2025 年 12 巻 p. 97-101
Cerebral amyloid angiopathy is a vascular disorder characterized by amyloid β deposition in leptomeningeal and cortical blood vessels. Rarely, amyloid β accumulation induces inflammatory responses, classified as cerebral amyloid angiopathy-related inflammation or amyloid β-related angiitis, with the latter being extremely rare. We report a case of a 74-year-old woman presenting with visual field disturbance, occipital pain, speech impairment, agraphia, and acalculia. Imaging revealed subarachnoid hemorrhage without an identifiable source on cerebral angiography. Magnetic resonance imaging demonstrated abnormal enhancement in the dura and pia mater of the left temporal and parietal lobes. Brain biopsy confirmed amyloid β-related angiitis, showing histopathological findings of amyloid deposition with granulomatous inflammation. Steroid pulse therapy led to marked clinical and radiological improvement. This case highlights the importance of considering amyloid β-related angiitis in the differential diagnosis of angiographically negative subarachnoid hemorrhage. Early recognition and immunosuppressive therapy are essential to reduce neurological deficits, with brain biopsy providing a definitive diagnosis.
Cerebral amyloid angiopathy (CAA) is a condition characterized by amyloid β (Aβ) protein deposition in subcortical or meningeal blood vessels, predominantly affecting elderly individuals.1,2) CAA is typically a non-inflammatory, age-related disorder associated with cerebral hemorrhage, infarcts, leukoencephalopathy, and dementia. However, in rare cases, Aβ deposition triggers an inflammatory response, which can be classified into CAA-related inflammation (CAA-RI) and Aβ-related angiitis (ABRA). CAA-RI and ABRA represent distinct pathological entities with no known correlation in their clinical manifestations. CAA-RI features inflammatory cell infiltration around Aβ-laden blood vessels without vasculitis. In contrast, ABRA is characterized by Aβ deposition with adjacent granulomatous inflammation, including granuloma formation and necrosis within the affected vasculature.3,4)
ABRA is an extremely rare vasculitis, most commonly observed in elderly patients presenting with cognitive dysfunction and stroke.2) A 2014 study by Danve et al.5) reviewed 94 cases of ABRA, reporting symptoms such as cognitive decline, microbleeds, and transient cerebral ischemia. Notably, no cases in the study presented with subarachnoid hemorrhage (SAH). This absence highlights a significant gap in the literature regarding ABRA as a potential cause of angiographically negative SAH.
This case report addresses this gap by describing an instance of ABRA presenting with SAH. It emphasizes the utility of brain biopsy for definitive diagnosis and highlights the role of immunosuppressive therapy in improving clinical outcomes. Through this report, we aim to enhance awareness of ABRA as a differential diagnosis in unexplained SAH and provide insights for early identification and management.
A 73-year-old woman presented with a headache and visual field disturbance and was referred to our hospital. Neurological examination revealed impairments in speech comprehension and word production, along with acalculia, agraphia, and right homonymous hemianopia. Cranial computed tomography (CT) imaging demonstrated faint high-density lesions in the cerebral sulci of the left parietal and occipital lobes, suggestive of SAH (Fig. 1). Brain magnetic resonance imaging (MRI) showed high signal intensity in the left temporal, parietal, and occipital lobes on diffusion-weighted imaging (Fig. 2A). Fluid-attenuated inversion recovery imaging revealed corresponding areas of high signal intensity, while susceptibility-weighted imaging demonstrated low signal consistent with the CT findings (Fig. 2B and C). Magnetic resonance angiography, CT angiography, and cerebral angiography were performed but failed to identify a clear source of bleeding. Cerebrospinal fluid analysis revealed xanthochromia, a slight increase in mononuclear cell count, and increased protein levels, confirming SAH and excluding infectious causes such as encephalitis or meningitis.
CT scan on admission. The image shows faint high-density lesions (arrowheads) in the cerebral sulcus of the left parietal and occipital lobes, suggesting a subarachnoid hemorrhage.
CT: computed tomography
MRI on admission. A: DWI shows high signal intensity in the left temporal, parietal, and occipital lobes. B: FLAIR imaging reveals high signal intensity in the same regions. C: SWI shows low signal intensity in areas corresponding to the high-density lesions observed in the CT scan.
CT: computed tomography; DWI: diffusion-weighted imaging; FLAIR: fluid-attenuated inversion recovery; MRI: magnetic resonance imaging; SWI: susceptibility-weighted imaging
The right homonymous hemianopia and language impairments were attributed to symptomatic epilepsy, and the patient was started on the anti-epileptic drug (AED) levetiracetam at 1000 mg/day. While her visual field deficit improved following AED administration, language impairment, acalculia, and agraphia showed minimal improvement. A follow-up MRI on the second day of hospitalization demonstrated abnormal contrast enhancement in the dura and pia mater, correlating with the site of the SAH (Fig. 3).
Contrast-enhanced MRI on day 2 of hospitalization. Abnormal contrast enhancement is observed in the dura and pia mater, consistent with the site of subarachnoid hemorrhage. Enhancement of both the pia-subarachnoid and dura-arachnoid patterns is observed.
MRI: magnetic resonance imaging
To establish a definitive diagnosis, a brain biopsy was performed using a neuronavigation-guided mini craniotomy. A cortical sample was obtained from the region displaying leptomeningeal contrast enhancement on MRI. Hematoxylin and eosin staining revealed vascular connective tissue changes, including intimal thickening, luminal narrowing, neutrophil infiltration, and fibrinoid necrosis in small to medium-sized blood vessels. Associated ischemic degeneration of the brain tissue was also observed (Fig. 4A). Amyloid deposition was confirmed on blood vessel walls through direct fast scarlet staining, which appeared red under standard light and displayed apple-green birefringence under polarized light (Fig. 4B and C). There were no pathological findings suggestive of infection, granulomas, or malignancy. Based on these findings, a diagnosis of Aβ-related vasculitis was confirmed.
Histopathology of cortical tissue sample. A: HE staining (original magnification ×40) of brain tissue containing vascular structures reveals intimal thickening, narrowing of the lumen, neutrophil infiltration, and fibrinoid necrosis in small to medium-sized blood vessels. Degeneration of brain tissue due to ischemia and inflammation spreading to veins with giant cells are also noted. B: Direct fast scarlet (DFS) staining (original magnification ×10) shows red-stained amyloid deposits in blood vessel walls. C: Under polarized light (original magnification ×20), green birefringence is observed using DFS staining, indicating amyloid deposits in blood vessel walls.
HE: hematoxylin and eosin
Steroid pulse therapy was initiated, starting with 1000 mg of methylprednisolone daily for 3 days, followed by maintenance therapy with 40 mg/day with gradual dose tapering. Biweekly follow-up MRIs done post-biopsy demonstrated progressive resolution of abnormal contrast enhancement in the pia and dura mater along the cerebral sulci.
The patient exhibited gradual improvement in language function, acalculia, agraphia, and overall cognitive abilities 2 weeks following the biopsy. She was discharged 48 days post-biopsy with a modified Rankin Scale score of 2. Since discharge, no symptom recurrence has been observed, and her oral steroid dose has been gradually reduced. She is currently maintained on 4 mg/day of methylprednisolone as an outpatient.
CAA is a small vessel disease involving amyloid deposition in the blood vessels, leading to risks such as intracerebral hemorrhage (ICH) and SAH. Among patients with CAA, the annual incidence rate of symptomatic ICH is 19%, compared with 7% in those without CAA. Effective hypertension management is critical for preventing such events, and caution is needed when prescribing antithrombotic medications.1,6-8)
In certain cases, an inflammatory reaction occurs associated with Aβ deposition, which can be classified as CAA-RI or ABRA. These inflammatory variants of CAA share overlapping clinical presentations but are quite distinct from non-inflammatory CAA. Inflammatory CAA more commonly presents with acute or subacute cognitive or functional decline, neurological deficits, or seizures. While cerebral hemorrhage is uncommon in inflammatory CAA, it can occur. Compared to non-inflammatory CAA, inflammatory CAA is also associated with a significantly younger age at onset (approximately 7 years younger) and exhibits more extensive white matter abnormalities on imaging, with a predominantly lobar distribution.9)
ABRA, a rare inflammatory subtype of CAA recognized in 2005, involved transmural or intramural inflammation of amyloid-laden blood vessels with surrounding microglia and macrophages. It typically presents at a mean age of 67, with symptoms such as altered mental status (75%), headache (32%), and seizures (32%).4,10-13)
In our patient's case, granulomatous changes with vascular wall destruction were observed pathologically, leading to a diagnosis of ABRA. This represents a very rare instance of ABRA presenting with SAH. Inflammatory CAA typically presents with symptoms such as headache, cognitive impairment, focal neurological deficits, and occasionally epileptic seizures or encephalopathy.14,15) Common radiological findings include parenchymal or leptomeningeal gadolinium enhancement, cortical superficial siderosis, and lobar hemorrhage. The primary differential diagnoses to exclude are primary angiitis of the central nervous system (PACNS) and tumors, particularly primary central nervous system lymphoma (PCNSL).12,16)
The Boston Criteria are widely utilized in evaluating patients for CAA, incorporating clinical, pathological, and radiographic parameters to assess its likelihood. Although brain biopsy is often considered the gold standard for definitive diagnosis, it is an invasive procedure associated with complications in approximately 18% of cases, including fever, neurological deficits, and brain abscesses.17) Consequently, brain biopsy should be reserved for cases with compelling clinical symptoms and imaging findings consistent with the Boston Criteria while weighing the risks and benefits of this invasive approach.
PACNS is defined as a vasculitis confined to the CNS, unassociated with systemic illness, and confirmed through histopathological or angiographic evidence. PACNS typically presents with a gradual onset of headache, mental status alterations (e.g., confusion, disorientation, or dementia), and focal neurological deficits, including hemiparesis, aphasia, amnesia, visual disturbances, and cranial nerve palsies. Unlike CAA or ABRA, PACNS primarily affects younger stroke patients without conventional cerebrovascular risk factors. While the clinical features are highly variable, PACNS may present with transient ischemic attacks, large cerebral infarcts, multi-infarct states, SAH, or intraparenchymal hemorrhage.18-20)
PCNSL is another critical differential diagnosis, characterized by its malignant and rapidly progressive course. Focal neurological deficits occur in approximately 70% of patients, with imaging typically demonstrating uniform contrast enhancement on CT and MRI. However, atypical presentations, including hemorrhage, calcification, cystic changes, or necrosis, may occasionally be observed.21,22) Given the nonspecific clinical and neuroradiological features of PCNSL, histopathological confirmation is essential for accurate diagnosis. While timely initiation of immunosuppressive treatment is crucial for managing PCNSL, avoiding unnecessary immunosuppressant use is paramount to minimizing potential harm.23)
ConclusionWe report a case in which ABRA was definitively diagnosed by brain biopsy in a patient with SAH of unknown origin, with symptom improvement following early steroid treatment.
In summary, CAA is a potential differential diagnosis for unexplained SAH, and brain biopsy may aid in establishing a definitive diagnosis.
Informed consent for publication was obtained from the patient.
All authors have no conflict of interest. The authors, who are members of the Japan Neurosurgical Society, have submitted the self-reported Conflicts of Interest Disclosure Statement Forms online.
