A 68-year-old female presented with subacute step-wise cognitive decline and behavioral abnormalities for the previous eight months. She was diagnosed with chronic nephritis 30 years ago and with hypertension and chronic renal failure 1 year prior to the current presentation. The family history was unremarkable. Head computed tomography (CT) plain scan conducted at another hospital after current symptom onset revealed multiple punctate high-density lesions and extensive low-density lesions in both cerebral hemispheres. Accompanying magnetic resonance imaging (MRI) showed extensive hyperintense lesions on both T2-weighted images (T2WI) and fluid-attenuated inversion recovery (FLAIR) images without gadolinium enhancement on T1-weighted images (T1WI). Brain susceptibility weighted imaging (SWI) was not conducted at that time. The patient is illiterate and scored 14/30 on the Mini-Mental State Examination (MMSE). The diagnosis was undetermined at that time and no specific therapies were given except for antihypertensive agents.
On admission at our institution, blood pressure was 143/102 mmHg. The patient was fully alert but disoriented and cognitive function tests revealed subacute cognitive decline, with MMSE score of 4/30, Montreal Cognitive Assessment (MoCA) score of 0/30, and Activities of Daily Living (ADL) scale score of 44/64. Results of cranial nerve and sensory examinations were negative, and motor examination revealed positive palmomental reflex bilaterally without weakness or dystonia of limbs.
Routine blood tests revealed low hemoglobin (97 g/L) and free triiodothyronine (2.97 pmol/L), and elevated urea nitrogen (10.52 mmol/L), creatinine (221.83 μmol/L), uric acid (371.12 μmol/L), brain natriuretic peptide (2131.00 pg/mL), homocysteine (26.46 μmol/L), erythrocyte sedimentation rate (ESR) (120 mm/h), and C-reactive protein (CRP) (28.35 mg/L). The titers of thyroglobulin antibody (TGAb) (> 500.00 U/ml) and thyroid peroxidase antibody (TPOAb) (197.90 U/ml) were elevated, as was CD19+ B-cell fraction among PBMCs (16.26%). Serum anti-Ro-52 was positive, while all other serum autoantibody tests were negative (including anti-nuclear, anti-Sjogren syndrome antigen A and antigen B, cytoplasmic antineutrophil, and anticardiolipin antibodies). Serum anti-human immunodeficiency virus antibodies and anti-Treponema pallidum antibodies were also negative. Serum cholesterol, triglyceride, coagulation function, tumor markers, folic acid, and vitamin B12 were within normal limits. Apolipoprotein E (APOE) genotype was ε4/ε4, indicating elevated CAA risk. Cerebrospinal fluid (CSF) analysis revealed elevated levels of total protein (80.00 mg/dL) and T-tau (583 pg/ml), low Aβ42 (486 pg/ml), normal nucleated cell count, and normal P-Tau (181p) (60.42 pg/ml). All TORCH panel assays were negative.
In accord with prior neuroimaging results, brain CT plain scans showed multiple punctiform hyperdensities in the bilateral lobes (Figure 1-A), and brain MRI scans showed extensive hypointense lesions on T1WI (Figure 1-B) and hyperintense lesions on T2WI (Figure 1-C) and FLAIR (Figure 1-D) images in bilateral cerebral hemispheres involving both grey and white matter. Diffusion-weighted imaging (DWI) results were unremarkable (Figure 1-E) but SWI scans revealed diffuse microbleeds mainly distributed in bilateral lobes and cerebellum (Figure 1-F). Head magnetic resonance angiography (MRA) revealed mild arteriosclerosis in bilateral internal carotid arteries and middle cerebral arteries. Carotid duplex ultrasound examination also revealed moderate stenoses (50%–70%) of the left carotid bulb and right subclavian artery.
After informed consent was obtained from the patient’s legal guardian, minimally invasive biopsy of affected white matter in the left occipitotemporal lobe was performed under stereotactic orientation. Hematoxylin and eosin staining of biopsy tissue revealed edema and glial cell proliferation, but no inflammatory infiltrations surrounding the blood vessels. No amyloid deposition in the vessel walls was found by Congo Red staining, under a polarizing microscope.
Based on these findings, the patient was diagnosed with probable CAA-related inflammation  and received intravenous methylprednisolone (IVMP) starting at 500 mg/d, followed by oral prednisone with slow tapering guided by monitoring of PBMC counts (Figure 2). Felodipine (10 mg/d), irbesartan (150 mg/d), and metoprolol (25 mg/d) were also administered for hypertension and blood pressure was controlled at about 140/90 mmHg. Folic acid was orally supplemented to lower serum homocysteine and atorvastatin (20 mg/d) to prevent arteriosclerosis. Cognitive symptoms started to improve on the third day of IVMP treatment at 500 mg/d as indicated by increased MMSE (7/30, compared to 4/30 at presentation), while MoCA remained 0/30 and ADL was lower than on presentation (34/64). Blood CRP level returned to normal and erythrocyte sedimentation rate dropped but was still elevated (80 mm/h) after the 5-day course of IVMP 500 mg/d (Figure 2). The patient was then treated with a 3-day course of IVMP 250 mg/d and a 3-day course of IVMP 120 mg/d, after which cognitive symptoms and daily living function improved, with MMSE increasing to 10/30, MoCA increasing to 6/30, and ADL decreasing to 26. Repeated MRI showed remarkable shrinkage of hyperintense lesions on FLAIR images (Figure 2). However, the CD19+ B-cell fraction among PBMCs was still markedly elevated at 45.33%. Oral prednisone 60 mg/d was then administered with tapering of 5 mg every three days.
When the dose of prednisone reached 30 mg daily, retests revealed normal ESR, while hemoglobin was slightly lower (95 g/L) and urea nitrogen (16.64 mmol/L), creatinine (279.31 μmol/L), uric acid (694.76 μmol/L), and homocysteine (38.87 μmol/L) slightly increased compared to measurements on admission. In addition, the MMSE and MoCA score continued to increase, reaching 14/30 and 9/30 respectively, and the ADL score further decreased to 20/64. Erythropoietin was then started at 4000 IU three times per week, and oral vitamins B12 and B6 were added to lower homocysteine level. The prednisone tapering interval was changed to 5 mg per week. When the dose reached 20 mg daily, CD19+ B-cell fraction among PBMCs was reduced to 30.75%, hemoglobin increased to 105 g/L, and levels of creatinine (247.07 μmol/L) and uric acid (681.55 μmol/L) slightly reduced. Repeated MRI scans showed further shrinkage of hyperintense lesions on T2WI images (Figure 2). Subsequently, the dose of prednisone was maintained at 20 mg daily.
After one month of 20 mg daily prednisone, the CD19+ B-cell fraction was normal (9.18%), hemoglobin was higher but still below normal (107 g/L), homocysteine (16.62 μmol/L) was normal, and both creatinine (294.85 μmol/L) and uric acid (709.46 μmol/L) were slightly higher compared to the previous measurement. There was further improvement in cognition as indicated by a MMSE of 20/30 and a MoCA of 13/30. Daily living function returned to normal, with the lowest score of 14/64 on ADL. Tapering of prednisone was then restarted at 5 mg every three days until reaching a maintenance does of 5 mg daily. Oral sodium bicarbonate was also administered to reduce uric acid. One month later, cognitive function was still stable, with a score of 22/30 on the MMSE and a score of MoCA of 13/30. Repeated MRI scans showed some residual hyperintensities in the deep white matter on FLAIR images (Figure 2). The CD19+ B-cell fraction among PBMCs was still in the normal range (10.53%). The dose of prednisone was then changed to 5 mg every other day for prevention of inflammation relapse. At one-year follow-up, the patient showed no signs of inflammation relapse or symptomatic intracerebral hemorrhage (ICH). The detailed clinical course as well as longitudinal changes in CD19+ B-cell and CD4+Th-cell fractions, cognition scale scores, and glucocorticoid therapy regimen are shown in Figure 2.