Patrizia Ripa

Migraine and Hemorrhagic Stroke A Meta-analysis

Background and Purpose— Several studies have assessed the possible increased risk of hemorrhagic stroke in migraineurs, drawing differing conclusions. No meta-analysis on the topic has been published to date. Methods— Multiple electronic databases (MEDLINE, EMBASE, Science Citation Index, and the Cochrane Library) were systematically searched up to March 2013 for studies dealing with migraine and hemorrhagic stroke. We selected case–control and cohort studies with a clear definition of the diagnostic criteria for migraine and hemorrhagic stroke, using an adjusted model or a matching procedure that could control for potential confounders, and reporting effect estimates with 95% confidence intervals (CIs) or enough data to allow calculation of those numbers. Adjusted odds ratios and hazard ratios were used to estimate effect size. Results— Of 11 264 records, we identified 8 studies (4 case–control and 4 cohort studies) involving a total of 1600 hemorrhagic strokes, which were included in the meta-analysis. The overall pooled adjusted effect estimate of hemorrhagic stroke in subjects with any migraine versus control subjects was 1.48 (95% CI, 1.16–1.88; P=0.002), with moderate statistical heterogeneity (I2=54.7%; P value for Q test=0.031). The risk of hemorrhagic stroke in subjects with migraine with aura (1.62; 95% CI, 0.87–3.03; P=0.129) was not significant. Compared with control subjects, the risk of hemorrhagic stroke was greater in females with any migraine (1.55; 95% CI, 1.16–2.07; P=0.003) and in female migraineurs aged less than 45 years (1.57; 95% CI, 1.10–2.24; P=0.012). Conclusions— Available studies suggest that subjects with migraine have an increased risk of hemorrhagic stroke. Further studies are needed to address the hemorrhagic stroke risk according to migraine type, age, sex, and hemorrhagic stroke type.

Peripheral vascular dysfunction in migraine: a review

Numerous studies have indicated an increased risk of vascular disease among migraineurs. Alterations in endothelial and arterial function, which predispose to atherosclerosis and cardiovascular diseases, have been suggested as an important link between migraine and vascular disease. However, the available evidence is inconsistent. We aimed to review and summarize the published evidence about the peripheral vascular dysfunction of migraineurs.We systematically searched in BIOSIS, the Cochrane database, Embase, Google scholar, ISI Web of Science, and Medline to identify articles, published up to April 2013, evaluating the endothelial and arterial function of migraineurs.Several lines of evidence for vascular dysfunction were reported in migraineurs. Findings regarding endothelial function are particularly controversial since studies variously indicated the presence of endothelial dysfunction in migraineurs, the absence of any difference in endothelial function between migraineurs and non-migraineurs, and even an enhanced endothelial function in migraineurs. Reports on arterial function are more consistent and suggest that functional properties of large arteries are altered in migraineurs.Peripheral vascular function, particularly arterial function, is a promising non-invasive indicator of the vascular health of subjects with migraine. However, further targeted research is needed to understand whether altered arterial function explains the increased risk of vascular disease among patients with migraine.

Migraine and risk of ischaemic heart disease: a systematic review and meta-analysis of observational studies

Several studies have assessed the risk of ischaemic heart diseases in migraineurs, drawing different conclusions. To define and update the issue, a systematic review and meta‐analysis of the available observational studies was performed.

Migraine and body mass index categories: a systematic review and meta-analysis of observational studies

BackgroundSeveral studies have assessed the associations between migraine and underweight, pre-obesity or obesity, with conflicting results. To assess the consistency of the data on the topic, we performed a systematic review and meta-analysis of the available observational studies.MethodsMultiple electronic databases were systematically searched up to October 2014 for studies assessing the association between migraine and body mass index categories (underweight, pre-obesity, or obesity).ResultsOut of 2,022 records, we included 15 studies. When considering the 11 studies following the World Health Organization BMI cutoffs, we found an increased risk of having migraine in underweight subjects (pooled adjusted effect estimate [PAEE] 1.21; 95% CI, 1.07-1.37; P = 0.002) and in obese women (PAEE 1.44; 95% CI, 1.05-1.97; P = 0.023) as compared with normal weight subjects; additionally, pre-obese subjects had an increased risk of having chronic migraine (PAEE 1.39; 95% CI, 1.13-1.71; P = 0.002). When considering all the 15 studies, we additionally found an increased risk of having migraine in obese as compared with normal weight subjects (PAEE 1.14; 95% CI, 1.02-1.27; P = 0.017); additionally, obese subjects had an increased risk of having chronic migraine (PAEE 1.75; 95% CI, 1.33-2.29; P < 0.001). The pooled analysis did not indicate an increased risk of having migraine in pre-obese subjects.ConclusionsThe meta-analysis of the available observational studies suggested an association between migraine and obesity likely mediated by gender and migraine frequency. Further studies taking into account gender, migraine type, frequency, activity, and duration could provide more robust evidence.

Migraine in menopausal women: a systematic review.

Evidence suggests that migraine activity is influenced by hormonal factors, and particularly by estrogen levels, but relatively few studies have investigated the prevalence and characteristics of migraine according to the menopausal status. Overall, population-based studies have shown an improvement of migraine after menopause, with a possible increase in perimenopause. On the contrary, the studies performed on patients referring to headache centers have shown no improvement or even worsening of migraine. Menopause etiology may play a role in migraine evolution during the menopausal period, with migraine improvement more likely occurring after spontaneous rather than after surgical menopause. Postmenopausal hormone replacement therapy has been found to be associated with migraine worsening in observational population-based studies. The effects of several therapeutic regimens on migraine has also been investigated, leading to nonconclusive results. To date, no specific preventive measures are recommended for menopausal women with migraine. There is a need for further research in order to clarify the relationship between migraine and hormonal changes in women, and to quantify the real burden of migraine after the menopause. Hormonal manipulation for the treatment of refractory postmenopausal migraine is still a matter of debate.

The renin–angiotensin system: a possible contributor to migraine pathogenesis and prophylaxis

The presence of a tissue-based renin-angiotensin system, independent of the systemic one, has been identified in several organs including the brain. Experimental models have suggested the involvement of the renin-angiotensin system in neurogenic inflammation, susceptibility to oxidative stress, endothelial dysfunction, and neuromodulation of nociceptive transmission, thus potentially contributing to the pathogenesis of migraine. Genetic factors that increase susceptibility to migraine may include angiotensin-converting enzyme polymorphism, although available data are controversial. Clinical studies have suggested that angiotensin-converting enzyme inhibitors and angiotensin receptor blockers may be effective in migraine prophylaxis. However, further research should clarify whether the postulated preventive effect is attributable to a pharmacological action over and above the antihypertensive effect and should test their tolerability in subjects with normal blood pressure values. In patients with contraindications or not responding to conventional prophylactic drugs and in patients with comorbid arterial hypertension, angiotensin-converting enzyme inhibitors and angiotensin receptor blockers may be used for migraine prophylaxis.

Insulin resistance in migraineurs: results from a case-control study.

Objectives: Several studies have suggested an association between migraine and insulin resistance (IR) without adequately addressing the issue according to migraine type. We assessed IR in subjects with migraine with aura (MwA) and migraine without aura (MwoA) to estimate the consistency of the possible association. Methods: In a case-control study we included case subjects with MwA and MwoA, who were consecutively selected from those referred to our Regional Headache Center from September 2011 to February 2013, and age-matched control subjects selected using general practitioners’ databases. IR was calculated by means of the homeostatic model assessment of IR (HOMA-IR), β-cell function (HOMA-B), and the quantitative insulin sensitivity check index (QUICKI) measuring glucose and insulin values in a blood sample collected in the morning after overnight fasting. Data regarding anthropometric measures, comorbidity risk factors, and migraine characteristics were also recorded. Results: We recruited 50 case subjects with MwA (38 women) and 50 with MwoA (40 women) and 50 control subjects (40 women). Proportions of arterial hypertension, cigarette smoking, hypercholesterolemia, use of oral contraceptives, and mean values of the body mass index (BMI) were similar in the three groups. We found significantly different glucose values among and within groups considering case subjects with MwA and MwoA and control subjects (4.9 ± 0.6 vs 4.7 ± 0.5 vs 4.6 ± 0.5 mmol/l; p = 0.018) in the absence of any difference in insulin (53.1 ± 24.0 vs 56.7 ± 34.4 vs 53.8 ± 24.4 pmol/l; p = 0.811), HOMA-IR (1.6 ± 0.8 vs 1.7 ± 1.0 vs 1.6 ± 0.7; p = 0.765), HOMA-B (121.4 ± 71.1 vs 149.2 ± 93.8 vs 162.8 ± 109.7; p = 0.107), and QUICKI (0.36 ± 0.03 vs 0.37 ± 0.03 vs 0.37 ± 0.03; p = 0.877) values. The logistic regression model showed increased odds of MwA in subjects exposed to the highest tertile of glucose values. This association was confirmed in the adjusted model, in which case subjects with MwA were compared with those with MwoA but not with control subjects. Conclusions: In contrast to what has been shown by the majority of the available studies, the results of our study do not support the association of migraine with IR. As our study was not population-based and several patients had low disease activity, these findings need further confirmation.

Spreading Depolarization May Link Migraine, Stroke, and Other Cardiovascular Disease

We read with interest the paper by Katharina Eikermann-Haerter about spreading depolarization as the possible link between migraine and stroke. The mechanisms underlying the relationship between migraine and stroke are still unclear, and their elucidation may provide the basis to explain the vascular risk associated with migraine. Dr. Eikermann-Haerter proposes that cortical hyperexcitability may be a mechanism common to migraine pathogenesis and to the increased risk of cerebral ischemia in migraineurs. As reported by the author, the genetic mouse models expressing migraine mutations (eg, familial hemiplegic migraine 1 and cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy) show a faster onset of ischemia-triggered spreading depolarization; an increased frequency of ischemic depolarization; enlarged infarcts with worse neurological outcomes (which could be prevented by anti-excitatory treatment); and more severe spreading of depolarizationinduced oligemia. While it is known that brain ischemia can induce spreading depression, triggers for the spontaneously occurring spreading depression in migraine remain uncertain. Recent experimental data in mice indicate that cerebral microembolism in the carotid circulation may cause a large reduction of local blood flow, which triggers cortical spreading depression without an obvious or enduring tissue signature. That same microembolic occlusion of cerebral arteries could trigger spreading depression in humans. Based on those observations and considering the association of both migraine and stroke with possible sources of cerebral microemboli, such as patent foramen ovale, it has been suggested that migraine and stroke might both be triggered by hypoperfusion and could therefore be part of a continuum of vascular complications in a subset of patients. However, because not all subjects with patent foramen ovale have migraine, the presence of cortical hyperexcitability is necessary in order to facilitate spreading depression. In our opinion, this theory, which advances the understanding of the link between migraine and stroke, should be expanded also to provide an explanation for the increased risk in migraineurs of other cardiovascular conditions such as ischemic heart disease, vascular retinopathy, and hemorrhagic stroke (Figure). Cortical hyperexcitability involves dysfunctions at the cellular level with increased influx of cations, disturbance of Na/K-ATPase activity, and decreased efflux of cations. The same alterations may be associated with functional and/or structural changes in blood vessels and hypoperfusion disorders. Similar electrophysiological changes could be present not only within the brain, but also in other tissues (eg, retina and heart), causing there the peculiar vascular vulnerability of migraineurs. Over time, and in the presence of other unknown factors, that vulnerability may lead to the development of vascular events. While no direct evidence of systemic cellular hyperexcitability in migraineurs has been documented, several lines of evidence document that, in migraineurs, the vascular system is impaired not only within the brain, but also at the systemic level. Indeed, an alteration of arterial function (greater stiffness or impaired compliance of the arterial system) and, according to some studies, also of endothelial function (altered flow-mediated dilation, reduced number of endothelial progenitor cells) has been shown in migraineurs, and summarized in a recent review. ISSN 0017-8748 doi: 10.1111/head.12436 Published by Wiley Periodicals, Inc. Headache

Migraine in pregnancy

Migraine is a predominantly female disorder. Evidence suggests that migraine activity is influenced by hormonal factors, and particularly by estrogen levels and fluctuations. During pregnancy, estrogen may reach one hundred times the normal level, whilst progesterone levels decrease, rising again towards the end of the pregnancy; however, hormonal fluctuations are not as pronounced as during the non-pregnant state[1]. Most women with migraine report an improvement of their attacks during pregnancy, from the first to the third trimestre, particularly women with a history of menstrual migraine and with migraine without aura[2]. This improvement may be due to the lack of hormonal fluctuations but also to the increased levels of natural pain-killing hormones (endorphins) induced by pregnancy[1, 3]. If no improvement is seen toward the end of the first trimestre, migraine is likely to continue throughout pregnancy and postpartum. Most women with migraine improving in pregnancy will experience attack recurrence shortly after delivery, likely in the first weeks[2]. This decline might be due to the precipitous drop in estradiol and endorphin levels occurring in the postpartum period[1, 3]. A small number of pregnant women experience a worsening of their migraine while a few others may even develop de novo migraine symptoms. In this context, migraine usually occurs during the first trimestre and is most often with aura[2]. Women continuing to experience migraine attacks throughout pregnancy may require treatment but we need to consider that not all medications used for migraine are safe in pregnancy. Paracetamol is the preferred drug for acute treatment throughout pregnancy. If paracetamol is not sufficiently effective, sporadic use of sumatriptan can be considered. NSAIDs such as ibuprofen can also be used under certain circumstances, though their intake in the first and third trimestres is associated with specific risks and contraindications. For prevention, non pharmacological approaches are always first-line treatment, and should also be used to complement any drug treatment. Some vitamins and dietary supplements have been proposed, such as, magnesium, riboflavin and coenzyme Q10. Preventive drug treatment should only be considered in the most severe cases and should include low doses of β-blockers and amitriptyline[4]. A personal history of migraine headaches can affect pregnancy outcomes. There is increasing evidence showing that migraine is a risk factor for several vascular complications during pregnancy, including gestational hypertension and preeclampsia, stroke, myocardial infarction, and venous thromboembolism; therefore, migraine should be considered a potential cardiovascular risk factor in obstetric care[5]. Further research is warranted to understand the mechanisms underlying the increased risk of vascular disease in pregnant migraineurs. Better understanding of those mechanisms could lead to potential treatment and earlier intervention, thereby reducing the health care costs of morbidity and mortality associated with adverse vascular events in this population.

Secondary headache in emergency.

Headache is one of the most common causes of access to Emergency Departments (ED). Primary headaches and headaches secondary to benign conditions (e.g headache attributed to acute sinusitis) represent the majority of cases, while secondary life-threatening headaches are less frequent. The primary objective in the ED setting is to decide whether the headache is primary or secondary and recognize serious life-threatening conditions presenting with headache and requiring prompt medical diagnosis and care, such as subarachnoid hemorrhage (SAH), intracerebral hemorrhage, cerebral venous sinus thrombosis (CVST), cervical artery dissection (CAD), brain tumors, pituitary apoplexy, spontaneous intracranial hypotension, or intracranial infections. Careful history taking and physical examination remain the most important part of the assessment of the headache patient[1]. A thorough history should investigate the onset of headache, quality, location and irradiation of pain, associated symptoms experienced before and during the headache, concomitant medical conditions, medication use, recent trauma or interventions. The examination should then target areas identified as abnormal during the headache history; funduscopy evaluation should be performed when symptoms may suggest an increased intracranial pressure; in addition, a complete neurological assessment including level of consciousness, cranial nerve testing, pupillary responses, motor strength and sensorial testing, and signs of meningeal irritation is essential[2]. Based on historical and physical findings “red flags” for secondary headache disorders are sudden onset, onset after 50 years of age, increased frequency, severity or significant change in the usual headache pattern, new onset with an underlying medical condition (such as cancer or immunodepression), concomitant signs of systemic illness (such as fever, neck stiffness, rash), focal neurologic signs or symptoms, papilledema, and head trauma[2]. In headache patients with one or more “red flags” a diagnostic workup is indicated including blood tests, neuroimaging studies, and cerebrospinal fluid (CSF) examinations, which are selected depending on the patients history and findings. Blood testing and dosage of inflammation indexes (erythrocyte sedimentation rate, C-reactive protein) should be performed in all headache patients especially when an infective or inflammatory condition is suspected. In the ED, non-contrast computed tomography (CT) is the preferred imaging study and is used to rule out hemorrhage, while most patients should perform a magnetic resonance imaging (MRI) brain scan followed by CT/MRI angiography if brain vessel disease is suspected (such as, CAD, aneurysms, and CVST). Lumbar puncture with CSF analysis may help to diagnose SAH, infection, tumor and disorders related to CSF hypertension or hypotension[3, 4]. Treatment and prognosis depend on the etiology of the headache. Prompt recognition and early treatment of secondary headache are essential to avoid some preventable complications.