JOURNAL OF NEUROSCIENCE AND NEUROSURGERY (ISSN:2517-7400)

Background: Subarachnoid haemorrhage (SAH) is associated with high mortality within the first 48 hours. Neurological damage after SAH occurs from multiple mechanisms, including early brain injury (EBI), delayed ischemic neurologic deficit (DIND), and cerebral vasospasm (CVS). Edaravone may prevent brain injury from EBI and DIND and in particular prevent cerebral vasospasm and improve neurological outcomes. In our hospital, we often use edaravone for patients with SAH. In this retrospective study, we investigated the presence of an association between edaravone and clinical outcomes in patients with aneurysmal SAH.

Method: We enrolled 16 patients at our institute who underwent coil embolisation and administration of edaravone for ruptured aneurysmal SAH. We reviewed their clinical background and if edaravone improved their clinical outcomes.

Results: Only one patient developed symptomatic CVS. For this patient, an arterial injection of fasudil hydrochloride hydrate was administered and percutaneous transluminal angioplasty was performed. Another two cases showed high intensity spots on diffusion-weighted imaging sequences on cranial magnetic resonance imaging performed after a period of cerebral vasospasm.

Conclusions: We found a low rate of DINDs due to CVS in patients with aneurysmal SAH treated with edaravone. Further studies are required to confirm this finding.

edaravone, cerebral vasospasm, early brain injury, delayed ischemic neurologic deficit

Subarachnoid haemorrhage (SAH) is associated with high mortality: 12.4% of patients experience sudden death, and 40%-60% die within the first 48 hours [1-3]. Neurological damage after SAH occurs from different mechanisms: early brain injury (EBI), delayed ischaemic neurologic deficit (DIND), and cerebral vasospasm (CVS). EBI describes the extensive brain injury that can occur in the period between initial bleeding and the onset of CVS [4]. Symptomatic vasospasm, or DIND, occurs in 32.5% of patients with SAH [5]; 30% of patients with DIND die, and permanent neurological deficits occur in 34% [5,6]. The prevention of brain injury from EBI and DIND is the goal of much contemporary research [7,8].Vasospasm can induce cerebral infarction, and shunt-dependent hydrocephalus occurs less frequently after coiling than clipping of an associated aneurysm [9]. Spinal drainage of cerebrospinal fluid (CSF) has been shown to decrease the incidence of DIND [10].

Edaravone has been shown to potentially prevent CVS and improve neurological outcomes in clinical research [11]. However, edaravone is not a standard treatment for SAH [6]. In addition, there are many reports from basic research that edaravone can prevent EBI and DIND due to reactive oxygen species (ROS) after SAH [4,12- 14]. In our hospital, we often use edaravone in patients with SAH who were likely to progress to DIND, and we believe that edaravone can improve clinical outcomes. In this retrospective study, we investigated for the presence of an association between edaravone and clinical outcomes.

We enrolled 16 patients who underwent coil embolisation and administration of edaravone for ruptured aneurysmal SAH between 1 January 2017 and 31 December 2019 at our institute. We retrospectively reviewed their clinical background and whether edaravone was associated with an improvement in clinical outcomes.

After patients arrived in the emergency room, we performed brain computed tomography (CT) to diagnose SAH. We also performed CT angiography and confirmed the location of any aneurysm(s). In all cases, the amount of blood on CT was documented using the Fisher grading system, and preoperative clinical status was assessed using the Hunt & Hess grading system. Aneurysms were treated by coil embolisation in the acute phase. After the procedure we administered edaravone, fasudil hydrochloride hydrate, and nicardipine hydrochloride in all cases [15]. In addition, we administered ozagrel sodium, concentrated glycerine, and albumin dependent on the patient’s symptoms [16]. Spinal CSF drainage was also used in almost all cases, except in cases of severe lumbar spondylosis [10].We performed cranial magnetic resonance imaging (MRI; as a minimum, diffusionweighted imaging [DWI], magnetic resonance angiography [MRA], and fluid-attenuated inversion recovery sequences) three times in the first two weeks after the onset of SAH. At day 1, we estimated the extent of coil embolization after the procedure. Then, at day 7, we estimated the extent of infarction caused by the procedure, and EBI. At day 14, we estimated infarction caused by DIND. If a patient had symptomatic CVS, we performed endovascular interventions to attempt to manage this [6] (Figure 1 and 2).

Before conducting this study, relevant study documents were placed on the bulletin board in the hospital and on the hospital website, and approval by the ethical review board of the hospital (Approval No.: Sairin 010) was received.

Of the 16 patients included in our study, there were 4 men and 12 women. The age range of included participants was 42 to 85 years old, and the mean age was 62.1 years old. Regarding the location of ruptured aneurysms, there were 7 internal carotid artery (IC)-posterior communicating artery (Pcom) cases, 3 distal anterior cerebral artery (ACA) cases, 3 anterior communicating artery (Acom) cases, 2 IC-anterior choroidal artery cases, and 1 dorsal IC case.

The number of cases by Hunt & Hess grade were as follows: grade 1 (n= 2), grade 2 (n=6), grade 3 (n=7), and grade 4 (n=1). By Fisher group, the distribution was as follows: group 2 (n=2), group 3 (n=13), group 4 (n=1) case (there were no Fisher group 1 cases). Different technical methods used during coil embolisation were as follows: simple technique (n=7), double catheter technique (n=2), balloon-assist technique (n=6), and stent-assist technique (n=1). There were 2 extravasations during coiling. We found DWI high-intensity regions in 2 cases on MRI performed the day after coiling.

In addition, we administered ozagrel sodium in 13 cases, concentrated glycerine in 9 cases, and albumin in 6 cases. Spinal CSF drainage was performed in 13 cases. Only one patient had symptomatic CVS, which was treated by an arterial injection of fasudil hydrochloride hydrate and percutaneous transluminal angioplasty. This case was discharged from the hospital with no neurological deficit. Another 2 cases showed high intensity spots on the DWI sequence of a cranial MRI scan after a period of CVS, but neither of the 2 cases had a neurological deficit.  

SAH is a devastating condition with high morbidity and mortality. Based on our experience, we hypothesised that edaravone could improve neurological outcomes in patients with SAH. We therefore retrospectively analysed whether edaravone influenced patients’ neurological outcomes. We found a low rate of DINDs due to CVS in patients with aneurysmal SAH treated with edaravone; only 1 of the 16 patients in our study developed symptomatic CVS.

The Japanese stroke guidelines describe a study authored by Munakata et al. who investigated the use of edaravone for DIND, but the use of edaravone was not enforced [11]. In their study, they randomized 91 patients into a control group and an edaravone treatment group. They analyzed the incidence of DIND and cerebral infarctions caused by CVS. They concluded that there was possibly a lower incidence of DIND and a lower incidence of a poor outcome due to CVS in those treated with edaravone [11] (Table 1).

In addition, there have been many nonclinical experiments involving edaravone [4,12-14]. In 2003, Nakagomi et al. [12] developed a model dog of SAH and showed that continuous administration of edaravone for seven days significantly reduced CVS. Munakata et al. [13] investigated, through the use of the double haemorrhage rabbit model, the possibility that free radical reactions play a role in CVS and attempted to delineate the mechanisms of signal transduction that causes CVS [13]. They measured the diameter of each basilar artery to evaluate the degree of CVS. The diameter of the basilar artery in the edaravone-treated group was significantly larger than those in the non-treated SAH group on day 4. The authors also evaluated the expression of Rho-kinase in the vascular wall, which was significantly reduced in the edaravone-treated group in comparison to the nontreated SAH group [13]. Free radical reactions mediated by oxyhaemoglobin (oxyHb) play a role in the Rho/Rhokinase pathway expressing Rho-kinase, and cause vasoconstriction and thus CVS.

Early brain injury is a particular problem in patients with SAH [4,14]. Oxidative stress plays a crucial role in the induction of diverse pathological changes in EBI. OxyHb, a component of blood clots distributed in the subarachnoid cavity, generates ROS. Mitochondrial and enzyme generation of ROS is also enhanced, whereas endogenous antioxidant protection systems are suppressed immediately after SAH onset. Thus, oxidative stress is dramatically elevated and influences various signalling pathways that lead to a variety of pathological changes in EBI. Diverse pathological changes include blood brain barrier (BBB) disruption, brain oedema, cerebral ischaemia, and neuronal cell death. Microcirculatory disturbance is a critical pathological change in EBI, since it influences various other pathological changes in EBI [4]. Vasoconstriction and thrombosis in microvessels cause cerebral ischaemia and neuronal cell death. Brain oedema occurs as a consequence of BBB disruption in the capillaries. In addition, microcirculatory disturbance is hypothesised to be involved in the development of delayed cerebral ischemia and poor outcomes. Yang et al. [14] have stated that edaravone decreases free radicals and suppresses apoptosis of neurons, thus mitigating EBI and improving neurological function. Fumoto et al. [4] have stated that edaravone suppresses oxidative stress in microvessels, and decreases BBB permeability, suppressing brain oedema [4]. Tight junctions, the main constitution of the BBB, have been shown to be disrupted and induce brain oedema after SAH. Edaravone treatment suppresses staining of nitrotyrosine and 8-hydroxydeoxyguanosine, especially in vascular cells, which are specific markers of oxidative stress in protein and DNA. Edaravone treatment prevents the expression and activation of MMp-9, and the subsequent degradation of tight junction proteins, claudin-5 and occludin. In addition to tight junctions, vascular endothelial cells are also important constituents of the BBB that limit transcellular transport. Edaravone treatment suppresses the induction of apoptosis, which indicates edaravone can preserve BBB integrity, not only by maintaining tight junctions, but also through endothelial cell barrier function. Edaravone also suppresses microspasm and microthrombosis. Microvessels have been shown to narrow near their apoptotic mural cells after SAH, and fibrin deposition on microvessels is increased after SAH. Edaravone treatment has also been shown to suppress microthombus formation (Table 2).

In our hospital, we used edaravone for patients with SAH, based on anecdotal evidence that edaravone improves neurological outcomes. In this report, we used edaravone for all SAH patients who received coil embolisation. It is difficult to distinguish between EBI and DIND in this report; only 1 patient had confirmed DIND (6.25%), which is a lower rate than that seen in previous reports. There were just two patients (12.5%) who had a high intensity spot on cranial MRI, but they had no neurological deficits and thus were not classified as having developed DIND. We believe that edaravone was one of the reasons that the rate of DINDs was low in our patients. Edaravone may not be required for all SAH patients but may be helpful in selected cases.

In conclusion, we found a low rate of DINDs and good neurological outcomes in our patients with SAH that were treated with edaravone. Based on our experience, edaravone appears to be useful for the treatment of patients with aneurysmal SAH.

We would like to thank Editage (www.editage.com) for English language editing.

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