Poor patient awareness and frequent misdiagnosis of migraine: findings from a large transcontinental cohort.

BACKGROUND AND PURPOSE: Although migraine is the second most disabling condition worldwide, there is poor awareness of it. The objective was to assess the awareness of migraine and previous diagnostic and therapeutic consultations and treatments in a large international population of migraineurs. METHODS: This was a multicentre study conducted in 12 headache centres in seven countries. Each centre recruited up to 100 patients referred for a first visit and diagnosed with migraine. Subjects were given a structured clinical questionnaire-based interview about the perceptions of the type of headache they suffered from, its cause, previous diagnoses, investigations and treatments. RESULTS: In all, 1161 patients completed the study. Twenty-eight per cent of participants were aware that they suffered from migraine. Sixty-four per cent called their migraine 'headache'; less commonly they used terms such as 'cervical pain' (4%), tension headache (3%) and sinusitis (1%). Eight per cent of general practitioners and 35% of specialists (of whom 51% were neurologists and/or headache specialists) consulted for migraine formulated the correct diagnosis. Before participating in the study, 50% of patients had undergone X-ray, computed tomography and/or magnetic resonance imaging of the cervical spine and 76% underwent brain and/or cervical spine imaging for migraine. Twenty-eight per cent of patients had received symptomatic migraine-specific medications and 29% at least one migraine preventive medication. CONCLUSIONS: Although migraine is a very common disease, poor awareness of it amongst patients and physicians is still an issue in several countries. This highlights the importance of the promotion of migraine awareness to reduce its burden and limit direct and indirect costs and the risk of exposure to useless investigations.

Mental Pain Questionnaire: An item response theory analysis.

BACKGROUND: The Mental Pain Questionnaire (MPQ) is a self-report questionnaire developed to assess mental pain. The aim of the present study was to test the clinimetric properties of the MPQ. METHODS: A sample of 200 migraine outpatients were enrolled; homogeneity of MPQ was assessed by Mokken Analysis; item-level severity and item-level sensitivity were calculated via Two-Parameter Logistic model; Total Information Function was evaluated to assess reliability of MPQ; internal consistency was calculated via Cronbach's alpha and Sijtsma and Molenaar rho; sensitivity and specificity were assessed via Receiver Operating Characteristic curves. RESULTS: The MPQ showed unidimensional factor structure; satisfactory homogeneity of the item and total score, except items 4 ("my pain is everywhere") and 6 ("I cannot understand why I feel this pain"); good discrimination, except item 7 ("I feel empty"); low information provided by items 4, 6, 7; good reliability for mild and high levels of mental pain; poor reliability for low levels of mental pain; acceptable internal consistency; acceptable sensitivity and specificity. LIMITATIONS: The sample size is barely sufficient to calculate item parameters; it is a monocentric study that enrolled outpatients from a tertiary facility; the study enrolled migraine outpatients not affected by other medical disease. CONCLUSIONS: The MPQ showed good psychometric properties. Items 4, 6, 7 should be considered with caution when migraine patients are evaluated. A score of at least 3 indicates mental pain clinically relevant, a score of at least 2 indicates distress. These data are preliminary and refer to migraine patients, results might be different in psychiatric populations.

Correction to: A PRISMA-compliant systematic review of the endpoints employed to evaluate symptomatic treatments for primary headaches.

Following publication of the original article [1], we have been notified that the name of author five was spelled incorrectly as M. Ferrili, when the correct spelling is MAN Ferilli.

A PRISMA-compliant systematic review of the endpoints employed to evaluate symptomatic treatments for primary headaches.

BACKGROUND: Primary headache are prevalent and debilitating disorders. Acute pain cessation is one of the key points in their treatment. Many drugs have been studied but the design of the trials is not usually homogeneous. Efficacy of the trial is determined depending on the selected primary endpoint and usually other different outcomes are measured. We aim to critically appraise which were the employed outcomes through a systematic review. METHODS: We conducted a systematic review of literature focusing on studies on primary headache evaluating acute relief of pain, following the PRISMA guideline. The study population included patients participating in a controlled study about symptomatic treatment. The comparator could be placebo or the standard of care. The collected information was the primary outcome of the study and all secondary outcomes. We evaluated the studied drug, the year of publication and the type of journal. We performed a search and we screened all the potential papers and reviewed them considering inclusion/exclusion criteria. RESULTS: The search showed 4288 clinical trials that were screened and 794 full articles were assessed for eligibility for a final inclusion of 495 papers. The studies were published in headache specific journals (58%), general journals (21.6%) and neuroscience journals (20.4%). Migraine was the most studied headache, in 87.8% studies, followed by tension type headache in 4.7%. Regarding the most evaluated drug, triptans represented 68.6% of all studies, followed by non-steroidal anti-inflammatories (25.1%). Only 4.6% of the papers evaluated ergots and 1.6% analyzed opioids. The most frequent primary endpoint was the relief of the headache at a determinate moment, in 54.1%. Primary endpoint was evaluated at 2-h in 69.9% of the studies. Concerning other endpoints, tolerance was the most frequently addressed (83%), followed by headache relief (71.1%), improvement of other symptoms (62.5%) and presence of relapse (54%). The number of secondary endpoints increased from 4.2 (SD = 2.0) before 1991 to 6.39 after 2013 (p = 0.001). CONCLUSION: Headache relief has been the most employed primary endpoint but headache disappearance starts to be firmly considered. The number of secondary endpoints increases over time and other outcomes such as disability, quality of life and patients' preference are receiving attention.

Quality indicators in headache care: an implementation study in six Italian specialist-care centres.

BACKGROUND: Headache disorders are highly prevalent, and have a substantial and negative impact on health worldwide. They are largely treatable, but differences in structure, objectives, organization and delivery affect the quality of headache care. In order to recognize and remedy deficiencies in care, the Global Campaign against Headache, in collaboration with the European Headache Federation, recently developed a set of quality indicators for headache services. These require further assessment to demonstrate fitness for purpose. This is their first implementation to evaluate quality in headache care as a multicentre national study. METHODS: Between September and December 2016, we applied the quality indicators in six Italian specialist headache centres (Bologna, Firenze, Modena, Padova, Roma Campus Bio-Medico and Roma Sapienza). We used five previously developed assessment instruments, translated into Italian according to Lifting The Burden's translation protocol for hybrid documents. We took data from 360 consecutive patients (60 per centre) by questionnaire and from their medical records, and by different questionnaires from their health-care providers (HCPs), including physicians, nurses, psychologists and nursing assistants. RESULTS: The findings, comparable between centres, confirmed the feasibility and practicability of using the quality indicators in Italian specialist headache centres. The questionnaires were easily understood by HCPs and patients, and were not unduly time-consuming. Diagnoses were almost all (> 97%) according to ICHD criteria, and routinely (100%) reviewed during follow-up. Diagnostic diaries were regularly used by 96% of physicians. Referral pathways from primary to specialist care existed in five of the six clinics, as did urgent referral pathways. Instruments to assess disability and quality of life were not used regularly, a deficiency that needs to be addressed. CONCLUSION: This Italy-wide survey confirmed in six specialist centres that the headache service quality indicators are fit for purpose. By establishing majority practice, identifying commonalities and detecting deficits as a guide to quality improvement, the quality indicators may be used to set benchmarks for quality assessment. The next step is extend use and evaluation of the indicators into non-specialist care.

Essential competencies in prescribing: A first european cross-sectional study among 895 final-year medical students.

European medical students should have acquired adequate prescribing competencies before graduation, but it is not known whether this is the case. In this international multicenter study, we evaluated the essential knowledge, skills, and attitudes in clinical pharmacology and therapeutics (CPT) of final-year medical students across Europe. In a cross-sectional design, 26 medical schools from 17 European countries were asked to administer a standardized assessment and questionnaire to 50 final-year students. Although there were differences between schools, our results show an overall lack of essential prescribing competencies among final-year students in Europe. Students had a poor knowledge of drug interactions and contraindications, and chose inappropriate therapies for common diseases or made prescribing errors. Our results suggest that undergraduate teaching in CPT is inadequate in many European schools, leading to incompetent prescribers and potentially unsafe patient care. A European core curriculum with clear learning outcomes and assessments should be urgently developed.

What is the evidence for the role of TRP channels in inflammatory and immune cells?

A complex network of many interacting mechanisms orchestrates immune and inflammatory responses. Among these, the cation channels of the transient receptor potential (TRP) family expressed by resident tissue cells, inflammatory and immune cells and distinct subsets of primary sensory neurons, have emerged as a novel and interrelated system to detect and respond to harmful agents. TRP channels, by means of their direct effect on the intracellular levels of cations and/or through the indirect modulation of a large series of intracellular pathways, orchestrate a range of cellular processes, such as cytokine production, cell differentiation and cytotoxicity. The contribution of TRP channels to the transition of inflammation and immune responses from a defensive early response to a chronic and pathological condition is also emerging as a possible underlying mechanism in various diseases. This review discusses the roles of TRP channels in inflammatory and immune cell function and provides an overview of the effects of inflammatory and immune TRP channels on the pathogenesis of human diseases.

Effects of hydrogen sulfide (H2S) on mesenteric perfusion in experimental induced intestinal ischemia in a porcine model.

INTRODUCTION: Insufficient mesenteric perfusion is a dramatic complication in critically ill patients. Hydrogen sulfide, a newly recognized endogenous gaseous mediator, acts as an intestinal vasoactive agent and seems to protect against mesenteric ischemic damage. We investigated whether sodium hydrogen sulfide, a hydrogen sulfide donor, can improve mesenteric perfusion in an experimental model of pigs, both in physiological and ischemic conditions. METHODS: The study was conducted at Careggi University Hospital (Florence, IT). Fourteen male domestic pigs (≈10 Kg) were anesthetized and mechanically ventilated. Animals were randomized in control and ischemia groups. Mesenteric ischemia was induced with a positive end-expiratory pressure of 15 cmH2O. After mini-laparotomy, each animal received incremental doses of sodium hydrogen sulfide every 20 minutes. Perfusion of both the jejunal mucosa and sternal skin were measured by laser Doppler flowmeter, and systemic hemodynamic parameters were monitored. RESULTS: In the control group, sodium hydrogen sulfide was able to significantly improve the mesenteric perfusion, showing a 50% increase from the baseline blood flow. In the ischemia group, NaHS-induced a two-fold increase of the mesenteric post-ischemic perfusion with a recovery up to 70% of pre- positive end-expiratory pressure mesenteric blood flow. Sodium hydrogen sulfide did not directly or indirectly (by blood flow redistribution) affect the sternal skin microcirculation, heart rates, or mean arterial pressure, suggesting a tissue-specific micro-vascular action. CONCLUSIONS: In a porcine model, we observed a mesenteric perfusion recovery mediated by administration of hydrogen sulfide donor without affecting general hemodynamic.

The TRPA1 channel in migraine mechanism and treatment.

Migraine remains an elusive and poorly understood disease. The uncertainty is reflected by the currently unsatisfactory acute and prophylactic treatments for this disease. Genetic and pharmacological information points to the involvement of some transient receptor potential (TRP) channels in pain mechanisms. In particular, the TRP vanilloid 1 (TRPV1) and TRP ankyrin 1 (TRPA1) channels seem to play a major role in different models of pain diseases. Recent findings have underscored the possibility that TRP channels expressed in the nerve terminals of peptidergic nociceptors contribute to the migraine mechanism. Among this channel subset, TRPA1, a sensor of oxidative, nitrative and electrophilic stress, is activated by an unprecedented series of irritant and pain-provoking exogenous and endogenous agents, which release the pro-migraine peptide, calcitonin gene-related peptide, through this neuronal pathway. Some of the recently identified TRPA1 activators have long been known as migraine triggers. Furthermore, specific analgesic and antimigraine medicines have been shown to inhibit or desensitize TRPA1 channels. Thus, TRPA1 is emerging as a major contributing pathway in migraine and as a novel target for the development of drugs for pain and migraine treatment.

Anaphylaxis during the first course of high-dose methotrexate: a case report and literature review.

WHAT IS KNOWN AND OBJECTIVE: Methotrexate (MTX) is widely used in the management of paediatric cancer with a generally favourable benefit/risk profile. We report an unusual adverse drug reaction with the first course of high-dose MTX in a paediatric patient and review the literature for similar cases. CASE SUMMARY: An 11-year-old boy with small-cell osteoblastic osteosarcoma in the lower limb experienced a case of life-threatening anaphylaxis during the first course of high-dose MTX. The adverse event occurred during the first course, likely due to an immune-mediated mechanism. We postulate that prior antineoplastic treatment might have contributed to the immune response to MTX. WHAT IS NEW AND CONCLUSION: Given that this reaction has rarely been reported, we discuss the present case with a review of other similar cases. Further studies are needed to substantiate this 'signal alarm' for serious MTX-related hypersensitivity reactions.

Genome-wide association study of serious blistering skin rash caused by drugs.

Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN) are rare but severe, potentially life threatening adverse drug reactions characterized by skin blistering. Previous studies have identified drug-specific and population-specific genetic risk factors with large effects. In this study, we report the first genome-wide association study (GWAS) of SJS/TEN induced by a variety of drugs. Our aim was to identify common genetic risk factors with large effects on SJS/TEN risk. We conducted a genome-wide analysis of 96 retrospective cases and 198 controls with a panel of over one million single-nucleotide polymorphisms (SNPs). We further improved power with about 4000 additional controls from publicly available datasets. No genome-wide significant associations with SNPs or copy number variants were observed, although several genomic regions were suggested that may have a role in predisposing to drug-induced SJS/TEN. Our GWAS did not find common, highly penetrant genetic risk factors responsible for SJS/TEN events in the cases selected.

Pleasant natural scent with unpleasant effects: cluster headache-like attacks triggered by Umbellularia californica.

Umbellularia californica, a shrub or tree indigenous to southwestern Oregon and northern California, is commonly known as headache tree, probably because it is reported that its scent can cause headache. Here, we report the case of a 69-year-old Italian gardener, affected during his young adult age by cluster headache, who, 10 years from his last cluster episode, developed shorter-lasting cluster-like headache attacks after and at any time he was exposed to U. californica scent. The present case indicates that, even though endogenous mechanisms causing the cluster headache were no longer present, susceptibility to exogenous triggers remains active in this patient, and suggests that identification of the constituent(s) of U. californica responsible for triggering cluster headache-like attacks may help in the understanding of the hitherto elusive mechanism of cluster headache.

Ethanol causes neurogenic vasodilation by TRPV1 activation and CGRP release in the trigeminovascular system of the guinea pig.

Ethanol stimulating transient receptor potential vanilloid 1 (TRPV1) on primary sensory neurons promotes neurogenic inflammation, including calcitonin gene-related peptide (CGRP)-mediated coronary dilation. Alcoholic beverages trigger migraine attacks and activation of trigeminal neurons plays a role in migraine. We have investigated in guinea pigs whether ethanol by TRPV1 stimulation causes neurogenic inflammation in the trigeminovascular system. Ethanol-evoked release of neuropeptides from slices of dura mater was abolished by Ca(2+) removal, capsaicin pretreatment and the TRPV1 antagonist, capsazepine. Intragastric ethanol increased plasma extravasation in dura mater, an effect abolished by capsazepine and the NK1 receptor antagonist, SR140333, and caused vasodilation around the middle meningeal artery, an effect abolished by capsazepine and the CGRP receptor antagonist, BIBN4096BS. Vasodilation of meningeal vessels by TRPV1 activation and CGRP release may be relevant to the mechanism by which alcohol ingestion triggers migraine attacks.

Pain pharmacology in migraine: focus on CGRP and CGRP receptors.

Over the last 100 years, the discovery of new analgesics has been a complex and difficult task. However, remarkable progress in the identification of novel molecular targets relevant for pain medicines has been reported. Here we will focus on the neuropeptide calcitonin generelated peptide (CGRP) and its receptors (CGRP-R) because of their role in migraine mechanism and migraine therapy. Recent preclinical and clinical data on the localisation, regulation and plasma levels of CGRP and on the function of CGRP-R will be summarised. The reviewed findings highlight the major function of CGRP in migraine and the use of CGRP-R antagonists as a novel approach for the treatment of migraine attack and, perhaps, as migraine prophylactic medicines.