Abstract
Intracerebral haemorrhage and subarachnoid haemorrhage are associated with considerable morbidity and mortality. Too often the focus is on acute treatment after a haemorrhage has occurred, instead of primary and secondary prevention. Medical therapies to control hypertension, achieve tobacco abstinence, and avoid excessive alcohol consumption can confer broad reductions in haemorrhage risk across pathophysiological subtypes. Judicious restriction of antiplatelet and anticoagulant therapies to only those individuals and those intensities for which they are indicated also can substantially reduce haemorrhagic stroke frequency. Specific endovascular and surgical therapies, judiciously employed, will further reduce risk of first or recurrent haemorrhage from structural vascular anomalies, including arteriovenous malformation, cavernous malformations, and saccular aneurysms. For unruptured intracranial aneurysms, features that favour consideration of preventive occlusion include include younger patient age, prior subarachnoid haemorrhage from a different aneurysm, familial intracranial aneurysms, large aneurysm size, irregular shape, basilar or vertebral artery location, and aneurysm growth on serial imaging. Among individuals who are technical candidates for either coiling or clipping, endovascular coiling is associated with a reduction in procedural morbidity and mortality but has a higher risk of recurrence.
Intracerebral haemorrhage (ICH) and subarachnoid haemorrhage (SAH) can be associated with considerable morbidity and mortality despite the most aggressive contemporary management strategies. Too often in medicine the focus is on treatment strategies after an event has occurred. With worldwide case fatality rates still approaching 50%, the ideal ‘treatment’ for ICH and SAH is prevention.
Intracerebral Haemorrhage
ICH accounts for 10–15% of all strokes, with a worldwide incidence of 10–20 haemorrhages per 100,000 people. As the current population ages, this incidence is expected to increase (Krishnamurthi et al., 2014). The mortality rate is staggering – less than 50% of individuals survive the first 30 days following an ICH (Sacco et al., 2009). Even those who survive often have significant morbidity; roughly 80% of survivors are functionally dependent 6 months after the haemorrhage (Kase and Kurth, 2011). Such dire outcomes highlight the importance of primary prevention. However, secondary prevention is also important for survivors of an ICH, as the recurrence rate is 2.1/100 in the first year and 1.2/100/year thereafter (Hanger et al., 2007).
Primary, non-traumatic ICH accounts for more than 80% of all ICHs, and results from damage to the blood vessels from either chronic hypertension or cerebral amyloid angiopathy. Secondary ICH is due to an underlying structural lesion such as an arteriovenous malformation (AVM) or neoplasm. Most of the literature pertains to primary, non-traumatic ICH. Therefore, this will be the primary focus of the chapter, although secondary ICH due to arteriovenous and cavernous malformations (CMs) will also be covered.
Prevention of primary, non-traumatic ICHs principally rests on risk factor management and judicious use of antithrombotic medications.
Risk Factors
Multiple risk factors for ICH have been identified. Several risk factors are non-modifiable, such as increasing age, male sex, and presence of either the ɛ2 or ɛ4 apolipoprotein E (APOE) polymorphism (Biffi et al., 2010; An et al., 2017). Modifiable risk factors include hypertension, smoking, excessive alcohol intake, diet, psychosocial factors, and antithrombotic and sympathomimetic drugs (Feldmann et al., 2005; O’Donnell et al., 2016; An et al., 2017). In the INTERSTROKE international study comparing 3059 ICH patients and case–controls, modifiable risk factors accounted for 87% of the population attributable risk of ICH (O’Donnell et al., 2016).
Evidence
Hypertension
Elevated blood pressure is a well-established risk factor for primary, non-traumatic ICH (Rapsomaniki et al., 2014; O’Donnell et al., 2016), including recurrent ICH (Rodriguez-Torres et al., 2018). In a population attributable risk analysis of the 32-country INTERSTROKE case–control study, hypertension was the single most important risk factor, contributing to fully 56.5% (95% confidence interval [CI]: 52.0–60.6) of all ICH cases (O’Donnell et al., 2016).
The major randomized trials of blood pressure lowering have unfortunately often reported only outcome event rates for all strokes, without distinguishing between ischaemic and haemorrhagic stroke. Blood pressure lowering does have a substantial benefit for prevention of all stroke. In a systematic review of 54 mixed primary and secondary prevention RCTs enrolling 265,323 individuals, every 10 mm Hg reduction in systolic blood pressure (SBP) significantly reduced stroke occurrence, relative risk (RR) 0.73 (95% CI: 0.68–0.77) (Ettehad et al., 2016). However, few trials have separately reported ICH as an endpoint. One large trial that did distinguish among outcome stroke subtypes found magnified relative benefit for ICH prevention. The PROGRESS trial enrolled 6105 patients with an index cerebrovascular event, including ICH in 11%, cerebral ischaemia in 84%, and unknown stroke type in 4% (PROGRESS Collaborative Group, 2001). All patients received standard long-term blood pressure control, and were randomly allocated to additional fixed-dose angiotensin-converting enzyme (ACE) inhibitor and thiazide diuretic or additional placebo. Assignment to additional fixed-dose antihypertensives was associated with a reduction in ICH over the mean 3.9-year follow-up period: 1.2% versus 2.4%, RR 0.50 (95% CI: 0.26–0.67). In contrast, for recurrent ischaemic stroke, the RR was 0.76 (95% CI: 0.65–0.90).
Smoking
For primary, non-traumatic ICH, a systematic review of 14 case–control and 11 cohort studies reported a combined RR of 1.31 (95% CI: 1.09–1.58) for current smokers (Ariesen et al., 2003). In the international INTERSTROKE case–control study, in a population attributable risk analysis, current smoking contributed to 3.6% (95% CI: 0.9–13.0) of all ICH cases (O’Donnell et al., 2016).
While no randomized trial has evaluated the effect of tobacco cessation interventions on ICH occurrence, observational studies suggest benefit. In a meta-analysis of nine case–control studies and three cohort studies, former smokers did not have increased risk of ICH, RR of 1.06 (95% CI: 0.89–1.26) (Ariesen et al., 2003).
Alcohol
Multiple studies have identified excess alcohol intake (variously defined) as an independent risk factor for ICH (Feldmann et al., 2005; Zhang et al., 2011; Larsson et al., 2016; O’Donnell et al., 2016; Bell et al., 2017). In a meta-analysis of 11 prospective cohort studies following 487,000 individuals over a total 9.9 million person-years, light and moderate alcohol drinking (up to 2 drinks/day) was not associated with ICH, high alcohol drinking (2–4 drinks/day) showed a non-significant trend towards association (RR 1.25, 95% CI: 0.93–1.67), and heavy alcohol drinking (>4 drinks/day) was associated (RR 1.67, 95% CI: 1.25–2.23) (Larsson et al., 2016). In the large international case–control study, INTERSTROKE, population attributable risk analysis indicated high or heavy episodic alcohol intake contributed to 9.8% (95% CI: 6.4–14.8) of all ICH cases (O’Donnell et al., 2016).
While no randomized trial has evaluated the effect of alcohol cessation or moderation interventions on ICH occurrence, the finding in observational studies of associations only with excessive, not moderate or abstinent, alcohol drinking suggests prevention benefit.
Diet
A systematic review identified longitudinal cohort studies evaluating the association of dietary fruits (seven studies) and dietary vegetables (five studies) with haemorrhagic stroke. In dose–response analyses, each 100 g/day increase in daily fruit intake was associated with reduced haemorrhagic stroke, RR 0.66 (95% CI: 0.50–0.86) and each 100 g/day increase in daily vegetable intake showed a non-significant trend towards reduced haemorrhagic stroke, RR 0.76 (95% CI: 0.55–1.06) (Aune et al., 2017). In the large, 32-country INTERSTROKE case–control study, diet quality was assessed using the modified alternative healthy eating index. Higher scores indicated greater adherence to dietary recommendations, including high intake of fruits, vegetables, whole grains, and nuts and a higher intake of fish relative to meat, poultry, and eggs. Population attributable risk analysis indicated that unhealthy diet contributed to 24.5% (95% CI: 16.5–34.8) of all ICH cases (O’Donnell et al., 2016).
Diabetes
Epidemiological studies have suggested, but not confirmed, a possible mild association of diabetes mellitus with ICH. In a systematic review, 19 case–control studies in aggregate indicated a mild increased risk of ICH with diabetes mellitus (odds ratio [OR] 1.23, 95% CI: 1.04–1.45), and 3 longitudinal studies qualitatively showed the same association (RR 1.27, 95% CI: 0.68–2.36) (Boulanger et al., 2016). However, in the later, larger, 32-country INTERSTROKE case–control study, diabetes mellitus was not a risk factor for ICH (O’Donnell et al., 2016).
Additional Modifiable Risk Factors and Relative Contributions
In addition to hypertension, tobacco, alcohol, and diet, the large, 32-country INTERSTROKE case–control study identified as independent risk factors for ICH: elevated waist-to-hip ratio (OR 1.33, 95% CI: 1.09–1.62); reduced regular physical activity (OR 1.59, 95% CI: 1.23–2.08); and psychosocial stress/depression (OR 2.84, 95% CI: 1.98–4.08) (O’Donnell et al., 2016).
Implications for Clinical Practice
Intracerebral haemorrhage is a highly preventable disease. Observational epidemiological studies suggest that up to 5 of every 6 ICHs can be prevented by optimal treatment of the seven modifiable risk factors of elevated blood pressure, unhealthy diet, sedentary physical activity, abdominal obesity, psychosocial stress/depression, tobacco use, and excessive alcohol use.
Among these, hypertension stands out as the single most important risk factor for ICH, contributing to more than half of all cases, and with confirmed benefit of treatment in at least one randomized clinical trial. This evidence supports an intensive approach to long-term blood pressure reduction in both primary and secondary prevention. The framework for management should be the contemporary definition of high blood pressure, which designates as normal less than 120/80; elevated SBP between 120 and 129 and diastolic blood pressure (DBP) less than 80; stage 1 hypertension SBP between 130 and 139 or DBP between 80 and 89; stage 2 hypertension SBP being 140–180 or DBP 90–120; and hypertensive crisis being SBP >180 or DBP >120 (Whelton et al., 2018). Individuals with elevated blood pressure within the normal range (SBP 120–129 and DBP <80) may be treated with nonpharmacological blood pressure management, including healthy diet, weight loss, physical activity, and moderate alcohol intake. Individuals with stage 1 hypertension (SBP 130–139 or DBP 80–89) who have no major risk factors for cardiovascular disease may also be treated with nonpharmacological management; those with stage 1 hypertension with age, diabetes, tobacco, cholesterol, or other risk factors placing them at a 10-year risk of cardiovascular events of 10% or more, or a first ICH, are best additionally treated with start of single-agent pharmacological antihypertensive therapy. Individuals with stage 2 hypertension (SBP ≥140 or DBP ≥90) should be treated with a combination of nonpharmacological management plus antihypertensive drug therapy, using two agents of different pharmacological classes. When pharmacological therapy is indicated, consideration should be given to including a calcium channel antagonist and to avoiding a beta-blocker to maximize stroke reduction (Whelton et al., 2018).
The additional modifiable risks factors for ICH should also be attentively treated. For obesity and physical activity, ideal goals have been defined in the Life’s Simple 7 programme for maintenance of neurovascular and cardiovascular health (Lloyd-Jones et al., 2010; Saver and Cushman, 2018): attaining a body mass index < 5 kg/m2 and participating in moderate-intensity physical activity 2.5 hours or more a week or vigorous-intensity physical activity 1.25 hours or more a week. For diet, the component of the Life’s Simple 7 ideal eating recommendations most relevant to ICH prevention is consuming ≥4.5 cups/day of fruits and vegetables. Tobacco abstinence and alcohol moderation or abstinence should be obtained with use of behavioural and, if needed, pharmacotherapies (Meschia et al., 2014).
Antithrombotics
Agents that block thrombus formation, while helpful in averting ischaemic vascular disease, necessarily carry a risk of bleeding, including at intracranial sites. The use of both antiplatelet and anticoagulant medications is associated with an increased risk of ICH (Hemphill et al., 2015). During the past several decades, randomized trials have serially expanded the prevention antithrombotic indications so that a greater proportion of middle-aged and elderly individuals are taking antiplatelet agents to avert ischaemic events of atherosclerotic origin and anticoagulant agents to avert ischaemic events from atrial fibrillation. Correspondingly, the incidence of antithrombotic-associated ICH has increased as well, especially in the elderly (Flaherty et al., 2007; Krishnamurthi et al., 2014). From 1990–2010, the age-standardized incidence rate for haemorrhagic stroke worldwide increased from 69.4 to 85.2 per 100,000 person-years (Krishnamurthi et al., 2014). In addition to occurring more frequently, anticoagulant-associated and antiplatelet-related haemorrhages also are more severe, with larger haematoma volumes and higher mortality rates (Lopes et al., 2017; Inohara et al., 2018). Therefore, prevention of ICH requires judicious use of these medications.
Evidence
Antiplatelet Agents
The Antithrombotic Trialists’ Collaboration performed an individual participant data pooled analysis of aspirin use aggregating data from primary prevention trials (6 RCTs, 95,000 individuals followed for 660,000 person-years) and secondary prevention trials (16 RCTs, 17,000 individuals followed for 43,000 person-years) (Antithrombotic Trialists’ Collaboration et al., 2009). In primary prevention trials, allocation to aspirin was associated with increased haemorrhagic stroke, 0.04% versus 0.03% per year, RR 1.32 (95% CI: 1.00–1.76). A qualitatively similar effect was seen in the more recent, large ASPREE primary prevention trial of 19,114 individuals followed for a mean 4.7 years, with haemorrhagic stroke rates of 0.1% versus 0.08% per year, hazard ratio (HR) 1.27 (95% CI: 0.81–2.00) (McNeil et al., 2018). In secondary prevention trials, a similar non-significant trend towards increased haemorrhagic stroke occurred with allocation to aspirin, 0.16% versus 0.08% per year, RR 1.67 (95% CI: 0.97–2.90) (Antithrombotic Trialists’ Collaboration et al., 2009). Overall, in contemporary primary prevention trials undertaken in the statin era, the benefit–risk ratio for prophylactic aspirin is exceptionally small, with reduced ischaemic vascular events not clearly outweighing increased haemorrhagic events (Ridker, 2018). In contrast, for secondary prevention after a first atherosclerotic ischaemic vascular event, the benefits of aspirin do outweigh the increased risks of bleeding.
Among patients who have had an ICH, the safety and benefits of resuming or starting antiplatelet agents to avert coronary or other ischaemic vascular events are uncertain. Observational series have not shown a higher rate of recurrent ICH among ICH survivors treated with antiplatelet therapy (Ding et al., 2018), but are prone to confounding by indication and cannot be considered to provide reliable guidance. Randomized trials are under way that will provide useful guidance when completed, including the RESTART trial (ISRCTN71907627).
Anticoagulants
In large randomized trials for stroke prevention in atrial fibrillation, the annual rate of intracranial haemorrhage ranges from 0.3% to 0.6% in patients taking warfarin or other vitamin K antagonists (VKAs) and from 0.1% to 0.2% in those taking direct oral anticoagulants (DOACs) (Steiner et al., 2017). The DOACs include direct thrombin inhibitors (e.g. dabigatran) and factor Xa inhibitors (e.g. rivaroxaban and apixaban). Large randomized controlled trials (RCTs) have generally reported rates of intracranial haemorrhage as a general category, subsuming not only haemorrhagic strokes (spontaneous ICHs and spontaneous SAHs) but also non-stroke bleeding (subdural haemorrhages, epidural haemorrhages, and also traumatic intracerebral and SAHs). However, a few trials have provided more detailed analyses, finding that, among all the intracranial bleeds, about half or a little more are haemorrhagic strokes (41–56% spontaneous ICHs and 3–6% spontaneous SAHs) (Hart et al., 2012; Hankey et al., 2014; Lopes et al., 2017).
Despite these risk elevations, the benefit–risk ratio of anticoagulation is favourable for the preponderance of patients with anticoagulation-responsive conditions placing them at high risk of thromboembolic events, such as atrial fibrillation, mechanical cardiac valves, and hypercoagulable states.
The lesser risk of ICH with DOACs compared with VKAs has been shown in DOAC class-specific systematic reviews. A systematic review in the Cochrane Library analysing factor Xa inhibitors compared with VKAs in atrial fibrillation identified 13 RCTs enrolling 67,688 patients (Bruins Slot and Berge, 2018). Random allocation to factor Xa inhibitors, compared with VKAs, was associated with fewer intracranial haemorrhages during trial follow-up, 0.6% versus 1.3%, OR 0.50 (95% CI: 0.42–0.59) (Figure 22.1). Similarly, a different systematic review analysing direct thrombin inhibitors identified 3 RCTs enrolling 25,442 patients (Providência et al., 2014). Random allocation to direct thrombin inhibitors, compared with VKAs, tended to be associated with fewer intracranial haemorrhages during trial follow-up, 0.5% versus 1.1%, RR 0.64 (95% CI: 0.28–1.48).
Figure 22.1 Forest plot showing the effects in patients with atrial fibrillation of factor Xa inhibitors vs vitamin K antagonists on intracranial haemorrhages. Typically, about half or a little more of these intracranial haemorrhages are haemorrhagic strokes (41–56% spontaneous intracerebral haemorrhages and 3–6% spontaneous subarachnoid haemorrhages).
A common clinical question is whether or not to resume anticoagulation following an ICH in a patient with atrial fibrillation or other enduring indication for anticoagulation. Observational series have not shown a higher rate of recurrent ICH among ICH survivors treated with anticoagulant therapy (Biffi et al., 2017), but are prone to confounding by indication and cannot be considered to provide reliable guidance. Randomized trials are under way that will provide useful guidance when completed, including the RESTART trial (ISRCTN71907627). An alternative to resuming lifelong anticoagulation is to perform left atrial appendage occlusion with devices that completely fill the appendage (e.g. the Watchman device) or devices that seal the appendage off from the circulation (e.g. the Lariat device). The devices frequently do require an abbreviated period of anticoagulation when they are first placed. A systematic review identified five RCTs enrolling 1285 patients with atrial fibrillation comparing left atrial appendage occlusion (LAAO) with medical therapies (antiplatelet, anticoagulant, or placebo) (Hanif et al., 2018). Random allocation to LAAO was associated with a non-significant decrease in stroke (RR 0.78, 95% CI: 0.47–1.29) and reduced mortality (RR 0.71, 95% CI: 0.51–0.99).
Statins – The use of HMG-COA reductase inhibitor medications (statins) that lower cholesterol levels and prevent ischaemic cerebral and cardiac events of atherosclerotic origin is widespread. In addition to cholesterol lowering, statins additionally exert antithrombotic effects, including inhibiting platelet activation and reducing procoagulant protein tissue factor expression (Owens and Mackman, 2014). The antithrombotic actions of statins have been recognized as mediating part of their benefits in reducing ischaemic cerebral and coronary events, but also raise the possibility that they could increase the frequency of ICH.
In a meta-analysis of 31 RCTs, no broad, statistically significant effect of statins on ICH was observed (OR 1.08, 95% CI: 0.88–1.32) (McKinney and Kostis, 2012). However, there does seem to be a small increase in ICH risk when statins are given at high dose or to patients with a history of cerebrovascular injury (stroke or transient ischaemic attack [TIA]). A systematic review of high-statin-dose RCTs identified 7 trials enrolling 62,204 patients (Pandit et al., 2016). During trial follow-up, ICH occurred more often in patients allocated to high-dose statin compared with no statin, 0.41% versus 0.27%, RR 1.53 (95% CI: 1.16–2.01). Similarly, a systematic review of statin treatment in patients with a history of cerebrovascular disease identified 2 trials enrolling 8011 patients reporting the occurrence of haemorrhagic stroke events (Vergouwen et al., 2008). During trial follow-up, haemorrhagic stroke occurred more often among patients allocated to statin compared with no statin, 1.9% versus 1.1%, RR 1.73 (95% CI: 1.19–2.50).
Despite the potential minor increase in ICH with high-dose statins or treatment of patients with prior stroke, the net benefit of statin therapy in patients with atherosclerotic disease or risk factors is well established. In a meta-analysis of 19 RCTs, statin therapy was associated with decreased all-cause mortality (RR 0.86, 95% CI: 0.80–0.93); stroke (RR 0.71, 95% CI: 0.62–0.82); and myocardial infarction (RR 0.64, 95% CI: 0.57–0.71) (Chou et al., 2016).
In patients at very high risk for ICH who require lipid-lowering therapy, treatment with PCSK9 inhibitors in lieu of statins is an option. PCSK9 inhibitors do not show similar off-target antithrombotic effects in physiological studies. In the FOURIER randomized clinical trial, enrolling 25,982 patients, allocation to a PCSK9 inhibitor (with lowering of low-density lipoprotein cholesterol from 92 mg/dL to 30 mg/dL) was not associated with an increase in haemorrhagic stroke, 0.21% versus 0.18%, HR 1.16 (95% CI: 0.68–1.98) (Sabatine et al., 2017).
Vitamin E
Vitamin E (alpha-tocopherol) is a lipid-soluble antioxidant widely taken as a dietary supplement. While its cytoprotective and anti-atherogenic properties potentially could confer benefits for varied medical conditions, vitamin E also has antiplatelet effects that could increase haemorrhagic stroke. Large trials evaluating vitamin E have generally shown overall disappointing results for primary aims of reducing cardiovascular disease, dementia, cancer, and other conditions. In addition, a potential adverse effect of increasing haemorrhagic stroke has been noted. A meta-analysis of 5 randomized trials involving 100,748 participants found that vitamin E supplementation was associated with more frequent haemorrhagic stroke during trial course, 0.44% versus 0.36%, RR 1.22 (95% CI: 1.00–1.48; p = 0.045). In terms of absolute risk, these findings indicate supplementation would result in one additional ICH for every 1250 individuals using vitamin E (Schurks et al., 2010).
Arteriovenous Malformations
Cerebral AVMs are congenital blood vessel anomalies characterized by a nidus of abnormal vessels that forms a direct connection between arteries and veins without an interposed capillary network. While cerebral AVMs have a prevalence of 0.05% as incidental findings on magnetic resonance imaging (MRI), their annual population-based symptomatic presentation (incidence) rate is about 1.3 per 100,000 persons (Morris et al., 2009; Derdeyn et al., 2017). The most common modes of presentation are with ICH, occurring in a little more than one-half of patients, and with seizures, occurring in one-third, with headache, progressive neurological deficits, or other symptoms occurring in one-tenth (Derdeyn et al., 2017). Annual bleeding rate estimates for AVMs range from 1 to 4% per year (Mohr et al., 2014).
Various interventions, including neurosurgical excision, endovascular occlusion, and radiation therapies, are used to obliterate an AVM and thus prevent haemorrhage. However, each carries risk of procedural complications and also of destabilizing an AVM leading to haemorrhage if incomplete obliteration occurs. An important predictor of future ICH under medical therapy is having had a prior ICH; the risk of recurrent ICH among patients with previously ruptured AVMs is 4-fold higher than of first-ever ICH among patients with unruptured AVMs (Kim et al., 2014).
Evidence
Among patients with unruptured AVMs, one randomized trial of treatment strategies has been performed, comparing interventional therapy (neurosurgery, embolization, or stereotactic radiotherapy, alone or in combination) added to medical management with medical management alone (pharmacological therapy for neurological symptoms as needed). Among 223 enrolled patients with mean follow-up of 2.8 years, allocation to medical management alone was associated with decreased death or symptomatic stroke: 10.1% versus 30.7%, HR 0.27 (95% CI: 0.14–0.54) (Mohr et al., 2014).
Among patients with ruptured AVMs, no randomized trial comparing broad treatment strategies for prevention of recurrent ICH has been performed. The frequency of recurrent ICH under medical management is high, about 5% per year, and is further increased by older age, female sex, a deep venous drainage pattern, and coexisting arterial aneurysms in feeding arteries (Derdeyn et al., 2017).
Implications for Practice
For unruptured AVMs, the ARUBA study is the only randomized trial to date, and, therefore, provides the best evidence for management. However, there were several criticisms of the trial. First, because the trial was halted early, the mean follow-up was only 33 months. This length of time does not capture an individual’s lifetime risk of AVM rupture. Furthermore, shorter duration of follow-up favours medical management, as the risks of intervention are immediate. Second, as the intervention(s) utilized were at the discretion of the treating physician, there was significant treatment heterogeneity. Finally, the exclusion criteria eliminated individuals with AVMs that were potentially at higher risk of rupture or for which treatment was not feasible (Knopman and Stieg, 2014). Nonetheless, initial medical management is a reasonable treatment strategy for most patients.
For ruptured AVMs, in the absence of randomized trials, treatment decisions must be guided by estimates of individual risk under medical and under different interventional strategies and their combinations (Derdeyn et al., 2017). Given the high rate of recurrent ICH under medical therapy, for many patients an interventional approach, if anatomically feasible, is reasonable.
Cavernous Malformations
Cavernous malformations are closely packed, enlarged blood vessels lacking muscular and elastic layers without interposed neural tissue. Occurring in sporadic and familial form, they are the second most common type of cerebrovascular anomaly. Based on autopsy and MRI series, they have a prevalence of about 0.5% in the general population, and comprise 10–15% of all vascular malformations (Flemming et al., 2017). The hereditary forms are more likely to develop multiple lesions and the preponderance arise from mutations in three genes, CCM1, CCM2, and CCM3, encoding proteins involved in junction formation between vascular endothelial cells (Spiegler et al., 2018). Most CM are asymptomatic and found incidentally. When symptomatic, seizure is the most common presenting symptom, followed by ICH.
Haemorrhages from CMs tend to be less severe compared with primary ICHs or AVM-associated haemorrhages, reflecting the reduced perfusion pressure within the vascular anomalies, but can cause severe deficits depending on the location of the CM (Brown et al., 2005). In an individual participant data pooled meta-analysis of 1620 patients from seven cohorts, the annual bleeding rate under medical management alone was 3.16% (95% CI: 2.74–3.58%). Factors increasing bleeding risk were prior ICH (HR 5.6, 95% CI: 3.2–9.7) and brainstem location (HR 4.4, 95% CI: 2.3–8.6) (Horne et al., 2016).
Leading interventional options to prevent ICH include surgical resection and stereotactic radiosurgery. There have been no randomized trials of these approaches. In a meta-analysis of 63 observational cohorts, neurosurgical excision was associated with a combined rate of subsequent non-fatal ICH, new neurological deficit without ICH, or death of 6.6% (95% CI: 5.7–7.5%) per year, over a median follow-up of 3.3 years. Stereotactic radiosurgery was associated with a combined rate of subsequent non-fatal ICH, new neurological deficit without ICH, or death of 5.4% (95% CI: 4.5–6.4%) per year, over a median follow-up of 4.1 years (Poorthuis et al., 2014). Accordingly, indirect comparison suggests that interventional treatment, compared with medical therapy alone, is associated with lower subsequent stroke and death rates in patients who have had a prior ICH, but higher stroke and death rates in patients with no history of ICH. As a result, complete surgical resection is a reasonable strategy in patients with a CM that has bled and is accessible (Akers et al., 2017). Stereotactic radiation is a reasonable option in patients with a CM that has bled but is surgically inaccessible due to location in deep-seated or eloquent brain regions. For patients with a CM that has not bled, medical therapy is a reasonable initial management strategy.
Subarachnoid Haemorrhage
Aetiologies for non-traumatic SAH are divided into aneurysmal or non-aneurysmal. There are numerous causes of non-aneurysmal SAH, including cerebral amyloid angiopathy, cerebral venous sinus thrombosis, cerebral vasculitides, reversible cerebral vasoconstriction syndrome, vascular malformations, intracranial arterial dissections, perimesencephalic (pre-truncal) hemorrhage sickle cell disease, pituitary apoplexy, and cerebral hyperperfusion following carotid endarterectomy. Despite having multiple aetiologies, non-aneurysmal SAHs account for only a minority of all non-traumatic SAHs. More than 80% of SAHs are due to rupture of an intracranial aneurysm (Brown, 2010). Hence, the focus of this section is the prevention of aneurysmal SAH (aSAH).
Unruptured intracranial aneurysms (UIAs) are not uncommon – roughly 2–5% of the general population harbours an aneurysm (Thompson et al., 2015). However, aneurysm rupture is uncommon, with an estimated annual incidence of aSAH around 6 per 100,000, though with substantial geographical regional variation in bleeding rates (Etminan et al., 2019). Although most aneurysms do not rupture, when one does the resultant morbidity and mortality is substantial. Mortality rates range from 25–50%, and roughly 15% of patients die before reaching a hospital. Even among survivors, a substantial proportion will have permanent neurological deficits.
Even in advance of identifying patients harbouring a saccular aneurysm, broad, population-directed treatment of vascular risk factors that promote aneurysm formation and rupture, such as high blood pressure and smoking, likely substantially reduces aSAH rates. Between 1980 and 2010, the incidence of SAH was reduced by one-third, from 10.2 to 6.1 per 100000 person-years, in tandem with improved blood pressure control and tobacco abstinence (Etminan et al., 2019). Prevention is importantly furthered by targeted strategies to prevent aSAH, consisting of identification and treatment of intracranial aneurysms prior to rupture. Several modifiable and non-modifiable factors have been identified for the development, growth, and rupture of intracranial aneurysms. The presence/absence of these factors can be used to guide which patients to screen for an UIA, and help predict which aneurysms are at risk for rupture. This information can further be used to decide whether or not to treat, and, if so, whether surgical or endovascular management is indicated.
Non-modifiable Factors
Age
Aneurysms are acquired lesions, so the risk of developing an aneurysm increases with age, especially after age 30 (Vlak et al., 2011). Correspondingly, the risk of aSAH increases with age, reaching a peak in the fifth or sixth decade of life, with a median age of 51.3 years in a prospective Finnish cohort study (Korja et al., 2014; Etminan et al., 2019).
Sex
The prevalence of UIAs is more than 1.6-fold higher in woman compared with men (Vlak et al., 2011). Women also have a higher incidence of aSAH, and female sex has been identified in several studies to be an independent risk factor for aSAH (Korja et al., 2014; Etminan et al., 2019), but large cohort studies have not found gender to be a risk factor for UIA rupture (International Study of Unruptured Intracranial Aneurysms Investigators, 1998; Morita et al., 2012).
Geographical Region
The prevalence of UIA does not vary significantly across countries (Vlak et al., 2011). In contrast, the incidence and risk of aSAH is higher in both the Finnish and Japanese populations (Greving et al., 2014; Etminan et al., 2019).
Genetic/Congenital Syndromic Conditions
Several genetic and congenital disorders are associated with an increased risk of developing intracranial aneurysms, including autosomal dominant polycystic kidney disease, type IV Ehlers–Danlos syndrome, Marfan syndrome, fibromuscular dysplasia, hereditary haemorrhagic telangiectasia, neurofibromatosis type 1, pseudoxanthoma elasticum, microcephalic osteodysplastic primordial dwarfism, coarctation of the aorta, and bicuspid aortic valve (Thompson et al., 2015).
Family or Personal History of UIA or SAH
First-degree relatives of an individual with a known UIA or previous aSAH are at somewhat higher risk for both compared to the general population. Reported familial occurrence of UIA ranges from 7 to 20% (Thompson et al., 2015). Based on a study conducted in the Netherlands, an estimated 4% of first-degree relatives of patients with aSAH harbour a UIA, and these individuals have a 3–7 times higher risk of aSAH (Raaymakers, 1999). The risk may be higher for siblings compared to children (Raaymakers, 1999). A UIA may be at slightly greater risk of rupture if there is a family history of a UIA (Broderick et al., 2009) but family history of UIA was not noted to be a risk factor for UIA haemorrhage in large UIA cohort studies (Wiebers et al., 2003). There are some data suggesting that a personal history of a prior aSAH increases the risk of rupture of small UIAs (Wiebers et al., 2003).
Modifiable Factors
Hypertension
A systematic review of longitudinal and case–control epidemiological studies investigating risk factors for aSAH identified hypertension (no defined blood pressure cut-point) as a statistically significant risk factor, with an OR of 2.6 (95% CI: 2.0–3.1) (Feigin et al., 2005b). An analysis of 26 cohort studies from the Asia-Pacific region also found hypertension (defined as SBP ≥140 mm Hg) to be a major risk factor for aSAH (HR 2.0 [95% CI: 1.5–2.7]), and the continuous variable analysis calculated a 31% (95% CI: 23–38%) increase in risk of aSAH for every 10 mm Hg increase in SBP (Feigin et al., 2005b). In an individual participant data pooled analysis of six prospective cohort studies with 29,166 person-years of follow-up, hypertension was an independent risk factor for rupture, with HR 1.4 (95% CI: 1.1–1.8) (Greving et al., 2014). Hypertension also increases the risk of rupture of small (<7 mm) aneurysms, with a HR of 2.6 (95% CI: 2.1–3.3) as reported in a prospective cohort study from Finland (Guresir et al., 2013).
There have been no randomized trials that have assessed whether treatment of hypertension prevents development or rupture of intracranial aneurysms. Based on the strong epidemiological associations and pathophysiological rationale, maintenance of normotension in patients with unruptured aneurysms is indicated. Evidence regarding whether aggressive, rather than conventional, long-term blood pressure control targets would further reduce aSAH will come from randomized trials, including the currently enrolling PROTECT-U study (NCT03063541) randomizing unruptured aneurysm patients to intensive blood pressure treatment (SBP <120 mm Hg) plus low-dose aspirin versus conventional blood pressure treatment (SBP <140 mm Hg) and no aspirin.
Tobacco
A systematic review identified 23 case–control and 14 cohort studies evaluating the relation of smoking and SAH. The longitudinal studies included 892 SAH incident cases during a cumulative 9.2 million person-years of follow-up, and the case–control studies added another 3936 SAH cases. In combined analysis, the overall RR for SAH was 2.2 (95% CI: 1.3–3.6) for current smokers (Feigin et al., 2005a). Among patients with known saccular aneurysms, continued smoking of tobacco is an important risk factor for aneurysm growth and rupture, and more than doubles the risk of aSAH (Brinjikji et al., 2016).
While no randomized trial has evaluated the effect of tobacco cessation interventions on SAH occurrence, observational studies suggest benefit in primary prevention. The worldwide decline in tobacco use between 1980 and 2010 coincided with a worldwide decline in SAH incidence. In a meta-analysis of 34 studies from 18 countries, smoking prevalence declined from 27% to 12%, and with every 1% decline, the age- and sex-adjusted incidence of SAH decreased by 2.4% (95% CI: 1.6–3.3) (Etminan et al., 2019).
Alcohol
A meta-analysis of 23 case–control and 14 cohort studies found no association of SAH with light and moderate drinking, but an association with heavy alcohol drinking (>1.8 drinks/day), with longitudinal studies showing RR 2.1 (95% CI: 1.5–2.8) and case–control studies RR 1.5 (95% CI: 1.3–1.8) (Feigin et al., 2005a).
While no randomized trial has evaluated the effect of alcohol cessation or moderation interventions on SAH occurrence, the finding in observational studies of associations only with excessive, not moderate or abstinent, current alcohol drinking suggests prevention benefit.
Medications/Drugs
Several medications/drugs have been implicated as factors influencing development of UIA and/or risk of aSAH.
Aspirin – Preclinical, pathological, and imaging studies suggest that chronic inflammation in the arterial wall contributes to aneurysm development and rupture (Tulamo et al., 2018; Wang et al., 2018). Accordingly, aspirin, despite its antithrombotic properties, has the potential to reduce aSAH through anti-inflammatory effects.
Several large observational studies have suggested a potential protective effect of aspirin therapy. For example, in a nested case–control study of the prospective International Study of Unruptured Intracranial Aneurysms (ISUIA), 58 cases developing aneurysm rupture were matched to 213 controls without rupture (Hasan et al., 2011). On multivariate analysis, taking aspirin ≥3 times/week, compared with never taking aspirin, was associated with reduced odds of aSAH, OR 0.27 (95% CI: 0.11–0.67). In another study, patients harbouring 1302 ruptured aneurysms were compared with those harbouring 5109 unruptured aneurysms (Can et al., 2018). In multivariate analysis, aspirin use was associated with decrease rupture (OR 0.60, 95% CI: 0.45–0.80), and the relationship showed an inverted dose–response. In contrast, among patients who had a rupture, aspirin use was associated with increased risk of re-rupture before surgical or endovascular treatment (OR 8.15, 95% CI: 2.22–30.0).
There are no large-scale randomized trials of aspirin use to avert aSAH. One small, imaging-endpoint, trial randomized 11 patients with unruptured intracranial aneurysms to aspirin 81 mg daily or control (Hasan et al., 2013). After 3 months of allocated therapy, all patients underwent vessel wall imaging MRI and then aneurysm clipping with aneurysm dome tissue harvest. Allocation to aspirin was associated with imaging findings of reduced aneurysm wall enhancement and histological findings of reduced macrophage infiltration and decreased expression of pro-inflammatory molecules. No difference in clinical course was noted. Large, clinical endpoint trials are needed, including the currently enrolling PROTECT-U study (NCT03063541) randomizing unruptured aneurysm patients to intensive blood pressure treatment (SBP <120 mm Hg) plus low-dose aspirin versus conventional blood pressure treatment (SBP <140 mm Hg) and no aspirin.
Oral Contraceptives – Women are more prone than men to intracranial aneurysm formation and rupture, with 1.5-fold increased frequency. Oestrogen accordingly has been hypothesized to potentially contribute to aSAH, although in different animal models it shows protective as well as pathogenic effects. Findings in epidemiological studies have shown variable findings, and a meta-analysis of 1 longitudinal and 7 case–control studies did not show a statistically significant increase in risk (RR 5.4, 95% CI: 0.7–43.5) (Feigin et al., 2005b).
Sympathomimetic Agents – Multiple studies have shown an increased risk of a SAH with the use of various sympathomimetic agents. These include phenylpropanolamine, a drug formerly commonly used in appetite suppressants and cough/cold remedies (Kernan et al., 2000), and illicit substances, such as cocaine (Chang et al., 2013) and methamphetamines (Lappin et al., 2017; Darke et al., 2018). Caffeine-containing medications have been reported to increase the risk of aSAH (Lee et al., 2013), but not beverages containing caffeine, such as coffee or tea (Larsson et al., 2008).
Diet
Diet may play a role in the risk of aSAH, although evidence is limited. Data regarding consumption of 15 common foods were gathered as part of the Australasian Cooperative Research on Subarachnoid hemorrhage Study (ACROSS), a multicentre population-based case–control study of patients with first-ever aSAH in Australia and New Zealand. In addition to smoking and hypertension, multivariate analysis identified eating the fat on meat or chicken skin >4 times/week (OR 1.75 [95% CI: 1.19–2.57]), drinking skim/reduced fat milk (OR 1.71 [95% CI: 1.23–2.36]), and eating fruit (OR 1.68 [95% CI: 1.17–2.40]) <4 times/week as significant independent risk factors for aSAH (Shiue et al., 2012). Additionally, analysis of a dietary questionnaire, completed as part of a randomized placebo-controlled trial assessing whether vitamin E or beta-carotene reduced cancer risk among male Finnish smokers, observed that yogurt intake (range 0–86 g/day) was associated with higher risk of aSAH (RR 1.83 [95% CI: 1.20–2.80]) for highest intake compared with no intake (Larsson et al., 2009a), whereas vegetable intake was associated with a lower risk (RR 0.62 [95% CI: 0.40–0.98]) for highest quintile (median intake 153.7 g/day) compared with the lowest quintile (25.4 g/day) (Larsson et al., 2009b). These data suggest that increased consumption of skim/reduced fat milk, fruit, and vegetables, and reduced intake of animal fat and yogurt may reduce the risk of aSAH.
Screening
Detecting unruptured intracranial aneurysms enables enhanced prevention targeted on patients with known vulnerable lesions. Awareness of aneurysm presence provides impetus to greater adherence to medical therapies, including blood pressure control and tobacco cessation, and allows neuroendovascular and surgical interventions to be undertaken in patients with particularly high-risk lesions.
Although incidental discovery of UIAs has increased with the development and widespread utilization of non-invasive imaging studies, especially computed tomography (CT) and MR angiography, most patients harbouring UIAs remain unaware of their presence. Screening the general population is unfeasible and cost-ineffective (Li et al., 2012). Therefore, algorithms have been explored to guide selective screening imaging, among individuals at high risk of harbouring a UIA.
Evidence
Determining who to screen is guided by cost-effectiveness models that have shown that magnetic resonance angiography (MRA) or computed tomography angiography (CTA) screening is generally not cost-effective in individuals with risk of harbouring UIAs equal to the general population (2–5%), is of uncertain cost-effectiveness in individuals with mildly increased risk (5–10%), and is cost-effective in individuals with moderately to highly increased risk (11–100%) (Takao et al., 2008; Bor et al., 2010). Features that increase likelihood of presence of a UIA include a personal history of a syndromic genetic/congenital disorder often associated with the development of an intracranial aneurysm or a family history of a UIA and/or aSAH. Using genetic disorders/family history to guide screening is additionally supported by the more severe phenotype of UIA in these patients, including: greater likelihood of having multiple UIAs; UIAs with greater rupture risk than in sporadic cases; UIAs that tend to rupture at an earlier age; and UIAs that tend to rupture at smaller sizes (Hitchcock and Gibson, 2017).
Genetic/congenital syndromic disorders associated with sufficiently high rates of UIA rates to support screening include: (1) type IV Ehler–Danlos syndrome (all individuals [12% risk] – modestly cost-effective); (2) coarctation of the aorta (all individuals [10% risk] – borderline cost-effective); (3) polycystic kidney disease (patients with one or more family members with history of UIA/SAH [16–23% risk] – cost-effective; patients without family history of UIA/SAH [6–11% risk] – uncertain cost-effectiveness).
While having a single affected family member does not sufficiently increase risk to justify screening, having two or more first-degree relatives further increases the risk towards cost-effective levels. For example, in a case–control study in Sweden, among 5282 SAH patients and 26,402 matched controls, the odds of SAH increased modestly for individuals with one affected first-degree relative (OR 2.15, 95% CI: 1.77–2.59) but increased sharply for individuals with two affected first-degree relatives (OR 51.0, 95% CI: 8.56–1117). The yield of screening will be further magnified by the presence of strong family aggregation and a history of hypertension or smoking. In the Familial Intracranial Aneurysm Study in the USA, MRA screening in individuals with at least 2 affected siblings or ≥3 affected family members, who also had either history of hypertension or smoking, identified UIAs in 19.1% of individuals (Brown et al., 2008).
Screening for UIA in families with ≥2 first-degree relatives with a history of aSAH is cost-effective and beneficial. Two separate studies, utilizing Markov models, reported that screening such individuals resulted in longer life expectancy (from 39.44 to 39.55 years), reduced morbidity (from 0.28% to 0.18%) and mortality (from 0.43% to 0.05%), with an incremental cost-effectiveness ratio of $37,400–38,410 per quality-adjusted life-year (QALY) (Takao et al., 2008; Bor et al., 2010). Based on one of these models, the optimal strategy would be to screen such individuals every 7 years from ages 20–80 years (Bor et al., 2010).
The optimal screening strategy to detect new or recurrent aneurysms in patients who have had a first aneurysm identified and treated is uncertain. Patients who had a first aSAH with successful clipping or coiling of the aneurysm that ruptured do have an elevated risk of subsequent de novo development of an additional aneurysm at a remote arterial site or of a recurrent aneurysm at the original site. In a study of 610 aSAH patients who underwent surgical clipping, follow-up CTAs, performed at a median 8.9 years, identified new aneurysms in 16% (95% CI: 13–19%), of which 81% were at a new site and 19% at the clip site. Whether routine screening after 5 years would be beneficial was not clear, as the findings were highly sensitive to the degree to which a patient’s quality of life would be lowered by being told that they had a small, low-risk recurrent aneurysm not requiring treatment (Wermer et al., 2008).
Related posts:
Chapter 5 – Supportive Care during Acute Cerebral Ischaemia
Chapter 12 – Neuroprotection for Acute Brain Ischaemia
Chapter 9 – Acute Antiplatelet Therapy for the Treatment of Ischaemic Stroke and Transient Ischaemic Attack
Chapter 18 – Drugs, Devices, and Procedural Therapies to Prevent Recurrent Cardiogenic Embolic Stroke
Chapter 25 – Using Pharmacotherapy to Enhance Stroke Recovery
Chapter 26 – Electrical and Magnetic Brain Stimulation to Enhance Post-stroke Recovery
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