Ketamine-induced prevention of SD-associated late infarct progression in experimental ischemia.

Spreading depolarizations (SDs) occur frequently in patients with malignant hemispheric stroke. In animal-based experiments, SDs have been shown to cause secondary neuronal damage and infarct expansion during the initial period of infarct progression. In contrast, the influence of SDs during the delayed period is not well characterized yet. Here, we analyzed the impact of SDs in the delayed phase after cerebral ischemia and the potential protective effect of ketamine. Focal ischemia was induced by distal occlusion of the left middle cerebral artery in C57BL6/J mice. 24 h after occlusion, SDs were measured using electrocorticography and laser-speckle imaging in three different study groups: control group without SD induction, SD induction with potassium chloride, and SD induction with potassium chloride and ketamine administration. Infarct progression was evaluated by sequential MRI scans. 24 h after occlusion, we observed spontaneous SDs with a rate of 0.33 SDs/hour which increased during potassium chloride application (3.37 SDs/hour). The analysis of the neurovascular coupling revealed prolonged hypoemic and hyperemic responses in this group. Stroke volume increased even 24 h after stroke onset in the SD-group. Ketamine treatment caused a lesser pronounced hypoemic response and prevented infarct growth in the delayed phase after experimental ischemia. Induction of SDs with potassium chloride was significantly associated with stroke progression even 24 h after stroke onset. Therefore, SD might be a significant contributor to delayed stroke progression. Ketamine might be a possible drug to prevent SD-induced delayed stroke progression.

Prevalence of visual snow syndrome in the UK.

BACKGROUND AND PURPOSE: Visual snow syndrome is a recently described condition of unknown prevalence. We investigated the prevalence in a representative population sample from the UK and tested the hypothesis that visual snow syndrome is associated with young age, headache, tinnitus and mood impairment. METHODS: Using a crowdsourcing platform, we recruited a representative sample of 1015 adult laypeople from the UK, matched for age, gender and ethnicity according to national census data. Participants were unprimed, i.e. were inquired about the 'frequency of certain medical conditions' but not 'visual snow syndrome'. RESULTS: A total of 38 of 1015 participants reported symptoms compatible with visual snow [3.7%; 95% confidence interval (CI), 2.7-5.2] and 22/1015 met criteria for visual snow syndrome (2.2%; 95% CI, 1.4-3.3). The female-to-male ratio for visual snow syndrome was 1.6:1. Subjects with visual snow syndrome were older (50.6 ± 14 years) than the population mean (44.8 ± 15 years), although this was not statistically different (P = 0.06). Of 22 participants with visual snow syndrome, 16 had mood symptoms (72.7%; P = 0.01), 12 had headache (54.5%; P = 0.06), including five with visual migraine aura (22.7%; P = 0.15) and 13 had tinnitus (59.1%; P < 0.001). No participant had diabetes or a cleft lip (control questions). Following a multivariable regression analysis to adjust for age and gender, only the association between visual snow syndrome and tinnitus remained significant (odds ratio, 3.93; 95% CI, 1.63-9.9; P = 0.003). CONCLUSIONS: The UK prevalence of visual snow syndrome is around 2%. We confirmed an association with tinnitus, but unprimed laypeople with visual snow syndrome are on average older than those seeking medical attention.

Cerebral lactate correlates with early onset pneumonia after aneurysmal SAH.

Pneumonia is a significant medical complication following aneurysmal subarachnoid hemorrhage (aSAH). The aSAH may initiate immune interactions leading to depressed immunofunction, followed by an increased risk of infection. It remains unclear as to whether there is a possible association between cerebral metabolism and infections. Clinical and microdialysis data from aSAH patients prospectively included in the CoOperative Study on Brain Injury Depolarisations protocol Berlin were analyzed. Levels of glucose, lactate, pyruvate, and glutamate were measured hourly using microdialysis in the cerebral extracellular fluid. The occurrence of pneumonia (defined by positive microbiological cultures) and delayed ischemic neurological deficits (DIND) was documented prospectively. Eighteen aSAH patients (52.7 ± 10.7 years), classified according to the World Federation of Neurological Surgeons in low (I-III, n = 9) and high (IV-V, n = 9) grades, were studied. Eight patients (45%) experienced DIND, 10 patients (56%) pneumonia (mean onset day 2.6). Lactate was elevated at day 3 in infected patients (n = 9, median = 6.82 mmol/L) vs. patient without infections (n = 6, median = 2.90 mmol/L, p = 0.036). The optimum cut-off point to predict pneumonia at day 3 was 3.57 mmol/L with a sensitivity of 0.77, and a specificity of 0.66 (area under curve was 0.833 with p = 0.034). Lactate at day 7 was higher in DIND patients compared to no-DIND-patients (p = 0.016). Early elevated lactate correlated with occurrence of bacterial pneumonia, while late elevations with DIND after aSAH. Future investigations may elucidate the relationship between cerebral lactate and markers of immunocompetence and more detailed to identify patients with higher susceptibility for infections.

Blood-brain barrier opening to large molecules does not imply blood-brain barrier opening to small ions.

Neuroimaging of exogenous tracer extravasation has become the technique of choice in preclinical and clinical studies of blood-brain barrier permeability. Such tracers have a larger molecular weight than small ions, neurotransmitters and many drugs. Therefore, it is assumed that tracer extravasation indicates both permeability to these and the cancelation of the electrical polarization across the barrier. Electrophysiological anomalies following intracarotideal administration of dehydrocholate, a bile salt causing extravasation of the albumin-binding tracer Evans blue, seemingly supported this. By contrast, electron microscopic studies suggested a different hierarchical pattern of blood-brain barrier dysfunction, a milder degree of impairment being characterized by increased function of the transcellular pathway and a severe degree by opening of the tight junctions. This would imply that the extravasation of macromolecules can occur before disruption of the electrical barrier. However, functional evidence for this has been lacking. Here, we further investigated the electrophysiological anomalies following intracarotideal application of dehydrocholate in rats and found that it caused focal cerebral ischemia by middle cerebral artery thrombosis, the electrophysiological recordings being characteristic of long-lasting spreading depolarization. These observations indicated that intracarotideal dehydrocholate is not a suitable model to study the isolated dysfunction of the blood-brain barrier. Second, we studied the topical application of dehydrocholate to the brain and the application of mannitol into the carotid artery. In both models, we found significant extravasation of Evans blue but no changes in either extracellular potassium or the CO(2)-dependent intracortical direct current deflection. The latter is assumed to depend on the proton gradient across the barrier in rats which we confirmed in additional experiments in vivo and in vitro. The stability of the extracellular potassium concentration and the CO(2)-dependent direct current deflection are two functional tests which indicate the integrity of the electrical barrier. Hence, our results provide functional evidence that the blood-brain barrier opening to large molecules does not necessarily imply the opening to small ions consistent with the hierarchy of damage in the previous electron microscopic studies.

Peri-infarct flow transients predict outcome in rat focal brain ischemia.

Spreading depolarizations are accompanied by transient changes in cerebral blood flow (CBF). In a post hoc analysis of previously studied control rats we analyzed CBF time courses after middle cerebral artery occlusion in the rat in order to test whether intra-ischemic flow, reperfusion, and different parameters of peri-infarct flow transients (PIFTs) (amplitude, number) can predict outcome. Sprague-Dawley rats anesthetized with either halothane (n=23) or isoflurane (n=32) underwent 90-min filament occlusion of the middle cerebral artery followed by 72 h of reperfusion. The infarct size was determined by 2,3,5-triphenyltetrazolium chloride staining. Relative CBF changes were monitored by laser Doppler flowmetry at 4-5 mm lateral, and 1-2mm posterior to Bregma. An additional filament occlusion study (n=12) was performed to validate that PIFTs were coupled to direct current shifts of spreading depolarization. The PIFT-direct current shift study revealed that every PIFT was associated with a negative direct current shift typical of spreading depolarization. Post-hoc analysis showed that the number of PIFTs, especially with the combination of intra-ischemic level of flow, can predict the development of cortical infarcts. These findings show that PIFTs can serve as an early biomarker in predicting outcome in preclinical animal studies.

Peri-infarct blood-brain barrier dysfunction facilitates induction of spreading depolarization associated with epileptiform discharges.

Recent studies showed that spreading depolarizations (SDs) occurs abundantly in patients following ischemic stroke and experimental evidence suggests that SDs recruit tissue at risk into necrosis. We hypothesized that BBB opening with consequent alterations of the extracellular electrolyte composition and extravasation of albumin facilitates generation of SDs since albumin mediates an astrocyte transcriptional response with consequent disturbance of potassium and glutamate homeostasis. Here we show extravasation of Evans blue-albumin complex into the hippocampus following cortical photothrombotic stroke in the neighboring neocortex. Using extracellular field potential recordings and exposure to serum electrolytes we observed spontaneous SDs in 80% of hippocampal slices obtained from rats 24 h after cortical photothrombosis. Hippocampal exposure to albumin for 24 h through intraventricular application together with serum electrolytes lowered the threshold for the induction of SDs in most slices irrespective of the pathway of stimulation. Exposing acute slices from naive animals to albumin led also to a reduced SD threshold. In albumin-exposed slices the onset of SDs was usually associated with larger stimulus-induced accumulation of extracellular potassium, and preceded by epileptiform activity, which was also observed during the recovery phase of SDs. Application of ifenprodil (3 µM), an NMDA-receptor type 2 B antagonist, blocked stimulus dependent epileptiform discharges and generation of SDs in slices from animals treated with albumin in-vivo. We suggest that BBB opening facilitates the induction of peri-infarct SDs through impaired homeostasis of K+.

A novel algorithm for the assessment of blood-brain barrier permeability suggests that brain topical application of endothelin-1 does not cause early opening of the barrier in rats.

There are a number of different experimental methods for ex vivo assessment of blood-brain barrier (BBB) opening based on Evans blue dye extravasation. However, these methods require many different steps to prepare the brain and need special equipment for quantification. We here report a novel, simple, and fast semiquantitative algorithm to assess BBB integrity ex vivo. The method is particularly suitable for cranial window experiments, since it keeps the spatial information about where the BBB opened. We validated the algorithm using sham controls and the established model of brain topical application of the bile salt dehydrocholate for early BBB disruption. We then studied spreading depolarizations in the presence and the absence of the vasoconstrictor endothelin-1 and found no evidence of early BBB opening (three-hour time window). The algorithm can be used, for example, to assess BBB permeability ex vivo in combination with dynamic in vivo studies of BBB opening.

Endothelin-1(1-31) induces spreading depolarization in rats.

BACKGROUND: The vasoconstrictor endothelin-1(1-21) (ET-1) seems to induce cerebral vasospasm after aneurismal subarachnoid hemorrhage (aSAH). Moreover, ET-1 causes spreading depolarization (SD) via vasoconstriction/ischemia. ET-1(1-31) is an alternate metabolic intermediate in the generation of ET-1. Our aim was to investigate whether endothelin-1(1-31) causes SD in a similar fashion to ET-1. METHOD: Increasing concentrations of either ET-1, ET-1(1-31) or vehicle were brain topically applied in 29 rats. Each concentration was superfused for one hour while regional cerebral blood flow (rCBF) and direct current electrocorticogram (DC-ECoG) were recorded. FINDINGS: In response to the highest concentration of 10(-6) M, all animals of both ET groups developed typical SD. At concentrations below 10(-6) M only ET-1 induced SD (n=14 of 19 rats). Thus, the efficacy of ET-1(1-31) to induce SD was significantly lower (P<0.001, two-tailed Fisher's Exact Test). CONCLUSIONS: Our findings suggest that ET-1(1-31) less potently induces SD compared to ET-1 which implicates that it is a less potent vasoconstrictor. Speculatively, it could be interesting to shift the metabolic pathway towards the alternate intermediate ET-1(1-31) after aSAH as an alternative strategy to ETA receptor inhibition. This could decrease ET-induced vasoconstriction and SD generation while a potentially beneficial basal ETA receptor activation is maintained.

The gamut of blood flow responses coupled to spreading depolarization in rat and human brain: from hyperemia to prolonged ischemia.

Cortical spreading depolarizations (SD) have been shown to occur frequently in patients with aneurysmal subarachnoid hemorrhage (SAH) and are associated with delayed ischemic brain damage. In animal models the link between SD and cell damage is the microvascular spasm coupled to the passage of SDs, resulting in spreading ischemia. Here we compared the hemodynamic changes induced by SD between human and rat cerebral cortex. Specifically, we addressed the question, whether the full spectrum of regional cerebral blood flow (rCBF) responses to SD is found in the human brain in a similar fashion to animal models. SDs were identified by slow potential changes in electrocorticographic recordings and the rCBF response profiles and magnitudes were analyzed. We found a large variability of rCBF changes concomitant to SDs in rat and in human recordings. The spectrum ranged from normal hyperemic responses to prolonged cortical spreading ischemia with intermediate forms characterized by biphasic (hypoemic-hyperemic) responses. The bandwidths of rCBF responses were comparable and the relative response magnitudes of hypo- and hyperperfusion phases did not differ significantly between rats and humans. The correspondence of the rCBF response spectrum to SD between human and animal brain underscores the importance of animal models to learn more about the mechanisms underlying the early and delayed pathological sequelae of SAH.

Application of stereological estimates in patients with severe head injuries using CT and MR scanning images.

Severe brain damage is often followed by serious complications. Quantitative measurements, such as regional volume and surface area under various conditions, are essential for understanding functional changes in the brain and assessing prognosis. The affected brain tissue is variable, hence traditional imaging methods are not always applicable and automatic methods may not be able to match the individual observer. Stereological techniques are alternative tools in the quantitative description of biological structures, and have been increasingly applied to the human brain. In the present study, we applied stereological techniques to representative CT and MRI brain scans from five patients to describe how stereological methods, when applied to scans of trauma patients, can provide a useful supplement to the estimation of structural brain changes in head injuries. The reliability of the estimates was tested by obtaining repeated intra- and interobserver estimates of selected subdivisions of the brain in patients with acute head injury, as well as in an MR phantom. The estimates of different subdivisions showed a coefficient of variation (CV) below 12% in the patients and below 7% for phantom estimation. The validity of phantom estimates was tested by the average deviation from the true geometric values, and was below 10%. The stereological methods were compared with more traditional region-based methods performed on medical imaging, which showed a CV below 7% and bias below 14%. It is concluded that the stereological estimates may be useful tools in head injury quantification.

Clearance of a status aurae migraenalis in response to thrombendarterectomy in a patient with high grade internal carotid artery stenosis.

We report a patient with high grade internal carotid artery (ICA) stenosis who had frequent migrainous aura-like symptoms for a period of 3 weeks (Latin: status aurae migraenalis). This syndrome has been described previously but it was unclear whether ischaemic damage was associated with it. Using MRI, we demonstrated widely scattered focal laminar cortical infarcts. Importantly, after ICA thrombendarterectomy, the status aurae migraenalis abruptly ceased which supports the concept that high grade ICA stenosis can be the cause of status aurae migraenalis.

Migraine and delayed ischaemic neurological deficit after subarachnoid haemorrhage in women: a case-control study.

The aim of the present case-control study was to investigate the role of migraine as a potential risk factor for a delayed ischaemic neurological deficit (DIND) after subarachnoid haemorrhage (SAH). A telephone interview was performed in patients or their relatives to determine the prevalence of migraine. Thirty-six women aged <60 years had SAH with Hunt & Hess grade I-III and DIND (group A). This group was compared with an age-matched group of 36 female SAH patients, Hunt & Hess grade I-III without DIND (group B). The two populations were also characterized regarding hypertension, smoking, diabetes mellitus and alcohol use. A significant difference was only found for the prevalence of migraine with 47% in group A and 25% in group B (P < 0.05; odds ratio: 2.68, confidence interval: 0.99-7.29). Migraineurs revealed similar prevalences of risk factors independently of the presence of DINDs. This retrospective study suggests that women with migraine have a higher risk to develop a DIND than women without migraine.

Blood-brain barrier disruption results in delayed functional and structural alterations in the rat neocortex.

Disruption of the blood-brain barrier (BBB) is a characteristic finding in common neurological disorders. Human data suggest BBB disruption may underlie cerebral dysfunction. Animal experiments show the development of epileptiform activity following BBB breakdown. In the present study we investigated the neurophysiological, structural and functional consequences of BBB disruption. Adult rats underwent focal BBB disruption in the rat sensory-motor cortex using the bile salt sodium deoxycholate (DOC). Magnetic resonance imaging in-vivo showed an early BBB disruption with delayed reduction in cortical volume. This was associated with a reduced number of neurons and an increased number of astrocytes. In-vitro experiments showed that the threshold for spreading depression and the propagation velocity of the evoked epileptic potentials were increased 1 month after treatment. Furthermore, animals' motor functions deteriorated during the first few weeks following BBB disruption. Treatment with serum albumin resulted in a similar cell loss confirming that the effect of DOC was due to opening of the BBB. Our findings suggest that delayed neurodegeneration and functional impairment occur following the development of the epileptic focus in the BBB-permeable cerebral cortex.

Opening of the blood-brain barrier preceding cortical edema in a severe attack of FHM type II.

The authors report a patient with familial hemiplegic migraine type II who developed a long-lasting attack including fever, right-sided hemiplegia, aphasia, and coma. Quantitative analysis of early gadolinium-enhanced MRI revealed a mild but significant left-hemispheric blood-brain barrier (BBB) opening limited to the cortex and preceding cortical edema. The findings suggest that the delayed cortical edema was vasogenic in the severe migraine aura variant of this ATP1A2 mutation carrier.

Variability of familial hemiplegic migraine with novel A1A2 Na+/K+-ATPase variants.

A1A2 Na+/K+-ATPase mutations cause familial hemiplegic migraine type 2 (FHM2). The authors identified three putative A1A2 mutations (D718N, R763H, P979L) and three that await validation (P796R, E902K, X1021R). Ten to 20% of FHM cases may be FHM2. A1A2 mutations have a penetrance of about 87%. D718N causes frequent, long-lasting HM, and P979L may cause recurrent coma. D718N and P979L may predispose to seizures and mental retardation. A1A2 does not play a major role in sporadic HM; only one variant, R383H, occurred in 1 of 24 cases.

[Risk factors in ischemic stroke. Review of evidence in primary prevention]. / Risikofaktoren des ischämischen Schlaganfalls. Ubersicht über die Evidenz in der Primärprävention.

Risk factors are traits which can increase disease risk. In the case of ischemic stroke, risk factors have important roles in primary prevention, clinical practice, and epidemiological research. However, the underlying models, methods, and suited study design are often unknown. Based on interventions, cohort studies, case control studies, and meta-analyses, we give an up-to-date overall survey of the most important established and modifiable risk factors in the primary prevention of ischemic stroke. Each risk factor was assessed using a uniform pattern and systematically analyzed according to intervention type, evidence level, risk reduction, and prevalence.

Valproic acid is effective in migraine prophylaxis at low serum levels: a prospective open-label study.

OBJECTIVE: We evaluated the efficacy of prophylactic valproic acid treatment (6 months) on the frequency of migraine attacks and the number of migraine headache days with respect to serum levels. BACKGROUND: Valproic acid, a GABAergic drug, has been shown to be effective for migraine prophylaxis. Results from several dose- and serum level-adjusted studies have recommended valproic acid doses within a range of 500 to 1500 mg per day for migraine prophylaxis. DESIGN AND METHODS: In this prospective open-label study, 52 patients received valproic acid doses of 300 to 1200 mg per day; 45 patients were treated per protocol. Valproic acid serum levels increased linearly in relation to the valproic acid dose and were between 21 and 107 microg/mL at the end of the treatment period. Patients were divided into two groups: those with valproic acid serum levels less than 50 microg/mL (group 1) and those with serum levels greater than 50 microg/mL (group 2). RESULTS: The frequency of migraine attacks was significantly reduced in group 1 from 3.5 +/- 0.9 to 2.0 +/- 0.9 attacks per month. Migraine headache days also decreased (6.4 +/- 3.5 to 4.6 +/- 2.9 days per month). In the high serum level group, a reduction of migraine attacks from 3.5 +/- 0.9 to 2.8 +/- 1.0 attacks per month and only a slight decrease in headache days (6.4 +/- 3.5 to 6.1 +/- 2.4 days per month) was observed. The outcome of group 1 (low serum level) was significantly better than that of group 2 with respect to both parameters (P<.05). Side effects were generally mild and temporary. CONCLUSIONS: Due to the lack of additional benefit from higher valproic acid doses (more than 600 mg per day), we recommend daily valproic acid doses of 500 to 600 mg with a target serum level less than 50 microg/mL for the prophylactic treatment of migraine.