BACKGROUND:. The role and impact of systemic inflammatory response after aneurysmal subarachnoid hemorrhage remain to be elucidated.OBJECTIVE:. To asses

Delayed ischemic neurological deficit (DIND) is a major driver of adverse outcomes in patients with aneurysmal subarachnoid hemorrhage (aSAH) defining an unmet need for therapeutic development. Cell-free hemoglobin that is released from erythrocytes into the cerebrospinal fluid (CSF) is suggested to cause vasoconstriction and neuronal toxicity and correlates with the occurrence of DIND. Cell-free hemoglobin in the CSF of patients with aSAH disrupted dilatory NO signaling ex vivo in cerebral arteries, which shifted vascular tone balance from dilation to constriction. We found that selective removal of hemoglobin from patient CSF with a haptoglobin-affinity column or its sequestration in a soluble hemoglobin-haptoglobin complex was sufficient to restore physiological vascular responses. In a sheep model, administration of haptoglobin into the CSF inhibited hemoglobin-induced cerebral vasospasm and preserved vascular NO-signaling. We identified two pathways of hemoglobin delocalization from CSF into the brain parenchyma and into the NO-sensitive compartment of small cerebral arteries. Both pathways were critical for hemoglobin-toxicity and were interrupted by the large hemoglobin-haptoglobin complex that inhibited spatial requirements for hemoglobin reactions with NO in tissues. Collectively, our data show that compartmentalization of hemoglobin by haptoglobin provides a novel framework for innovation aimed at reducing hemoglobin-driven neurological damage after subarachnoid bleeding.

Object: The supraorbital approach through an eyebrow incision offers the opportunity to access a wide variety of lesions of the anterior, middle, and even the posterior fossa. The minimally invasive keyhole craniotomy limits brain exploration and retraction and offers the potential for improved surgical outcomes and reduced approach-related complications. Patient satisfaction, however, has not yet been reported in the literature. Methods: From January 2002 through December 2011, the lead author (R.R.) used a supraorbital approach through an eyebrow incision for 418 patients with cerebral aneurysms, brain tumors or cystic lesions, and other miscellaneous pathological conditions. For 408 of these patients, a detailed retrospective case note review was conducted to extract data on surgical outcomes and complications, and 375 patients completed a follow-up patient satisfaction questionnaire. Results: During the early perioperative period, 8 patients died (overall mortality rate 2.0%). Among patients surveyed, the overall level of satisfaction was high. Patients rated pain from the scar and headache on a scale from 1 to 5 (1 = no pain, 5 = severe pain) as follows: pain was a score of 1 for 289 patients (77.0%), 2 for 46 (12.3%), 3 for 22 (5.9%), 4 for 12 (3.2%), and 5 for 6 (1.6%). Patients also rated cosmetic outcome on a scale from 1 to 5 (1 = very pleasant, 5 = very unpleasant) as follows: outcome was a score of 1 for 315 patients (84.0%), 2 for 33 (8.8%), 3 for 14 (3.7%), 4 for 10 (2.7%), and 5 for 3 (0.8%). Postoperative chewing difficulty was reported for 8 patients (8 [2.1%] temporary, 0 permanent); palsy of the frontal muscle for 21 patients (5.6%; 13 [3.5%] temporary, 8 [2.1%] permanent); frontal hypesthesia for 31 patients (8.3%; 18 [4.8%] temporary, 13 [3.4%] permanent); and hyposmia for 11 patients (2.9%; 3 [0.8%] temporary, 8 [2.1%] permanent). Conclusions: The supraorbital approach to the anterior, middle, and posterior fossae through an eyebrow incision offers a favorable rate of approach-associated surgical complications and high patient satisfaction with cosmetic outcome.

Secondary brain injury after aneurysmal subarachnoid hemorrhage (SAH-SBI) contributes to poor outcomes in patients after rupture of an intracranial aneurysm. The lack of diagnostic biomarkers and novel drug targets represent an unmet need. The aim of this study was to investigate the clinical and pathophysiological association between cerebrospinal fluid hemoglobin (CSF-Hb) and SAH-SBI. In a cohort of 47 patients, we collected daily CSF-samples within 14 days after aneurysm rupture. There was very strong evidence for a positive association between spectrophotometrically determined CSF-Hb and SAH-SBI. The accuracy of CSF-Hb to monitor for SAH-SBI markedly exceeded that of established methods (AUC: 0.89 [0.85-0.92]). Temporal proteome analysis revealed erythrolysis accompanied by an adaptive macrophage response as the two dominant biological processes in the CSF-space after aneurysm rupture. Ex-vivo experiments on the vasoconstrictive and oxidative potential of Hb revealed critical inflection points overlapping CSF-Hb thresholds in patients with SAH-SBI. Selective depletion and in-solution neutralization by haptoglobin or hemopexin efficiently attenuated the vasoconstrictive and lipid peroxidation activities of CSF-Hb. Collectively, the clinical association between high CSF-Hb levels and SAH-SBI, the underlying pathophysiological rationale, and the favorable effects of haptoglobin and hemopexin in ex-vivo experiments position CSF-Hb as a highly attractive biomarker and potential drug target.

Aneurysmal subarachnoid hemorrhage (aSAH) is a devastating form of stroke frequently affecting young to middle-aged adults, with an unmet need to improve outcome. This special report focusses on the development of intrathecal haptoglobin supplementation as a treatment by reviewing current knowledge and progress, arriving at a Delphi-based global consensus regarding the pathophysiological role of extracellular hemoglobin and research priorities for clinical translation of hemoglobin-scavenging therapeutics. After aneurysmal subarachnoid hemorrhage, erythrocyte lysis generates cell-free hemoglobin in the cerebrospinal fluid, which is a strong determinant of secondary brain injury and long-term clinical outcome. Haptoglobin is the body’s first-line defense against cell-free hemoglobin by binding it irreversibly, preventing translocation of hemoglobin into the brain parenchyma and nitric oxide-sensitive functional compartments of cerebral arteries. In mouse and sheep models, intraventricular administration of haptoglobin reversed hemoglobin-induced clinical, histological, and biochemical features of human aneurysmal subarachnoid hemorrhage. Clinical translation of this strategy imposes unique challenges set by the novel mode of action and the anticipated need for intrathecal drug administration, necessitating early input from stakeholders. Practising clinicians (n=72) and scientific experts (n=28) from 5 continents participated in the Delphi study. Inflammation, microvascular spasm, initial intracranial pressure increase, and disruption of nitric oxide signaling were deemed the most important pathophysiological pathways determining outcome. Cell-free hemoglobin was thought to play an important role mostly in pathways related to iron toxicity, oxidative stress, nitric oxide, and inflammation. While useful, there was consensus that further preclinical work was not a priority, with most believing the field was ready for an early phase trial. The highest research priorities were related to confirming haptoglobin’s anticipated safety, individualized versus standard dosing, timing of treatment, pharmacokinetics, pharmacodynamics, and outcome measure selection. These results highlight the need for early phase trials of intracranial haptoglobin for aneurysmal subarachnoid hemorrhage, and the value of early input from clinical disciplines on a global scale during the early stages of clinical translation.