Conditioning-based therapeutics for aneurysmal subarachnoid hemorrhage - A critical review.

Aneurysmal subarachnoid hemorrhage (SAH) carries significant mortality and morbidity, with nearly half of SAH survivors having major cognitive dysfunction that impairs their functional status, emotional health, and quality of life. Apart from the initial hemorrhage severity, secondary brain injury due to early brain injury and delayed cerebral ischemia plays a leading role in patient outcome after SAH. While many strategies to combat secondary brain injury have been developed in preclinical studies and tested in late phase clinical trials, only one (nimodipine) has proven efficacious for improving long-term functional outcome. The causes of these failures are likely multitude, but include use of therapies targeting only one element of what has proven to be multifactorial brain injury process. Conditioning is a therapeutic strategy that leverages endogenous protective mechanisms to exert powerful and remarkably pleiotropic protective effects against injury to all major cell types of the CNS. The aim of this article is to review the current body of evidence for the use of conditioning agents in SAH, summarize the underlying neuroprotective mechanisms, and identify gaps in the current literature to guide future investigation with the long-term goal of identifying a conditioning-based therapeutic that significantly improves functional and cognitive outcomes for SAH patients.

Dural arteriovenous fistula-induced thalamic dementia: report of 4 cases.

Nonhemorrhagic neurological deficits are underrecognized symptoms of intracranial dural arteriovenous fistulas (dAVFs) having cortical venous drainage. These symptoms are the consequence of cortical venous hypertension and portend a clinical course with increased risk of neurological morbidity and mortality. One rarely documented and easily misinterpreted type of nonhemorrhagic neurological deficit is progressive dementia, which can result from venous hypertension in the cortex or in bilateral thalami. The latter, which is due to dAVF drainage into the deep venous system, is the less common of these 2 dementia syndromes. Herein, the authors report 4 cases of dAVF with venous drainage into the vein of Galen causing bithalamic edema and rapidly progressive dementia. Two patients were treated successfully with endovascular embolization, and the other 2 patients were treated successfully with endovascular embolization followed by surgery. The radiographic abnormalities and presenting symptoms rapidly resolved after dAVF obliteration in all 4 cases. Detailed descriptions of these 4 cases are presented along with a critical review of 15 previously reported cases. In our analysis of these 19 published cases, the following were emphasized: 1) the clinical and radiographic differences between dAVF-induced thalamic versus cortical dementia syndromes; 2) the differential diagnosis and necessary radiographic workup for patients presenting with a rapidly progressive thalamic dementia syndrome; 3) the frequency at which delays in diagnosis occurred and potentially dangerous and avoidable diagnostic procedures were used; and 4) the rapidity and completeness of symptom resolution following dAVF treatment.

Potassium channel blockers attenuate hypoxia- and ischemia-induced neuronal death in vitro and in vivo.

BACKGROUND AND PURPOSE: In light of recent evidence suggesting that an upregulation of K+ efflux mediated by outward delayed rectifier (I(K)) channels promotes central neuronal apoptosis, we sought to test the possibility that blockers of I(K) channels might be neuroprotective against hypoxia/ischemia-induced neuronal death. METHODS: Membrane currents were recorded with the use of patch clamp recordings in cultured murine cortical neurons. Protective effects of K+ channel blockers were examined in rats subjected to transient middle cerebral artery occlusion followed by 14-day reperfusion. RESULTS: The K+ channel blocker tetraethylammonium (TEA) (5 mmol/L) selectively blocked I(K) without affecting N-methyl-D-aspartate receptor-mediated current or voltage-gated Ca2+ currents. Both TEA and a lipophilic K+ channel blocker, clofilium, attenuated neuronal apoptosis induced by hypoxia in vitro and infarct volume induced by ischemia in vivo. CONCLUSIONS: These data are consistent with the idea that K+ channel-mediated K+ efflux may contribute to ischemia-triggered apoptosis and suggest that preventing excessive K+ efflux through K+ channels may constitute a therapeutic approach for the treatment of stroke.