Cerebral vasospasm (CVS) caused by aneurysmal subarachnoid hemorrhage has been one of the hot topics of research in neuroscience for half a century, and the problems of diagnosis, treatment, prevention and prognosis of CVS have been partially solved, but there are still many problems that are difficult to understand and need to be solved. In terms of treatment, the death and disability rates of CVS have decreased from 30% in the 1960s to 15% in the 1980s. According to statistics, 12% of SAH patients with CVS die before treatment, 25% die within 24 h, and another 40% to 60% die within 30 d, which shows the great danger [1].
Three important causes of poor outcome in SAH patients are: (i) the direct result of SAH, including acute ischemic neurological disorder (AIND), hematoma, and cerebral edema; (ii) rebleeding, which occurs in about 20% at 2 weeks after SAH; (iii) CVS can cause cerebral ischemia or brain damage, which is major cause of death or disability after aneurysm rupture. With the improvement of technology and efficacy of aneurysm surgery or endovascular treatment, the problem of rebleeding has been better solved, and the study of CVS prevention and management has become more and more important.
1. Definition
CVS has become a clinical term referring to a specific type of constriction of the cerebral arteries, defined by Mayberg [2] as a delayed stenosis of the large arteries at the base of the brain after SAH, often accompanied by reduced perfusion in the distal distribution of the affected vessels. Terms that have appeared in the literature to refer to the same condition include: post-subarachnoid hemorrhage vasculopathy, constrictive angiopathy of subarachnoid hemorrhage (SAH) [3 ].
2 , Diagnostic methods
2.1 Cerebral angiography
The greatest advantage of DSA is its ability to identify spastic vessels, allowing immediate angioplasty or intra-arterial injection of vasodilators. However, DSA also has disadvantages, including the need for the patient to leave the ICU and the risks of manipulation (e.g., medically induced stroke, catheter-induced vessel rupture and dissection).
2.2 CT scan
Routine CT scans do not directly detect CVS, but other signs may be used to determine the risk of developing CVS. The commonly used CT staging criteria are Fisher’s method [4], type I: no hemorrhage findings and almost no CVS; type II: diffuse thin SAH, 1 mm thick, with an area of 5 mm × 3 mm or more in the sagittal or cross-sectional plane, with a CVS incidence of 96%; type IV: intracerebral or intraventricular hemorrhage without SAH and almost no CVS. 2006 Frontera Grade 0: no hemorrhage, incidence of CVS is 3%; Grade I: hemorrhage only in the basal pool, incidence of CVS is 14%; Grade II: hemorrhage in the peripheral or lateral fissure pool, incidence of CVS is 38%; Grade III: extensive SAH with intracerebral parenchymal hematoma, incidence of CVS is 57%; Grade IV: thicker hemorrhage in the basal and peripheral pools and lateral fissure pool accumulation of blood, the incidence of CVS was 57%. Perfusion CT, with brightened areas in the ischemic risk zone, allows detection of cerebral blood flow based on the distribution of contrast throughout time.
2.3 Transcranial Doppler ultrasound (TCD)
Repeated cerebral angiograms are not necessary to detect CVS; TCD examination of flow changes can detect the onset and progression of CVS. the MCA is the most suitable artery for TCD examination, with a normal flow velocity of 30-80 cm/s. Cerebral angiograms showing CVS generally have a flow velocity >120 cm/s; if it is >140 cm/s, it is indicative of delayed ischemic neurological deficits ( Delayed ischemic neurological deficits DIND); if >200 cm/s, cerebral infarction will occur in most cases, and by this time, the canal stenosis will have exceeded 50% of the original canal diameter [6]. The velocity of blood flow in the beginning segment of the MCA compared to the extracranial segment of the ICA is usually referred to as the Lindigarrd ratio. If this value is >3, the presence of CVS is established. similar metrics are used in the posterior circulation to compare the rate of intracranial versus extracranial vertebral arteries, and the rate of basilar versus extracranial vertebral arteries. TCD testing is usually required daily during the period of high risk of CVS, i.e., 3 to 10 d after bleeding. 2001 Lysakowski et al [7] reported a comparative study of TCD versus DSA for the diagnosis of CVS, with a sensitivity and specificity of 67% and 99%, respectively, and positive and negative predictive values of 97% and 78%, respectively, for the MCA. tCD is useful in assessing distal spasm in the MCA is unreliable compared to proximal. In continuous monitoring, there is significant variability in instant-to-moment blood flow velocity, so the accuracy of this technique has been questioned [8].
2.4 Single photon emission computerized scanning (SPECT)
SPECT is another non-invasive examination method that provides direct anatomical site of brain perfusion. It can detect areas of hypoperfusion before the onset of delayed ischemic neurologic deficits (DIND) and detect asymptomatic CVS.Jabre et al [9] observed in their study that SPECT is less sensitive than TCD for symptomatic CVS, but more specific than TCD.
2.5 Xenon-enhanced CT/cerebral blood flow examination
XeCT has a higher diagnostic value than CT plain scan and provides cerebral blood flow information corresponding to the anatomical site. DIND can occur in areas with cerebral blood flow ≤20 ml?100g-1?min-1, and cerebral infarction may occur with cerebral blood flow <15 ml?100g-1?min-1. Although this method has a high diagnostic value, it is not suitable for use in patients with SAH in an emergency setting because it is time-consuming and difficult for patients to cooperate.
2.6 MRI and MRA
The sensitivity of MRI facilitates the detection of asymptomatic infarcts in patients at risk of developing DIND. in a study of 125 consecutive patients with SAH who underwent MRI, Shimoda et al [10] found delayed ischemic lesions in 57% of patients, half of whom were asymptomatic. mRA is a noninvasive test that shows vascular morphology, but it is less accurate than cerebral angiography. in 1997 Tamatani et al [11] showed that spasm could be detected on MRA in 86.4% of patients with CVS demonstrated by cerebral angiography. The reasons that prevent MRA from diagnosing CVS are intracerebral hematoma, high SAH bleeding and aneurysm clamping artifacts.
2.7 CTA
The morphology of the cerebral arteries can be revealed by using an electron beam imaging system (EBIS fast CT), or spiral CT for continuous volume thin-layer scanning, followed by three-dimensional reconstruction of the images. The clarity of the resulting images is close to DSA and more realistic and rapid than MRA [12]. It has been reported that CTA and DSA are highly consistent in evaluating the severity of CVS in proximal and distal arteries [13].
2.8. Perfusion CT and MRI perfusion-weighted imaging
These two methods of detecting cerebral blood flow provide clues to sensitive ischemic vascular distribution areas based on specific radiographic features that show local perfusion asymmetry. Based on the contrast distribution throughout time, they show cooler areas in the ischemic risk zone and allow for semi-quantitative determination. Perfusion MRI in combination with diffusion-weighted images sensitive to acute ischemia is extremely valuable in identifying high-risk areas [14].Yavagal et al [15] showed that perfusion MRI in patients with TCD and DSA without evidence of CVS with or without diffusion-weighted imaging abnormalities and with unexplained clinical deterioration can identify and detect microvascular or distal vascular spasm. In patients with aneurysmal SAH studied with perfusion weighting, hypoperfusion zones, which correlate well with DIND and are larger than the abnormal zones with concurrent diffusion weighting, were found. 15 patients with DIND showed perfusion-weighted changes, while TCD found evidence of CVS in only 7 cases [16]
2.9. jugular venous oxygen saturation testing
Methods with some invasiveness to detect cerebral blood flow are jugular venous oximetry and direct cerebral oxygen testing. The dominant jugular vein (mostly the right internal jugular vein) is usually chosen because this side of the vein receives most of the blood from cerebral drainage. The head end of the catheter needs to be placed on the mouth side of the jugular bulb, and the initial readings are calibrated with simultaneous arterial blood gases and oxygen saturation. The fiber optic at the head end of the catheter allows for direct measurement of instantaneous venous oxygen saturation, from which cerebral oxygen extraction fraction (OEF), cerebral oxygen metabolic rate, and cerebral blood flow can be inferred. However, with this method of detecting jugular venous oxygen saturation, areas of local ischemia due to vasospasm can be missed, so it is preferable to use a brain tissue oxygen tension probe, which also has the advantage of simultaneously monitoring intracranial pressure.
2.10 Others
Cerebral microdialysis is a technique to monitor neurochemical markers of ischemia and to detect CVS and delayed cerebral ischemia. It can also be combined with intracranial pressure monitoring, detection of glutamate, lactate and other metabolic by-products, and continuous monitoring of bedside enzyme kinetic reactions to screen for excitotoxic (excitotoxic) cell injury [17, 18]. In a study of 97 patients with aneurysmal SAH, neurochemical changes suggestive of ischemia were observed in 83% of patients with DIND before the onset of symptoms [19]. Another study reported that the type of ischemia in cerebral metabolism preceded the onset of DIND by a mean of 11 h [20]. While these results are encouraging, the use of brain microanalysis has its limitations, including difficulties in extrapolating measurements obtained in very limited tissue areas, reactive gliosis around the catheter tip that reduces the accuracy of measurements, variability of the underlying neurochemical values, and tissue trauma after probe placement [21]. These limitations do not support the use of this technique as a routine diagnostic modality in patients with aneurysmal SAH [22].
3. clinical diagnostic criteria for CVS
It is generally accepted that the diagnostic criteria for CVS are (i) occurring 5-12 d after SAH, the patient presents with decreased level of consciousness, focal neurological deficits, increased intracranial pressure, signs of meningeal irritation, elevated blood pressure, headache, fever, and hyponatremia, suggesting possible CVS [23]; (ii) the above symptoms should exclude rebleeding, intracranial hematoma, hydrocephalus, and electrolyte disturbances; (iii) TCD examination, the Blood flow velocity >120 cm/s in MCA, mean flow velocity >90 cm/s in posterior cerebral artery, and mean blood flow velocity >60 cm/s in vertebrobasilar system can be diagnosed as vasospasm. The use of TCD examination to monitor the occurrence of CVS is gaining attention gradually; ④ Cerebral angiography shows intracranial vasospasm.
According to cerebral angiography, CVS can be classified as, ① diffuse: stenosis up to 2 cm or more in the proximal and distal parts of the aneurysm, where the diameter reduction is 25% to 50% in mild cases and more than 50% in severe cases; ② peripheral: stenosis up to 2 cm in the distal part of the vessel; ③ confined: single local stenosis; ④ multiple confined: multiple local stenoses.
According to the mean flow velocity of MCA examined by TCD, >120 cm/s is considered mild CVS, moderate is 140-200 cm/s, and severe is >200 cm/s.
Although most scholars regard DIND as a direct consequence of CVS, the range of CVS shown by cerebral angiography does not exactly match the severity of clinical symptoms, and sometimes cerebral angiography shows significant CVS without clinical symptoms, and sometimes there are severe clinical symptoms without CVS on angiography. There is no significant improvement, but the clinical ischemic symptoms are improved. Therefore, the occurrence of DIND is not only related to CVS, but also to microcirculatory changes in brain tissue after SAH, including changes in blood vessels, changes in blood flow, changes in BBB, and brain metabolism. In particular, microvascular spasm causes the formation of extensive microemboli in the microvasculature, resulting in cortical microcirculatory disorders, which may be an important cause of the development of DIND [24]. In addition, delayed neurological dysfunction due to other causes, such as hydrocephalus, cerebral edema, or rebleeding, should be considered in the diagnosis of DIND, so it can be considered that DIND is caused by multiple factors.
4.The prevention and treatment of CVS
Proper management of chronic CVS and prevention of DIND is an important factor in determining the prognosis of SAH patients, but the treatment of CVS is full of difficulties and challenges. Since not a single mechanism can cause CVS, it is difficult to implement a standard treatment plan in a planned manner. Given the complexity and multi-causal nature of CVS, it is necessary to apply different approaches to treatment. In late onset CVS starting 3-4 d after SAH, all treatments are difficult to be effective once the patient has ischemic symptoms. Therefore, early treatment appears necessary, preferably starting immediately after interventional or surgical treatment of the ruptured aneurysm. In addition, it should be noted that there is no treatment for CVS that is free of adverse effects.
In theory, there are five aspects of CVS management: (1) prevention of CVS as early as possible after SAH; (2) correction of arterial stenosis after the occurrence of CVS; (3) prevention of cerebral ischemia caused by arterial stenosis; (4) treatment of cerebral ischemia caused by arterial stenosis; and (5) protection of brain tissue from ischemic injury. The treatment of the latter three aspects is the same as the medical treatment of cerebral ischemia, and the following focuses on the first two aspects of treatment
4.1 Methods to prevent CVS
4.1.1 Prevention of aneurysm formation or rupture
This includes avoiding smoking and drug use, screening for aneurysms in individuals at risk and clamping unruptured aneurysms, and diagnosing and treating aneurysms with warning leaks.
4.1.2 Removal of clots from the subarachnoid space
Removal of subarachnoid clots 48 h after the onset of SAH is not effective in preventing CVS, and removal of subarachnoid clots presupposes proper management of ruptured aneurysms, without which the patient is unsafe. Therefore, it is advisable to complete endovascular treatment within 24 h and surgical treatment within 48 h to obtain early clearance of subarachnoid blood clots.
Mechanical removal: In patients undergoing surgical clamping of the aneurysm, after clamping of the ruptured aneurysm, all the accumulated blood in the cerebral pool that can be revealed is removed as much as possible by suction.
Cerebrospinal fluid drainage: Common methods include (1) repeated lumbar puncture to release bloody cerebrospinal fluid; (2) placement of a tube in the cerebral pool or ventricle to continuously drain cerebrospinal fluid; (3) placement of a tube in the lumbar spine to continuously drain; and (4) placement of a tube in the greater occipital pool to continuously drain. Cerebrospinal fluid drainage has been shown to be an effective method to prevent and treat CVS and is widely used in clinical practice [25].In 2000, Hamada [26], a Japanese scholar, introduced occipital pool drainage for the prevention of CVS. Its indications were Fisher classification of grade III and Hunt-Hess classification of grade I to III, performed after complete embolization of the aneurysm.In a study by Hamada et al [27] in 2003, a microcatheter was placed into the occipital pool after embolization of the aneurysm with an electrolytic detachable spring coil (GDC), and 60,000 U urokinase + 10 ml isotonic saline was infused with a micropump at a rate of 0.5 ml/min Intrathecal perfusion was performed at a rate of 0.5 ml/min with a micropump, and the catheter was removed after 12 h of repeated perfusion. 48 h later, CT review confirmed the absence of clots in the basal pool. The incidence of symptomatic CVS was 8.9%, lower than the 30.2% in the group without urokinase, and the incidence of hydrocephalus requiring treatment was 6%, lower than the 19% in the control group. The effectiveness of occipital pool drainage within 48 h was emphasized. Our clinical practice shows that a significant reduction in bleeding can be observed on the second day after drainage when CT is repeated, and the mean CT value of the central hematoma and the hemoglobin concentration in the drainage fluid decrease with the duration of drainage.
Chemical clearance: the commonly used drugs are tissue-type fibrinolytic plasminogen activator (tPA) and urokinase, and the routes of administration are currently using cerebral pool, ventricular, or lumbar puncture or occipital greater pool placement injection, with comparative effectiveness yet to be clarified [28]. Some studies have shown that the use of cerebrospinal fluid drainage + urokinase or tPA injection after SAH can effectively prevent the development of lesions, leaving little pathological changes in the vasculature and brain tissue without increasing adverse effects, and is more effective [29]. Vitamin C + urokinase brain pool perfusion is also effective in preventing delayed CVS. Intracerebral pool infusion of anticoagulants or antithrombotic drugs and shaking the patient’s head (head shaking), which aims to promote the flow and reabsorption of blood in the subarachnoid space, may increase the efficacy [30].
4.1.3 Pharmacological prevention of CVS
Calcium channel blockers: Calcium channel blockers are currently the most commonly used drugs for the prevention of CVS, and the timing of their application starts within 72 h of the acute phase after SAH. Commonly used drugs include nimodipine, nicardipine and nifedipine. Nimodipine is currently recognized as the most effective, improving the prognosis of patients with all levels of SAH with CVS. The usual dose of nimodipine is 2 mg/h intravenously and 40 mg/4 h orally for 2 to 3 weeks. The effect of treatment with nimodipine in 123 patients in 21 neurosurgical centers in Germany showed that death, vegetative state and severe disability due to cerebral vasospasm decreased from 55% to 25.9% with 6O-90 mg/d and discontinuation after 3 weeks [31]. Nicardipine is widely used as a protective treatment for CVS and DIND mainly in Japan, but it causes more severe systemic hypotension than nimodipine [32].
Fasudil: Fasudil is a 5-isoquinolinesulfonamide derivative, also known as AT877 or HAl077,which used to be considered as an intracellular calcium antagonist but is now clearly a Rho-kinase inhibitor that dilates blood vessels by inhibiting phosphorylation of the light chain of myosin, the final stage of smooth muscle contraction. It is another potent vasodilator for the treatment of CVS as it can dilate medium and small arteries (e.g. Willis ring) and improve the symptoms of cerebral ischemia caused by CVS. There were no serious adverse effects of fasudil, but a few patients had mild hypotensive effects, mostly within 5 min after injection, with a drop of about 2 mm Hg [33]. The efficacy of fasudil in the treatment of CVS has been confirmed by a double-blind randomized controlled trial [34]. In 276 patients with SAH, for moderate and severe CVS on cerebral angiography, there was a 38% reduction in the treatment group compared to the control group (P = 0.002 3); for symptomatic CVS, there was a 30% reduction in the treatment group compared to the control group (P = 0.024); and for adverse outcomes such as severe disability, vegetative state and death, there was a 54% reduction in the treatment group compared to the control group (P = 0.015 2). The differences in the time to symptomatic CVS and the incidence of rebleeding between the two groups were not statistically significant.In 2006, in a controlled trial of fasudil versus nimodipine, it was confirmed that the incidence of symptomatic CVS was lower in the fasudil trial group than in the nimodipine control group [35].After the launch of fasudil in 2007, a total of 1462 patients from 1995-2000 were investigated and studied patients were treated, further confirming that fasudil was superior or at least equivalent to nimodipine in terms of efficacy, with fewer adverse effects and simpler administration [36]. However, the drug still has some limitations, such as dehydration and short duration of action, and it is still not possible to determine the effective concentration in the target tissue and the best method of input. This drug has been produced in China, and phase II clinical trials have been conducted, resulting in no significant difference in efficacy between the application of fasudil and nimodipine, but the safety of use and compliance of fasudil is superior to nimodipine [37].
Sodium Ozagrel is a powerful TXA2 synthase inhibitor that inhibits TXA production and promotes PGI production, thus having anti-platelet aggregation, vasodilatation, increased blood flow and oxygenation, and is often used in combination with fasudil or other drugs for the treatment of CVS in Japan. Ozagrel sodium for injection, trade name LAIO, is 80 mg for adults, diluted in 250 ml of isotonic saline or 5% glucose solution and administered intravenously twice a day for two weeks. Although, there are isolated reports of its ineffectiveness, most studies support the ability of Ozagrel sodium to reduce the severity of CVS and increase CBF by inhibiting platelet coagulation in spastic arteries, but there are no multicenter, controlled, double-blind studies to demonstrate the effectiveness of its treatment.
Others: In terms of pharmacological prevention of CVS, endothelin (ET) receptor antagonists and their synthesis inhibitors, drugs that promote nitric oxide (NO) synthesis, K-ion channel activators, platelet coagulation inhibitors, and platelet activating factor (PAF) receptor antagonists have been shown to be effective in CVS in experiments, but clinical use has still not been reported. Mitogen-activated protein kinase (MAPK) inhibitors, serine protease inhibitors, and adenosine polydiphosphate (ADP) ribopolysaccharide inhibitors, these drugs may have good prospects. In addition, the application of drug slow-release devices, which can effectively control the concentration of local drugs and avoid serious adverse reactions, has a good prospect of application.
4.2 Treatment of CVS
4.2.1 Treatment of ruptured aneurysms in the high-risk phase of CVS
In the CVS stage, the risk of aneurysm rebleeding is higher and postponing surgery is not a good solution.Wikholm et al. (38) compared the results of endovascular treatment performed 3 to 14 d after SAH versus 0 to 2 d and found no significant difference in short-term efficacy between the two groups, suggesting that endovascular treatment in the CVS stage does not increase the risk.Murayama et al. [39] reported that endovascular treatment with the development of endovascular treatment results for severe CVS aneurysms, with six excellent, two moderate, three severe disabilities, and one death in 12 patients. In addition, endovascular treatment at the stage of CVS does not require opening the brain pool and pulling the swollen brain tissue, and does not require controlled pressure reduction and the use of temporary clips to block the aneurysm-carrying artery, thus reducing the occurrence of cerebral ischemia. Among 165 patients with ruptured cerebral aneurysms in the Department of Neurosurgery at Ruijin Hospital, 45 received endovascular treatment from 4 to 14 d after SAH, and 37 had excellent GOS scores, 3 had moderate disability, 2 had severe disability, and 3 had death at 3 months (severe diffuse CVS). We believe that endovascular treatment should be performed as early as possible in patients with SAH admitted at the CVS stage, as long as the microcatheter can pass through the narrowed aneurysm-carrying artery, regardless of the presence of CVS.