No abstract

Objective-Patent foramen ovale and pulmonary arteriovenous shunts are associated with serious complications such as cerebral emboli, stroke, and migraine with aura. The pathophysiological mechanisms that link these conditions are unknown. We aimed to establish a mechanism linking microembolization to migraine aura in an experimental animal model. Methods-We introduced particulate or air microemboli into the carotid circulation in mice to determine whether transient microvascular occlusion, insufficient to cause infarcts, triggered cortical spreading depression (CSD), a propagating slow depolarization that underlies migraine aura.Results-Air microemboli reliably triggered CSD without causing infarction. Polystyrene microspheres (10μm) or cholesterol crystals (<70μm) triggered CSD in 16 of 28 mice, with 60% of the mice (40% of those with CSD) showing no infarcts or inflammation on detailed histological analysis of serial brain sections. No evidence of injury was detected on magnetic resonance imaging examination (9.4T; T2 weighted) in 14 of 15 selected animals. The occurrence of CSD appeared to be related to the magnitude and duration of flow reduction, with a triggering mechanism that depended on decreased brain perfusion but not sustained tissue damage.Interpretation-In a mouse model, microemboli triggered CSD, often without causing microinfarction. Paradoxical embolization then may link cardiac and extracardiac right-to-left shunts to migraine aura. If translatable to humans, a subset of migraine auras may belong to a spectrum of hypoperfusion disorders along with transient ischemic attacks and silent infarcts. Migraine headaches are among the most common and debilitating conditions and occur in 10 to 12% of the general population. 1 Migraine with aura accounts for 15% of cases, and the aura is characterized most commonly by visual or somatosensory symptoms that often anticipate the onset of headache by 20 to 40 minutes. Certain patients with migraine auras are at greater risk for stroke. 2,3 Despite the multiplicity of potential mechanisms linking migraine aura and stroke, 4 experimental evidence linking the triggering of migraine aura attacks to microvascular dysfunction is lacking. Cortical spreading depression (CSD) may be important to this link.CSD is a slowly propagating intense neuronal and glial depolarization that spreads at a characteristic rate of 3 to 5mm per minute. It is a property of all mammalian cortices, but varies in susceptibility between the rodent and more resistant human brain. 5 A number of high-and low-resolution brain imaging studies have led to the conclusion that CSD causes migraine aura. [6][7][8] For example, during visual aura, a slowly propagating wave of cerebral blood oxygenation level-dependent (BOLD) signal change was recorded in calcarine cortex in a migraineur using near continuous high-resolution functional magnetic resonance imaging (MRI). 6 The observed perturbations of the BOLD signal were retinotopically congruent with the patient's visual percept, and displaye...

Migraine attacks with auras are sometimes associated with underlying hereditary or acquired cerebrovascular disorders. A unifying pathophysiological explanation linking migraine to these conditions has been diffcult to identify. On the basis of genetic and epidemiological evidence, we suggest that changes in blood vessels, hypoperfusion disorders, and microembolisation can cause neurovascular dysfunction and evoke cortical spreading depression, an event that is widely thought to underlie aura symptoms. In fact, recent experimental data have indicated that focal, mild, and transient ischaemia can trigger cortical spreading depression without an enduring tissue signature. Although migraine with aura has many causes (eg, neuronal network excitability), it seems that migraine and stroke might both be triggered by hypoperfusion and could therefore exist on a continuum of vascular complications in a subset of patients who have these hereditary or acquired comorbid vascular conditions.

Background-Mild hypothermia improves outcome when induced after cardiac arrest in humans. Recent studies in both dogs and mice suggest that induction of mild hypothermia during cardiopulmonary resuscitation (CPR) greatly enhances its efficacy. In this study, we evaluate the time window for the beneficial effect of intra-arrest cooling in the setting of prolonged CPR in a clinically relevant large-animal model. Methods and Results-Seventeen dogs had ventricular fibrillation cardiac arrest no flow of 3 minutes, followed by 7 minutes of CPR basic life support and 50 minutes of advanced life support. In the early hypothermia group (nϭ9), mild hypothermia (34°C) was induced with an intravenous fluid bolus flush and venovenous blood shunt cooling after 10 minutes of ventricular fibrillation. In the delayed hypothermia group (nϭ8), hypothermia was induced at ventricular fibrillation 20 minutes. After 60 minutes of ventricular fibrillation, restoration of spontaneous circulation was achieved with cardiopulmonary bypass for 4 hours, and intensive care was given for 96 hours. In the early hypothermia group, 7 of 9 dogs survived to 96 hours, 5 with good neurological outcome. In contrast, 7 of 8 dogs in the delayed hypothermia group died within 37 hours with multiple organ failure (Pϭ0.012). Conclusions-Early application of mild hypothermia with cold saline during prolonged CPR enables intact survival. Delay in the induction of mild hypothermia in this setting markedly reduces its efficacy. Our data suggest that if mild hypothermia is used during CPR, it should be applied as early as possible. Key Words: cardiopulmonary resuscitation Ⅲ cooling Ⅲ heart arrest Ⅲ hypothermia Ⅲ resuscitation A fter successful resuscitation from cardiac arrest (CA), hypothermia has been shown in several experimental studies to improve cerebral outcome. [1][2][3][4][5] On the basis of recent clinical studies, therapeutic mild hypothermia is recommended by the American Heart Association and the International Liaison Committee on Resuscitation for Unconscious Survivors of CA. 6,7 Despite a relatively late and slow surface cooling technique, these clinical trials in Europe and Australia documented neurological benefits with mild hypothermia in survivors of out-of-hospital CA. 8,9 Because evidence exists that a delay in cooling negates the beneficial effect of mild hypothermia, 4,10 some have suggested that hypothermia should be initiated as soon as possible after resuscitation or, preferably, during cardiopulmonary resuscitation (CPR) attempts. 5,10 In a recent study of CA in mice, application of mild hypothermia during CPR was shown to enhance outcome compared with its application after restoration of spontaneous circulation (ROSC). 11 Similarly, in a clinically relevant study of prolonged ventricular fibrillation (VF) in dogs, we documented that mild or moderate hypothermia Clinical Perspective p 2696induced during 40 minutes of CPR attempts preserves organ viability and significantly improves outcome. 12 Intact survival was achieved despite 40 mi...