48 Cerebral Amyloid Angiopathy
48.1 Case Description
48.1.1 Case 1: Patient with Seizures and Cognitive Impairment
A 75-year-old man presented to the emergency department for assessment of loss of consciousness. While sitting on the edge of the bed and staring, he suddenly developed a generalized tonic clonic seizure that lasted 10 minutes. His past medical history was negative except for well-controlled hypertension and dyslipidemia. He did not have prior cerebrovascular events or cognitive deficits. His family history was negative for dementia. He lived with his family and was fully independent at baseline. On examination, he was confused, and not oriented to place or time. He had a right gaze preference and head deviation to the right, with continuous right-sided clonic movements. Given his complex presentation, he was promptly intubated for airway protection and received a loading dose of phenytoin.
48.1.2 Investigations and Imaging
Noncontrast CT (NCCT) of the head at the time of presentation (Fig. 48.1a) showed multifocal left occipital hyperattenuation, consistent with intraparenchymal hemorrhage (ICH). CT angiography (CTA) did not show any underlying vascular malformation and dural venous sinuses were patent.
An MRI of the brain was performed 2 days later (Fig. 48.1b–d), showing acute left occipital hemorrhage with associated vasogenic edema. There was no definite evidence of an underlying lesion. Scattered microhemorrhages with a posterior predilection at the cortical/subcortical junctions were suggestive of cerebral amyloid angiopathy (CAA).
Electroencephalography (EEG) revealed intermittent frequent focal polymorphic delta theta waves involving the left anterior and mid temporal regions, reflective of underlying subcortical white matter dysfunction.
48.1.3 Treatment and Outcome
The patient remained intubated for 2 days; after extubation, he was delirious for 3 days without any signs of infection or electrolyte disturbance, but once subtherapeutic phenytoin levels were corrected his delirium resolved. He required two antiepileptic medications for breakthrough complex partial seizures: on levetiracetam 1,500 mg orally twice daily and phenytoin 300 mg orally once daily, the patient did not have any further seizure recurrence. Through his hospital stay, his blood pressure was well controlled with an average of less than 140/90 while on three antihypertensive agents. On cognitive assessment, his Mini Mental State Examination (MMSE) score was 17/30, with recall and attention domains mostly affected. At discharge, the patient could sit without assistance, but he needed assistance for mobility, bathing, grooming, and dressing. He was discharged home after 2 weeks with community care support and a modified Rankin scale (mRS) functional status of 3.
48.1.4 Final Diagnosis
CAA presenting with intraparenchymal hemorrhage and multiple cerebral microbleeds.
48.2 Case 2: Patient with Rapidly Progressive Cognitive Decline
48.2.1 Clinical Presentation
An 82-year-old woman, with a history of polymyalgia rheumatica on low-dose prednisone, was originally referred to the stroke prevention clinic after the incidental discovery of a chronic cerebellar infarct on an MRI of the brain performed as part of a workup for gait instability and headache. The MRI showed a small area of encephalomalacia from remote infarct in the inferior cerebellar vermis and moderate white matter microangiopathy, but no evidence of prior hemorrhage (Fig. 48.2). The right vertebral artery was chronically occluded on MR angiography. The patient had no known vascular risk factors such as hypertension, dyslipidemia, diabetes, or tobacco use, although she had taken hormone replacement therapy after menopause. Echocardiogram showed no cardiac source of embolus, so the patient was advised to take daily 81 mg aspirin and was discharged from the stroke clinic.
Sixteen months after being assessed at the stroke clinic, the patient presented to the emergency room. Her husband reported that the patient was cognitively intact until two months before, when he noticed that she had forgotten to pay bills. In the last month, she had become increasingly disoriented, her gait instability had worsened, and she had developed speech difficulties. Her husband brought her to the emergency room once she no longer recognized him.
48.2.2 Investigations and Imaging
NCCT scan performed at the time of admission showed small volume subarachnoid hemorrhage (SAH) in the left cingulate sulcus (Fig. 48.3a, b), with a background of white matter low attenuation and generalized brain parenchymal volume loss.
C-reactive protein (CRP) was elevated at 42 mg/L, and erythrocyte sedimentation rate (ESR) was elevated at 39 mm/hour. The white blood cell count was at the upper limits of normal, 7.4 × 109/L. Rheumatologic investigations including antineutrophil cytoplasmic antibodies (ANCA), antinuclear antibodies (ANA), rheumatoid factor (RF), and anti-dsDNA antibodies were negative.
Cerebrospinal fluid (CSF) analysis showed no evidence of infection with viruses, fungi, mycoplasma, tuberculosis, syphilis, or other bacteria. CSF cell count and differential were normal. Cytology showed no evidence of malignant cells. CSF glucose was low at 2.1 mmol/L, and CSF protein was high at 1.61 g/L.
Contrast-enhanced MRI (Fig. 48.3c–f) showed diffuse high fluid-attenuated inversion recovery (FLAIR) signal in the cerebral sulci, and extensive white matter hyperintensity, with multifocal leptomeningeal enhancement and interval development of cerebral subcortical microhemorrhages.
A brain biopsy in the region of leptomeningeal enhancement in the right frontal lobe showed vasculocentric granulomatous inflammation. Immunohistochemistry for beta–amyloid showed abundant reactivity in leptomeningeal and cortical blood vessels, suggesting amyloid angiitis. Frequent neuritic and diffuse amyloid plaques were seen in the cortex.
48.2.3 Treatment and Outcome
At the time of admission, the patient was treated with high-dose intravenous (IV) methylprednisolone for five days, which resulted in mild cognitive improvement. The methylprednisolone was continued for a further five days with the addition of cyclophosphamide, and the patient was then switched to 50 mg of oral prednisone daily. Tapering of the prednisone resulted in deterioration, so MMF 500 mg PO BID was added.
Follow-up MRI (Fig. 48.4) showed moderate reduction, but not resolution, in the leptomeningeal enhancement. After three months in hospital, the patient was discharged to a long-term care facility, as she required assistance with her activities of daily living (mRS score of 4).
48.2.4 Final Diagnosis
Amyloid-beta–related angiitis (ABRA), causing vasculocentric granulomatous inflammation and resulting SAH.
CAA is a brain condition characterized by amyloid protein deposition within the media and adventitia of the leptomeningeal and cortical arterioles and small arteries of the brain cerebrum and cerebellum. CAA is classified based on the type of the amyloid protein involved in the process. The sporadic amyloid β-protein (Aβ)-type CAA is most commonly found in older individuals and in patients with Alzheimer disease (AD). So far, the following seven amyloid proteins have been reported in CAA: Aβ, cystatin C, prion protein, ABri/ADan, transthyretin, gelsolin, and immunoglobulin light chain amyloid.
Whereas the senile plaques of Alzheimer disease deposited within the neuropil are mostly composed of the longer 42–43 amino acid cleavage peptide Aβ42, the aggregates seen in CAA are typically composed of the shorter 40 amino acid peptide Aβ40. The Aβ42 peptide aggregates more readily than Aβ40 and therefore forms amyloid near its site of production from neurons within the brain parenchyma, while Aβ40 is transported by interstitial fluid flow to blood vessels, where it aggregates on vascular basement membranes.
48.3.1 Clinical Presentations of CAA
The accumulation of the amyloid causes CAA-associated vasculopathy and fragility of the arterioles and small arteries, leading to clinical or subclinical hemorrhagic lesions: lobar intracerebral macrohemorrhage, cortical microhemorrhage, and focal convexity SAH. The occipital lobe is preferentially affected, while CAA is uncommon in the basal ganglia, thalamus, and brainstem; spontaneous hemorrhages in these regions are more commonly hypertensive in etiology.
CAA-related lobar ICH is often multiple and recurrent. Clinical manifestations depend on the function of the brain region at the site of hemorrhage and include motor paresis, disturbance of consciousness, aphasia, and visual loss. Patients often present with headache at the acute stage, and dementia and seizures during chronic stages. Headache with meningeal signs is likely caused by SAH accompanying lobar ICH.
CAA is a frequent cause of cortical superficial siderosis/focal convexity SAH, a subtype of nonaneurysmal SAH, in patients older than 60 years and in those with AD. Notably, cortical superficial siderosis is closely associated with microhemorrhages in lobar locations in the general population; it is highly prevalent in CAA and is found in 60.5% of pathologically confirmed cases.
CAA-related cerebral hypoperfusion or occlusive small-vessel disease may cause progressive white matter lesions and cortical microinfarcts. Patients with CAA-related ICH exhibit occipital dominant white matter hyperintensities on MRI, compatible with the predilection of CAA pathology for posterior brain regions.
Dementia was noted in 74% of individuals with severe CAA at autopsy. Moderate-to-very severe CAA is associated with impaired performance in specific cognitive domains, most notably perceptual speed, which is separate from the effect of AD pathology.