Biopsy-Proven Amyloid-Beta Related Angiitis with Unusual Presentation and Long-Term Follow-Up

Abstract

Amyloid-beta related angiitis (ABRA) is a rare central nervous system inflammatory and vasculitic process. It is seen in patients with cerebral amyloid angiopathy (CAA) and thought to be mediated by an autoimmune reaction against cerebrovascular β-amyloid. We describe the case of a patient with ABRA with clinical information and brain imaging over a 10-year period. The patient was hospitalized in 2018 for altered mental status, paranoia and hallucinations. Her symptoms started in 2009 with an episode of vertigo and loss of consciousness. From 2011-2019, she had multiple episodes of transient focal neurological deficits with overall cumulative progressive decline in cognition and functional status. Retrospective and comparative reviews of brain magnetic resonance imaging (MRI) from 2009-2019 showed waxing and waning vasogenic cerebral edema with overall progression of white matter hyperintensities and peripheral micro-hemorrhages consistent with inflammatory CAA. Re-examination of a brain biopsy from 2009 showed ABRA, and immunostaining was positive for β-amyloid. She was treated with intravenous steroids with minimal symptomatic improvement. She was lost to our follow-up after hospital discharge. We describe the temporal progression of ABRA through serial brain imaging over a 10-year period. To our knowledge, this is the longest published follow-up duration of ABRA. The patient in our case had severe cognitive impairment and disability despite treatment with steroids.

Introduction

Cerebral amyloid angiopathy (CAA) is characterized by deposition of amyloid-beta (Aβ) in the media and adventitia of cortical and leptomeningeal vessels and formation of amyloid plaques.^1-4 The amyloid-laden blood vessels can be associated with vascular inflammation (termed inflammatory CAA), of which 2 patterns are recognized.^5-7 Amyloid-beta related angiitis (ABRA) is characterized by granulomatous inflammation with angiodestruction of blood vessels with Aβ in the vessel wall. ⁸ The pathological hallmark of CAA-related inflammation (CAA-RI) is the presence of lymphocytic perivascular inflammatory infiltrate with absence of granuloma formation and angiodestruction. ⁴ The first case of ABRA was described in a Down syndrome patient in 1974 with the pathological features described above. ⁹ Since then, many cases have been reported but this continues to be a rare disease. ¹⁰ We present a patient with the temporal clinical and imaging progression of ABRA on serial brain MRI over a time course of 10years. To our knowledge, this is the longest-known follow-up of ABRA in the literature.

Case Presentation

A 65-year-old woman presented to a hospital in 2009 for a described episode of vertigo and loss of consciousness. Brain MRI performed for further evaluation showed left temporal lobe contrast enhancement suspicious for neoplasm (Figure 1). At that time, a biopsy was performed which revealed a multifocal granulomatous process affecting small caliber blood vessels with Periodic Acid-Schiff (PAS) stain. Fungal molecular analysis was performed on the biopsy material due to presence of granulomas, but no fungal DNA was detected. No definitive diagnosis was made. In 2010, she was diagnosed with rheumatoid arthritis (RA) and immunosuppressive therapy with adalimumab and methotrexate was started. Unfortunately, records from outside hospital were limited and did not indicate how the diagnosis of RA was made or the rationale for starting immunosuppressive treatment. In 2015, she presented to a hospital for progressive gait imbalance and cognitive decline. MRI brain at that time showed confluent white matter changes on T2 and Fluid-Attenuation Inversion Recovery (FLAIR) sequences. Progressive multifocal leukoencephalopathy (PML) was suspected as the patient was on adalimumab, but her cerebrospinal fluid (CSF) PCR was negative for JC virus. Her memory continued to decline and she relied on her husband for assistance with several activities of daily living. In 2017, she experienced progressive leg weakness, gait imbalance and worsening falls. Brain MRI at that time showed subcortical and periventricular white matter T2 signal abnormalities. Her symptoms were attributed to vascular Parkinsonism.

Figure 1.

Brain MRI from 2009 showing left temporal lobe contrast enhancement on T1 with gadolinium contrast (A), with corresponding increased signal on T2 FLAIR (B).

She was admitted to our hospital in October 2018, for worsening confusion, paranoia, agitation, and hallucinations. Brain MRI at that time showed bilateral cerebral hemisphere white matter changes, diffuse microhemorrhages, and leptomeningeal enhancement suggestive of inflammatory CAA. CSF analysis showed elevated protein (82mg/dl), elevated IgG synthesis rate (40.5mg/day), elevated CSF index (.98), normal white cell count (2/cmm) and negative JC virus DNA (quantitative and qualitative methods).

Brain MRI studies from outside hospitals done during the period of 2009-2019 were obtained and reviewed. Images were compared, though the reason for each individual scan was unique: vertigo with loss of consciousness (2009), progressive gait imbalance with cognitive decline (2015), bilateral lower limb weakness with gait instability (2017), altered mental status with abnormal head CT with possible intracranial hemorrhage (2018), and altered mental status (2019) (Figure 2). The serial scans documented T2 FLAIR abnormalities associated with waxing and waning vasogenic edema and overall disease progression. T2 FLAIR sequence on brain MRI from 2019 showed mild improvement in posterior vasogenic edema compared to the prior scan, possibly secondary to treatment with steroids at that time. T2* Gradient Recalled Echo (GRE) images showed progressively cumulative peripheral microhemorrhages. No acute infarcts were seen on serial MRI scans. Tissue material obtained from the brain biopsy done in 2009 was retrieved and reviewed at our institution (RDM). Additional staining for amyloid deposition was performed, including Congo red, thioflavin T, and immunostaining for beta-amyloid 1-42 (Abcam, mOC64, rabbit monoclonal antibody ab271968), which was not done on the original biopsy in 2009. Amyloid angiopathy with mural inflammation, giant cell formation, and vascular wall damage were identified, suggestive of ABRA (Figure 3).

Figure 2.

Imaging findings: (A) T2 FLAIR shows waxing and waning vasogenic edema with overall progression from 2009 to 2019. The T2 FLAIR on brain MRI from 2019 showed mild improvement in posterior vasogenic edema, possibly secondary to treatment with steroids at that time. (B) T2* Gradient Recalled Echo (GRE) shows progressive increase in peripheral microhemorrhages from 2012 through 2019.

Figure 3.

Pathology findings: (A) and (B) show amyloid deposition in vessel wall with Congo Red stain. (C) shows amyloid deposition in vessel wall with Thioflavin-T stain. (D) shows amyloid deposition in vessel wall with β-amyloid immunostain. (E) shows amyloid plaques in cerebral cortex with β-amyloid immunostain. (F) shows vascular wall damage and vasculitic inflammation with granuloma formation consisting of multi-nucleated giant cells and lymphocytes with Congo Red stain.

The patient was treated with IV steroids leading to improvement in agitation, paranoia, and hallucinations. However, she remained severely demented. She refused further imaging and was subsequently lost to follow-up after hospital discharge. The timeline of the events is illustrated in figure 4.

Figure 4.

Timeline of events from 2009-2019.

Discussion

ABRA is a rare form of central nervous system (CNS) vasculitis. It is 1 of the subtypes of inflammatory CAA and is distinct from primary CNS angiitis. The characteristic angiodestruction, vascular and perivascular inflammatory infiltrate, and granuloma formation described in ABRA are limited to the blood vessels with Aβ deposition. ⁸ The association with RA in our patient that was treated with adalimumab and methotrexate adds a new element of interest. Although these are immuosuppressive medications, they are not typically used in the treatment of inflammatory CAA and evidence of efficacy in this disorder is lacking.^11,12 Discussion of alternative immunosuppressive treatment was planned based on clinical response, but the patient was lost to follow up. Since the patient was on immunosuppressive medication, PML featured in the differential diagnosis based on the imaging characteristics. In PML, however, CSF studies are usually positive for JC virus DNA which was negative in our patient, and the brain MRI GRE sequences do not show microhemorrhages which are typical in ABRA. ¹³

Clinically, ABRA can present with variable neurological symptoms including altered mental status, headaches, focal neurological deficits, seizures and cognitive decline.^6,8,11,14,15 Neuropsychiatric symptoms including delusions, hallucinations and psychosis have also been described. ⁸ Patients often respond to immunosuppressive treatment, though relapses are possible. ¹⁶

Diagnosis is made using a multi-modal approach including CSF analysis, imaging, and brain biopsy. CSF analysis may show markers of active inflammation such as elevated protein, IgG synthesis rate, and CSF index, but these findings are non-specific and may not be present in every case. ⁸ Interestingly, the elevated IgG synthesis rate seen in our patient was reported once in the literature. ¹⁷ Piazza and colleagues investigated the role of anti-Aβ autoantibodies in the acute and remission phases of CAA-RI. ¹⁸ They found that anti-Aβ autoantibodies were increased during the acute phase of CAA-RI and directly correlated with Aβ mobilization. The autoantibodies returned to control levels following clinical and radiological remission and the soluble Aβ decreased in parallel. They suggested that the pathogenesis of CAA-RI may be mediated by a selective autoimmune reaction against cerebrovascular Aβ, directly related to autoantibody concentration and soluble Aβ. ¹⁸

Brain MRI is a non-invasive technique that can aid in diagnosis of ABRA.^5,8,11,16 The findings typically include cortical and subcortical hyperintense lesions on T2-weighted sequences. These lesions can be unifocal or multifocal and are usually asymmetric.^14-16 Leptomeningeal or parencyhmal enhancement can also be seen. The presence of leptomeningeal enhancement can be used to differentiate ABRA from CAA without inflammation with moderate sensitivity and high specificity.^14,16 Additionally, brain MRI typically shows corticosubcortical hemorrhagic lesions in the form of cerebral macrobleeds, microbleeds, or cortical superficial siderosis on GRE or susceptibility weighted (SWI) sequences.^14-16 The initial brain MRIs of our patient did not have GRE or SWI sequences which may have delayed the diagnosis. The presence of peripheral cortico-subcortical microbleeds with T2-hyperintense lesions is highly suggestive of inflammatory CAA and hence, it is important to include GRE/SWI sequences in the imaging protocol for elderly patients with infiltrative lesions on MRI brain.

The gold standard for diagnosing ABRA is tissue biopsy that demonstrates angiodestruction and granulomatous reaction in blood vessels with amyloid deposition.^5,8,9,19-21 The presence of angiodestruction helps differentiate ABRA from CAA-RI that has perivascular inflammation without angiodestruction. Amyloid can be seen with the help of special stains like Congo Red and immunostaining can help determine the amyloid type. ²² Amyloid staining was not performed on the initial biopsy, contributing to the delayed diagnosis. More recent clinical and radiographic criteria have been proposed to make a diagnosis of inflammatory CAA without reliance on biopsy. Although biopsy is still required for definitive diagnosis, patients can be categorized as possible or probable CAA-RI based on a combination of criteria including age, clinical features, MRI findings, presence of corticosubcortical hemorrhagic lesions, and exclusion of alternative causes.^14,15

Treatment is often targeted at the underlying inflammatory process, typically with use of steroids or other immunosuppressive agents such as cyclophosphamide, azathioprine, mycophenolate mofetil, or intravenous immunoglobulin.^5,6,11,12 Unfortunately, randomized trials are lacking given the rarity of the disease. A systematic review of inflammatory CAA in 2015 did not show a significant difference in functional outcomes between those treated with steroids as opposed to other immunosuppressive medications. Over half of the patients receiving treatment showed improvement. ²³ A study looking at a large series of patients with CAA-RI suggested that early treatment can improve the initial disease course and reduce the likelihood of recurrence. The authors raised the possibility that early blunting of the autoimmune response may have long-term benefits for the subsequent disease course. ¹² Another study suggested that following treatment, the disease can either improve, remain stable, relapse or progress. ⁶ Patients can have persistent mild, moderate or severe disability. ⁵ It is unclear how the use of immunosuppressant medications for RA impacted the overall disease course in our patient.

Conclusion

ABRA is a rare form of CNS vasculitis that is pathologically distinct from primary CNS vasculitis. We do not know whether treatment can delay or arrest the progression of the disease. This case, through serial brain imaging, demonstrates the progression of ABRA over the course of a decade. To our knowledge, this is the longest follow up for ABRA reported in the literature. ABRA is a potentially treatable cause of cognitive impairment and therefore, early recognition of this rare disease is important.

ORCID iD

Navnika Gupta https://orcid.org/0000-0001-8044-7539