Transl. Stroke Res. DOI 10.1007/s12975-015-0398-6
EDITORIAL
Aneurysmal Subarachnoid Hemorrhage—Status Quo and Perspective Nima Etminan 1
Received: 26 March 2015 / Accepted: 31 March 2015 # Springer Science+Business Media New York 2015
Aneurysmal subarachnoid hemorrhage (SAH) accounts for about 5 % of all strokes and continues to be a major cause of morbidity and mortality, especially in younger patients (mean age of 52). The global incidence of SAH is 9 per 100, 000 per year with some regional variations [1]. Data from population-based studies suggests a distinct decrease in case fatality (0.9 % per year) over the past four decades to about 30 %, which is likely originated in earlier and more advanced aneurysm repair as well as improved neurocritical care of SAH patients following aneurysm repair [2]. Nevertheless, the incidence of poor functional outcome in SAH patients remains high (about one third of patients). The main determinants for poor outcome after SAH are the degree of early brain injury (EBI) and the incidence of delayed cerebral ischemia (DCI) (see below) [3, 4]. The clinical course of SAH is complex and can be divided into an acute stage (the initial 72 h after SAH ictus) and a subacute stage, which lasts up until 20 days after SAH ictus. The potential main complications in the acute phase are EBI, rebleeding from the ruptured aneurysms, with a frequency of up to 23 % within the first 72 h, and acute hydrocephalus, occurring in about 20 % of the patients, whereas the main complications occurring in the subacute phase are DCI (formerly referred to as Bvasospasm,^ see below), cardiopulmonary or other medical complications, as well as permanent hydrocephalus [5–7]. The term EBI refers not only to direct
* Nima Etminan [email protected] 1
Department of Neurosurgery, Medical Faculty, Heinrich-HeineUniversity, Moorenstraße 5, 40225 Düsseldorf, Germany
mechanical damage to the brain tissue due to the hemorrhage but also to a cascade of different pathomechanisms, incl. a temporary increase of intracranial pressure, consecutive reduction of cerebral blood flow and/or microcirculatory spasm, transient global ischemia, neuronal injury or apoptosis, and edema formation [8]. The degree of EBI is a strong and independent predictor for clinical outcome after SAH [9, 3, 4]. The term DCI describes a complex phenomenon as a consequence of several pathomechanisms, incl. (1) macrovascular or angiographic vasospasm, i.e., narrowing of proximal cerebral arteries, (2) microvascular spasm, (3) microthromboembolism, (4) cortical spreading depolarization/ischemia, (5) autoregulatory dysfunction, and (6) inflammation [10–13, 7, 14–17]. The radiological term vasospasm has been widely replaced with the clinical term DCI, which describes a secondary neurological deterioration in the course SAH, excluding other causes of neurological deterioration; an explicit definition for DCI has been proposed by a multidisciplinary research group [16]. This Bparadigm shift^ came along with the insight that angiographic vasospasm occurs in up to 70 % of SAH patients, whereas only 30 % of SAH patients develop clinical features of DCI and, moreover, because pharmaceutical treatments exclusively targeting of angiographic vasospasm failed to improve neurological outcome after SAH [18–20]. However, in those clinical studies where cerebral infarction due to DCI was effectively reduced by experimental pharmaceutical treatments, a significant improvement of clinical outcome was also seen. These data further underlined the concept that DCI comprises several, pro-ischemic pathomechanisms, which ultimately result in cerebral infarction, but the individual importance of each of these pro-ischemic pathomechanisms remains to elucidated [21, 22]. The general shift in scientific focus, i.e., away from ‘vasospasm’ towards DCI and EBI, can also be
Transl. Stroke Res.
appreciated in the research topics of more recent SAH studies: Recent experimental studies investigated mechanisms of EBI and potential pharmaceutical or interventional means to limit or even reverse the extent of EBI with the aim to reduce the incidence of DCI or improve neurological outcome [8, 23–26]. The relevance of apoptosis inhibitors or attenuation of other causes of early neuronal injury and inflammation (e.g., p53, caspase, matrix metalloproteinase-9, aquaporin-1, VEGF, etc.) have been reported in the setting of experimental SAH [23, 25, 27–30]. Pharmacokinetics and in vivo characteristics of intrathecally or intracisternally administered, sustained-release formulations for prevention of DCI (e.g., nicardipine, nimodipine) have gained increasing interest [31, 32]. The same holds true for experimental studies investigating pathomechanisms involved in microcirculatory impairment or the role of the neurovascular unit in the pathogenesis of DCI [18, 33, 34]. Consequently, existing experimental SAH models have also been refined or modified to allow for more comprehensive experimental studies on mechanisms of EBI and DCI [35–39]. Thus, it will be interesting to see whether the promising data from these experimental studies on EBI and DCI could also be reproduced in future clinical studies. Recent clinical studies have further investigated radiological means to detect EBI and DCI, the appropriate neurocritical management of SAH patients as well as novel pharmaceutical concepts for prevention of DCI or poor outcome. Further, the efficacy of antifibrinolytic drugs (e.g., aminocaproic acid, tranexamic acid) for prevention of early aneurysm rerupture remains unclear and is currently being investigated in a clinical trial [40, 41, 6]. Interestingly and despite the increasing data on the merits of perfusion CT imaging as a more sensitive radiological means to detect DCI, a recent decision analysis based on Markov modeling underlined that the neurological status of SAH patients seems to remain the most sensitive surrogate for the presence of DCI [42–44]. Here, automated analyses and harmonized PCT algorithms may help to further establish the standardized use of perfusion CT imaging for the more accurate detection or even prediction of DCI [45]. For patients with clinical features of DCI, induced hypertension and euvolemia instead of hypervolemia have been proposed as rescue therapy, but the beneficial use of such strategies remains to be proven in a randomized, controlled trial [46–48]. In case of refractory DCI, some studies have suggested pharmaceutical or balloon angioplasty, but these treatments remain controversial since robust evidence is lacking [49]. Numerous clinical trials studied novel pharmaceutical treatments (i.e., nicardipine, tirilazad, statins, clazosentan, magnesium, etc.) against DCI, but oral nimodipine remains the only drug to improve neurological outcome in SAH patients [50, 19, 51, 20, 52]. Whether the lack of efficacy of these drugs originated from small sample sizes, insensitive
outcome measures, insensitive pharmacological targets, or detrimental systemic effects is uncertain [53]. To further investigate this, a multidisciplinary research group has been established to build a Subarachnoid Hemorrhage International Trialists (SAHIT) data repository based on prospectively collected SAH patient data from over 14,000 patients; these data may help to establish a novel SAH outcome prediction model based on this very large prospective patient cohort [54–56]. In line with the improved clinical outcomes of SAH patients, a growing body of data highlights that frequently used SAH outcome grading scales (e.g., modified Rankin Scale or Glasgow Outcome Scale) may be somewhat insensitive to detect neuropsychological (depression, anxiety, etc.) or cognitive deficits in SAH patients [57–59]. In summary, the ongoing SAH research seems to address (a) the further analysis of pathomechanisms of early brain injury and DCI; (b) Bbridge the gap^ between experimental and clinical research; (c) the optimization and harmonization of neurocritical care in SAH patients; (d) new imaging techniques or biomarkers to detect and measure EBI or DCI as surrogates for clinical outcome; (e) the efficacy of systemic versus local administration of vasodilators; (f) mechanisms, sequelae, and potential treatments of neuropsychological deficits after SAH; and (g) novel pharmaceutical targets strategies to limit or reverse the extent of early brain injury and DCI. New insights are to be expected from the ongoing clinical trials investigating the effect of systemic (prostacyclin, ketamine) or local (EG-1962) pharmaceutical treatment for prevention of DCI, pharmacologic (hemodynamic therapy, NCT 01613235) or interventional rescue therapy (intra-arterial vasodilators, NCT 01996436 or balloon angioplasty), or ischemic preconditioning (NCT01158508) or hypercapnia (NCT00930072) [60–62]. Ultimately, all the studies briefly discussed here underline that a large variety of promising scientific angles are being pursued from SAH research groups around the globe to build upon and expand on the already striking progress in the research and treatment of SAH. Conflict of Interest NE served as a scientific advisor for Edge Therapeutics Inc.
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EDITORIAL
Aneurysmal Subarachnoid Hemorrhage—Status Quo and Perspective Nima Etminan 1
Received: 26 March 2015 / Accepted: 31 March 2015 # Springer Science+Business Media New York 2015
Aneurysmal subarachnoid hemorrhage (SAH) accounts for about 5 % of all strokes and continues to be a major cause of morbidity and mortality, especially in younger patients (mean age of 52). The global incidence of SAH is 9 per 100, 000 per year with some regional variations [1]. Data from population-based studies suggests a distinct decrease in case fatality (0.9 % per year) over the past four decades to about 30 %, which is likely originated in earlier and more advanced aneurysm repair as well as improved neurocritical care of SAH patients following aneurysm repair [2]. Nevertheless, the incidence of poor functional outcome in SAH patients remains high (about one third of patients). The main determinants for poor outcome after SAH are the degree of early brain injury (EBI) and the incidence of delayed cerebral ischemia (DCI) (see below) [3, 4]. The clinical course of SAH is complex and can be divided into an acute stage (the initial 72 h after SAH ictus) and a subacute stage, which lasts up until 20 days after SAH ictus. The potential main complications in the acute phase are EBI, rebleeding from the ruptured aneurysms, with a frequency of up to 23 % within the first 72 h, and acute hydrocephalus, occurring in about 20 % of the patients, whereas the main complications occurring in the subacute phase are DCI (formerly referred to as Bvasospasm,^ see below), cardiopulmonary or other medical complications, as well as permanent hydrocephalus [5–7]. The term EBI refers not only to direct
* Nima Etminan [email protected] 1
Department of Neurosurgery, Medical Faculty, Heinrich-HeineUniversity, Moorenstraße 5, 40225 Düsseldorf, Germany
mechanical damage to the brain tissue due to the hemorrhage but also to a cascade of different pathomechanisms, incl. a temporary increase of intracranial pressure, consecutive reduction of cerebral blood flow and/or microcirculatory spasm, transient global ischemia, neuronal injury or apoptosis, and edema formation [8]. The degree of EBI is a strong and independent predictor for clinical outcome after SAH [9, 3, 4]. The term DCI describes a complex phenomenon as a consequence of several pathomechanisms, incl. (1) macrovascular or angiographic vasospasm, i.e., narrowing of proximal cerebral arteries, (2) microvascular spasm, (3) microthromboembolism, (4) cortical spreading depolarization/ischemia, (5) autoregulatory dysfunction, and (6) inflammation [10–13, 7, 14–17]. The radiological term vasospasm has been widely replaced with the clinical term DCI, which describes a secondary neurological deterioration in the course SAH, excluding other causes of neurological deterioration; an explicit definition for DCI has been proposed by a multidisciplinary research group [16]. This Bparadigm shift^ came along with the insight that angiographic vasospasm occurs in up to 70 % of SAH patients, whereas only 30 % of SAH patients develop clinical features of DCI and, moreover, because pharmaceutical treatments exclusively targeting of angiographic vasospasm failed to improve neurological outcome after SAH [18–20]. However, in those clinical studies where cerebral infarction due to DCI was effectively reduced by experimental pharmaceutical treatments, a significant improvement of clinical outcome was also seen. These data further underlined the concept that DCI comprises several, pro-ischemic pathomechanisms, which ultimately result in cerebral infarction, but the individual importance of each of these pro-ischemic pathomechanisms remains to elucidated [21, 22]. The general shift in scientific focus, i.e., away from ‘vasospasm’ towards DCI and EBI, can also be
Transl. Stroke Res.
appreciated in the research topics of more recent SAH studies: Recent experimental studies investigated mechanisms of EBI and potential pharmaceutical or interventional means to limit or even reverse the extent of EBI with the aim to reduce the incidence of DCI or improve neurological outcome [8, 23–26]. The relevance of apoptosis inhibitors or attenuation of other causes of early neuronal injury and inflammation (e.g., p53, caspase, matrix metalloproteinase-9, aquaporin-1, VEGF, etc.) have been reported in the setting of experimental SAH [23, 25, 27–30]. Pharmacokinetics and in vivo characteristics of intrathecally or intracisternally administered, sustained-release formulations for prevention of DCI (e.g., nicardipine, nimodipine) have gained increasing interest [31, 32]. The same holds true for experimental studies investigating pathomechanisms involved in microcirculatory impairment or the role of the neurovascular unit in the pathogenesis of DCI [18, 33, 34]. Consequently, existing experimental SAH models have also been refined or modified to allow for more comprehensive experimental studies on mechanisms of EBI and DCI [35–39]. Thus, it will be interesting to see whether the promising data from these experimental studies on EBI and DCI could also be reproduced in future clinical studies. Recent clinical studies have further investigated radiological means to detect EBI and DCI, the appropriate neurocritical management of SAH patients as well as novel pharmaceutical concepts for prevention of DCI or poor outcome. Further, the efficacy of antifibrinolytic drugs (e.g., aminocaproic acid, tranexamic acid) for prevention of early aneurysm rerupture remains unclear and is currently being investigated in a clinical trial [40, 41, 6]. Interestingly and despite the increasing data on the merits of perfusion CT imaging as a more sensitive radiological means to detect DCI, a recent decision analysis based on Markov modeling underlined that the neurological status of SAH patients seems to remain the most sensitive surrogate for the presence of DCI [42–44]. Here, automated analyses and harmonized PCT algorithms may help to further establish the standardized use of perfusion CT imaging for the more accurate detection or even prediction of DCI [45]. For patients with clinical features of DCI, induced hypertension and euvolemia instead of hypervolemia have been proposed as rescue therapy, but the beneficial use of such strategies remains to be proven in a randomized, controlled trial [46–48]. In case of refractory DCI, some studies have suggested pharmaceutical or balloon angioplasty, but these treatments remain controversial since robust evidence is lacking [49]. Numerous clinical trials studied novel pharmaceutical treatments (i.e., nicardipine, tirilazad, statins, clazosentan, magnesium, etc.) against DCI, but oral nimodipine remains the only drug to improve neurological outcome in SAH patients [50, 19, 51, 20, 52]. Whether the lack of efficacy of these drugs originated from small sample sizes, insensitive
outcome measures, insensitive pharmacological targets, or detrimental systemic effects is uncertain [53]. To further investigate this, a multidisciplinary research group has been established to build a Subarachnoid Hemorrhage International Trialists (SAHIT) data repository based on prospectively collected SAH patient data from over 14,000 patients; these data may help to establish a novel SAH outcome prediction model based on this very large prospective patient cohort [54–56]. In line with the improved clinical outcomes of SAH patients, a growing body of data highlights that frequently used SAH outcome grading scales (e.g., modified Rankin Scale or Glasgow Outcome Scale) may be somewhat insensitive to detect neuropsychological (depression, anxiety, etc.) or cognitive deficits in SAH patients [57–59]. In summary, the ongoing SAH research seems to address (a) the further analysis of pathomechanisms of early brain injury and DCI; (b) Bbridge the gap^ between experimental and clinical research; (c) the optimization and harmonization of neurocritical care in SAH patients; (d) new imaging techniques or biomarkers to detect and measure EBI or DCI as surrogates for clinical outcome; (e) the efficacy of systemic versus local administration of vasodilators; (f) mechanisms, sequelae, and potential treatments of neuropsychological deficits after SAH; and (g) novel pharmaceutical targets strategies to limit or reverse the extent of early brain injury and DCI. New insights are to be expected from the ongoing clinical trials investigating the effect of systemic (prostacyclin, ketamine) or local (EG-1962) pharmaceutical treatment for prevention of DCI, pharmacologic (hemodynamic therapy, NCT 01613235) or interventional rescue therapy (intra-arterial vasodilators, NCT 01996436 or balloon angioplasty), or ischemic preconditioning (NCT01158508) or hypercapnia (NCT00930072) [60–62]. Ultimately, all the studies briefly discussed here underline that a large variety of promising scientific angles are being pursued from SAH research groups around the globe to build upon and expand on the already striking progress in the research and treatment of SAH. Conflict of Interest NE served as a scientific advisor for Edge Therapeutics Inc.
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