Cerebral amyloid angiopathy and thrombolysis-related intracerebral haemorrhage

Intracerebral haemorrhage is a complication of thrombolytic therapy for acute myocardial infarction, pulmonary embolism, and ischaemic stroke. There is increasing evidence that cerebral amyloid angiopathy (CAA), which itself can cause haemorrhage (CAAH), may be a risk factor for thrombolysis-related intracerebral haemorrhage. CAAH and thrombolysis-related intracerebral haemorrhage share some clinical features, such as predisposition to lobar or superficial regions of the brain, multiple haemorrhages, increasing frequency with age, and an association with dementia. In vitro work showed that accumulation of amyloid-beta peptide causes degeneration of cells in the walls of blood vessels, affects vasoactivity, and improves proteolytic mechanisms, such as fibrinolysis, anticoagulation, and degradation of the extracellular matrix. In a mouse model of CAA there is a low haemorrhagic threshold after thrombolytic therapy compared with that in wild-type mice. To date only a small number of anecdotal clinicopathological relations have been reported; neuroimaging advances and further study of the frequency and role of CAA in patients with thrombolysis-related intracerebral haemorrhage are required.     

Fatal streptokinase-induced intracerebral haemorrhage in cerebral amyloid angiopathy

A fatal intracerebral haemorrhage (ICH) associated with streptokinase (SK) treatment of an acute myocardial infarction is described. Autopsy examination showed a lobar ICH and severe cerebral amyloid angiopathy (CAA). The close temporal relationship between SK administration and intracranial haemorrhage, the absence of pretreatment risk factors for ICH, and the presence of CAA suggests that these are related phenomena. Accordingly: 1. There may be a synergistic relationship between CAA and intracranial haemorrhage induced by fibrinolytic agents; 2. Thrombolytic agents may induce more frequent than expected intracranial haemorrhage in conditions associated with a high incidence of CAA, notably old age and Alzheimer's disease; 3. A regional defect in haemostasis other than vessel fragility may contribute to the intracranial haemorrhagic predisposition of CAA; 4. Autopsy examination of cases of ICH is an essential part of the audit of clinical trials of fibrinolytic agents.     

Convexity subarachnoid haemorrhage has a high risk of intracerebral haemorrhage in suspected cerebral amyloid angiopathy

The risk of future symptomatic intracerebral haemorrhage (sICH) remains uncertain in patients with acute convexity subarachnoid haemorrhage (cSAH) associated with suspected cerebral amyloid angiopathy (CAA). We assessed the risk of future sICH in patients presenting to our comprehensive stroke service with acute non-traumatic cSAH due to suspected CAA, between 2011 and 2016. We conducted a systematic search and pooled analysis including our cohort and other published studies including similar cohorts. Our hospital cohort included 20 patients (mean age 69 years; 60% male); 12 (60%) had probable CAA, and 6 (30%) had possible CAA according to the modified Boston criteria; two did not meet CAA criteria because of age <55 years, but were judged likely to be due to CAA. Fourteen patients (70%) had cortical superficial siderosis; 12 (60%) had cerebral microbleeds. Over a mean follow-up period of 19 months, 2 patients (9%) suffered sICH, both with probable CAA (annual sICH risk for probable CAA 8%). In a pooled analysis including our cohort and eight other studies (n = 172), the overall sICH rate per patient-year was 16% (95% CI 11–24%). In those with probable CAA (n = 104), the sICH rate per patient-year was 19% (95% CI 13–27%), compared to 7% (95% CI 3–15%) for those without probable CAA (n = 72). Patients with acute cSAH associated with suspected CAA are at high risk of future sICH (16% per patient-year); probable CAA might carry the highest risk.     

Unexpectedly low prevalence of intracerebral hemorrhages in sporadic cerebral amyloid angiopathy

In a retrospective study of a consecutive autopsy series of 2060 elderly subjects (mean age 78.5 ± 6.8 SD years), sporadic cerebral amyloid angiopathy (CAA) of various degrees was detected in 73.2% and in 98.5% of autopsy-confirmed cases of typical (plaque and tangle) Alzheimer disease (AD). Spontaneous (non-traumatic) intracerebral hemorrhages (ICH) (excluding microbleeds) were seen in 5.6% of the total cohort and in 7.2% of definite AD cases; CAA was found in 49% of brains without and in 48.7% with ICH which was not significantly different. The latter groups showed a significantly higher frequency of severe degrees of CAA than those without ICH (80.4 vs 30.9%, p < 0.001). Patients with CAA were older than those without CAA, showing a higher frequency of clinical dementia and pathologically confirmed AD, but signs of hypertension (history and/or autopsy) were seen in 41 and 33.6% of these cases, respectively, compared to 70–75% in patients with non-CAA related ICHs. CAA-related ICH much more frequently involved cerebral lobes or hemispheres, while non-CAA related lesions were more often located in basal ganglia and brainstem. The data of a lower prevalence of CAA in cases without than with ICH, but a similar prevalence of ICH with and without CAA do not support the concept that CAA represents the most evident risk factor for ICH in the aged. While severe degrees of CAA were indeed associated with ICH, the general prevalence of large ICH in this autopsy cohort was much higher in cases without CAA, probably due to other risk factors including hypertension, which was documented in around 40% of cases with CAA-related ICH. APOE ε3/4 and ε4/4 were significantly more frequent in AD (n = 163) than in age-matched controls (n = 47) and were associated with more severe degrees of CAA, but no general genotyping in ICHs with and without CAA was performed. Hence, the role of APOE in the pathogenesis of ICH with and without CAA needs further elucidation.     

Cerebral amyloid angiopathy, recurrent intracerebral haemorrhages and Down's syndrome

Middle-age Down's syndrome patients develop dementia with antomicopathological changes that are characteristic for Alzheimer's disease. Cerebral amyolid angiopathy (CAA) most commonly manifests itself as a lobar intracerebral haemorrhage that tends to recur. Multiple haemorrhages may occur simultaneously. CAA is frequently associated with Alzheimer's disease, however the relationship between CCA and Down's syndrome is poorly know. Although there are established clinical criteria for the diagnosis of CAA related to lobar intracerebral haemorrhage, definitive CAA needs anatomicopathologial confirmation. This paper presents the case of a male with Down's syndrome and recurrent lobar intracerebral haemorrhage. An autopsy showed lesions in leptomeningeal and cortical arteries which are characteristic of CAA in addition to anatomicopathological changes of Alzheimer s disease that were mostly seen in entorhinal cortex and hippocampus. The paper also discusses the pathological association between beta-amyloid protein, apolipoprotein alleles, CAA, Alzheimer's disease and Down's syndrome.     

Cerebral amyloid angiopathy in Chinese: incidence and significance.

Histological sections of 210 randomly selected autopsy brains and 49 consecutive autopsy cases of spontaneous intracerebral haemorrhage in the Chinese population aged over 40 years were examined by H&E and congo red stain with and without polarized light. In the randomly selected group, 10% of cases are positive for cerebral amyloid angiopathy (CAA) while 8.2% of cases are positive in the group with haemorrhage. The incidence is strongly age-related. Compared with Western figures. Chinese are less frequently and less severely affected by CAA. Although CAA does account for some cases of spontaneous intracerebral haemorrhage, it cannot account for the high incidence of cerebral haemorrhage among Chinese. Its significance in Chinese is much lower than in Caucasians.     

Cerebral amyloid angiopathy in aged Chinese: a clinico-neuropathological study

To investigate the prevalence and clinico-neuropathological characteristics of cerebral amyloid angiopathy (CAA) in aged Chinese and its relationship to dementia and cerebrovascular lesions, we examined 362 archived brains of elderly with immunohistochemical staining for beta-amyloid peptide and Congo red, Bodian and Luxol fast blue stains. We found that: (1) CAA appeared in 31.7% examined brains without sexual preponderance, and the incidence increased with age; (2) the frontal lobe was most frequently involved in CAA, followed by occipital and parietal lobe; (3) subcortical white matter and cerebellum dentate nucleus areas may also be affected by CAA; (4) CAA has a close relationship to Alzheimer's disease and multiple cerebrovascular lesions; (5) CAA alone may result in dementia.     

Recurrent intracerebral lobar hematoma in cerebral amyloid angiopathy. A clinicopathologic case

The clinico-pathological case of a 71 year-old woman who presented 5 lobar intracerebral hematomas in 27 months is reported. There were no familial factor nor arterial hypertension. Amyloid deposits in cortical and meningeal arteries were present at post-mortem examination. There were no lesions of the Alzheimer type.     

Cerebral hemorrhage with biopsy-proved amyloid angiopathy.

Clinical, radiological, and immunohistochemical findings in brain biopsy specimens from six patients with cerebral amyloid angiopathy-associated intracerebral hemorrhage were reviewed. Acute clinical presentations included headache, nausea and vomiting, loss of consciousness, and focal neurological deficits such as hemiplegia and blindness. Transient ischemic attacks experienced by one patient and referable to one hemisphere did not indicate impending hemorrhage in that region. Computed tomographic scans revealed acute, irregular, superficial, lobar hemorrhage with occasional ring enhancement. Immunohistochemical studies were performed on biopsy specimens using primary antibodies against portions of the Alzheimer A4 (beta-) peptide or gamma-trace peptide (the vascular amyloid protein in patients with hereditary cerebral hemorrhage with amyloidosis-Icelandic type). In all patients, anti-A4 and anti-gamma-trace labeled cerebral microvessels. Immunoreactive senile plaques were few compared with the numbers of stained microvessels. Reactive astrocytes in some patients were labeled by both antiserum samples, suggesting uptake or production of these proteins by the astrocytes. This study demonstrates the heterogeneous clinical and radiological features of cerebral amyloid angiopathy-related brain hemorrhage and the value of anti-A4 and anti-gamma-trace immunohistochemical study of biopsy material from patients with suspected cerebral amyloid angiopathy-related intraparenchymal bleeding.     

Cerebral amyloid angiopathy related inflammation: three case reports and a review

Cerebral amyloid angiopathy related inflammation (CAA-I), previously described under various names, is a treatable encephalopathy usually occurring in older adults. Here, three patients are described with histopathologically confirmed CAA-I, and summarised data from the published literature are presented. CAA-I has a characteristic combination of clinical and radiological features. Definite diagnosis requires brain and leptomeningeal biopsy. A favourable response to immunosuppressive therapy is common and treatment without brain biopsy may be considered in selected patients. Diagnostic criteria for CAA-I are proposed.     

Cerebral amyloid angiopathy presenting as a brain tumor: case report

We describe the unusual case of a 45-year-old male patient harboring an intracranial mass due to cerebral amyloid angiopathy whose clinical and radiological features were those of a low grade glioma. Biopsy revealed cerebral amyloid angiopathy. The clinical, radiological and pathological findings are discussed as we review the available literature.     

Cerebral amyloid angiopathy in dementia and old age.

A necropsy study of 159 elderly patients drawn mainly from a prospectively assessed geriatric hospital population was carried out to investigate the relationship of cerebral amyloid angiopathy to Alzheimer's disease, other CNS disease and ageing. About half the patients were demented and the majority of these had Alzheimer's disease. In Alzheimer's disease there was an incidence of cerebral amyloid angiopathy of 82%. Among the other groups of patients, both demented and non-demented, the incidence of cerebral amyloid angiopathy was a little over 30%, and remained constant between 60 and 102 years of age.