Lessons Learned from Phase II and Phase III Trials Investigating Therapeutic Agents for Cerebral Ischemia Associated with Aneurysmal Subarachnoid Hemorrhage.

One of the challenges in bringing new therapeutic agents (since nimodipine) in for the treatment of cerebral ischemia associated with aneurysmal subarachnoid hemorrhage (aSAH) is the incongruence in therapeutic benefit observed between phase II and subsequent phase III clinical trials. Therefore, identifying areas for improvement in the methodology and interpretation of results is necessary to increase the value of phase II trials. We performed a systematic review of phase II trials that continued into phase III trials, evaluating a therapeutic agent for the treatment of cerebral ischemia associated with aSAH. We followed the Preferred Reporting Items for Systematic reviews and Meta-Analyses guidelines for systematic reviews, and review was based on a peer-reviewed protocol (International Prospective Register of Systematic Reviews no. 222965). A total of nine phase III trials involving 7,088 patients were performed based on eight phase II trials involving 1558 patients. The following therapeutic agents were evaluated in the selected phase II and phase III trials: intravenous tirilazad, intravenous nicardipine, intravenous clazosentan, intravenous magnesium, oral statins, and intraventricular nimodipine. Shortcomings in several design elements of the phase II aSAH trials were identified that may explain the incongruence between phase II and phase III trial results. We suggest the consideration of the following strategies to improve phase II design: increased focus on the selection of surrogate markers of efficacy, selection of the optimal dose and timing of intervention, adjustment for exaggerated estimate of treatment effect in sample size calculations, use of prespecified go/no-go criteria using futility design, use of multicenter design, enrichment of the study population, use of concurrent control or placebo group, and use of innovative trial designs such as seamless phase II to III design. Modifying the design of phase II trials on the basis of lessons learned from previous phase II and phase III trial combinations is necessary to plan more effective phase III trials.

Reversible cerebral vasoconstriction with thunderclap headache: A case report.

RATIONALE: Reversible cerebral vasoconstriction syndrome (RCVS) is often accompanied by thunderclap headaches. Although symptoms usually resolve spontaneously within 2 months, it can cause fatal complications, such as cerebral hemorrhage, and is difficult to differentiate from a migraine and other headaches on the basis of symptoms and Imaging study. In this case report, we explore clinical findings and appropriate treatment methods for RCVS through the case study of a female patient who experienced severe headache upon defecation PATIENT CONCERNS:: A 42-year-old female patient complained of a severe throbbing headache with a Numeric Rating Scale (NRS) score of 10 after defecation. The pain subsided temporarily after treatment with diclofenac 75 mg and Tridol 50 mg propacetamol 1 g, but the headache returned upon defecation; soon after, the patient complained again of regular headaches at 4 to 6-hour intervals irrespective of defecation. DIAGNOSIS: Brain computed tomography (CT) and head and neck magnetic resonance angiography, performed during a headache episode, revealed no specific neurological findings. Blood analysis was also normal. Head and neck CT angiography, performed one month after the start of the headaches, revealed RCVS. INTERVENTIONS: Treatment commenced with pregabalin (150 mg), oxycodone HCl/naloxone (10/5 mg), Alpram (0.5 mg), milnacipran (25 mg), and frovatriptan 25 mg, but there was no improvement in the headaches. The patient received bilateral trigger point injections (TPI) in the temporal muscles on four occasions at the pain clinic. OUTCOMES: Medication showed no effect, but after the patient received four sessions of bilateral TPI in the temporal muscles her NRS score eventually decreased from 10 to 2. The patient is currently continuing medication while still experiencing headaches at reduced intensities. LESSONS: RCVS is difficult to diagnose; moreover, it is difficult differentiate RCVS from other headaches. However, as it can cause fatal complications, it should not be overlooked. It is essential to consider diagnostic treatment for all types of headaches because RCVS can be accompanied by headaches originating from other causes.

Endovascular treatment of cerebral vasospasm after subarachnoid hemorrhage: More is more.

OBJECTIVE: Delayed cerebral ischemia (DCI) is strongly associated with poor outcome after subarachnoid hemorrhage (SAH). Cerebral vasospasm is a major contributor to DCI and requires special attention. To evaluate the effect of vasospasm management on SAH outcome, we performed a pooled analysis of 2 observational SAH cohorts. MATERIALS: Data from 2 institutional databases with consecutive patients with SAH treated between 2005 and 2012 were pooled. The effect of 2 institutional standards of conservative and endovascular vasospasm treatment (EVT) on the rates of DCI (new cerebral infarcts not visible on the post-treatment imaging) and unfavorable outcome (modified Rankin Scale score >2) at 6 months follow-up was analyzed. RESULTS: The final analysis included 1,057 patients with SAH. There was no difference regarding demographic (age and sex), clinical (Hunt & Hess grades, acute hydrocephalus, treatment modality, and infections), and radiographic (Fisher grades and aneurysm location) characteristics of the populations. However, there was a significant difference in the rate (24.4% [121/495] vs 14.4% [81/562], p < 0.0001) and timing (first treatment on day 6 vs 8.9 after SAH, p < 0.0001) of EVT. The rates of DCI (20.8% vs 29%, p = 0.0001) and unfavorable outcome (44% vs 50.6%, p = 0.04) were lower in the cohort with more frequent and early EVT. Multivariate analysis confirmed independent effect of EVT standard on DCI risk and outcome. CONCLUSIONS: A preventive strategy utilizing frequent and early EVT seems to reduce the risk of DCI in patients with SAH and improve their functional outcome. We recommend prospective evaluation of the value of preventive EVT strategy on SAH. CLASSIFICATION OF EVIDENCE: This study provides Class III evidence that for patients with SAH, a frequent and early EVT to treat vasospasm reduces the risk of DCI and improves functional outcome.

Pharmacokinetic Modeling of Intra-arterial Nimodipine Therapy for Subarachnoid Hemorrhage-Related Cerebral Vasospasm.

PURPOSE: Intra-arterial (IA) administration of nimodipine has been shown to be an effective treatment for subarachnoid hemorrhage-related cerebral vasospasm. The concentrations achieved in cerebral arteries during this procedure, though, are unknown. Therefore, there are no clinical studies investigating dose-dependent effects of nimodipine. We aimed at providing a pharmacokinetic model for IA nimodipine therapy for this purpose. METHODS: A two-compartment pharmacokinetic model for intravenous nimodipine therapy was modified and used to assess cerebral arterial nimodipine concentration during IA nimodipine infusion into the internal carotid artery (ICA). RESULTS: According to our simulations, continuous IA nimodipine infusion at 2 mg/h and 1 mg/h resulted in steady-state cerebral arterial concentrations of about 200 ng/ml and 100 ng/ml assuming an ICA blood flow of 200 ml/min and a clearance of 70 l/h. About 85 % of the maximal concentration is achieved within the first minute of IA infusion independent on the infusion dose. Within the range of physiological and pharmacokinetic data available in the literature, ICA blood flow has more impact on cerebral arterial concentration than nimodipine clearance. CONCLUSION: The presented pharmacokinetic model is suitable for estimations of cerebral arterial nimodipine concentration during IA infusion. It may, for instance, assist in dose-dependent analyses of angiographic results.

Comparison of the Effects and Mechanism of the Curcumin with Different Drugs in Experimental Vasospasm After Subarachnoid Hemorrhage.

AIM: Cerebral vasospasm following subarachnoid hemorrhage (SAH) is the most important complication that effects the mortality and morbidity of patients with intracranial aneurysm. Today, the mechanisms of vasospasm are not understood in spite of experimental and clinical researches. The aim of our study was to investigate the effects of curcumin on vasospasm following SAH. MATERIAL AND METHODS: In this study, 64 rats (200-250 g weight) were divided into 7 groups. Group 1: having no treatment after SAH; Group 2: treatment with nimodipine after SAH; Group 3: treatment with nicorandil after SAH; Group 4: treatment with sildenafil citrate after SAH; Group 5: treatment with 150 mg/kg curcumin after SAH; Group 6: treatment with 300 mg/kg curcumin after SAH, Group 7: treatment with 600 mg/kg curcumin after SAH. The experimental SAH was induced by injection of autologous blood into the cisterna magna. After medical treatment, in the first hour, blood was taken for quantified the levels of TNF-α, IL-1ß and IL-6. Then, cerebrum and cerebellum were removed for analysis. Basilar artery luminal diameter was measured and apoptotic cell count was performed with tissue samples. RESULTS: Histopathological findings showed that, in sufficient dose, curcumin dilated the basilar artery beside anti-oxidant effect. CONCLUSION: Curcumin can be used for the treatment of vasospasm as a new medical drug.

ω-3 Fatty Acids Ethyl Esters Suppress Cerebral Vasospasm and Improve Clinical Outcome Following Aneurysmal Subarachnoid Hemorrhage.

OBJECTIVE: Occurrence of cerebral vasospasm after onset of aneurysmal subarachnoid hemorrhage (SAH) is a critical factor determining clinical prognosis. Eicosapentaenoic acid and docosahexaenoic acid, both ω-3 fatty acids (ω-3FA), can suppress cerebral vasospasm, and docosahexaenoic acid can relax vessel vasoconstriction and have neuroprotective effects. We investigated whether administration of ω-3FA prevented cerebral vasospasm occurrence and improved clinical outcomes after aneurysmal SAH. METHODS: From 2012 to 2015, 100 consecutive patients with aneurysmal SAH were divided into 2 periods. Between 2012 and 2013 (control period), 45 patients received standard management. Between 2014 and 2015 (ω-3FA period), 55 patients were prospectively treated with additional ω-3FA. Occurrence of cerebral vasospasm, occurrence of cerebral infarction caused by vasospasm, and modified Rankin Scale scores at 30 days and 90 days after onset of SAH for each period were evaluated and compared. RESULTS: The frequency of angiographic cerebral vasospasm in the ω-3FA period was significantly lower than in the control period (12 patients vs. 23 patients, P = 0.004). The frequency of new infarction caused by vasospasm in the ω-3FA period was also significantly lower than in the control period (5 patients vs. 14 patients, P = 0.011). There was a significant difference in modified Rankin Scale scores at 90 days after onset of SAH between the groups (P = 0.031). No adverse events were associated with ω-3FA administration. CONCLUSIONS: Administration of ω-3FA after aneurysmal SAH may reduce the frequency of cerebral vasospasm and may improve clinical outcomes.

Posterior reversible encephalopathy syndrome with thalamic involvement during vasopressor treatment of vertebrobasilar vasospasm after subarachnoid hemorrhage.

Hemodynamic augmentation is the primary medical intervention employed to reverse neurological deficits associated with vasospasm and delayed cerebral ischemia following aneurysmal subarachnoid hemorrhage. Failure to improve despite induced hypertension (IH) may raise concern for persistent hypoperfusion and prompt even more aggressive blood pressure augmentation. However, posterior reversible encephalopathy syndrome (PRES) is a hyperperfusion syndrome reported as a rare complication of IH that may confound this picture. We report a case of PRES with prominent thalamic involvement and impaired level of consciousness secondary to blood pressure augmentation for the treatment of symptomatic vertebrobasilar vasospasm. Recognition of this syndrome in distinction to worsening ischemia is particularly critical, as normalization of blood pressure should lead to rapid clinical improvement.

4'-O-ß-D-glucosyl-5-O-methylvisamminol, an active ingredient of Saposhnikovia divaricata, attenuates high-mobility group box 1 and subarachnoid hemorrhage-induced vasospasm in a rat model.

BACKGROUND: High-mobility group box 1 (HMGB1) was observed to be an important extracellular mediator involved in vascular inflammation associated with subarachnoid hemorrhage (SAH). This study is of interest to examine the efficacy of 4'-O-ß-D-glucosyl-5-O-methylvisamminol (4OGOMV), C22H28O10, on the alternation of cytokines and HMGB1 in an animal model. METHODS: A rodent double hemorrhage SAH model was employed. Administration with 4OGOMV was initiated 1 h after animals were subjected to SAH. Basilar arteries (BAs) were harvested and cortexes examined for HMGB1 mRNA, protein expression (Western blot) and monocyte chemoattractant protein-1 (MCP-1) immunostaining. Cerebrospinal fluid samples were collected to examine IL-1ß, IL-6, IL-8 and MCP-1 (rt-PCR). RESULTS: Morphological findings revealed endothelial cell deformity, intravascular elastic lamina torture, and smooth muscle necrosis in the vessels of SAH groups. Correspondently, IL-1ß, IL-6 and MCP-1 in the SAH-only and SAH-plus vehicle groups was also elevated. 4OGOMV dose-dependently reduced HMGB1 protein expression when compared with the SAH groups.(p < 0.01) Likewise, 400 µg/kg 4OGOMV reduced IL-1ß, MCP-1 and HMGB1 mRNA levels as well as MCP-1(+) monocytes when compared with the SAH groups.. CONCLUSION: 4OGOMV exerts its neuro-protective effect partly through the dual effect of inhibiting IL-6 and MCP-1 activation and also reduced HMGB1 protein, mRNA and MCP-1(+) leukocytes translocation. This study lends credence to validating 4OGOMV as able to attenuate pro-inflammatory cytokine mRNA, late-onset inflammasome, and cellular basis in SAH-induced vasospasm.

Effect of endothelin receptor antagonists on clinically relevant outcomes after experimental subarachnoid hemorrhage: a systematic review and meta-analysis.

In clinical trials, endothelin receptor antagonists (ETRAs) reduced vasospasm but did not improve functional outcome after subarachnoid hemorrhage (SAH). We assessed the effects of treatment with ETRAs on clinically relevant outcomes in animal studies modelling SAH by performing a systematic review of the literature for controlled animal studies of ETRAs for the treatment of SAH. Primary outcomes were neurobehavioral outcomes and case fatality. Secondary outcomes were cerebral vasospasm and cerebral blood flow. Summary estimates were calculated using normalized mean difference random effects meta-analysis. We included 27 studies (55 experiments, 639 animals). Neurobehavioral scores were reported in none of the experiments, and case fatality in 8 (15%). Treatment with ETRAs was associated with a pooled odds ratio for case fatality of 0.61 (95% confidence interval (CI), 0.27 to 1.39); a 54% increase (95% CI, 39 to 69) in cerebral arterial diameter; and a 93% increase (95% CI, 58 to 129) in cerebral blood flow. We conclude that there is no evidence from animal studies that treatment with an ETRA improves clinically relevant outcomes after SAH. The reduction in cerebral vasospasm observed in animal studies is consistent with that observed in clinical trials, an effect that is not associated with better functional outcome in patients.

Vasospastic transient monocular visual loss: effect of treatment with different doses of nifedipine.

Transient monocular visual loss (TMVL) usually is due to hypoperfusion of the optic nerve or retinal circulation. After the exclusion of thromboembolic and carotid artery diseases, retinal vasospasm should be considered as an underlying cause of TMVL. We report a patient with an increasing number of transient attacks of unilateral blindness. Vasospasm was confirmed as the etiology by fundus photography during an attack. Nifedipine 10 mg/d decreased the severity of the visual loss and the number of attacks. The patient was relieved of symptoms entirely with a nifedipine dose of 20 mg/d.

New daily persistent headache with a thunderclap headache onset and complete response to nimodipine (a new distinct subtype of NDPH).

At present new daily persistent headache is just a group of conditions that are connected based on the temporal profile of their mode of onset. If new daily persistent headache is a true distinct syndrome like migraine then we need to start to define subtypes that have specific effective treatments such has been noted for migraine sub-forms. We present what we believe is the first recognized subtype of new daily persistent headache that which starts with a thunderclap headache onset. A patient presented with a 13 month history of a daily headache from onset which initiated as a thunderclap headache along with persistent acalculia. All neuroimaging studies for secondary causes were negative. Nimodipine rapidly and completely alleviated her headache and associated neurologic symptoms. We propose that this subtype of new daily persistent headache is caused by a very rapid increase in CSF tumor necrosis factor alpha levels leading to cerebral artery vasospasm with a subsequent thunderclap headache, then continuous or near continuous cerebral artery vasospasm leading to a persistent daily headache. Nimodipine which not only inhibits cerebral artery vasospasm but also tumor necrosis factor alpha production appears to be a specific treatment for this distinct subtype of new daily persistent headache.

Effects of nimodipine on cerebral vasospasm in patients with aneurysmal subarachnoid hemorrhage treated by endovascular coiling.

BACKGROUND: An aneurysmal subarachnoid hemorrhage could be complicated with cerebral vasospasm and resultant ischemia, causing neurological deficit. OBJECTIVES: The aim of our study was to compare early and late outcomes in patients with subarachnoidal hemorrhage (SAH) treated by endovascular coiling, who either received or did not receive prophylaxis of cerebral vasospasm with nimodipine. MATERIAL AND METHODS: In this retrospective cross-sectional study, the data was collected from the histories of 68 patients (38 females and 30 males, age range 29-71 years) with spontaneous aneurysmal SAH in clinical stage HH I-IV, treated at Kragujevac Clinical Center, Serbia, from January 2008 till June 2009. The study population was divided into two groups: (1) the group of 42 patients who received intravenous prophylaxis with nimodipine for 3 weeks, and (2) the group of 26 patients who did not receive nimodipine prophylaxis. RESULTS: Prophylactic use of nimodipine did not decrease the rate of neurological deficit after one month, but the rates of both cerebral vasospasm (symptomatic and asymptomatic) and the morphological signs of ischemia using nuclear magnetic resonance imaging (MRI) were significantly lower in the nimodipine-protected group. Cerebral vasospasm was detected by Digital Subtraction Angiography (DSA) in the group protected by nimodipine as discrete in 2 patients (5%), and as apparent in 0 patients (0%). On the other hand, in the group unprotected by nimodipine, cerebral vasospasm was detected by DSA as discrete in 9 patients (35%), and as apparent in 6 patients (23%). Up to one month after the endovascular coiling, in the nimodipine-protected group, the T1W hypointense zones were detected by MRI as "small" in 5 patients (12%), as "medium" in 1 patient (2.5%), as "large" in 1 patient (2.5%), and as "multiple" in 2 patients (5%). In the nimodipine-unprotected group, the T1W hypointense zones were detected by MRI as "small" in 4 patients (16%), as "medium" in 2 patients (8%), as "large" in 3 patients (12%), and as "multiple" in 4 patients (16%). The difference between the groups was significant. CONCLUSIONS: When a patient with SAH is treated with the endovascular clipping procedure, prophylactic administration of nimodipine is mandatory due to the reduced rate of cerebral vasospasm and delayed cerebral ischemia.

Free Fatty acids and delayed cerebral ischemia after subarachnoid hemorrhage.

BACKGROUND AND PURPOSE: The purpose of this study was to understand factors related to increases in serum free fatty acid (FFA) levels and association with delayed cerebral ischemia (DCI) after subarachnoid hemorrhage. METHODS: We performed serial measurement of systemic oxygen consumption by indirect calorimetry and FFA levels by liquid chromatography/mass spectrometry in the first 14 days after ictus in 50 consecutive patients with subarachnoid hemorrhage. Multivariable generalized estimating equation models identified associations with FFA levels in the first 14 days after SAH and Cox proportional hazards model used to identified associations with time to DCI. RESULTS: There were 187 measurements in 50 patients with subarachnoid hemorrhage (mean age, 56±14 years old; 66% women) with a median Hunt-Hess score of 3. Adjusting for Hunt-Hess grade and daily caloric intake, n-6 and n-3 FFA levels were both associated with oxygen consumption and the modified Fisher score. Fourteen (28%) patients developed DCI on median postbleed Day 7. The modified Fisher score (P=0.01), mean n-6:n-3 FFA ratio (P=0.02), and mean oxygen consumption level (P=0.04) were higher in patients who developed DCI. In a Cox proportional hazards model, the mean n-6:n-3 FFA ratio (P<0.001), younger age (P=0.05), and modified Fisher scale (P=0.004) were associated with time to DCI. CONCLUSIONS: Injury severity and oxygen consumption hypermetabolism are associated with higher n-FFA levels and an increased n-6:n-3 FFA ratio is associated with DCI. This may indicate a role for interventions that modulate both oxygen consumption and FFA levels to reduce the occurrence of DCI.

Medidas protectoras frente a la isquemia cerebral tras hemorragia subaracnoidea (I) / Protective measures against cerebral ischemia following subarachnoid hemorrhage: part 1

Objetivos: La presencia de vasoespasmo cerebral tras hemorragia subaracnoidea aneurismática contribuye a la importante morbimortalidad de esta entidad. Por ello, se han desarrollado múltiples estudios con diferentes tratamientos dirigidos a su prevención, aunque la evidencia sobre su eficacia es limitada. Nuestro objetivo fue realizar una revisión bibliográfica de las diferentes terapias con evidencia científica para la prevención del vasoespasmo cerebral posthemorragia subaracnoidea aneurismática. Métodos: Búsqueda en MEDLINE (desde 1950 hasta octubre 2009) y revisión bibliográfica de las publicaciones halladas sobre prevención del vasoespasmo cerebral posthemorragia subaracnoidea aneurismática. Se restringió la búsqueda a artículos en inglés, francés y español. Se emplearon las palabras clave [cerebral vasospasm, subarachnoid hemorrhage, therapy, nimodipine, triple h, clazosentan, statins, magnesium] y sus combinaciones. Además se llevó a cabo una búsqueda manual en las referencias de los artículos seleccionados. Se incluyeron artículos que reunieran las siguientes condiciones: estudios controlados aleatorizados, metaanálisis, estudios clínicos no aleatorizados, estudios descriptivos, estudios analíticos observacionales, artículos de opinión y revisión. Resultados: La parte 1 analiza el tratamiento con calcioantagonistas y la triple terapia (hipertensión, hemodilución e hipervolemia) y la parte 2 analiza nuevas terapias como son el clazosentán, el magnesio y las estatinas. Hallamos 597 referencias de las cuales 283 fueron seleccionadas. Se incluyeron finalmente 61, las cuales se distribuyeron en 2 artículos de opinión, 21 estudios controlados aleatorizados, 22 artículos de revisión, 3 metaanálisis, 4 estudios clínicos no aleatorizados, 1 estudio descriptivo y 5 estudios analíticos observacionales. Tres estudios (2 metaanálisis y un estudio controlado aleatorizado) demostraron un beneficio en términos de morbimortalidad del uso del nimodipino en pacientes con hemorragia subaracnoidea aneurismática. Por el contrario en el análisis del resto de fármacos (clazosentán, estatinas y magnesio) no se objetivó un beneficio clínico estadísticamente significativo. Conclusiones: En la actualidad no hay suficiente evidencia para apoyar la utilización de triple terapia, clazosentán, estatinas y sulfato de magnesio para la prevención del vasoespasmo cerebral posthemorragia subaracnoidea aneurismática. El único tratamiento preventivo recomendado es el nimodipino(AU)

Background and objectives: Cerebral vasospasm following aneurysmal subarachnoid hemorrhage contributes significantly to morbidity and mortality. Many studies on the various treatments aimed at preventing cerebral vasospasm have been carried out, but evidence of efficacy is limited. Our aim was to review the literature on the various therapies for which there is scientific evidence of protection against cerebral vasospasm following aneurysmal subarachnoid hemorrhage. Methods: MEDLINE search (1950 to the october 2009) and review of articles found on the prevention of cerebral vasospasm following aneurysmal subarachnoid hemorrhage. The search was restricted to articles in English, French, and Spanish. The keywords were cerebral vasospasm, subarachnoid hemorrhage, therapy, nimodipine, triple H, clazosentan, statins, and magnesium in addition to the word forms derived from them. We also searched manually for references cited in the selected articles. A title was included if it was a randomized controlled trial, meta-analysis, nonrandomized clinical trial, descriptive study, observational study with statistical analysis, opinion article, or expert review. Results: Part 1 analyzed treatment with calcium antagonists and triple-H therapy (hypertension, hemodilution, and hypervolemia). Part 2 analyzed new therapies such as clazosentan, magnesium, and statins. A total of 597 titles were located; 283 were initially selected. The 61 articles finally selected for review were of the following types: 2 opinion articles, 21 randomized controlled trials, 22 expert review articles, 3 meta-analyses, 4 nonrandomized clinical trials, 1 descriptive study, and 5 observational studies with statistical analysis. Three studies (2 meta-analyses and 1 randomized controlled trial) demonstrated that nimodipine use confers benefits (reduced morbidity and mortality) for patients with aneurysmatic subarachnoid hemorrhage. Statistically significant clinical benefits ould not be demonstrated for the other drugs (clazosentan, statins, and magnesium). Conclusions: Insufficient evidence is available to support the use of the triple-H therapy, clazosentan, statins, or magnesium sulfate for the prevention of cerebral vasospasm following subarachnoid hemorrhage. Nimodipine is the only preventative treatment that can be recommended(AU)

The effects of Nigella sativa against oxidative injury in a rat model of subarachnoid hemorrhage.

OBJECTIVE: The aim of the study was to investigate the putative neuroprotective effect of Nigella sativa oil (NSO) treatment against subarachnoid hemorrhage (SAH) in rats. METHODS: To induce SAH, rats were injected with 0.3 ml blood into their cisterna magna. Male Wistar albino rats were divided as control, vehicle-treated SAH, and NSO-treated (0.2 ml/kg, intraperitoneally) SAH groups. Forty-eight hours after SAH induction, neurological examination scores were recorded and the rats were decapitated. Brain tissue samples were taken for blood brain barrier permeability, brain water content, or determination of malondialdehyde (MDA) and glutathione (GSH) levels, myeloperoxidase (MPO), and Na(+)-K(+)-ATPase activities. RESULTS AND DISCUSSION: On the second day of SAH induction, neurological examination scores were increased in SAH groups, while SAH caused significant decreases in brain GSH content and Na(+)-K(+)-ATPase activity, which were accompanied with significant increases in MDA levels and MPO activity. The histological observation showed vasospasm of the basillary artery. On the other hand, NSO treatment markedly improved the neurological scores while all oxidant responses were prevented, implicating that NSO treatment may be of therapeutic use in preventing oxidative stress due to SAH.

Effect of acute cocaine use on vasospasm and outcome in aneurysmal subarachnoid hemorrhage.

BACKGROUND: Although acute cocaine use has been correlated with aneurysmal subarachnoid hemorrhage, its effect on vasospasm and outcome is controversial. We investigated the effect of acute cocaine use on response to vasospasm treatment and neurologic outcome in patients with aneurysmal subarachnoid hemorrhage. METHODS: Data from 600 patients with aneurysmal subarachnoid hemorrhage admitted to the University of Illinois Medical Center in Chicago between June 2002 and July 2007 were retrospectively analyzed. Patients who were positive for cocaine on urine toxicology or admitted to cocaine use within 72 hours of admission were compared with control patients with no history of cocaine use. Patients with unknown or remote history were excluded. RESULTS: Of the 600 patients with aneurysmal subarachnoid hemorrhage, 27 (5%) were excluded. Thirty-one patients (5%) acutely used cocaine before admission. Cocaine users were younger than control (45.1 vs 54.1; P ≤ .0003), and were more likely to smoke tobacco, drink alcohol, and have renal dysfunction. There was no significant difference in Hunt-Hess or Fisher grade. In univariate and multivariate analyses, there was no difference in unfavorable short-term outcome (modified Rankin scale > 3), incidence of symptomatic or radiologic vasospasm, stroke, or death. The number of interventional procedures for the treatment of vasospasm did not differ between the two groups. CONCLUSIONS: There is no significant difference in incidence of symptomatic vasospasm or neurologic outcome between cocaine users and nonusers. The severity of the vasospasm and the response to treatment, as indicated by the number of vasospasm interventions, did not differ between the two groups.

Murine cerebral malaria is associated with a vasospasm-like microcirculatory dysfunction, and survival upon rescue treatment is markedly increased by nimodipine.

Brain hemodynamics in cerebral malaria (CM) is poorly understood, with apparently conflicting data showing microcirculatory hypoperfusion and normal or even increased blood flow in large arteries. Using intravital microscopy to assess the pial microvasculature through a closed cranial window in the murine model of CM by Plasmodium berghei ANKA, we show that murine CM is associated with marked decreases (mean: 60%) of pial arteriolar blood flow attributable to vasoconstriction and decreased blood velocity. Leukocyte sequestration further decreased perfusion by narrowing luminal diameters in the affected vessels and blocking capillaries. Remarkably, vascular collapse at various degrees was observed in 44% of mice with CM, which also presented more severe vasoconstriction. Coadministration of artemether and nimodipine, a calcium channel blocker used to treat postsubarachnoid hemorrhage vasospasm, to mice presenting CM markedly increased survival compared with artemether plus vehicle only. Administration of nimodipine induced vasodilation and increased pial blood flow. We conclude that vasoconstriction and vascular collapse play a role in murine CM pathogenesis and nimodipine holds potential as adjunctive therapy for CM.

Post stroke depression: treatments and complications in a young adult.

Post-stroke depression has been noted to be one of the most frequent complications of stroke with an estimated prevalence of as high as 80%. However, the incidence of stroke in the young is extremely low and evidence based therapy for this complication is quite limited. The case of a 28-year-old woman who experienced a basilar artery vasospasmic stroke resulting in anoxic brain injury to the midbrain and paramedian thalamus is presented, along with a literature review of psychiatric complications of this injury to include post-stroke depression (PSD). Therapeutic modalities such as TCAs, SSRIs, atypical antipsychotics and stimulant medications are also reviewed as these medications may aid in the treatment of such patients but may also contribute to psychiatric sequelae.