10th March 2019, Dr Chee L Khoo
About 10% of all strokes are haemorrhagic strokes. In about 10% of cases of primary intracerebral haemorrhage (ICH), cerebral amyloid angiopathy (CAA) is regarded as a possible cause. The recurrence rate of ICH is significantly higher in patients with CAA. With improvements in MRI technology, CAA is increasingly recognised as a cause of ICH. (1). Can you spot CAA when you see one?
So, what is CAA? We often think of Alzheimers disease (AD) when we think about amyloid deposits but amyloid deposits are associated with at least 50 human diseases. CAA refers to the deposition of β-amyloid in the media and adventitia of small and mid-sized arteries of the cerebral cortex and the leptomeninges. The amyloid deposits in AD is primarily Aβ42 whereas the amyloid protein in CAA is primarily Aβ40.The amyloid deposits in CAA result in fibrinoid necrosis and microaneurysm formation, predisposing to haemorrhage.
CAA is often found in brains of older patients who are neurologically healthy. In a community-based autopsy cohort, CAA was shown to be more common in demented versus non-demented individuals with an overall frequency of 84.9%. CAA is also associated with cognitive impairment, increased ICH and increased mortality.
CAA can be diagnosed on the basis of clinical and imaging findings in accordance with the modified Boston criteria (2). The radiological manifestations of CAA are:
- Lobar ICH,
- Convexal subarachnoid hemorrhage (cSAH),
- Cerebral microbleeds (CMBs),
- Cortical superficial siderosis (cSS), and
- White matter hyperintensity in posterior brain regions
The true incidence and prevalence of cerebral amyloid angiopathy (CAA) are hard to specify, as definite CAA is a pathologic diagnosis typically obtained post mortem. A series of 400 autopsies found evidence of CAA in the brains of 18.3% of men and 28% of women aged 40-90 years.
Anti-platelet therapy
Aspirin is the established agent for secondary prevention of cardiovascular and cerebro-vascular disease. Apart from gastrointestinal bleeding, a not so uncommon undesired effect is intracranial bleeding. A meta-analysis of studies of primary prevention showed only a slightly increased risk of ICH, with an odds ratio of 1.4 (3). Microbleeds with a lobar distribution are more frequent during treatment with ASA than during treatment with other anti-platelet drugs (4).
Microbleeds occurring during anti-platelet treatment are more often associated with ICH than with cerebral ischemia (5). Microbleeds occurring during anti-platelet treatment are more often associated with ICH than with cerebral ischemia (5). In other words, if you have signs of CAA (microbleeds with a lobar distribution), then you are more likely to have ICH.
Clopidogrel inhibits platelet function longer than aspirin. Data from the Rotterdam study show that clopidogrel leads to a higher rate of microbleeds than aspirin (6). The combination of clopidogrel with ASA increased the incidence of fatal bleeds compared to ASA alone (7).
Thrombolysis therapy
In thrombotic strokes, thrombolysis is the mainstay of acute management. Of course, the dreaded complication is intracranial bleeding. In 2.4% to 10% of cases, symptomatic bleeding occurs within 24 to 36 hours of thrombolysis and can be disabling or even fatal, depending on its extent (8). In 20% of cases, the bleeding occurs outside the region of the ischaemic stroke. In a retrospective analysis of 570 patients who received lysis therapy after suffering ischemic stroke, the risk of symptomatic ICH was twice as high (although still not significantly different) in those with microbleeds on MRI (5.8%) compared to those without microbleeds (2.7%) (9). Remember, microbleeds is one of the hallmarks of CAA.
Patients with prior CAA related ICH had an almost 5-fold hazard, compared with deep hypertensive-related ICH, of having recurrent ICH (15).
Anti-coagulation
One of the most feared adverse effects of anti-coagulation is intracranial bleeding. Both CAA and atrial fibrillation are more common in older patients and anti-coagulation is necessary for stroke prevention. In a large autopsy study, CAA was present in 7 out of 10 cases where lobar bleeding occur during warfarin therapy and not a single case of CAA was present in non-lobar bleeding.
The newer NOAC appears to be safer than warfarin, at least so far. They do not increase the number of microbleeds.
The HAS-BLED score is used to estimate the bleeding risk with anti-coagulation but it does not adequately account for CAA, Should we screen all patients we are about to start on anti-coagulants for CAA? Current guidelines do not recommend this yet. If you have a patient with atrial fibrillation who needs anti-coagulation, should you go looking for CAA before?
Statin therapy
Improving lipid profile with statin therapy has been shown in numerous studies to reduce cardiovascular events in patients with cardiovascular risk factors. In patients with ischaemic stroke, statin therapy has also been shown to reduce the incidence of stroke but the data is less robust than data on cardiovascular events. However, statin therapy has been associated with increase in haemorrhagic stroke in patients with haemorrhagic strokes. Interestingly, Epidemiologic studies have suggested an association between low cholesterol levels and brain hemorrhage.17-19.
it was calculated that statin therapy in patients with lobar ICH increases the recurrence rate from 14% to 22% (40). When deciding whether to continue or stop statin treatment after an ICH, therefore—in addition to distinguishing between lobar and hypertension-related ICH—the clinician should take into account a prehistory of myocardial or cerebral infarction.
Hypertension remains the major risk factor for both ischaemic and haemorrhagic stroke. rigorous treatment of arterial hypertension has been shown to reduce rates of ICH. Subgroup analysis in the PROGRESS study showed that, for patients with a probable diagnosis of CAA, active treatment in comparison to placebo reduced the risk of further bleeds by 77%.
Lobar ICH is associated with a lower mortality rate (11-32%) and a better functional outcome than are hypertensive deep ganglionic bleeds. But patients with CAA related haemorrhagic strokes have a 25-40% recurrence rate with the highest risk in the first year. Those with recurrent haemorrhage have a mortality rate of 40%.
In summary, not all haemorrhagic strokes are the same. There are a significant number of haemorrhagic strokes with features suggestive of CAA. The management of these patients is different from those without CAA.
References:
- Yeh SJ, Tang SC, Tsai LK, Jeng JS: Pathogenetical subtypes of recurrent intracerebral hemorrhage: designations by SMASH-U classification system. Stroke 2014; 45: 2636–42.
- https://radiopaedia.org/articles/modified-boston-criteria-for-cerebral-amyloid-angiopathy-1
- Gorelick PB, Weisman SM: Risk of hemorrhagic stroke with aspirin use: an update. Stroke 2005; 36: 1801–7.
- Vernooij MW, Haag MD, van der Lugt A, et al.: Use of antithrombotic drugs and the presence of cerebral microbleeds: the Rotterdam Scan Study. Arch Neurol 2009; 66: 714–20.
- Lovelock CE, Cordonnier C, Naka H, et al.: Antithrombotic drug use, cerebral microbleeds, and intracerebral hemorrhage: a systematic review of published and unpublished studies. Stroke 2010; 41: 1222–8.
- Cordina SM, Hassan AE, Ezzeddine MA: Prevalence and clinical characteristics of intracerebral hemorrhages associated with clopidogrel. J Vas Interv Neurol 2009; 2: 136–8. 29.
- Darweesh SK, Leening MJ, Akoudad S, et al.: Clopidogrel use is associated with an increased prevalence of cerebral microbleeds in a stroke-free population: the Rotterdam Study. J Am Heart Assoc 2013; 2: e000359.
- Derex L, Nighoghossian N: Intracerebral haemorrhage after thrombolysis for acute ischaemic stroke: an update. J Neurol Neurosurg Psychiatry 2008; 79: 1093–9.
- Fiehler J, Albers GW, Boulanger JM, et al.: Bleeding risk analysis in stroke imaging before thromboLysis (BRASIL): pooled analysis of T2*-weighted magnetic resonance imaging data from 570 patients. Stroke 2007; 38: 2738–44.