Differences in homeostatic model assessment (HOMA) values and insulin levels after vitamin D supplementation in healthy men: a double-blind randomized controlled trial.

Vitamin D is thought to play a role in glucose metabolism. The aim of the present study was to determine the effect of vitamin D supplementation on markers of insulin sensitivity and inflammation in men without diabetes with vitamin D deficiency/insufficiency. In this 1-year double-blind randomized controlled trial, 130 men aged 20-65 years (mean age 47.52 ± 11.84 years) with serum 25-hydroxyvitamin D levels <50 nmol/l (mean 38.89 ± 8.64 nmol/l) were randomized to treatment (100 000 IU vitamin D bimonthly) or placebo. Anthropometric measurements, demographic questionnaires, and blood indices (fasting glucose, insulin, high-sensitivity C-reactive protein, lipids) were collected and repeated after 6 and 12 months. The compliance rate was 98.5%. Multivariate models, adjusted for baseline levels, age, body mass index, sun exposure, physical activity and LDL, showed significant differences in insulin and homeostatic model assessment of insulin resistance (HOMA-IR) values between groups. Levels of insulin and HOMA-IR values remained steady during the study period in the treatment group but increased by 16% in the control group (p = 0.038 and p = 0.048, respectively). Vitamin D supplementation administered for 12 months in healthy men maintained insulin levels and HOMA-IR values relative to the increase in the control group. Further studies are needed to establish the long-term effect of vitamin D supplementation on the risk of diabetes.

Identifying the threshold for vitamin D insufficiency in relation to cardiometabolic markers.

BACKGROUND AND AIMS: To determine the association between vitamin D status and cardiometabolic indicators, and to determine the vitamin threshold that affects these parameters. METHODS AND RESULTS: High-tech employees were recruited from a periodic occupational health examination clinic and via the study's website. Diastolic and systolic blood pressure (DBP, SBP), body mass index (BMI), and waist circumference were measured. Serum concentrations of 25(OH)D, fasting plasma insulin (FPI), fasting plasma glucose (FPG), triglycerides (TG), and high sensitive C-Reactive Protein (hs-CRP) were measured in fasting blood samples. Of the 400 men who agreed to participate, 358 (90%) completed the study. Mean age was 48.8 ± 10.2 y, BMI 27.0 ± 3.8 k/m(2), serum 25(OH)D 22.1 ± 7.9 ng/l. Deficiency (defined as serum 25(OH)D < 12 ng/ml) was observed among 10.6%, 29.9% were insufficient (12 < 25(OH)D < 20 ng/ml), and 59.5% had sufficient levels (25(OH)D > 20 ng/ml). BMI, waist circumference, FPI, HOMA-IR, TG, hs-CRP levels, DBP, and SBP were negatively associated with serum 25(OH)D. A curved linear association was found with insulin and HOMA-IR with a significant spline knot at 11 ng/ml. For hs-CRP a spline knot at 14 ng/ml was observed. TG, SBP, and DBP exhibited linear associations with 25(OH)D. CONCLUSIONS: Vitamin D status is related to cardiometabolic indicators in healthy men. We suggest a 25(OH)D threshold of 11-14 ng/ml for these outcomes. Future studies are required to address temporal relationships and the impact of vitamin D supplementation.

Preventive treatment in migraine and the new US guidelines.

Migraine headaches are among the most common headache disorders seen in various practices. The prevalence of migraine headaches is 18% in women and 6% in men. While millions of Americans suffer from migraine headaches, roughly 3%-13% of identified migraine patients are on preventive therapy, while an estimated 38% actually need a preventive agent. The challenge among physicians is not only when to start a daily preventive agent but which preventive agent to choose. Circumstances warranting prevention have been described in the past, and in 2012, a new set of guidelines with an evidence review on preventive medications was published. A second set of guidelines provided evidence on nonsteroidal anti-inflammatory drugs, herbs, minerals, and vitamins for prevention of episodic migraine. This article describes the updated US guidelines for the prevention of migraines and also outlines the major studies from which these guidelines were derived.

Link between confusional migraine, hemiplegic migraine and episodic ataxia type 2: hypothesis, family genealogy, gene typing and classification.

An association between hemiplegic migraine (HM) and episodic ataxia type 2 (EA2) has been described; both disorders are linked to mutations in the CACNA1A gene. Although confusion occurs in 21% of patients with HM, we found only one case in the literature of confusional episodes associated with ataxia without hemiplegia. These findings raise the possibility of confusional episodes being part of both the HM and EA2 phenotype. However, a patient with episodic ataxia, confusional spells and CACNA1A gene mutations has not been identified. We describe four individuals, spanning three generations of a family, with episodic ataxia without hemiplegia and confusion, in association with a CACNA1A mutation. We follow with a description of the relationship between the CACNA1A mutations and the three syndromes, suggesting a potential need for a new classification in which the conditions can be subsumed.

Key points in migraine prophylaxis: patient perspective.

Migraine is a chronic neurological condition with heterogeneous presentation. It is associated with significant pain, disability, and diminished quality of life in a large proportion of patients. Patients with severe and/or frequent migraines require prophylaxis, which implies daily administration of anti-migraine compounds for several months, with potential adverse events or contraindications. This paper reviews the main factors influencing patient acceptance of anti-migraine prophylaxis, providing practical suggestions to maximize patient agreement with, and adherence to, preventive treatment.

New daily persistent headache in the paediatric population.

We conducted a clinic-based study focusing on the clinical features of new-onset chronic daily headaches (CDH) in children and adolescents. The clinical records and headache diaries of 306 children and adolescents were reviewed, to identify 187 with CDH. Relevant information was transferred to a standardized form that included operational criteria for the diagnoses of the headaches. Since we were interested in describing the clinical features of these headaches, we followed the criteria A and B of the 2nd edn of the International Classification of Headache Disorders (ICHD-2) and refer to them as new daily persistent headaches (NDPH) regardless of the presence of migraine features (therefore, this is a modified version of the ICHD-2 criteria). From the 56 adolescents with NDPH, most (91.8%) did not overuse medications. Nearly half (48.1%) reported they could recall the month when their headaches started. NDPH was more common than chronic tension-type headache in both adolescents overusing and not overusing medication. Individuals with NDPH had headaches fulfilling criteria for migraine on an average of 18.5 days per month. On most days, they had migraine-associated symptoms (one of nausea, photophobia or phonophobia)). NDPH is common in children and adolescents with CDH. Most subjects do not overuse medication. Migraine features are common.

Zolmitriptan nasal spray in the acute treatment of cluster headache: a double-blind study.

OBJECTIVE: To evaluate the efficacy and tolerability of zolmitriptan 5 mg and 10 mg nasal spray (ZNS) vs placebo in the acute treatment of cluster headache. Design/ METHODS: We conducted a multicenter, double-blind, randomized, three-period crossover study using ZNS 5 mg, ZNS 10 mg, and placebo. Headache intensity was rated by a 5-point scale: none, mild, moderate, severe, or very severe. The primary efficacy measure was headache response (pain reduced from moderate, severe, or very severe at baseline, to mild or none) at 30 minutes. Logistic regression was used to account for treatment period effect as well as for cluster headache subtype effect. RESULTS: A total of 52 adult patients treated 151 attacks. For the primary endpoint, both doses reached significance at 30 minutes (placebo = 30%, ZNS 5 mg = 50%, ZNS 10 mg = 63.3%). For headache relief, ZNS 10 mg separated from placebo at 10 minutes (24.5% vs 10%). Zolmitriptan 5 mg separated from placebo at 20 minutes (38.5% vs 20%). For pain-free status, ZNS 10 mg was superior to placebo at 15 minutes (22.0% vs 6%). Both doses had higher pain-free rates than placebo at 30 minutes (placebo = 20%, ZNS 5 mg = 38.5%, ZNS 10 mg = 46.9%). Side effects were mild and seen in 16% of those attacks treated with placebo, 25% of attacks treated with ZNS 5 mg, and 32.7% treated with ZNS 10 mg. CONCLUSIONS/RELEVANCE: Zolmitriptan nasal spray, at doses of 5 and 10 mg, is effective and tolerable for the acute treatment of cluster headache.

The patent foramen ovale-migraine question.

A strong association between migraine with aura and patent foramen ovale (PFO) with shunting has been suggested. Similarly, an association of migraine with aura and Osler-Weber-Rendu disease, probably also due to shunting though pulmonary arteriovenous malformations has been proposed. PFOs are also comorbid with cryptogenic strokes, refractory hypoxaemia in right ventricular infarction or severe lung disease, orthostatic oxygen desaturation and decompression illness in scuba divers.Multiple open-label, retrospective and case-controlled studies of PFO closure report improvement of migraine with aura. MIST, the only prospective sham-controlled study of PFO closure for migraine with aura, did not reach its primary endpoint for migraine resolution, although it clearly demonstrated an association between migraine with aura and the severity of the PFO shunt. One reported secondary endpoint showed a significant 42% reduction of migraine days, suggesting the need for further randomised, sham-controlled PFO closure studies.

Post-traumatic headache: emphasis on chronic types following mild closed head injury.

The syndrome known as chronic post-traumatic headache (CPTH) is controversial, particularly when it occurs following mild closed head injury or "whiplash". Problems with the diagnosis include issues related to classification, epidemiology, pathophysiology (psychogenic vs. organic) and treatment. In addition, there are cultural differences that may influence prevalence and diagnosis, as in some countries with little medico-legal recourse the disorder is virtually unknown. In this paper we review some of these controversies clinicians are left to formulate their own understanding based on available evidence and clinical experience. This is perhaps as it should be given that the best practice combines knowledge of the evidence with individual clinical experience.

Migraine and adiponectin: is there a connection?

Migraine is a common disorder, characterized by recurrent episodes of headache and associated symptoms. The full pathophysiology of migraine is incompletely delineated. Current theories suggest that it is a neurovascular disorder involving cortical depression, neurogenic inflammation and vasodilation. Various neuropeptides and cytokines have been implicated in the pathophysiology of migraine including calcitonin gene-related peptide, interleukin (IL)-1, IL-6 and tumour necrosis factor (TNF)-alpha. There is evidence demonstrating an association between migraine and processes associated with inflammation, atherosclerosis, immunity and insulin sensitivity. Similarly, adiponectin, an adipocytokine secreted by adipose tissue, has protective roles against the development of insulin resistance, dyslipidaemia and atherosclerosis and exhibits anti-inflammatory properties. The anti-inflammatory activities of adiponectin include inhibition of IL-6 and TNF-induced IL-8 formation, as well as induction of the anti-inflammatory cytokines IL-10 and IL-1 receptor antagonist. Adiponectin levels are also inversely correlated with C-reactive protein (CRP), TNF-alpha and IL-6 levels. Likewise, recent studies have shown a possible correlation between CRP, TNF-alpha and IL-6 and migraine attacks. In addition, insulin sensitivity is impaired in migraine and obesity is a risk factor for the transformation from episodic to chronic migraine. In this review we discuss the basic science of adiponectin and its potential connection to the pathophysiology of migraine. Future research may focus on how adiponectin levels are potentially altered during migraine attacks, and how that information can be potentially translated into migraine therapy.

The International Classification of Headache Disorders revised criteria for chronic migraine­field testing in a headache specialty clinic.

In the absence of a biological marker and expert consensus on the best approach to classify chronic migraine (CM), recent revised criteria for this disease has been proposed by the Headache Classification Committee of the International Headache Society. This revised criteria for CM is now presented in the Appendix. Herein we field test the revised criteria for CM. We included individuals with transformed migraine with or without medication overuse (TM+ and TM­), according to the criteria proposed by Silberstein and Lipton, since this criterion has been largely used before the Second Edition of the International Classification of the Headache Disorders (ICHD-2). We assessed the proportion of subjects that fulfilled ICHD-2 criteria for CM or probable chronic migraine with probable medication overuse (CM+), as well as the revised ICHD-2 (ICHD-2R) criteria for CM (15 days of headache, 8 days of migraine or migraine-specific acute medication use­ergotamine or triptans). We also tested the ICHD-2R vs. three proposals. In proposal 1, CM/CM+ would require at least 15 days of migraine or probable migraine per month. Proposal 2 required 15 days of headache per month and at least 50% of these days were migraine or probable migraine. Proposal 3 required 15 days of headache and at least 8 days of migraine or probable migraine per month. Of the 158 patients with TM­, just 5.6% met ICHD-2 criteria for CM. According to the ICHD-2R, a total of 92.4% met criteria for CM (P < 0.001 vs. ICHD-2). The ICHD-2R criterion performed better than proposal 1 (47.8% of agreement, P < 0.01) and was not statistically different from proposals 2 (87.9%) and 3 (94.9%). Subjects with TM+ should be classified as medication overuse headache (MOH), and not CM+, according to the ICHD-2R. Nonetheless, we assessed the proportion of them who had 8 days of migraine per month. Of the 399 individuals with TM+, just 10.2% could be classified as CM+ in the ICHD-2. However, most (349, 86.9%) had 8 days of migraine per month and could be classified as MOH and probable CM in the ICHD-2R(P < 0.001 vs. ICHD-2). We conclude that the ICHD-2R addresses most of the criticism towards the ICHD-2 and should be adopted in clinical practice and research. In the population where use of specific acute migraine medications is less common, the agreement between ICHD-2R CM and TM may be less robust.

Cluster-like headache secondary to idiopathic intracranial hypertension.

Few cluster-like headaches have been described. Idiopathic intracranial hypertension (IIH) presents with headaches in more than 90% of patients. We describe a male patient with new onset cluster-like headache secondary or related to IIH.

Which triptan for which patient?

The triptans were developed for the acute treatment of a migraine attack and have revolutionised the treatment of this disorder since their introduction in the early 1990s. Although their mechanisms of actions are similar and based on the stimulation of specific serotonin (5-hydroxytryptamine) receptors including peripheral 1B and central and peripheral 1D subtypes, each triptan has its own distinctive pK properties that result in different profiles of efficacy and tolerability. Triptans work by decreasing neurogenic inflammation peripherally in the meninges, vasoconstriction of meningeal vessels and by modulating secondary-order neurons in the brain stem. Studies of patient attitudes towards their acute care regimens reveal that they are often unhappy with some aspect of their treatment-usually the speed of action, degree of efficacy, presence of adverse events and the need for additional doses due to frequent and/or rapid recurrence. The majority of patients, when asked in a clinical trial performed at tertiary care headache centres, are willing to try another triptan. The aim of this article is to review the pK and clinical characteristics of these acute care, migraine-specific triptan medications and discuss how their individual characteristics lead to their preferred choice in various clinical scenarios. The pK and clinical efficacy data presented are taken from older published studies in which triptans were compared to placebo or each other, but the patients were asked to wait till the headache reached moderate or severe intensity prior to taking study medication. New studies have looked at early treatment paradigms and result in better efficacy data, but are difficult to compare due to different endpoints.

Headache prevention outcome and body mass index.

A population-based longitudinal study suggests that obesity is a strong risk factor for the development of headaches on 15 or more days per month. Little is know about the influence of weight on the response to headache preventive treatment. Herein we prospectively assessed the influence of the baseline body mass index (BMI) on the response to headache preventive treatment. We included adults with episodic or chronic migraine (ICHD-2), or transformed migraine (Silberstein and Lipton criteria) that sought care in a headache clinic. BMI was assessed in the first visit. Baseline information included headache frequency, number of days with severe headache (prospectively obtained over 1 month), and headache-related disability (HIT-6). The same information was obtained after 3 months of preventive treatment. Subjects were categorized based on BMI in: normal weight (/=30). We contrasted the headache end-points using anova with post-test and Kruskal-Wallis with post-test. We used logistic regression to model BMI and headache parameters adjusting for covariates. Our sample consisted of 176 subjects (79.5% women, mean of 44.4 years). At baseline 40.9% had normal weight, 29.5% were overweight and 27.3% were obese. No significant differences were observed in the number of headache days at baseline. After treatment, frequency declined in the entire population, but no significant differences were found by BMI group. Regarding the number of days with severe pain per month, there were also no significant differences at baseline (normal = 6.1, overweight = 6.5, obese = 6.7), and improvement overall (P = 0.01). However, changes were greater in the obese (reduction in 2.7 days with treatment) and overweight (3.9) vs. normal (1.5, P < 0.01). Finally, HIT scores at baseline did not differ by BMI group (normal weight = 63.8, overweight = 64.1, obese = 63.6). However, compared with the normal weighted group, change in HIT scores (follow-up baseline) were greater in the obese (6.4 vs. 3.5, P < 0.05) and overweight groups (6.8 vs. 3.5, P < 0.05). In the logistic regression model, BMI did not account for changes in disability, headache frequency, or in the number of days with severe headache per month, after adjusting for covariates. Contrary to what we hypothesized, obesity at baseline does not seem to be related to follow-up refractoriness to preventive treatment.

Field testing alternative criteria for chronic migraine.

The criteria for chronic migraine (CM), as proposed by the Second Edition of the International Classification of Headache Disorders (ICHD-2) is very restrictive, excluding most patients that evolve from episodic migraine. In this study we empirically tested three recent proposals for revised criteria for CM. We included individuals with transformed migraine (TM) with or without medication overuse, according to the criteria proposed by Silberstein and Lipton. All individuals had headache calendars for at least three consecutive months. We assessed the proportion of subjects that fulfilled ICHD-2 criteria for CM or probable chronic migraine with probable medication overuse (CM+). We also tested three proposals for making the CM criteria more inclusive. In proposal 1, CM/CM + would require at least 15 days of migraine or probable migraine per month. Proposal 2 suggests that CM/CM + would be classified in those with >or= 15 days of headache per month, where at least 50% of these days are migraine or probable migraine. Proposal 3 suggests that CM/CM + would be classified in those with chronic daily headache and at least 8 days of migraine or probable migraine per month. Among TM sufferers, 399 (62.5%) had TM with medication overuse, and just 10.2% were classified as CM+ 158 (37.5%) had TM without medication overuse; just nine (5.6%) met current ICHD-2 criteria for CM. Using the alternative criteria, proposal 1 included 48.7% of patients with TM without medication overuse; proposal 2 captured 88%, and proposal 3 classified 94.9% of these patients. For TM with medication overuse, the proportions for proposals 1-3 were, respectively, 37%, 81% and 91%. The differences were statistically significant, favouring proposal 3. Consistently, criteria for CM and CM+ should be revised to require at least 8 days of migraine or probable migraine per month, in individuals with 15 or more days of headache per month.