Evaluation of the concomitant use of oral preventive treatments and onabotulinumtoxinA in chronic migraine: the PREVENBOX study.

BACKGROUND AND PURPOSE: OnabotulinumtoxinA is an effective preventive treatment for chronic migraine (CM). In CM, in addition to a reduction in headache frequency, a decreased reliance on oral prophylactics is also indicative of treatment effectiveness. This study aimed to quantify the change in the use of oral prophylactics after treatment with onabotulinumtoxinA in patients with CM. METHODS: This was a retrospective, multicentric, cross-sectional study. Patients with CM (International Classification of Headache Disorders-3beta) that had been treated with onabotulinumtoxinA were enrolled consecutively. We collected parameters related to each patient's pre-treatment situation, as well as their current situation, focusing on frequency and intensity of migraine, number of oral prophylactics and the respective cycle of onabotulinumtoxinA. Univariate and logistic regression analyses were performed. RESULTS: We included 542 patients, 90.0% of whom were taking oral preventive treatments. During treatment with onabotulinumtoxinA, 47.8% withdrew at least one prophylactic and 41.6% stopped using oral prophylactics altogether. Factors associated with a reduction or cessation of oral prophylactics were >50% improvement in frequency and intensity, remission to episodic migraine, use of topiramate as an initial treatment, increased number of infiltrations and shorter chronification period (P < 0.05). The multivariate analysis showed that a chronification period <20 months, more than five cycles of onabotulinumtoxinA, >50% improvement in pain intensity and topiramate as an initial treatment were predictors of a reduction in oral prophylactics (area under the curve, 70.3%; P < 0.001). CONCLUSIONS: Our study demonstrated the efficacy and safety of onabotulinumtoxinA. This treatment reduced the use of oral prophylactics. Withdrawal of oral prophylactics was most likely to occur after five cycles of treatment.

Diagnosis and treatment of disorders of intracranial pressure: consensus statement of the Spanish Society of Neurology's Headache Study Group.

Primary intracranial pressure disorders include idiopathic intracranial hypertension and spontaneous intracranial hypotension. Remarkable advances have been made in the diagnosis and treatment of these 2entities in recent years. Therefore, the Spanish Society of Neurology's Headache Study Group (GECSEN) deemed it necessary to prepare this consensus statement, including diagnostic and therapeutic algorithms to facilitate and improve the management of these disorders in clinical practice. This document was created by a committee of experts belonging to GECSEN, and is based on a systematic review of the literature, incorporating the experience of the participants, and establishes practical recommendations with levels of evidence and grades of recommendation.

The cost of headache disorders in Europe: the Eurolight project.

BACKGROUND AND PURPOSE: Headache disorders are very common, but their monetary costs in Europe are unknown. We performed the first comprehensive estimation of how economic resources are lost to headache in Europe. METHODS: From November 2008 to August 2009, a cross-sectional survey was conducted in eight countries representing 55% of the adult EU population. Participation rates varied between 11% and 59%. In total, 8412 questionnaires contributed to this analysis. Using bottom-up methodology, we estimated direct (medications, outpatient health care, hospitalization and investigations) and indirect (work absenteeism and reduced productivity at work) annual per-person costs. Prevalence data, simultaneously collected and, for migraine, also derived from a systematic review, were used to impute national costs. RESULTS: Mean per-person annual costs were €1222 for migraine (95% CI 1055-1389; indirect costs 93%), €303 for tension-type headache (TTH, 95% CI 230-376; indirect costs 92%), €3561 for medication-overuse headache (MOH, 95% CI 2487-4635; indirect costs 92%), and €253 for other headaches (95% CI 99-407; indirect costs 82%). In the EU, the total annual cost of headache amongst adults aged 18-65 years was calculated, according to our prevalence estimates, at €173 billion, apportioned to migraine (€111 billion; 64%), TTH (€21 billion; 12%), MOH (€37 billion; 21%) and other headaches (€3 billion; 2%). Using the 15% systematic review prevalence of migraine, calculated costs were somewhat lower (migraine €50 billion, all headache €112 billion annually). CONCLUSIONS: Headache disorders are prominent health-related drivers of immense economic losses for the EU. This has immediate implications for healthcare policy. Health care for headache can be both improved and cost saving.

Calcitonin gene-related peptide in migraine: from pathophysiology to treatment.

INTRODUCTION: It has been observed in recent years that levels of such molecules as calcitonin gene-related peptide (CGRP) and, to a lesser extent, the pituitary adenylate cyclase-activating peptide are elevated during migraine attacks and in chronic migraine, both in the cerebrospinal fluid and in the serum. Pharmacological reduction of these proteins is clinically significant, with an improvement in patients' migraines. It therefore seems logical that one of the main lines of migraine research should be based on the role of CGRP in the pathophysiology of this entity. DEVELOPMENT: The Spanish Society of Neurology's Headache Study Group decided to draft this document in order to address the evidence on such important issues as the role of CGRP in the pathophysiology of migraine and the mechanism of action of monoclonal antibodies and gepants; and to critically analyse the results of different studies and the profile of patients eligible for treatment with monoclonal antibodies, and the impact in terms of pharmacoeconomics. CONCLUSIONS: The clinical development of gepants, which are CGRP antagonists, for the acute treatment of migraine attacks, and CGRP ligand and receptor monoclonal antibodies offer promising results for these patients.

The Eurolight project: the impact of primary headache disorders in Europe. Description of methods.

The Eurolight project is the first at European Union level to assess the impact of headache disorders, and also the first of its scale performed by collaboration between professional and lay organizations and individuals. Here are reported the methods developed for it. The project took the form of surveys, by structured questionnaire, conducted in ten countries of Europe which together represented 60% of the adult population of the European Union. In Lithuania, the survey was population-based. Elsewhere, truly population-based studies were impractical for reasons of cost, and various compromises were developed. Closest to being population-based were the surveys in Germany, Luxembourg, the Netherlands, Italy and Spain. In Austria, France and UK, samples were taken from health-care settings. In addition in the Netherlands, Spain and Ireland, samples were drawn from members of national headache patient organizations and their relatives. Independent double data-entry was performed prior to analysis. Returned questionnaires from 9,269 respondents showed a moderate female bias (58%); of respondents from patients' organizations (n = 992), 61% were female. Mean age of all respondents was 44 years; samples from patients' organizations were slightly older (mean 47 years). The different sampling methods worked with differing degrees of effectiveness, as evidenced by the responder-rates, which varied from 10.8 to 90.7%. In the more population-based surveys, responder-rates varied from 11.3 to 58.8%. We conclude that the methodology, although with differences born of necessity in the ten countries, was sound overall, and will provide robust data on the public ill-health that results from headache in Europe.

Neuromodulation in headache and craniofacial neuralgia: guidelines from the Spanish Society of Neurology and the Spanish Society of Neurosurgery. / Neuromodulación en cefaleas y neuralgias craneofaciales: Guía de la Sociedad Española de Neurología y de la Sociedad Española de Neurocirugía.

INTRODUCTION: Numerous invasive and non-invasive neuromodulation devices have been developed and applied to patients with headache and neuralgia in recent years. However, no updated review addresses their safety and efficacy, and no healthcare institution has issued specific recommendations on their use for these 2 conditions. METHODS: Neurologists from the Spanish Society of Neurology's (SEN) Headache Study Group and neurosurgeons specialising in functional neurosurgery, selected by the Spanish Society of Neurosurgery (SENEC), performed a comprehensive review of articles on the MEDLINE database addressing the use of the technique in patients with headache and neuralgia. RESULTS: We present an updated review and establish the first set of consensus recommendations of the SEN and SENC on the use of neuromodulation to treat headache and neuralgia, analysing the current levels of evidence on its effectiveness for each specific condition. CONCLUSIONS: Current evidence supports the indication of neuromodulation techniques for patients with refractory headache and neuralgia (especially migraine, cluster headache, and trigeminal neuralgia) selected by neurologists and headache specialists, after pharmacological treatment options are exhausted. Furthermore, we recommend that invasive neuromodulation be debated by multidisciplinary committees, and that the procedure be performed by teams of neurosurgeons specialising in functional neurosurgery, with acceptable rates of morbidity and mortality.

Document of revision and updating of medication overuse headache (MOH). / Documento de revisión y actualización de la cefalea por uso excesivo de medicación (CUEM).

INTRODUCTION: Medication overuse headache is a secondary headache in which the regular or frequent use of analgesics can increase the frequency of the episodes, causing the transition from episodic to chronic headache. The prevalence of medication overuse headache is approximately 1-2%, with higher rates among women aged 30-50 years and with comorbid psychiatric disorders such as depression or anxiety, or other chronic pain disorders. It is important to be familiar with the management of this disease. To this end, the Spanish Society of Neurology's Headache Study Group has prepared a consensus document addressing this disorder. DEVELOPMENT: These guidelines were prepared by a group of neurologists specialising in headache after a systematic literature review and provides consensus recommendations on the proper management and treatment of medication overuse headache. The treatment of medication overuse headache is often complex, and is based on 4 fundamental pillars: education and information about the condition, preventive treatment, discontinuation of the drug being overused, and treatment for withdrawal symptoms. Follow-up of patients at risk of recurrence is important. CONCLUSIONS: We hope that this document will be useful in daily clinical practice and that it will update and improve understanding of medication overuse headache management.

Evidence of and experience with the use of onabotulinumtoxinA in trigeminal neuralgia and primary headaches other than chronic migraine. / Evidencia y experiencia del uso de onabotulinumtoxinA en neuralgia del trigémino y cefaleas primarias distintas de la migraña crónica.

INTRODUCTION: In the field of headaches, onabotulinumtoxinA (onabotA) is well established as a treatment for chronic migraine (CM). In recent years, it has been used increasingly to treat other primary headaches (high-frequency episodic migraine, trigeminal-autonomic cephalalgias, nummular headache) and trigeminal neuralgia. As this treatment will progressively be incorporated in the management of these patients, we consider it necessary to reflect, with a fundamentally practical approach, on the possible indications of onabotA, beyond CM, as well as its administration protocol, which will differ according to the type of headache and/or neuralgia. DEVELOPMENT: This consensus document was drafted based on a thorough review and analysis of the existing literature and our own clinical experience. The aim of the document is to serve as guidelines for professionals administering onabotA treatment. The first part will address onabotA's mechanism of action, and reasons for its use in other types of headache, from a physiopathological and clinical perspective. In the second part, we will review the available evidence and studies published in recent years. We will add an "expert recommendation" based on our own clinical experience, showing the best patient profile for this treatment and the most adequate dose and administration protocol. CONCLUSION: Treatment with onabotA should always be individualised and considered in selected patients who have not responded to conventional therapy.

Evidence and experience with onabotulinumtoxinA in chronic migraine: Recommendations for daily clinical practice. / Evidencia y experiencia de bótox en migraña crónica: Recomendaciones para la práctica clínica diaria.

OnabotulinumtoxinA has been demonstrated to be effective as a preventive treatment in patients with chronic migraine (CM). Five years after the approval of onabotulinumtoxinA in Spain, the Headache Study Group of the Spanish Society of Neurology considered it worthwhile to gather a group of experts in treating patients with CM in order to draw up, based on current evidence and our own experience, a series of guidelines aimed at facilitating the use of the drug in daily clinical practice. For this purpose, we posed 12 questions that we ask ourselves as doctors, and which we are also asked by our patients. Each author responded to one question, and the document was then reviewed by everyone. We hope that this review will constitute a practical tool to help neurologists treating patients with CM.

Calcitonin gene-related peptide in migraine: from pathophysiology to treatment. / CGRP en migraña: de la fisiopatología a la terapéutica.

INTRODUCTION: It has been observed in recent years that levels of such molecules as calcitonin gene-related peptide (CGRP) and, to a lesser extent, the pituitary adenylate cyclase-activating peptide are elevated during migraine attacks and in chronic migraine, both in the cerebrospinal fluid and in the serum. Pharmacological reduction of these proteins is clinically significant, with an improvement in patients' migraines. It therefore seems logical that one of the main lines of migraine research should be based on the role of CGRP in the pathophysiology of this entity. DEVELOPMENT: The Spanish Society of Neurology's Headache Study Group decided to draft this document in order to address the evidence on such important issues as the role of CGRP in the pathophysiology of migraine and the mechanism of action of monoclonal antibodies and gepants; and to critically analyse the results of different studies and the profile of patients eligible for treatment with monoclonal antibodies, and the impact in terms of pharmacoeconomics. CONCLUSIONS: The clinical development of gepants, which are CGRP antagonists, for the acute treatment of migraine attacks, and CGRP ligand and receptor monoclonal antibodies offer promising results for these patients.

Potential of the Migraine Disability Assessment (MIDAS) Questionnaire as a public health initiative and in clinical practice.

Migraine is not always well managed in clinical practice, often being under-diagnosed and under-treated. As a result, many sufferers never consult a physician or lapse from care after physician contact. Although most migraine care is provided by general practitioners, others, including specialists, emergency room physicians, pharmacists, and alternative practitioners, may also be involved. A method of standardizing clinical information about migraine is essential for coordinated, logical, and systematic care. The impact of migraine on the patient is an important clinical parameter but one that is seldom inquired about, perhaps because it exhibits such marked variability among and within individuals. Headache-related disability can be an objective and measurable index of this impact. The Migraine Disability Assessment (MIDAS) Questionnaire is a simple and validated instrument with potential for use in clinical practice, research, and public health. It can improve communication between patients and health-care professionals regarding the impact of migraine which, in turn, allows tailoring of the intensity of treatment to the severity of the illness. Changes in the MIDAS score may serve as an end point in assessing treatment efficacy. In populations, MIDAS scores may indicate the burden of migraine in the community and spark public health initiatives to improve management.

[Lumbosacral plexopathy caused by aneurysms of the abdominal aorta]. / Plexopatía lumbosacra por aneurismas de la aorta abdominal.

We report three patients who presented pain in the sciatic-crural region as presenting feature of an aneurysm of the abdominal aorta. The first patient developed a fullblown plexopathy with bad condition due to a large aneurysm of common iliac artery. The remaining two patients had abdominal aneurysms each that manifested as femoral neuropathy in one case and as L5-S1 radiculopathy in the other patient. The mechanism of neural involvement is discussed and those clinical and radiologic findings which may prompt us to think of such etiology in front of painful clinical pictures in this region are emphasized.

[Ictus, pregnancy and contraception]. / Ictus, embarazo y contracepción.

PIP: Ictus is a severe complication of pregnancy and the puerperium and a significant cause of maternal mortality. The risk of ictus increases by 3-13 times during pregnancy because of a tendency toward hypercoagulability, hemodynamic alterations related to increased blood volume, and severe arterial hypertension. This work outlines the incidence, etiology, diagnosis, and treatment of ischemic cerebrovascular pathology, cerebral venous thrombosis, and hemorrhagic cerebrovascular pathology occurring during pregnancy. Risk factors are indicated. The role of oral contraceptives (OCs) as a risk factor for cerebrovascular pathology is then discussed. Various prospective and retrospective studies to establish the causal or casual relationship between OC use and ictus have been published since 1962. Two important studies published in 1969 found a statistically significant increased relative risk of ischemic cerebrovascular accident in OC users. The Collaborative Group for the Study of Stroke in Young Women included hemorrhagic ictus in a retrospective study for the first time in 1973, finding that the risk of thrombotic and hemorrhagic cerebrovascular accident was significantly greater in OC users. In 1975, using the same sample, the group found a positive relation between increased blood pressure and risk of ischemic and hemorrhagic events in OC users. The largest prospective study, begun by the Royal College of General Practitioners in England in 1968, found an increased risk of mortality from circulatory diseases in OC users, with mortality risks for coronary ischemia and subarachnoid hemorrhage statistically significant. The study found that the use of OCs increased the risk of fatal subarachnoid hemorrhage, especially in women over 35 who smoked. Other prospective studies found an increased incidence of nonfatal cerebrovascular accident, with relative risks for all cerebrovascular accidents ranging from 5 to 6.5. A recent continuation of the Royal College Study found that patients using OCs had a relative risk for cerebrovascular accidents of 1.5. The risk was increased at higher doses and for some specific progestins.^ieng

[The medical treatment of intracerebral hemorrhage]. / Tratamiento médico de la hemorragia intracerebral.

OBJECTIVE: To review the main aspects of the practical management of intracerebral hemorrhage. DEVELOPMENT: We begin by briefly reviewing the pathophysiology, clinical features and recommended complementary investigations which are necessary for satisfactory diagnosis and treatment. These vary depending on the characteristics of the bleeding on neuroimaging, age and clinical situation of the patient. We particularly consider the therapeutic aspects, basically of medical treatment but also some aspects of surgical treatment, both during the acute phase of bleeding, when the main objective is to prevent and treat the neurobiological and systemic complications, such as the specific underlying disorder or lesion causing the intracerebral hemorrhage, so as to prevent further bleeding. THE MEDICAL TREATMENT: General measures, mechanical ventilation, control of blood pressure, the prevention and treatment of raised intracranial pressure and the possibilities of specific medical treatment in reducing the zone of ischemic penumbra are also reviewed. Since surgical treatment is controversial, we have considered the most generally accepted indications for this and the different techniques used. Finally we review the risk factors identified in cerebral hemorrhage which permit primary prevention.

[Hospital stay after cerebral hemorrhage]. / Estancia hospitalaria en hemorragias intracerebrales.

INTRODUCTION AND OBJECTIVES: Patients with intracerebral haemorrhage (ICH) make up 10-12% of the total number of patients admitted to hospital. In this paper we evaluate the period of time during which the maximum benefit is obtained by a patient with this type of ictus. DEVELOPMENT AND CONCLUSIONS: We therefore review the aetiology, physiopathological course and complications of HIC in order to better understand the circumstances which affect the average hospital stay and identify the factors which can be acted upon and when to do so. We conclude that the average hospital stay does not depend on the type of ictus, in the sense of whether it is ischaemic or haemorrhagic, but on its severity which mainly depends on the size of the lesion. We find no justification for a patient with ICH spending more time in hospital than one with an ischaemic ictus, except where it is suspected that a cerebral aneurysm is the cause of the haemorrhage.

[Intake patterns of analgesics in patients with headache who came to the neurologist]. / Patrón de consumo de analgésicos en el paciente con cefalea que acude a la consulta de neurología.

We have analysed the pattern of analgesic use in a group of patients that came for the first time to the neurologist. We have examined the first intention analgesic use in patients with headache, before the therapeutic intervention of the neurologist. During a month, we have followed a group of 40 patients. 20 of them were admitted as ambulatory patients at a Headache Unit at a Hospital and the other 20 were attended as outpatients by a general neurologist. 'Over-the-counter' analgesics were the most commonly used (paracetamol, acetylsalicylic acid and combinations of them with other products such as caffeine). More than a half of the patients had consumed a combination of analgesics. At the time of the investigation, the mean of analgesic use were greater in the group attended at the Headache Unit than in the one attended by the general neurologist. This could depend on the fact that chronic daily headache was more frequent in the first group and that they were older than the other group. These findings could be in relation with a larger evolution of their headache.

[Cerebrovascular disease in young adults. A study of its course in 167 patients]. / Enfermedad vascular cerebral en el adulto joven. Estudio evolutivo en 167 pacientes.

INTRODUCTION: Few studies have been made of the prognosis of ictus in the young adult. The objective of this paper is to study the short term evolution of 167 patients, aged between 15 and 45 years, with cerebral vascular disease. MATERIAL AND METHODS: Since 1986 a protocolized study has been made of all patients aged between 15 and 45 who were admitted to the Neurology Department of the Hospital General Universitario in Valencia for a cerebral vascular incident. The results obtained up to 1993 have been recorded in a data base. In this paper the demographic data and information as to intrahospital evolution have been used with the Canadian, modified Rankin and Barthel Scales in the various ictus groups. RESULTS: 28.7% of the patients were AIT and 71.3% were diagnosed as established ictus, of whom 38.8% were haemorrhagic and 61.2% were ischaemic. 29.8% of the HIP, 33.3% of the embolic infarcts and 18.2% of the atherothrombotic infarcts were severely disabled on discharge from hospital. Mortality was 4.2% when AIT were excluded. DISCUSSION: Most studies are basically aetiopathological and much fewer include evaluation of prognosis. In our series, the patients had a satisfactory clinical course and low short-term mortality. As in the other series, the two groups with the worst prognosis were the HIP and the cardioembolic infarcts. Patients with HSA and HIV made outstandingly good progress.

Efficacy of three drugs for protecting against gentamicin-induced hair cell and hearing losses.

BACKGROUND AND PURPOSE Exposure to an ototoxic level of an aminoglycoside can result in hearing loss. In this we study investigated the otoprotective efficacy of dexamethasone (DXM), melatonin (MLT) and tacrolimus (TCR) in gentamicin (GM)-treated animals and cultures. EXPERIMENTAL APPROACH Wistar rats were divided into controls (treated with saline); exposed to GM only (GM); and three GM-exposed groups treated with either DXM, MLT or TCR. Auditory function and cochlear surface preparations were studied. In vitro studies of oxidative stress, pro-inflammatory cytokine mRNA levels, the MAPK pathway and caspase-3 activation were performed in organ of Corti explants from 3-day-old rats. KEY RESULTS DXM, MLT and TCR decreased levels of reactive oxygen species in GM-exposed explants. The mRNA levels of TNF-α, IL-1ß and TNF-receptor type 1 were significantly reduced in GM + DXM and GM + MLT groups. Phospho-p38 MAPK levels decreased in GM + MLT and GM + TCR groups, while JNK phosphorylation was reduced in GM + DXM and GM + MLT groups. Caspase-3 activation decreased in GM + DXM, GM + MLT and GM + TCR groups. These results were consistent with in vivo results. Local treatment of GM-exposed rat cochleae with either DXM, MLT or TCR preserved auditory function and prevented auditory hair cell loss. CONCLUSIONS AND IMPLICATIONS In organ of Corti explants, GM increased oxidative stress and initiated an inflammatory response that led to the activation of MAPKs and apoptosis of hair cells. The three compounds tested demonstrated otoprotective properties that could be beneficial in the treatment of ototoxicity-induced hearing loss.