No abstract

SAH is a life-threatening condition that requires immediate diagnosis, transfer to a neurovascular center, and treatment without delay.

Pathophysiological processes following subarachnoid hemorrhage (SAH) present survivors of the initial bleeding with a high risk of morbidity and mortality during the course of the disease. As angiographic vasospasm is strongly associated with delayed cerebral ischemia (DCI) and clinical outcome, clinical trials in the last few decades focused on prevention of these angiographic spasms. Despite all efforts, no new pharmacological agents have shown to improve patient outcome. As such, it has become clear that our understanding of the pathophysiology of SAH is incomplete and we need to reevaluate our concepts on the complex pathophysiological process following SAH. Angiographic vasospasm is probably important. However, a unifying theory for the pathophysiological changes following SAH has yet not been described. Some of these changes may be causally connected or present themselves as an epiphenomenon of an associated process. A causal connection between DCI and early brain injury (EBI) would mean that future therapies should address EBI more specifically. If the mechanisms following SAH display no causal pathophysiological connection but are rather evoked by the subarachnoid blood and its degradation production, multiple treatment strategies addressing the different pathophysiological mechanisms are required. The discrepancy between experimental and clinical SAH could be one reason for unsuccessful translational results.

The majority of metastases (62%) were 5-AIF positive, suggesting a potential impact of 5-AIF for improved visualization of metastatic tumor tissue within the brain. However, residual 5-AIF after macroscopically complete resection of a metastasis needs to be interpreted with caution because of the limited specificity for detection of residual tumor tissue.

Summary:Purpose: Recently the Ca v 2.3 (E/R-type) voltagegated calcium channel (VGCC) has turned out to be not only a potential target for different antiepileptic drugs (e.g., lamotrigine, topiramate) but also a crucial component in the pathogenesis of absence epilepsy, human juvenile myoclonic epilepsy (JME), and epileptiform activity in CA1 neurons. The aim of our study was to perform an electroencephalographic analysis, seizuresusceptibility testing, and histomorphologic characterization of Ca v 2.3 −/− mice to unravel the functional relevance of Ca v 2.3 in ictogenesis.Methods: Generalized and brain-specific Ca v 2.3 knockout animals were analyzed for spontaneous epileptiform discharges by using both electrocorticographic and deep intracerebral recordings. In addition, convulsive seizure activity was induced by systemic administration of either 4-aminopyridine (4-AP; 10 mg/kg, i.p.) or pentylenetetrazol (PTZ; 80 mg/kg, s.c.) to reveal possible alterations in seizure susceptibility. Besides histomorphologic analysis, expression studies of other voltage-gated Ca 2+ channels in Ca v 2.3 −/− brains were carried out by using semiquantitative reverse transcription-polymerase chain reaction (RT-PCR).Results: Both electrocorticographic and deep intrahippocampal recordings exhibited no spontaneous epileptiform discharges indicative of convulsive or nonconvulsive seizure activity during long-term observation. Gross histology and expression levels of other voltage-gated Ca 2+ channels remained unchanged in various brain regions. Surprisingly, PTZ-induced seizure susceptibility was dramatically reduced in Ca v 2.3-deficient mice, whereas 4-AP sensitivity remained unchanged.Conclusions: Ca v 2.3 ablation results in seizure resistance, strongly supporting recent findings in CA1 neurons that Ca v 2.3 triggers epileptiform activity in specialized neurons via plateau potentials and afterdepolarizations. We provide novel insight into the functional involvement of Ca v 2.3 in ictogenesis and seizure susceptibility on the whole-animal level.