Novel Treatments in Neuroprotection for Aneurysmal Subarachnoid Hemorrhage

Abstract

New neuroprotective treatments aimed at preventing or minimizing "delayed brain injury" are attractive areas of investigation and hold the potential to have substantial beneficial effects on aneurysmal subarachnoid hemorrhage (aSAH) survivors. The underlying mechanisms for this "delayed brain injury" are multi-factorial and not fully understood. The most ideal treatment strategies would have the potential for a pleotropic effect positively modulating multiple implicated pathophysiological mechanisms at once. My personal management (RFJ) of patients with aneurysmal subarachnoid hemorrhage closely follows those treatment recommendations contained in modern published guidelines. However, over the last 5 years, I have also utilized a novel treatment strategy, originally developed at the University of Maryland, which consists of a 14-day continuous low-dose intravenous heparin infusion (LDIVH) beginning 12 h after securing the ruptured aneurysm. In addition to its well-known anti-coagulant properties, unfractionated heparin has potent anti-inflammatory effects and through multiple mechanisms may favorably modulate the neurotoxic and neuroinflammatory processes prominent in aneurysmal subarachnoid hemorrhage. In my personal series of patients treated with LDIVH, I have found significant preservation of neurocognitive function as measured by the Montreal Cognitive Assessment (MoCA) compared to a control cohort of my patients treated without LDIVH (RFJ unpublished data presented at the 2015 AHA/ASA International Stroke Conference symposium on neuroinflammation in aSAH and in abstract format at the 2015 AANS/CNS Joint Cerebrovascular Section Annual Meeting). It is important for academic physicians involved in the management of these complex patients to continue to explore new treatment options that may be protective against the potentially devastating "delayed brain injury" following cerebral aneurysm rupture. Several of the treatment options included in this review show promise and could be carefully adopted as the level of evidence for each improves. Other proposed neuroprotective treatments like statins and magnesium sulfate were previously thought to be very promising and to varying degrees were adopted at numerous institutions based on somewhat limited human evidence. Recent clinical trials and meta-analysis have shown no benefit for these treatments, and I currently no longer utilize either treatment as prophylaxis in my practice.

Can Amantadine Ameliorate Neurocognitive Functions After Subarachnoid Haemorrhage? A Preliminary Study

“…Early repair of aneurysms and management of SAH-related complications, such as hydrocephalus and delayed cerebral ischemia, are thought to improve the functional outcome (15). Several studies on neuroprotection in SAH are being conducted (17). The drug memantine has been studied for this purpose, and its efficacy on neuroprotection in experimental SAH models has been demonstrated before (13).…”

Neuroprotective Strategies in Aneurysmal Subarachnoid Hemorrhage (aSAH)

“…The selective inhibition of the aforementioned pathophysiological events has been tested in experimental models of stroke, traumatic brain injury and aSAH as well as treatments targeting platelets [ 145 , 146 , 147 , 148 , 149 ], clot clearance [ 150 ], brain inflammation and immune cell infiltration [ 111 , 151 , 152 , 153 , 154 ]. These potential neuroprotective approaches are summarized in Table 2 .…”

Inflammatory Events Following Subarachnoid Hemorrhage (SAH)

“…Ischemic preconditioning has been en vogue during the last years, e.g . in tumor treatment, transplantation-, or (cardio-) vascular surgery [17, 31, 85-98]. The goal is to pre-sensitize the organ at risk to the impending situation, using a (remote) stimulus of the same kind, but of significantly less intensity.…”

“…Uncoupling of secondary brain injury and cerebral vasospasm, thanks to several position papers, has only begun a few years ago and is an ongoing process, which is still controversially discussed [14-17].…”