Neuro-ophthalmology and Cerebral Amyloid Angiopathy

Key points at a glance

Cerebral amyloid angiopathy (CAA) is an age-related disease in which β-amyloid deposition in the walls of cerebral blood vessels causes lobar hemorrhage and microbleeds.
The most common ophthalmic presentation is homonymous hemianopia due to occipital lobe lesions, which can lead to cortical visual impairment when bilateral.
It is found in 30–50% of healthy older adults and is the second most common cause of intracerebral hemorrhage after hypertension.
CAA frequently coexists with Alzheimer disease (80–90%) and is often accompanied by cognitive decline.
Definitive diagnosis requires biopsy, but clinical diagnosis based on MRI findings is possible using the Boston criteria version 2.0.
There is no curative treatment; blood pressure control is most important. Steroids may be effective for CAA-related inflammation.
In recent years, new clinical challenges such as iatrogenic CAA and ARIA associated with anti-amyloid antibody therapy have gained attention.

1. Neuro-ophthalmology and Cerebral Amyloid Angiopathy

Cerebral amyloid angiopathy (CAA) is a disease in which small and medium-sized blood vessels in the brain and leptomeninges are affected by the accumulation of beta-amyloid (Aβ) plaques in the adventitia and media of the vessel walls. Sporadic CAA is age-dependent and rare before the age of 60–65 years. It is found in approximately 30–50% of healthy elderly individuals ³⁾ and is the second most common cause of intracerebral hemorrhage after hypertension ³⁾.

There is a strong association with Alzheimer’s disease (AD), with 80–90% of AD patients having concomitant CAA ³⁾. However, CAA can also occur alone without AD.

Hereditary CAA and Iatrogenic CAA

Hereditary CAA (h-CAA) is rarer than sporadic CAA and often shows autosomal dominant inheritance. It is broadly classified into Aβ type and non-Aβ type ²⁾.

Aβ type (APP gene mutation, chromosome 21): Dutch type (onset in 50s, dementia predominant), Flemish type (age 45–), Italian type (50s, lobar hemorrhage + cortical calcification), Iowa type (50–60s), etc.
Non-Aβ type: Icelandic type (cystatin C, chromosome 20, young onset in 20s–30s), familial British dementia (ABri), familial Danish dementia (ADan)

Iatrogenic CAA (iCAA) is a relatively new concept that develops following cadaveric dura mater transplantation (e.g., Lyodura) or instrument manipulation of the brain and spinal cord. The incubation period is 30–40 years, and more than 50 cases have been reported ⁴⁾. Although it was previously thought to occur mainly in young-onset cases (under 55 years), a report of 5 cases (mean age at onset 73.6 years, mean incubation period 33.8 years) showed that it can also occur in individuals aged 65 years and older ⁴⁾.

CAA is classified into four categories based on the pattern of β-amyloid deposition and the presence or absence of inflammation: typical CAA, inflammatory CAA (I-CAA), Aβ-related angiitis (ABRA), and primary angiitis of the central nervous system (PACNS).

Q Is cerebral amyloid angiopathy related to Alzheimer's disease?

CAA is present in 80–90% of patients with AD, and the two are closely related. However, CAA can also occur alone without AD. For details, see the section “Pathophysiology and Detailed Mechanisms of Onset”.

2. Main Symptoms and Clinical Findings

Subjective Symptoms

CAA is usually asymptomatic, but when clinical symptoms appear, they depend on the location and size of the hemorrhage.

Visual impairment and visual field defects: Manifest as homonymous hemianopia or cortical visual impairment due to damage to the occipital lobe or optic radiation. This is the most common ophthalmologic symptom.
Cognitive decline: Progressive memory impairment and executive dysfunction. More pronounced in cases with concurrent AD.
Headache: Acute onset associated with lobar hemorrhage or subarachnoid hemorrhage.
Seizures: Occurring with hemorrhagic lesions or cortical damage.
Focal neurological deficits: Hemiparesis, aphasia, sensory disturbances, etc., depending on the bleeding site.
Transient focal neurological episodes (TFNE/amyloid spells): Transient sensory disturbances (numbness, tingling) or visual disturbances (e.g., flashing lights, dancing letters)⁴⁾⁸⁾

Clinical Findings (Findings Confirmed by Physician Examination)

The most common ophthalmologic clinical presentation in CAA is occipital lobe lesions, causing homonymous hemianopia or, in bilateral cases, cortical visual impairment. Occipital lobe damage may occur without other neurological symptoms besides homonymous hemianopia.

Homonymous hemianopia: Contralateral visual field defect due to hemorrhagic or ischemic lesions of the occipital lobe or optic radiation. The responsible site is often the occipital lobe.
Cortical visual impairment: Bilateral occipital lobe lesions cause bilateral vision loss. May present with Anton syndrome, in which the patient denies being blind.
Visual agnosia: Occurs due to damage to the visual association cortex. Lesions in the fusiform face area have been reported to cause prosopagnosia.
Retinal findings: Optical coherence tomography (OCT) may detect thinning of the retinal nerve fiber layer (RNFL), which could be an early indicator of the disease. An association with inflammatory retinal vasculitis has also been noted.
Rare findings: Optic disc edema, retinal hemorrhage, peripapillary hemorrhage. In one case of sporadic CAA, vision loss occurred due to neovascular glaucoma secondary to retinal ischemia.

Q Can cerebral amyloid angiopathy cause decreased vision?

Hemorrhage or ischemia in the occipital lobe or optic radiation can cause homonymous hemianopia or cortical visual impairment, leading to vision and visual field deficits. This is the most common ophthalmic finding in CAA. For details, see the “Diagnosis and Testing” section.

3. Causes and Risk Factors

The underlying cause of CAA is abnormal production and impaired clearance of Aβ, generated from amyloid precursor protein (APP), leading to Aβ accumulation in the vessel walls and disruption of normal structure.

The main risk factors are as follows.

Aging: The greatest risk factor. Incidence increases markedly in older age groups.
Genetic factors: ApoE-ε4 increases the risk of developing CAA, while ApoE-ε2 promotes fibrinoid necrosis and vascular rupture, increasing the risk of hemorrhagic complications ³⁾. In ABRA cases, the ApoE-4/4 genotype is predominant ³⁾.
Hypertension: Poor blood pressure control increases the frequency of CAA-related bleeding.
Alzheimer’s disease: High coexistence rate with AD pathology (80–90%) ³⁾.
Iatrogenic exposure: Cadaveric dura mater grafts (e.g., Lyodura) and surgical manipulation of the brain or spinal cord may cause prion-like transmission of Aβ ⁴⁾⁸⁾.

Q Is there a hereditary form of cerebral amyloid angiopathy?

Several hereditary forms of CAA (h-CAA) are known, including the Dutch, Flemish, and Icelandic types. They are caused by mutations in the APP gene or the cystatin C gene and tend to occur at a younger age than sporadic CAA. For details, see the section “What is neuro-ophthalmology and cerebral amyloid angiopathy?”.

4. Diagnosis and Testing Methods

Definitive Diagnosis

A brain biopsy is required for a definitive diagnosis of CAA. Pathologically, it is positive for Congo red staining and shows the characteristic “apple-green” birefringence of amyloid under polarized light³⁾. However, most cases are diagnosed clinically without pathological confirmation during life.

Boston Criteria v2.0 (Clinical Diagnosis by MRI)

The Boston criteria v2.0, revised in 2022, incorporate emerging MRI markers to improve the accuracy of clinical diagnosis of CAA¹⁾.

Classification	Criteria
Definite	Severe CAA vascular pathology confirmed at autopsy
Probable (with pathological support)	Hemorrhage + some degree of CAA findings
Probable (MRI/CT)	Age ≥50, strictly lobar hemorrhagic lesions ≥2, or ≥1 + white matter lesions ≥1
Suspected (MRI/CT)	Age ≥55, single lobar hemorrhage

In the report by Schroeder et al. (2023), the sensitivity for definite cases according to the Boston criteria v2.0 was 74.5% (95% CI 65.4–82.4), specificity was 95.0% (95% CI 83.1–99.4), and the AUC of 0.798 was significantly better than the old criteria (p=0.0005)¹⁾.

Edinburgh CT criteria

In settings where MRI is difficult to perform, the Edinburgh criteria based on CT are used as an adjunct¹⁾. The probability of CAA is stratified by the presence of finger-like projections in lobar hemorrhage and subarachnoid hemorrhage. The specificity of high risk (both present) is 87.1%, but the sensitivity is only 58.5%.

Imaging tests

MRI (GRE/SWI): Depicts extravasation due to microangiopathy as hypointense areas. It is the most useful imaging test for evaluating CAA.
Cortical superficial siderosis: Known as a finding specific to CAA.
Centrum semiovale enlarged perivascular spaces (CSO-EPVS): A finding observed in all cases of iCAA⁴⁾.
OCT: Retinal nerve fiber layer thinning may be an early indicator.

Biomarkers

Complement C3: 0.43 u/mL in CAA group vs 0.35 u/mL in non-CAA group (p=0.040), AUCROC 0.68¹⁾
Cerebrospinal fluid biomarkers: Decreased Aβ42, increased tau, pTau-181, and NfL have been reported in iCAA⁵⁾⁸⁾

Differential Diagnosis

It is necessary to differentiate from other causes of intracerebral hemorrhage.

Hemorrhagic tumor, cerebral arteriovenous malformation (AVM), trauma
Hemorrhagic stroke, hypertensive hemorrhagic microangiopathy
Neurocysticercosis

5. Standard Treatment

A curative treatment for CAA has not been established at present ³⁾. Treatment mainly involves managing complications and preventing recurrence.

Blood Pressure Management

Blood pressure control is most important in preventing CAA-related bleeding. The target blood pressure is less than 130/80 mmHg ⁷⁾.

Dilemma of Antithrombotic Therapy

In patients with CAA, both antiplatelet and anticoagulant drugs may increase the risk of recurrent bleeding. In cases with atrial fibrillation (AF), balancing stroke prevention and bleeding risk poses a major therapeutic dilemma ⁷⁾.

Stollberger et al. (2023) reported an 83-year-old man with AF, CAA, and ICH who was managed with blood pressure control alone without antiplatelet drugs, anticoagulants, or left atrial appendage closure, and remained free of bleeding and ischemic events for 27 months. In the Rochester study, among 35 patients with AF, CAA, and ICH, only 1 ischemic stroke occurred during 2.7 years of follow-up in 25 patients not using antithrombotic drugs ⁷⁾.

Left atrial appendage closure (LAAC) is considered as an alternative in patients with AF, but it should be noted that post-procedural antiplatelet therapy is required, there is a risk of heart failure due to left atrial dysfunction, and evidence is limited ⁷⁾.

The role of statin therapy is also debated. Theoretically, it has been suggested that it may increase the risk of recurrent bleeding in CAA.

Surgical Treatment

In the absence of significant mass effect, surgical removal of intracerebral hemorrhage has not been shown to improve survival.

In CAA-ri/ABRA, steroids may be effective in some cases²⁾³⁾⁵⁾.

Acute phase: Methylprednisolone intravenous 1 g/day for 5 days²⁾⁵⁾
Maintenance therapy: Prednisolone oral 60 mg/day, tapered by 5 mg/week⁵⁾
In some cases, response to steroids is insufficient, or recurrence has been reported³⁾

Others

Follow-up of cognitive function and rehabilitation are important in long-term management ³⁾. Antiepileptic drugs are used for epileptic seizures.

Q Is there an effective drug treatment for cerebral amyloid angiopathy?

There is no curative drug. Blood pressure control is most important and helps reduce the risk of bleeding. Steroids may be effective for CAA-related inflammation (CAA-ri/ABRA). Research on anti-Aβ antibody drugs is ongoing, but monitoring for side effects such as ARIA is necessary.

6. Pathophysiology and detailed pathogenesis

The pathology of CAA results from abnormal production and impaired clearance of Aβ derived from APP. When Aβ accumulates in the walls of small and medium-sized cerebral blood vessels, normal vascular structure is damaged, leading to the following pathologies.

Hemorrhagic complications

Aβ deposition in the vessel wall induces fibrinoid necrosis, leading to weakening and rupture of the arterial wall ³⁾. This is the main mechanism of lobar hemorrhage. Fusiform arterial dilation and amyloid-induced disruption of the arterial wall cause lobar hemorrhage.

Ischemic complications

Progressive occlusion of the arterial lumen and microvascular occlusion due to Aβ deposition cause cortical microinfarcts, white matter ischemia, and leukoencephalopathy ²⁾³⁾.

The mechanism of CAA-ri/ABRA is not fully understood, but it is thought to involve an autoimmune reaction against Aβ deposited in the vessel wall ³⁾⁵⁾. There have been reports of anti-Aβ autoantibodies detected in cerebrospinal fluid ³⁾. ABRA is characterized by granulomatous inflammation with multinucleated giant cells that phagocytose amyloid in the vessel wall ³⁾.

Prion-like propagation of iatrogenic CAA

In iCAA, it is hypothesized that Aβ transmitted through medical procedures acts as a “seed” and causes prion-like chain accumulation ⁴⁾⁸⁾. The incubation period is approximately 30–40 years, and transmission via Lyodura has been most frequently reported. Inflammatory findings on imaging were observed in 27.4% of iCAA patients, indicating that inflammation can also occur in iCAA ⁵⁾.

Mechanism of ARIA due to anti-Aβ antibodies

During Aβ clearance by anti-Aβ monoclonal antibodies (e.g., lecanemab), the integrity of the blood vessel wall is further compromised, leading to vasogenic edema (ARIA-E) and microhemorrhages (ARIA-H)⁶⁾. Immune-mediated inflammatory reactions are also thought to be involved.

Effects on the retina

The retina is embryologically part of the brain, and the blood-retinal barrier has a structure similar to the blood-brain barrier. Deposition of Aβ in the vessel walls affects blood supply to the retina, and thinning of the RNFL detected by OCT has been reported.

7. Latest research and future perspectives (reports at the research stage)

Evolution of Diagnostic Criteria

Schroeder et al. (2023) reported that the Boston criteria v2.0, by incorporating emerging MRI markers such as enlarged perivascular spaces in the centrum semiovale and multispot white matter hyperintensities, enable more sensitive diagnosis than the previous criteria¹⁾.

Complement C3 has emerged as a candidate biomarker for CAA (AUCROC 0.68), but validation in large cohorts including dementia patients is needed in the future¹⁾.

Growing Recognition of Iatrogenic CAA

Panteleinenko et al. (2024) reported iatrogenic CAA in five elderly patients aged 65 years or older, showing that iCAA can occur in a wider age range than previously thought. All patients had a history of neurosurgery, with a latency period of 30–39 years⁴⁾.

The importance of checking past medical procedure history (especially possible use of cadaveric dura mater) in all CAA patients, regardless of age, is emphasized⁴⁾.

Treatment Potential of CAA-ri in iCAA

Panteleinenko et al. (2025) reported the first detailed clinical case of CAA-ri (CAA-related inflammation) complicating iCAA. A 49-year-old woman received steroid therapy (methylprednisolone 1 g/day for 5 days, then prednisolone 60 mg tapering), and vasogenic edema and leptomeningeal enhancement resolved within 2 months⁵⁾.

This report suggests that steroid therapy may be considered in a wide range of CAA subtypes, including not only sporadic CAA but also iatrogenic and hereditary forms.

Anti-Aβ antibody therapy and ARIA

Wang et al. (2025) reported two cases who developed ARIA-E (edema) and ARIA-H (microhemorrhage) during lecanemab treatment. Pre-existing CAA and ApoE ε4 carriers are major risk factors, and lecanemab is contraindicated when the number of pretreatment microhemorrhages exceeds four ⁶⁾.

Clinical application of CSF biomarkers

Cepin et al. (2025) reported a 42-year-old iCAA case with decreased CSF Aβ42 (353 ng/L), elevated tau (1,534 ng/L), and markedly elevated NfL (21,360 ng/L), demonstrating the diagnostic value of CSF biomarkers when angiography shows no abnormalities ⁸⁾.

Early screening with OCT

The retina is susceptible to Aβ deposition, and RNFL thinning on OCT is being studied as an early indicator of CAA. Its advantages include being noninvasive and repeatable, but further research is needed to establish diagnostic specificity for CAA.

8. References

Schroeder BE, Robertson NP, Hughes TAT. Cerebral amyloid angiopathy: an update. J Neurol. 2023;270:2809-2811.
Maramattom BV. Cerebral Amyloid Angiopathy with Lobar Haemorrhages and CAA-Related Inflammation in an Indian Family. Cerebrovasc Dis Extra. 2022;12:23-27.
Reisz Z, Troakes C, Sztriha LK, Bodi I. Fatal thrombolysis-related intracerebral haemorrhage associated with amyloid-beta-related angiitis in a middle-aged patient. BMC Neurol. 2022;22:500.
Panteleienko L, Mallon D, Oliver R, et al. Iatrogenic cerebral amyloid angiopathy in older adults. Eur J Neurol. 2024;31:e16278.
Panteleienko L, Mallon D, Htet CMM, et al. Cerebral Amyloid Angiopathy-Related Inflammation in Iatrogenic Cerebral Amyloid Angiopathy. Eur J Neurol. 2025;32:e70198.
Wang Y, Yu Q, Chen B, et al. Two cases of Amyloid-Related Imaging Abnormalities (ARIA) following lecanemab treatment for Alzheimer’s disease and a literature review. BMC Neurol. 2025;25:281.
Stollberger C, Finsterer J, Schneider B. Stroke prevention in an octogenarian with atrial fibrillation, cerebral amyloid angiopathy and intracerebral hemorrhage. Clin Case Rep. 2023;11:e7630.
Cepin U, Straus L, Zupan M, et al. Atypical presentation of cerebral amyloid angiopathy in a 42-year-old man with recurrent lobar hemorrhages and neuropsychiatric symptoms. Surg Neurol Int. 2025;16:554.

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