Cerebral Amyloid Angiopathy - UpToDate

4/18/2017 Cerebral amyloid angiopathy - UpToDate
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Cerebral amyloid angiopathy
Author: Steven M Greenberg, MD, PhD
Section Editor: Scott E Kasner, MD
Deputy Editor: Janet L Wilterdink, MD
All topics are updated as new evidence becomes available and our peer review process is complete.
Literature review current through: Mar 2017. | This topic last updated: Oct 31, 2013.
INTRODUCTION — Cerebral amyloid angiopathy (CAA) is characterized by amyloid beta peptide deposits within
small to mediumsized blood vessels of the brain and leptomeninges. Although CAA is usually asymptomatic, it is
an important cause of primary lobar intracerebral hemorrhage in the elderly [1,2]. It can occur as a sporadic
disorder, sometimes in association with Alzheimer disease (AD), or as a certain familial syndrome. In addition to
intracerebral hemorrhage, CAA may present with transient neurological symptoms, an inflammatory
leukoencephalopathy, as a contributor to cognitive impairment, or with incidental microhemorrhages or
hemosiderosis on MRI.
EPIDEMIOLOGY — The incidence of cerebral amyloid angiopathy (CAA), like Alzheimer disease (AD), is
strongly age dependent. Based upon a series of 784 autopsy cases, we estimated the prevalence of moderate to
severe CAA as 2.3 percent for patients between the ages of 65 and 74, 8.0 percent between the ages of 75 and
84, and 12.1 percent over the age of 85 [3]. Although sporadic, CAArelated symptoms are uncommon at ages
younger than 60 to 65 they can more rarely affect individuals in their 50s as well.
There is no strong predilection for gender. Although the association of CAA with hypertension is debated, it is
clear that many patients with CAArelated hemorrhage are normotensive [46].
PATHOGENESIS — Vascular amyloid deposits in sporadic cerebral amyloid angiopathy (CAA) are biochemically
similar to the material comprising senile plaques in Alzheimer disease (AD) [1]. The primary constituent of each is
amyloid betapeptide, a 39 to 43 amino acid fragment of the amyloid precursor protein. There is essentially no
clinical overlap between CAA and the nonCNS systemic amyloidoses, such as primary (amyloid AL) and
secondary (amyloid AA) amyloidosis.
Mutant amyloid precursor protein — Mutations in the gene that encodes the amyloid precursor protein (APP)
are responsible for some cases of "presenile" CAA. While most of these mutations are also associated with at
least some of the neuropathologic features of AD, at least one APP mutation (Leu34Val) has been reported to
cause autosomal dominant CAA without parenchymal amyloid plaques or neurofibrillary tangles [7].
There is invitro evidence that the Dutch, Iowa, Italian, and Arctic mutations in APP may increase the toxicity of
the peptide towards components of the vessel wall [8,9]. Another potentially pathogenic effect of these mutations
is to decrease the susceptibility of the amyloid beta peptide to proteolysis [10] or clearance from the central
nervous system [11]. These findings highlight various mechanisms by which mutant APP might contribute to CAA
in heritable forms of the disease.
Apolipoprotein E — The factors that initiate or promote amyloid betapeptide deposition in CAA that occurs later
in life are not well understood. However, a number of observations have begun to enhance our understanding of
this disorder. Perhaps best studied has been the relationship between CAA and alleles of apolipoprotein E
(APOE). Patients carrying the APOE epsilon 2 (ε2) or epsilon 4 (ε4) alleles appear to be at greater risk for CAA
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related hemorrhage than those with only the common APOE epsilon 3 (ε3) allele [1218]. One systematic review
found that there is good evidence for a dosedependent association between APOE ε4 and sporadic CAA [19].
Data from a prospective cohort indicate that one or both of these alleles are present in approximately twothirds
of patients with CAA compared with only about onequarter of elderly controls without hemorrhage. These alleles
are associated with an increased likelihood of having a CAArelated hemorrhage [14,15], earlier age of disease
onset (mean age of first hemorrhage 75 versus 82 years in patients who are not carriers of APOE ε2 or ε4), and a
greater risk of hemorrhage recurrence (two year cumulative recurrence rate of 28 percent in carriers of ε2 or ε4
versus 10 percent for the APOE ε3/ε3 genotype) [20]. Patients with CAA who have both APOE ε2 and ε4 alleles
appear to have a particularly early onset of disease and a high risk of early recurrence [15,20]. Carriers of the
APOE ε2 allele also have larger ICH volumes, increased mortality, and worse functional outcomes compared to
noncarriers, while these associations are not seen for carriers of the APOE ε4 allele [21].
Data from a populationbased, casecontrol study suggest that the risk of lobar ICH associated with APOE alleles
may be modified by variation elsewhere in the APOE gene [22]. Notably, overall APOE haplotype (combination of
multiple alleles on one chromosome) was also independently associated with lobar ICH, suggesting the presence
of regulatory variants that could influence the effect of APOE ε2 or ε4 on the risk of lobar ICH [23].
Other factors that interact with the ε2 genotype may promote cerebral hemorrhage. In one report, antiplatelet or
anticoagulant medication, hypertension, or minor head trauma were significantly more common antecedents of
CAArelated hemorrhage among ε2 carriers than among nonε2 carriers (81 versus 35 percent) [24]. The authors
hypothesized that this may result from an APOE isoformspecific effect upon amyloid laden blood vessels that
causes the vessels to be more vulnerable to rupture in the presence of these other factors.
Vascular rupture and bleeding in CAA appears to be a multistep process involving the deposition of amyloid beta
peptide in the vascular wall and subsequent vascular changes such as cracking of the vascular wall. It has been
suggested that the ε2 and ε4 alleles act via separate mechanisms: ε4 increased amyloid betapeptide deposition
[25]; and ε2 causes amyloidladen vessels to undergo changes such as cracking and necrosis that predispose to
rupture [15,26].
There is additional evidence that APOE ε4 alleles affect amyloid betapeptide deposition. Among patients with
severe head injury, for example, the APOE ε4 allele is associated with an increased risk of deposition of amyloid
betapeptide [27]. This allele also promotes deposition of amyloid betapeptide in AD [25].
Other factors — Other molecular factors likely contribute to the pathogenesis of CAA. As an example,
transgenic mice overexpressing the inflammatory cytokine transforming growth factor (TGF) beta1 show
increased amyloid betapeptide deposition in cerebral blood vessels [28]. This finding may be applicable to
humans, since postmortem studies have found that TGF beta1 mRNA levels correlate strongly with amyloid
betapeptide deposition in damaged blood vessels in patients with CAA.
A casecontrol genetic association study that included a prospective followup of 178 ICH survivors found that a
variant within the CR1 gene (rs6656401) influences the risk and recurrence of CAArelated ICH [29]. In the same
report, this genetic variant was also associated with the severity of vascular amyloid deposition on pathologic
examination of 544 autopsy studies from two communitybased clinicalpathological studies of aging.
CLINICAL AND RADIOLOGIC FEATURES
Intracerebral hemorrhage
Presenting features — The most common clinical manifestation of cerebral amyloid angiopathy (CAA) is
spontaneous lobar hemorrhage (image 1) [30] The term lobar refers to location in the cortex and subcortical white
matter; this site is in contrast to the deep locations characteristic of hypertensive hemorrhage such as putamen,
thalamus, and pons. (See "Spontaneous intracerebral hemorrhage: Pathogenesis, clinical features, and
diagnosis".)
The lobar location of the hemorrhages reflects the underlying distribution of the vascular amyloid deposits, which
favor cortical vessels and largely spare white matter, deep gray matter, and the brainstem. The cerebellum
contains variable amounts of vascular amyloid and may be a site of CAArelated hemorrhage [31]. CAArelated
hemorrhages are also more likely to arise in posterior brain regions. Analysis of the spatial distribution of 321
intracerebral hemorrhages on gradient echo MRI in 59 patients with probable CAA revealed that hemorrhages
were significantly more likely to occur in the temporal and occipital than the frontal and parietal lobes (ratio of
actual to expected hemorrhages 1.37, 1.43, 0.58, and 1.0, respectively) [32]. The explanation for the posterior
brain clustering of CAA hemorrhages is undetermined, but it may be related to as yet unknown characteristics of
posterior circulation vessels that influence beta amyloid peptide elimination, or to increased vulnerability of these
brain regions to minor trauma [32,33].
Because of their superficial location, CAArelated hemorrhages often extend into the subarachnoid space, and
less frequently rupture into ventricles. Despite extensive pathologic involvement of the leptomeningeal vessels,
primary subarachnoid hemorrhage related to CAA is rare; however, superficial CAArelated bleeding can often be
identified [34]. (See 'Hemosiderosis' below.)
The clinical presentation of CAArelated hemorrhage varies with the lesion's size and location. Large lobar
hemorrhages, particularly those extending towards the ventricles, can cause hemiplegia and depressed
consciousness; in comparison, smaller lobar hemorrhages can cause more limited focal deficits, seizure, or
headache. Tiny asymptomatic hemorrhages appear to be common [35,36].
In addition to its role in spontaneous hemorrhage, CAA underlies a substantial proportion of hemorrhages related
to thrombolytic or anticoagulant agents. In a series of warfarinrelated lobar hemorrhages, for example, advanced
CAA was present in 7 of 11 patients with available pathology [37]. Similarly, the TIMI II trial evaluating the use of
tissuetype plasminogen activator for acute myocardial infarction identified severe CAA at postmortem
examination in two of five patients with intracerebral hemorrhage [38]. The importance of CAA may contribute to
the agedependence of these medicationinduced hemorrhages [39,40].
Prognosis — Lobar hemorrhage in general is associated with features that are both favorable — their
superficial location and tendency to spare the ventricles — and unfavorable to outcome — older age, and
somewhat larger hematoma size [12,41,42]. Overall mortality in lobar hemorrhage due to CAA is in the range of
10 to 30 percent [41,42], with the best prognosis for patients with smaller hematomas (<50 mL) and greater level
of consciousness on admission (Glasgow coma scale ≥8).
Although the acute outcome may be somewhat better in CAAassociated than in hypertensive hemorrhage, CAA
carries a substantially higher risk of hemorrhage recurrence. A cohort of 71 consecutive survivors of lobar
hemorrhage had a two year cumulative recurrence rate of 21 percent [20]. While in this series, recurrent
hemorrhages were typically in a different location from the index hemorrhage, in another study, recurrent
hemorrhages tended to arise in areas of prior hemorrhage [32]. Areas of high amyloid deposition on amyloid
imaging appear to predict sites for future hemorrhage [43]. (See 'Other testing' below.)
Age, sex, and hypertension did not predict recurrence; however, those patients with history of hemorrhage prior
to study entry were at approximately six times the risk as those without a previous history. The risk for recurrent
hemorrhages is even higher in those who have had more than one prior ICH [44]. Recurrent hemorrhage is also
more likely with increasing number of microhemorrhages and in patients with posterior white matter hypodensity
on CT scan. As noted above, carriers of the ε2 or ε4 APOE alleles are also at increased risk compared to the
more common APOE ε3/ε3 genotype (see 'Apolipoprotein E' above) [20].
Microhemorrhages — Neuroimaging data suggest that small subclinical leaks of blood called cerebral
microhemorrhages (also known as microbleeds) are relatively common in CAA. Gradient echo or T2*weighted
MRI can detect these remnants of hemorrhage as 2 to 10 mm focal or multifocal areas of hemosiderin deposition.
(See 'Gradientecho MRI' below.)
In populationbased studies, cerebral microhemorrhages are detected in 5 to 23 percent of older individuals [45
48]. The underlying age of the population studied and the sensitivity of the MRI techniques used probably
account for some of the variability in the observed prevalences. While microhemorrhages in general are not
specific to CAA, a distribution that primarily involves the cerebral cortex suggests CAA, while those that primarily
arise from the basal ganglia, thalamus, or pons are believed to more likely result from hypertensive
microangiopathy [49]. The association between lobar microhemorrhages and APOE ε4 in the Rotterdam and
other studies support the hypothesis that these lesions originate from CAA [18,47,48,50,51]. Imaging studies
have also associated the presence and distribution of microbleeds with concentrated amyloid deposition as seen
on positron emission tomography using the amyloid ligand, Pittsburgh compound B [52,53].
In the Rotterdam cohort, microbleeds were also more prevalent among those using antiplatelet agents [54]. In
another case series, microbleeds were also found to be more common in patients with ICH associated with
aspirin use compared to those with ICH who did not use aspirin and compared to aspirin users without ICH [55].
The findings in one report suggest that microhemorrhages arise from an amyloidbased pathology that is in some
respects distinct from that of macrohemorrhages [56]. Analysis of neuroimaging studies of 46 consecutive
patients with CAA demonstrated a bimodal, rather than continuous, distribution of hemorrhage volumes. In a
subset of patients who underwent autopsy, those with a large number of microbleeds had amyloidpositive
vessels with thicker walls compared to those with a lower proportion of, or no microbleeds.
Hemosiderosis — There is some evidence that superficial hemorrhage in the cortical sulci (typically referred to
as hemosiderosis or superficial siderosis when chronic) can also represent a focus of bleeding related to CAA.
Accumulation of evidence from small case series suggests an association between superficial siderosis and CAA
[5760]. As examples, two retrospective studies found that superficial siderosis was commonly found in patients
with CAA (40 to 60 percent), but was unusual in patients with ICH of other cause (0 to 4 percent) [60,61]. In the
latter study, superficial siderosis was found to occur in patients with or without lobar ICH, but appeared to be
highly associated with transient neurologic symptoms.
Superficial siderosis can have a number of other unrelated causes (eg, prior trauma, vascular malformation).
Disseminated superficial siderosis appeared to be a more specific finding for CAA in one study, but this requires
independent confirmation [61].
Transient neurologic symptoms — A less common, but clinically important manifestation of CAA is transient
neurologic symptoms [62]. Affected patients complain of recurrent, brief (minutes), often stereotyped spells of
weakness, numbness, paresthesias, or other cortical symptoms that can spread smoothly over contiguous body
parts. In one cohort, transient neurologic symptoms occurred in 14 percent of patients with CAA, and positive
symptoms (positive visual aura, limb jerking) were as common as negative symptoms (vision loss, limb
weakness, dysphasia) [63].
These episodes may reflect abnormal activity (either focal seizure or spreading depression) of the surrounding
cortex in response to the small hemorrhages. The anecdotal observation that anticonvulsants may stop the
attacks is consistent with this hypothesis [62]. In the above cohort, patients with transient neurologic symptoms
were more likely to have superficial cortical siderosis or subarachnoid hemorrhage than did CAA patients without
these symptoms (50 versus 19 percent) [63].
Features that help distinguish these spells from true transient ischemic attacks include the smooth spread of the
symptoms, the absence of hemodynamically significant stenosis in the relevant vascular supply, and the
presence of small hemorrhage in the corresponding region of cortex (best shown with gradientecho MRI; see
below). Avoiding misdiagnosis is critical since the administration of anticoagulants for a presumed TIA can
increase the risk of hemorrhagic stroke from CAA. In the same series, transient neurologic symptoms in a patient
with CAA appeared to predict a high early risk of symptomatic ICH, which occurred in 50 percent of patients over
a median followup period of 14 months [63].
Other entities to consider in the differential diagnosis of transient neurologic symptoms are discussed separately.
(See "Differential diagnosis of transient ischemic attack and stroke", section on 'Transient neurologic events'.)
CAArelated inflammation — CAArelated inflammation appears to represent a distinct subset of CAA [64,65].
The clinical presentation is that of acute or subacute cognitive decline rather than hemorrhage [66,67]. Seizures,
headache, and focal neurologic signs are common. Viral and autoimmune encephalitis and cerebral neoplasm
are sometimes considered in the differential diagnosis, as are other causes of rapidly progressive dementia [68
70].
Diagnostic studies in this setting typically include neuroimaging, brain biopsy and cerebrospinal fluid analysis,
both to make a positive diagnosis of CAArelated inflammation as well to exclude other conditions:
● Neuroimaging shows a potentially reversible leukoencephalopathy consisting of patchy or confluent white
matter hyperintensities on T2 weighted MRI sequences; multiple microhemorrhages are seen on gradient
echo sequences (image 2). Angiography or MRA does not show evidence of vasculitis.
● Neuropathology shows perivascular inflammation with multinucleated giant cells that is associated with
amyloid laden vessels. ESR and Creactive protein are commonly normal [67].
● Cerebrospinal fluid analysis may be normal, but often shows a pleocytosis and/or mildly elevated protein.
Antiamyloid autoantibodies have been detected in the CSF during the acute phase of inflammation and
return to control levels during remission [7173]. CSF assay for antiamyloid antibodies is not yet
commercially available, but may eventually emerge as a diagnostic test. Clinical and radiographic
improvement may occur with immunosuppressive treatment [64,65,67,74]. (See 'Immunosuppression'
below.)
The syndrome of CAArelated perivascular inflammation appears to be closely linked to the reported Abeta
related angiitis [7577]. These two inflammatory syndromes, distinguished by the presence or absence of true
vasculitis on neuropathological examination, appear to share similar clinical presentations, imaging properties,
and response to treatment. The Abetarelated secondary vasculitis also resembles primary CNS vasculitis in its
clinical presentation and response to immunosuppressive treatment [75]. There appears to be a spectrum of
CAArelated autoimmune reaction that ranges from perivascular inflammation to a true vasculitis with
inflammation within as well as around the vessel wall, with a corresponding range in clinical severity of its
manifestations. (See "Primary angiitis of the central nervous system in adults".)
Cognitive impairment — Advanced CAA is associated with cognitive impairment. An autopsy series found that
moderate to severe CAA (present in 19 percent of the study population) was associated with impairments of
perceptual speed and episodic memory, independently of age, sex, education, AD pathology, and other potential
covariates [78]. Other studies have estimated that over 40 percent of patients with CAArelated ICH suffer
cognitive decline during their life [79].
The precise mechanism by which advanced CAA contributes to cognitive impairment remains unknown.
Many reports point to a vascular mechanism:
● Some patients with extensive CAA present with progressive dementia along with ischemic white matter
damage that is similar to patients with hypertensive vasculopathy and subcortical vascular dementia [62,80
82]. Cerebral amyloid burden was found to correlate with the volume of white matter hyperintensity in one
cohort [82].
● Other studies have correlated the number and presence of microbleeds in both population or hospitalbased
subjects with cognitive impairment and dementia, raising the possibility that these lesions are contributors to
neurologic dysfunction, as well as markers of small vessel disease [83,84]. In one study of patients who
underwent MRI because of TIA or stroke, a finding of lobar microhemorrhage, but not deep
microhemorrhage, was associated with cognitive impairment [85].
● Another potential mechanism for CAArelated cognitive dysfunction is infarction. One MRI study
demonstrated a relatively high prevalence (15 percent) of clinically silent subacute cerebral infarcts in
patients with CAA [86]. The presence of these lesions was associated with the hemorrhage burden, but not
with conventional atherosclerotic risk factors, suggesting that the pathogenesis is related to CAA rather than
to comorbid ischemic cerebrovascular disease.
● Finally, a functional MRI study of 25 nondemented patients with probable CAA found evidence of impaired
vascular reactivity in response to visual stimulation [87]. These findings were confirmed in another study
which also noted that the fMRI response correlated negatively with the microbleed count and volume of white
matter hyperintensity [88].
● Vascular dementia is discussed in more detail separately. (See "Etiology, clinical manifestations, and
diagnosis of vascular dementia", section on 'White matter lesions' and "Etiology, clinical manifestations, and
diagnosis of vascular dementia", section on 'Cerebral amyloid angiopathy'.)
CAA is also particularly common in conjunction with AD, appearing in moderate to severe form in 30 of 117 (26
percent) AD brains in an autopsy series; CAA with hemorrhage occurred in six (5.1 percent) [78,89]. Another
autopsy study found that patients with both CAA and AD had more severe cognitive impairment than patients
with AD alone [90]. Similarly, an MRI study in AD patients found that the presence of multiple microbleeds was
associated with worse cognitive performance [91].
DIAGNOSIS
Diagnostic criteria — The presence of CAA should be suspected clinically in patients over the age of 60 who
have multiple lobar hemorrhages in the absence of an obvious cause [92]. According to proposed diagnostic
criteria for CAA (table 1), the disease can be definitively diagnosed only by full postmortem examination of the
brain. However, there are two approaches toward making the diagnosis of "probable CAA" during life: gradient
echo MRI and examination of tissue.
Gradientecho MRI — Gradientecho MRI accentuates the signal dropout caused by ironcontaining deposits
left by old hemorrhages (image 3). Susceptibilityweighted MRI may be even more sensitive [93].
To make the diagnosis of probable CAA (table 1) with gradientecho MRI, it is reasonable to look for the presence
of two or more hemorrhages restricted to those regions typical of CAA (cortex or "greywhite" junction) and
entirely sparing regions typical of hypertensive hemorrhage (basal ganglia, thalamus, or pons). These criteria are
supported by both a limited amount of direct pathological correlation [94] and by more extensive correlation of
APOE genotypes in clinically and pathologically diagnosed patients [92]. Application of these criteria to a
population of patients with hereditary CAA of the Dutch type, using DNA analysis as the gold standard, found an
overall sensitivity of 48 percent [95]. However, nearly half of the mutation carriers were asymptomatic. Among
symptomatic individuals with CAA, the sensitivity was 93 percent.
The gradientecho images should be reviewed with some care, since lesions and structures other than
intraparenchymal hemorrhage can produce signal dropout. These include hemosiderosis within a brain sulcus (a
frequent consequence of subarachnoid extension of a lobar hemorrhage), flowvoid from a cortical vessel, or
adjacent air in the nasal sinuses. When establishing the presence of at least two hemorrhages, lesions that do
not clearly represent independent hemorrhagic foci (for example, small blood deposits close to a larger
hematoma) should not be counted.
Inclusion of microhemorrhages (or hemosiderosis) in the MRI criteria for probable MRI increases the sensitivity of
the criteria (table 1) [95]. However, it is important to note that the acceptance of only a single microhemorrhage
as indicative of CAA may lead to erroneous assignment of nonamyloid microhemorrhages as CAA. Microbleeds
may also occur in hypertensive microangiopathy and in infective endocarditis [96], although they tend to have a
somewhat different anatomic distribution in these conditions. (See "Spontaneous intracerebral hemorrhage:
Pathogenesis, clinical features, and diagnosis", section on 'Pathogenesis'.)
In addition to its role in the diagnosis of CAA, a finding of multiple microhemorrhages on gradientecho MRI may
provide prognostic information. In a study of 94 consecutive survivors of primary lobar hemorrhage, the three
year cumulative risk of recurrent hemorrhage for patients with one, two, three to five, and six or greater
hemorrhages on the baseline gradientecho MRI was 14, 17, 38, and 51 percent, respectively (hazard ratio 1.7,
95% CI 1.22.4 for each increase in category) [97]. Higher numbers of hemorrhages also predicted a greater risk
for future cognitive impairment, loss of functional independence, and death. Another study found that an
incidental finding of multiple lobar microhemorrhages in an older adult was associated with a sevenfold risk of
strokerelated death compared to individuals without lobar microhemorrhages [98].
Pathologic examination — Brain biopsies are done rarely for the diagnosis of CAA, except in the setting of
CAArelated inflammation [67]. (See 'CAArelated inflammation' above.)
Evacuated hematoma specimens and accompanying leptomeningeal or parenchymal tissue from elderly patients
should routinely be examined with Congo red stain for CAA. Based upon data from a postmortem model, nearly
all blocks of tissue from brains with CAArelated hemorrhage demonstrate some degree of CAA [3], often with
evidence of advanced disease such as complete amyloid replacement of the smooth muscle layer or the
appearance of vessel breakdown [99101]. Signs of advanced disease are rare in single tissue specimens from
asymptomatic elderly brains; thus, their presence points toward a degree of CAA severe enough to cause
hemorrhage.
Other testing — Because a bleeding tendency can cause or contribute to bleeding initiated by CAA, evaluation
for a bleeding disorder (platelet count, prothrombin time, and activated partial thromboplastin time) should be
performed in every patient with an ICH.
Decreased levels of cerebrospinal fluid (CSF) amyloid ß42 and ß40 protein are found in Alzheimer disease. One
study found that these levels were decreased to an even greater extent in patients with CAA [102]. In
combination with the finding of increased total tau levels, CSF analysis distinguished patients with CAA from
normal controls with a high degree of accuracy. These findings await independent confirmation.
Positron emission tomography using 11CPittsburgh compound B (PIB), a ligand that binds to betaamyloid,
demonstrates increased uptake in patients with CAArelated hemorrhage compared with normal controls
[103,104]. Compared with patients with Alzheimer disease, median binding of PIB is lower in CAA, and may differ
in its distribution. Current and future hemorrhagic lesions in patients with CAA appear to occur preferentially in
local regions of concentrated amyloid detected by PIB [43,52]. More studies are needed to define a potential role
for this imaging technique in CAA.
There is as yet no clearly defined clinical role for genetic testing in CAA. In particular, APOE genotype is neither
sensitive nor specific for the diagnosis of CAA, as the ε2 and ε4 alleles are present in only a subset of patients
[14,15]. Although, as noted above, AD is relatively common in CAA, only about 25 percent of CAA patients
appear to have clinical histories of dementia prior to their first hemorrhage [12]. Thus, dementia is not included in
the diagnostic criteria for CAA.
DIFFERENTIAL DIAGNOSIS — Other relatively common causes of nontraumatic lobar hemorrhage include:
● Lobar extension of a hypertensive putaminal hemorrhage
● Hemorrhagic transformation of an ischemic stroke
● Arteriovenous malformation (AVM)
● Hemorrhagic tumor
Differentiation of CAA from these conditions depends upon the clinical setting (eg, most first AVMrelated
hemorrhages occur before age 35 to 40 [105]) and radiographic appearance. Gradientecho MRI can be helpful
in this regard by establishing the presence and distribution of previous hemorrhages. Another helpful study is a
followup MRI performed two to three months after the primary hemorrhage to rule out underlying vascular
malformation or tumor.
Multiple hemorrhages can be seen with CNS vasculitis, hypertensive encephalopathy, multiple cavernous
malformations, or coagulopathy. These conditions generally can be distinguished from CAA by the clinical setting
and distribution of hemorrhages, which typically do not follow the same anatomic pattern as CAA (restriction to
cortical or greywhite regions).
The differential diagnosis of other clinical presentations of CAA are discussed in the sections above.
TREATMENT
Acute intracerebral hemorrhage — Acute CAArelated hemorrhage is treated like other acute intracerebral
hemorrhages, with attention to intracranial pressure and control of blood pressure. (See "Spontaneous
intracerebral hemorrhage: Pathogenesis, clinical features, and diagnosis" and "Evaluation and management of
elevated intracranial pressure in adults".)
Surgical hematoma resection appears to carry little or no additional risk in CAA compared with other types of
intracerebral hemorrhage and can be performed when indicated. In one series of 37 patients who were treated
surgically, for example, 54 percent had a good outcome and only 11 percent died [106]. Age ≥75 and
intraventricular hemorrhage were associated with a worse prognosis.
Avoiding anticoagulants and antiplatelet agents — Because of the high recurrence rate, the general rule for
patients with diagnosed CAA is to avoid anticoagulant and antiplatelet agents. (See "Risk of intracerebral
bleeding in patients treated with anticoagulants".)
● Warfarin increases both the frequency (approximately 7 to 10fold) and severity (approximately 60 percent
mortality) of cerebral hemorrhage [37,107], and should be avoided, if possible, in patients with CAA.
● Aspirin at commonly prescribed doses increases the risk of hemorrhage to a lesser extent. In one
prospective cohort of patients with primary lobar ICH, aspirin was associated with an increased risk of ICH
recurrence (HR = 3.95; 95% CI: 1.6 to 8.3) when controlling for other hemorrhage risk factors [44]. Aspirin
use can nonetheless be considered in selected patients with CAA if they have clear indications for
antiplatelet therapy. Similar caution is warranted with the nonsteroidal antiinflammatory drugs. Among these
agents, the nonacetylated salicylates (eg, choline magnesium trisalicylate) do not appear to affect platelet
function.
Blood pressure control — Although the vascular pathology in CAA does not appear to be pathogenetically
linked to hypertension, control of blood pressure within normal limits is nonetheless advisable. Recent support for
lowering of blood pressure in patients diagnosed with CAA came from a secondary analysis of data from the
PROGRESS trial [6]. Randomization to active treatment (perindopril plus indapamide) when there was either no
indication or a contraindication to diuretics in this study resulted in a 77 percent reduction in the risk of probable
CAArelated ICH.
Avoiding statins — There are insufficient data to recommend general restrictions on the use of statin agents
[108].
While a number of studies have found an inverse relationship between total and LDLcholesterol and the risk of
ICH [109117], treatment with statins does not appear to increase the risk of primary ICH or to negatively impact
prognosis according to a number of studies and metaanalyses [118124]. Given the conflicting data, it seems
reasonable to weigh the benefits of statin therapy against the possible risks in individual patients with cerebral
amyloid angiopathy because there is a high risk of ICH recurrence [125127]. (See "Spontaneous intracerebral
hemorrhage: Treatment and prognosis", section on 'Recurrence'.)
Immunosuppression — While data are limited, available evidence suggests that the rare inflammatory forms of
CAA (sometimes called Abetarelated angiitis) may be responsive to immunosuppressive therapy. (See 'CAA
related inflammation' above.)
The largest series involved 12 patients with welldocumented CAArelated perivascular inflammation and mean
followup of 47 months [65]. Treatment with glucocorticoids or pulsed cyclophosphamide resulted in sustained
clinical improvement in seven patients, improvement with subsequent clinical flares in three, and no clinical
response in two [65]. Glucocorticoid therapy appears to be most often used in this setting [73,128,129]; other
immunosuppressive treatments that have been effective in isolated cases include cyclophosphamide, cytoxan,
methotrexate and mycophenolate mofetil [67,130,131]. Approximately 70 percent of patients improve with
treatment; a clinical response is typically seen in one to three weeks. Our treatment protocol (based on clinical
experience) is methylprednisolone 500 mg to 1 gm per day for five days, followed by an oral steroid taper.
SUMMARY AND RECOMMENDATIONS — Cerebral amyloid angiopathy (CAA), although usually asymptomatic,
is an important cause of primary lobar intracerebral hemorrhage (ICH) in the elderly.
● The incidence of symptomatic CAA increases with age; it is relatively unusual in individuals younger than 60
years. (See 'Epidemiology' above.)
● CAA can occur as a sporadic disorder, with or without associated Alzheimer disease (AD), or as a familial
syndrome. (See 'Pathogenesis' above.)
● CAA is characterized by the deposition of congophilic material in small to mediumsized blood vessels of the
brain and leptomeninges. This weakens the structure of the vessel wall and makes them prone to bleeding.
(See 'Pathogenesis' above.)
● CAA usually manifests with a spontaneous lobar hemorrhage. This location helps distinguish CAArelated
ICH from hypertensive ICH that more commonly arises in the putamen, thalamus, and pons. (See
'Intracerebral hemorrhage' above.)
● Transient neurologic symptoms are another manifestation of CAA. These are recurrent, brief (minutes), often
stereotyped spells of weakness, numbness, paresthesias, or other cortical symptoms that can spread
smoothly over contiguous body parts. The pathogenesis of these spells is not certain; they are not believed
to be transient ischemic attacks in most cases. (See 'Transient neurologic symptoms' above.)
● CAArelated inflammation is a distinct disease subtype characterized by subacute cognitive decline, seizures
and unifocal or multifocal white matter MRI T2 hyperintensities extending to the subcortical white matter or
sulci. Clinical and radiographic improvement can occur with immunosuppressive therapy. (See 'CAArelated
inflammation' above and 'Immunosuppression' above.)
● CAA and Alzheimer disease frequently coexist. CAA may also be associated with a vascular dementia. (See
'Cognitive impairment' above.)
● CAA is suspected clinically in a patient over the age of 60 with a spontaneous lobar hemorrhage, particularly
if there is not associated hypertension. Recurrent lobar hemorrhages in an older patient are particularly likely
to represent CAA. (See 'Diagnosis' above.)
● While the diagnosis of CAA is made definitively by pathologic examination, a probable diagnosis of CAA can
be made when MRI demonstrates the presence of two or more hemorrhages or microhemorrhages restricted
to those regions typical of CAA (cortex or "greywhite" junction) and entirely sparing regions typical of
hypertensive hemorrhage (basal ganglia, thalamus, or pons) (table 1). Hemorrhage involving the cortical
sulci (“superficial siderosis”) can also be suggestive of CAA. (See 'Diagnosis' above and 'Gradientecho MRI'
above and 'Microhemorrhages' above.)

MRI studies are also performed in patients with lobar ICH to exclude other causes (eg, vascular
malformation, tumor). (See 'Differential diagnosis' above.)
● The acute management of a patient with CAArelated ICH is similar to that as for other spontaneous ICH.
(See "Spontaneous intracerebral hemorrhage: Pathogenesis, clinical features, and diagnosis".)
● CAArelated ICH are frequently recurrent. Because anticoagulant and antiplatelet agents increase the
frequency and severity of ICH, these (particularly anticoagulant agents) should be avoided in individuals who
have probable CAA. Control of blood pressure may also limit the risk of ICH. (See 'Avoiding anticoagulants
and antiplatelet agents' above and 'Blood pressure control' above.)
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Topic 1128 Version 13.0
GRAPHICS
Lobar hemorrhage in cerebral amyloid angiopathy
Acute superficial lobar hemorrhage in the left frontal lobe seen on CT scan in a patient with
cerebral amyloid angiopathy (Panel A). Flair MR image performed one week later shows the high
signal intensity of subacute hemorrhage with surrounding edema extending into the subcortical
white matter (Panel B). Hemorrhage (now low signal intensity consistent with hemosiderin) and
edema are mostly resolved on a threemonth followup study (Panel C).
Courtesy of Eric D Schwartz, MD.
Graphic 50480 Version 3.0
CAArelated perivascular inflammation
(A) T2 weighted axial MR image shows periventricular white matter hyperintensity in a patient
who presented with memory difficulties.
(B) Gradient echo MR image from the same patient shows multiple low intensity foci (arrows)
consistent with microhemorrhages, which are not seen on the T2 weighted image (A). The
microhemorrhages are located peripherally, as opposed to hypertensive related hemorrhages
that may occur centrally.
(C) FLAIR MR image demonstrates patchy and confluent periventricular white matter
hyperintensity.
CAA: cerebral amyloid angiopathy; MR: magnetic resonance; FLAIR: fluidattenuated inversion
recovery.
Courtesy of Eric D Schwartz, MD.
Boston criteria for CAArelated hemorrhage
Classic Boston criteria
Definite CAA Full postmortem examination demonstrating:
Lobar, cortical, or corticosubcortical hemorrhage
Severe CAA with vasculopathy
Absence of other diagnostic lesion
Probable CAA with Clinical data and pathologic tissue (evacuated hematoma or cortical biopsy)
supporting pathology demonstrating:
Lobar, cortical, or corticosubcortical hemorrhage
Some degree of CAA in specimen
Absence of other diagnostic lesion
Probable CAA Clinical data and MRI or CT demonstrating:
Multiple hemorrhages restricted to lobar, cortical, or corticosubcortical regions
(cerebellar hemorrhage allowed)
Age ≥55 y
Absence of other cause of hemorrhage
Possible CAA Clinical data and MRI or CT demonstrating:
Single lobar, cortical, or corticosubcortical hemorrhage
Age ≥55 y
Absence of other cause of hemorrhage
CAA: cerebral amyloid angiopathy.
Reproduced with permission from: Linn J, Halpin A, Demaerel P, et al. Prevalence of superficial siderosis in patients with
cerebral amyloid angiopathy. Neurology 2010; 74:1346. Copyright © 2010 Lippincott Williams & Wilkins.
Old hemorrhages on gradient echo MRI
Comparison of CT scan (A), T2 weighted MRI (B), and gradient echo MRI (C)
demonstrates the utility of the last for detecting old hemorrhages consistent with
cerebral amyloid angiopathy. In addition to the the left frontoparietal hemorrhage
seen on all studies (arrowheads), the gradientecho sequence demonstrates multiple
areas of decreased signal in graywhite regions (arrows) consistent with chronic
hemorrhage.
CT: computed tomography; MRI: magnetic resonance imaging.
Reproduced with permission from Greenberg SM, Finklestein SP, Schaefer PW. Petechial
hemorrhages accompanying lobar hemorrhage: detection by gradientecho MRI. Neurology
1996; 46:1751.

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