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The diagnostic value of white matter hyperintensities (WMH) in different types of migraineare unknown. To evaluate the WMH pattern of different subtypes in migraine patients with no vascular risk factors. 92 migraine patients (73 females, mean age 34.6 ± 8.9; 61 episodic migraine, 31 chronic migraine, 36 migraine with aura, 56 migraine without aura) without vascular risk factors underwent brain MRI (3 T). We also included a matched healthy control group with no migraine (n = 24). The prevalence of WMH in different types of migraine was similar and ranged from 38.7 to 44.4%; the control group showed no WMH at all. Lesions were located within frontal, parietal and temporal lobes (in order of decreasing incidence) in juxtacortical and/or deep white matter. WMH appeared as round or slightly elongated foci with a median size of 2.5 mm [1.5; 3]. Total number, size and prevalence of WMH by lobes and white matter regions were similar between groups, and no interaction with age or sex was found. The number of lesions within the frontal lobe juxtacortical white matter correlated with the age of patients (r = 0.331, p = 0.001) and the duration since migraine onset (r = 0.264, p = 0.012). Patients with different migraine subtypes and without vascular risk factors are characterized by a similar pattern of WMH in the absence of subclinical infarctions or microbleedings. Therefore, WMH have no relevant prognostic value regarding the course of migraine and vascular complications. WMH pattern may be used to differentiate migraine as a primary disorder and other disorders with migraine-like headache and WMH.

Epidemiological estimates indicate that individuals with epilepsy are more likely to experience headaches, including migraine, than individuals without epilepsy. Headaches can be temporally unrelated to seizures, or can occur before, during or after an episode; seizures and migraine attacks are mostly not temporally linked. The pathophysiological links between headaches (including migraine) and epilepsy are complex and have not yet been fully elucidated. Correct diagnoses and appropriate treatment of headaches in individuals with epilepsy is essential, as headaches can contribute substantially to disease burden. Here, we review the insights that have been made into the associations between headache and epilepsy over the past 5 years, including information on the pathophysiological mechanisms and genetic variants that link the two disorders. We also discuss the current best practice for the management of headaches co-occurring with epilepsy and highlight future challenges for this area of research.Headaches and epilepsy frequently co-exist in the same individual, but the pathophysiological mechanisms underlying this relationship are not yet clear. Here, the authors discuss the epidemiological and pathophysiological links between epilepsy and headache, and apply this knowledge to the clinical management of the two disorders.

Migraine is a prevalent disorder, affecting 15.1% of the world’s population. In most cases, the migraine attacks are sporadic; however, some individuals experience a gradual increase in attack frequency over time, and up to 2% of the general population develop chronic migraine. The mechanisms underlying this chronicity are unresolved but are hypothesized to involve a degree of inflammation. In this article, we review the relevant literature related to inflammation and migraine, from the initiation of attacks to chronification. We propose that the increase in migraine frequency leading to chronic migraine involves neurogenic neuroinflammation, possibly entailing increased expression of cytokines via activation of protein kinases in neurons and glial cells of the trigeminovascular system. We present evidence from preclinical research that supports this view and discuss the implications for migraine therapy.

Migraine is a complex disorder with multigenic inheritance and is characterized by the cardinal symptom of unilateral headache. Many genes are responsible for increasing the susceptibility of disease within different populations. Therefore, our primary aim in this review was to catalog the many genes that have been studied in India and after collecting the necessary information, we calculated a more precise risk relationship between an identified variation and migraine. The gene and its associated risk variant were discovered in the Indian population using a PRISMA-based systematic literature review guideline from online databases such as PubMed & Google Scholar. We constructed pooled odds ratios with 95% confidence intervals using multiple genetic models. Also, we looked for heterogeneity using Cochran's Q Test and the I2 statistic. Publication bias was analyzed using Begg's and Egger's tests. A p-value less than 0.05 was judged to be statistically significant for all tests. After a critical analysis, a total of 24 studies explored about 21 genes with 31 variants out of which only nine genes have been studied more than two times in the Indian population and thus were found eligible for the meta-analysis. It has been found, that the ACE- DD variant (allele model: OR: 1.37 [1.11–1.69], I 2  = 0%/ fixed model), ESR1- PvuII (allele model: OR: 1.47 [1.24–1.74], I 2  = 0%/ fixed model) significantly increases the risk of migraine in Indian population. Also, a protective role of the LRP1 -rs11172113variant was observed for both migraine and its clinical subtype i.e., MA (allelic model: OR of 0.65 [0.50–0.83] I 2  = 44% and allele: OR: 0.54 [0.37–0.78], I 2  = 52%) respectively. Overall, the results of this meta-analysis indicated that the ACE-DD variant and the ESR1-PvuII were associated with an increased risk of migraine in the Indian community, while the LRP1-rs11172113 variant was associated with protection from migraine in this population.

Key Points A key feature of migraine is that various factors can trigger an attack, thereby providing a unique opportunity to investigate disease mechanisms by experimentally inducing migraine attacks Experimental studies in humans have provided evidence that a number of signalling compounds, including nitric oxide and the neuropeptides CGRP and PACAP, are involved in migraine pathophysiology Migraine can be elicited by activation of cGMP and cAMP signalling pathways Provocation studies have predicted the efficacy of CGRP-based small molecules and antibody-based antimigraine treatment Migraine provocation by PACAP suggests that the PACAP receptor is a novel target for migraine treatment Experimental studies in humans, combined with advanced neuroimaging, will help to improve our understanding of basic migraine neurobiology and guide the search for new mechanism-based antimigraine drugs In the ongoing search for new and better migraine treatments, human models have a key role in the discovery of novel targets for antimigraine drugs. This Review summarizes existing experimental models of migraine in humans, and describes the development and use of these models in the identification of key molecular pathways, biomarkers and drug targets. Migraine is a complex disorder characterized by recurrent episodes of headache, and is one of the most prevalent and disabling neurological disorders. A key feature of migraine is that various factors can trigger an attack, and this phenomenon provides a unique opportunity to investigate disease mechanisms by experimentally inducing migraine attacks. In this Review, we summarize the existing experimental models of migraine in humans, including those that exploit nitric oxide, histamine, neuropeptide and prostaglandin signalling. We describe the development and use of these models in the discovery of molecular pathways that are responsible for initiation of migraine attacks. Combining experimental human models with advanced imaging techniques might help to identify biomarkers of migraine, and in the ongoing search for new and better migraine treatments, human models will have a key role in the discovery of future targets for more-specific and more-effective mechanism-based antimigraine drugs.

Migraine is a common, chronic, disorder that is typically characterized by recurrent disabling attacks of headache and accompanying symptoms, including aura. The aetiology is multifactorial with rare monogenic variants. Depression, epilepsy, stroke and myocardial infarction are comorbid diseases. Spreading depolarization probably causes aura and possibly also triggers trigeminal sensory activation, the underlying mechanism for the headache. Despite earlier beliefs, vasodilation is only a secondary phenomenon and vasoconstriction is not essential for antimigraine efficacy. Management includes analgesics or NSAIDs for mild attacks, and, for moderate or severe attacks, triptans or 5HT 1B/1D receptor agonists. Because of cardiovascular safety concerns, unreliable efficacy and tolerability issues, use of ergots to abort attacks has nearly vanished in most countries. CGRP receptor antagonists (gepants) and lasmiditan, a selective 5HT1 F receptor agonist, have emerged as effective acute treatments. Intramuscular onabotulinumtoxinA may be helpful in chronic migraine (migraine on ≥15 days per month) and monoclonal antibodies targeting CGRP or its receptor, as well as two gepants, have proven effective and well tolerated for the preventive treatment of migraine. Several neuromodulation modalities have been approved for acute and/or preventive migraine treatment. The emergence of new treatment targets and therapies illustrates the bright future for migraine management. Migraine is a common headache disorder. This Primer by Ferrari and colleagues summarizes the epidemiology, pathophysiology, diagnosis and treatment of migraine. Moreover, quality of life issues faced by patients with migraine and future research avenues are discussed.

Medication overuse headache (MOH) is a secondary headache disorder attributed to overuse of acute headache medications by a person with an underlying headache disorder, usually migraine or tension-type headache. MOH is common among individuals with 15 or more headache days per month. Although MOH is associated with substantial disability and reductions in quality of life, this condition is often under-recognized. As MOH is both preventable and treatable, it warrants greater attention and awareness. The diagnosis of MOH is based on the history and an unremarkable neurological examination, and is made according to the diagnostic criteria of the International Classification of Headache Disorders third edition (ICHD-3). Pathophysiological mechanisms of MOH include altered descending pain modulation, central sensitization and biobehavioural factors. Treatment of MOH includes the use of headache preventive therapies, but essential to success is eliminating the cause, by reducing the frequency of use of acute headache medication, and perhaps withdrawing the overused medication altogether. Appropriate treatment is usually highly effective, leading to reduced headache burden and acute medication consumption. Medication overuse headache is a secondary headache disorder that occurs in those with a primary headache disorder (commonly tension-type headache or migraine). This Primer reviews the epidemiology, pathophysiology, diagnosis and treatment of medication overuse headache, and discusses how this disorder affects the quality of life of patients.

Tension-type headache (TTH) is the most prevalent neurological disorder worldwide and is characterized by recurrent headaches of mild to moderate intensity, bilateral location, pressing or tightening quality, and no aggravation by routine physical activity. Diagnosis is based on headache history and the exclusion of alternative diagnoses, with clinical criteria provided by the International Classification of Headache Disorders , third edition. Although the biological underpinnings remain unresolved, it seems likely that peripheral mechanisms are responsible for the genesis of pain in TTH, whereas central sensitization may be involved in transformation from episodic to chronic TTH. Pharmacological therapy is the mainstay of clinical management and can be divided into acute and preventive treatments. Simple analgesics have evidence-based effectiveness and are widely regarded as first-line medications for the acute treatment of TTH. Preventive treatment should be considered in individuals with frequent episodic and chronic TTH, and if simple analgesics are ineffective, poorly tolerated or contraindicated. Recommended preventive treatments include amitriptyline, venlafaxine and mirtazapine, as well as some selected non-pharmacological therapies. Despite the widespread prevalence and associated disability of TTH, little progress has been made since the early 2000s owing to a lack of attention and resource allocation by scientists, funding bodies and the pharmaceutical industry. This Primer discusses the epidemiology, pathophysiology, diagnosis and treatment of tension-type headache. This Primer also summarizes the quality of life issues faced by patients and future research priorities in this field.

Cluster headache is a debilitating primary headache disorder that affects approximately 0.1% of the population worldwide. Cluster headache attacks involve severe unilateral pain in the trigeminal distribution together with ipsilateral cranial autonomic features and a sense of agitation. Acute treatments are available and are effective in just over half of the patients. Until recently, preventive medications were borrowed from non-headache indications, so management of cluster headache is challenging. However, as our understanding of cluster headache pathophysiology has evolved on the basis of key bench and neuroimaging studies, crucial neuropeptides and brain structures have been identified as emerging treatment targets. In this Review, we provide an overview of what is known about the pathophysiology of cluster headache and discuss the existing treatment options and their mechanisms of action. Existing acute treatments include triptans and high-flow oxygen, interim treatment options include corticosteroids in oral form or for greater occipital nerve block, and preventive treatments include verapamil, lithium, melatonin and topiramate. We also consider emerging treatment options, including calcitonin gene-related peptide antibodies, non-invasive vagus nerve stimulation, sphenopalatine ganglion stimulation and somatostatin receptor agonists, discuss how evidence from trials of these emerging treatments provides insights into the pathophysiology of cluster headache and highlight areas for future research.In this Review, Wei and Goadsby discuss the pathophysiology of cluster headache, the treatments available and their mechanisms, and the insights being provided by results from trials of emerging treatments, which indicate mechanistic differences between episodic and chronic cluster headache.

Headache is increasingly being reported as a detrimental effect of mobile phone (MP) use. However, studies aimed to investigate the association between MP use and headache yielded conflicting results. To assess the consistency of the data on the topic, we performed a systematic review and meta-analysis of the available cross-sectional studies. Published literature from PubMed and other databases were retrieved and screened, and 7 cross-sectional studies were finally included in this meta-analysis. The pooled odds ratio (OR) and 95% confidence interval (CI) were calculated. We found that the risk of headache was increased by 38% in MP user compared with non-MP user (OR, 1.38; 95% CI, 1.18–1.61, p  < 0.001). Among MP users, the risk of headache was also increased in those who had longer daily call duration (2–15 min vs. <2 min: OR, 1.62; 95% CI, 1.34–1.98, p  < 0.001; >15 min vs. <2 min: OR, 2.50; 95% CI, 1.76–3.54, p  < 0.001) and higher daily call frequency (2–4 calls vs. <2 calls: OR, 1.37; 95% CI, 1.07–1.76, p  < 0.001; >4 calls vs. <2 calls: OR, 2.52; 95% CI, 1.78–3.58, p  < 0.001). Our data indicate that MP use is significantly associated with headache, further epidemiologic and experimental studies are required to affirm and understand this association.