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Background: Resistant and refractory migraine are commonly encountered in specialized headache centers. Several comorbidities, mostly psychiatric conditions, have been linked to migraine worsening; however, there is little knowledge of the comorbidity profile of individuals with resistant and refractory migraine., Methods: REFINE is a prospective observational multicenter international study involving individuals with migraine from 15 headache centers. Participants were categorized into three groups based on the European Headache Federation criteria: non-resistant and non-refractory (NRNRM), resistant (ResM), and refractory (RefM). We explored the prevalence of 20 comorbidities at baseline in the three groups., Results: Of the 689 included patients (82.8% women), 262 (38.0%) had ResM, 73 (10.4%) had RefM and 354 (51.4%) NRNRM. A higher prevalence of psychiatric comorbidities, trigger points, temporomandibular joint disorders, thyroiditis, and cerebrovascular diseases was observed in the RefM group, followed by ResM and NRNRM. Multiple comorbidities were more common in the RefM group, followed by the ResM group and by the NRNRM group (41.6% vs. 24.5% vs. 14.1% respectively; p < 0.001). At the sensitivity analysis, exploring participants with chronic migraine, significant differences among the NRNRM, ResM, and RefM groups were found in the prevalence of anxiety (p < 0.001), asthma and rhinitis (p = 0.013), bipolar and other psychiatric disorders (p = 0.049), cerebrovascular diseases (p < 0.001), depression (p < 0.001), obesity (p = 0.002), thyroiditis (p < 0.001), and trigger points (p = 0.008)., Conclusion: REFINE data indicate that individuals with ResM and RefM have a higher burden of comorbidities than those with NRNRM. It can be postulated that those comorbidities may have an impact on the progression of migraine from a form that is easy to treat to a form that is resistant or refractory to treatments. Longitudinal studies are needed to understand the direction of the association between ResM or RefM and those comorbidities and if proper treatment of comorbidities might help overcome treatment resistance or refractoriness., Competing Interests: Declarations. Competing interests: P.M. serves as the Editor-in-Chief of The Journal of Headache and Pain., (© 2024. The Author(s).)

Purpose: Treatments in medicine impact individuals beyond their intended effects, due to phenomena such as the placebo and nocebo effects. The placebo effect arises from the positive expectation of a treatment being beneficial, while the nocebo effect stems from the negative expectation of a treatment causing harm. Both in real-world practice and clinical trials, treatments can lead to outcomes unrelated to their intended mechanism of action, which we categorize as placebo and nocebo responses. These responses, combined with the inherent fluctuation in a condition's natural progression, regression to the mean, and random comorbidities, make up a significant part of the therapeutic experience. Particularly in pain management, placebo and nocebo effects play a substantial role. By addressing modifiable contextual factors such as patient expectations, lifestyle choices, and the therapeutic relationship, healthcare providers can enhance the effectiveness of migraine treatments, paving the way for a more comprehensive, individualized approach to patient care. We must also consider non-modifiable factors like personal experiences, beliefs, and information from social media and the internet., Conclusion: This review offers a summary of our current understanding of the placebo and nocebo effects in migraine management., Competing Interests: Declaration of conflicting interestsThe authors declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Background: Although acute headache following COVID-19 vaccination is widely acknowledged, the long-term progression of these headaches remains poorly understood. Our objective was to identify various phenotypes of prolonged or worsened headaches associated with COVID-19 vaccination and document any changes in these phenotypes over an extended period. Additionally, we aimed to document the diverse headache presentations among patients with pre-existing primary headaches., Methods: A multinational, prospective observational study was conducted to investigate prolonged or worsened headaches associated with COVID-19 vaccination. Questionnaires assessing COVID-19 vaccination-related headaches at three time points (initial visit, 3 rd month follow-up, and 6th month follow-up) were developed for the study. Headache specialists/clinicians evaluated patients using these questionnaires in a prospective manner. Repeated K-means cluster analysis was performed to identify patient profiles with prolonged or worsened headaches related to COVID-19 vaccination., Results: Among the 174 patients included in the study, there was a female-to-male ratio of 128 (73.6%) to 46 (26.4%). The mean age of the patient group was 45.2 ± 13.3 years, and 107 patients (61.5%) had a pre-existing history of primary headaches. Through the analysis, two major clusters were identified based on headache characteristics at each visit. During the first visit (n = 174), Cluster 1 primarily comprised patients with a history of primary headaches, frontal localization of pain, throbbing pain type, more severe headaches accompanied by symptoms such as nausea, phonophobia, photophobia, and osmophobia, and worsened by physical activity. In contrast, Cluster 2 consisted of patients with longer headache durations (over one month) and a stabbing/pressing quality of pain. Patients in Cluster 1 had a higher prevalence of migraine as the pre-existing primary headache disorder compared to Cluster 2 (90.48% vs. 68.18%, respectively; p = 0.005)., Conclusion: The identification of two distinct phenotypes of prolonged or worsened headaches related to COVID-19 vaccination can provide valuable clinical insights. Having an awareness of the potential worsening of headaches following COVID-19 vaccination, particularly in patients with a primary headache disorder such as migraine, can help clinicians and headache experts anticipate and adjust their treatment strategies accordingly. This knowledge can aid in preplanning treatment modifications and optimize patient care., (© 2023. Springer-Verlag Italia S.r.l., part of Springer Nature.)

Aim: To evaluate glatiramer acetate (GA) or IFN-β effects on quality of life (QoL) in people with relapsing/remitting multiple sclerosis (PwRRMS) in Greece. Methods: A prospective, practice-based study. QoL/function/symptoms were assessed by seven questionnaires/scales. Results: Significant increases in Short Form-36 (SF-36) health survey scores occurred with GA in four of the eight domains and three of the eight domains at 6 and 12 months, respectively, versus baseline. Similar and significant SF-36 score improvements occurred with GA in treatment-naive PwRRMS. SF-36 scores were unaffected in GA-treated, IFN-β treatment-experienced PwRRMS, or with IFN-β versus baseline. Slight improvements in fatigue and sexual satisfaction were evident (6 months). No deteriorations were seen in the other four instruments. Conclusion: The findings show that 12-month treatment with GA, but not IFN-β, improved certain QoL parameters in treatment-naive PwRRMS.

Background: Health economic evaluations support health-care decision-making by providing information on the costs and consequences of health interventions. No universally accepted methodology exists for modelling effectiveness and cost-effectiveness of interventions designed to close treatment gaps for headache disorders in countries of Europe (or elsewhere). Our aim here, within the European Brain Council's Value-of-Treatment project, was to develop headache-type-specific analytical models to be applied to implementation of structured headache services in Europe as the health-care solution to headache., Methods: We developed three headache-type-specific decision-analytical models using the WHO-CHOICE framework and adapted these for three European Region country settings (Luxembourg, Russia and Spain), diverse in geographical location, population size, income level and health-care systems and for which we had population-based data. Each model compared current (suboptimal) care vs target care (delivered in accordance with the structured headache services model). Epidemiological and economic data were drawn from studies conducted by the Global Campaign against Headache; data on efficacy of treatments were taken from published randomized controlled trials; assumptions on uptake of treatments, and those made for Healthy Life Year (HLY) calculations and target-care benefits, were agreed with experts. We made annual and 5-year cost estimates from health-care provider (main analyses) and societal (secondary analyses) perspectives (2020 figures, euros)., Results: The analytical models were successfully developed and applied to each country setting. Headache-related costs (including use of health-care resources and lost productivity) and health outcomes (HLYs) were mapped across populations. The same calculations were repeated for each alternative (current vs target care). Analyses of the differences in costs and health outcomes between alternatives and the incremental cost-effectiveness ratios are presented elsewhere., Conclusions: This study presents the first headache-type-specific analytical models to evaluate effectiveness and cost-effectiveness of implementing structured headache services in countries in the European Region. The models are robust, and can assist policy makers in allocating health budgets between interventions to maximize the health of populations., (© 2021. The Author(s).)

Background: There have been several calls for estimations of costs and consequences of headache interventions to inform European public-health policies. In a previous paper, in the absence of universally accepted methodology, we developed headache-type-specific analytical models to be applied to implementation of structured headache services in Europe as the health-care solution to headache. Here we apply this methodology and present the findings., Methods: Data sources were published evidence and expert opinions, including those from an earlier economic evaluation framework using the WHO-CHOICE model. We used three headache-type-specific analytical models, for migraine, tension-type-headache (TTH) and medication-overuse-headache (MOH). We considered three European Region case studies, from Luxembourg, Russia and Spain to include a range of health-care systems, comparing current (suboptimal) care versus target care (structured services implemented, with provider-training and consumer-education). We made annual and 5-year cost estimates from health-care provider and societal perspectives (2020 figures, euros). We expressed effectiveness as healthy life years (HLYs) gained, and cost-effectiveness as incremental cost-effectiveness-ratios (ICERs; cost to be invested/HLY gained). We applied WHO thresholds for cost-effectiveness., Results: The models demonstrated increased effectiveness, and cost-effectiveness (migraine) or cost saving (TTH, MOH) from the provider perspective over one and 5 years and consistently across the health-care systems and settings. From the societal perspective, we found structured headache services would be economically successful, not only delivering increased effectiveness but also cost saving across headache types and over time. The predicted magnitude of cost saving correlated positively with country wage levels. Lost productivity had a major impact on these estimates, but sensitivity analyses showed the intervention remained cost-effective across all models when we assumed that remedying disability would recover only 20% of lost productivity., Conclusions: This is the first study to propose a health-care solution for headache, in the form of structured headache services, and evaluate it economically in multiple settings. Despite numerous challenges, we demonstrated that economic evaluation of headache services, in terms of outcomes and costs, is feasible as well as necessary. Furthermore, it is strongly supportive of the proposed intervention, while its framework is general enough to be easily adapted and implemented across Europe., (© 2021. The Author(s).)

Introduction and Objective: Multiple sclerosis (MS) is the most frequent autoimmune demyelinating disease of the central nervous system. MS patients usually present with lower urinary tract dysfunction (LUTD). Objective of this study is to evaluate and compare the efficacy and safety of treating MS patients with LUTD with either a b3 agonist (mirabegron) or anticholinergics. The study's primary outcome is the LUTD symptom improvement., Material and Methods: This is a multi-center, single-blinded, comparative study including 91 MS patients with LUTD. At baseline, patients underwent thorough clinical examination, urine cultivation and abdominal ultrasound and completed urination diaries and specific, validated questionnaires (NBSS, MusiQoL). At second visit, patients were administered either mirabegron or anticholinergics. Treatment was always carried out alongside with MS treatment. Reevaluation was performed 3 months after first visit. Patients underwent the same clinical and imaging tests that were carried out at first visit., Results: We compared several clinical and imaging parameters between the two groups at first visit and month 3 after treatment. Νo statistical difference was noted between the mirabegron group and the anticholinergic group in terms of LUTD improvement. In both groups, improvement from baseline regarding LUTD was recorded. Statistical analysis was performed using the paired and unpaired t test method. No patient discontinued either medication due to side effects., Conclusions: MS patients receiving either mirabegron or anticholinergic therapy for LUTD showed improvement. Nevertheless, no statistical difference was noted between the two cohorts at 3 months in terms of drug efficacy in all the statistically significant parameters., (© 2021. The Author(s), under exclusive licence to Springer-Verlag GmbH, DE part of Springer Nature.)

Nocebo effects, denoting unfavourable outcomes after a medical intervention because of negative expectations rather than a direct pharmacologic action, are an important cause of dropout from clinical trials and non-adherence to medication, and may be especially pertinent for older adults. Several characteristics of aging individuals and their medical care have a potential to augment nocebo susceptibility, such as depression and anxiety, neurodegenerative diseases and chronic pain states, adverse healthcare experiences, generic drug use, age-related stereotypes, and strained patient-physician communication. Nocebo-related research in older adults is hindered by under-representation in clinical trials, medical complexity of geriatric patients, and lack of validated tools to accurately assess susceptibility and efficacy of preventive efforts., (Copyright © 2020 Elsevier B.V. All rights reserved.)

Aims: To assess the reimbursement options and accessibility of three effective medicines for cluster headache (CH) (subcutaneous sumatriptan, oxygen, and zolmitriptan spray) across the European Union (EU)., Methods: A brief survey investigating the availability of symptomatic treatments for CH was sent by email in January 2017 to at least one headache specialist for every single country in the EU., Results: The questionnaire was completed by 26 headache specialists (93% of the EU countries, representing 99.75% of the European population) and by 10 CH patients representative of patient organizations. Oxygen was reimbursable for 63% of the CH population. Oxygen device was reimbursable for 50% of the CH EU population. Subcutaneous sumatriptan was reimbursable for 66% and was accessible without restrictions for 45% of the CH EU population. Zolmitriptan spray was reimbursable for 23.7% and accessible without restrictions for 30.9% of the CH EU population., Conclusion: Only 47% of the EU population had unrestricted access to effective CH treatments, with unacceptable inequalities between eastern countries and the rest of Europe. Headache societies and patient associations should pressure European and national health authorities to improve the availability of effective symptomatic treatments for CH.

Psoriatic arthritis (PsA) patients are at a higher risk of systemic inflammatory sequelae, leading to microalbuminuria, cardiovascular (CVD) and neuropsychiatric (NPD) disease. Our aim is to present the existing literature about the relationship between CVD, kidney and NPD in PsA. The literature evaluation of PsA revealed that chronic T-cell activation and increased levels of circulating immune complexes can cause glomerular injury leading to microalbuminuria, which predicts CVD and all-cause mortality in both diabetic and non-diabetic patients. Furthermore, it is a marker of preclinical brain damage and identifies patients at higher risk of NPD/CVD events. Among the currently used imaging modalities in PsA, magnetic resonance imaging (MRI) maintains a crucial role, because it is ideal for concurrent evaluation of brain/heart involvement and serial follow up assessment. There is increasing evidence regarding the relationship between kidneys, heart and brain in PsA. Although currently there are no official recommendations about a combined brain/heart MRI in PsA, it could be considered in PsA with microalbuminuria, arrhythmia, HF, cognitive dysfunction and/or depression.

Background: Trigeminal neuralgia (TN) is a severe, disabling form of painful cranial neuropathy. Even though TN has a typical clinical picture, diagnosis it is often missed or delayed in clinical practice. In order to investigate the occurrence of diagnostic and therapeutic errors in TN, we studied 102 patients suffering from TN recruited through a multicentric survey., Methods: We performed a Pubmed database search on errors and pittfalls in TN diagnosis and management. Then, patients with TN were consecutively enrolled in the period from February 2017 to October 2019, by several European Headache Centers participating in the study, following a call of the Headache and Pain Scientific Panels of the European Academy of Neurology (EAN). Diagnosis of Classical Trigeminal Neuralgia (CTN) was made according to the International Headache Society (IHS) criteria (Tölle et al., Pain Pract 6:153-160, 2006). All the patients were evaluated using telephone/frontal interviews conducted by headache/pain specialists using an ad hoc questionnaire., Results: A number of 102 patients were recruited, mostly females (F:M ratio 2.64:1). Eighty-six percent of the patients consulted a physician at the time they experienced the first pain attacks. Specialists consulted before TN diagnosis were: primary care physicians (PCP) (43.1%), dentists (in 30.4%), otorhinolaryngologists (3.9%), neurosurgeons (3.9%), neurologists or headache specialists (14.7%), others (8%). The final diagnosis was made mainly by a neurologist or headache specialist (85.3%), and the mean interval between the disease onset and the diagnosis made by a specialist was 10.8 ± 21.2 months. The "diagnostic delay" was 7.2 ± 12.5 months, and misdiagnoses at first consultation were found in 42.1% of cases. Instrumental and laboratory investigations were carried out in 93.1% of the patients before the final diagnosis of TN., Conclusion: While TN has typical features and it is well defined by the available international diagnostic criteria, it is still frequently misdiagnosed and mistreated. There is a need to improve the neurological knowledge in order to promptly recognize the clinical picture of TN and properly adhere to the specific guidelines. This may result in a favorable outcome for patients, whose quality of life is usually severely impaired.

Purpose of Review: To present the interaction between brain/heart and emphasize the role of combined brain/heart magnetic resonance imaging (MRI) in patients with rheumatoid arthritis (RA) and other seronegative spondyloarthropathies (SNA)., Recent Findings: Both traditional cardiovascular disease (CVD) risk factors and intrinsic RA/SNA features contribute to the increased CVD-related morbidity/mortality. CVD in RA usually occurs a decade earlier than age- and sex-matched controls, and RA patients are twice more likely to develop myocardial infarction irrespective of age, history of prior CVD, and traditional CVD risk factors. RA also increases risk of non-ischemic heart failure (HF), valvular disease, and myo-pericarditis. CVD in SNA affects more commonly patients with long-standing disease. Ascending aortitis, aortic/mitral insufficiency, conduction defects, and diastolic dysfunction are the commonest findings in ankylosing spondylitis (AS). CVD is also the leading cause of death in psoriatic arthritis (PsA), due to myopericarditis, diastolic dysfunction, and valvular disease. Brain damage, due to either ischemic or hemorrhagic stroke and silent vascular damage, such as white matter hyperenhancement (WMH), is increased in both RA/SNA and may lead to cognitive dysfunction, depression, and brain atrophy. Magnetic resonance imaging (MRI) is ideal for serial brain/heart evaluation of patients with systemic diseases. RA/SNA patients are at high risk for brain/heart damage at early age, irrespectively of classic risk factors. Until more data will be obtained, a combined brain/heart MRI evaluation can be proposed in RA/SNA with new onset of arrhythmia and/or HF, cognitive dysfunction and/or depression.

Introduction: Non-invasive vagus nerve stimulation (nVNS; gammaCore®) has the potential to prevent migraine days in patients with migraine on the basis of mechanistic rationale and pilot clinical data., Methods: This multicentre study included a 4-week run-in period, a 12-week double-blind period of randomised treatment with nVNS or sham, and a 24-week open-label period of nVNS. Patients were to administer two 120-second stimulations bilaterally to the neck three times daily (6-8 hours apart)., Results: Of 477 enrolled patients, 332 comprised the intent-to-treat (ITT) population. Mean reductions in migraine days per month (primary outcome) were 2.26 for nVNS (n = 165; baseline, 7.9 days) and 1.80 for sham (n = 167; baseline, 8.1 days) ( p  = 0.15). Results were similar across other outcomes. Upon observation of suboptimal adherence rates, post hoc analysis of patients with ≥ 67% adherence per month demonstrated significant differences between nVNS (n = 138) and sham (n = 140) for outcomes including reduction in migraine days (2.27 vs. 1.53; p  = 0.043); therapeutic gains were greater in patients with aura than in those without aura. Most nVNS device-related adverse events were mild and transient, with application site discomfort being the most common., Conclusions: Preventive nVNS treatment in episodic migraine was not superior to sham stimulation in the ITT population. The "sham" device inadvertently provided a level of active vagus nerve stimulation. Post hoc analysis showed significant effects of nVNS in treatment-adherent patients. Study identification and registration: PREMIUM; NCT02378844; https://clinicaltrials.gov/ct2/show/NCT02378844.

Objective: This study evaluated the benefit-risk profile of erenumab relative to other therapies approved for migraine prophylaxis and available in the majority of European countries., Methods: Trials were identified via a published systematic literature review updated to December 2017 using MEDLINE. Erenumab's pivotal trials study reports were also included (NCT02066415, NCT02456740). From these sources, ≥ 50% responder rates and discontinuations due to adverse events were extracted to generate numbers needed to treat and harm and likelihood of being helped or harmed, a quantitative benefit-risk measure., Results: Eleven articles (nine randomized clinical trials) met the inclusion/exclusion criteria. Low numbers needed to treat (range: 4-13) were observed for most treatments, while numbers needed to harm showed substantial differences (erenumab's higher numbers needed to harm indicating better tolerability). In chronic and episodic migraine, likelihoods of being helped or harmed for erenumab 70 mg were 143 and 167, and 42 and 167 for erenumab 140 mg. Likelihoods of being helped or harmed in chronic migraine were 2 and 3 for topiramate (two studies) and 4 for onabotulinumtoxinA. In episodic migraine, likelihoods of being helped or harmed were 2 for topiramate and 2 for propranolol., Conclusions: While all prophylactic treatments were more likely to help than harm (likelihood of being helped or harmed > 1), erenumab showed a likelihood of being helped or harmed of high magnitude, supporting its favorable benefit-risk profile across the entire migraine frequency spectrum, in contrast with other prophylactic treatments.

In joint initiatives, the European Headache Federation and Lifting The Burden have described a model of structured headache services (with their basis in primary care), defined service quality in this context, and developed practical methods for its evaluation.Here, in a continuation of the service quality evaluation programme, we set out ten suggested role- and performance-defining standards for specialized headache centres operating as an integral component of these services. Verifiable criteria for evaluation accompany each standard. The purposes are five-fold: (i) to inspire and promote, or stimulate the establishment of, specialized headache centres as centres of excellence; (ii) to define the role of such centres within optimally structured and organized national headache services; (iii) to set out criteria by which such centres may be recognized as exemplary in their fulfilment of this role; (iv) to provide the basis for, and to initiate and motivate, collaboration and networking between such centres both nationally and internationally; (v) ultimately to improve the delivery and quality of health care for headache.

OnabotulinumtoxinA is being increasingly used in the management of chronic migraine (CM). Treatment with onabotulinumtoxinA poses challenges compared with traditional therapy with orally administered preventatives. The European Headache Federation identified an expert group that was asked to develop the present guideline to provide recommendations for the use of onabotulinumtoxinA in CM. The expert group recommend onabotulinumtoxinA as an effective and well-tolerated treatment of CM. Patients should preferably have tried two to three other migraine prophylactics before start of onabotulinumtoxinA. Patients with medication overuse should be withdrawn from the overused medication before initiation of onabotulinumtoxinA if feasible, if not onabotulinumtoxinA can be initiated from the start or before withdrawal. OnabotulinumtoxinA should be administered according to the PREEMPT injection protocol, i.e. injecting 155 U-195 U to 31-39 sites every 12-weeks. We recommend that patients are defined as non-responders, if they have less than 30% reduction in headache days per month during treatment with onabotulinumtoxinA. However other factors such as headache intensity, disability and patient preferences should also be considered when evaluating response. Treatment should be stopped, if the patient does not respond to the first two to three treatment cycles. Response to continued treatment with onabotulinumtoxinA should be evaluated by comparing the 4 weeks before with the 4 weeks after each treatment cycle. It is recommended that treatment is stopped in patients with a reduction to less than 10 headache days per month for 3 months and that patients are re-evaluated 4-5 months after stopping onabotulinumtoxinA to make sure that the patient has not returned to CM. Questions regarding efficacy and tolerability of onabotulinumtoxinA could be answered on the basis of scientific evidence. The other recommendations were mainly based on expert opinion. Future research on the treatment of CM with onabotulinumtoxinA may further improve the management of this highly disabling disorder.

This document presents the consensus recommendations of the Hellenic Stroke Organization which can be of assistance to the treating stroke physicians.

This systematic review summarizes the existing data on headache and pregnancy with a scope on clinical headache phenotypes, treatment of headaches in pregnancy and effects of headache medications on the child during pregnancy and breastfeeding, headache related complications, and diagnostics of headache in pregnancy. Headache during pregnancy can be both primary and secondary, and in the last case can be a symptom of a life-threatening condition. The most common secondary headaches are stroke, cerebral venous thrombosis, subarachnoid hemorrhage, pituitary tumor, choriocarcinoma, eclampsia, preeclampsia, idiopathic intracranial hypertension, and reversible cerebral vasoconstriction syndrome. Migraine is a risk factor for pregnancy complications, particularly vascular events. Data regarding other primary headache conditions are still scarce. Early diagnostics of the disease manifested by headache is important for mother and fetus life. It is especially important to identify "red flag symptoms" suggesting that headache is a symptom of a serious disease. In order to exclude a secondary headache additional studies can be necessary: electroencephalography, ultrasound of the vessels of the head and neck, brain MRI and MR angiography with contrast ophthalmoscopy and lumbar puncture. During pregnancy and breastfeeding the preferred therapeutic strategy for the treatment of primary headaches should always be a non-pharmacological one. Treatment should not be postponed as an undermanaged headache can lead to stress, sleep deprivation, depression and poor nutritional intake that in turn can have negative consequences for both mother and baby. Therefore, if non-pharmacological interventions seem inadequate, a well-considered choice should be made concerning the use of medication, taking into account all the benefits and possible risks.

The diagnosis of primary headache disorders is clinical and based on the diagnostic criteria of the International Headache Society (ICHD-3-beta). However several brain conditions may mimic primary headache disorders and laboratory investigation may be needed. This necessity occurs when the treating physician doubts for the primary origin of headache. Features that represent a warning for a possible underlying disorder causing the headache are new onset headache, change in previously stable headache pattern, headache that abruptly reaches the peak level, headache that changes with posture, headache awakening the patient, or precipitated by physical activity or Valsalva manoeuvre, first onset of headache ≥50 years of age, neurological symptoms or signs, trauma, fever, seizures, history of malignancy, history of HIV or active infections, and prior history of stroke or intracranial bleeding. All national headache societies and the European Headache Alliance invited to review and comment the consensus before the final draft. The 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 require brain MRI, MRA and MRV. Brain MRI with detailed study of the pituitary area and cavernous sinus, is recommended for all TACs. For primary cough headache, exercise headache, headache associated with sexual activity, thunderclap headache and hypnic headache apart from brain MRI additional tests may be required. Because there is little and no good evidence the committee constructed a consensus based on the opinion of experts, and should be treated as imperfect.

Background and Purpose: Nocebo refers to adverse events (AEs) generated by patient's negative expectations that medical treatment will likely harm instead of heal and can be assessed in placebo-controlled randomized controlled trials (RCTs). We examined AEs following placebo administration in RCTs for Parkinson's disease (PD)., Methods: After a systematic Medline search for RCTs for PD pharmacologic treatments published between 2000 and 2010, we assessed percentages of placebo-treated patients reporting at least one AE or discontinuing due to placebo intolerance and searched for factors influencing nocebo's extent., Results: Data were extracted from 41 RCTs fulfilling search criteria. Of 3544 placebo-treated patients, 64.7% (95% CI: 53.6-74.4) reported at least one AE and 8.8% (95% CI: 6.8-11.5) discontinued placebo treatment due to intolerance. The number of AEs per 100 person-months was 25.9 (95% CI: 16.8-39.8). Nocebo dropout rate was positively related to study population size and year of publication. Increased number of AEs per 100 person-months was negatively correlated with the duration of treatment. AE rates, dropout rates, and AEs per 100 person-months in placebo- and active drug-treated patients were strongly correlated (r = 0.941, 0.695, and 0.824, respectively)., Conclusions: Our analysis indicates a significant dropout rate related to nocebo in trials for PD treatment. Adherence and efficacy may be adversely affected with additional implications for clinical practice., (© 2012 The Author(s) European Journal of Neurology © 2012 EFNS.)

Background: Nocebo refers to adverse effects (AEs) generated by negative expectations that medical treatment will likely harm instead of heal and can be assessed in placebo-controlled randomized clinical trials (RCTs). We examined AEs following placebo administration in RCTs for fibromyalgia (FM), a condition characterized by patients' poor medication adherence, which may affect outcome and/or increase healthcare costs., Methods:   Following a systematic Medline search for RCTs for FM pharmacologic treatment published between 2001 and 2010, we assessed percentages of placebo-treated patients reporting at least one AE or discontinuing because of placebo intolerance and searched for factors influencing nocebo's extent. Percentages were compared with those revealed by similar meta-analyses of RCTs for multiple sclerosis and primary headaches., Results:   Data were extracted from 16 RCTs fulfilling search criteria. Of 2026 placebo-treated patients, 67.2% (95%CI: 51.0-81.5%) reported at least one AE, and 9.5% (95%CI: 8.3-10.9%) discontinued placebo treatment because of intolerance. AEs in placebo arms corresponded quantitatively and qualitatively to those in active drug arms (ρ > 0.88, P < 0.0001). Younger age and larger placebo arm size were associated with increased dropout rates. Patients with depression were more likely to withdraw from trials. Nocebo dropouts in FM trials were fourfold and twofold higher than in RCTs for multiple sclerosis treatment and migraine preventive treatment, respectively., Conclusions:   Nocebo is remarkably prevalent in FM patients participating in RCTs. Because nocebo contributes to drug intolerance and treatment failure in clinical practice, identification of predisposing factors and efforts to prevent nocebo by educating these patients appropriately may be important for FM outcome., (© 2011 The Author(s). European Journal of Neurology © 2011 EFNS.)

Current views suggest that prothrombotic properties of antiphospholipid antibodies (aPL) have a role in the development of acute transverse myelitis (ATM) in patients with systemic lupus erythematosus (SLE). Consequently, empiric anticoagulation may be included in these patients' treatment. We performed a systemic review of the literature to explore the clinical value of the presence of aPL in patients with lupus myelitis and the possible effectiveness of anticoagulation. We analyzed clinical and laboratory data extracted from published cases of SLE-associated ATM, fulfilling the Transverse Myelitis Consortium Working Group diagnostic criteria, that provided information on aPL. We report on a total of 70 patients. aPL, detected upon ATM onset in 54% of patients, neither predicted the involvement of the thoracic part of the spine, which has been postulated to reflect a predominantly thrombosis-induced injury, nor correlated with relapsing ATM, additional lupus CNS manifestations, or worse clinical outcome. An unfavorable outcome could be predicted by paralysis (P=0.02) and abnormal CSF findings at presentation (P=0.02). Whilst all patients received major immunosuppressive regimens, severe neurologic impairment (estimated Expanded Disability Status Scale score>7) was found primarily in aPL-negative patients (P=0.03). Anticoagulation was more frequently applied in aPL-positive patients (P=0.04), but any additional therapeutic effect was not evident. Detection of circulating aPL at ATM onset appears unreliable to suggest a thrombotic cause and perhaps not enough to dictate therapeutic anticoagulation. Registry creation of ATM in patients with SLE is needed to obtain more definite answers on the role of aPL in this condition., (© 2010 The Author(s). European Journal of Neurology © 2010 EFNS.)

Background: Tension-type headache (TTH) is the most prevalent headache type and is causing a high degree of disability. Treatment of frequent TTH is often difficult., Objectives: To give evidence-based or expert recommendations for the different treatment procedures in TTH based on a literature search and the consensus of an expert panel., Methods: All available medical reference systems were screened for the range of clinical studies on TTH. The findings in these studies were evaluated according to the recommendations of the EFNS resulting in level A, B or C recommendations and good practice points., Recommendations: Non-drug management should always be considered although the scientific basis is limited. Information, reassurance and identification of trigger factors may be rewarding. Electromyography (EMG) biofeedback has a documented effect in TTH, whilst cognitive-behavioural therapy and relaxation training most likely are effective. Physical therapy and acupuncture may be valuable options for patients with frequent TTH, but there is no robust scientific evidence for efficacy. Simple analgesics and non-steroidal anti-inflammatory drugs are recommended for the treatment of episodic TTH. Combination analgesics containing caffeine are drugs of second choice. Triptans, muscle relaxants and opioids should not be used. It is crucial to avoid frequent and excessive use of analgesics to prevent the development of medication-overuse headache. The tricyclic antidepressant amitriptyline is drug of first choice for the prophylactic treatment of chronic TTH. Mirtazapine and venlafaxine are drugs of second choice. The efficacy of the prophylactic drugs is often limited, and treatment may be hampered by side effects., (© 2010 The Author(s). Journal compilation © 2010 EFNS.)

Objective: To estimate the incidence and severity of nocebo responses in trials of symptomatic treatments (STs) and disease-modifying treatments (DMTs) for multiple sclerosis (MS)., Methods: We conducted a systematic Medline search for all randomised, placebo-controlled MS trials published between 1989 and 2009. Meta-analysis of the incidence of nocebo responses was performed by pooling the percentage of placebo-treated patients that exhibited adverse events. Nocebo severity was calculated from the percentage of placebo-treated patients that dropped-out due to drug-related adverse events., Results: Data were extracted from 56 DMT and 44 ST eligible trials. The pooled incidence of nocebo responses was 74.4% (95% CI: 69.92-88.30) in DMT trials and 25.3% (95% CI: 15.24-36.90) in ST trials and was significantly higher in the former (p < 0.0001). The pooled nocebo severity was 2.1% (95% CI: 1.6-2.67) in DMT and 2.34% (95% CI: 1.54-3.29) in ST trials. Meta-regression analysis revealed a higher nocebo incidence in parallel design ST studies compared to crossover ones (p = 0.013) and a higher nocebo severity in phase II ST studies compared to phase III ones (p = 0.0001). Nocebo severity in DMT trials exhibited an association with the year of study publication (p = 0.011) and the frequency of drug administration (p = 0.0082)., Conclusions: Nocebo responses in MS trials are substantial and appear to have increased significantly in recent years with important implications for both trial design and clinical practice. Furthermore, nocebo responses exhibit an association with medication and trial-related factors.

Objectives: To examine whether ideomotor apraxia exists in patients with subcortical ischemic lesions., Patients and Methods: A matched-control, prospective and multi-centered research design was used. Ideomotor apraxia, anxiety and depression were assessed by the Movement Imitation Test and the Hamilton scales, respectively., Results: Forty two consecutive patients with subcortical ischemic stroke and an equal number of healthy participants, matched in age and sex were included. Paired-sample t-tests showed that patients had significantly more apractic elements in their movements (t = 5.03, P < 0.01), higher anxiety (t = -2.55, P = 0.0014) and depression levels (t = -2.61, P = 0.012) than their healthy matched participants. Participants with higher anxiety and depression scores performed worse on the Movement Imitation Test., Conclusions: Ischemic damage of subcortical modular systems may affect praxis.

In order to investigate the plausible association of migraine recurrence with anxiety and depressive symptoms, a multicentre, randomized, double-blind, placebo-controlled, crossover clinical trial was conducted using sumatriptan as a vehicle drug. Migraineurs were randomly assigned to receive either 50 mg sumatriptan or placebo for three consecutive migraine attacks, and then cross over to the other treatment for three more migraine attacks. The primary measurements were the observed rate of migraine recurrence in relation to (i) patient's mood condition, measured by the Hamilton rating scales for depression and anxiety and (ii) patient's general health and functioning measured by the Symptom Checklist (SCL)-90-R. Migraine recurrence was defined as any migrainous headache that occurred within 24 h post treatment, only when pain free at 2 h was achieved. The analysis of efficacy was performed on 376 migraine attacks treated with sumatriptan and 373 attacks treated with placebo. Recurrence ratio was 14.1% and 5.1%, respectively (P = 0.045). The number needed to treat for pain free at 2 h post dose was 5.4. Recurrence was not affected by Hamilton scores for depression or anxiety, SCL-90-R scores or treatment. Apparently, depressive or anxiety symptoms do not influence headache recurrence in acute pharmaceutical migraine treatment, but further investigation is required.

The Clinical Trials Subcommittee of the International Headache Society published its first edition of the guidelines on controlled trials of drugs in tension-type headache in 1995. These aimed 'to improve the quality of controlled clinical trials in tension-type headache', because 'good quality controlled trials are the only way to convincingly demonstrate the efficacy of a drug, and form the basis for international agreement on drug therapy'. The Committee published similar guidelines for clinical trials in migraine and cluster headache. Since 1995 several studies on the treatment of episodic and chronic tension-type headache have been published, providing new information on trial methodology for this disorder. Furthermore, the classification of the headaches, including tension-type headache, has been revised. These developments support the need for also revising the guidelines for drug treatments in tension-type headache. These Guidelines are intended to assist in the design of well-controlled clinical trials in tension-type headache.

The aim was to investigate the comorbidity of chronic refractory headache with obstructive sleep apnoea syndrome (OSAs). Seventy-two patients (51 women and 21 men) with chronic and refractory headaches, whose headache occurred during sleep or whose sleep was accompanied by snoring, were submitted to polysomnography. Patients diagnosed with OSAs (respiratory disturbance index > 10) began continuous positive airway pressure (C-PAP) treatment and were followed up for >or= 6 months. Twenty-one cases of OSAs were identified (29.2% of the total investigated, 13.7% of the women and 66.6% of the men). Headaches were classified into several headache disorders, medication overuse headache and cluster headache being the most prevalent (nine and six of the 21 cases, respectively). In one case (1.4% of the total sample, 4.7% of all the men), the criteria for hypnic headache were fulfilled. Multivariate regression analysis revealed that age, male gender and body mass index were associated with OSAs. C-PAP treatment improved both sleep apnoea and headache in only a third of the cases. Patients suffering from chronic refractory headache associated with sleep or snoring, in particular those who are also middle-aged, overweight men, should be considered for polysomnography. C-PAP treatment alone does not seem to improve headache, but further investigation is needed.

The aim of this study was to evaluate in a double-blind, randomized, placebo-controlled study the safety and efficacy of venlafaxine extended release (XR) in the prophylactic treatment of out-patients with tension-type headache (TTH) and no current depression or anxiety disorders. Sixty neurology and headache clinic out-patients meeting the International Headache Society diagnostic criteria for TTH were treated with venlafaxine XR (150 mg/day, n = 34) or placebo (n = 26) for 12 weeks. The primary efficacy variable was the decline in number of days with headache. At end-point, the venlafaxine XR group had a significantly greater decrease in the number of days with headache compared with placebo (P = 0.05). Differences with regard to secondary efficacy variables where not significant. The number needed to treat for responders (>or=50% reduction in days with headache) was 3.48. Six patients in the venlafaxine XR group interrupted therapy due to adverse events, while no patients in the placebo group did so for the same reason. The number needed to harm was 5.58. This study provides preliminary evidence for the efficacy and safety of venlafaxine XR 150 mg/day in reducing the number of days with TTH.

The scope of the paper is to summarise key issues in methodology used in clinical trials on multiple sclerosis (MS) treatment and help clinicians to better understand articles reporting the results of these trials. Relapsing ratio and disability progression based on the Expanded Disability Status Scale are currently used as clinical efficacy primary outcomes, but more global measurements should be used in future such as the MS Functional Composite. For magnetic resonance imaging (MRI) outcomes, new MRI composites and indexes are already available (Z4 score, conventional MRI-derived end-points) that, together with new MRI techniques (magnetisation- transfer MRI and proton resonance spectroscopy), offer more precise neuroimaging assessments of the disease. These efficacy measurements should be presented in articles as number needed to treat, which assists the reader to calculate and compare the treatments' power and safety.

Animal models of human disease have been extremely helpful both in advancing the understanding of brain disorders and in developing new therapeutic approaches. Models for studying headache mechanisms, particularly those directed at migraine, have been developed and exploited efficiently in the last decade, leading to better understanding of the potential mechanisms of the disorder and of the action for antimigraine treatments. Model systems employed have focused on the pain-producing cranial structures, the large vessels and dura mater, in order to provide reproducible physiological measures that could be subject to pharmacological exploration. A wide range of methods using both in vivo and in vitro approaches are now employed; these range from manipulation of the mouse genome in order to produce animals with human disease-producing mutations, through sensitive immunohistochemical methods to vascular, neurovascular and electrophysiological studies. No one model system in experimental animals can explain all the features of migraine; however, the systems available have begun to offer ways to dissect migraine's component parts to allow a better understanding of the problem and the development of new treatment strategies.

An open, prospective, observational study was performed to assess efficacy and adverse-event profile of topiramate as add-on therapy in epilepsy. Outpatient neurology clinics from 11 general hospitals in Greece participated in the study. In total, 211 patients with treatment resistant partial-onset seizures who met the inclusion criteria, were studied. After baseline evaluation, topiramate was given at a target dose of 200mg/day over a 1-month titration period. In the subsequent maintenance period, the topiramate dose could be varied according to the clinical results. Patients were followed for in total 6 months, with monthly visits and regular physical, neurological and laboratory examinations. Seizure frequencies decreased to 35--40% of baseline values following 3 months of treatment and remained relatively constant thereafter. The average monthly seizure frequency over the 6-month study period was 4.61, compared to 9.21 at baseline. The number of responders (patients with at least 50% reduction in seizure frequency) followed a similar pattern, i.e., increase during the first 3 months levelling off at a final 80--85% response rate. Of those completing the study, 30% had been seizure-free for at least 3 months and 12% for 5 months. Topiramate was well tolerated, no deviations in laboratory values were found. Adverse events appeared to occur less frequently, and antiepileptic effects were more pronounced in this prospective open-label study than in earlier reports from randomised controlled trials. The nature of the patient population and the application of individualised dose optimisation are proposed as contributing factors to explain the favourable results of this study.

Despite occasional case reports, the influence of migraine on time perception has not been systematically investigated. We used an experimental technique to study the estimation of auditory duration in 40 migraineurs at different tone intervals in the ms and in the 1-s range and compared their performance with 40 matched normal subjects. With a time awareness questionnaire we also evaluated the subjective experience of elapsing time for long durations involving long-term memory processes. Migraine did not influence temporal judgements in either of the tests, suggesting that migraineurs do not generally over- or underestimate temporal events. The subgroup of migraineurs with a depressive disorder, however, showed a marked speeding up of their internal timekeeping mechanisms, pointing to depression as an important covariable in time perception.

In order to investigate the c-fos response within the trigeminal nucleus caudalis (Sp5C) after noxious meningeal stimulation, capsaicin (0.25, 0.5, 1 and 5 nmol) was administered intracisternally in urethane (1 g/kg) and alpha-chloralose (20 mg/kg) anaesthetized male mice. Capsaicin induced a robust and dose-dependent c-fos-like immunoreactivity (c-fos LI) within Sp5C. C-fos LI was observed within laminae I and II of the entire brain stem from the area postrema to C2 level, being maximum at the decussatio pyramidum level. The area postrema, solitary tract, medullary and lateral reticular nuclei were also labelled. The 5-hydroxytryptamine(1B/1D/1F) receptor agonist sumatriptan (0.01, 0.1, 1 and 10 mg/kg), administered intraperitoneally 15 min before capsaicin stimulation (1 nmol), decreased the c-fos response within Sp5C, but not within solitary tract. The novel specific 5-hydroxytryptamine1F agonist LY 344864 (0.1 and 1 mg/kg, i.p.) significantly decreased the c-fos LI within the Sp5C as well. These findings suggest that intracisternally administered capsaicin activates the trigeminovascular system and that the pain neurotransmission can be modulated by 5-hydroxytryptamine(1B/1D/1F) receptors in mice. Thus, the availability of this model in mice, taken together with the possibility of altering the expression of specific genes in this species, may help to investigate further the importance of distinct proteins in the neurotransmission of cephalic pain.

In intracranial structures unmyelinated C- and Adelta-fibers of the trigeminal nerve transmit pain stimuli from meninges to the trigeminal nucleus caudalis (Sp5C). Peripheral nerve endings surround meningeal vessels (the so-called trigeminovascular system) and contain vasoactive neuropeptides (calcitonin gene-related peptide, substance P and neurokinin A). Activation of the trigeminovascular system promotes a meningeal sterile inflammatory response through the release of neuropeptides by peripheral endings. Orthodromic conduction along trigeminovascular fibers transmits information centrally with induction of immediate early c-fos gene within post-synaptic Sp5C neurons, as a marker of neuronal activity within central nociceptive pathways. In laboratory animals the system is activated by either electrical stimulation of the TG, chemical stimulation of the meninges, electrical or mechanical stimulation of the superior sagittal sinus or by induction of cortical spreading depression. All these techniques induce c-fos within Sp5C and are used as a rodent/feline model of vascular headache in humans. Up-to-date there is evidence that at least ten receptors (5-HT(1B), 5-HT(1D), 5-HT(lF), 5-HT(2B), NK-1, GABA(A), NMDA, AMPA, class III metabotropic glutamate receptors, and opioids mu receptors) modulate c-fos expression within Sp5C. These receptors represent potential targets for anti-migraine drugs as shown by triptans (5-HT(1B/1D/1F)) and ergot alkaloids (5-HT(1A1B/1D/1F)). This review discusses the importance of c-fos expression within Sp5C as a marker of cephalic nociception, the different cephalic pain models that induce c-fos within Sp5C, the receptors involved and their potential role as targets for anti-migraine drugs.

We examined the effects of butalbital (30, 100, and 1000 micrograms/kg) on the number of cells expressing c-fos-like immunoreactivity (c-fos-LI), a marker of neuronal activation, within lamina I, IIo of the trigeminal nucleus caudalis and the nucleus of the solitary tract 2 hours after the intracisternal injection of capsaicin (0.1 mL; 15.25 mg/mL) or vehicle in urethane-anesthetized guinea pigs (N = 45). Robust c-fos-LI was observed within nuclei of cells in the trigeminal nucleus caudalis after capsaicin (329 +/- 35). Butalbital dose-dependently reduced the number of labeled cells to a maximum of 66% (1000 micrograms/kg intraperitoneally [i.p.], P < .01) in lamina I, IIo but not within area postrema, medial reticular nucleus, or the nucleus of the solitary tract. Pretreatment with bicuculline (30 micrograms/kg i.p.) blocked the effect of butalbital, thereby suggesting the importance of the GABAA receptor to activation involved in the transmission of nociceptive information. Our studies suggest the possibility that GABAA receptors might provide an important therapeutic target in migraine and related headache disorders.

Using perfusion weighted imaging, we studied 28 spontaneous migraine episodes; 7 during visual aura (n = 6), 7 during the headache phase following visual aura (n = 3), and 14 cases of migraine without aura (n = 13). The data were analyzed using a region-of-interest-based approach. During aura, relative cerebral blood flow (rCBF) was significantly decreased (27% +/- 0.07) in occipital cortex contralateral to the affected hemifield. rCBV was decreased (15% +/- 0.12) and mean transit time increased (32% +/- 0.3), persisting up to 2.5 h into the headache phase. Other brain regions did not show significant perfusion changes. During migraine without aura, no significant hemodynamic changes were observed. In one patient who experienced both migraine with and without aura, perfusion deficits were observed only during migraine with aura. These findings suggest that decremental blood flow changes in occipital lobe are most characteristic of migraine with aura.

1. We examined the effects of the alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA)/kainate receptor antagonists 6-cyano-7-nitroquinoxaline-2,3-dione (CNQX) and 1,2,3,4-tetrahydro-6-nitro-2,3-dioxo-benzol[f]quinoxaline-7-sulpho namide (NBQX), the kainate receptor antagonists gamma-(R-)-glutamylaminomethanesulphonic acid (GAMS) and 6,7,8,9-tetrahydro-5-nitro-1H-benz[g]indole-2,3-dione-3-oxime (NS-102), and the group III metabotropic glutamate receptor (mGluR) agonist 2-amino-4-phosphono-S-butanoic acid (L-AP4) on c-fos-like immunoreactivity (c-fos LI) in trigeminal caudalis (Sp5C), lateral reticular (LRt), medullary reticular (Md) and solitary tract (Sol) nuclei, after intracisternal injection of capsaicin in urethane anaesthetized Sprague-Dawley rats. 2. Few c-fos labelled cells were observed within Sp5C in capsaicin-vehicle treated animals. The number of positive c-fos cells increased by 17 fold after intracisternal capsaicin (5 nmol) administration. 3. Pretreatment with CNQX (0.02, 0.1, 0.6, 3 and 15 mg kg-1) or NBQX (0.01, 0.1 and 1 mg kg-1), administered intraperitoneally 15 min before capsaicin, significantly reduced labelled cells within Sp5C by a maximum of 45 and 34%, respectively. The number of c-fox LI cells within LRt, Md and Sol was not affected. Pretreatment with L-AP4 (1, 3 and 10 mg kg-1) decreased the number of Sp5C c-fos LI cells by a maximum of 30%, whereas GAMS (1 and 10 mg kg-1) and NS-102 (1 and 5 mg kg-1) did not show any significant effect. 4. These results suggest that blockade of AMPA receptors, but not kainate receptors, or the activation of group III mGluRs, decrease the response of Sp5C neurons to trigeminovascular activation. Thus, in addition to NMDA receptors, mGluRs and AMPA receptors may modulate cephalic pain and may provide a potential therapeutic target for antimigraine drugs.

The goal of the present study was to investigate the clinical profile of patients with primary headache syndromes who also suffer from mood disorders. Four-hundred-and-seventy headache outpatients (170M, 300F) and 150 age- and sex-matched healthy subjects were screened using a specific questionnaire that included the Hamilton rating scales for anxiety and depression. The average scores of the Hamilton rating scales for anxiety and depression were significantly higher in headache sufferers (17.4 and 14.2, respectively) than in healthy people (6.8 and 5.7, respectively). The frequency of headache attacks, the history of headaches, and gender (women more than men) were correlated with the score of the Hamilton rating scale for both anxiety and depression. Sixteen headache patients (3.4%) achieved the DSM-IV criteria for major depression or dysthymia versus one among headache-free subjects (0.6%; OR 5.2). Patients suffering from drug-overuse and migraine with aura showed the higher odds ratios (35 and 17, respectively). These results suggest that those headache patients with long history and high frequency of headaches, or patients suffering from migraine with aura and drug-overuse might benefit from psychiatric evaluation.

A possible mechanism of action of antimigraine drugs such as sumatriptan is inhibition of the trigeminovascular pathway. Sumatriptan's effects might be mediated by 5-HT1B, 5-HT1D or 5-HT1F receptors. To establish the relative importance of these subtypes, we compared the effects of sumatriptan with those of a selective 5-HT1F receptor agonist (LY 344864) on c-fos protein expression in the trigeminal nucleus caudalis. c-fos expression was induced in urethane-anaesthetized rats by intracisternal capsaicin administration. Sumatriptan and LY 344864 decreased the number of capsaicin-induced c-fos-like immunoreactive cells within trigeminal nucleus caudalis (ID50 = 0.04 and 0.6 mg kg(-1)). The effect of sumatriptan, but not of LY 344864, was prevented by pretreatment with the antagonist SDZ 21-009, which displays high affinity for rat 5-HT1B receptors. LY 344864 appears to attenuate c-fos-like immunoreactivity via 5-HT1F receptors, while sumatriptan acts via 5-HT1B receptors. The fact that activation of 5-HT1F receptors is sufficient to modulate the activity of the trigeminal system suggests that this receptor may be a target for antimigraine drugs with improved safety profile.

The effect of the N-methyl-D-aspartate (NMDA) receptor antagonist (5R, 10S)-(+)-5-methyl-10,11-dihydro-5H-dibenzo[a,d]cyclo-hepten-5,10-i mine hydrogen maleate (MK-801) was examined on c-fos-like immunoreactivity (c-fos-LI) in urethane-anesthetized Sprague-Dawley rats using a polyclonal antibody. C-fos, an indicator of neuronal activation, was assessed within the trigeminal nucleus caudalis (TNC), area postrema. lateral reticular and solitary tract nuclei 2 h after intracisternal injection of capsaicin. C-fos-positive cells were counted at three representative levels corresponding to obex, -2.05 mm and -6.45 mm in 18 tissue sections (50 microm). A weighted average was obtained reflecting total brainstem expression within lamina I, II of TNC using a recently validated method. Capsaicin (0.1, 1, 5, 10 and 15 nmol) caused a dose-dependent labeling of cells in lamina I, II at obex similar to that previously reported after intracisternal blood or carrageenin administration in rats and guinea pigs. MK-801 (0.3, 1 and 3 mg/kg) administered i.p. 30 min before capsaicin (5 nmol in 100 microl artificial CSF) reduced significantly and dose-dependently (12%, 36% and 47%, respectively) the c-fos-LI cells in TNC at each level from rostral to caudal but not in solitary tract, area postrema and lateral reticular nuclei, and for unexplained reasons, increased c-fos-LI within the inferior olive. These results suggest that NMDA receptors provide a potential therapeutic target for cephalic pain (e.g. migraine) due to trigeminovascular activation from meningeal afferents.

The aim of this study was to investigate the fasciculation potentials (FPs) in the small-peripheral muscles of the foot and hand and the possible associated factors, in a healthy population. One hundred-twenty-two normal individuals (65 men and 57 women), aged 17-67 years (mean 39.96, SD=12.76) participated in the study. A special questionnaire consisting of 47 questions was devised as the basic instrument of the interview, which included the Hamilton anxiety rating scale. The extensor digitorum brevis (EDB), the flexor hallucis brevis (FHB) and the first dorsal interosseous (FDI) muscles were studied bilaterally using surface electrodes. In 94 (58 men and 36 women) from 122 participants (65 men and 57 women) FPs were recorded (men 89.2%, women 63.1%, all 77%). The mean FPs per minute and muscle, in all three muscles, was 8.0 (SD=4.6). More FPs were recorded in the muscles of foot than in FDI (p<0.01) and in FHB than in EDB (p<0.001). FPs were correlated to gender, body height and weight and to the score of the Hamilton scale (r2>0.1, p<0.01). The syndrome of benign FPs was observed in 2 men (1.6% of men). These results suggest that FPs are a very common phenomenon in the peripheral muscles of healthy persons.

Intractable headaches, the so-called 'lupus headaches', have been long thought of as a common and characteristic manifestation of systemic lupus erythematosus (SLE). Seventy-eight patients with SLE, including 10 patients with definite central nervous system (CNS) involvement, and 89 healthy individuals matched for age, sex and socioeconomic status, were studied by a specific questionnaire addressing the characteristics and type of headache. Clinical features of SLE, neurological manifestations and treatment, disease severity and autoantibody profiles were correlated to the presence of headache. One year prevalence of headache was similar between patients (32%) and otherwise healthy individuals (30%). No significant differences regarding frequency, family history of headache and need for analgesic medication were observed. Headache refractory to analgesic treatment, but responsive to corticosteroid regimen, was recorded in only one patient. Clinical and serological features of SLE, including Raynaud's phenomenon and the presence of anticardiolipin antibodies, were not significantly different between headache sufferers and non-sufferers. In the majority of patients reporting headache, anxiety and/or depression co-existed. Episodic tension headache was the most frequent type, while migraine was traced in a quarter of headache sufferers. Neither the presence nor the clinical type of headache was related to, or predictive of, the development of seizures or psychosis. These results indicate that headache is not specifically related to SLE expression or severity, and suggest that accepting the presence even of a severe headache as a neurological manifestation of SLE in the absence of seizures or overt psychosis may result in overestimation of the disease status.

Objectives: The aim of this study was to explore the efficacy of buspirone (BSR), in comparison with amitriptyline (AML) in the prophylactic treatment of chronic tension-type headache (CTH), in an open and randomized clinical trial., Material and Methods: Twenty-six CTH patients (10 men and 16 women) were treated with BSR (30 mg daily) for 12 weeks. A parallel group of 32 CTH patients (12 men and 20 women) was treated with AML (50 mg daily). The major clinical parameters evaluated were the headache index (days with headache per month), the frequency of drug use for the acute management of headaches, the patients' opinion for the treatment and the Hamilton anxiety and depression rating scales., Results: During the study 9 patients dropped out (4 from the BSR group and 5 from the AML group). Twelve (54.4%) patients from the BSR group responded to treatment (> 50% reduction in the headache index), compared to 17 (60.7%) from the AML group. In the BSR group, 14 (53.8%) patients reported various mild side effects (nausea most frequently), vs 21 (65.5%) of the AML group (mouth dryness more frequently). Patients treated with AML had better opinion and used less drugs for the acute treatment of headaches than the BSR treated patients., Conclusion: These results suggest that BSR may be effective in the prophylactic treatment of CTH, and that further investigation in a placebo controlled study is needed.