A Case of Severe Cerebral Amyloid Angiopathy-Related Inflammation in a 81-Year-Old Woman with Rapid Cognitive Decline

Abstract

Introduction

Cerebral amyloid angiopathy (CAA) is a vasculopathy characterized by amyloid-beta (Aβ) deposition in the walls of the leptomeningeal and cortical blood vessels. In a minority of patients with CAA, the presence of Aβ deposition triggers an autoimmune inflammatory reaction, referred to as CAA-related inflammation (CAA-ri). It can present in two forms, either as perivascular CAA-ri or as Aβ-related angiitis. The mechanism underlying CAA-ri remains unclear. Symptoms are subacute mental disorders and behavioral or cognitive changes, headaches, seizures, and focal neurological deficits. Most commonly, CAA-ri is a monophasic illness. Relapses occur often years after the initial presentation and are correlated with corticosteroid tapering or immunosuppression cessation. Treatment is often prolonged but effective. We present a rare and instructive case with CAA-ri characterized by rapid cognitive decline, therapy resistance, and fatal outcome and discuss current literature.

Case Presentation

We describe a case of an 81-year-old female who presented with progressive confusion, behavior alterations, recurrent falls, and vomiting for 2 weeks. There was a rapid cognitive decline and fatal outcome. The diagnosis of a probable CAA-ri was made based on the clinical presentation and brain MR imaging. To allow long-term corticosteroid replacement, azathioprine was initiated for second-line immunosuppression.

Conclusion

This case report of CAA-ri describes the diagnostic and therapeutic challenges in an elderly patient with rapid cognitive decline. It highlights the severe nature of the condition, the limitations of available treatments, and the importance of early recognition based on the diagnostic criteria and MR imaging and the start of the therapy, while acknowledging that outcomes may remain poor despite intervention.

Introduction

Cerebral amyloid angiopathy (CAA) is a vasculopathy characterized by amyloid-beta (Aβ) deposition in the walls of the leptomeningeal and cortical blood vessels [1–3]. In a minority of patients with CAA, the presence of Aβ deposition triggers an autoimmune inflammatory reaction, referred to as CAA-related inflammation (CAA-ri) [4]. It leads to local blood-brain barrier leakage and vessel rupture and is associated with increased concentrations of autoantibodies in the cerebrospinal fluid (CSF) targeting the Aβ protein [5, 6]. It can present in two forms, either as perivascular CAA-ri or as Aβ-related angiitis [2]. The mechanism underlying CAA-ri remains unclear [3]. There are three current hypotheses: (1) coexistence of vascular Aβ and vascular inflammation implies that Aβ is a bystander of angiitis; (2) inflammation promotes accumulation of Aβ in the vessel wall; (3) Aβ deposition triggers the inflammatory response. The immune response is also involved in the clearance of vascular Aβ from the brain [5]. Currently, most evidence favors the hypothesis that inflammation is triggered by an autoimmune response to the deposited Aβ protein [3]. Symptoms are subacute mental disorders and behavioral or cognitive changes, headaches, seizures, and focal neurological deficits. Dizziness, nausea, and vomiting may occur, but general constitutional symptoms are not prominent and are often absent [2].

Most commonly, CAA-ri is a monophasic illness [1]. Relapses are possible but occur most often 2–7 years after the initial presentation with white matter vasogenic edema and/or infarcts colocalizing with cerebral microbleeds in locations distinct from those associated with the initial presentation and were often correlated with corticosteroid tapering or immunosuppression cessation. Treatment is often prolonged but effective.

We present a rare and instructive case with CAA-ri characterized by rapid cognitive decline, therapy resistance, and fatal outcome and discuss current literature. This case report adheres to the CARE guidelines for case reporting, and the CARE Checklist is included as supplementary material (for all online suppl. material, see https://doi.org/10.1159/000550075).

Case Report

An 81-year-old female, diagnosed with Alzheimer dementia in 2022 but still living at home, presented 1 year later at the emergency department with progressive confusion, behavior alterations, recurrent falls, and vomiting for 2 weeks. At presentation, body temperature was 37°C. Clinical examination showed a slight neck stiffness, hypertonic lower extremities, and a left-sided hyperreflexia with extensor plantar reflex. Serum blood tests showed no elevated infection parameters or Borrelia species antibodies. Anti-Aβ autoantibodies were not tested in serum and CSF. CSF analysis showed no pleocytosis (4 white blood cells/µL [<5]), normal glucose (70 mg/dL [40–70]) with increased protein (146 mg/dL [15–45]) and immunoglobulin G (14.6 mg/dL [<5.5]). Oligoclonal bands, Borrelia species antibodies, and neuronal (anti-Hu [ANNA-1], anti-Yo [PCA-1], anti-Ri [ANNA-2], anti-CV2, anti-PNMA2 [Ma2/Ta], anti-amphiphysin) on CSF were absent. A thoracic and abdominal CT scan and dermatologic examination were performed to rule out an underlying primary tumor. Serum tumor markers (CEA, CA 15.3, CA 125, alpha-fetoprotein, and NSE) and neuronal antibodies were negative.

The diagnosis of a probable CAA-ri was made based on brain MR imaging and became clearer during hospitalization. Brain MR imaging was performed on day 1, with additional susceptibility-weighted imaging sequences on day 2 and control on day 10 (shown in Fig. 1). The probable diagnosis of CAA-ri could be made based on the criteria published by Auriel et al. [7] as the MRI showed asymmetric hyperintense abnormal subcortical and leptomeningeal contrast enhancement [1, 2, 7] (shown in Table 1). There were also (scattered) foci of diffusion restriction on diffusion-weighted imaging. The brain biopsy, obtained from the right frontal leptomeninges by stereotactic needle biopsy under navigation, was subject to sampling error and showed only dense, cell-poor connective tissue with some bone fragments. No sign of vasculitis, inflammation, infection of neoplastic pathology was detected.

Fig. 1.

MR imaging of severe cerebral amyloid angiopathy-related inflammation (CAA-ri) in a 81-year-old woman with rapid cognitive decline on day 1–2 (a–d) and 10 (e–h). a Axial T1 weighted image: spontaneous hyperintense subcortical lesion in the right occipital lobe indicating a subacute lobar hemorrhage. b Axial T2 weighted image: central hyperintense lesion with peripheral hemosiderin rim in the right anterior cranial fossa, suggestive for chronic lobar hemorrhage. c, d Axial susceptibility-weighted imaging (SWI) imaging: gyriform hypointense appearance of different cortical areas (superficial siderosis) and diffuse peripheral asymmetric hemosiderin depositions (microbleeds). e, f 3D axial T1 MPRAGE: diffuse reticular to reticulonodular pathological leptomeningeal contrast enhancement in the cerebral regions (predominantly involving the right frontoparietal lobe) and in the cerebellar regions. g Fluid-attenuated inversion recovery (FLAIR): asymmetric subcortical white matter hyperintense zones (cerebral vasogenic edema) in the right frontoparietal and left frontal region. h Diffusion-weighted imaging (DWI): acute foci of diffusion restriction in both cerebellar hemispheres.

Table 1.

Clinicoradiological criteria for the diagnosis of cerebral amyloid angiopathy-related inflammation (CAA-ri)

Diagnosis	Criteria
Possible CAA-ri	Criteria published in JAMA Neurology in 2016 Age ≥40 years Presence of ≥1 of the following clinical features: headache, decrease in consciousness, behavioral change, or focal neurological signs and seizures; the presentation is not directly attributable to an acute ICH MRI shows WMH lesions that extend to the immediately subcortical white matter Presence of ≥1 of the following corticosubcortical haemorrhagic lesions: cerebral macrobleed, cerebral microbleed, or cortical superficial siderosis Absence of neoplastic, infectious, or other cause
Probable CAA-ri	Criteria published in JAMA Neurology in 2016 Age ≥40 years Presence of ≥1 of the following clinical features: headache, decrease in consciousness, behavioral change, or focal neurological signs and seizures; the presentation is not directly attributable to an acute ICH MRI shows unifocal or multifocal WMH lesions (corticosubcortical or deep) that are asymmetric and extend to the immediately subcortical white matter; the asymmetry is not due to past ICH Presence of ≥1 of the following corticosubcortical haemorrhagic lesions: cerebral macrobleed, cerebral microbleed, or cortical superficial siderosis Absence of neoplastic, infectious, or other cause

Adapted from Auriel et al. [7].

At the emergency department, empiric triple therapy was started (ceftriaxone, ampicillin, and aciclovir), associated with intravenous methylprednisolone 1 gram daily. As CSF cultures (aerobic, anaerobic, yeasts, fungi, and mycobacteria) and the PCR meningitis panel (Escherichia coli, Haemophilus influenza, Listeria monocytogenes, Neisseria meningitidis, Streptococcus agalactiae, S. pneumoniae, Cryptococcus neoformans/gattii, VZV, HSV-1/2/6, CMV, enteroviruses, and parechoviruses) remained negative, the triple therapy was stopped after 5 days. Methylprednisolone was switched to an oral regimen of 64 mg once a day on day 8. MRI on day 10 showed no improvement; on the contrary, diffusion-weighted imaging showed more pronounced lesions (Fig. 1).

After an initial period of rapid progression, the patient stabilized, exhibiting only intermittent confusion under corticosteroid therapy. Methylprednisolone was gradually tapered by 8 mg every 3 weeks. Azathioprine, at a dose of 1 mg/kg, was initiated as second-line immunosuppression to allow long-term corticosteroid replacement. The patient was discharged to a nursing home. Unfortunately, the patient died 3 weeks following hospital discharge, for reasons that remain unknown. No informed consent for autopsy could be obtained. Consequently, a follow-up brain MRI after initiation of second-line immunosuppressants could not be performed. Genetic analysis showed no presence of apolipoprotein E (ApoE) ε4 nor ε2.

Discussion

Diagnosis

CAA-ri is rare but now increasingly recognized and diagnosed in a spectrum of different neurologic and neuroradiological manifestations, although it was thought to be restricted only to patients with CAA [3, 6]. Patients can present with atypical symptoms which may lead to an incorrect diagnosis [3]. Some cases present with involuntary movement, systemic diseases, cerebral hernia caused by severe edema, uveitis, multiple malignancies, extracranial vasculitis, or vascular dysplasia at baseline. Further research is needed to clarify whether the etiology of these comorbidities, such as autoimmunity, or their treatment, such as radiation therapy, is related to CAA-ri. Due to these atypical symptoms, advanced imaging is an important tool in the diagnostic process. The age and symptoms of our patient were quite characteristic for CAA-ri. It is important to also consider CAA-ri in case of rapid decline in cognitive and neurological functions, despite it usually having a slow course [1, 8].

The clinical-radiological criteria for CAA-ri were updated by Auriel et al. [7] in 2016 as white matter hyperintensity patterns were defined, specifically for distinguishing between probable and possible CAA-ri [3, 7]. Based on these criteria, the diagnosis of probable CAA-ri could be made in our patient [7]. The volume of white matter hyperintensities correlates with the severity of clinical symptoms and can probably be used as a measure of treatment success [2]. This case demonstrates the importance of extensive MR imaging, including T1 + Gd, T2/fluid-attenuated inversion recovery, and susceptibility-weighted imaging, to obtain the diagnosis of CAA-ri [1–3, 9].

Serum and CSF findings are not included in the Auriel criteria for the diagnosis of CAA-ri [7]. Inflammatory serum markers are elevated in less than half of the cases of CAA-ri [2]. CSF is abnormal in the majority of patients and may show mild-to-moderate increased protein, and in some cases, a lymphocytic pleocytosis, the latter not being present in our patient. As expected, no oligoclonal bands were detected in our case [1, 3]. Anti-Aβ autoantibodies in serum or CSF were not tested in our case, but they can be used as a biomarker for both diagnosis and monitoring the effect of the treatment [3]. Infectious, autoimmune, and neoplastic causes were excluded.

Although brain biopsy is considered the gold standard for definite diagnosis [2, 3, 8], it is invasive and is prone to sampling error, as was the case in our patient, and thus, the diagnosis of possible or probable CAA-ri is mostly based on clinical and radiological features [2, 3]. However, in selected cases, e.g., non-responders to first-line immunosuppression, biopsy should be considered [2]. The diagnosis was not anatomo-pathologically confirmed.

Therapy

Our patient was treated with high-dose intravenous glucocorticoids followed by oral methylprednisolone to reduce inflammation, which should reverse the acute clinical deficits and radiological findings of vasogenic edema [2]. Despite the rapid deterioration, second-line immunosuppressive therapy was associated as the patient showed stabilization under oral methylprednisolone.

There are no evidence-based recommendations on the choice of medication, dosage, and duration of treatment [3, 10]. Generally, an initial corticosteroid therapy is started, and then slow oral tapering is recommended to prevent the development of recurrences and to ensure clinical stabilization [10]. We can benefit from trials with alternative immunosuppressants, including cyclophosphamide, mycophenolate mofetil, methotrexate, rituximab, and intravenous immunoglobulin [1–3]. Outcomes and responses to immunosuppressive therapy for CAA-ri are poorly understood, but a study showed that early administration may improve the initial disease course and reduce the likelihood of recurrence [11, 12]. Most patients respond well to immunotherapy, but some patients have a poor response or relapse [8, 12]. Future research should focus on gaining a clearer understanding of the immune system’s dynamic role throughout the different stages of CAA pathology as this may help identify new specific immunosuppressive targets [5]. In the near future, rational decision criteria for the choice of more aggressive immunosuppressive regimens in the initial as well as follow-up therapy of CAA-ri need to be defined, which might consider patient characteristics as well as clinical, radiological, and CSF findings [10]. Further studies should also answer the question of whether intensification of immunosuppression only in case of clinical and radiological deterioration or a direct start with highly potent immunosuppressive therapy represents the right way in the long-term therapy of CAA-ri.

Prognosis

Our patient did not carry an ApoE ε4 nor ε2 allele. ApoE ε4 carriers present with more severe symptoms [8]. The ApoE ε2 genotype is associated with risks of perivascular and spontaneous intracerebral haemorrhages [1]. Early diagnosis and prompt, aggressive treatment may improve prognosis as the mortality rate of CAA-ri is not negligible [1, 3]. Delayed treatment, a lack of CSF pleocytosis or leptomeningeal enhancement, and cognitive dysfunction were identified as negative prognostic factors [1]. Further research focusing on identifying prognostic factors for CAA-ri can help in more frequent detection and determine optimal treatment strategies [3, 9].

Conclusions

This case report of CAA-ri describes the diagnostic and therapeutic challenges in an elderly patient with rapid cognitive decline. Despite characteristic MR findings and initiation of immunosuppressive therapy, the disease progressed and the patient passed away. This highlights the severe nature of CAA-ri, the limitations of available treatments, and the importance of early recognition and the start of therapy, while acknowledging that outcomes may remain poor despite intervention.

Statement of Ethics

No supplementary interventions have been performed other than the indicated diagnostic interventions. Ethical approval is not required for this case report in accordance with local or national guidelines. Written informed consent was obtained from the patient’s next of kin for publication of the details of their medical case and any accompanying images.

Conflict of Interest Statement

The authors have no conflicts of interest to declare.

Funding Sources

This case report was not supported by any sponsor or funder.

Author Contributions

Eline De la Meilleure is the first author, who has written the article. Harald De Cauwer critically reviewed the article. Dieter Vanneste provided the MR imaging and critically reviewed the radiologic part. Caroline M.J. Loos critically reviewed the article and was involved in the management of the patient.

Funding Statement

This case report was not supported by any sponsor or funder.

Data Availability Statement

The data that support the findings of this case report are not publicly available due to privacy reasons but are available from the digital medical file in the regional Hospital St-Dimpna, Geel, Belgium, and Antwerp University Hospital (UZA), Belgium, upon reasonable request.