avoidance of sounds/noise

Medication use

97%(n=58)

95%(n=57)

77%(n=46)

Funding

This study was funded by Novartis AG, Switzerland.

Acknowledgements

This poster has been previously presented at the 18th Congress of the International Headache Society, 7-10th September 2017, Vancouver, Canada.

P94 Efficacy of Onabotulinumtoxin A and Physical Therapy combined treatment in chronic migraine

Antonio Granato1; Antonella Monticco2; Manuela Deodato2; Ugogiulio Sisto1; Mariana Ridolfi1; Roberto Marcovich2; Paolo Manganotti1

1Department of Medical, Technological and Translational Sciences, Headache Centre, University of Trieste, Italy; 2University of Trieste, Italy

Background

Physical therapy (PT) is used as single or complementary treatment for headache. Onabotulinum toxin A (BoNT-A) has proven to be effective in chronic migraine (CM) prophylaxis. Currently no clinical studies about BoNT-A plus PT combined treatment (CT) are available.

Objectives

To compare the efficacy of BoNT-A plus PT combined treatment with the single therapeutic options in CM.

Material and methods

A three-arm randomized perspective study of patients suffering from CM admitted to the Headache Centre of the University of Trieste was performed. All the patients underwent a clinical postural evaluation at the beginning of the study. They had a one-month observation period (baseline), then they were treated with BoNT-A, PT or CT. BoNT-A was administred following the “fixed site/fixed dose” and “follow-the-pain” protocol, PT was based on combination of postural advice, relaxation training, exercises and manual treatment on trigger points, reinforcement and postural modification. Number of responders (>50% reduction of headache days), headache days, headache hours, symptomatic drug intake, disability (MIDAS) in baseline and at the three-month follow-up visit were analyzed with SPSS 21.0.

Results

We enrolled 25 patients (22 F, 3 M; mean age 54 [34-79] years), 13 patients were treated with BoNT-A, 8 patients with CT, 4 patients with PT. Both groups of patients treated with BoNT-A and CT had a reduction of number of headache days (BoNT-A: Baseline=26 [16-30] vs Three-month visit=12 [4-30] (p=0.003); CT: Baseline=21 [13-30] vs Three-month visit=11 [3-29] (p=0.012)), symptomatic drugs (BoNT-A: Baseline=21 [6-57] vs Three-month visit=14 [0-21] (p=0.025); CT: Baseline=22 [11-41] vs Three-month visit=9 [1-41] (p=0.018)), and MIDAS (BoNT-A: Baseline=93 [62-210] vs Three-month visit=57 [10-179] (p=0.002); CT: Baseline=85 [35-124] vs Three-month visit=34 [12-187] (p=0.03)). The reduction of headache days, symptomatic drugs and MIDAS were comparable in both BoNT-A and CT patients (p=NS). Only patients treated with BoNT-A improved in total headache hours (BoNT-A: Baseline=241 [46-737] vs Three-month visit=121 [12-214] (p=0.005)). Percentage of responders was higher in CT than in BoNT-A group (CT=62% vs BoNT-A= 38%). Effectiveness measures did not improved in the four patients who received only PT.

Conclusions

Physical therapy is an effective add-on treatment to BoNT-A for CM prophylaxis. Patients treated with combined therapy BoNT-A plus PT had a higher percentage of responders than patients treated with only BoNT-A. The other treatment efficacy measures equally reduced in both CT and BoNT-A groups. The few patients treated with only PT did not improved, however a higher sample is required.

P95 The antimigraine butterbur ingredient, isopetasin, desensitizes peptidergic nociceptors via the TRPA1 channel activation in vitro

De Logu F1, Benemei S1, Li Puma S1, Marone IM1, Coppi E1, Ugolini F1, Liedtke W2, Pollastro F3, Appendino G3, Geppetti P1, Materazzi S1 and Nassini R1

1Department of Health Sciences, Section of Clinical Pharmacology and Oncology, University of Florence, Florence, Italy; 2Departments of Neurology, Anesthesiology and Neurobiology, Clinics for Headache, Head-Pain and Trigeminal Sensory Disorders, Duke University, Durham, NC 27710 USA; 3Department of Pharmaceutical Sciences, University of Eastern Piedmont, Novara, Italy
Correspondence: De Logu F

For hundreds of years, butterburs (Petasites), herbaceous perennial plants belonging to the Asteraceae, which includes also Tanacetum parthenium L., have been used by folk medicine of northern Eurasia and America for therapeutic purposes, including treatment of fever, respiratory diseases, spasms, and pain. Among the number of compounds contained in common butterbur [Petasites hybridus (L.) Gaertn.], the major constituents, petasin and isopetasin, are considered responsible for the antimigraine effects of the herbal extract. The mechanism of the antimigraine action of butterbur [Petasites hybridus (L.) Gaertn.] is unknown. Here, we investigated the ability of isopetasin, a major butterbur constituent, to specifically target the transient receptor ankyrin 1 (TRPA1) channel and to affect functional responses relevant to migraine.

Single cell calcium imaging and patch-clamp recordings in human and rodent TRPA1-expressing cells, neurogenic motor responses in isolated rat urinary bladder, release of calcitonin gene related peptide (CGRP) from mouse spinal cord in vitro, were examined. Isopetasin produced (i) calcium responses and currents in rat/mouse trigeminal ganglion (TG) neurons and in cells expressing the human TRPA1, (ii) substance P-mediated contractions of isolated rat urinary bladders and (iii) CGRP release from mouse dorsal spinal cord, responses that were selectively abolished by TRPA1 genetic deletion/pharmacological antagonism. Preexposure to isopetasin produced marked desensitization of allyl isothiocyanate (AITC, TRPA1 agonist)- or capsaicin (TRPV1 agonist)-evoked currents in rat TG neurons, contractions of rat urinary bladder and CGRP release from central terminals of primary sensory neurons.

TRPA1 agonism by isopetasin results in excitation of neuropeptide-containing nociceptors that is followed by remarkable neuronal desensitization. Such attenuation in pain and neurogenic inflammation may account for the antimigraine action of butterbur.

P96 Use of acute headache and migraine medications in patients with episodic migrainein the STRIVE Phase 3 trial of erenumab for migraine prevention

Uwe Reuter1, Jo Bonner2, Gregor Broessner3, Yngve Hallstrom4, Hernan Picard5, Sunfa Cheng5, Feng Zhang5, Dan Mikol5, Jan Klatt6

1Department of Neurology, Charité Universitätsmedizin Berlin, Berlin, Germany; 2Mercy Research, St Louis, MO, USA; 3Department of Neurology, Medical University of Innsbruck, Innsbruck, Austria; 4Stockholm Neuro Center, Stockholm, Sweden; 5Amgen Inc., Thousand Oaks, CA, USA; 6Novartis Pharma AG, Basel, Switzerland
Correspondence: Uwe Reuter (uwe.reuter@charite.de)

Background

Erenumab is a fully human monoclonal antibody that selectively inhibits the calcitonin gene-related peptide (CGRP) receptor. In the STRIVE placebo-controlled Phase 3 trial in patients with episodic migraine (EM; clinicaltrials.gov NCT02456740), erenumab 70 mg and 140 mg administered monthly by subcutaneous injection achieved the primary endpoint of significantly reducing the number of monthly migraine days versus placebo. Erenumab also achieved the secondary endpoint of reducing the number of days/month versus placebo on which patients used acute migraine-specific medications (AMSM, triptans or ergotamines; −0.9 and −1.4 days/month averaged over Months 4−6 for erenumab 70 mg and 140 mg, respectively [p<0.001 for each dose]). This outcome, measured for the overall study population, was achieved despite ~40% of patients not taking AMSM at baseline, for whom change could only be ≥0. Here we present two further analyses: (A) change in any acute headache medication days/month (AHM, including AMSM as well as paracetamol, NSAIDS etc,) in the overall study population as 97.7% used AHM during baseline; (B) change in AMSM days/month in the subgroup who used AMSM during baseline.

Methods

Patients recorded medication use with a daily eDiary throughout the 4-week baseline period and subsequent 6-month double-blind treatment period. The number of days per month on which AMSM and AHM were taken was calculated. Change from baseline was analyzed using a linear mixed effects model including covariates of treatment, visit, treatment by visit interaction, stratification factors (region and migraine prophylaxis medication status), and baseline value. Nominal p-values were provided without multiplicity adjustment.

Results

(A) During baseline, the mean number of AHM days/month in the overall population was 6.91, 6.58, and 6.60 in the placebo, erenumab 70 mg, and erenumab 140 mg groups, respectively. Erenumab significantly reduced AHM days/month versus placebo from Month 1 onward (Fig. 1). (B) During baseline, 561 of 955 patients (58.7%) used AMSM. Mean number of AMSM days/month in patients who used AMSM during baseline was 5.68, 5.67, and 5.67 in the placebo, erenumab 70 mg, and erenumab 140 mg groups, respectively. Erenumab significantly reduced AMSM days/month versus placebo; treatment difference −1.57 days (−2.04, −1.10; p<0.001) for 70 mg and −2.30 days (−2.77, −1.83; p<0.001) for 140 mg, averaged over Months 4−6.

Conclusion

Erenumab significantly reduced both AHM and AMSM days/month versus placebo in patients with EM.
Fig. 1 (abstract P105).

Study design

P97 Ex-Migraine: Clinical and Neurophysiological Analysis

Vera Osipova1, Alexey Sergeev2, Elena Snopkova1, Ada Artemenko1, Guzial Tabeeva2, Zaza Katsarava3,4

1Research Department of Neurology, Sechenov University, Moscow, Russia; 2Department of Neurology and Neurosurgery, Sechenov University, Moscow, Russia; 3Department of Neurology, University of Duisberg-Essen, Essen, Germany; 4Department of Neurology, Evangelical Hospital Unna, Unna, Germany

Background

The evolution of migraine (M) after the age of 50 has been insufficiently studied; sub-population with former M was not studied at all. Aim of investigation was two-fold: 1. to present clinical portrait of patients with former/Ex-Migraine (Ex-M) with special focus on retrospective analysis of M in the active period of the disease (at the age of 30-40) and 2. to study the level of cortical excitability in elderly Ex-M subjects.

Material and methods

The Ex-M group (n=18) was inhomogeneous and composed of subjects with complete regress of M attacks (both pain and M aura; CRM, n=11, m. age 60.0±9) and those keeping M aura only - painless M/Late-life Migraine Accompaniments (LLMAs, n=7, m.age 54.0±7). All patients underwent clinical interview focused on present and former clinical manifestations and confirming past-diagnosis of M using Migraine History Inventory specially elaborated by us for this study. Cortex excitability (amplitude and habituation for the N75-P100 component) was measured using pattern-reversal visual evoked potentials (PR-VEP)

Results

Compared to subjects with LLMAs in patients with CMR migraine terminated a decade later (39±9 vs 49.7, p<0.05), in the active period of disease the majority of patients had MoA (72.7% vs 42.9%, p<0.05), more long (5.0±8h vs 24.0±18h) and typical attacks with throbbing pain and vomiting; subjects with LLMAs more often suffered from MA. At the time of investigation CRM-Group had completely normal amplitude and habituation for the N75-P100 component, while LLMAs-Group demonstrated the signs of cortical hyperexcitability typical for actual M, namely, significant increase in total N75-P100 (p<0.05) and more marked dishabituation

Conclusions
  1. 1.

    LLMAs-Group (painless M with preserved aura) initially more often had MA, short and less typical attacks and even after loosing pain attacks keep the signs of cortical hyper excitability. It could be presumed that the phenomenon of cortical hyperexcitability in patients of any age serves the basis for preservation of M aura/LLMAs but not M pain.

     
  2. 2.

    Ex-M elderly patients who are completely free of both pain and M aura and have normal level of cortical excitability and habituation initially used to have MoA with long and typical attacks. Total normalization of brain reactivity could be regarded as a principal neurophysiological factor for complete regress of both pain and aura.

     

P98 Reducing the impact of migraine on functioning: Results from the STRIVE trial, a phase 3, randomised, double-blind, placebo-controlled study of erenumab in patients with episodic migraine

Dawn C Buse1, Richard B Lipton1, Daniel D Mikol2, Andrew V Thach2, Pooja Desai2, Hernan Picard2, Yumi Kubo2, Asha Hareendran3, Ariane K Kawata4

1Department of Neurology, Albert Einstein College of Medicine and Montefiore Medical Center, Bronx, NY, USA; 2Amgen Inc., Thousand Oaks, CA, USA; 3Evidera, London, UK; 4Evidera, Bethesda, MD, USA
Correspondence: Dawn C Buse (DBUSE@montefiore.org)

Background

The Migraine Functional Impact Questionnaire (MFIQ) is a newly developed 31-item patient-reported outcome instrument assessing the impact of migraine on functional outcomes over 7 days. The MFIQ includes 4 domains: impact on physical function, usual activities, social function, and emotional function with scores ranging from 0–100 (higher scores indicate greater impact; negative change scores represent reduction in impact [improvement]). In this phase 3 trial (NCT02456740), we evaluated the effect of erenumab, which is being developed as a preventive treatment for migraine in adults, on functional outcomes using the MFIQ.

Methods

In STRIVE, a total of 955 patients with episodic migraine aged 18–65 years were randomised 1:1:1 to receive monthly subcutaneous placebo, erenumab 70 or 140 mg. The MFIQ was completed at baseline and every 4 weeks for 24 weeks. The MFIQ scores were evaluated as change from baseline to the last three months of the double-blind treatment phase (defined as the average of scores in Months 4–6 [Weeks 13–24]). Pairwise comparisons of least squares mean changes from baseline in MFIQ domain scores were assessed for each treatment vs placebo. The p-values were nominal and not adjusted for multiplicity.

Results

Baseline MFIQ scores were similar in the erenumab and placebo groups in all 4 MFIQ domains (70 mg: mean±standard deviation [SD] 33.3±20.9; 140 mg: 32.0±21.2; placebo: 33.1±24.5). Greater reductions in impact from baseline were observed for each MFIQ domain with erenumab compared with placebo (Table 1).

Conclusions

Over 24 weeks, compared with placebo, patients treated with erenumab experienced greater reductions in the MFIQ scores, reflecting less impact of migraine on their physical functioning, usual activity, and social and emotional functioning, with numerically greater reductions for 140 mg compared with 70 mg. These improvements complement the efficacy of erenumab demonstrated by the clinical outcome measures in the STRIVE study.
Table 1 (abstract P98).

Changes from baseline in the Migraine Functional Impact Questionnaire domain scores

 

Least squares mean changes (95% confidence interval)

p-values (Erenumab vs Placebo)

Erenumab 70 mg

Erenumab 140 mg

Placebo

Erenumab 70 mg

Erenumab 140 mg

Physical function

−13.7 (−15.5, −11.9)

−15.1 (−17.0, −13.3)

−9.4 (−11.3, −7.6)

<0.001

<0.001

Usual activities

−12.3 (−13.9, −10.6)

−13.4 (−15.1, −11.8)

−8.3 (−10.0, −6.6)

<0.001

<0.001

Social function

−13.2 (−14.9, −11.4)

−14.5 (−16.2, −12.8)

−9.5 (−11.3, −7.7)

0.003

<0.001

Emotional function

−16.4 (−18.4, −14.5)

−18.4 (−20.3, −16.5)

−11.2 (−13.1, −9.2)

<0.001

<0.001

P99 Reducing impaired days: Results from the STRIVE trial, a phase 3, randomised, double-blind study of erenumab for episodic migraine

Asha Hareendran1, Dawn C Buse2, Richard B Lipton2, Martha S Bayliss3, Daniel D Mikol4, Dennis A Revicki5, Feng Zhang4, Pooja Desai4, Hernan Picard4, Ariane K Kawata5

1Evidera, London, UK; 2Montefiore Medical Center, Albert Einstein College of Medicine, Bronx, NY, USA; 3Optum, Lincoln, RI, USA; Amgen Inc., Thousand Oaks, CA, USA; Evidera, Bethesda, MD, USA
Correspondence: Asha Hareendran (asha.hareendran@evidera.com)

Background

Migraine Physical Function Impact Diary (MPFID) is a 13-item patient-reported outcome (PRO) measure that assesses the impact of migraine on Everyday Activities (EA) and Physical Impairment (PI) domains. We report the effect of erenumab, a preventive treatment for episodic migraine (EM) in adults, on monthly days with impairment as measured by the MPFID.

Methods

The MPFID was completed using an electronic diary every evening during a global, placebo-controlled, double-blind, 6-month, phase 3 STRIVE trial (NCT02456740) in which 955 adults with EM (18–65 years) were randomised 1:1:1 to subcutaneous, monthly placebo or erenumab 140mg or 70mg. Reponses to items in the MPFID EA and PI domains are on a 1–5 scale, with higher numbers indicating greater negative impact. A day with a response ≥3 on at least one item in a domain was defined an ‘impaired day’ (ID) for that domain, (i.e. EA-ID and PI-ID). Mean monthly number of IDs were summarised for the 4-week baseline period and each subsequent 4-week period. Changes from baseline in mean monthly EA-ID and PI-ID over the final 3 months (months 4–6) of the double-blind treatment phase (DBTP) were assessed as pre-specified exploratory endpoints in the STRIVE trial; primary and secondary endpoints are reported separately. All p-values are descriptive and not adjusted for multiplicity.

Results

At baseline, subjects in the erenumab and placebo groups had a similar number of mean monthly EA-ID (140mg: mean±standard deviation 6.62±4.20; 70mg: 7.21±4.56; placebo: 7.12±4.85) and PI-ID (140mg: 5.81±4.32; 70mg: 6.09±4.60; placebo: 6.20±5.05). Over the final 3 months of the DBTP, greater reductions from baseline in EA-IDs and PI-IDs were observed with erenumab 140mg and 70mg groups than placebo. For EA-IDs, subjects treated with erenumab 140mg (Least Squares [LS] mean=−3.01 days (95% confidence interval [CI]: −3.45,−2.57) and 70mg (−2.83 days [−3.27,−2.39]) experienced larger reductions compared with placebo (−1.71 [−2.16,−1.27], both p<0.001). Greater reductions in mean monthly PI-ID days were also observed in the erenumab groups (140mg: LS mean=−2.51 days (95% CI: −2.93,−2.09); 70mg: −2.25 days [−2.68,−1.83]) compared with placebo (−1.16 [−1.59,−0.74], both p<0.001).

Conclusion

Compared with placebo, EM subjects treated with erenumab 140mg and 70mg experienced greater reductions from baseline in mean monthly MPFID EA-ID and PI-ID during the 6 month DBTP. Numerically greater reductions were observed with 140mg than 70mg. Erenumab-treated patients experience reductions in functional impairment due to migraine, which complements improvements observed with standard efficacy measures.

P100 Patient-reported outcomes in patients with chronic migraine receiving placebo or erenumab (AMG 334) in a phase 2, randomised, double-blind study

Richard B Lipton1, Stewart J Tepper2, Uwe Reuter3, Stephen Silberstein4, Walter Stewart5, Dean Leonardi6, Pooja Desai6, Sunfa Cheng6, Daniel D Mikol6, Robert A Lenz6

1Department of Neurology, Albert Einstein College of Medicine, Bronx, New York, NY, USA; 2Geisel School of Medicine at Dartmouth, Hanover, NH, USA; 3Department of Neurology, Charité Universitätsmediz in Berlin, Berlin, Germany; 4Jefferson Headache Center, Thomas Jefferson University, Philadelphia, PA, USA; 5Sutter Health, Walnut creek, CA, USA; 6Amgen Inc., Thousand Oaks, CA, USA
Correspondence: Richard B Lipton (Richard.Lipton@einstein.yu.edu)

Background

Migraine is a disabling disease associated with substantial burden on patients and society. Erenumab (AMG334) is a fully human anti-calcitonin gene-related peptide (CGRP) receptor monoclonal antibody in clinical development for migraine prevention. The objective of this study was to evaluate patient-reported outcomes in a phase 2 clinical trial of erenumab for chronic migraine (CM) (NCT02066415).

Methods

667 adults with CM were randomised (3:2:2) to monthly subcutaneous placebo or erenumab 70 mg or 140 mg. Primary and secondary endpoints were assessed at Week 12. Exploratory endpoints included: change from baseline in migraine-specific quality of life (QoL) measured by the Migraine-Specific QoL Questionnaire (MSQ), headache impact measured by the Headache Impact Test (HIT-6), and migraine-related disability measured by the Migraine Disability Assessment Test (MIDAS). No formal hypothesis was tested; p-values (placebo vs erenumab dose-groups) are descriptive.

Results

Baseline scores were similar between groups. Improvements were observed for all endpoints in both erenumab groups at Week 12. The mean (95% CI) changes for placebo vs 70 mg and 140 mg groups, respectively, were 11.8 (9.4, 14.1) vs 17.7 (14.9, 20.6), p=0.002 and 19.1 (16.3, 22.0), p<0.001 for MSQ role function-restrictive scores, 8.9 (6.8, 11.0) vs 13.0 (10.5, 15.6), p=0.013 and 13.8 (11.3, 16.4), p=0.003 for MSQ role function-preventive scores, and 9.9 (7.3, 12.5) vs 18.2 (15.0, 21.3), p<0.001 and 18.8 (15.6, 21.9), p<0.001 for MSQ emotional-function scores. Mean changes in HIT-6 scores were −3.1 (−3.9, −2.3) for placebo vs −5.6 (−6.5, −4.6), p<0.001 for both erenumab groups. Corresponding mean changes in the placebo, 70 mg, and 140 mg dose-groups were −7.5 days (−12.4, −2.7) vs −19.4 days (−25.2, −13.6), p=0.002 and −19.8 days (−25.6, −14.0), p=0.001 for MIDAS days of lost productivity, −5.2 days (−8.0, −2.4) vs −10.3 days (−13.6, −6.9), p=0.023 and −10.2 days (−13.6, −6.8), p=0.024 for MIDAS-absenteeism, and −1.9 days (−4.7, 0.8) vs −9.3 days (−12.6, −6.1), p<0.001 and −9.9 days (−13.2, −6.7), p<0.001 for MIDAS-presenteeism.

Conclusions

Erenumab-treated CM patients experienced consistent and clinically significant improvements in patient-reported outcomes including migraine-specific QoL and reductions in headache impact and disability.

P101 Treatment-Induced Improvement in Migraine Classification in the Fremanezumab HFEM Study

Robert Noble1, Ernesto Aycardi2, Marcelo Bigal3, Pippa Loupe4

1Statistics, Teva Global Medical Affairs, Hamilton; 2Global Clinical Development; 3Clinical Development, Teva Global Research and Development, Frazer; 4Academic Affairs and Network, Teva Global Research and Development, Overland Park , United States
Correspondence: Robert Noble

Objectives

Fremanezumab is a fully humanized monoclonal antibody targeting the calcitonin-gene related peptide (CGRP) ligand, a validated target for migraine preventive therapy. Fremanezumab was found to be effective and well-tolerated as a preventive treatment for migraine in a high frequency episodic migraine (HFEM) phase 2 study. Study participants included patients classified as having episodic migraine (EM) per the ICHD III beta. Herein, we determined whether there was a treatment-induced shift in the number of patients who met the criteria for classification as having high frequency EM (HFEM) to moderate frequency episodic migraine (MFEM) and low frequency episodic migraine (LFEM) during the HFEM study.

Methods

Patients were randomized to receive either fremanezumab doses (225mg or 675mg) or placebo every 28 days for 12 weeks. Headache information was captured daily using an electronic headache diary. For the post-hoc analysis, the frequency of headache days (days of headaches lasting > 4 hours) and migraine days (days with headaches classified as migraine, probable migraine or treated with triptan or ergot compounds) per month were categorized into four types of migraine classification: Chronic migraine (CM) as having ≥15 headache days with 8 migraine days; HFEM 8 to 14 headache days with 8 migraine days; MFEM 4 to 7 headache days and 4-7 migraine days; LFEM 0 to 3 headache days and 0-3 migraine days. Analyses on the shifts for migraine classification from baseline to month 3 were performed to determine the percent of patients who showed improvement (HFEM to MFEM or LFEM), worsening (HFEM to CM) and those who remained classified as HFEM.

Results

Overall, the fremanezumab arms showed significant improvement in migraine classification compared to the placebo arm at month 3 (Patients on 225mg 73% vs 49% for placebo, 95% CI: 0.098 to 0.358 and patients on 675mg 71% vs 49% placebo, 95% CI: 0.079 to 0.341, Table 1A). Chi square analyses indicated that the shift of migraine classification during the study was not independent of treatment, X2 =31.64, p=1.91E-05. As shown in Table 1B, 45% and 52% of patients on fremanezumab 225mg and 675mg showed a shift in migraine category from HFEM to LFEM in 3 months compared to 20% of placebo patients.

Conclusion

As treated patients were more likely to improve and less likely to worsen compared to those on placebo, this study suggests that fremanezumab may potentially prevent the progression of migraine to more chronic forms.
Table 1 (abstract P101).

Patient classification in migraine categories during the HFEM study

Table 1A.

Overall shift in migraine categorya

Placebo

n = 104

Fremanezumab

225 mg

n = 95

Fremanezumab

675 mg

n = 96

 Worsen

7 (7%)

2 (2%)

3 (3%)

 Stable

42 (40%)

14 (15%)

17 (18%)

 Improve

51 (49%)

69 (73%)

68 (71%)

 Discontinued

4 (4%)

10 (11%)

8 (8%)

Table 1B:

Migraine Categories

Num (%) patients in 3rd month

Placebo

(n = 98)b

Fremanezumab

225 mg

(n = 88)

Fremanezumab

675 mg

(n = 91)

 CM

7 (7%)

2 (2%)

2 (2%)

 HFEM

41 (42%)

14 (16%)

17 (19%)

 MFEM

28 (29%)

22 (25%)

21 (23%)

 LFEM

20 (20%)

40 (45%)

47 (52%)

aShift in migraine category, worsen = HFEM to CM, stable = HFEM to HFEM, improve = HFEM to MFEM or HFEM to LFEM, discontinued = left study bn values indicate the patients per treatment group meeting HFEM classification at baseline

Trial registration

Clinicaltrials.gov NCT02025556

Competing Interest

Fremanezumab HFEM Study supported by Teva Pharmaceutical Industries Global Research and Development, Netanya Israel. RN, EA, MEB, and PL are employees of Teva Pharmaceutical Industries, Israel.

P102 Analysis of blood pressure following short-term and long-term treatment with erenumab

Stewart J Tepper1, Julio Pascual2, Uwe Reuter3, Hernan Picard4, Frank Hong5, Marie-Louise Trotman4, Fei Xue4, Dan Mikol4, Jan Klatt5

1Geisel School of Medicine at Dartmouth, Hanover, NH, USA; 2Service of Neurology, University Hospital Marqués de Valdecilla and IDIVAL, Santander, Spain; 3Department of Neurology, Charité Universitätsmedizin Berlin, Berlin, Germany; 4Amgen Inc., Thousand Oaks, CA, USA; 5Novartis Pharma AG, Basel, Switzerland
Correspondence: Stewart J Tepper

Background

Erenumab is a fully human monoclonal antibody that selectively targets and inhibits the calcitonin gene-related peptide (CGRP) receptor and is under investigation for migraine prevention. As the ligand CGRP is a vasodilator, inhibition of the CGRP pathway might theoretically increase blood pressure (BP). Addressing this theoretical risk through ancillary safety studies has been an important focus during the clinical development of erenumab. This report summarises BP findings from the erenumab clinical development programme.

Methods

Systolic and diastolic BP values were obtained at baseline and every 4 weeks in four placebo-controlled erenumab clinical trials (clinicaltrials.gov NCT01952574, NCT02066415/NCT02174861, NCT02456740, NCT02483585). Blood pressure was recorded as the average of ≥2 measurements taken ≥5 minutes apart with subjects lying supine and rested for ≥5 minutes. Pooled placebo-controlled data from baseline and treatment Weeks 4, 8, and 12 are presented. In categorical analyses, a notable increase in BP was defined as an increase from baseline of ≥10 mmHg in diastolic and/or ≥20 mmHg in systolic BP. In a separate Phase 1 study (NCT01723514), 24-hour continuous BP was assessed in healthy volunteers receiving erenumab monthly over 12 weeks.

Results

Blood pressure was similar across treatment groups at baseline, and remained stable throughout the 12-week period (Fig. 1), with no difference observed between erenumab and placebo. Mean (SD) change from baseline at 12 weeks in systolic BP was −0.4 (9.6), −0.5 (10.0), and −1.0 (9.8) mmHg, and mean change in diastolic BP was −0.6 (7.1), −0.3 (7.7), and −0.4 (7.2) mmHg, in subjects treated with placebo, erenumab 70 mg, and erenumab 140 mg, respectively. The proportion of subjects with a notable increase at any visit was similar across treatment groups. In a 24-hour continuous BP assessment, erenumab 70 mg and 140 mg did not increase BP and had no effect on diurnal rhythm (Fig. 2).

Conclusion

Selectively blocking the CGRP receptor with erenumab 70 and 140 mg had no relevant effect on BP in subjects with migraine over 12 weeks versus placebo, and was not associated with significant 24-hour BP changes in healthy volunteers.

P103 The role of peripheral CGRP on the vasculature in a preclinical mouse model of migraine

Bianca Mason

The neuropeptide calcitonin gene-related peptide (CGRP) is a key player in migraine. While migraine can be induced by peripherally administered CGRP (intravenous) and can be treated using CGRP antagonists that act peripherally, the relevant sites of CGRP action remain unknown. To address the role of CGRP both within and outside the central nervous system, we used a mouse model of photophobia. Photophobia is an abnormal discomfort to non-noxious levels of light and is experienced by approximately 90% of migraine patients. We have previously shown that peripheral (intraperitoneal, IP) injection of CGRP resulted in light aversive behavior in wild-type CD1 mice similar to aversion previously seen following central (intracerebroventricular, ICV) injection. Importantly, two clinically effective migraine drugs, the 5-HT1B/D agonist sumatriptan and a CGRP-blocking monoclonal antibody, attenuated the peripheral CGRP-induced light aversion and motility behaviors. To begin to address the mechanism of peripheral CGRP action, first we used transgenic CGRP-sensitized mice that have elevated levels of the CGRP receptor hRAMP1 subunit in nervous tissue (nestin/hRAMP1). Surprisingly, sensitivity to low light was not seen after IP CGRP injection, but was only seen after ICV CGRP injection. Next, we used transgenic CGRP-sensitized mice that have globally elevated levels of hRAMP1 (global hRAMP1) in all tissues. Interestingly, sensitivity to low light after IP CGRP in these mice was observed. These results suggest that CGRP can act in both the periphery and the brain by distinct mechanisms. This also suggests that peripheral CGRP actions may be transmitted to the CNS via indirect sensitization of peripheral nerves and likely not on CGRP receptors in the nervous system to cause migraine-like photophobia. We have now begun investigating the role of the vasculature in peripheral CGRP-induced light aversion and allodynic pain responses by using two approaches (1) injection of phenylephrine to minimize vasodilation induced by CGRP (2) genetic overexpression of the CGRP receptor in the vasculature. We have found that CGRP has actions on smooth muscle cells that may contribute to the induction of migraine-like photophobia and that vasodilation may also, in part, play a role in this migraine-like behavior.

P104 Peripheral vagal nerve stimulation modulates the nociceptive withdrawal reflex in healthy subjects: a cross-over sham-controlled study

Roberto De Icco1,2, Daniele Martinelli1,2, Eric Liebler3, Marta Allena2, Vito Bitetto1, Grazia Sances2, Giorgio Sandrini1,2, Giuseppe Nappi1,2, Cristina Tassorelli1,2

1Department of Brain and Behavioral Sciences, University of Pavia, 27100, Pavia, Italy; 2 Headache Science Center, C. Mondino National Neurological Institute, 27100, Pavia, Italy; 3 electroCore LLC, Basking Ridge, NJ, 07920, USA
Correspondence: Roberto De Icco (rob.deicco@gmail.com)

Objectives: Peripheral non-invasive vagal nerve stimulation (nVNS) has become a target for the treatment of primary headaches, though its exact mechanisms are unclear. Different studies showed that nVNS modulates both spinal and supra-spinal nociceptive pathways in an inhibitory direction. The nociceptive flexion reflex paradigm is widely used to investigate modulation of nociception and represents a reliable objective measure of the functional activation of the nociceptive network. The aim of our study is to evaluate the effect of nVNS on the nociceptive withdrawal reflex in healthy subjects.

Materials and Methods: We enrolled 10 healthy subjects (5 males, age 26.5±2.2 years) in a cross-over sham-controlled study. Subjects were randomly assigned to: 1) nVNS: one 120-s electrical stimulation on each side of the neck using the gammaCore device and b) Sham: one 120-s electrical stimulation of the median nerve on each wrist using the gammaCore device. Nociceptive withdrawal reflex was evaluated in the right lower limb according to a standardized paradigm: electrical stimulation delivered at the sural nerve and electromyographic muscular response recorded from the ipsilateral biceps femoris. The single stimulus reflex threshold (RT-SS) was the lowest intensity (mA) needed to elicit a stable muscular response. The temporal summation threshold (RT-TS) was evaluated using a train of 5 stimuli at 2 Hz.

Results: At T0 the neurophysiological parameters were comparable between groups. In particular RT-SS was 13.86±3.67 and 16.15±3.53 in nVNS and Sham groups, respectively (p=0.086), while RT-TS was 11.0±2.79 in nVNS group and 12.64±3.67 in Sham group (p=0.107).

nVNS caused a significant increase in the RT-SS at T5 (+14.5%±4.2, p=0.023) and T30 (+25.9%±6.6, p=0.011). Also RT-TS significantly increased following nVSN at T30 (+21.7±6.7, p=0.031). Sham stimulation did not induce any significant modification on the reflex parameters. When comparing groups, we found that the increase of RT-SS at T5 and T30 was significantly higher in nVNS vs. Sham (p=0.008 and p=0.007 respectively). The percentage increase of RT-TS at T30 was significantly higher in the nVNS vs. SHAM (p=0.013).

Conclusion: Using a reliable method, we demonstrated that nVNS induces a rapid onset analgesia in healthy subjects. Because of its neurophysiological signatures, this analgesic activity is likely related to the inhibition of pain facilitation mechanisms occurring at the spinal and/or supra-spinal level. The mechanistic bases of this activity are to be elucidated, but the present observation provides additional evidence for the role of nVNS in the acute and prophylactic treatment of primary headaches.

P105 Non-invasive vagal nerve stimulation reduces provoked cranial parasympathetic output in healthy volunteers

Celina F. Schroeder*, Maike Moeller*, Arne May

Department of Systems Neuroscience, University Medical Center Eppendorf, Hamburg, 20246, Germany

*The authors contributed equally to this article.

Background

Cranial autonomic symptoms such as lacrimation and conjunctival injection are characteristic features in some primary headache disorders [1]. Recent studies proposed non-invasive vagal nerve stimulation (nVNS) as a novel treatment approach for migraine and cluster-headache patients [2-4]. However, nVNS seems to be more efficient when autonomic symptoms are present and the underlying mechanisms of action remain to be elucidated. Here, we aimed to investigate the effect of nVNS on provoked cranial autonomic symptoms (lacrimation) in healthy volunteers.

Methods

Healthy volunteers were recruited and participated in a single-blind, placebo-controlled within-subject design (Fig. 1). nVNS was performed using the gammaCore device (electrocore LLC, Basking Ridge, NJ, USA) and kinetic oscillation stimulation (KOS) (Chordate Medical AB, Stockholm, Sweden) of the nasal mucosa was used to generate quantifiable cranial parasympathetic output (lacrimation) [5]. Lacrimation was quantified using a Schirmer’s II test. Sham controlled stimulation was applied in a pseudorandomized order for 3x2 minutes after baseline-measurement. As an indicator of autonomic activation, the lacrimation difference between baseline and KOS after each of the three experimental conditions was calculated.

Results

KOS-induced lacrimation was significantly reduced after nVNS compared to sham stimulation and no stimulation. This effect was only observed on the ipsilateral but not the contralateral eye. During nVNS- treatment only small side effects, including facial muscle convulsion and tingling sensations were reported by the volunteers.

Conclusion

These data show a physiologically measurable effect of nVNS on the trigeminal autonomic reflex in humans, suggesting an interaction between the trigeminal and the vagal system. These results support previous findings that the vagal system modulates central structures of the trigeminal autonomic reflex [6] that play a crucial role in various primary headache disorders.
Fig. 1 (abstract P121).

Slump test

Acknowledgement

This study was supported by an unrestricted scientific grant from Chordate medical.

References

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

2. Goadsby PJ, Grosberg BM, Mauskop A, Cady R, Simmons KA. Effect of noninvasive vagus nerve stimulation on acute migraine: an open-label pilot study. Cephalalgia. 2014;34(12):986-93.

3. Gaul C, Diener HC, Silver N, Magis D, Reuter U, Andersson A, et al. Non-invasive vagus nerve stimulation for PREVention and Acute treatment of chronic cluster headache (PREVA): A randomised controlled study. Cephalalgia. 2016;36(6):534-46.

4. Silberstein SD, Calhoun AH, Lipton RB, Grosberg B, Cady R, Dorlas S, et al. Chronic migraine headache prevention with noninvasive vagus nerve stimulation The EVENT study. Neurology. 2016;87:529-538.

5. Moeller M, Haji A, Hoffmann J, May A. Peripheral provocation of cranial autonomic symptoms is not sufficient to trigger cluster headache attacks. Cephalalgia. in press.

6. Akerman S, Simon B, Romero-Reyes M. Vagus nerve stimulation suppresses acute noxious activation of trigeminocervical neurons in animal models of primary headache. Neurobiol Dis. 2017;102:96-104.

P106 Obesity is more prevalent in chronic migraine than in episodic migraine

Brad D Torphy1, Nicole Montes Buckley2

1Diamond Headache Clinic, Chicago, IL, 60642, USA; 2Adler University, Chicago, IL, 60602, USA
Correspondence: Brad D Torphy

BACKGROUND: Migraine and obesity are two major public health problems in the USA and around the world. In the USA 12% of individuals have migraine and 37% of adults are obese1. Evidence suggests a possible link between migraine and obesity, but research has been mixed. There are several potential mechanisms for this link, including physiological, psychological, and behavioral.

PURPOSE OF STUDY: The purpose of our study was to determine if obesity is more prevalent in chronic migraine than in episodic migraine.

RESULTS: We analyzed the body mass index (BMI) at presentation of all new patients seen by the lead author in a tertiary headache center for a period of one year. The mean BMI of chronic migraine (CM) patients was 28.8% versus 25.3% for episodic migraine (EM) patients, both of which are defined as “overweight.” 34.4% of CM patients and 5.4% of EM patients were obese (BMI ≥ 30).

CONCLUSIONS: Obesity was prevalent in CM patients than in EM patients treated at a tertiary headache center. Furthermore, BMI was significantly higher in patients with CM than in EM patients.

References