Nora Sandow

Delayed Cerebral Ischemia and Spreading Depolarization in Absence of Angiographic Vasospasm after Subarachnoid Hemorrhage

It has been hypothesized that vasospasm is the prime mechanism of delayed cerebral ischemia (DCI) after aneurysmal subarachnoid hemorrhage (aSAH). Recently, it was found that clusters of spreading depolarizations (SDs) are associated with DCI. Surgical placement of nicardipine prolonged-release implants (NPRIs) was shown to strongly attenuate vasospasm. In the present study, we tested whether SDs and DCI are abolished when vasospasm is reduced or abolished by NPRIs. After aneurysm clipping, 10 NPRIs were placed next to the proximal intracranial vessels. The SDs were recorded using a subdural electrode strip. Proximal vasospasm was assessed by digital subtraction angiography (DSA). 534 SDs were recorded in 10 of 13 patients (77%). Digital subtraction angiography revealed no vasospasm in 8 of 13 patients (62%) and only mild or moderate vasospasm in the remaining. Five patients developed DCI associated with clusters of SD despite the absence of angiographic vasospasm in three of those patients. The number of SDs correlated significantly with the development of DCI. This may explain why reduction of angiographic vasospasm alone has not been sufficient to improve outcome in some clinical studies.

Propagation of cortical spreading depolarization in the human cortex after malignant stroke

Objective: To investigate hemodynamic response pattern and spatiotemporal propagation of cortical spreading depolarization in the peri-infarct region of malignant hemispheric stroke. Methods: In this prospective observational case study we used intraoperative laser speckle technology to measure cerebral blood flow in patients with malignant hemispheric stroke. Additionally, postoperative occurrence of cortical spreading depolarization was monitored using a subdural recording strip for electrocorticography and infarct progression was assessed by serial MRI. Results: In 7 of 20 patients, 19 blood flow changes typical of cortical spreading depolarizations occurred during a 20-minute period. Thirteen events were characterized by increase, 2 by biphasic response, and 4 by decrease of blood flow. Propagation velocity ranged from 1.7 to 9.2 mm/min and propagation area from 0.1 to 4.8 cm2. Intrinsic optical signal alterations preceded and low-frequency vascular fluctuations were suppressed during the hemodynamic responses. A mean number of 56 ± 82 cortical spreading depolarizations per patient was recorded and a mean infarct progression of 30 ± 13 cm3 was detected in 5 of 7 patients. Conclusions: We visualize the spatiotemporal propagation of spreading depolarizations in the human cerebral cortex intraoperatively. In patients with focal ischemia, multiple cortical spreading depolarizations with either hyperemic or hypoemic flow responses occurred. Our data suggest that, in patients with focal ischemia, cortical spreading depolarizations are associated with both unfavorable and protective hemodynamic responses.

Impaired neurovascular coupling to ictal epileptic activity and spreading depolarization in a patient with subarachnoid hemorrhage: Possible link to blood–brain barrier dysfunction

Spreading depolarization describes a sustained neuronal and astroglial depolarization with abrupt ion translocation between intraneuronal and extracellular space leading to a cytotoxic edema and silencing of spontaneous activity. Spreading depolarizations occur abundantly in acutely injured human brain and are assumed to facilitate neuronal death through toxic effects, increased metabolic demand, and inverse neurovascular coupling. Inverse coupling describes severe hypoperfusion in response to spreading depolarization. Ictal epileptic events are less frequent than spreading depolarizations in acutely injured human brain but may also contribute to lesion progression through increased metabolic demand. Whether abnormal neurovascular coupling can occur with ictal epileptic events is unknown. Herein we describe a patient with aneurysmal subarachnoid hemorrhage in whom spreading depolarizations and ictal epileptic events were measured using subdural opto‐electrodes for direct current electrocorticography and regional cerebral blood flow recordings with laser‐Doppler flowmetry. Simultaneously, changes in tissue partial pressure of oxygen were recorded with an intraparenchymal oxygen sensor. Isolated spreading depolarizations and clusters of recurrent spreading depolarizations with persistent depression of spontaneous activity were recorded over several days followed by a status epilepticus. Both spreading depolarizations and ictal epileptic events where accompanied by hyperemic blood flow responses at one optode but mildly hypoemic blood flow responses at another. Of note, quantitative analysis of Gadolinium‐diethylene‐triamine‐pentaacetic acid (DTPA)–enhanced magnetic resonance imaging detected impaired blood–brain barrier integrity in the region where the optode had recorded the mildly hypoemic flow responses. The data suggest that abnormal flow responses to spreading depolarizations and ictal epileptic events, respectively, may be associated with blood–brain barrier dysfunction.

In vitro seizure like events and changes in ionic concentration

BACKGROUND In vivo, seizure like events are associated with increases in extracellular K(+) concentration, decreases in extracellular Ca(2+) concentration, diphasic changes in extracellular sodium, chloride, and proton concentration, as well as changes of extracellular space size. These changes point to mechanisms underlying the induction, spread and termination of seizure like events. METHODS We investigated the potential role of alterations of the ionic environment on the induction of seizure like events-considering a review of the literature and own experimental work in animal and human slices. RESULTS Increasing extracellular K(+) concentration, lowering extracellular Mg(2+) concentration, or lowering extracellular Ca(2+) concentration can induce seizure like events. In human tissue from epileptic patients, elevation of K(+) concentration induces seizure like events in the dentate gyrus and subiculum. A combination of elevated K(+) concentration and 4-AP or bicuculline can induce seizure like events in neocortical tissue. CONCLUSIONS These protocols provide insight into the mechanisms involved in seizure initiation, spread and termination. Moreover, pharmacological studies as well as studies on mechanisms underlying pharmacoresistance are feasible.

Drug Resistance in Cortical and Hippocampal Slices from Resected Tissue of Epilepsy Patients: No Significant Impact of P-Glycoprotein and Multidrug Resistance-Associated Proteins

Drug resistant patients undergoing epilepsy surgery have a good chance to become sensitive to anticonvulsant medication, suggesting that the resected brain tissue is responsible for drug resistance. Here, we address the question whether P-glycoprotein (Pgp) and multidrug resistance-associated proteins (MRPs) expressed in the resected tissue contribute to drug resistance in vitro. Effects of anti-epileptic drugs [carbamazepine (CBZ), sodium valproate, phenytoin] and two unspecific inhibitors of Pgp and MRPs [verapamil (VPM) and probenecid (PBN)] on seizure-like events (SLEs) induced in slices from 35 hippocampal and 35 temporal cortex specimens of altogether 51 patients (161 slices) were studied. Although in slice preparations the blood brain barrier is not functional, we found that SLEs predominantly persisted in the presence of anticonvulsant drugs (90%) and also in the presence of VPM and PBN (86%). Following subsequent co-administration of anti-epileptic drugs and drug transport inhibitors, SLEs continued in 63% of 143 slices. Drug sensitivity in slices was recognized either as transition to recurrent epileptiform transients (30%) or as suppression (7%), particularly by perfusion with CBZ in PBN containing solutions (43, 9%). Summarizing responses to co-administration from more than one slice per patient revealed that suppression of seizure-like activity in all slices was only observed in 7% of patients. Patients whose tissue was completely or partially sensitive (65%) presented with higher seizure frequencies than those with resistant tissue (35%). However, corresponding subgroups of patients do not differ with respect to expression rates of drug transporters. Our results imply that parenchymal MRPs and Pgp are not responsible for drug resistance in resected tissue.

Glutamine induces epileptiform discharges in superficial layers of the medial entorhinal cortex from pilocarpine-treated chronic epileptic rats in vitro

Purpose:  Glutamine (GLN) is a precursor for synthesis of glutamate and γ‐aminobutyric acid (GABA) and has been found in the cerebrospinal fluid (CSF) at mean concentrations of 0.6 mM. Experiments on slices are usually performed in artificial CSF (aCSF) kept free of amino acids. Therefore, the role of glutamine, particularly in tissue of epileptic animals, remains elusive.

Excitotoxicity and Metabolic Changes in Association With Infarct Progression

Background and Purpose— We investigated to what extent excitotoxicity and metabolic changes in the peri-infarct region of patients with malignant hemispheric stroke are associated with delayed infarct progression. Methods— In 18 patients with malignant hemispheric stroke, 2 microdialysis probes were implanted within the peri-infarct tissue at a distance of 5 and 15 mm to the infarct. Precise probe placement was achieved by intraoperative laser speckle imaging. Glutamate, glucose, pyruvate, and lactate levels were monitored for 5 days after surgery. Delayed infarct progression was determined from serial MRI on the day after surgery and after the monitoring period. Results— Initial stroke volume ranged from 122 to 479 cm3 with a median of 295 cm3. Nine of 18 patients (50%) had delayed infarct progression (median, 44 cm3; range, 19–93 cm3). In these patients, glucose and individual pyruvate levels were significantly lower when compared with patients without infarct progression, whereas glutamate and the lactate–pyruvate ratio were significantly elevated in patients with infarct progression early after surgery (12–36 hours) at the 15-mm microdialysis probe location. Lactate was elevated but without difference between groups. Conclusions— Excitotoxic or metabolic impairment was associated with delayed infarct progression and could serve as a treatment target.

Reduced ictogenic potential of 4-aminopyridine in the hippocampal region in the pilocarpine model of epilepsy

It was previously shown that the ictogenic potential of 4-aminopyridine (4-AP) was reduced in the parahippocampal region of kainate treated chronic epileptic rats. In the actual study we investigated the potential of 4-aminopyridine (50 and 100μM) to induce seizure like events (SLEs) in combined entorhinal cortex hippocampal slices from Wistar rats following pilocarpine induced status epilepticus. The potential of 4-AP to induce SLEs in the entorhinal cortex was reduced in the latent period and in slices of chronic epileptic animals with a high seizure incidence in vivo (>2seizures/24h). 4-AP induced SLEs in slices from animals with a low incidence of seizures in vivo (<2seizures/24h) in a similar manner as compared to controls. The hippocampal formation displayed no SLEs, instead short recurrent epileptiform discharges (REDs) were evoked by application of 4-AP in areas CA3 and CA1. The incidence of REDs was largest in slices from control animals. This study shows that the reduced ictogenic potential of 4-AP is not restricted to kainate treated chronic epileptic animals as it can be found in the pilocarpine model as well. The underlying mechanisms may relate to altered expression and editing of voltage gated potassium channels.

Extra-Intracranial Standard Bypass in the Elderly: Perioperative Risk, Bypass Patency and Outcome

Background: Patients with chronic atherosclerotic vessel occlusion and cerebrovascular hemodynamic insufficiency may benefit from extra-intracranial (EC-IC) bypass surgery. Due to demographic changes, an increasing number of elderly patients presents with cerebrovascular hemodynamic insufficiency. So far, little data for EC-IC bypass surgery in elderly patients suffering occlusive cerebrovascular disease are available. We therefore designed a retrospective study to address the question whether EC-IC bypass is a safe and efficient treatment in a patient cohort ≥70 years. Methods: 50 patients underwent EC-IC standard bypass surgery with translocation of the superficial temporal artery to an M2 segment of the medial cerebral artery. Criteria for bypass surgery were presence of symptomatic occlusive cerebrovascular disease of the anterior circulation and proof of a severely restricted or abrogated reserve capacity (detected by H2O-photon emission tomography or single photon emission computer tomography - before and after forced vessel dilatation by diamox). The incidence of perioperative neurological and surgical complications, bypass patency, bypass function and short-term outcome were retrospectively analyzed. Results: The study cohort consisted of 16 patients ≥70 years (mean = 74.3 years, SE 1.3). It was compared to a cohort of 34 patients <70 years (mean = 61.2 years, SE 1.0). Both groups underwent EC-IC bypass surgery after careful preoperative work-up. Both patient groups did not differ significantly in gender, vascular pathology, previous history of diseases/comorbidity or clinical symptoms. The number of patients which underwent stenting or other endovascular treatments of the internal or common carotid artery prior to EC-IC bypass surgery was significantly higher in the group of patients ≥70 years (37.5 vs. 0%, p < 0.001). Perioperative stroke rate was 0% in both groups and mild morbidity occurred in 18.8 and 14.7%, respectively (p = 0.699). One 84-year-old female patient died due to perioperative endocarditis. Initial bypass patency was 93.8% in patients above the age of 70 years and 97.1% in the younger group (p = 0.542). Secondary occlusion rate was low in both groups (≥70 years: 0% vs. <70 years 3.7%). No new neurologic deficit occurred in patients with a patent bypass during the follow-up period (median 18 ± 13.1 months). Two patients with an initially occluded bypass and one with a secondary bypass occlusion suffered from new neurological symptoms. Conclusions: Our data show comparable safety and efficiency of EC-IC bypass surgery in patients under and above the age of 70 years due to a careful preoperative work-up and a strict indication for bypass surgery.

Infarct prediction by intraoperative laser speckle imaging in patients with malignant hemispheric stroke

Currently, a reliable method for real-time prediction of ischemia in the human brain is not available. Here, we took a first step towards validating non-invasive intraoperative laser speckle imaging (iLSI) for prediction of infarction in 22 patients undergoing decompressive surgery for treatment of malignant hemispheric stroke. During surgery, cortical perfusion was visualized and recorded in real-time with iLSI. The true morphological infarct extension within the iLSI imaging field was superimposed onto the iLSI blood flow maps according to a postoperative MRI (16 h [95% CI: 13, 19] after surgery) with three-dimensional magnetization-prepared rapid gradient-echo and diffusion-weighted imaging reconstruction. Based on the frequency distribution of iLSI perfusion values within the infarcted and non-infarcted territories, probability curves and perfusion thresholds of normalized cerebral blood flow predictive of eventual infarction or non-infarction were calculated. Intraoperative LSI predicted and excluded cortical ischemia with 95% probability at normalized perfusion levels below 40% and above 110%, respectively, which represented 73% of the entire cortical surface area. Together, our results suggest that iLSI is valid for (pseudo-) quantitative assessment of blood flow in the human brain and may be used to identify tissue at risk for infarction at a given time-point in the course of ischemic stroke.