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SAH_CT.JPG
Subarachnoid hemorrhage (arrows) secondary to anterior communicating artery rupture
An aneurysmal rupture most often results in a subarachnoid hemorrhage, the bleeding into the subarachnoid space. While aneurysmal subarachnoid hemorrhage (SAH) comprises only of a small proportion of stroke cases (5-7%), it is associated with an early median age of onset and poor outcome[1]. In terms of productive life years lost, it is comparable to cerebral infarction, the most common stroke form. The main risk factors for aSAH are hypertension, female gender and smoking. Patients most often present clinically with severe headache and confusion, likely due to the sharp and sudden increase in intracranial pressure[2]. An SAH can be confirmed with a CT, MRI or lumbar puncture and upon diagnosis, it is critical that the aneurysm be endovascularly clipped or coiled to prevent rebleeding or re-rupture[3].
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After surgical intervention, SAH is associated with a myriad of complications, most markedly; about 28.5% of patients will develop delayed cerebral ischemia (DCI)[4]. DCI is represented clinically as a decline in neurological and cognitive function, typically arising 4-10 days after the initial ictus[5]. Approximately 46% of patients that develop DCI will have poor functional outcome, and of these, about 50% die[4]. Its pathogenesis is not well understood, and there is no established biomarker or neuroradiological technique to confirm the presence of DCI[5]. Currently, presence of angiographic vasospasm is the most commonly used clinical indicator of DCI development, though the correlation is modest[2]. In addition to cerebral vasospasm, various other putative mechanisms have been proposed as to the origin of DCI, with most revolving around the microvasculature. These include microvascular constriction, cortical spreading depression and microembolism[6].
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In terms of treatments, most are targeted at reversing cerebral vasospasm, though none have been found to be particularly effective at reducing the poor outcome after SAH[3]. In terms of future therapeutics, drugs targeting the microvasculature are currently being investigated.
Contents [Show/Hide]

      Clinical presentation
            4.1 Neurological symptoms
            4.2 Grading scales
      Delayed cerebral ischemia
            5.1 Defining criterion
            5.2 Pathogenesis
                  5.2.1 Cerebral vasospasm
                  5.2.2 Microvascular constriction
                  5.2.3 Cortical spreading depression
                  5.2.4 Microembolism
      Treatment
            6.1 Vasospasm
                  6.1.1 Pharmacological
                  6.1.2 Non-pharmacological Treatment
            6.2 Clinical trials
     References
     External links


Clinical presentation


Neurological symptoms

An SAH typically presents itself as a sudden onset headache (often described as the ‘worst of their life’), with vomiting, nausea, retinal hemorrhage and possibly a reduced level of consciousness[7],[8]. There are also several characteristic focal neurological signs that can be traced back to the type of aneurysmal rupture[7]. A third nerve palsy is indicative of posterior communicating artery rupture, low extremity weakness indicates anterior cerebral artery rupture, and lastly, aphasia and visuospatial neglect are typical of a middle cerebral artery rupture. More rarely, patients can also present with loss of consciousness, seizures, epilepsy, and confusion. In ~40% of patients, the only symptom that is displayed is a headache, which may be transient, but severe, lasting for minutes to hours. This is often referred to as a ‘thunderclap headache’, and is indicative of a ‘minor leak’ in the aneurysmal sac. This symptom is considered a warning sign of an upcoming severe SAH, usually occurring within 3 weeks of the first thunderclap headache. Emergency and diagnostic evaluation is recommended for these individuals.

Grading scales

Appropriate assessment of clinical condition at time of admission is critical as it is a reliable predictor for outcome after SAH[9]. Currently, there are three numerical scales used to characterize the clinical condition of SAH patients; the Hunt and Hess (H&H) scale, scale for the World Federation of Neurological Surgeons (WFNS) and Prognosis on Admission of Aneurysmal Subarachnoid Hemorrhage scale (PAASH). The Hunt & Hess scale is a 5-category scale that separates patients based on their surgical risk[10]. The WFNS scale was derived from the Glasgow Coma Score (GCS) in 1988, and the scale ranges from 0-15 (0: moribund; 15: asymptomatic)[11]. Cut-off points between grades are based on consensus among neurosurgeons rather than formal analysis. The PAASH scale was introduced in 1999 by Japanese neurosurgeons, based also on the GCS[12]. However, cut-offs were derived based on outcomes of patients, with each cut-off point representing significantly different 6-month outcome. Both PAASH and WFNS scales are preferred over the H&H, as they take into account focal neurological deficits and are highly reliable for evaluation of consciousness[7],[9]. Furthermore, there is less variability between observers in the PAASH and WFNS grading scales. This is particularly important for clinical trials and studies in order to allow for cross comparisons of patient admission data across global centers.

Delayed cerebral ischemia


Defining criterion

Delayed cerebral ischemia (DCI) is a feared complication associated with SAH and a significant contributor to poor outcome and mortality[5]. DCI usually arises 4-10 days after the ictus. It may present itself as headache, confusion, and/or diminished level of consciousness. Focal neurological signs such as hemiparesis or aphasia may be observed as well. DCI can be reversed, but in many cases, it progresses to cerebral infarction, leading to disability and death. DCI affects approximately 28.5% of SAH patients, of these, around 30% will die and a further 30% will have a poor functional outcome[4].
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The criterion for DCI has been recently redefined by an international ad-hoc panel of experts in the field of SAH[5]. In sum, DCI is currently defined as the occurrence of a focal neurological deficit or at least a two point decrease in the GSC, lasting at least 1 hour and not apparent immediately after aneurysmal rupture. Furthermore, this deficit cannot be due to any other cause that is identifiable by clinical, radiological or laboratory testing.

Pathogenesis

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Cerebral vasospasm

Cerebral vasospasm refers to the constriction of the major conducting cerebral arteries as evaluated by angiography or cerebral blood flow velocity measurement by transcranial Doppler ultrasound (TCD)[13]. It is a major complication that can be detected in approximately 70% of SAH patients. If the arterial constriction exceeds 50%, there will be a reduction in cerebral blood flow, leading to cerebral infarction. Vasospasm arises in approximately the same time frame as DCI, usually 3-14 days after the ictus.
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vasospasm.JPG
Vertebral Angiograms, A) After SAH; B)12 days after SAH. The arrowhead in A is pointing at a dissected AICA aneurysm. The arrow in B is pointing to the vasoconstricted right P2 PCA segment.
It is almost certain vasospasm arises due to the persistent blood clot encasing the circle of Willis arteries[13]. The severity of the vasospasm corresponds with increased volumes of blood in the subarachnoid space and onset is consistent with the lysis of the blood clot. However, despite intense research, it is still not clear what factors induces the vessel constriction[14]. Currently, it is believed that ferrous hemoglobin released during blood clot lysis is likely a key player, through its role as a nitric oxide (NO) scavenger, involvement in free radical production, and/or inducing endothelial membrane channel modifications[14],[15]. Other potential theories as to the genesis of vasospasm after SAH include increased synthesis of the potent vasoconstrictor, endothelin-1 (ET-1), reduced capacity of vessels to respond to NO, as well as signaling cascades that may increase calcium sensitivity in smooth muscle cells[6],[15],[16].
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For many years, cerebral vasospasm was considered to be the most treatable prognostic factor as a means to reverse DCI. Since it was first reported in 1951, there has been intense research and work done to understand and reverse this complication after SAH[17]. However, critics have suggested there are long-withstanding problems with treating vasospasm as the sole or main contributor to DCI after SAH[14]. Firstly, DCI has been shown to develop without the presence of angiographic vasospasm. Only 22% of patients display both DCI and vasospasm, while up to 70% have angiographically detectable vasospasm[18]. Secondly, some series have shown that the predictive value of vasospasm is poor, less than 50% in one series [19], though this is not universal, as some others have found strong correlations between presence of vasospasm and DCI [20]. Lastly, the location of cerebral infarction can only be predicted by vasospasm in <75% of cases[21]. Most recently, the clinical trial of clazosentan, an ET-1 antagonist, further called into question the tenuous relationship between vasospasm and DCI [22]. Most markedly, while clazosentan was able to reduce relative risk for moderate to severe vasospasm by 65%, it was not found to improve outcome after SAH. With compounding evidence that macrovessel constriction cannot fully account for the development of DCI, several novel hypothesis have been proposed, including microvascular constriction, cortical spreading depression and microembolism[6].

Microvascular constriction

OPS_imaging.jpg
OPS imaging of cortical microvessels after SAH. (A) Arterioles show impaired autoregulatory response to hypocapnia (29)
While large vessel spasm has well documented in human cases of SAH, whether cerebral microvascular constriction occurs is not clear. Experimental models of SAH and clinical studies have yielded contradicting evidence, in part due to the difficulty in observing and manipulating the cerebral microvasculature.

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As early as 1975, extraparenchymal pial arterioles in guinea pigs have been observed to constrict in vivo in response to placement of blood in the subarachnoid space[23]. More recently, pial arteriole constriction has been observed to occur as early as 3 hours after SAH induction, with 70% of middle cerebral artery branches showing constriction[24]. In a dog model of SAH, histological evaluation of intraparenchymal microvasculature diameters revealed brainstem arterioles were consistently constricted 3 and 7 days post-induction[25]. Contrastingly, a subsequent study employing the same experimental paradigm found these arterioles were dilated, highlighting the inherent variability in evaluation of microvasculature[26].
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Initial clinical studies of cerebral blood flow, volume and metabolism, found that in response to severe vasospasm, there was a large increase cerebral blood volume (CBV)[27]. This suggested that cerebral arterioles were dilated after SAH. However, further studies found that regional decreases in CBV corresponded to region of vessel spasm. These results indicate cerebral arterioles fail to dilate in response to decreased proximal perfusion pressures (i.e., impaired autoregulatory function)[28]. Recently, orthogonal polarizing spectral imaging has been applied to directly image cortical arterioles after SAH[29]. It was shown that approximately 60% of cortical arterioles are constricted, and the cortical microcirculation displayed an impaired autoregulatory response to hypocapnia. As it stands, experiment and clinical evidence for microvascular constriction is still inconclusive, though it is there is likely some disturbance to the vascular homeostasis after SAH.

Cortical spreading depression

Spreading depolarization is an electrophysiological phenomenon that has recently been linked to a variety of neurological conditions, including ischemic stroke, migraine and SAH[30]. Spreading depolarization refers to a wave of mass depolarization that spreads across the cerebral grey matter, associated with a near complete breakdown of ion homeostasis, and loss of membrane resistance[30],[31]. All these events lead to a sustained depolarization above the threshold for action potential generation, resulting a silencing of brain activity (hence, cortical spreading depression). The ion fluxes in spreading depolarization are similar to physiological neuronal activity, and require metabolic energy for sodium and calcium pumps to restore the resting membrane potential[32] ,[33]. This increased energy demand is reflected by a 100% increase in regional cerebral blood flow, through endogenous neurovascular coupling mechanisms[34].
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csd_final.JPG
Effects of CSD in the physiological (Blue) vs. pathogical (red) brain. A) rCBF, B)Neuronal Membrane potential, C) Electrocorticographic recording of brain silencing (30).
Spreading depolarization is unlikely to occur in the physiological brain, but it can be induced by a variety of noxious stimuli, including potassium, hemoglobin, hypoxia and ischemia [30]. Under certain conditions, spreading depolarizations can induce neuronal damage. For example, when spreading depolarizations are induced in a pathological brain, the hyperemic response is converted to a prolonged hypoperfusion of brain tissue, often referred to as ‘spreading ischemia
[34]. This neurovascular uncoupling will then convert a relatively harmless neuronal depolarization wave into an event that leads to widespread cortical infarct. Correspondingly, in rat models of spreading ischemia, widespread cortical necrosis has been observed[35].
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Cortical spreading depression (CSD) has been documented to occur quite frequently in the human brain after SAH. It is believed to be initiated by products of blood clot lysis, as administration potassium and hemoglobin to the subarachnoid space have been observed to initiate CSD in rats[35]. CSD in human SAH patients was first reported by Dreier et al. (2006), in a study of 18 patients[36]. CSD were recorded in 12 of these patients, and the presence and frequency of the depolarizations correlated with DCI development. In a subsequent study, a strong spatial and temporal association was found between CSD and a decrease in tissue oxygen partial pressures[33]. This provided evidence that CSD is coupled with spreading ischemia after SAH, and the authors suggested that neurovascular uncoupling may occur through the downregulation of endogenous vasodilators. Most recently, it has recently been shown that the number of spreading depolarizations correlated with DCI even without the presence of angiographic vasospasm[37]. This data provides further evidence that vasospasm is not necessary for DCI development.
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As it stands, it is not certain if blocking CSD after SAH can prevent poor outcome, though clinical trials of CSD inhibitors has not been found to be beneficial in other neurological conditions[30]. Furthermore, Reversing the downstream spreading ischemia could also be a potential target for future therapeutics. Lastly, at the present time, CSD can only be measured by cortical surface electrodes, as waves of spreading depolarizations do not appear to penetrate the scalp, limiting the usefulness of CSD as a biomarker. However, it has been suggested that spreading depolarizations and subsequent depression correlate strongly with time compressed scalp AC and DC electroencephalographic recordings[38].

Microembolism

microthrombi.JPG
Brain section illustrating microclots after SAH in human, in A) Pial arterioles and B) Intraparenchymal vessels. Scale bar 50uM (41).
Clinical studies have shown a pro-coagulatory state arises after SAH[2]. Clotting factors and coagulatory markers such as Von Willebrand factor, thromboxane B2, soluble P-selectin, platelet activating factor appear to be upregulated serologically. Furthermore, the fibrinolytic cascade appears to be inhibited after SAH, with tissue plasminogen inhibiting factor upregulated, prevent clot breakdown. This hyperaggreable state is thought to induce thrombus formation in large intracranial vessels, which could break off and lodge in cerebral microvasculature, causing scattered cortical microinfarct. The increase in serological markers of coagulation appear prior to vasospasm and therefore has been suggested as a more proximal cause of DCI as compared to CSD and vasospasm.

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Evidence for microclot formation after SAH was first reported in an autopsy study of a single SAH patient in 1983, and confirmed in subsequent post-mortem studies[39]. Later, the same group found that patients who displayed clinical signs of DCI prior to death had significantly higher microclot burdens than those who had died from aneurysmal rebleeding or hydrocephalus[40]. The microclots were found to be a mixture of aggregated platelets and multi-nucleated leukocytes. More recently, Stein et al. (2006) collaborated the prior findings and also determined that the microclot burden is correlated to the volume of subarachnoid blood at admission[41].
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aThe post-mortem studies are consistent with clinical studies using TCD to detect embolic signals after SAH[42]. Embolic signals were detected in 70% of the patients tested, and level of embolic signals correlated with DCI development. However, many who had embolic signals did not display any clinical signs of DCI, indicating that emboli themselves may not be enough to elicit ischemic deficits.

Treatment


Vasospasm

The goal of reversing cerebral vasospasm after subarachnoid hemorrhage is to increase the cerebral blood flow, increasing oxygen delivery to tissues, reducing the degree of ischemic damage.

Pharmacological
Currently, the only pharmacological treatments are approved for treatment after SAH are oral nimodipine in North America and fasudil in Japan[13]. The premise for administration is to reverse or prevent cerebral vasospasm. Fasudil has been shown to antagonize the effects of endothelin on vessel constriction in animal models[43]. A recent meta-analysis of 8 clinical trials revealed that fasudil significantly reversed vasospasm and improved outcome[44]. In experimental models, Nimodipine has been shown to antagonize calcium influx through L-type calcium channels, and thereby reverses vasospasm[13]. However, a meta-analysis of 10 clinical trials found that while nimodipine improves outcome, it does not appear have any significant effect on cerebral vasospasm in human[45]. In light of this finding, several groups have suggested that nimodipine improves outcome through either increasing fibrinolytic activity, or reversing spreading ischemia[46] ,[47].

Non-pharmacological treatment

There are a variety of post-operative non-pharmacological treatments aimed to reverse cerebral vasospasm, including hemodynamic therapy, angioplasty and intra-arterial infusion of vasodilatators[13]. Though none have any particularly high level evidence to support their safety and efficacy, these are still nonetheless administered to SAH patients who develop vasospasm. In particular, hemodynamic therapy (consisting of hemodilution, hypervolemia and hypertension) has been associated with pulmonary and cerebral edema, congestive heart failure, rupture of secured aneurysms, amongst other concerns[48] ,[49]. Currently, both hemodilution and hypervolemia have fallen out of favor in terms of treatment[49]. However, a recent conference on neurocritical care concluded hypertension (of systemic circulation) had some clinical benefit. Balloon angioplasty is also often administered after SAH, to force open the spasming cerebral vessels[13]. A single clinical trial found significant reduction in DCI associated with therapeutic angioplasty, but not prophylactic administration[50]. Lastly, various retrospective studies have found some benefit in reduction of vasospasm after intra-arterial infusion of vasodilators[51]. In sum, more prospective randomized clinical trials are necessary in order to make any conclusive statements about the efficacy of non-pharmacological treatment of vasospasm in improving outcome.

Clinical trials

There have been many clinical trials involving pharmaceuticals that target vasospasm, and more recently, other secondary complications after SAH. The largest double blinded randomized controlled trials to date were the CONCIOUS-1 and CONCIOUS-2 trials of clazosentan[22],[52]. The results of these studies were largely disappointing; even though clazosentan reduced risk for vasospasm, there was no significant improvement in outcome. Other clinical trials have attempted to target the coagulatory cascade after SAH, including the MASH trial, which tested the effect of acetylsalicylic acid on functional outcome[53]. This trial was stopped prematurely at an interim analysis, as it revealed that chances of a positive outcome were statistically insignificant. Authors cited dosage or the timing of administration as potential problems. Intravenous albumin after SAH is currently under investigation, as it has been shown albumin can act as an anti-oxidant, reduce inflammation, as well as improve microcirculatory flow [54]. A preliminary dose finding trial yielded promising results, and treatment was found to have some neuroprotective effect. Clinical trials for simvastatin, and Sildenafil, are underway, both of which aim to reduce cerebral vasospasm after SAH.
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Of importance, there are several considerations that should be taken when interpreting data from clinical trials in the field of SAH. Firstly, many definitions of DCI are used by clinical studies, making aggregation of clinical data for a meta-analysis unfeasible[55]. Secondly, not all studies measure vasospasm or define it in the same way. While the most sensitive and specific test for vasospasm detection is digital subtraction angiography, other trials utilize TCD as a surrogate measure of vasospasm. However, studies have shown TCD to be poor at predicting vasospasm, ranging from 37-73% depending on which artery was used[56]. Lastly, the lack of a proper outcome measure in SAH clinical trials may result in a failure in capturing some beneficial effect of the treatment.

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External links


Subarachnoid Hemorrhage at eMedicine
Brain Aneurysm at John Hopkins Medicine
Subarachnoid Hemorrhage at Wikipedia