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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

[Almotriptan vs. ergotamine plus caffeine for acute migraine treatment. A cost-efficacy analysis]. / Almotriptán frente a ergotamina más cafeína en el tratamiento de las crisis agudas de migraña. Análisis de coste-eficacia.

INTRODUCTION: Almotriptan has proven to be more efficacious and tolerable than ergotamine plus caffeine but is more expensive, thus raising the question about its cost-efficacy. METHODS: The course of migraine attacks during 24 hours treated with almotriptan and ergotamine plus caffeine was modelled with a decision tree, using efficacy data from a recent randomized, double-blind clinical trial comparing the two drugs. Costs were calculated from the social perspective (including indirect costs due to absenteeism and loss of productivity) and from the Spanish National Health System (NHS) perspective (only including drug costs). The impact on quality of life was estimated using utilities assigned in the literature to different health states of migraine patients. RESULTS: Treatment response was 57.7% for patients treated with almotriptan vs. 44.5% with ergotamine plus caffeine. Sustained pain-free status was achieved by 20.3% vs. 11.5%. Working days lost due to absenteeism and reduced productivity amounted to 0.24 vs. 0.38 days. Quality of life during attacks was estimated at an average utility of 0.548 vs. 0.422. From the NHS perspective, incremental costs per attack treated with almotriptan vs. ergotamine plus caffeine was euro 5.05, rendering an incremental cost-efficacy ratio of euro38.26 per additional response, euro57.39 per additional complete response, and euro14,709 per quality- adjusted life-year gained. From the social perspective almotriptan saved euro7.50 vs. ergotamine plus caffeine. CONCLUSIONS: Almotriptan can be considered cost-efficacious vs. ergotamine plus caffeine from the NHS perspective and is the dominant option (both more efficacious and more economical) from the social perspective.

[Recommendations guide for the treatment of migraine in the clinical practice]. / Guía de recomendaciones para el tratamiento de la migraña en la práctica clínica.

Migraine is the most frequent neurological reason for consultation. The differences regarding health care system, type of professional seeing these patients and therapeutic armamentarium available in the different countries are important, which makes it very recommendable to have an action guide that reflects the local clinical practice. Following the year 2005 WHO recommendations in its "Global Campaign" against migraine, the coordinators of the Headache Study Groups of the Spanish Society of Neurology, the Spanish Society of Family and Community Medicine, the Spanish Society of Rural and General Medicine, the Spanish Society of General Medicine and the Global Campaign decided to jointly make this guide. To do so, they made a search in MEDLINE, using the terms "migraine", "migraine treatment" and "headache guidelines" and "migraine guidelines". The most relevant articles were analyzed, including the references that we considered to be of interest. Furthermore, we reviewed the most important textbooks on headache and migraine. In this paper, we detail the recommendations agreed on, according to the evidence grade, on symptomatic and preventive treatment of migraine.

[Proteus syndrome with cerebral vascular malformations]. / Síndrome de Proteus con malformaciones vasculares cerebrales.

INTRODUCTION: Proteus syndrome is a congenital hamartomatous dysplasia. This sporadic disorder involves the skeletal system, soft tissues, skin and vascular system. The most likely pathogenesis involves somatic mosaicism. Main manifestations included soft-tissue and epidermal nevi, partial gigantism, hemihypertrophy, exostoses, lipomas and vascular anomalies. The most common brain abnormalities are hemimegencephaly and migrational disorders. We present a case of Proteus syndrome with cerebral vascular anomalies which are not described previously. CLINICAL CASE: Our patient is a 61 year-old male who has hypertrophy of the four limbs, macrodactyly and hypertrophy of chest and abdomen asymmetric with mild facial asymmetry. Prominent and abundant of the four extremities and trunk, also asymmetric. Vascular tumors in the skin of trunk and left limb. Cerebral MRI shows venous angiomas and multiple cavernous malformations. CONCLUSION: Clinical diagnostic criteria of Proteus syndrome are documented in our patient. He also has brain vascular malformations which are not described previously in the literature. We consider that both findings are not a product of causality due to the high prevalence of systemic vascular hamartomatous malformations in these patients. We hypothesize that a single mutation, probably involving genes in relation with apoptotic control will be responsible of Proteus syndrome and cerebral vascular anomalies in our patient, due to a defect of angiogenesis.

[Is migraine a progressive cerebral disease?]. / La migraña es una enfermedad cerebral progresiva?

Migraine is a primary neurovascular headache which affects approximately 12% of the adult population. Migraine particularly affects women of working age and is associated with significant disability and reduced quality of life. During migraine attacks, the capacity to engage in daily activities such as child care, work, and social activities is reduced, and relationships with family members and friends become strained. In this respect, migraine places a heavy economic burden on both the individual and society. It is also known migraine is a risk factor for ischemic stroke in young women with migraine with aura. Recently, it was reported that some individuals that experience migraine with and without aura may be at an increased risk for subclinical lesions in certain areas of the brain. Cerebral white matter lesions (WMLs) are a common finding on cerebral MRI scans. Although, it appears that cerebral WMLs are more common in migraineurs than in the general population, the nature, association and the clinical significance of cerebral WMLs in migraineurs are not yet conclusive. Furthermore, there is no good evidence to support the notion that cerebral WMLs in migraineurs can predict subclinical or clinical stroke in these individuals. Needless to say, the need for more longitudinal and prospective migraine research is immense. The aim of the future migraine research should be to obtain more information about the natural course of migraine as well as evaluate the association between migraine and cerebral WMLs and their consequences. In addition, continuing genetic identification of key proteins involved in migraine will improve our understanding of this common and sometimes most debilitating disorder, which can strike during the most productive years of a person's life.

[Spanish contribution to the clinical development of eletriptan: an analysis of controlled studies]. / Contribución española al desarrollo clínico de eletriptán: un análisis de los estudios controlados.

INTRODUCTION: Eletriptan is a recently marketed second-generation triptan with a potent agonist activity on 5-HT1B/ 1D receptors. Our aim has been to analyze the specific results from the Spanish participation in phase IIIa and IIIb clinical trials vs placebo and compare them with the results obtained in the global clinical development of eletriptan. PATIENTS AND METHODS: Analysis of the results obtained in 40 centers in Spain (358 patients) vs global sample 4,677 patients) for the first migraine attack in 6 controlled clinical trials with eletriptan 40 mg, eletriptan 80 mg and placebo. This ad hoc analysis was carried out for those treatment groups with more than 50 patients, which reduced the final number of patients from Spain to 250. RESULTS: The proportion of patients with relief at 2 hours (main endpoint) in the Spanish sample was 22 %, 59 % and 67 % for placebo, eletriptan 40 mg and eletriptan 80 mg, respectively. These values were significantly higher (p < 0.05) than those of placebo and similar to those from the total sample. The proportion of pain free patients at 2 hours in the Spanish sample was 10 %, 36 % and 41 % for placebo, eletriptan 40 mg and eletriptan 80 mg, respectively. These values were significantly better than those for placebo (p < 0.05) and about 15 %-20 % higher than those from the total sample. Recurrence rate in the Spanish sample was 50 %, 16 % and 25 % for placebo, eletriptan 40 and eletriptan 80 mg, respectively, and did not differ from that of the total sample. Sustained relief for the two eletriptan doses was 46 % for both eletriptan 40 and eletriptan 80, this being significant (p < 0.05) over placebo (11 %) for the Spanish sample and similar to that of the global sample. The results for other efficacy parameters, such as need of rescue medication, functional response at 2 hours, complete response for pain-freeness and acceptability followed a similar pattern. Eletriptan was, in general, well-tolerated. Adverse events were slight-moderate in intensity, transient and were not different, either in profile or proportion, from those from the global sample. CONCLUSIONS: These results confirm eletriptan 40 mg and 80 mg as an excellent option for the symptomatic treatment of migraine in our setting.