Gazing Into the Crystal Ball: Calciphylaxis Causing Striking Retinal Vascular Calcification, Ocular Ischemic Syndrome, Crystalline Retinopathy, and Ischemic Optic Neuropathy

A 72-year-old woman with membranous glomerulonephritis and failed renal transplant on peritoneal dialysis presented with bilateral vision loss. She reported several months of diminishing right eye vision that worsened after cataract extraction. On presentation, visual acuity was hand motion in the right and 20/100 in the left eye with a right afferent pupillary defect. Confrontation visual fields were constricted bilaterally. Intraocular pressure was 23 in the right eye, and there was diffuse right eye central corneal opacity with iris neovascularization. Fundus examination revealed bilateral pale optic nerves with cotton wool spot inferior to the left optic disc and diffuse arteriolar whitening with crystalline deposits in the left macula. Given fundus appearance, concurrent ischemic optic neuropathy, and ocular ischemic syndrome, ocular calciphylaxis was suspected. The patient reported development of painful gluteal nodules a month prior, and biopsy revealed calcinosis cutis, a dermatopathologic finding on the spectrum of calcific vasculitides. Her vision continued to decline in both eyes with left eye vision of 20/400. Intravenous sodium thiosulfate through hemodialysis was started with initial improvement in left eye vision to 20/125, but subsequently declined despite treatment. Pathogenesis of systemic calciphylaxis is poorly understood but believed to result from upregulation of osteogenesis and decreased inhibition of vascular calcification in parathyroid axis dyscrasias due to end-stage renal disease. Excess serum calcium-phosphate deposits in blood vessels causing tissue infarction, most commonly in the skin. Prior case reports have described ischemic optic neuropathy mimicking giant cell arteritis and crystalline retinopathy with ocular ischemic syndrome separately. Treatment with empiric intravenous sodium thiosulfate and calcium chelation may preserve vision in some patients.

Photo and Video Essay Section Editors: Melissa W. Ko, MD Dean M. Cestari, MD Peter Quiros, MD Gazing Into the Crystal Ball: Calciphylaxis Causing Striking Retinal Vascular Calcification, Ocular Ischemic Syndrome, Crystalline Retinopathy, and Ischemic Optic Neuropathy Neena R. Cherayil, MD, Drew Scoles, MD, PhD, Anna M. Moran, MD, David E. Elder, MBChb, Madhura A. Tamhankar, MD FIG. 1. External photograph of the right eye demonstrating stippled corneal epithelial opacities. Abstract: A 72-year-old woman with membranous glomerulonephritis and failed renal transplant on peritoneal dialysis presented with bilateral vision loss. She reported several months of diminishing right eye vision that worsened after cataract extraction. On presentation, visual acuity was hand motion in the right and 20/100 in the left eye with a right afferent pupillary defect. Confrontation visual fields were constricted bilaterally. Intraocular pressure was 23 in the right eye, and there was diffuse right eye central corneal opacity with iris neovascularization. Fundus examination revealed bilateral pale optic nerves with cotton wool spot inferior to the left optic disc and diffuse arteriolar whitening with crystalline deposits in the left macula. Given fundus appearance, concurrent ischemic optic neuropathy, and ocular ischemic syndrome, ocular calciphylaxis was suspected. The patient reported development of painful gluteal Department of Neurology (NRC, MAT), University of Pennsylvania, Philadelphia, Pennsylvania; Department of Ophthalmology (NRC, DS, MAT), Scheie Eye Institute, Philadelphia, Pennsylvania; and Department of Pathology (AMM, DEE), University of Pennsylvania, Philadelphia, Pennsylvania. The authors report no conflicts of interest. Address correspondence to Neena R. Cherayil, MD, Department of Neurology, Department of Ophthalmology, Feinberg School of Medicine, Northwestern Medicine 259 E Erie St, Suite 1520 Chicago, IL 60611; E-mail: [e-mail] e212 nodules a month prior, and biopsy revealed calcinosis cutis, a dermatopathologic finding on the spectrum of calcific vasculitides. Her vision continued to decline in both eyes with left eye vision of 20/400. Intravenous sodium thiosulfate through hemodialysis was started with initial improvement in left eye vision to 20/125, but subsequently declined despite treatment. Pathogenesis of systemic calciphylaxis is poorly understood but believed to result from upregulation of osteogenesis and decreased inhibition of vascular calcification in parathyroid axis dyscrasias due to end-stage renal disease. Excess serum calcium-phosphate deposits in blood vessels causing tissue infarction, most commonly in the skin. Prior case reports have described ischemic optic neuropathy mimicking giant cell arteritis and crystalline retinopathy with ocular ischemic syndrome separately. Treatment with empiric intravenous sodium thiosulfate and calcium chelation may preserve vision in some patients. Journal of Neuro-Ophthalmology 2021;41:e212–214 doi: 10.1097/WNO.0000000000001090 © 2020 by North American Neuro-Ophthalmology Society A 72-year-old woman presented with several months of progressive bilateral vision loss that was initially attributed to cataracts in both eyes. She underwent Cherayil et al: J Neuro-Ophthalmol 2021; 41: e212-e214 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. Photo and Video Essay FIG. 2. A–B. Fundus photographs of the right (A) and left eye (B) demonstrating optic nerve pallor and diffuse whitening of the retinal arterioles. In the left eye, the arrow points to a cotton wool spot inferotemporal to the disc and the arrowheads indicate one of many glistening crystalline deposits in the macula. uncomplicated cataract extraction of the right eye with precipitous decline in vision after surgery. She denied headaches, jaw claudication, proximal myalgia, or other eye trauma. Her medical history was notable for end-stage renal disease due to membranous glomerulonephritis and prior failed renal transplant on peritoneal dialysis for 10 years. She also had type 2 diabetes, hypertension, and systolic heart failure, and reported variable adherence with medications and dialysis. Visual acuity was hand motion in the right eye and 20/100 in the left eye with a right afferent pupillary defect. Color vision was 2 of 11 plates in the left eye. Confrontation visual fields were diffusely constricted in the right eye and constricted inferonasally in the left eye. Intraocular pressure was 23 and 16 mm Hg, and there were stippled corneal epithelial opacities and iris neovascularization in the right eye (Fig. 1). Fundus examination revealed pale optic nerves in both eyes with cotton wool spot inferior to the left optic disc and diffuse arteriolar whitening in both eyes with crystalline deposits in the left macula (Fig. 2). Given her history of end-stage renal disease, differential considerations for corneal deposits, crystalline retinopathy, ischemic optic neuropathy, and ocular ischemic syndrome included retinal oxalosis and calciphylaxis. Serum calcium corrected for albumin was 9.4 mg/dL (normal 8.7–10.4 mg/dL), phosphate was elevated at 12.8 mg/dL (normal 2.4–5.1 mg/dL), and corrected calcium-phosphate product was 120.3 (normal 21–53); intact parathyroid hormone was 1,365 pg/mL (normal 18–80 pg/mL) and creatinine was 16.70 mg/dL (normal 0.50–1.10 mg/dL). Serum oxalate levels were 23.0 mmol/L (normal #1.9 mmol/L). On further inquiry, she reported development of superficial gluteal nodules concurrent with vision loss. Biopsy of nodule revealed calcinosis cutis (Fig. 3), a dermatopathologic finding on the spectrum of calcific vasculitides. Her vision continued to worsen to light perception in the right eye and 20/400 in the left eye with increasing visual field constriction over next few weeks. Intravenous sodium thiosulfate through hemodialysis was started with initial improvement of left eye vision to 20/125. Calciphylaxis, also known as calcific uremic arteriolopathy, is a rare microangiopathy that most commonly affects patients with kidney dysfunction. In older patients with kidney disease presenting with acquired crystalline retinopathy, retinal oxalosis is another main consideration, especially in those supplementing ascorbic acid; however, intravascular crystal deposition is more common and extensive in calciphylaxis than retinal oxalosis (1). Calciphylaxis typically manifests with intensely painful, necrotic cutaneous lesions on the adipose-rich areas of the trunk or proximal limbs. Risk factors include dialysis dependence—peritoneal more so than hemodialysis—female sex, warfarin use, obesity, diabetes, and hyperparathyroidism (2,3). Pathogenesis of systemic calciphylaxis is poorly understood but is believed to result from imbalance of vascular calcification homeostasis. Specifically, patients with chronic kidney disease often have upregulation of bone morphogenetic proteins 2 and 4, which cause vascular smooth muscle cells to increase transcription of procalcific factor runt-related transcription factor 2. Concurrent downregulation of vascular calcification inhibitors such as carboxylated matrix G1a protein (c-MGP), fetuin A, and inorganic pyrophosphate also promote cell-based deposition of crystalline hydroxyapatite—a calcium-phosphate precipitate. FIG. 3. A–C. A. Hematoxylin and eosin (H&E) staining of gluteal skin nodule biopsy demonstrating large irregular deposits of calcium (arrow) associated with background fibrosis in the epidermis and upper and deep dermis. B and C. H&E staining at ·10 showing large and small deposits of calcium with surrounding histiocytic and giant cell reaction in the dermis (arrows). Background fibrosis is also noted. Cherayil et al: J Neuro-Ophthalmol 2021; 41: e212-e214 e213 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. Photo and Video Essay Vitamin K deficiency, either iatrogenic through warfarin use or as result of malnutrition, blocks MGP carboxylation thereby promoting mineralization. Vascular endothelial growth factor-A released by adipocytes may also influence arteriolar calcification (3). This complex pathway ultimately causes downstream vessel narrowing and thrombosis leading to target tissue ischemia. Histopathologically, biopsy specimen of affected tissue will show coarse calcification, fibrointimal hyperplasia, and microvascular thrombosis with surrounding inflammation or necrosis. Sodium thiosulfate, an antioxidant, is hypothesized to treat calciphylaxis by promoting vasodilation and inhibiting adipocyte procalcification pathways (3). Ocular calciphylaxis is exceedingly rare with only a few prior case reports describing crystalline retinopathy (1) or ischemic optic neuropathy mimicking giant cell arteritis (4– 12). Patients often have progressive unilateral or bilateral vision loss with pallid optic nerve swelling with or without systemic symptoms associated with giant cell arteritis. All but one of these reported patients (5) had end-stage renal disease. Our patient is the first reported case of combined ischemic optic neuropathy, crystalline retinopathy, and ocular ischemic syndrome as manifested by elevated intraocular pressures, band keratopathy, and iris neovascularization. In this case, surgical trauma from cataract extraction likely accelerated progression of calciphylaxis in the right eye causing extensive corneal and vascular calcium-phosphate precipitation with resultant ocular ischemia. Treatment with empiric intravenous sodium thiosulfate and calcium chelation may preserve vision in some patients, although use of this medication is not well established. STATEMENT OF AUTHORSHIP Category 1: a. Conception and design: N. R. Cherayil, D. Scoles, A. H. Moran, D. E. Elder, and M. A Tamhankar; b. Acquisition of data: N. R. Cherayil, D. Scoles, A. H. Moran, and D. E. Elder; c. Analysis and e214 interpretation of data: N. R. Cherayil, D. Scoles, A. H. Moran, and D. E. Elder. Category 2: a. Drafting the manuscript: N. R. Cherayil and M. A. Tamhankar; b. Revising it for intellectual content: N. R. Cherayil and M. A. Tamhankar. Category 3: a. Final approval of the completed manuscript: N. R. Cherayil and M. A. Tamhankar. REFERENCES 1. Naysan J, Dansingani KK, Balaratnasingam C, Mrejen S, Levasseur S, Merkur A, Yannuzzi LA. Crystalline retinopathy and retinal vasculopathy in calciphylaxis. Retin Cases Brief Rep. 2018;12:331–335. 2. Udomkarnjananun S, Kongnatthasate K, Praditpornsilpa K, Eiam-On S, Jaber BL, Susantitaphong P. Treatment of calciphylaxis in CKD: a systemic review and meta-analysis. Kidney Int Rep. 2018;4:231–244. 3. Nigwekar SU, Thadhani R, Brandenburg VM. Calciphylaxis. NEJM. 2018;387:1704–1714. 4. Sekulic M, Tuskinovsky AM. Metaplastic ossification of the temporal artery with osteoclast-like giant cells: a mimicker of giant cell (temporal) arteritis. Eur J Ophthalmol. 2017;27:e99–103. 5. Sivertsen MS, Strøm EH, Endre KMA, Jørstad ØK. Anterior ischemic optic neuropathy due to calciphylaxis. J Neuroophthalmol. 2018;38:54–56. 6. Awwad ST, Ghosn S, Hogan RN. Calciphylaxis of the temporal artery masquerading as temporal arteritis. Clin Exp Ophthalmol. 2010;38:511–513. 7. Hepschke JL, Masselos K, Sandbach J, Fraser CL. Seeing the difference—painless progressive vision loss in a vasculopath. Surv Ophthalmol. 2019;64:123–131. 8. Korzets A, Schwartz A, Rosenblatt I, Herman M, Ori Y. Ischemic optic neuropathy in dialyzed patients: a previously unrecognized manifestation of calcific uremic arteriolopathy. Am J Kidney Dis. 2004;44:E93–E97. 9. Farooqui S, Chan ASY, Cullen JF, Milea D. Too young to undergo temporal artery biopsy? Calciphylaxis-related anterior ischemic optic neuropathy. Neuroophthalmology. 2019;43:252–255. 10. Shah M, Roppolo M. Calciphylaxis: temporal artery calcification preceding widespread skin lesion and penile necrosis. Case Rep Nephrol. 2012;2012:309727. 11. Al-Absi AI, Wall BM, Cooke CR. Medial arterial calcification mimicking temporal arteritis. AJKD. 2004;44:73–78. 12. Roverano S, Ortiz A, Henares E, Eletti M, Paira S. Calciphylaxis of the temporal artery masquerading as temporal arteritis: case presentation and review of literature. Clin Rheum. 2015;344:1985–1988. Cherayil et al: J Neuro-Ophthalmol 2021; 41: e212-e214 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited.