Carl Muroi

ADAMTS13 gene deletion aggravates ischemic brain damage: a possible neuroprotective role of ADAMTS13 by ameliorating postischemic hypoperfusion.

Reperfusion after brain ischemia causes thrombus formation and microcirculatory disturbances, which are dependent on the platelet glycoprotein Ib-von Willebrand factor (VWF) axis. Because ADAMTS13 cleaves VWF and limits platelet-dependent thrombus growth, ADAMTS13 may ameliorate ischemic brain damage in acute stroke. We investigated the effects of ADAMTS13 on ischemia-reperfusion injury using a 30-minute middle cerebral artery occlusion model in Adamts13(-/-) and wild-type mice. After reperfusion for 0.5 hours, the regional cerebral blood flow in the ischemic cortex was decreased markedly in Adamts13(-/-) mice compared with wild-type mice (P < .05), which also resulted in a larger infarct volume after 24 hours for Adamts13(-/-) compared with wild-type mice (P < .01). Thus, Adamts13 gene deletion aggravated ischemic brain damage, suggesting that ADAMTS13 may protect the brain from ischemia by regulating VWF-platelet interactions after reperfusion. These results indicate that ADAMTS13 may be a useful therapeutic agent for stroke.

THERAPEUTIC HYPOTHERMIA IN PATIENTS WITH ANEURYSMAL SUBARACHNOID HEMORRHAGE, REFRACTORY INTRACRANIAL HYPERTENSION, OR CEREBRAL VASOSPASM

OBJECTIVETo evaluate the feasibility and safety of mild hypothermia treatment in patients with aneurysmal subarachnoid hemorrhage (SAH) who are experiencing intracranial hypertension and/or cerebral vasospasm (CVS). METHODSOf 441 consecutive patients with SAH, 100 developed elevated intracranial pressure and/or symptomatic CVS refractory to conventional treatment. Hypothermia (33–34°C) was induced and maintained until intracranial pressure normalized, CVS resolved, or severe side effects occurred. RESULTSThirteen patients were treated with hypothermia alone, and 87 were treated with hypothermia in combination with barbiturate coma. Sixty-six patients experienced poor-grade SAH (Hunt and Hess Grades IV and V) and 92 had Fisher Grade 3 and 4 bleedings. The mean duration of hypothermia was 169 ± 104 hours, with a maximum of 16.4 days. The outcome after 1 year was evaluated in 90 of 100 patients. Thirty-two patients (35.6%) survived with good functional outcome (Glasgow Outcome Scale [GOS] score, 4 and 5), 14 (15.5%) were severely disabled (GOS score, 3), 1 (1.1%) was in a vegetative state (GOS score, 2), and 43 (47.8%) died (GOS score, 1). The most frequent side effects were electrolyte disorders (77%), pneumonia (52%), thrombocytopenia (47%), and septic shock syndrome (40%). Of 93 patients with severe side effects, 6 (6.5%) died as a result of respiratory or multi-organ failure. CONCLUSIONProlonged systemic hypothermia may be considered as a last-resort option for a carefully selected group of SAH patients with intracranial hypertension or CVS resistant to conventional treatment. However, complications associated with hypothermia require elaborate protocols in general intensive care unit management.

Neurogenic pulmonary edema in patients with subarachnoid hemorrhage.

Neurogenic pulmonary edema (NPE), leading to cardiopulmonary dysfunction, is a potentially life-threatening complication in patients with aneurysmal subarachnoid hemorrhage (SAH). We sought to assess the clinical presentation and risk factors for the development of NPE after SAH. The database contained prospectively collected information on 477 patients with SAH. Baseline characteristics, clinical and radiologic severity of the bleeding, localization of the ruptured aneurysm, and clinical outcome of patients with NPE were compared with those of patients without NPE. Further, in patients with NPE, intracranial pressure, serum cardiac biomarkers, and hemodynamic parameters during the acute phase were evaluated retrospectively. The incidence of NPE was 8% (39 of 477 patients). Most patients with NPE were severely impaired and all of them presented with radiologically severe hemorrhage. The incidence of NPE was significantly higher in patients with ruptured aneurysm in the posterior circulation. Elevated intracranial pressure was found in 67%, pathologically high cardiac biomarkers in up to 83% of patients with NPE. However, no patient suffered from persistent cardiac dysfunction. Compared with patients without NPE, patients with NPE showed poor neurologic outcome (Glasgow outcome scale 1 to 3 in 25% vs.77% of patients). In conclusion, patients with NPE have a high mortality rate more likely due to their severity grade of the bleeding. Morbidity and mortality due to cardiopulmonary failure might be reduced by appropriate recognition and treatment. The awareness of and knowledge about occurrence, clinical presentation, and treatment of NPE, are essential for all those potentially confronted with patients with SAH in the acute phase.

Surgical management of tuberculum sellae meningioma: Role of selective extradural anterior clinoidectomy

A retrospective analysis of 32 patients with tuberculum sellae meningiomas who underwent surgery via a unilateral pterional approach was performed. A selective extradural anterior clinoidectomy (SEAC) technique was added in 20 patients. All patients had visual dysfunction preoperatively. Macroscopically complete removal with Simpson grade II was performed in 28 patients (87.5%). The postoperative visual function improved in 25 (78.1%), did not change in 3 (9.4%), and worsened in 4 patients (12.5%). The SEAC technique was effective, especially for removal of the tumour extending into the sellae/pituitary stalk (9 patients), the optic canal (4 patients) and hypothalamus (4 patients) with preservation of the visual and endocrinological function. These results were superior to those of surgery without SEAC technique. This technique is therefore recommended for complete resection of the tuberculum sellae meningiomas extending to the surrounding anatomical structures as the SEAC procedure reduces the risk of intraoperative optic nerve injury considerably.

Correlation among systemic inflammatory parameter, occurrence of delayed neurological deficits, and outcome after aneurysmal subarachnoid hemorrhage.

BACKGROUND The role and impact of systemic inflammatory response after aneurysmal subarachnoid hemorrhage remain to be elucidated. OBJECTIVE To assess the time course and correlation of systemic inflammatory parameters with outcome and the occurrence of delayed ischemic neurological deficits (DINDs) after subarachnoid hemorrhage. METHODS Besides the baseline characteristics, daily interleukin-6 (IL-6), procalcitonin, C-reactive protein levels, and leukocyte counts were prospectively measured until day 14 after subarachnoid hemorrhage. Occurrence of infectious complications and application of therapeutic hypothermia were assessed as confounding factors. The primary end point was outcome after 3 months, assessed by Glasgow outcome scale; the secondary end point was the occurrence of DINDs. RESULTS During a 3-year period, a total of 138 patients were included. All inflammatory parameters measured were higher in patients with unfavorable outcome (Glasgow outcome scale score, 1-3). After adjustment for confounding factors, elevated IL-6 and leukocyte counts remained significant risk factors for unfavorable outcome. The odds ratio for log IL-6 was 4.07 (95% confidence interval, 1.18 to 14.03; P = .03) and for leukocyte counts was 1.24 (95% confidence interval, 1.06-1.46, P = .008). The analysis of the time course established that IL-6 was the only significantly elevated parameter in the early phase in patients with unfavorable outcome. Higher IL-6 levels in the early phase (days 3-7) were associated with the occurrence of DINDs. The adjusted odds ratio for log IL-6 was 4.03 (95% confidence interval, 1.21-13.40; P = .02). CONCLUSION Higher IL-6 levels are associated with worse clinical outcome and the occurrence of DINDs. Because IL-6 levels were significantly elevated in the early phase, they might be a useful parameter to monitor.

Novel treatments for vasospasm after subarachnoid hemorrhage.

Purpose of reviewCerebral vasospasm (CVS) after aneurysmal subarachnoid hemorrhage remains a considerable challenge in neurocritical care medicine. This review aims to cover the recent novel aspects and results in CVS treatment. Recent findingsOn the basis of the recent literature, treatment focusing on CVS alone is outdated. A considerable amount of evidence suggests CVS not to be the sole cause of delayed cerebral ischemia (DCI) and poor outcome. Early brain injury, cortical spreading depolarization, inflammation and microthrombosis have recently been discussed as additional factors. The results of a well designed phase III trial, using an endothelin-1 antagonist, indicated a decrease in the occurrence of CVS but did not change the clinical outcome significantly. Induced hypertension is currently recommended for treating suspected DCI, whereas hemodilution and hypervolemia are not. Endovascular intervention is only recommended in case of refractory symptomatic CVS. A couple of newer treatment strategies are under evaluation. Phase III trials are underway for magnesium sulfate and statins. Clinical trials aiming specifically at recently discussed factors other than CVS have not been reported. SummaryReviewing the recent literature, there have been some updates on recommendations and newer treatment modalities are under evaluation. However, a novel treatment with convincing evidence has not been reported so far.

Monitoring of the Inflammatory Response After Aneurysmal Subarachnoid Haemorrhage in the Clinical Setting: Review of Literature and Report of Preliminary Clinical Experience

BACKGROUND Clinical and experimental studies showed a marked inflammatory response in aneurysmal subarachnoid haemorrhage (SAH), and it has been proposed to play a key role in the development of cerebral vasospasm (CVS). Inflammatory response and occurrence of CVS may represent a common pathogenic pathway allowing point of care diagnostics of CVS. Therefore, monitoring of the inflammatory response might be useful in the daily clinical setting of an ICU. The aim of the current report is to give a summary about factors contributing to the complex pathophysiology of inflammatory response in SAH and to discuss possible monitoring modalities. METHODS Review and analysis of the existing literature and definition of own study protocols. RESULTS In cerebrospinal fluid, interleukin (IL)-6 has been found to be significantly higher in patients with CVS during the peri-vasospasm period. While systemic inflammatory response syndrome, high C-reactive protein levels and leukocyte counts has been linked with the occurrence of CVS, less has been reported about cytokines levels in the jugular bulb of the internal jugular vein and in the peripheral blood. Preliminary evaluation of own data suggests, that IL-6 values in the peripheral blood and the arterio-jugular differences of IL-6 are increased with the inflammatory response after SAH. CONCLUSION Monitoring of the inflammatory response, in particular IL-6, might be a useful tool for the daily clinical management of patients with SAH and CVS.

Combined therapeutic hypothermia and barbiturate coma reduces interleukin-6 in the cerebrospinal fluid after aneurysmal subarachnoid hemorrhage.

Inflammatory response with cytokine release is reported to correlate with clinical outcome after aneurysmal subarachnoid hemorrhage (SAH). In selected cases, hypothermia and barbiturate coma are applied as means for neuroprotection after severe SAH. Hypothermia and high-dose barbiturate are reported to attenuate the inflammatory response. In this pilot study, we assessed the effect of the combined therapy on the inflammatory response. In 15 patients with SAH, daily cerebrospinal fluid (CSF) and plasma samples were collected. Interleukin (IL)-6, tumor necrosis factor alpha (TNF-α), IL-1β, systemic leukocyte, and leukocyte counts in the CSF were quantified. Group 1 represented 7 cases treated with combined therapeutic hypothermia (33°C) and barbiturate coma. Group 2 represented 8 cases without combined therapy. Compared with the systemic levels, all cases showed higher cytokine levels in the CSF. Mean IL-6 level in the CSF was significantly lower in group 1 (P<0.001). The ratio between IL-6 levels in the CSF and plasma, as a parameter for intrathecal synthesis, was significantly lower in group 1 (P=0.014). Mean CSF and systemic levels of TNF-α of group 1 were significantly higher compared with group 2 (P=0.009 and P<0.001). The mean systemic IL-1β level was significantly lower in group 1 (P<0.001), as well as the leukocyte counts, both, systemic and in the CSF (P<0.001 and P=0.032). The present data show a most pronounced decrease of IL-6 levels in the CSF, beside decrease in systemic IL-1β levels, systemic leukocyte counts, and CSF leukocyte counts in group 1, which would be expected to reflect an attenuation of inflammatory response. The impact and role of TNF-α remains unclear.

Seasonal variations in hospital admissions due to aneurysmal subarachnoid haemorrhage in the state of Zurich, Switzerland

SummaryIntroduction. In clinical practice, the occurrence of aneurysmal subarachnoid haemorrhage (SAH) often coincides with a particular season. Our objective was to examine seasonal variations in hospital admissions due to aneurysmal SAH. Methods. The study population consisted of 489 patients with aneurysmal SAH who were admitted to the Department of Neurosurgery, University Hospital of Zurich, Switzerland, between 1st of January 1996 and 31st of December 2002. Statistical significance of seasonal variation was determined by applying Roger’s r test. Results. Statistically significant seasonal variation was only found among patients younger than 60 years, showing a first peak in spring and second lower peak in autumn (Roger’s r=6.89, p<0.05). A borderline significance was found in men younger than 60 years (Roger’s r=5.96, p=0.051). A trend was observed in patients presenting with Fisher grade 1–2 (Roger’s r=5.70, p=0.058). Conclusions. Previous studies from different countries have shown significant seasonal variations, with the peak period for aneurysmal SAH differing widely. There appears to be some link between aneurysmal SAH and the season of the year or variations in weather conditions. Further investigations are desirable to evaluate which weather or climatic parameters correlate well with SAH.

Extracranial–intracranial bypass in atherosclerotic cerebrovascular disease: report of a single centre experience

Despite the failure of the international extracranial–intracranial (EC–IC) bypass study in showing the benefit of bypass procedure for prevention of stroke recurrence, it has been regarded to be beneficial in a subgroup of well-selected patients with haemodynamic impairment. This report includes the EC–IC bypass experience of a single centre over a period of 14 years. All consecutive 72 patients with atherosclerotic occlusive cerebrovascular lesions associated with haemodynamic compromise treated by EC–IC bypass surgery were retrospectively reviewed. Pre-operatively, 61% of patients presented with minor stroke and the remaining 39% with recurrent transient ischemic attacks (TIAs) despite maximal medical therapy. Angiography revealed a unilateral internal carotid artery (ICA) stenosis/occlusion in 79%, bilateral ICA stenosis/occlusion in 15%, MCA stenosis/occlusion in 3% and other multiple vessel stenosis/occlusion in 3% of the cases. H215O positron emission tomography (PET) or 99mTc-HMPAO SPECT with acetazolamide challenge was performed for haemodynamic evaluation of the cerebral blood flow (CBF). All the patients had impaired haemodynamics pre-operatively in terms of reduced regional cerebrovascular reserve capacity and rCBF. Standard STA-MCA bypass procedure was performed in all patients. A total of 68 patients with 82 bypasses were reviewed with a mean follow-up period of 34 months. Stroke recurrence took place in 10 patients (15%) resulting in an annual stroke risk of 5%. Improved cerebral haemodynamics was documented in 81% of revascularised hemispheres. Patients with unchanged or worse haemodynamic parameters had significantly more post-operative TIAs or strokes when compared to those with improved perfusion reserves (30% vs.5% of patients, p < 0.05). In conclusion, EC–IC bypass procedure in selected patients with occlusive cerebrovascular lesions associated with haemodynamic impairment has revealed to be effective for prevention of further cerebral ischemia, when compared with a stroke risk rate of 15% reported to date in patients only under antiplatelet agents or anticoagulant therapy.