Migraine as a systemic vasculopathy.

Epidemiological studies suggests that migraine is associated with disorders of the cerebral, coronary, retinal, dermal and peripheral vasculature. There is evidence that migraine is associated with endothelial dysfunction, both as a cause and a consequence. Endothelial dysfunction, a vascular risk factor, is characterized by endothelial activation and impaired vascular reactivity. Plasma and genetic biomarkers for these conditions have been identified. The clinical significance lies in the potential for the rapid identification of migraineurs at increased risk of ischaemic stroke and vascular disease through ascertainment of endothelial dysfunction biomarkers. It is uncertain whether stroke, myocardial infarction and other vasculopathies can be prevented by migraine prophylaxis, endothelial repair, platelet inhibition or a combination of these strategies.

Association of von Willebrand factor activity with ACE I/D and MTHFR C677T polymorphisms in migraine.

Angiotensin-converting enzyme (ACE) insertion (I)/deletion (D) and methylenetetrahydrofolate reductase (MTHFR) C677T polymorphisms are linked to endothelial dysfunction and to cerebral white matter lesions. Objectives of this study were to determine if ACE and MTHFR gene polymorphisms are associated with von Willebrand factor (vWF) activity, an endothelial dysfunction marker, and with a distinct headache phenotype. We enrolled 64 women (18-50 years old) with International Classification of Headache Disorders, 2nd edn migraine without aura (MoA) and 61 with aura (MA). Genotypic frequencies: ACE DD 35%, ID 42%, II 23%, and MTHFR TT 17%, CT 40%, CC 43%. Those with ACE DD genotype had higher levels of vWF activity (152%) compared with ID and II genotypes. Levels were highest (179%) with combined ACE DD and MTHFR TT genotypes. ACE DD was associated with higher headache frequency, and MTHFR TT was associated with MA. In migraine, vWF activity may be a marker of endothelial-mediated genetic risk for ischaemic conditions.

History of childhood maltreatment is associated with comorbid depression in women with migraine.

BACKGROUND: A bidirectional relationship between migraine and depression suggests a neurobiological link. Adverse experiences, particularly childhood maltreatment, may alter neurobiological systems, and predispose to a multiplicity of adult chronic disorders. Our objective is to determine, within a headache clinic population of women, if depression moderates the abuse-migraine relationship. METHODS: At six headache specialty clinics, women with migraine were diagnosed using ICHD-II criteria, and frequency was recorded. A questionnaire regarding maltreatment history, headache characteristics, current depression, and somatic symptoms was completed. RESULTS: A total of 949 women with migraine completed the survey: 40% had chronic headache (> or =15 headache days/month) and 72% had "very severe" headache-related disability. Major depression was recorded in 18%. Physical or sexual abuse was reported in 38%, and 12% reported both physical and sexual abuse in the past. Migraineurs with current major depression reported physical (p < 0.001) and sexual (p < 0.001) abuse in higher frequencies compared to those without depression. Women with major depression were more likely to report sexual abuse occurring before age 12 years (OR = 2.30, 95% CI: 1.14 to 4.77), and the relationship was stronger when abuse occurred both before and after age 12 years (OR = 5.08, 95% CI: 2.15 to 11.99). Women with major depression were also twice as likely to report multiple types of maltreatment (OR = 2.07, 95% CI: 1.27 to 3.35) compared to those without depression. CONCLUSIONS: Childhood maltreatment was more common in women with migraine and concomitant major depression than in those with migraine alone. The association of childhood sexual abuse with migraine and depression is amplified if abuse also occurs at a later age.

High prevalence of somatic symptoms and depression in women with disabling chronic headache.

OBJECTIVE: To better define, in women with headache, the relationship of depression and somatic symptoms to headache, characterized by diagnoses, frequency, and disability. METHODS: At six headache specialty clinics, women with headache were classified using ICHD-II criteria, and frequency was recorded. A questionnaire addressing demographics, age at onset of headache, headache-related disability, somatic symptom, and depression severity was completed. Logistic regression was performed to measure the associations of headache frequency and headache-related disability with somatic symptom and depression severity. RESULTS: A total of 1,032 women with headache completed the survey, 593 with episodic (96% with migraine) and 439 with chronic headache (87% with migraine). Low education and household income was more common in chronic headache sufferers and in persons with severe headache disability. Somatic symptom prevalence and severity was greater in persons with chronic headache and with severe headache-related disability. Significant correlation was observed between PHQ-9 and PHQ-15 scores (r = 0.62). Chronic headache, severe disability, and high somatic symptom severity were associated with major depressive disorder (OR = 25.1, 95% CI: 10.9 to 57.9), and this relationship was stronger in the subgroup with a diagnosis of migraine (OR = 31.8, 95% CI: 12.9 to 78.5). CONCLUSIONS: High somatic symptom severity is prevalent in women with chronic and severely disabling headaches. Synergistic relationship to major depression exists for high somatic symptom severity, chronic headache, and disabling headache, suggesting a psychobiological underpinning of these associations.

Thrombolytic therapy of acute ischemic stroke during pregnancy.

The authors report eight pregnant women with acute ischemic stroke treated with thrombolysis (rt-PA [recombinant human tissue plasminogen activator] or urokinase). Seven women recovered. Two extracranial and two asymptomatic intracranial hemorrhages complicated treatment; one woman died of arterial dissection complicating angiography. Three patients had therapeutic abortions, two fetuses were miscarried, and two babies were delivered healthy. Although pregnant women may be treated safely with thrombolytics, risks and benefits to mother and fetus must be carefully weighed.

Sneddon's syndrome: another migraine-stroke association?

Sneddon's syndrome refers to the enigmatic association of ischaemic stroke and livedo reticularis. We review the Sneddon's syndrome literature examining the association of this condition with headache, including migraine. Case reports and series are stratified into two groups based on headache reference. In the group without a reference to headache, there are 208 persons, with a female to male ratio of 3 : 1. In the headache reference group, there are 175 persons, with a female to male ratio of 3.5 : 1. The proportion with headache in this second group is 58% (102 individuals), with headache described as migraine in 28 (27.5%) of the headache subjects, including six with migraine with aura. The frequency of headache is not significantly higher in persons with positive anti-phospholipid antibodies compared with the negative cohort (43% vs. 32%, P = 0.07). A review of the histopathological, radiological and serological data in Sneddon's syndrome and migraine underscores the plausibility of an association. Considered in the context of increased risk of stroke with migraine, a higher frequency of livedo in migraineurs with stroke, and the association of migraine and livedo reticularis, the question of whether livedo reticularis may be a risk marker for stroke in migraineurs is an area for further study.

Increased von Willebrand factor in migraine.

The authors determined von Willebrand factor (vWF) in 63 persons with migraine, 11 persons with migraine and prior stroke, and 35 frequency-matched controls. Additional studies were done in a subset with migraine without aura who were headache free for >7 days. Migraineurs with prior stroke had significantly higher vWF antigen (170% versus 106%) and activity (162% versus 108%) than the control group. vWF antigen (126%) and activity (130%) were also significantly higher in migraineurs without stroke. Multimers and protease activity were normal in the interictal subset.

Migrainous aura versus transient ischemic attack in an elderly migraineur.

In older patients with migraine, the distinction between a migrainous aura and a transient ischemic episode can be difficult, as this case illustrates.

The relationship of migraine and stroke.

Migraine, a common disorder of uncertain pathogenesis, is linked to ischemia in a variety of ways. In some cases the relationship is coincidental. In others, migraine may be causally related to stroke, although the mechanism of migrainous stroke, if not due to arterial dissection, is unclear. In young women, additional risk factors for stroke such as cigarette smoking, use of combined oral contraceptives and anticardiolipin antibody immunoreactivity may potentiate migraine, especially migraine with aura, as a stroke risk factor. The complexity of the relationship is highlighted in certain genetic conditions such as cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy and mitochondrial encephalopathy with lactic acidosis and stroke in which migraine and stroke are both prominent clinical features.

Vertebrobasilar artery ectasia presenting as hydrocephalus.

Symptomatic hydrocephalus in association with basilar artery ectasia is a rare occurrence. We report an 81-year-old woman with progressive dementia, gait disturbance, and sphincter incontinence. Brain computed tomography (CT) and magnetic resonance imaging (MRI) scans showed obstructive hydrocephalus with compression of the fourth ventricle by a large ectatic basilar artery. After ventriculoperitoneal shunting, the patient showed rapid resolution of symptoms. This case illustrates that ventricular obstruction due to basilar artery ectasia can mimic the classical triad of normal pressure hydrocephalus.

Neuropsychological deficits associated with antiphospholipid antibodies.

Neurologic events associated with antiphospholipid antibodies (aPAs) include transient ischemic attack, stroke, and vascular dementia in individuals much younger than is typically observed with these disorders. The present study evaluated 27 non-elderly adults with aPAs but without concurrent disease processes or history of neurologic event and 27 age- and education-matched controls. MANOVA (p <.01) indicated group differences in executive functioning, verbal learning and memory, and visuospatial ability. In contrast, gross attentional processes and fine motor skills appeared unaffected by the syndrome. Moreover, the frequency of impaired neuropsychologic performance was greater among individuals with aPAs than among controls (p <.01). The presence of cognitive deficits in otherwise asymptomatic patients with aPAs indicates a preclinical phase of neurologic involvement and may prove to be the most sensitive markers of the syndrome.

Cerebrovascular ischemic events with high positive anticardiolipin antibodies.

BACKGROUND AND PURPOSE: The aim of our study was to characterize the patient profile and prognostic value associated with high positive IgG (>100 GPL) anticardiolipin antibodies (aCL). METHODS: We studied the clinical, laboratory, radiological, and prospective historical features of ischemic cerebrovascular disease in patients with >100 GPL titers. From our neurology department, 27 consecutive patients were prospectively identified and followed up (mean follow-up time, 34 months). RESULTS: The mean age of our cohort was 41 years. Lupuslike illness occurred in 3; 23 had primary antiphospholipid syndrome, including 3 who met criteria for Sneddon's syndrome; 1 patient had progressive systemic sclerosis. Cerebral infarcts occurred in 74% and were recurrent in 37%. Systemic ischemic events, most commonly deep vein thrombosis, occurred in 37%. Tobacco use was documented in 85%, hyperlipidemia in 74%, hypertension in 44%, and diabetes mellitus in 7% of patients. A prominent headache history was present in 67%. Lupus anticoagulant (LA) was present in 72%, approximately one half had positive antinuclear antibodies and thrombocytopenia, and one quarter had a false-positive VDRL. We compared mean GPL levels in patients testing positive for specific laboratory features of antiphospholipid syndrome with those testing negative for these parameters. Only the LA(+) group had a significantly higher mean GPL than the LA(-) group (P=0.006). Brain imaging showed nonlacunar infarcts in 73% and lacunes in 12%. Of 19 cerebral angiograms, 5 (26%) showed large-vessel occlusive disease and 6 (32%) branch obstruction. Echocardiograms were abnormal in 75%: thickened left-sided valves in 33% and vegetations in 12%. Recurrent cerebrovascular ischemic events were observed in 96%, with transient events (mean rate, 25%/y) occurring 5 times more frequently than strokes (mean rate, 5%/y). Using a standardized disability scale blinded to aCL titer, neurological impairment was severe in 7%, moderate in 30%, and mild or nonexistent in 63%, and unrelated to mean GPL value (P=0.567). Titers fluctuated greatly for individual patients, and most did not consistently test as highly positive. An analysis of fluctuation in symptom severity with concurrent GPL values did not show a statistically significant correlation. Compared with historical controls having a wide range of positive titers, the presence of high IgG aCL titers did not confer a worse prognosis for disability and recurrent ischemic events. CONCLUSIONS: Our data suggest that cerebrovascular events associated with high positive GPL are frequently multiple and minor (with no disability-titer correlation), present in relatively young patients, and often associated with tobacco abuse, hyperlipidemia, LA, systemic ischemic events, and occult cardiac disease.

Role of anticardiolipin antibodies in young persons with migraine and transient focal neurologic events: a prospective study.

Anticardiolipin antibodies (aCL) are a risk factor for cerebral ischemia. In migraine, the association is controversial, with widely varying results in different small series. The controversy in part may be due to the inherent difficulty in distinguishing the transient focal neurologic events (TFNE) of migraine from TIA. To assess the frequency of aCL in migraine, we prospectively evaluated consecutive adults under 60 years of age with migraine without aura and with recent TFNE (<24-hour duration) clinically suggestive of either migraine with aura or TIA. We concomitantly enrolled persons with no CNS disease. Each person was interviewed and had blood drawn for solid-phase ELISA with IgG and IgM aCL isotyping. Neuroradiologic studies were reviewed. Patients with TFNE were followed every 6 months for the duration of the 3-year study. The frequency of aCL positivity (IgG >20, IgG >40, IgM >7.5) for the 645 patients with TFNE (8.8, 3.1, 4.2%), the 518 persons in the TFNE subgroup with migraine with aura (8.9, 3.3, 4.1%), the 497 persons with migraine without aura (7.0, 2.0, 3.6%), and the 366 control subjects (9.3, 3.6, 3.9%) did not differ significantly between groups. In TFNE patients with elevated aCL titer, the association was positive with diabetes mellitus, TFNE duration <15 minutes, and diplopia and was negative with hemiparesis, tinnitus, and family history of stroke. Findings on imaging consistent with cerebral ischemia were more frequent in aCL-positive persons. The short-term risk of stroke was uniformly low. In young persons, aCL is not associated with migraine or with TFNE, although diabetes mellitus, negative family history of stroke, and brief duration of symptoms (including diplopia) may predict immunoreactivity. Imaging studies suggest an ischemic etiology of TFNE in this cohort.

A review of neurological sequelae and cognitive deficits associated with antiphospholipid antibodies.

Antiphospholipid Antibodies (aPAs) are specific circulating immunoglobulins that lead to a hypercoagulant state and recurrent arterial and venous thromboembolic events. The cerebral circulation is the most common site of arterial occlusion in aPAs, and neurologic events include amaurosis fugax, migrainous cephalalgia, transient ischemic attacks (TIA), stroke, ischemic encephalopathy, and vascular dementia. A review of the literature yields numerous studies citing neurocognitive and neuropsychiatric symptoms associated with this syndrome in a much younger population than is seen in other cerebrovascular disorders. These associated features include focal and generalized cognitive deficits, early-onset vascular dementia, and neuropsychiatric symptoms such as affective and thought disorders. These neurocognitive and neurobehavioral manifestations may be underemphasized in this population and aPAs should be considered in a differential diagnosis. Largescale prospective studies are needed to quantify psychiatric and neuropsychological sequelae of this disorder.

Serotonin syndrome complicating migraine pharmacotherapy.

Serotonin syndrome, a condition with numerous clinical neurological manifestations, is the result of central serotonergic hyperstimulation. Features of the syndrome include mental status and behavioral changes (agitation, excitement, hypomania, obtundation), motor system involvement (myoclonus, hemiballismus, tremor, hyperreflexia, motor weakness, dysarthria, ataxia) and autonomic symptoms (fever, chills, diarrhea). Serotonin syndrome has been reported exclusively in patients on medications for psychiatric illness and Parkinsonism, despite the fact that the putative action of many antimigraine agents also involves the serotonin system. We herein report six patients with migraine who developed symptoms suggestive of the serotonin syndrome. Five were taking one or more serotomimetic agents for migraine prophylaxis (sertraline, paroxetine, lithium, imipramine, amitriptyline). In each case the symptoms and signs developed in close temporal proximity with use of a migraine abortive agent known to interact with serotonin receptors. In three instances the agent was subcutaneous sumatriptan and, in three, intravenous dihydroergotamine. In each instance the symptoms were transient and there was full recovery. With the ever increasing use of migraine medications active at serotonin receptor sites, cases of serotonin syndrome will likely occur more frequently. It is important that physicians treating migraine are aware of the serotonin syndrome and are able to recognize its varying presentations.