Retinal Angiographic Evidence of Creutzfeldt-Jakob Disease Prion Disease in Humans

Clinical Correspondence Section Editors: Robert Avery, DO Karl C. Golnik, MD Caroline Froment, MD, PhD An-Gour Wang, MD Retinal Angiographic Evidence of Creutzfeldt-Jakob Disease Prion Disease in Humans Norah S. Lincoff, MD, Lucia L. Balos, MD, David Hojnacki, MD, Osman Farooq, MD A lthough it has been recognized for years that prion disease in Creutzfeldt-Jakob Disease (CJD) involves the retina, most cases of CJD visual loss in the literature only discusses cortical blindness and ophthalmoplegia found late in the disease course (1,2). We describe a case of a 57year-old man with visual blurring and retinopathy before his diagnosis. He initially had reduced central vision in the absence of obvious peripheral field loss. Although formal FIG. 1. A, B. Right and left fundoscopy revealing serpiginous maculopathy. C, D. Right and left fluorescein angiography revealing bilateral hyperfluorescence at the level of the retinal pigment epithelium. D, E. Right and left OCT autofluorescence revealed hyperfluorescence of the lesions. OCT, optical coherence tomography. Departments of Neurology (NSL, DH, OF) and Pathology (LLB), Jacobs School of Medicine, University at Buffalo, Buffalo, New York. The authors report no conflicts of interest. Address correspondence to Norah S. Lincoff, MD, Department of Neurology, 1001 Main Street, Buffalo, NY 14203; E-mail: lincoff@ buffalo.edu Lincoff et al: J Neuro-Ophthalmol 2021; 41: e163-e165 visual field testing was not done, visual fields by confrontation were repeatedly normal. To our knowledge, this finding has not been recognized in the medical literature, but likely represents the significant known involvement of prion proteins in the deep outer layers of the retina, and other structures of the eye. This can potentially be used as e163 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. Clinical Correspondence FIG. 2. A. Diffusion-weighted MRI revealed a hyperintense cortical ribbon. B, C: Frontal lobe biopsy specimen at ·400 magnification. D. Reveals hematoxylin and eosin (H&E) stain demonstrating spongiform change and reactive astrocytosis. E. Reveals prion immunohistochemical staining after predigestion to remove normal prion protein. In patients without prion disease, no prion protein remains after protease digestion. a screening tool in patients with acute psychological changes, leading to an earlier diagnosis in patients with CJD. A 57-year-old man experienced a change in behavior, including the diagnosis of a fugue state, and depression. His past medical history was significant for non–insulin dependent diabetes mellitus, hypertension, and sleep apnea. Seven months later, he noted blurring of his right . left eye and unsteadiness causing him to fall twice. His imaging only showed scattered white matter disease. He was found to have 20/70 vision bilaterally, no obvious field defect by history or confrontation, and an otherwise normal exam. Formal visual field testing was not done, and therefore it is unclear whether he had findings of early cortical visual loss as well at that time. Neuroophthalmology questioned multiple foci of outer retinal layer maculopathy, which was confirmed on fluorescein angiography. This revealed numerous hyperfluorescent areas of transmission, without leakage, mainly throughout both maculae (Figs. 1A, B). On autofluorescence, he also showed hyperfluorescence of the lesions (Figs. 1C, D). Three months later, he developed signs of obvious cortical blindness in the form of a dense right hemianopsia and ophthalmoplegia. He also had word finding difficulties, myoclonus, and periodic sharp wave complexes on EEG. Repeat MRI of the brain revealed new cortical ribboning (Fig. 2A), that is consistent with CJD. Autopsy and immunohistochemical staining confirmed frontal lobe spongiform change and reactive astrocytosis (Figs. 2B, C). Cerebrospinal fluid analysis confirmed the presence of very high levels of T-tau protein and 14-3-3 protein diagnostic of sporadic CJD. CJD is a rare fatal neurodegenerative disease that commonly presents with rapid onset of dementia. Death occurs in 90% of individuals within 1 year (2,3). Sporadic CJD originates from chance conversion of the normal form of the prion protein to an abnormal form in the brain of e164 affected individuals. Early symptoms of CJD are often memory loss, marked personality changes, symptoms of obsessive-compulsive disorder, and depression. Bizarre color perception, generalized or hemianopic visual loss, and diplopia may be presenting features of CJD (1–4). Significant outer retinal changes have been reported in the veterinary literature and medical literature on post mortem human donor tissue (5). Prion proteins are typically first found in aggregates in the outer plexiform layer and then cause toxicity and damage to the photoreceptors and retinal pigment epithelium. In animal models, the retinal changes seem to precede the cortical damage. Our patient’s retinal findings are consistent with changes that one would expect to see with prion disease affecting the outer retinal layers; this is where prion proteins are known to deposit and cause toxicity noted from analysis in post mortem tissue and animal models (5). McElvanney et al reported a similar retinal finding in 1999 in a patient with CJD, but reported it as incidental (3). We propose that fluorescein angiography and optical coherence tomography autofluorescence testing seem to be valuable tests that should be considered early in the work up of patients presenting with idiopathic progressive encephalopathy. Retinal angiographic evidence of CJD prion disease in humans has not previously been reported, and we feel that this is likely a relevant true retinal finding of CJD. It is our hope that the fluorescein angiography finding of transmission defects in the maculae becomes a recognized finding that will allow earlier diagnosis in patients with this fatal disease. This will not only help in patient care, but can also help families often frustrated by the lack of an earlier diagnostic tool. STATEMENT OF AUTHORSHIP Category 1: a. Conception and design: N. S. Lincoff and O. Farooq; b. Acquisition of data: N. S. Lincoff and O. Farooq; c. Analysis and interpretation of data: N. S. Lincoff and O. Farooq. Category 2: a. Drafting the manuscript: N. S. Lincoff, L. L. Balos, D. Hojnacki, Lincoff et al: J Neuro-Ophthalmol 2021; 41: e163-e165 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. Clinical Correspondence and O. Farooq; b. Revising it for intellectual content: N. S. Lincoff, L. L. Balos, D. Hojnacki, and O. Farooq. Category 3: a. Final approval of the completed manuscript: N. S. Lincoff, L. L. Balos, D. Hojnacki, and O. Farooq. REFERENCES 1. Head MW, Northcott V, Rennison K, Ritchie D, McCardle L, Bunn TJ, McLennan NF, Ironside JW, Tullo AB, Bonshek RE. Prion protein accumulation in eyes of patients with sporadic and variant Creutzfeldt Jakob disease. Invest Ophthalmol Vis Sci. 2003;44:342–346. Lincoff et al: J Neuro-Ophthalmol 2021; 41: e163-e165 2. Hurley D. Prion seeding detected throughout eye tissue in large postmortem CJD series. Neurol Today 2019;19:7–8. 3. McElvanney AM, Boodhoo MG. Creutzfeldt-Jakob disease presenting with visual disturbance. Eye 1999;13:693–695. 4. Orrú CD, Soldau K, Cordano C, Llibre-Guerra J, Green AJ, Sanchez H, Groveman BR, Edland SD, Safar JG, Lin JH, Caughey B, Geschwind MD, Sjgurdson CJ. Prion seeds distribute throughout the eyes of sporadic Creutzfeldt-Jakob disease patients. mBio 2018;9:e02095–e02118. 5. Greenlee MH, Smith JD, Platt EM, Juarez JR, Timms LL, Greenlee JJ. Changes in retinal function and morphology are early clinical signs of disease in cattle with bovine spongiform encephalopathy. PLoS One 2015;10:E0119431. e165 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited.