Discussion
Cerebral amyloid angiopathy (CAA), also known as congophilic angiopathy or cerebrovascular amyloidosis, is a primary process in which amyloid infiltrates the media and adventitia of blood vessels, in the absence of systemic amyloidosis. In this condition, beta A4-amyloid (beta- amyloid) is deposited in the small and medium arteries and veins of the cortex and leptomeninges, with characteristic sparing of the basal ganglia, corpus callosum, thalamus, cerebellum, and brain stem (although, deep central gray matter and cerebellar hemorrhages have been reported in a small percentage of these patients). CAA typically occurs in aged individuals, most commonly during the seventh through ninth decades of life, with an equal sex incidence. The frequency of CAA in the elderly is high, with estimates ranging from 23% to 57% in unselected autopsy series (amyloid deposition in cerebral vasculature may occur as part of the normal aging process). The hereditary form of CAA, which is identified in Iceland and is due to the deposition of another chemical type of amyloid (hereditary cystatin C amyloid angiopathy of the Icelandic type), often presents at a lower age. Beta-amyloid deposition in small and medium sized cerebral blood vessels can also be found in association with several different pathologic conditions, such as arteriovenous malformation, radiation necrosis, demyelinating disease, Down's syndrome, chronic vasculitis, familial cerebral hemorrhage, amyloidoma, Alzheimer's disease (AD) and senile dementia of Alzheimer's type (over 90% of patient's with pathologically confirmed AD will have CAA; about 40% of CAA patients have dementia or overt AD).
The most common presentation of CAA is intracerebral hemorrhage (ICH). CAA has long been recognized as a common cause for hemorrhage in the elderly in the absence of hypertension or coagulopathy, in fact it has been cited as the cause of 2% to 9.3% of spontaneous ICH in elderly, nonhypertensive individuals. ICH associated with CAA are usually superficial, multiple and lobar, with irregular borders; they are often surrounded by an edematous zone.The hematomas are usually large (sometimes even massive), and there may be evidence of prior hemorrhage. Pathologically, CAA is more severe in patients with lobar hemorrhage than in age-matched controls and may display distinctive pathologic features such as fibrinoid necrosis, which usually causes microaneurysmal dilatation of the vessel wall. These microaneurysms could be responsible for the ICH observed in CAA patients. Hematomas are most common in the frontal (35%) and parietal (26%) regions, less common in the occipital (19%) and temporal (14%) regions, and unusual in the deep central gray matter (4%) and cerebellum (2%).These percentages suggest that for unclear reasons, the location of the lobar hematomas does not reflect the more frequent pathological location of CAA in the parieto-occipital cortex. Clinical presentations (other than ICH) may consist of transient neurologic symptoms (repetitive, stereotyped episodes with spread of symptoms to contiguous body areas during the episodes), rapidly progressive dementia (with progression from intact baseline to profound dementia in spans of a few days to 2 years), or an intracranial mass lesion.
CAA can be diagnosed definitely only at postmortem; however, it might be diagnosed during life with gradient echo (GE) MRI sequences, and determination of apolipoprotein E genotype, in the absence of brain biopsy. A working set of diagnostic criteria has been established by Greenberg et al for CAAH (CAA hemorrhage). In the absence of another cause for hemorrhage, 'definite CAAH' is defined as lobar ICH with severe CAA found on autopsy; 'probable CAAH' is defined as a single lobar ICH with pathologic demonstration of CAA or two foci of lobar ICH seen on gradient-echo MRI; and 'possible CAAH' is defined as a single lobar ICH without pathologic confirmation. In the appropriate clinical setting, multiple petechial bleeds restricted to cortical and/or corticosubcortical territories (detected by GE MRI) that accompany a lobar hemorrhage, are also supportive of a diagnosis of probable CAA. Some studies have demonstrated a significant association betwen apolipoprotein-epsilon 4 and CAAH, also patients with this genotype seem to have an earlier onset of intraparenchymal hemorrhage compared with the noncarriers of this genotype. The apolipoprotein-epsilon 2 has also been reported to occur with high frequency in CAA patients and it may elevate the risk of hemorrhage in these patients by promoting vessel wall degradation (fibrinoid necrosis). Testing for apo E genotype in patients presenting with a lobar hemorrhage without a clear etiology, may have a crude prognostication value for determining the risk of recurrent ICH (with a higher recurrent risk for carriers of either the epsilon 4 or epsilon 2 allele).
As mentioned previously, imaging, especially GE MRI sequences have an important role in the diagnosis of CAA. In the acute setting CT scan elegantly demonstrates the intraparenchymal hematoma in those CAA patients presenting with ICH (with occasional intraventricular or subarachnoid extension of the hemorrhage). On conventional angiography, no intrinsic vessel abnormality can be demonstrated. MR imaging in these patients may show the following findings:
-ICH, which is usually superficial and lobar and which may be multiple.
-Evidence of prior hemorrhage on T2-weighted (SE or fast-SE ) sequences and/or GE images (this technique enhances the magnetic susceptibility and resultant signal dropout, produced by chronic blood products, thus increasing sensitivity for hemorrhage). Hypointensities due to blood breakdown products may be seen as small petechial hemosiderin deposits (microbleeds), larger hematomas, or curvilinear gyral hypointensities. Usually the hemosiderin deposits have a lobar distribution; involvement of the central deep gray and infratentorial structures, although not characteristic, may nevertheless be observed in this disorder. The latter situation may be due to the simultaneous occurence of cerebral amyloid and hypertensive microangiopathies (approximately a third of CAA patients have a history of hypertension).
-White matter hyperintensities (WMH), in the subcortical and/or deep white matter (observed on T2-weighted and FLAIR sequences), which may be a reflection of tissue hypoperfusion. The morphologic background of these hyperintensities may vary and includes ischemic demyelination as well as reactive gliosis and transient edema.The latter may be responsible for the mass effect and transient appearance of some of these WMH reported in CAA patients in the literature. Cortical hyperintensities (probably ischemic in nature), may also be observed in these patients.
Reports of the following presentations (on imaging) of pathologically proven CAA can be found in the literature: a nonhemorrhagic, infiltrating mass, a nonhemorrhagic diffuse encephalopathy (one such patient was given a diagnosis of multifocal glioma before brain biopsy), or even unilateral hemorrhages in a patient demonstrating both mass effect and meningeal enhancement
Although the literature emphasizes the diagnosis of CAA and its association with hemorrhage and dementia, very little information is available concerning its treatment. These patients demonstrate a high mortality rate related to their advanced age and debilitation; lobar hemorrhages in this setting are frequently associated with death.
