Antiphospholipid syndrome and its role in pediatric cerebrovascular diseases: A literature review

Antiphospholipid syndrome (APS) or Hughes syndrome is an acquired thromboinflammatory disorder. Clinical criteria of APS diagnosis are large- and small-vessel thrombosis as well as obstetric problems; laboratory criteria are the presence of antiphospholipid antibodies (lupus anticoagulant, anticardiolipin antibodies and anti-β2-glycoprotein-1). The presence of at least 1 clinical and 1 laboratory criterion allows definitive diagnosis of APS. Primary APS is diagnosed in patients without features of connective tissue disease; secondary APS is diagnosed in patients with clinical signs of autoimmune disease. A high frequency of catastrophic APS as well as a high tendency to evolve from primary APS to secondary syndrome during the course of lupus and lupus-like disease is a feature of pediatric APS. The most characteristic clinical presentation of APS in the pediatric population is venous thrombosis, mainly in the lower limbs, and arterial thrombosis causing ischemic brain stroke. Currently, no diagnostic criteria for pediatric APS exist, which probably results in an underestimation of the problem. Similarly, no therapeutic procedures for APS specific for children have yet been established. In the present literature review, we discussed data concerning APS in children and its role in cerebrovascular diseases, including pediatric arterial ischemic stroke, migraine and cerebral venous thrombosis.     

Migraine and antiphospholipid antibodies

Antiphospholipid antibodies have been detected in patients with transient neurologic symptoms including migraine aura. The role of these antibodies in the pathogenesis of migraine is not fully understood. The available data suggest an association between the migraine-like phenomena and antiphospholipid antibodies, but not between migraine headache and antiphospholipid antibodies. To elucidate the actual role of antiphospholipid antibodies in migraine, prospective, controlled studies are needed.     

Current views of the risk of stroke for migraine with and migraine without aura

The association between migraine and stroke is complex and is a continued focus of attention. Several observational studies have identified migraine as an independent risk factor for ischemic stroke. However, a distinction should be made between migraine with and migraine without aura. The migraine-stroke association is mostly apparent for young women with migraine with aura. The association between migraine with aura and stroke is weaker in older age groups, which may be due to the fact that traditional cardiovascular risk factors are more prominent with increasing age. Most studies have not found an association between migraine without aura and ischemic stroke. Although there are several hypotheses about the biologic link between migraine with aura and ischemic stroke, the precise mechanisms remain unclear. However, because the absolute risk of stroke is low in patients with migraine with aura, and migraine without aura is likely not associated with ischemic stroke, most migraine patients will not experience a stroke event.     

Clinical implications of migraine in systemic lupus erythematosus: relation to cumulative organ damage

The aim of this study was to determine the clinical implications of migraine in systemic lupus erythematosus (SLE) using the cumulative organ damage scores (SLICC-DI). Eighty SLE, 40 rheumatoid arthritis (RA) patients and 40 controls (non SLE, nor RA out-patients), all women, were included. Migraine was defined according to the International Headache Society (IHS) criteria for neuropsychiatric SLE. Disease activity was measured by MEX-SLEDAI and cumulative organ damage by SLICC-DI. Statistics were obtained by Chi-square and Fischer's exact tests. anova was used for comparing means. Migraine was identified in 42.5% of SLE patients, compared to 12.5% of RA patients (P < 0.05) and 10.0% (P < 0.05) in the control group. In the SLE group, a significant association between migraine and Raynaud's phenomenon (P = 0.003, OR = 10.1; 95%CI 2.9-35) and antiphospholipid antibodies (P = 0.0012; OR = 7.5; 95%CI 2.5-22.9) was noted. SLE patients with active migraine had higher MEX-SLEDAI scores than SLE patients without migraine. SLE patients with past history of migraine had significantly higher SLICC scores than SLE patients without migraine. History of migraine was associated with greater organ damage. Active migraine was associated with higher disease activity, antiphospholipid antibodies and worsening of Raynaud's phenomenon. The increased cumulative organ damage in SLE patients with past history of migraine justifies the routine evaluation of migraine in clinical practice.     

Prothrombotic genetic risk factors in patients with coexisting migraine and ischemic cerebrovascular disease

The role of hemostatic elements in stroke has been clearly defined but several prothrombotic polymorphisms of hemostatic factors, important for other thromboembolic disorders, seem not to be very significant in stroke. Recently, the high prevalence of factor V Leiden in patients with stroke and a history of migraine has suggested an association between migraine and prothrombotic genetic risk factors. Stroke being a multifactorial disease, the aim of this study was to test whether prothrombotic tendencies increase the risk of stroke in patients with migraine. We determined the prevalence of four prothrombotic genetic risk factors (factor V R/Q 506, factor II 20210 G/A, decanucleotide insertion/deletion in the factor VII promoter, and the platelet HPA-1 alloantigen system) in 17 patients with coexisting ischemic cerebrovascular disease and migraine, 107 patients with ischemic cerebrovascular disease, 106 patients with migraine, and 202 control subjects. Genotyping for all polymorphisms analyzed in our study were performed after specific genomic polymerase chain reaction, and confirmed by single-strain conformation polymorphism analysis. In the group of patients with coexisting ischemic cerebrovascular disease and migraine, the prevalence of prothrombotic genotypes (factor V Leiden, 5.8%; factor II 20210 A, 0%; factor VII A1, 70.6%; and HPA-1b, 35.3%) was similar to that obtained in all other groups. We can conclude that the studied polymorphisms do not seem to be associated with the development of ischemic cerebrovascular disease in those patients with migraine.     

Migraine and Anti-Phospholipid Antibodies

Anti-phospholipid antibodies (APA), initially described with SLE, have in recent years received much attention because of an associated increased risk of thrombo-embolic disease, recurrent abortion and thrombocytopenia. Although commonly seen with SLE or other collagen vascular diseases, the antibodies frequently occur in the absence of any such disease. Neurologic complications include transient or permanent ischemic episodes, migraine or related phenomena, myelopathy and a Guillain-Barré type syndrome. In this report we describe the presenting features and clinical course of six patients with anti-phospholipid antibodies where migraine was an early and prominent symptom. All six patients, however, were recognized only after a second more serious event had occurred. As this entity becomes more widely recognized and better treatments evolve an earlier diagnosis of patients with migraine as the only manifestation of APA may prevent the development of other serious complications.     

Valsalva maneuver as migraine inducer: a case report of a woman with patent foramen ovale and an ischemic stroke

The association between patent foramen ovale, ischemic stroke, and migraine with aura is well known. It is, however, complicated and generates a considerable debate about the features and clinical consequences of the phenomenon. We report a case of a woman for whom patent foramen ovale has possibly acted as an inducer of both migraine attacks and ischemic stroke.     

Basilar and middle cerebral artery reactivity in patients with migraine

BACKGROUND: Migraine has been reported as a possible risk factor for ischemic stroke. The mechanisms underlying this association are unknown. OBJECTIVES: To evaluate cerebrovascular reactivity to hypercapnia in the anterior and posterior circulation of patients with migraine, as reduced cerebrovascular reactivity is associated with a predisposition to stroke in various clinical conditions. METHODS: Using transcranial Doppler ultrasonography, changes in flow velocity during apnea were measured in both middle cerebral arteries and in the basilar artery of 15 control subjects and 30 patients with migraine (15 with aura and 15 without aura) during an attack-free period. Cerebrovascular reactivity was evaluated using the breath-holding index, which is calculated by dividing the percent increase in mean flow velocity recorded during a breath-holding episode by its duration (in seconds) after a normal inspiration. RESULTS: Vascular reactivity in the middle cerebral arteries was similar in patients and controls and significantly lower in the basilar artery of patients with migraine with aura compared with the other 2 groups (P <.0001). CONCLUSIONS: These findings show that in patients with migraine with aura, there is an impairment in the adaptive cerebral hemodynamic mechanisms in the posterior circulation. This fact could have pathogenetic implications since the association between migraine and stroke frequently regards patients with migraine with aura, and cerebral infarcts occur more commonly in the vertebrobasilar district.     

The association between migraine and juvenile stroke: a case-control study

BACKGROUND: Several studies suggest an association between migraine and juvenile stroke. Because of some shortcomings, we designed another case-control study of a homogenous group of patients with juvenile cerebral ischemia. This study is part of a larger German epidemiological research project on the association of migraine with cerebrovascular disease. METHODS: We enrolled 160 consecutive patients under the age of 46 years with first-ever ischemic stroke or transient ischemic attack and 160 strictly sex- and age-matched controls. Patients suffering from arterial dissection, brain hemorrhage, cranial sinus thrombosis, lacunar stroke, or from migrainous infarction were excluded. Migraine was diagnosed according to the criteria of the International Headache Society by the same 2 independent interviewers. For analyzing the data, nonparametric statistical methods including odds ratio and 95% confidence interval were used. RESULTS: Migraine was a significant risk factor for juvenile stroke for the total sample with an odds ratio of 2.11 (confidence interval, 1.16 to 3.82). The odds ratio was even higher in the subgroup under the age of 35 (3.26) and in the female subgroup (2.68). We found migraine to be independent from other vascular risk factors, from etiology, and from the territory of stroke. CONCLUSION: We can confirm the findings of previous studies showing a significant association between migraine and juvenile stroke in women. Furthermore, our data suggest migraine to be an even more significant risk factor for patients under the age of 35 and to be independent from other vascular risk factors.     

Newest aspects on the association between migraine and cardiovascular disease: The role of modifying factors

Migraine has been established as a risk factor for ischemic stroke. Further evidence suggests that migraine is also associated with other ischemic vascular events, including myocardial infarction and cardiovascular death. However, these associations appear to be limited to the subgroup of patients with migraine with aura (MA). Moreover, there is increasing evidence that among patients with MA, additional subgroups exist that carry particular increased risk. The association with ischemic stroke is, for example, particularly strong for younger women with MA who smoke and/or use oral contraceptives. Results from recent studies support an even more complex interrelationship characterized by additional modifying effects of other factors on the association between MA and ischemic vascular events. These include vascular risk factors, migraine attack frequency, and genetic variants. In addition, there appear to be differential effects with regard to ischemic stroke and myocardial infarction. These new findings await confirmation in independent patient populations and are currently not sufficient to argue for a change in diagnostic testing or treatment.     

Antiphospholipid syndrome

Antiphospholipid syndrome has received considerable attention from the medical community because of its association with a number of serious clinical disorders, including arterial and venous thromboembolism, acute ischemic encephalopathy, recurrent pregnancy loss, thrombocytopenia, and livido reticularis. It can occur within the context of several diseases, mainly autoimmune disorders, and is then called secondary antiphospholipid syndrome. However, it may be also be present without any recognizable disease, or so-called primary antiphospholipid syndrome. There is no defined racial predominance for primary antiphospholipid syndrome, although a higher prevalence of systemic lupus erythematosus (SLE) occurs in African Americans and the Hispanic population. Multiple terms exist for this syndrome, some of which can be confusing. Lupus anticoagulant syndrome, for example, is a misleading term, because patients may not necessarily have SLE, and it is associated with thrombotic rather than hemorrhagic complications. To avoid further confusion, antiphospholipid syndrome is currently the preferred term for this clinical syndrome. Antiphospholipid antibodies are found in 1% to 5% of young healthy control subjects; however, the incidence increases with age and coexistent chronic disease. The syndrome occurs most commonly in young to middle-aged adults; however, it also can occur in children and the elderly. Among patients with SLE, the prevalence of antiphospholipid antibodies is high, ranging from 12% to 30% for anticardiolipin antibodies, and 15% to 34% for lupus anticoagulant antibodies. In general, anticardiolipin antibodies occur approximately five times more often then lupus anticoagulant in patients with antiphospholipid syndrome. This syndrome is the most common cause of acquired thrombophilia, associated with either venous or arterial thrombosis or both. It is characterized by the presence of antiphospholipid antibodies, recurrent arterial and venous thrombosis, and spontaneous abortion. Rarely, patients with antiphospholipid syndrome may have fulminate multiple organ failure, or catastrophic antiphospholipid syndrome. This is caused by widespread microthrombi in multiple vascular beds, and can be devastating. Patients with catastrophic antiphospholipid syndrome may have massive venous thromboembolism, along with respiratory failure, stroke, abnormal liver enzyme concentrations, renal impairment, adrenal insufficiency, and areas of cutaneous infarction. According to the international consensus statement, at least one clinical criterion (vascular thrombosis, pregnancy complications) and one laboratory criterion (lupus anticoagulant, antipcardiolipin antibodies) should be present for a diagnosis of antiphospholipid syndrome. The hallmark result from laboratory tests that defines antiphospholipid syndrome is the presence of antibodies or abnormalities in phospholipid-dependent tests of coagulation, such as dilute Russell viper venom time. There is no consensus for treatment among physicians. Overall, there is general agreement that patients with recurrent thrombotic episodes require life-long anticoagulation therapy and that those with recurrent spontaneous abortion require anticoagulation therapy and low- dose aspirin therapy during most of gestation. Prophylactic anticoagulation therapy is not justified in patients with high titer anticardiolipin antibodies with no history of thrombosis. However, if a history of recurrent deep vein thrombosis or pulmonary embolism is established, long-term anticoagulant therapy with international normalized ratio (INR) of approximately 3 is needed.     

Risk for ischemic stroke and coronary heart disease associated with migraine and migraine medication among older adults

BackgroundMigraine has been associated with cardiovascular disease (CVD) events among middle-aged adults. The objective of this study was to determine the risk for ischemic stroke and coronary heart disease (CHD) events among older adults with versus without migraine.MethodsThis retrospective cohort study was conducted using data from US adults ≥66 years of age with Medicare health insurance between 2008 and 2017. After stratification by history of CVD, patients with a history of migraine were matched 1:4 to those without a history of migraine, based on calendar year, age, and sex. Patients were followed through December 31, 2017 for ischemic stroke and CHD events including myocardial infarction or coronary revascularization. All analyses were done separately for patients with and without a history of CVD.ResultsAmong patients without a history of CVD (n = 109,950 including n = 21,990 with migraine and n = 87,960 without migraine), 1789 had an ischemic stroke and 3552 had a CHD event. The adjusted hazard ratio (HR) among patients with versus without migraine was 1.20 (95% confidence interval [95%CI], 1.07–1.35) for ischemic stroke and 1.02 (95%CI, 0.93–1.11) for CHD events. Compared to patients without migraine, those with migraine who were taking an opioid medication had a higher risk for ischemic stroke (adjusted HR 1.43 [95%CI, 1.20–1.69]), while those taking a triptan had a lower risk for CHD events (adjusted HR 0.79 [95%CI, 0.67–0.93]). Among patients with a history of CVD (n = 79,515 including n = 15,903 with migraine and n = 63,612 without migraine), 2960 had an ischemic stroke and 7981 had a CHD event. The adjusted HRs (95%CI) for ischemic stroke and CHD events associated with migraine were 1.27 (1.17–1.39) and 0.99 (0.93–1.05), respectively. Patients with migraine taking an opioid medication had a higher risk for ischemic stroke (adjusted HR 1.21 [95%CI, 1.07–1.36]), while those taking a triptan had a lower risk for CHD events (adjusted HR 0.83 [95%CI, 0.72–0.95]), each versus those without migraine.ConclusionsOlder adults with migraine are at increased risk for ischemic stroke. The risk for ischemic stroke among older adults with migraine may differ by migraine medication classes.Supplementary InformationThe online version contains supplementary material available at 10.1186/s10194-021-01338-z.     

Migraine and the lupus anticoagulant

Lupus anticoagulants (LA) are antiphospholipid serum immunoglobulins generally associated with autoimmune conditions, especially systemic lupus erythematosus (SLE). They have recently been linked to thrombotic events, including stroke. A possible association of migraine with LA is now forwarded with the presentation of two cases and a literature review. Our two patients, both in their forties, had migrainous phenomena without SLE or thrombotic events. Eight other cases were found in the literature, suggesting more than a chance association. Relevance to migraine pathophysiology is discussed and may come from the ability of the LA to alter prostaglandins and platelet activity and to interact with neuronal phospholipids. Further, larger studies are needed to support this association.     

Migraine,Migraine Features,and Cardiovascular Disease

(Headache 2010;50:1031‐1040) Background.— Many studies support an association between migraine and cardiovascular disease (CVD). This association appears particularly in migraine with aura and is also modified by additional factors. Objective.— We sought to investigate whether the association between migraine and CVD in addition to aura status is affected by certain migraine features. Methods.— Cohort study among 27,840 women, participating in the Women's Health Study. We had detailed self‐reported information on migraine and migraine features among women with active migraine (migraine during the year prior to baseline). Incident CVD events were confirmed after medical record review. We used Cox proportional hazards models to evaluate the association between migraine and incident CVD. The results have been presented in part before. We ran additional analyses according to migraine features. Results.— At baseline, 5125 (18.4%) women reported history of migraine; 39.7% of the 3610 women with active migraine indicated aura. During a mean of 11.9 years of follow‐up, 708 CVD events occurred. Migraine with aura doubled the risk for CVD, ischemic stroke, and myocardial infarction. With regard to ischemic stroke, this association seemed stronger in the absence than in the presence of migraine features. This was most pronounced in the absence (hazard ratio = 3.27; 95% CI = 1.93‐5.51; P < .0001) than in the presence of nausea/vomiting (hazard ratio = 0.91; 95% CI = 0.43‐1.93; P = .80). In contrast, the association with myocardial infarction did not reveal a certain pattern. Conclusions.— These data suggest that the association between migraine with aura and ischemic stroke may differ by absence or presence of migraine features.     

Migrainous Infarction: Aspects on Risk Factors and Therapy

Migraine and stroke are related in more than one way. Migraine with aura is a risk factor for ischemic stroke in women under age 45?years, particularly when combined with other risk factors such as smoking and oral contraceptives. Further, individuals with migraine with aura seem to have more white matter lesions and ischemic infarctions than control patients. Migraine has been correlated to cervical artery dissection, the symptoms of which can mimic migraine. Correspondingly, migraine with aura sometimes is mistaken for stroke. Migrainous infarction is a rare but specific type of ischemic stroke developing during an attack of migraine with aura. It is important to recognize this unusual complication of migraine because the management probably is important. In this review, we will discuss the present knowledge of migrainous infarction, the clinical picture, possible mechanisms, and potential prevention and treatment.     

Migraineurs show a high prevalence of antiphospholipid antibodies

Summary. Background: It has been observed that migraineurs show a higher risk of thrombosis and that the most frequent symptom reported by patients with antiphospholipid syndrome is headache, especially migraine. Objectives: The aim of our research was to evaluate the prevalence of antiphospholipid antibodies (aPL) in a random cohort of migraineurs. Patients/Methods: This analytic, comparative case study was performed to evaluate the prevalence of antiphospholipid antibodies by comparing a population of migraineurs with and without aura with sex‐ and age‐matched controls. Both the diagnosis of migraine and the laboratory diagnosis of aPL positivity were made on the basis of the most recent international guidelines. Results: Between September 2008 and August 2009, we recruited 284 consecutive patients (225 women and 59 men, 203 without aura and 81 with aura) and 225 controls (174 women and 51 men). Positivity for at least one test for aPL (LAC, ACA IgG or antiß2GLP1 IgG) was detected and confirmed in 12% (n = 33) of patients and in 3% (n = 7) of controls (odds ratio, 4.08; confidence interval, 1.77–9:39; P = 0.0004). Two of the patients had triple positivity for aPL (LAC, ACA and antiß2GLP1) and one had double positivity (LAC and antiß2GLP1); none of the controls showed multiple positivity. Conclusions: Our data show that migraineurs have a significantly higher prevalence of antiphospholipid antibodies, and point towards the fact that the two conditions may be comorbid or even that migraine may be an early sign for identifying patients with aPL positivity.     

Association between migraine and headache attributed to stroke: a case-control study

Background.— Several studies were carried out to investigate the occurrence of headache attributed to acute stroke in patients with a lifetime history of migraine. Methods.— In a case–control series of 96 acute stroke patients with a lifetime history of migraine (M+) and 96 stroke patients without (M?), ischemic stroke patients only, without secondary infarction, were selected. The headache attributed to acute ischemic stroke was then analyzed. Results.— (M+) patients complained of headache more often than (M?) patients (P < .0001), mainly in the 24 hours before stroke onset (P < .0001). Migraine‐like features of headache were recognized in a greater proportion of cases in the (M+) patient group with ischemic stroke (P < .018). A preferential brainstem location of ischemic stroke in (M+) patients emerged compared with (M?) patients (P = .014). Discussion.— The high prevalence of headache attributed to stroke in (M+) patients, in a relevant proportion of cases presenting as a sentinel headache, suggests that cerebral ischemia lowers the threshold for head pain more easily in these “susceptible” patients. The most frequent involvement of the brainstem in (M+) patients with ischemic infarction concurs with recent reports that emphasized a greater headache frequency when cerebral infarctions are localized in this structure or deep brain gray matter.     

Antiphospholipid Antibodies in Migraine

We studied the presence of serum antiphospholipid antibodies (APA) in 35 patients with migraine and 75 controls. None of the controls showed APA, while we found these antibodies in five patients out of the 35 studied (p = 0.003). The clinical features of migraineurs with APA were similar to those of patients without them. After a follow-up of one to two years, no patient suffered any neurological complications or developed any clinical features that would suggest the presence of autoimmune disease. Our results suggest that APA are not prominent in the pathogenesis of migraine attacks, or significant in the course of otherwise healthy migraine patients.     

How Imaging Can Help Us Better Understand the Migraine-Stroke Connection

Migraine and stroke are among the most prevalent and disabling neurological diseases. Epidemiologic studies showed that there is an association between migraine and stroke. Migraineurs, especially those with aura, are more likely to develop subclinical infarct-like lesions in the brain and are at risk for cryptogenic or cardioembolic stroke. Migrainous headache can be found at the onset of acute ischemic stroke in some patients, and in rare instances, an infarction can be directly attributed to a prolonged migraine aura, ie, migrainous infarction. Importantly, recent studies suggest that in the event of cerebral artery occlusion, even a history of migraine is sufficient to accelerate infarct progression and worsen outcomes. The mechanisms underlying the migraine-stroke connection are multifactorial, with genetic predisposition, aura-related electrophysiological mechanisms (cortical spreading depolarization), and cerebral microembolism being the most convincing ones at this point. Here, we provide a comprehensive overview on recent imaging studies that have helped us better understand the complex association between migraine and stroke.     

Hemiplegic migraine aura begins with cerebral hypoperfusion: imaging in the acute phase

Imaging studies of spontaneous migraine aura have proved challenging because of the episodic and unpredictable nature of migraine attacks. Two patients with signs of acute ischemic stroke were evaluated for thrombolysis and turned out to suffer from familial hemiplegic migraine. It was possible to record the early phase of the hemiplegic aura with computed tomography with perfusion sequences and magnetic resonance imaging. We found cerebral hypoperfusion in the relevant cortical areas within the first hour after onset of aura symptoms. This report supports the concept that migraine aura across the migraine spectrum is caused by similar mechanisms. In a setting with efficient cooperation between headache and stroke neurologists, thrombolysis centers provide the set-up and opportunity to record aura symptoms at an early phase. Furthermore, in the time of ready access to acute systemic thrombolysis treatment, these cases underscore the importance of an accurate headache history, especially in younger patients.