All Three Supersystems-Nervous, Vascular, and Immune-Contribute to the Cortical Infarcts After Subarachnoid Hemorrhage.

The recently published DISCHARGE-1 trial supports the observations of earlier autopsy and neuroimaging studies that almost 70% of all focal brain damage after aneurysmal subarachnoid hemorrhage are anemic infarcts of the cortex, often also affecting the white matter immediately below. The infarcts are not limited by the usual vascular territories. About two-fifths of the ischemic damage occurs within ~ 48 h; the remaining three-fifths are delayed (within ~ 3 weeks). Using neuromonitoring technology in combination with longitudinal neuroimaging, the entire sequence of both early and delayed cortical infarct development after subarachnoid hemorrhage has recently been recorded in patients. Characteristically, cortical infarcts are caused by acute severe vasospastic events, so-called spreading ischemia, triggered by spontaneously occurring spreading depolarization. In locations where a spreading depolarization passes through, cerebral blood flow can drastically drop within a few seconds and remain suppressed for minutes or even hours, often followed by high-amplitude, sustained hyperemia. In spreading depolarization, neurons lead the event, and the other cells of the neurovascular unit (endothelium, vascular smooth muscle, pericytes, astrocytes, microglia, oligodendrocytes) follow. However, dysregulation in cells of all three supersystems-nervous, vascular, and immune-is very likely involved in the dysfunction of the neurovascular unit underlying spreading ischemia. It is assumed that subarachnoid blood, which lies directly on the cortex and enters the parenchyma via glymphatic channels, triggers these dysregulations. This review discusses the neuroglial, neurovascular, and neuroimmunological dysregulations in the context of spreading depolarization and spreading ischemia as critical elements in the pathogenesis of cortical infarcts after subarachnoid hemorrhage.

Kinetics of Hepatitis E Virus Infections in Asymptomatic Persons.

To determine the kinetics of hepatitis E virus (HEV) in asymptomatic persons and to evaluate viral load doubling time and half-life, we retrospectively tested samples retained from 32 HEV RNA-positive asymptomatic blood donors in Germany. Close-meshed monitoring of viral load and seroconversion in intervals of ≈4 days provided more information about the kinetics of asymptomatic HEV infections. We determined that a typical median infection began with PCR-detectable viremia at 36 days and a maximum viral load of 2.0 × 104 IU/mL. Viremia doubled in 2.4 days and had a half-life of 1.6 days. HEV IgM started to rise on about day 33 and peaked on day 36; IgG started to rise on about day 32 and peaked on day 53. Although HEV IgG titers remained stable, IgM titers became undetectable in 40% of donors. Knowledge of the dynamics of HEV viremia is useful for assessing the risk for transfusion-transmitted hepatitis E.

Signatures of migraine aura in high-density-EEG.

OBJECTIVE: Cortical spreading depolarization is highly conserved among the species. It is easily detectable in direct cortical surface recordings and has been recorded in the cortex of humans with severe neurological disease. It is considered the pathophysiological correlate of human migraine aura, but direct electrophysiological evidence is still missing. As signatures of cortical spreading depolarization have been recognized in scalp EEG, we investigated typical spontaneous migraine aura, using full band high-density EEG (HD-EEG). METHODS: In this prospective study, patients with migraine with aura were investigated during spontaneous migraine aura and interictally. Time compressed HD-EEG were analyzed for the presence of cortical spreading depolarization characterized by (a) slow potential changes below 0.05 Hz, (b) suppression of faster activity from 0.5 Hz - 45 Hz (c) spreading of these changes to neighboring regions during the aura phase. Further, topographical changes in alpha-power spectral density (8-14 Hz) during aura were analyzed. RESULTS: In total, 26 HD-EEGs were recorded in patients with migraine with aura, thereof 10 HD-EEGs during aura. Eight HD-EEGs were recorded in the same subject. During aura, no slow potentials were recorded, but alpha-power was significantly decreased in parieto-occipito-temporal location on the hemisphere contralateral to visual aura, lasting into the headache phase. Interictal alpha-power in patients with migraine with aura did not differ significantly from age- and sex-matched healthy controls. CONCLUSIONS: Unequivocal signatures of spreading depolarization were not recorded with EEG on the intact scalp in migraine. The decrease in alpha-power contralateral to predominant visual symptoms is consistent with focal depression of spontaneous brain activity as a consequence of cortical spreading depolarization but is not specific thereof. SIGNIFICANCE: Cortical spreading depolarization is relevant in migraine, other paroxysmal neurological disorders and neurointensive care.

Similarities in the Electrographic Patterns of Delayed Cerebral Infarction and Brain Death After Aneurysmal and Traumatic Subarachnoid Hemorrhage.

While subarachnoid hemorrhage is the second most common hemorrhagic stroke in epidemiologic studies, the recent DISCHARGE-1 trial has shown that in reality, three-quarters of focal brain damage after subarachnoid hemorrhage is ischemic. Two-fifths of these ischemic infarctions occur early and three-fifths are delayed. The vast majority are cortical infarcts whose pathomorphology corresponds to anemic infarcts. Therefore, we propose in this review that subarachnoid hemorrhage as an ischemic-hemorrhagic stroke is rather a third, separate entity in addition to purely ischemic or hemorrhagic strokes. Cumulative focal brain damage, determined by neuroimaging after the first 2 weeks, is the strongest known predictor of patient outcome half a year after the initial hemorrhage. Because of the unique ability to implant neuromonitoring probes at the brain surface before stroke onset and to perform longitudinal MRI scans before and after stroke, delayed cerebral ischemia is currently the stroke variant in humans whose pathophysiological details are by far the best characterized. Optoelectrodes located directly over newly developing delayed infarcts have shown that, as mechanistic correlates of infarct development, spreading depolarizations trigger (1) spreading ischemia, (2) severe hypoxia, (3) persistent activity depression, and (4) transition from clustered spreading depolarizations to a negative ultraslow potential. Furthermore, traumatic brain injury and subarachnoid hemorrhage are the second and third most common etiologies of brain death during continued systemic circulation. Here, we use examples to illustrate that although the pathophysiological cascades associated with brain death are global, they closely resemble the local cascades associated with the development of delayed cerebral infarcts.

Memantine inhibits cortical spreading depolarization and improves neurovascular function following repetitive traumatic brain injury.

Cortical spreading depolarization (CSD) is a promising target for neuroprotective therapy in traumatic brain injury (TBI). We explored the effect of NMDA receptor antagonism on electrically triggered CSDs in healthy and brain-injured animals. Rats received either one moderate or four daily repetitive mild closed head impacts (rmTBI). Ninety-three animals underwent craniectomy with electrocorticographic (ECoG) and local blood flow monitoring. In brain-injured animals, ketamine or memantine inhibited CSDs in 44 to 88% and 50 to 67% of cases, respectively. Near-DC/AC-ECoG amplitude was reduced by 44 to 75% and 52 to 67%, and duration by 39 to 87% and 61 to 78%, respectively. Daily memantine significantly reduced spreading depression and oligemia following CSD. Animals (N = 31) were randomized to either memantine (10 mg/kg) or saline with daily neurobehavioral testing. Memantine-treated animals had higher neurological scores. We demonstrate that memantine improved neurovascular function following CSD in sham and brain-injured animals. Memantine also prevented neurological decline in a blinded, preclinical randomized rmTBI trial.

Isoflurane lowers the cerebral metabolic rate of oxygen and prevents hypoxia during cortical spreading depolarization in vitro: An integrative experimental and modeling study.

Cortical spreading depolarization (SD) imposes a massive increase in energy demand and therefore evolves as a target for treatment following acute brain injuries. Anesthetics are empirically used to reduce energy metabolism in critical brain conditions, yet their effect on metabolism during SD remains largely unknown. We investigated oxidative metabolism during SD in brain slices from Wistar rats. Extracellular potassium ([K+]o), local field potential and partial tissue oxygen pressure (ptiO2) were measured simultaneously. The cerebral metabolic rate of oxygen (CMRO2) was calculated using a reaction-diffusion model. By that, we tested the effect of clinically relevant concentrations of isoflurane on CMRO2 during SD and modeled tissue oxygenation for different capillary pO2 values. During SD, CMRO2 increased 2.7-fold, resulting in transient hypoxia in the slice core. Isoflurane decreased CMRO2, reduced peak [K+]o, and prolonged [K+]o clearance, which indicates reduced synaptic transmission and sodium-potassium ATPase inhibition. Modeling tissue oxygenation during SD illustrates the need for increased capillary pO2 levels to prevent hypoxia. In the absence thereof, isoflurane could improve tissue oxygenation by lowering CMRO2. Therefore, isoflurane is a promising candidate for pre-clinical studies on neuronal survival in conditions involving SD.

Diversity of cortical activity changes beyond depression during Spreading Depolarizations.

Spreading depolarizations (SDs) are classically thought to be associated with spreading depression of cortical activity. Here, we found that SDs in patients with subarachnoid hemorrhage produce variable, ranging from depression to booming, changes in electrocorticographic activity, especially in the delta frequency band. In rats, depression of activity was characteristic of high-potassium-induced full SDs, whereas partial superficial SDs caused either little change or a boom of activity at the cortical vertex, supported by volume conduction of signals from spared delta generators in the deep cortical layers. Partial SDs also caused moderate neuronal depolarization and sustained excitation, organized in gamma oscillations in a narrow sub-SD zone. Thus, our study challenges the concept of homology between spreading depolarization and spreading depression by showing that SDs produce variable, from depression to booming, changes in activity at the cortical surface and in different cortical layers depending on the depth of SD penetration.

Prediction of Stroke Outcome in Mice Based on Noninvasive MRI and Behavioral Testing.

BACKGROUND: Prediction of poststroke outcome using the degree of subacute deficit or magnetic resonance imaging is well studied in humans. While mice are the most commonly used animals in preclinical stroke research, systematic analysis of outcome predictors is lacking. METHODS: We intended to incorporate heterogeneity into our retrospective study to broaden the applicability of our findings and prediction tools. We therefore analyzed the effect of 30, 45, and 60 minutes of arterial occlusion on the variance of stroke volumes. Next, we built a heterogeneous cohort of 215 mice using data from 15 studies that included 45 minutes of middle cerebral artery occlusion and various genotypes. Motor function was measured using a modified protocol for the staircase test of skilled reaching. Phases of subacute and residual deficit were defined. Magnetic resonance images of stroke lesions were coregistered on the Allen Mouse Brain Atlas to characterize stroke topology. Different random forest prediction models that either used motor-functional deficit or imaging parameters were generated for the subacute and residual deficits. RESULTS: Variance of stroke volumes was increased by 45 minutes of arterial occlusion compared with 60 minutes. The inclusion of various genotypes enhanced heterogeneity further. We detected both a subacute and residual motor-functional deficit after stroke in mice and different recovery trajectories could be observed. In mice with small cortical lesions, lesion volume was the best predictor of the subacute deficit. The residual deficit could be predicted most accurately by the degree of the subacute deficit. When using imaging parameters for the prediction of the residual deficit, including information about the lesion topology increased prediction accuracy. A subset of anatomic regions within the ischemic lesion had particular impact on the prediction of long-term outcomes. Prediction accuracy depended on the degree of functional impairment. CONCLUSIONS: For the first time, we developed and validated a robust tool for the prediction of functional outcomes after experimental stroke in mice using a large and genetically heterogeneous cohort. These results are discussed in light of study design and imaging limitations. In the future, using outcome prediction can improve the design of preclinical studies and guide intervention decisions.

Dual-Temperature Microbiological Control of Cellular Products: A Potential Impact for Bacterial Screening of Platelet Concentrates?

An experimental study by the Paul-Ehrlich Institute (PEI) demonstrated that temperatures between 35 and 37 °C are too high for the growth of some bacterial strains (e.g., Pseudomonas fluorescens), leading to false negative results. Thus, the question of whether it is necessary to adapt incubation temperatures for the microbiological control of blood products, especially platelet concentrates (PCs), to enhance safety and regulatory compliance has arisen. In order to further elucidate this issue, the growth capability of different bacterial strains of interest in PCs and the detection efficacy of cultivation of these at different incubation temperatures must be taken into account. Therefore, we inoculated PCs with 46 different strains (3-6 PCs from different donors per strain) from different origins (PC isolates, reference strains) and stored PCs at 20-22 °C under constant agitation. On day three of storage, the inoculated PCs were sampled; aerobic and anaerobic culture bottles (BacT/Alert AST/NST) were each inoculated with 5 mL of sample, and culture bottles were incubated at 25 and 35 °C using the automated BacT/Alert Dual-temperature system. Bacterial proliferation was enumerated using a colony-forming assay. All strains of Enterobacteriacae (n = 5), Staphy-lococcus spp. (n = 11), Streptococcus spp. (n = 5), and Bacillus spp. (n = 4) and most Pseudomonas aeruginosa strains (4 of 5) tested showed the capability to grow in most inoculated PCs, revealing a faster time to detection (TTD) at an incubation temperature of 35 °C. The tested Pseudomonas putida (n = 3) strains showed a noticeably reduced capability to grow in PCs. Nonetheless, those with a notable growth capability revealed a faster TTD at an incubation temperature of 35 °C. Only one of the four Pseudomonas fluorescens strains tested (strain ATCC 13525) was able to grow in PCs, showing a faster TTD at an incubation temperature of 25 °C but also detection at 35 °C. The commonly detected bacteria involved in the bacterial contamination of PCs showed a superior TTD at 35 °C incubation. Only one P. fluorescens strain showed superior growth at 25 °C; however, the microbiological control at 35 °C did not fail to identify this contamination. In conclusion, the use of PC screening using a dual-temperature setting for microbiological control is presently not justified according to the observed kinetics.

Near-death experiences are associated with rapid eye movement (REM) sleep intrusions in migraine patients, independent of migraine aura.

BACKGROUND AND PURPOSE: Migraine aura, near-death experiences (NDEs), and rapid eye movement (REM) sleep intrusions might share common mechanisms. Here, we investigated the prevalence of NDEs and REM sleep intrusions in people with migraine. We hypothesized that NDEs and REM sleep intrusions are more prevalent in migraine patients with aura than in those without. METHODS: We conducted a prospective cross-sectional cohort study at a tertiary headache center, based on a prespecified sample size (n = 808). Migraine patients completed a series of questionnaires, including questions about demographic and headache characteristics, the 16-item Greyson NDE scale, four questions about REM sleep intrusions, and the Depression, Anxiety, and Stress Scale 21 (DASS-21). RESULTS: Of 808 migraine patients (mean age 44.4 ± 13.3 years, 87.0% women), 353 (43.7%) had a current or previous history of migraine aura. Prevalence of NDE was 2.7% and not different in patients with and without aura (2.8% vs. 2.6%; p > 0.999). REM sleep intrusions were reported by 5.4% of participants and in a similar proportion of patients with and without aura (6.3% vs. 4.9%; p = 0.43). However, participants with REM sleep intrusions had had an NDE more often than participants without REM sleep intrusions (n = 5/44, 11.4% vs. n = 17/754, 2.2%; p = 0.005). Higher DASS-21 scores were associated with REM sleep intrusions (p < 0.001). CONCLUSIONS: In this tertiary center cohort study, the prevalence of NDE and REM sleep intrusions was not influenced by migraine aura status. However, we identified an association between NDE and REM sleep intrusions, which corroborates the notion that they might share pathophysiological mechanisms.

Improving Neurotrauma by Depolarization Inhibition With Combination Therapy: A Phase 2 Randomized Feasibility Trial.

BACKGROUND AND OBJECTIVES: Spreading depolarizations (SDs) are a pathological mechanism that mediates lesion development in cerebral gray matter. They occur in ∼60% of patients with severe traumatic brain injury (TBI), often in recurring and progressive patterns from days 0 to 10 after injury, and are associated with worse outcomes. However, there are no protocols or trials suggesting how SD monitoring might be incorporated into clinical management. The objective of this protocol is to determine the feasibility and efficacy of implementing a treatment protocol for intensive care of patients with severe TBI that is guided by electrocorticographic monitoring of SDs. METHODS: Patients who undergo surgery for severe TBI with placement of a subdural electrode strip will be eligible for enrollment. Those who exhibit SDs on electrocorticography during intensive care will be randomized 1:1 to either (1) standard care that is blinded to the further course of SDs or (2) a tiered intervention protocol based on efficacy to suppress further SDs. Interventions aim to block the triggering and propagation of SDs and include adjusted targets for management of blood pressure, CO 2 , temperature, and glucose, as well as ketamine pharmacotherapy up to 4 mg/kg/ hour. Interventions will be escalated and de-escalated depending on the course of SD pathology. EXPECTED OUTCOMES: We expect to demonstrate that electrocorticographic monitoring of SDs can be used as a real- time diagnostic in intensive care that leads to meaningful changes in patient management and a reduction in secondary injury, as compared with standard care, without increasing medical complications or adverse events. DISCUSSION: This trial holds potential for personalization of intensive care management by tailoring therapies based on monitoring and confirmation of the targeted neuronal mechanism of SD. Results are expected to validate the concept of this approach, inform refinement of the treatment protocol, and lead to larger-scale trials.

Spreading depolarization and angiographic spasm are separate mediators of delayed infarcts.

In DISCHARGE-1, a recent Phase III diagnostic trial in aneurysmal subarachnoid haemorrhage patients, spreading depolarization variables were found to be an independent real-time biomarker of delayed cerebral ischaemia. We here investigated based on prospectively collected data from DISCHARGE-1 whether delayed infarcts in the anterior, middle, or posterior cerebral artery territories correlate with (i) extravascular blood volumes; (ii) predefined spreading depolarization variables, or proximal vasospasm assessed by either (iii) digital subtraction angiography or (iv) transcranial Doppler-sonography; and whether spreading depolarizations and/or vasospasm are mediators between extravascular blood and delayed infarcts. Relationships between variable groups were analysed using Spearman correlations in 136 patients. Thereafter, principal component analyses were performed for each variable group. Obtained components were included in path models with a priori defined structure. In the first path model, we only included spreading depolarization variables, as our primary interest was to investigate spreading depolarizations. Standardised path coefficients were 0.22 for the path from extravascular bloodcomponent to depolarizationcomponent (P = 0.010); and 0.44 for the path from depolarizationcomponent to the first principal component of delayed infarct volume (P < 0.001); but only 0.07 for the direct path from bloodcomponent to delayed infarctcomponent (P = 0.36). Thus, the role of spreading depolarizations as a mediator between blood and delayed infarcts was confirmed. In the principal component analysis of extravascular blood volume, intraventricular haemorrhage was not represented in the first component. Therefore, based on the correlation analyses, we also constructed another path model with bloodcomponent without intraventricular haemorrhage as first and intraventricular haemorrhage as second extrinsic variable. We found two paths, one from (subarachnoid) bloodcomponent to delayed infarctcomponent with depolarizationcomponent as mediator (path coefficients from bloodcomponent to depolarizationcomponent = 0.23, P = 0.03; path coefficients from depolarizationcomponent to delayed infarctcomponent = 0.29, P = 0.002), and one from intraventricular haemorrhage to delayed infarctcomponent with angiographic vasospasmcomponent as mediator variable (path coefficients from intraventricular haemorrhage to vasospasmcomponent = 0.24, P = 0.03; path coefficients from vasospasmcomponent to delayed infarctcomponent = 0.35, P < 0.001). Human autopsy studies shaped the hypothesis that blood clots on the cortex surface suffice to cause delayed infarcts beneath the clots. Experimentally, clot-released factors induce cortical spreading depolarizations that trigger (i) neuronal cytotoxic oedema and (ii) spreading ischaemia. The statistical mediator role of spreading depolarization variables between subarachnoid blood volume and delayed infarct volume supports this pathogenetic concept. We did not find that angiographic vasospasm triggers spreading depolarizations, but angiographic vasospasm contributed to delayed infarct volume. This could possibly result from enhancement of spreading depolarization-induced spreading ischaemia by reduced upstream blood supply.

Deep Isoflurane Anesthesia Is Associated with Alterations in Ion Homeostasis and Specific Na+/K+-ATPase Impairment in the Rat Brain.

BACKGROUND: Maintenance of ion homeostasis is essential for normal brain function. Inhalational anesthetics are known to act on various receptors, but their effects on ion homeostatic systems, such as sodium/potassium-adenosine triphosphatase (Na+/K+-ATPase), remain largely unexplored. Based on reports demonstrating global network activity and wakefulness modulation by interstitial ions, the hypothesis was that deep isoflurane anesthesia affects ion homeostasis and the key mechanism for clearing extracellular potassium, Na+/K+-ATPase. METHODS: Using ion-selective microelectrodes, this study assessed isoflurane-induced extracellular ion dynamics in cortical slices of male and female Wistar rats in the absence of synaptic activity, in the presence of two-pore-domain potassium channel antagonists, during seizures, and during spreading depolarizations. The specific isoflurane effects on Na+/K+-ATPase function were measured using a coupled enzyme assay and studied the relevance of the findings in vivo and in silico. RESULTS: Isoflurane concentrations clinically relevant for burst suppression anesthesia increased baseline extracellular potassium (mean ± SD, 3.0 ± 0.0 vs. 3.9 ± 0.5 mM; P < 0.001; n = 39) and lowered extracellular sodium (153.4 ± 0.8 vs. 145.2 ± 6.0 mM; P < 0.001; n = 28). Similar changes in extracellular potassium and extracellular sodium and a substantial drop in extracellular calcium (1.5 ± 0.0 vs. 1.2 ± 0.1 mM; P = 0.001; n = 16) during inhibition of synaptic activity and two-pore-domain potassium suggested a different underlying mechanism. After seizure-like events and spreading depolarization, isoflurane greatly slowed extracellular potassium clearance (63.4 ± 18.2 vs. 196.2 ± 82.4 s; P < 0.001; n = 14). Na+/K+-ATPase activity was markedly reduced after isoflurane exposure (greater than 25%), affecting specifically the α2/3 activity fraction. In vivo, isoflurane-induced burst suppression resulted in impaired extracellular potassium clearance and interstitial potassium accumulation. A computational biophysical model reproduced the observed effects on extracellular potassium and displayed intensified bursting when Na+/K+-ATPase activity was reduced by 35%. Finally, Na+/K+-ATPase inhibition with ouabain induced burst-like activity during light anesthesia in vivo. CONCLUSIONS: The results demonstrate cortical ion homeostasis perturbation and specific Na+/K+-ATPase impairment during deep isoflurane anesthesia. Slowed potassium clearance and extracellular accumulation might modulate cortical excitability during burst suppression generation, while prolonged Na+/K+-ATPase impairment could contribute to neuronal dysfunction after deep anesthesia.

Cerebrovascular Pressure Reactivity According to Long-Pressure Reactivity Index During Spreading Depolarizations in Aneurysmal Subarachnoid Hemorrhage.

BACKGROUND: Spreading depolarization (SD) has been linked to the impairment of neurovascular coupling. However, the association between SD occurrence and cerebrovascular pressure reactivity as a surrogate of cerebral autoregulation (CA) remains unclear. Therefore, we analyzed CA using the long-pressure reactivity index (L-PRx) during SDs in patients with aneurysmal subarachnoid hemorrhage (aSAH). METHODS: A retrospective study of patients with aSAH who were recruited at two centers, Heidelberg (HD) and Berlin (BE), was performed. Continuous monitoring of mean arterial pressure (MAP) and intracranial pressure (ICP) was recorded. ICP was measured using an intraparenchymal probe in HD patients and was measure in BE patients through external ventricular drainage. Electrocorticographic (ECoG) activity was continuously recorded between 3 and 13 days after hemorrhage. Autoregulation according to L-PRx was calculated as a moving linear Pearson's correlation of 20-min averages of MAP and ICP. For every identified SD, 60-min intervals of L-PRx were averaged, plotted, and analyzed depending on SD occurrence. Random L-PRx recording periods without SDs served as the control. RESULTS: A total of 19 patients (HD n = 14, BE n = 5, mean age 50.4 years, 9 female patients) were monitored for a mean duration of 230.4 h (range 96-360, STD ± 69.6 h), during which ECoG recordings revealed a total number of 277 SDs. Of these, 184 represented a single SD, and 93 SDs presented in clusters. In HD patients, mean L-PRx values were 0.12 (95% confidence interval [CI] 0.11-0.13) during SDs and 0.07 (95% CI 0.06-0.08) during control periods (p < 0.001). Similarly, in BE patients, a higher L-PRx value of 0.11 (95% CI 0.11-0.12) was detected during SDs than that during control periods (0.08, 95% CI 0.07-0.09; p < 0.001). In a more detailed analysis, CA changes registered through an intraparenchymal probe (HD patients) revealed that clustered SD periods were characterized by signs of more severely impaired CA (L-PRx during SD in clusters: 0.23 [95% CI 0.20-0.25]; single SD: 0.09 [95% CI 0.08-0.10]; control periods: 0.07 [95% CI 0.06-0.08]; p < 0.001). This group also showed significant increases in ICP during SDs in clusters compared with single SD and control periods. CONCLUSIONS: Neuromonitoring for simultaneous assessment of cerebrovascular pressure reactivity using 20-min averages of MAP and ICP measured by L-PRx during SD events is feasible. SD occurrence was associated with significant increases in L-PRx values indicative of CA disturbances. An impaired CA was found during SD in clusters when using an intraparenchymal probe. This preliminary study validates the use of cerebrovascular reactivity indices to evaluate CA disturbances during SDs. Our results warrant further investigation in larger prospective patient cohorts.

Stroke-prone salt-sensitive spontaneously hypertensive rats show higher susceptibility to spreading depolarization (SD) and altered hemodynamic responses to SD.

Spreading depolarization (SD) occurs in a plethora of clinical conditions including migraine aura, delayed ischemia after subarachnoid hemorrhage and malignant hemispheric stroke. It describes waves of near-breakdown of ion homeostasis, particularly Na+ homeostasis in brain gray matter. SD induces tone alterations in resistance vessels, causing either hyperperfusion in healthy tissue; or hypoperfusion (inverse hemodynamic response = spreading ischemia) in tissue at risk. Observations from mice with genetic dysfunction of the ATP1A2-encoded α2-isoform of Na+/K+-ATPase (α2NaKA) suggest a mechanistic link between (1) SD, (2) vascular dysfunction, and (3) salt-sensitive hypertension via α2NaKA. Thus, α2NaKA-dysfunctional mice are more susceptible to SD and show a shift toward more inverse hemodynamic responses. α2NaKA-dysfunctional patients suffer from familial hemiplegic migraine type 2, a Mendelian model disease of SD. α2NaKA-dysfunctional mice are also a genetic model of salt-sensitive hypertension. To determine whether SD thresholds and hemodynamic responses are also altered in other genetic models of salt-sensitive hypertension, we examined these variables in stroke-prone spontaneously hypertensive rats (SHRsp). Compared with Wistar Kyoto control rats, we found in SHRsp that electrical SD threshold was significantly reduced, propagation speed was increased, and inverse hemodynamic responses were prolonged. These results may have relevance to both migraine with aura and stroke.

Eighteen-hour inhibitory effect of s-ketamine on potassium- and ischemia-induced spreading depolarizations in the gyrencephalic swine brain.

Spreading depolarizations (SDs) are characterized by near-complete breakdown of the transmembrane ion gradients, cytotoxic edema, and glutamate release. SDs are associated with poor neurological outcomes in cerebrovascular diseases and brain trauma. Ketamine, a N-methyl-d-aspartate receptor antagonist, has shown to inhibit SDs in animal models and in humans. However, little is known about its SD-inhibitory effect during long-term administration. Lissencephalic animal models have shown that ketamine loses its SD-blocking effect after some minutes to hours. Physio-anatomical differences between lissencephalic and the more evolved gyrencephalic animals may affect their SDs-blocking effect. Therefore, information from the last may have more translational potential. Therefore, the aim of this study was to investigate the 18 h-effect of s-ketamine as a basis for its possible long-term clinical use for neuroprotection. For this purpose, two gyrencephalic swine brain models were used. In one, SDs were elicited through topical application of KCl; in the other model, SDs were spontaneously induced after occlusion of the middle cerebral artery. S-ketamine was administered at therapeutic human doses, 2, 4 and 5 mg/kg BW/h for up to 18 h. Our findings indicate that s-ketamine significantly reduces SD incidence and expansion without clear evidence of loss of its efficacy. Pharmacological susceptibility of SDs to s-ketamine in both the ischemic gyrencephalic brain and well-perfused brain was observed. SDs were most potently inhibited by s-ketamine doses that are above the clinically recommended (4 mg/kg BW/h and 5 mg/kg BW/h). Nonetheless, such doses are given by neurointensivists in individual cases. Our results give momentum to further investigate the feasibility of a multicenter, neuromonitoring-guided, proof-of-concept clinical trial.

Increased Direct Current-Electroencephalography Shifts During Induction of Anesthesia in Elderly Patients Developing Postoperative Delirium.

Background: Changes in the direct current (DC) electroencephalography (EEG), so-called DC shifts, are observed during hypoxia, hypo-/hypercapnia, anesthetic administration, epileptic seizures, and spreading depolarizations. They are associated with altered cerebral ion currents across cell membranes and/or the blood-brain barrier (BBB). Here, we measured DC shifts in clinical practice during hyperventilation (HV) and anesthesia induction, and investigated whether such DC shifts correlate with the occurrence of postoperative delirium (POD) in older patients. Methods: In this prospective observational study (subproject of the BioCog study, NCT02265263; EA2/092/14), a continuous pre- and perioperative DC-EEG was recorded in patients aged ≥65 years. The preoperative DC-EEG included a 2 min HV with simultaneous measurement of end-tidal CO2. Of the perioperative recordings, DC-EEG segments were chosen from a 30 s period at the start of induction of anesthesia (IOA), loss of consciousness (LOC), and during a stable anesthetic phase 30 min after skin incision (intraOP). The DC shift at Cz was determined in µV/s. All patients were screened twice daily for the first seven postoperative days for the occurrence of POD. DC-EEG shifts were compared in patients with (POD) and without postoperative delirium (noPOD). Results: Fifteen patients were included in this subproject of the BioCog study. DC shifts correlated significantly with concurrent HV, with DC shifts increasing the more end-tidal CO2 decreased (P = 0.001, Spearman's rho 0.862). During the perioperative DC-EEG, the largest DC shift was observed at LOC during IOA. POD patients (n = 8) presented with significantly larger DC shifts at LOC [POD 31.6 (22.7; 38.9) µV/s vs. noPOD 4.7 (2.2; 12.5) µV/s, P = 0.026]. Conclusion: DC shifts can be observed during HV and IOA in routine clinical practice. At anesthesia induction, the DC shift was greatest at the time of LOC, with POD patients presenting with significantly stronger DC shifts. This could indicate larger changes in gas tensions, hypotension and impaired cerebral autoregulation or BBB dysfunction in these patients. Clinical Trial Registration: www.clinicaltrials.gov, identifier NCT02265263.

Course of Preexisting Migraine Following Spontaneous Subarachnoid Hemorrhage.

Background: Our objective was to observe the course of preexisting migraine following subarachnoid hemorrhage (SAH) in patients with and without craniotomy. Methods: We designed an exploratory analysis and hypothesis-generating study of prospectively collected data starting by recruiting patients suffering from SAH with the Hunt and Hess scale score of ≤ 4. Out of 994 cases, we identified 46 patients with preexisting active migraine defined by at least four attacks in the year before SAH. According to the treatment, we subdivided the patients into two groups: the first group included patients with surgical aneurysm clipping with transection of the middle meningeal artery (MMA) and accompanying trigeminal nerve branches and the second group included patients with endovascular aneurysm coiling or without any interventional treatment. During the follow-up, we recorded the course of migraine frequency, duration, intensity, and character. Results: For both groups (craniotomy n = 31, without craniotomy n = 15), a significant improvement regarding the preexisting migraine during a mean follow-up of 46 months (min. 12 months, max. 114 months) was seen regarding complete remission or at least >50% reduction in migraine attacks (p < 0.001 and p = 0.01). On comparing the groups, this effect was significantly more pronounced in patients with craniotomy (for no recurrence of migraine: p = 0.049). After craniotomy, 77.4% of the patients had no further attacks of migraine headache and 19.4% showed a reduction of >50% while only 2.2% did not report any relevant change. In the non-surgical group, 46.7% had no further migraine attacks, 20% had a reduction of >50%, while no change was noted in 33.3%. Conclusions: Our study provides evidence that the dura mater might be related to migraine headaches and that transection of the MMA and accompanying trigeminal dural nerve branches might disrupt the pathway leading to a reduction of migraine attacks. However, coiling alone ameliorated migraine complaints.