Ophthalmological involvement in wild-type, hereditary transthyretin and light chain amyloidosis: a multimodal imaging study

Background: The prevalence and clinical relevance of transthyretin (ATTR) amyloidosis has been growing continuously in recent years, particularly for the increasing knowledge of the wild type form (ATTRwt). Ophthalmological abnormalities have been reported in hereditary transthyretin (ATTRv, v for variant) amyloidosis but only anecdotally in ATTRwt amyloidosis. The present study aimed at investigating the ophthalmologic involvement in ATTRwt, also compared with ATTRv and light chain (AL) amyloidosis and the possible role of non-invasive imaging modalities in the ocular assessment of these patients. Methods: This was a cross-sectional, non-interventional study. Patients affected by ATTR or AL amyloidosis referred to the Department of Neuroscience of the University of Padua were recruited. Patients’ records were reviewed for assessing the systemic involvement of amyloidosis, the presence of genetic mutations and detecting other systemic comorbidities, such as diabetes, to be taken into account as potential confounders in the analysis. An age-matched control group of healthy subjects was also studied. All the patients underwent a complete eye examination, including best-corrected visual acuity assessment (BCVA), anterior segment examination, evaluating in particular the presence of any deposits and alterations involving the iris and the lens, intraocular pressure, fundus examination, optical coherence tomography (OCT, for the evaluation of the retinal layers) and OCT angiography (for the non-invasive evaluation of the retinal vasculature) and in vivo corneal confocal microscopy (CCM, for the non-invasive study of corneal structures, in particular of the corneal nerve plexuses). Results: Thirty-five patients were enrolled: 17 ATTRwt, 9 ATTRv, 2 pre-symptomatic carriers and 7 AL. The mean age was 70.1  11 years. In the control group, 49 healthy subjects with a mean age of 66.2  10.2 years were enrolled (p=0.0964). Visual acuity was significantly reduced in all patients (and particularly those with ATTRwt amyloidosis) compared to controls (p=0.0001). Seven patients were affected by glaucoma, two of them (ATTRwt) newly diagnosed; one of them presented a picture of pseudoexfoliatio lentis. Fifty percent of ATTRwt patients had cataract and 38% had already undergone cataract surgery. Eighteen patients presented with abnormal findings of the retinal pigment epithelium at OCT, with advanced macular degeneration in three patients. Six patients had alterations of the vitreomacular interface. Vitreous opacities were identified in 7 patients. Corneal deposits were identified in 6 ATTRwt patients. CCM showed corneal deposits in 16 patients, reduced nerve fiber length (p=0.0230) and tortuous stromal nerves (p=0.0094) compared to controls. OCT showed a reduction in macular volume and in the peripapillary nerve fiber layer thickness. OCT angiography found a significant impairment of the retinal vascularization, both of radial peripapillary capillary plexus and macular vascular plexuses (p<0.05), compared to controls. Conclusions: Ophthalmologic manifestations are common in amyloidosis patients, particularly in ATTRwt amyloidosis, potentially leading to a significant reduction in visual acuity and quality of life. Although age may have influenced the results, the prevalence and severity of the pathological findings suggests a relevant pathogenic role of amyloid in their development. Therefore, it is important to emphasize the importance of multidisciplinary management and thorough ophthalmological assessment, follow-up and timely treatment, when necessary. Moreover, non-invasive imaging modalities, such as CCM and OCT may allow the identification and follow-up of signs of damage at the level of specific structures, such as small nerve fibers and small vessels, more difficult to analyze at a systemic level.