Spreading depolarizations may contribute to delayed cerebral ischemia after aneurysmal subarachnoid hemorrhage, but the effect of spreading depolarizations on brain lesion progression after subarachnoid hemorrhage has not yet been assessed directly. Therefore, we tested the hypothesis that artificially induced spreading depolarizations increase brain tissue damage in a rat model of subarachnoid hemorrhage. Subarachnoid hemorrhage was induced by endovascular puncture of the right internal carotid bifurcation. After one day, brain tissue damage was measured with T2-weighted MRI, followed by application of 1 M KCl (SD group, N = 16) or saline (no-SD group, N = 16) to the right cortex. Cortical laser-Doppler flowmetry was performed to record spreading depolarizations. MRI was repeated on day 3, after which brains were extracted for assessment of subarachnoid hemorrhage severity and histological damage. 5.0 ± 2.7 spreading depolarizations were recorded in the SD group. Subarachnoid hemorrhage severity and mortality were similar between the SD and no-SD groups. Subarachnoid hemorrhage-induced brain lesions expanded between days 1 and 3. This lesion growth was larger in the SD group (241 ± 233 mm(3)) than in the no-SD group (29 ± 54 mm(3)) (p = 0.001). We conclude that induction of spreading depolarizations significantly advances lesion growth after experimental subarachnoid hemorrhage. Our study underscores the pathophysiological consequence of spreading depolarizations in the development of delayed cerebral tissue injury after subarachnoid hemorrhage.

Delayed cerebral ischemia (DCI) is a common and feared complication after subarachnoid hemorrhage (SAH), which occurs in approximately one third of patients. 1 The mechanisms that are involved in DCI development are largely unknown. Spreading depolarizations (SDs) have been suggested to be associated with DCI in experimental and clinical SAH studies. 2 SDs are waves of depolarizations of neurons and glial cells that spread across brain tissue at a speed of 2 to 6 mm/min. 3 SD is the underlying mechanism of a migraine aura, but may also be associated with other brain diseases. In migraine aura, the tissue recovers from the electrolyte imbalance caused by SDs, presumably through temporary hyperperfusion. 4 However, after an acute ischemic brain insult, such as SAH, SDs may cause permanent tissue injury arising from spreading ischemia because of an inverse hemodynamic response to SD combined with an increased metabolic demand. 2,5 In a small study of SAH patients who needed surgery for their ruptured aneurysm, SDs were recorded by electrocorticography and seemed associated with the development of DCI.5 Inhibition of SD is, therefore, a potential therapeutic approach to prevent brain injury after SAH.Multiple drugs, including antiepileptic drugs and migraine prophylactics, have SD-inhibiting properties. 6 For SAH patients, nimodipine is the only established drug for the clinical prevention of DCI.1 Although the mechanism of action Background and Purpose-Spreading depolarizations (SDs) may contribute to delayed cerebral ischemia after subarachnoid hemorrhage (SAH). We tested whether SD-inhibitor valproate reduces brain injury in an SAH rat model with and without experimental SD induction. Methods-Rats were randomized in a 2×2 design and pretreated with valproate (200 mg/kg) or vehicle for 4 weeks. SAH was induced by endovascular puncture of the right internal carotid bifurcation. One day post-SAH, brain tissue damage was measured with T 2 -weighted magnetic resonance imaging, followed by cortical application of 1 mol/L KCl (to induce SDs) or NaCl (no SDs). Magnetic resonance imaging was repeated on day 3 followed by histology to confirm neuronal death. Neurological function was measured with an inclined slope test. Results-In the groups with KCl application, lesion growth between days 1 and 3 was 57±73 mm3 in the valproate-treated versus 237±232 mm3 in the vehicle-treated group. In the groups without SD induction, lesion growth in the valproateand vehicle-treated groups was 8±20 mm3 versus 27±52 mm3. On fitting a 2-way analysis of variance model, we found a significant interaction effect between treatment and KCl/NaCl application of 161 mm3 (P=0.04 9-11 Intraperitoneal injection of valproate was found to decrease lesion size after ischemic stroke in a rat model, 12 where SDs have been shown to contribute to lesion growth. 13,14 Valproate treatment has also been shown to improve the outcome in a mouse model with SAH induced by subarachnoid blood injection.15 However, the mechanisms through which valproate may reduce b...

Objectives Migraine is a risk factor for stroke, which might be explained by a higher prevalence in anatomical variants in the circle of Willis (CoW). Here, we compared the presence of CoW variants in patients with stroke with and without migraine. Materials and Methods Participants were recruited from the prospective Dutch acute Stroke Study. All participants underwent CT angiography on admission. Lifetime migraine history was assessed with a screening questionnaire and confirmed by an interview based on International Classification of Headache Disorders criteria. The CoW was assessed for incompleteness/hypoplasia (any segment <1 mm), for anterior cerebral artery asymmetry (difference > 1/3), and for posterior communicating artery (Pcom) dominance (Pcom–P1 difference > 1/3). Odds ratios with adjustments for age and sex ( aOR ) were calculated with logistic regression. Results We included 646 participants with stroke, of whom 52 had a history of migraine. Of these, 45 (87%) had an incomplete or hypoplastic CoW versus 506 (85%) of the 594 participants without migraine ( aOR : 1.47; 95% CI : 0.63–3.44). There were no differences between participants with and without migraine in variations of the anterior or posterior CoW, anterior cerebral artery asymmetry ( aOR : 0.86; 95% CI : 0.43–1.74), or Pcom dominance ( aOR : 0.64; 95% CI : 0.32–1.30). There were no differences in CoW variations between migraine patients with or without aura. Conclusion We found no significant difference in the completeness of the CoW in acute stroke patients with migraine compared to those without.