Amyloidosis is a heterogeneous group of protein misfolding disorders characterized by the deposition of insoluble β-pleated amyloid fibrils in organs/tissues.^{Reference Gertz and Dispenzieri1,Reference Soontrapa, Jones and Milone2} Amyloid deposition may be localized or systemic, with widespread organ involvement. In systemic amyloidosis, commonly affected organs include blood vessels (BVs), heart, kidney, nerves, liver, lungs and bowel.^{Reference Gertz and Dispenzieri1,Reference Soontrapa, Jones and Milone2} The central nervous system (CNS) is rarely involved, particularly in immunoglobulin light chain amyloidosis (AL), the most common form. Although there have been occasional reports of CNS AL amyloidosis, these typically present as localized amyloidomas without systemic involvement.^{Reference Schröder, Deckert and Linke3–Reference Bray, Rich, Ellis, Pradilla and Barrow7}

On the other hand, cerebral amyloid angiopathy (CAA) is most commonly caused by β-amyloid deposition and represents a localized process frequently associated with Alzheimer’s disease.^{Reference Schröder, Deckert and Linke3} While AL amyloidosis can involve CNS BVs,^{Reference Schröder, Deckert and Linke3–Reference Löhr, Kessler and Monoranu5} the distinction between β-amyloid CAA and AL amyloid vascular deposition lies in their underlying pathogenesis, resulting in clinical, radiologic and pathologic differences. Here, we present a unique case of AL amyloidosis manifesting as CAA with concomitant lung nodules.

The patient was a 52-year-old female who presented to the multiple sclerosis (MS) clinic with a two-year history of dizziness, light-headedness and left arm sensory loss. Her medical history included post-menopause, arthritis, dyslipidemia, hypertension, hypothyroidism, Raynaud syndrome and sciatica. On examination, she had left appendicular ataxia and hyperreflexia. Brain MRI revealed stable T2/fluid-attenuated inversion recovery white matter hyperintensities in the right cerebellum, bilateral occipital lobes and right posterior limb of internal capsule with extension into corona radiata and centrum semiovale (Figure 1A). Interestingly, these lesions exhibited irregular linear and stapled enhancement, and were associated with branching vessels (Figure 1B). Susceptibility weighted imaging demonstrated blooming artifacts (Figure 1C) that likely represented calcification deposits previously seen on CT head (Figure 1D). Nevertheless, given the branching vessels, the possibility of a congenital mixed venous malformation was entertained.

Figure 1.

Radiographic imaging of the brain and lung lesions. Axial T2/FLAIR MRI brain showing abnormal white matter hyperintensities (white arrows) in the right cerebellum, bilateral occipital lobes, and right corona radiata with extension into the posterior limb of internal capsule (A). Axial T1 post-gadolinium MRI brain demonstrating irregular linear and stapled enhancement (white arrows) of these lesions with associated branching vessels (red arrow) (B). Axial SWI MRI brain showing peri-lesional blooming artifacts (white arrows) (C). Axial CT head displaying calcifications (blue arrows) (D). Coronal CT Chest showing aright lower lobe nodule with calcifications (orange arrow) (E). SWI = susceptibility weighted imaging; FLAIR = fluid-attenuated inversion recovery.

Given the lesions’ atypical properties, a broad set of investigations was conducted to investigate autoimmune, infectious and neoplastic etiologies. A CT chest (Figure 1E) showed two right lower lobe nodules that were managed conservatively due to benign features, including stability over years, calcifications and lack of mediastinal lymphadenopathy. A core needle lung biopsy was performed and showed hyalinized acellular material with infrequent multinucleated giant cells and limited calcification. However, the biopsy was negative for malignancy or infectious agents. Serum analysis indicated positive ribonucleoprotein (RNP, 3.3), but she did not meet the criteria for CNS inflammatory or mixed connective tissue disease. All other serum and cerebrospinal fluid analyses were normal, including serum immunoglobulin light chains, Kappa and Lambda. Although multiple sclerosis was considered unlikely, visual evoked potentials demonstrated prolonged P100 latencies, raising the possibility of a demyelinating process.

The patient underwent two stereotactic intracranial biopsies. The first biopsy was performed two years after initial presentation and targeted the right cerebellar lesion. The biopsy was non-diagnostic. Due to the development of left-sided weakness, the second biopsy was performed three years later and targeted the left occipital lesion.

Histopathological examination of the occipital lesion demonstrated vasculopathic changes with prominent amyloid deposition within BV walls and perivascular areas (Figure 2A–E). The amyloid deposition was detected by positive Congo red staining with green birefringence under polarized light, and confirmed by electron microscopy identification of amyloid fibrils. Calcifying/calcified granules were also seen in BV walls (Figure 2F), which is in keeping with the CT and MRI findings (Figure 1C,D). Immunohistochemistry revealed limited beta-amyloid positivity, but strongly positive Lambda with weakly positive Kappa (Figure 2G–I), suggestive of Lambda predominance. The adjacent cerebral tissue exhibited variable astrocytic gliosis and inflammatory cell infiltrates, including scattered CD68-positive macrophages/microglia and CD3-positive T-cells (Figure 2J–L), without significant amyloid deposition. Subsequent proteomic analysis by mass spectrometry indicated amyloid deposition of lambda type. These pathologic findings are diagnostic of Lambda AL amyloidosis causing CAA. Re-examination of the prior lung biopsy showed amorphous material with limited inflammatory and epithelial cells (Figure 2M–O). The amorphous material was positive for Congo red staining and for Lambda immunostaining with weaker Kappa immunostaining, suggestive of Lambda predominance in lung AL amyloidosis.

Figure 2.

Amyloid deposition in the brain and lung. A biopsy of the left parietal lobe shows vasculopathic changes with variably thickened blood vessels and prominent deposition of amorphous eosinophilic material in the vessel walls and perivascular areas (A). Amorphous eosinophilic material is positive for Congo red staining (B) with green birefringence under polarized light (C). Electron microscopy reveals amyloid fibrils within the blood vessel wall (D, *) and perivascular areas (D, *, focally forming nodules). The blood vessels also exhibit calcifying/calcified granules (F, Von Kossa staining for calcium). Immunohistochemistry demonstrates limited perivascular beta-amyloid positivity (G, negative in the vessel walls), strongly positive Lambda (H) with weakly positive Kappa (I, compared to strongly positive granules and H), glial fibrillary acidic protein (GFAP)-positiveastrocytic gliosis in the adjacent cerebral tissue (J), scattered CD68-positive macrophages/microglia (K), and infrequent CD3-positive T-cells (L). Re-examination of the prior lung biopsy showed amorphous material with limited inflammatory and epithelial cells (M) and positive Congo red staining in amorphous material (N) with green birefringence under polarized light (O). Scale bar: 50 μm (A-C, N, O), 2 μm (D), 4 μm (E; insetof higher magnification from □), 20 μm (F-M).

At the six-month follow-up, the patient’s serum and urine protein electrophoresis remained normal. A bone marrow biopsy of the iliac crest showed mildly hypercellular bone marrow with adequate hematopoiesis and less than 10% plasma cells.

Our present case reveals two novel findings. First, CNS AL amyloidosis can manifest as CAA without significant amyloid deposition in the parenchyma. Second, CNS AL amyloidosis is not always isolated; it may occur with involvement of other organs, such as the lung. Therefore, the etiological workup for CNS angiopathy/vasculopathy should include consideration of AL amyloidosis, particularly when clinicoradiological or pathological findings are atypical of conventional CAA. As demonstrated in this case, unusual MRI features of AL amyloidosis may mimic a vascular malformation. Furthermore, the identification of CNS AL amyloidosis should prompt an aggressive search for coexisting systemic amyloidosis affecting other organs/systems.

CNS AL amyloidosis is typically presented as a tumor-like lesion (amyloidoma) in the parenchyma without evidence for systemic amyloidosis.^{Reference Schröder, Deckert and Linke3–Reference Bray, Rich, Ellis, Pradilla and Barrow7} The parenchymal involvement usually occurs in the white matter or both white and gray matter. AL amyloid deposition within cerebral BVs has occasionally been described particularly in cases with Lambda AL amyloidosis.^{Reference Schröder, Deckert and Linke3–Reference Löhr, Kessler and Monoranu5} One autopsy case demonstrated extensive amyloid deposition in most BVs throughout the cerebral and cerebellar white matter, basal ganglia and thalamus with diffuse leukoencephalopathy.^{Reference Schröder, Deckert and Linke3} Another autopsy case showed well-demarcated, granular amyloid foci, involving periventricular regions, bilateral subcortical white matter and upper pontine nuclei, with variable inflammatory cell infiltrates.^{Reference Pejhan, Budhram, Hammond and Zhang6} AL amyloid angiopathy may mimic venous malformation, as reported previously^{Reference Bray, Rich, Ellis, Pradilla and Barrow7} and shown in our case. The present case demonstrates both brain and lung AL amyloidosis. In contrast to brain AL amyloidosis, lung AL amyloidosis can be localized or associated with systemic involvement and present in a nodular, diffuse alveolar-septal or tracheobronchial pattern. Localized and systemic lung AL amyloidosis have markedly different prognoses.^{Reference Baumgart, Stuhlmann-Laeisz and Hegenbart8} Although amyloidosis in our case involves multiple organs/systems, both brain and lung amyloid deposits are relatively localized. It is possible that our case represents a localized or low-burden plasma cell disorder, as the patient has normal serum Kappa and Lambda levels, normal serum protein electrophoresis without measurable urinary proteins and a long-standing, relatively stable disease course. Given the broad spectrum of AL amyloidosis, greater awareness of CNS AL amyloidosis is crucial to facilitate prompt diagnosis and appropriate management.